Ebook Principles and practice of PET and PET/CT: Part 2

(BQ) Part 2 book Principles and practice of PET and PET/CT presents the following contents: Neurologic applications, psychiatric disorders, cardiac applications, PET/CT imaging of infection and inflammation, PET and drug development, PET Imaging as a biomarker, emerging opportunities.

C H A P T E R

Movement Disorders, Stroke, and Epilepsy NICOLAAS I BOHNEN

479

9.1

natomic imaging, such as computed tomography (CT) andmagnetic resonance imaging (MRI), has revolutionized thediagnosis and management of the neurological patient

However, a brain lesion may be present functionally rather than

asso-ciated with a macroscopic structural abnormality detectable by

non-invasive anatomical imaging For example, anatomical imaging in

early idiopathic Parkinson disease may not reveal disease-specific

changes, while positron emission tomography (PET) has clearly

demonstrated the dopaminergic system abnormalities in this disorder

PET is a molecular imaging technique that uses radiolabeled

molecules to image molecular interactions of biological processes

in vivo Low doses of positron emitting radiotracers are being used

for the radiolabeling of molecules or drugs that have binding sites

in the brain, such as receptors, follow regional cerebral blood flow,

or are metabolized by cerebral enzymes PET can be used to form neurochemical and functional brain imaging studies of cere-bral blood flow or glucose metabolism

per-Neurochemical imaging studies allow assessment of theregional distribution and quantitative measurement of neurotrans-mitters, enzymes, or receptors in the living brain Neurochemicalimaging studies are mainly performed for research purposes.Functional brain imaging studies can measure regional cerebralblood flow or glucose metabolism These studies may be performed

in the resting state or following a specific intervention (e.g., a tal task, sensory stimulus or motor task) to “activate” specificregions in the brain

men-479

GENERAL PRINCIPLES OF CEREBRAL BLOOD

FLOW AND METABOLIC IMAGING: FUNCTIONAL

COUPLING AND PHYSIOLOGICAL CORRELATES

READING BRAIN PET IMAGES: NORMAL

VARIANTS, AGING, AND OTHER FACTORS THAT

MAY AFFECT BLOOD FLOW OR GLUCOSE

METABOLISM

Normal Variants Normal Aging: From Infancy to Adulthood Normal Aging: From Adulthood to the Elderly Factors that May Affect Resting Cerebral Blood Flow

or Glucose Metabolic Studies Diaschisis: Remote Functional Effects of Focal BrainLesions

MOVEMENT DISORDERS

Parkinson Disease Parkinsonian or Lewy Body Dementia Progressive Supranuclear Palsy Corticobasal Degeneration Multiple System Atrophy Essential Tremor

Huntington Disease and Choreiform MovementDisorders

Dopaminergic Neurochemical Imaging: Diagnosis ofParkinson Disease

Pre- and Postsynaptic DopaminergicNeurochemical Imaging: Atypical Parkinsonian Disorders

Dopaminergic Neurochemical Imaging: DifferentialDiagnosis of Parkinsonian or Lewy Body Dementiafrom Alzheimer Disease

STROKE

Measurement of Cerebral Oxygen Metabolism,Cerebral Blood Volume, and Oxygen ExtractionFraction Using PET

Acute Ischemic Stroke Subacute Changes in Ischemic Stroke Chronic Arterial Occlusive Disease and HemodynamicReserve

Hemorrhagic Stroke Estimation of Prognosis After Stroke Clinical Applicability of Multitracer PET in theManagement of Patients with Stroke New Emerging Clinical Applications of PET in Stroke:Neuronal and Hypoxia Imaging

Glucose Metabolic PET Studies in Lennox-GastautSyndrome

Interictal H2[15O] Cerebral Blood Flow PET Studies Ictal PET

Mapping of Cognitive or Language Functions Emerging Clinical Applications of BenzodiazepineNeuroreceptor and Serotonin Synthesis Imaging inEpilepsy

CONCLUSION

A

Imaging of resting glucose metabolism and/or blood flow in

the brain represent the major clinical applications of PET in

neu-rology and will be mainly discussed in this chapter The recent

introduction of PET/CT into clinical practice may have limited

util-ity when evaluating small lesions that are better visualized on MRI

but offers the advantage of increased spatial accuracy when

evaluat-ing normal metabolic variants or artifacts due to partial volume

effects In addition, the intrinsically registered nature of the CT

images from PET/CT can be helpful in both lesion localization as

well as attenuation correction specific for the patient PET studies

of specific neurochemical markers, in particular dopamine, will

also be discussed when clinically useful or promising The precise

correlation of anatomic findings with PET through image fusion is

often useful and is facilitated through PET/CT fusion imaging as

well as software fusion of PET with MRI images

GENERAL PRINCIPLES OF CEREBRAL

BLOOD FLOW AND METABOLIC

IMAGING: FUNCTIONAL COUPLING

AND PHYSIOLOGICAL CORRELATES

The energy metabolism of the adult human brain depends almost

completely on the oxidation of glucose (1) Because the brain is

unable to store either oxygen or glucose, it is thought that regional

cerebral blood flow (rCBF) is continuously regulated to supply

these substrates locally The functional coupling of rCBF and local

cerebral glucose metabolism has been established in a wide range of

experiments using autoradiographic techniques in animals as well

as double-tracer techniques in humans Increased function of the

central neurons results in increased neuronal metabolism and, as a

consequence, increased concentration of metabolic end products

(H, K, adenosine) results in increased rCBF (2)

A model has been proposed where neurogenic stimuli via

perivascular nerve endings may act as rapid initiators responsible

for moment-to-moment dynamic adjustment of rCBF to the

meta-bolic demands (2) Functional activation of the brain (e.g., motor

or visual activity) is accompanied by increases in rCBF and glucose

consumption but only minimal increases in oxygen consumption

(3,4) Therefore, large changes in blood flow are required to support

small changes in the oxygen metabolic rate during neuronal

stimu-lation (5) Increased oxygen consumption may result from a

com-bined effect of increased blood flow and increased oxygen diffusion

capacity in the region of brain activation (6) Factors other than

local requirements in oxygen also underlie the increase in rCBF

associated with physiological activation (7)

Oxygen-15 radiolabeled water (H2[15O]) is the most commonly

used PET tracer for the measurement of rCBF CBF can also be

assessed by the inhalation of Oxygen-15 labeled carbon dioxide

(C[15O2]) The very short half-life of oxygen-15 [15O] (123 seconds)

allows repeated and rapid rCBF assessments in the same individual

Fluorine-18 [18F]-fluorodeoxyglucose (FDG) is a PET tracer used for

the study of regional cerebral glucose metabolism The majority of

glucose in the brain is needed for maintenance of membrane

poten-tials and restoration of ion gradients The linking between synaptic

activity and glucose utilization is a central physiological principle of

brain function that has provided the basis for FDG brain PET

imag-ing (8) Although the FDG PET signal represents neuronal and more

specifically synaptic activity (9), glutamate-mediated uptake of the

radioligand into astrocytes also appears to be a major mechanism

(10) The basic mechanism involves glutamate-stimulated aerobicglycolysis: the sodium-coupled reuptake of glutamate by astrocytesand the ensuing activation of the sodium-potassium-adenosinetriphosphatase (Na-K-ATPase) triggers glucose uptake and process-ing via glycolysis, resulting in the release of lactate from astrocytes.Lactate can then contribute to the activity-dependent fueling of theneuronal energy demands associated with synaptic transmission

An operational model, the astrocyte-neuron lactate shuttle, is

supported experimentally by a large body of evidence, which vides a molecular and cellular basis for interpreting data obtainedfrom functional brain imaging studies (8) In addition, this neuron-glia metabolic coupling undergoes plastic adaptations in parallelwith adaptive mechanisms that characterize synaptic plasticity (8)

pro-READING BRAIN PET IMAGES:

NORMAL VARIANTS, AGING, AND OTHER FACTORS THAT MAY AFFECT BLOOD FLOW OR GLUCOSE

METABOLISM

The spatial resolution of the PET camera determines the extent ofthe partial volume effect that causes the edges of small brain struc-tures to blur one another due to averaging of radioactivity There-fore, the size of the imaged structure determines the recovery ofcounts by the camera from that structure (11) A structure musthave dimensions greater than twice the resolution of the PET cam-era at full width half maximum in order to recover 100% of true tis-sue activity from that structure

Partial volume effects may give a blurred or smoothed scanappearance of small brain structures, atrophied gyri, and smallerbrain volumes, such as the inferior orbitofrontal and inferior tem-poral regions Conversely, a cerebral sulcus, where two gray mattergyri face each other closely, may show relatively higher activitywhen a scanner does not have sufficient spatial resolution to resolvethe two gyri (12) For instance, the pre- and postcentral gyriopposed at the central sulcus may form a single focus of relativelyhigh activity (12) Similarly, the adjacent areas of the insular cortexand the superior temporal gyral cortex generate sufficiently similarFDG activity so that they may appear as one lateral mass at certainlevels of scanning (13) Higher resolution PET cameras can help inthis regard and are available in some centers

It should be noted that a normal individual’s brain is not pletely symmetric For example, the sylvian fissure in right-handedindividuals is longer and more horizontal in the left hemisphere.Normal irregularity of gyral convolutions may give a heterogeneousscan appearance Therefore, a commonly observed rule of visualPET analysis is the requirement that an area of apparent functionalalteration of a brain structure should be seen on at least severaladjacent slices in order to be deemed significant (13) Further,direct correlation with an anatomic imaging study is often required

com-to recognize normal structural variability

Studies of left-to-right hemispheric asymmetries in normalsubjects are limited and have not been conclusive An rCBF PETstudy reported slightly higher mean right hemispheric flow com-pared to left-sided values (14) An rCBF single-photon computedemission tomography (SPECT) study demonstrated consistenthemispheric asymmetry (right side greater than left side) in thecuneus, occipital cortex, occipital pole, middle temporal gyrus, andposterior middle frontal gyrus in 83% to 100% of individuals (15)

480 Principles and Practice of PET and PET/CT

LWBK053-3787G-9.01[479-499].qxd 14-08-2008 05:56 PM Page 480 Aptara Inc

FDG PET studies have indicated that hemispheric asymmetries

may depend on whether subjects are studied with open versus

closed eyes or ears that are covered (16) For example, studies

per-formed on subjects with eyes closed and ears covered demonstrated

greater left than right hemispheric glucose metabolism Subjects

studied with closed eyes and ears also had a progressive overall

decrease in glucose metabolism, reflecting general sensory

depriva-tion (16) Decreased tracer uptake in the visual cortex is typical as

well in patients whose eyes are covered

Normal Variants

There are several normal variants that should be recognized when

interpreting cerebral metabolic or blood flow PET scans Some

nor-mal brain regions have focally more prominent metabolic or flow

activity These include the frontal eye fields (which can be

asym-metric), posterior cingulate cortex and adjacent angular gyrus,

Wernicke’s region, the visual cortex (when subjects are injected

with the eyes open), and an area of more intense uptake in the

pos-terior parietal lobe (Fig 9.1.1) (17,18)

The frontal eye fields have an approximate dimension of about

1 cm and are located a few centimeters anterior to the primary

motor cortex (17) Wernicke’s region is defined as an area of

mod-erately intense activity measuring a few centimeters in size and is

located in the posterior-superior temporal lobe The posterior

cin-gulate cortex is situated superior and anterior to the occipital

cor-tex An area of focally intense activity in the posterior parietal

region is seen in about 50% of the normal population and appears

mostly symmetric (Table 9.1.1) (17,18) Basal ganglia to cortex

ratios are greater than unity, indicating relatively higher activity inthe basal ganglia compared to the average cortex (17) Some brainregions, like the very anterior aspect of the frontal poles, may haveless prominent or decreased tracer uptake (17)

Normal Aging: From Infancy to Adulthood

CBF PET studies in children have shown lower flow values inneonates compared to older children (19) The rCBF will reachadult values during adolescence (19) No major difference in rCBFhas been observed between the basal ganglia and cortical gray mat-ter in children with the exception of more prominent occipital flow.FDG metabolic studies in infants and children have shown thatinfants less than 5 weeks old have highest metabolic activity in thesensorimotor cortex, thalamus, brainstem, and cerebellar vermis

By 3 months, metabolic activity increases in parietal, temporal, andoccipital cortices, basal ganglia, and cerebellar cortex (20) Frontaland dorsolateral occipital cortical regions display a maturationalrise in glucose metabolic activity by approximately 6 to 8 months.Absolute values of glucose metabolic rate for various gray mat-ter regions are low at birth (13 to 25 mol/min/100 g), and rapidly

rise to reach adult values (19 to 33 mol/min/100 g) by 2 years.

Glucose metabolic rate continues to rise until, by 3 to 4 years, ing values of 49 to 65 mol/min/100 g in most regions (20) These

reach-high rates are maintained until approximately 9 years, when theybegin to decline, and reach adult rates again by the latter part of thesecond decade The highest increases over adult values have beennoted in cerebral cortical structures Lesser increases have beenfound to be present in the basal ganglia and cerebellum This timecourse of metabolic change matches the process describing initialoverproduction and subsequent elimination of excessive neurons,synapses, and dendritic spines known to occur in the developingbrain

An FDG PET study of infants during the first 6 months of lifereported glucose metabolic rates for various cortical brain regionsand the basal ganglia to be low at birth (from 4 to 16 mol/min/100 g)

(21) In infants 2 months of age and younger rates were highest inthe sensorimotor cortex, thalamus, and brainstem By 5 months,rates had increased in the frontal, parietal, temporal, occipital, andcerebellar cortical regions In general, the whole brain glucosemetabolic activity correlated with postconceptional age, reflectingthe functional maturation of these brain regions (21)

A statistical brain mapping study of metabolic aging from 6 to 38years found greatest age-associated changes in the thalamus and ante-rior cingulate cortex (22) These findings were explained by relative

Chapter 9.1 • Movement Disorders, Stroke, and Epilepsy 481

FIGURE 9.1.1 PET images showing normal

glucose metabolic variants in healthy

volun-teers Examples of more prominent uptake in

the frontal eye fields (A), posterior cingulate

cortex (B), and an area of more intense uptake

in the posterior parietal lobe (C) are shown by

arrows The angular gyrus is demonstrated by

Frequency of Prominent Normal Fluorodeoxyglucose Brain PET Variants in the General Population

(From Loessner A, Alavi A, Lewandrowski KU, et al Regional cerebral

function determined by FDG-PET in healthy volunteers: normal patterns

and changes with age J Nucl Med 1995;36:11411149, with

permission.)

T A B L E 9 1 1

increase of synaptic activities in the thalamus, possibly as a

conse-quence of improved corticothalamic connections Knowledge of the

changing metabolic patterns during normal brain development is a

necessary prelude to the study of abnormal brain development

Normal Aging: From Adulthood to the Elderly

Postmortem studies have shown relatively stable neuronal numbers

but loss in cell size and a decreased number of glial cells with

advanc-ing age (23) However, it remains a matter of controversy as to whether

cerebral perfusion declines with healthy aging H2[15O] rCBF PET

studies have shown a negative correlation between age and rCBF in

the mesial frontal cortex, involving the anterior cingulate region (24)

Age-related flow decreases have also been reported for the cingulate,

parahippocampal, superior temporal, medial frontal, and posterior

parietal cortices bilaterally, and in the left insular and left posterior

prefrontal cortices (25) It should be realized that the affected areas

represent limbic or neocortical association areas and, therefore, bias

from possible preclinical dementia cannot be excluded

It has been suggested that lack of partial volume correction for

the dilution effect of age-related cerebral volume loss on PET

mea-surements may be another reason for the observed age-related

decline For example, one study found a significant difference in

mean cortical CBF between young/midlife (age range, 19 to 46

years; mean  standard deviation [SD], 56  10 mL/100 mL/min)

and elderly (age range, 60 to 76 years; mean  SD, 49  2.6 mL/100

mL/min) subgroups before correcting for partial-volume effects

(26) However, this group difference resolved after partial-volume

correction (young/midlife: mean  SD, 62 10 mL/100 mL/min;

elderly: mean  SD, 61  4.8 mL/100 mL/min)

FDG PET imaging studies have shown decreased cortical

metabolism with normal aging, particularly in the frontal lobes

(17) Temporal, parietal, and occipital lobe metabolism varied

con-siderably among subjects within the same age group as well as over

decades (17) Basal ganglia, hippocampal area, thalami, cerebellum,

posterior cingulate gyrus, and visual cortex remained metabolically

unchanged with advancing age (17) An FDG PET study found

bilateral medial prefrontal, including anterior cingulate cortices,

and dorsolateral prefrontal reductions with normal aging (27)

Brain scans of the aging and atrophied brain will demonstrate

widened cerebral sulci, increased separation of the caudate nuclei

and thalami, as well as widening of the anterior fissure However, a

Japanese study found that age-associated metabolic reductions that

were present in bilateral perisylvian and medial frontal regions

largely resolved after correction for partial volume effects (28)

Factors that May Affect Resting Cerebral

Blood Flow or Glucose Metabolic Studies

A number of other factors need to be considered when interpreting

brain PET images Metabolism or blood flow activity will be most

prominent in gray matter when compared to white matter (about

four times higher) It should be emphasized that brain glucose

metabolic or blood flow PET images are functional in nature For

example, if a patient is moving or talking around the time of

injec-tion, increased activity in specific brain regions like the basal

gan-glia, motor cortex, or language centers may be present Subjects

studied with eyes open will have increased metabolic activity in the

visual cortex when compared to a baseline with the eyes closed (16)

An FDG PET study found that passive audiovisual stimulation

(watching a movie) led to significant glucose metabolic increases invisual and auditory cortical areas but significant decreases in frontalareas in normal volunteers (29)

Metabolic factors,such as hyperglycemia,may impair cortical FDGuptake (30) Therefore, knowledge of the clinical or behavioral state ofthe patient at the time of the injection and study is critical for properimage interpretation As with any nuclear medicine study, better imagequality will depend on improved count statistics Since PET images are

an average of radioactivity over a certain period of time, FDG tions taken over 10 to 30 minutes will lead to better image quality com-pared to short-lasting (1 to 2 minutes) H2[15O] CBF studies

acquisi-Drugs are also known to induce cerebral blood flow or glucosemetabolic changes For example, diazepam sedation has been found toreduce cerebral glucose metabolism globally by about 20% (31) Astudy by Wang et al (32) found that lorazepam significantly decreasedwhole-brain metabolism over 10% However, regional effects oflorazepam were largest in the thalamus and occipital cortex (about20% reduction) An FDG PET study of propofol sedation in childrenfound significant hypometabolism in the medial parieto-occipital cor-tex bilaterally, including the lingual gyrus, cuneus, and middle occipi-tal gyrus (33) The bilateral parieto-occipital hypometabolism is likely

to be a sedation-specific effect and should be taken into account whenevaluating cerebral FDG PET scans in sedated patients

Antiepileptic drugs have also been found to reduce glucosemetabolism and rCBF Studies of valproate have shown global FDG(9% to 10%) and global CBF (about 15%) reductions with greatestregional reductions in the thalamus (34) Phenytoin has been found

to cause an average reduction of cerebral glucose metabolism by13% (35) Cerebellar metabolism may also be reduced by pheny-toin, although the effect of the drug is probably less than that due toearly onset of uncontrolled epilepsy (Fig 9.1.2) (36,37)

Lamotrigine may cause regional cerebral hypometabolism inthe bilateral thalami, basal ganglia, and multiple regions of the cere-bral cortex (38) Studies of the barbiturate phenobarbital and cere-bral glucose metabolism have shown very prominent global reduc-tions of about 37% (39) Neuroleptic drugs can cause differentialregional metabolic effects For example, haloperidol caused cerebel-lar and putaminal glucose metabolic increases, while significantreductions were evident in the frontal, occipital, and anterior cin-gulate cortex in normal volunteers (40)

482 Principles and Practice of PET and PET/CT

FIGURE 9.1.2 A fluorodeoxyglucose PET image of a patient with

epilepsy showing bilateral cerebellar hypometabolism Cerebellarhypometabolism may be caused by phenytoin therapy, although theeffect of the drug is probably less than that due to early onset of uncon-trolled epilepsy

LWBK053-3787G-9.01[479-499].qxd 14-08-2008 05:56 PM Page 482 Aptara Inc

Diaschisis: Remote Functional

Effects of Focal Brain Lesions

The functional nature of PET images may reveal metabolic or blood

flow changes as a result of focal disturbance in another remote but

functionally connected brain region This phenomenon of remote

effect is called diaschisis and was originally recognized by Von

Mon-akow (41) in 1914 (42) Diaschisis in the cerebellum was first

described by Baron and Marchal (43) in a patient whose PET study

showed cerebellar hypoperfusion contralateral to a supratentorial

stroke Remote metabolic depression is characterized by coupled

reductions in perfusion and metabolism in brain structures remote

from, but connected with, the area damaged by a structural lesion

This effect has been explained as depressed synaptic activity as a

result of disconnection (either direct or transneural) (44) Thus,

remote effects allow mapping of the disruption in distributed

net-works as a result of a focal brain lesion

Diaschisis may also occur as subcorticocortical effects

Subcor-ticocortical effects may lead to clinical symptoms, like subcortical

aphasia due to thalamic or thalamocapsular stroke Right-sided

subcortical lesions may present with left hemineglect (subcortical

neglect) (43) Small thalamic infarcts may induce metabolic

depres-sion of the ipsilateral cortical mantle (thalamocortical diaschisis)

(45) Striatal and thalamic hypometabolism ipsilateral to

cortico-subcortical stroke is a frequent finding

Thalamic hypometabolism may develop a few days after a

stroke and presumably represents retrograde degeneration of

dam-aged thalamocortical neurons, whereas striatal hypometabolism

probably reflects loss of glutamatergic input from the cortex (43)

Crossed cerebrocerebellar diaschisis may occur as early as 3 hours

after stroke, is closely related to the volume of supratentorial

hypoperfusion, and might be reversible (46) Persistence of

diaschi-sis after stroke is strongly associated with outcome (46)

SPECT studies performed as ictal studies during seizure

activ-ity have demonstrated a pattern called reverse crossed

cerebrocerebel-lar diaschisis where a supratentorial ictal seizure focus of

hyperper-fusion is associated with contralateral cerebellar hyperperhyperper-fusion

(Fig 9.1.3) (47) This phenomenon also can be detected with PET

MOVEMENT DISORDERS

PET imaging of cerebral blood flow, metabolic pathways, or transmission systems has contributed to researchers’ understanding

neuro-of the pathophysiology neuro-of movement disorders PET measurements

of dopaminergic pathways in the brain have confirmed the tance of dopamine and the basal ganglia in the pathophysiology ofmovement disorders, such as Parkinson disease Brain activationstudies can be performed using CBF or FDG PET These studiescompare regional brain activity during specific motor or mentaltasks compared to control conditions Activation studies haveshown that the basal ganglia are activated whenever movements areperformed, planned, or imagined (48) These studies support theexistence of functionally independent distributed basal gangliafrontal loops The caudate–prefrontal loop appears to mediatenovel sequence learning, problem solving, and movement selection,while the putamen–premotor loop may facilitate automatic sequen-tial patterns of limb movement and implicit acquisition of motorskills (48) Patients with movement disorders may have abnormalblood flow or metabolism in the basal ganglia (Table 9.1.2).Cortical changes may represent primary cortical abnormalities

impor-or deafferentation effects because of subcimpor-ortical abnimpor-ormalities.Patients with movement disorders who also develop dementia typ-ically will show more widespread cortical metabolic or blood flowchanges Table 9.1.3 provides a summary of the major subcorticaland cortical glucose metabolic changes in neurodegenerative move-ment disorders

Parkinson Disease

Parkinson disease is a clinical syndrome consisting of a variablecombination of symptoms of tremor, rigidity, postural imbalance,and bradykinesia (49,50) Although Parkinson disease accounts formost patients who have parkinsonian symptoms, parkinsonism can

be seen with neurodegenerative disorders other than Parkinson ease, such as progressive supranuclear palsy (PSP) or multiple sys-tem atrophy (MSA) (49) Idiopathic Parkinson disease distin-guishes itself from other parkinsonian syndromes by markedleft–right asymmetry in symptom severity and good symptomaticresponse to levodopa therapy (49,50) The additional presence ofcertain clinical findings may raise the clinical suspicion for an atyp-ical parkinsonian syndrome, such as prominent autonomic dys-function, cerebellar symptoms, or abnormal eye movements (49).Chapter 9.1 • Movement Disorders, Stroke, and Epilepsy 483

FIGURE 9.1.3 A: A diagrammatic representation of crossed

cerebro-cerebellar diaschisis showing cerebro-cerebellar hypoperfusion contralateral to

a supratentorial structural lesion B: Reverse crossed cerebrocerebellar

diaschisis can be observed during ictal seizure activity where a

supra-tentorial ictal focus of hyperperfusion is associated with contralateral

cerebellar hyperperfusion

Examples of Disorders or Conditions with Altered Glucose Metabolism of the Basal Ganglia

Increased fluorodeoxyglucose Early Parkinson disease(FDG) metabolic activity basal Hepatocerebral

T A B L E 9 1 2

The clinical features of Parkinson disease to a large degree

result from loss of nigrostriatal nerve terminals in the striatum

sec-ondary to the degeneration of dopamine-producing pigmented

neurons in the substantia nigra in the brainstem (51,52) The

greater the neuronal loss in the substantia nigra, the lower the

con-centration of dopamine in the striatum, and the more severe the

parkinsonian symptoms It should be noted that the cellular

com-ponent of nigrostriatal nerve terminals within the striatum is far

less than the number of intrinsic striatal interneurons and

projec-tion neurons Therefore, resting glucose metabolic studies

primar-ily reflect the synaptic activity of interneurons and only to a lesser

extent afferent projection neurons

Resting glucose metabolic and cerebral blood flow studies of

patients with early Parkinson disease have shown increased striatal

activity contralateral to the clinically most affected body side,

which may represent a compensatory mechanism of intrinsic

stri-atal cells (53,54) However, stristri-atal glucose metabolism may

decrease with advancing disease (55,56) FDG PET studies have

also been used to predict levodopa response in parkinsonian

patients A study found that relatively increased FDG activity in the

striatum contralateral to the clinically most affected body side was

associated with a good levodopa response In contrast, relatively

decreased striatal FDG uptake was associated with poor levodopa

responsiveness (57)

Parkinsonian or Lewy Body Dementia

Alzheimer disease is the most common type of dementia The

sec-ond most common form of degenerative dementia in most clinical

series is parkinsonian or Lewy body dementia (58) An arbitrary but

generally accepted distinction has been made in current

interna-tional consensus diagnostic criteria between patients presenting

with parkinsonism prior to the onset of dementia (Parkinson

disease dementia) and developing parkinsonism and dementia

con-currently (dementia with Lewy bodies) (59–61) These

duration-based criteria would diagnose patients with Parkinson disease who

subsequently develop dementia more than 1 year after their initial

Parkinson disease motor symptoms as Parkinson disease dementia

Patients meeting the 1-year rule between the onset of dementia and

parkinsonism would be diagnosed as dementia with Lewy bodies(60)

Although there are relative differences in temporal tion and relative severity of clinical symptoms between these clini-cally defined subgroups of parkinsonian dementia, the underlyingneuropathological findings are more similar than dissimilar andsuggest these subgroups should be grouped together (62) Parkin-sonian dementia is characterized neuropathologically by neuronallosses and Lewy body inclusions in midbrain dopaminergic nuclei(as in Parkinson disease), but involving limbic and neocorticalregions as well (58,60)

manifesta-Cortical neuropathologic changes in Alzheimer disease are erogeneous topographically but are not randomly distributed Ithas been demonstrated that primary somatosensory and motorcortical regions are relatively spared, while association cortices aremore severely involved (63) In the Alzheimer brain, FDG PETimaging reveals characteristic hypometabolism in neocorticalstructures, especially in posterior cingulate/precuneus, parietal,temporal, and to a lesser and more variable degree in frontal associ-ation cortices, the same locations where coexisting cortical neu-ronal degeneration is also found in postmortem studies (64,65).Parietotemporal hypometabolism can also be seen with parkinson-ian or Lewy body dementias

het-Vander Borght et al (56) compared metabolic differencesbetween Alzheimer disease and parkinsonian dementia matched forseverity of dementia and found similar glucose metabolic reduc-tions globally and regionally, involving the lateral parietal, lateraltemporal, lateral frontal association cortices, and posterior cingu-late gyrus when compared to controls However, patients withparkinsonian dementia had greater metabolic reductions in the pri-mary visual cortex and relatively preserved metabolism in themedial temporal lobe

Decreased occipital metabolism has also been observed in demented patients with Parkinson disease (66) Patients withAlzheimer disease showed only mild reductions in the visual cortexbut relatively more pronounced reduction in the medial temporallobe Metabolic reduction in the posterior cingulate cortex and pre-cuneus demonstrated in Alzheimer disease has also been found inparkinsonian dementia (56) (Table 9.1.4)

non-484 Principles and Practice of PET and PET/CT

Changes in Neurodegenerative Movement Disorders

(fronto-poroparietal, dementia) frontal) parietal)precuneus,

aContralateral to (most) involved body side

LWBK053-3787G-9.01[479-499].qxd 14-08-2008 05:56 PM Page 484 Aptara Inc

Progressive Supranuclear Palsy

PSP or Steele-Richardson-Olszewski syndrome is an atypical

parkinsonian syndrome characterized by severe gait and balance

dis-turbances, abnormal eye movements (especially vertical

supranu-clear gaze palsy), and pseudobulbar palsy More advanced disease is

often associated with a frontal lobe type of dementia Pathological

changes consist of neurofibrillary tangle formation and neuronal

loss in the superior colliculi, brainstem nuclei, periaqueductal gray

matter, and basal ganglia (67)

PET studies of patients with progressive supranuclear palsy

have shown reduced glucose metabolism in the caudate nucleus,

putamen, thalamus, pons, and cerebral cortex, but not in the

cere-bellum (68) There are significant metabolic reductions in most

regions throughout the cerebral cortex but are more prominent in

the frontal lobe (Fig 9.1.4) (69) Although frontal metabolism

decreases with increasing disease duration, relative frontal

hypome-tabolism has been found to already be present in the early stages of

the disease (70)

Statistical brain mapping studies have demonstrated decreased

glucose metabolism in the anterior cingulate, adjacent

supplemen-tary motor area, precentral cortex, middle prefrontal cortex,

mid-brain tegmentum, globus pallidus, and ventrolateral and

dorsome-dial nuclei of the thalamus (71,72) Clinical parkinsonian motor

scores have been reported to correlate with caudate and thalamic

glucose metabolic values (70) These data highlight predominant

metabolic impairment in subcorticocortical connections in PSP

Corticobasal Degeneration

Corticobasal degeneration is an atypical parkinsonian syndrome

characterized clinically by marked asymmetric limb rigidity with

apraxia Patients may also exhibit alien limb phenomenon, cortical

sensory loss, and myoclonus Cognitive functions are relatively well

preserved in most patients Neuropathological findings consist of

swollen, achromatic, tau-staining Pick bodies that may be present

in the inferior parietal, posterior frontal, and superior temporal

lobes, dentate nucleus, and substantia nigra (73) FDG PET studies

have shown significantly reduced cerebral glucose metabolism in

the hemisphere contralateral to the clinically most affected side.This reduction can occur in the dorsolateral frontal, medial frontal,inferior parietal, sensorimotor, and lateral temporal cortex as well

as in the corpus striatum and the thalamus in patients with cobasal degeneration (74–76)

corti-Statistical brain mapping analysis of patients with corticobasaldegeneration have confirmed the asymmetric glucose metabolicimpairment in the putamen, thalamus, precentral, lateral premotorand supplementary motor areas, dorsolateral prefrontal cortex, andparietal cortex (77) A Japanese study found the most prominentloss in the parietal lobe in patients with corticobasal degeneration

Chapter 9.1 • Movement Disorders, Stroke, and Epilepsy 485

Parkinsonian Dementia

Alzheimer Disease Parkinsonian Dementia

There are similar glucose metabolic reductions globally and regionally involving the lateral parietal, lateraltemporal, lateral frontal association cortices, and posterior cingulate gyrus when compared to controls

However, patients with parkinsonian dementia have greater metabolic reductions in the primary visualcortex and relatively preserved metabolism in the medial temporal lobe In contrast, patients withAlzheimer disease showed only mild reductions in the visual cortex but relatively more pronouncedhypometabolism in the medial temporal lobe

(From Vander Borght T, Minoshima S, Giordani B, et al Cerebral metabolic differences in Parkinson’s andAlzheimer’s disease matched for dementia severity J Nucl Med 1997;38:797–802, with permission.)

FIGURE 9.1.4 A fluorodeoxyglucose PET image of patient with

pro-gressive supranuclear palsy showing prominent frontal lism

hypometabo-(78) These results confirm the marked asymmetric cerebral

involvement, particularly in the parietal cortex and thalamus, in

patients with corticobasal degeneration (Fig 9.1.5) (72,78–80)

Multiple System Atrophy

MSA is an atypical parkinsonian syndrome covering a clinical

spec-trum of parkinsonism in variable combination with symptoms of

cerebellar ataxia or dysautonomia This group of disorders includes

Shy-Drager syndrome (MSA of the dysautonomia type),

olivopon-tocerebellar atrophy (MSA of the cerebellar type), and striatonigral

degeneration, which resembles Parkinson disease but does not

respond to dopaminergic drugs The pathology of MSA is distinct

from Parkinson disease and consists of neuronal loss in the

sub-stantia nigra, striatum, cerebellum, brainstem, and spinal cord with

argyrophilic and glial inclusions (81)

An FDG PET study found reduced caudate, putaminal,

cerebel-lar, brainstem, and frontal and temporal cortical glucose

metabo-lism in patients with MSA compared to normal controls (82) A

voxel-based analysis of glucose metabolism found significant

hypometabolism in the putamen, pons, and cerebellum in patients

with MSA (83)

Reductions of cerebellar and brainstem glucose metabolism

have been reported to be most prominent in patients with

olivo-pontocerebellar atrophy (84) Although cerebellar and brainstem

glucose metabolism correlated with the severity of MRI-measured

atrophy, some patients who had no MR evidence of tissue atrophy

still showed decreased glucose metabolism in these regions (85)

Patients with the striatonigral degeneration subtype had relatively

preserved brainstem and cerebellar glucose metabolic rates (85)

Essential Tremor

Essential tremor represents a variable combination of postural and

kinetic tremor It most commonly affects the hands, but also occurs

in the head, voice, face, trunk, and lower extremities (86)

Post-mortem studies have found evidence of cerebellar degeneration;

Lewy body deposition in the brainstem including the locus ceruleushas been found in a subset of subjects (87,88) A PET study foundsignificant glucose hypermetabolism of the medulla and thalami,but not of the cerebellar cortex in patients with essential tremorduring resting conditions (89) CBF PET studies using [15O]-water

in patients with essential tremor demonstrated abnormallyincreased bilateral cerebellar, red nuclear, and thalamic blood flowduring tremor (90–93) Therefore, the cerebellum and thalamusappear to play important roles as part of a cerebral circuitry that isabnormally activated during tremor

Huntington Disease and Choreiform Movement Disorders

Huntington disease is an autosomal dominant neurodegenerativedisorder with complete penetrance (94) The gene for Huntingtondisease, containing an amplified number of cytosine-adenine-guanine(CAG) trinucleotide repeats, is located on the short arm of chro-mosome 4 (95) Chorea is the most commonly recognized involun-tary movement abnormality in adult patients with Huntington dis-ease, but the presence of psychiatric symptoms and dementia mayvary (96) Pathologically, Huntington disease is characterized bymarked neuronal loss and atrophy in the caudate nucleus and puta-men (97,98) Glucose metabolic PET studies in Huntington diseasehave demonstrated decreased glucose utilization in the caudatenucleus and putamen even before striatal atrophy is apparent onbrain CT or MRI scans (99–101) Metabolic covariance analysis ofFDG PET data of patients with Huntington disease not onlydemonstrated caudate and putaminal hypometabolism, but therewere reductions in mediotemporal metabolism as well as relativemetabolic increases in the occipital cortex (102)

Chorea as a hyperkinetic movement disorder can also be seenwith other disorders, such as dentatorubropallidoluysian atrophy,neuroacanthocytosis, or Sydenham chorea Striatal, especially cau-date, glucose hypometabolism has been demonstrated in denta-torubropallidoluysian atrophy and neuroacanthocytosis This issimilar to Huntington disease but striatal glucose metabolism hasbeen found to be increased in a patient with Sydenham chorea and

in a patient with antiphospholipid antibody syndrome and chorea(103–107) Patients with hyperglycemia-induced unilateral basalganglion lesions with and without hemichorea may have reducedipsilateral glucose metabolism (108)

Dopaminergic Neurochemical Imaging:

Diagnosis of Parkinson Disease

The basal ganglia and the neurotransmitter dopamine have been keytargets for research exploring the pathophysiology underlyingmovement disorders Dopaminergic neurons from the substantianigra project as nigrostriatal nerve terminals to the striatum wherethey have synaptic connections with striatal interneurons or projec-tion neurons Presynaptic nigrostriatal dopaminergic activity can beimaged using PET radiotracers like [18F]-fluorodopa (FDOPA) ordopamine transporter protein ligands, such as the cocaine analogue[11C]-WIN35428 (Fig 9.1.6) (109–111) Postsynaptic dopamine

D2 receptor binding can be imaged using the PET tracer [11raclopride (112)

C]-PET studies using presynaptic dopaminergic tracers have tively demonstrated nigrostriatal nerve terminal loss in Parkinsondisease even at a very early or preclinical stage of the disease (113)

objec-486 Principles and Practice of PET and PET/CT

FIGURE 9.1.5 A fluorodeoxyglucose PET image of patient with

cor-ticobasal degeneration showing regionally prominent asymmetric

(right) parietal hypometabolism.

LWBK053-3787G-9.01[479-499].qxd 14-08-2008 05:56 PM Page 486 Aptara Inc

Reductions are more severe in the posterior putamen (when

com-pared to the anterior putamen and caudate nucleus) and

contralat-eral to the clinically most affected body side (Fig 9.1.7) (114,115)

Putaminal FDOPA uptake is also correlated with clinical

mea-sures of disease severity, particularly bradykinesia (54,116–118)

Therefore, these techniques can provide neurochemical markers to

follow progression of disease or evaluate the effects of therapeutic

or neurorestorative interventions For example, fiber outgrowth

from transplanted embryonic dopamine neurons, as indicated by

an increase in putaminal FDOPA uptake, was detected in patients

with severe Parkinson disease (119)

Pre- and Postsynaptic Dopaminergic

Neurochemical Imaging: Atypical

Parkinsonian Disorders

Nigrostriatal denervation is not specific for Parkinson disease

Pre-synaptic dopaminergic denervation has also been demonstrated in

patients with multiple system atrophy, PSP, corticobasal

degenera-tion, or spinocerebellar atrophy (120–122) Imaging of nigrostriatal

dopaminergic system in PSP reveals consistent reductions, with

rel-ative regional differences in the intrastriatal pattern of denervation

in comparison to Parkinson disease (121,123–127) For example,

Ilgin et al (128) found that striatal dopamine transporter reductionswere more pronounced in the posterior putamen in patients withParkinson disease, while patients with PSP had a relatively uniformdegree of involvement of the caudate and putamen

In addition to presynaptic changes in the nigrostriatal neurons,striatal dopamine receptors are altered in Parkinson disease Forinstance, in early idiopathic Parkinson disease uptake of [11C]-raclopride, which is a selective dopamine D2 receptor ligand,increases in the striatum contralateral to the predominant parkin-sonian symptoms compared to the uptake in the ipsilateral striatum(129) This up-regulation may disappear 3 to 5 years later (130) Acombined FDG and D2receptor PET study found a positive corre-lation between striatal glucose metabolic activity and receptorexpression in Parkinson disease (131)

Studies of the postsynaptic D2status have demonstrated normal

or increased D2 receptor density in early Parkinson disease anddecreased receptor density in patients with advanced Parkinson dis-ease or atypical parkinsonism, such as multiple system atrophy andprogressive supranuclear palsy Therefore, combined pre- and post-synaptic dopaminergic imaging may distinguish early idiopathicParkinson disease from atypical parkinsonian disorders (Table 9.1.5).However, combined pre- and postsynaptic dopaminergic imagingmay not be able to distinguish atypical parkinsonian disorders fromeach other or from advanced idiopathic Parkinson disease

Dopaminergic PET studies should not be used as a substitutefor the clinical diagnosis of Parkinson disease However, neuro-chemical and functional activation studies may play an importantclinical role in the selection of patients with abnormal movementswho may benefit from electrical deep brain stimulation Dopamin-ergic studies may have a limited clinical role in the diagnosis ofpatients with symptoms suggestive of Parkinson diseases yet do notrespond to typical anti-Parkinson drugs There is some interest inusing dopaminergic PET tracers to aid in the differential diagnosis

of essential tremor from early Parkinson disease

Dopaminergic Neurochemical Imaging:

Differential Diagnosis of Parkinsonian or Lewy Body Dementia from Alzheimer Disease

Nigrostriatal dopamine neurons are involved in virtually all patientswith parkinsonian dementia, and imaging research studies havedemonstrated reduced presynaptic nigrostriatal markers (132,133).Striatal dopaminergic markers are, conversely, normal in Alzheimerdisease, and therefore presynaptic dopaminergic imaging can be usedfor the differential diagnosis between parkinsonian dementia andAlzheimer disease A subset of patients with parkinsonian dementiapresent clinically with Parkinson disease, followed later by cognitivedecline These demented subjects have subtle differences from

Chapter 9.1 • Movement Disorders, Stroke, and Epilepsy 487

FIGURE 9.1.6 A schematic overview of the nigrostriatal dopamine

nerve terminal and a postsynaptic dopamine neuron Dopamine

metab-olism (DOPA decarboxylase enzyme activity), vesicular monoamine

transporter type 2 (VMAT2), synaptic membrane dopamine transporter,

and postsynaptic dopamine receptor type 1 and 2 activity can be

stud-ied by PET neurochemical imaging

FIGURE 9.1.7 Carbon-11() dihydroletrabenazine

(DTBZ) PET images of a normal person (left), patient

with Parkinson disease (middle), and parkinsonian

dementia (right) There is prominent predominant

posterior putaminal (arrow) and asymmetric (dashed

arrow) dopaminergic denervation in the patient with

Parkinson disease The patient with parkinsonian

dementia has more diffuse and bilateral striatal

dopaminergic denervation involving both the putamen

and caudate nucleus

Parkinson disease in their nigrostriatal dopamine imaging patterns,

with relatively symmetrical and diffuse reduction in presynaptic

markers in comparison with the side-to-side and

putamen-to-cau-date nucleus heterogeneity typical of Parkinson disease (Fig 9.1.7)

STROKE

Current management of patients with acute stroke is centered on CT

and MRI CT has traditionally played a prominent role by detecting

the presence of hemorrhage However, gradient recalled echo MR

may be as accurate as CT for the detection of acute hemorrhage and

is also more accurate than CT for the detection of chronic

intracere-bral hemorrhage (134) MR blood oxygen level-dependent

func-tional imaging is now playing a key role in the very early diagnosis of

ischemic stroke (135,136) Multitracer PET imaging has allowed

major new insights into the pathophysiology of stroke in humans

(137–139) Determinations of CBF, cerebral blood volume (CBV),

and cerebral metabolic rate of oxygen (CMRO2) permit the

discrim-ination of various compensatory mechanisms in occlusive vascular

disease For example, compensatory changes in the CBF/CBV ratio

(indicating a perfusion reserve) and increases in the oxygen

extrac-tion fracextrac-tion (OEF, a marker of metabolic reserve), may prevent

ischemic tissue damage during graded flow decreases (138) It has

been possible to document the compensatory responses of the brain

to reductions in perfusion pressure using PET and to directly relate

these responses to prognosis (139)

Measurement of Cerebral Oxygen

Metabolism, Cerebral Blood Volume, and

Oxygen Extraction Fraction Using PET

PET measurements of rCBF, cerebral blood volume, oxygen

extrac-tion, oxygen and glucose consumption permit a detailed

investiga-tion of the pathophysiology of stroke (140) The short-lived PET

tracer [15O] (half-life of 123 seconds) was first used to study CBF and

cerebral oxygen utilization in man by Ter-Pogossian et al (141,142)

Jones et al (143) described a noninvasive inhalational method, using

steady state kinetics, to measure the distribution of CBF and OEF in

the human brain The continuous inhalation of either molecular

[15O] or C15[O2] produces complementary images in that they relate

to regional oxygen uptake and blood flow, offering a direct insight to

the regional demand-to-supply relationships within the brain (144)

The method of quantitative measurement of rCBF and CMRO2

has been described in detail by Frackowiak et al (145) OEF reflects

the arterial-venous oxygen difference divided by the arterial oxygen

content Reliable OEF estimates can be obtained by combiningdynamic C[15O] and [15O2] scans (146) An expression for OEF can

be obtained by dividing the cerebral activity obtained during [15O]inhalation by that obtained during C15[O2] inhalation with someadditional computations (145) The CMRO2can be derived fromthe relationship (145):

CMRO2= CBF  OEF  Total blood oxygen count

(from arterial blood sample)

Using these methods Frackowiak et al found normal values ofCMRO2of 1.81  0.22 mL O2/100 mL/min in mean white matterand 5.88  0.57 mL O2/100 mL/min in temporal gray matter Cor-responding values for CBF were 21.4  1.9 mL /100 mL/min inmean white matter and 65.3  7.0 mL /100 mL/min in mean tem-poral lobe gray matter (145)

Methods other than the steady-state inhalation method havebeen developed to measure CBF and CMRO2, such as the autoradi-ographic CBF method using intravenous H2[15O] and newerdynamic methods (147) Cerebral blood volume can be measured

by inhalation of C[15O] (148) Quantitative imaging of the OEF hasbeen shown to be of invaluable help in the assessment of the pattern

of CBF-CMRO2coupling (149) Ideally, glucose utilization should

be measured simultaneously with CMRO2in order to provide anaccurate assessment of regional energy metabolism Glucose uti-lization and oxygen use may become uncoupled in acute stroke andthis uncoupling may go in two opposite directions, either aerobicglycolysis with relatively increased glucose consumption, or use ofsubstrates for oxidation other than glucose (149) Table 9.1.6

488 Principles and Practice of PET and PET/CT

Parkinson Disease and Atypical Parkinsonian Disorders

Presynaptic Dopaminergic Postsynaptic StriatalNigrostriatal Activity Dopamine Receptor Activity

progressive supranuclear palsy or multiple system atrophy)

Conditions in Stroke

Luxury perfusion low/normal/high low lowCBF, cerebral blood flow; CMRO2, cerebral metabolic rate of oxygen;OEF, oxygen extraction fraction

(From Baron JC, Frackowiak RS, Herholz K, et al Use of PET methodsfor measurement of cerebral energy metabolism and hemodynamics incerebrovascular disease J Cereb Blood Flow Metab 1989;9:723–742,

with permission.)

LWBK053-3787G-9.01[479-499].qxd 14-08-2008 05:56 PM Page 488 Aptara Inc

summarizes different pathophysiological conditions in stroke

(from Baron et al [149])

Acute Ischemic Stroke

Brain tissue infarction may follow a critical reduction in rCBF and

may lead to neurological deficits The more severe the drop in

per-fusion the higher the chance of irreversible brain tissue damage

(150) The development of methods of determining rCBF has made

possible the determination of thresholds for the appearance of

cere-bral ischemia (Table 9.1.7) These thresholds vary depending on the

method used for assessing cerebral ischemia The presence of low

attenuation changes on CT in acute stroke has been found to

corre-late with severe hypoperfusion (less than 12 mL/100 g/min) on CBF

PET (151) It should be noted that not only the level of residual CBF

but also the duration of ischemia will determine the presence of

irreversible infarction

A prerequisite for the successful treatment of acute ischemic

stroke is the existence of viable tissue that is morphologically intact

but functionally impaired due to flow decreases below a certain

threshold The ischemic penumbra is defined as tissue with flow

falling within the thresholds for maintenance of function and of

morphologic integrity (152) Early in the course of acute ischemia,

CBF and CMRO2levels falling below certain thresholds may lead to

irreversible tissue damage, while preservation of CMRO2 with

decreased flow resulting in increased OEF (“misery” perfusion) still

suggests viable tissue (“penumbra”) (153)

Identification of viable or penumbra tissue is the key target for

interventional therapy in acute ischemic stroke Rapid restoration

of blood flow to the penumbra even in the presence of a fixed deficit

at the center of the stroke may improve stroke outcome

Identifica-tion of penumbra tissue can be achieved by multitracer PET (138)

It should be noted that MR-defined mismatch between

diffusion-weighted and perfusion-diffusion-weighted imaging does not reliably detect

elevated OEF and overestimates the penumbra defined by PET

(154) Diffusion-weighted imaging lesions on MR showed impaired

tissue integrity (low CMRO2and low OEF); mismatch areas were

viable (normal CMRO) but showed largely varying OEF (154)

Therefore, the MR-defined diffusion-perfusion mismatch mates the volume of penumbra and therefore the tissue at risk

overesti-Subacute Changes in Ischemic Stroke

In subacute states of cerebral ischemia reduced blood flow can becompensated by increased blood volume and, when perfusionreserve is exhausted, OEF may increase up to 48 hours after theonset of stroke (138) This condition, also called misery perfusion,implies that blood flow is inadequate relative to the energy meta-bolic tissue demand for oxygen (138) Penumbra tissue can be seen

as a stable rim of tissue surrounding the core of infarction but mayalso change in time as a dynamic phenomenon, involving new adja-cent tissue compartments while others are becoming permanentlynecrotic (138) Studies identifying penumbra tissue could be ofvalue in the development of effective therapeutic strategies even inthe subacute stage of stroke (138)

Some patients may have postischemic reactive hyperemia thatoccurs within hours or days after stroke onset This phenomenon iscalled luxury perfusion and is seen in the periphery of an ischemicstroke Unlike misery perfusion, luxury perfusion is seen asincreased CBF and a low OER (138,149) Luxury perfusion mayreflect recanalization of an occluded artery (149)

Chronic Arterial Occlusive Disease and Hemodynamic Reserve

Hemodynamic factors may play an important role in the esis of ischemic stroke in patients with cerebrovascular disease(155) Patients with arterial occlusive disease are protected againstischemic episodes to a certain extent by compensatory mechanisms,which may help to prevent ischemia when perfusion pressure drops(138) Severe atherosclerotic disease of the carotid and vertebralarteries may lead to reduced perfusion pressure (156) This maycause hemodynamic impairment of the distal cerebral circulation

pathogen-It should be noted that CBF studies alone do not adequately assesscerebral hemodynamic status as CBF may be maintained byautoregulatory vasodilation and even low CBF values may not cor-relate with perfusion pressures (155)

Functional imaging techniques can be used to assess two basiccategories of hemodynamic impairment The first category reflects

a state of autoregulatory vasodilation secondary to reduced sion pressure that can be assessed by the measurement of eitherincreased cerebral blood volume or an impaired CBF response to avasodilatory stimulus The second category is defined on the basis

perfu-of OEF measurements (increased OEF) (155)

Compensatory regional vasodilation may manifest itself as afocal increase in CBV in the supply territory of the occluded artery(138,157) Here, the ratio of CBF to CBV has been used as an indi-cator of local perfusion pressure or perfusion reserve (normal: 10)(138) The lower the value, the lower the flow velocity (138) Whenthe perfusion pressure is exhausted (i.e., at maximal vasodilata-tion), any further decrease in arterial input pressure will produce aproportional decrease in both CBF and the CBF/CBV ratio (138)

In this type of hemodynamic decompensation, the brain willexploit oxygen carriage reserve to prevent energy failure and loss offunction, as evidenced by an increase in OEF (156,157)

The relative importance of hemodynamic factors in the genesis of stroke in patients with carotid arterial occlusive diseasewas investigated in the St Louis Carotid Occlusion Study (158,159)

patho-Chapter 9.1 • Movement Disorders, Stroke, and Epilepsy 489

Cerebral Blood Flow in Human and Nonhuman Primates

CBF Threshold Clinical Correlates

20 cc/100 g/min EEG and evoked cortical potential

abnormalities appear, paralysis seen inawake monkeys

15 cc/100 g/min EEG and evoked cortical potentials are

lost

12 cc/100 g/min Flow values at this level in excess of

120 minutes produce infarction inanimals

6 cc/100 g/min Massive loss of intracellular potassium

CBF, cerebral blood flow; EEG, electroencephalogram

(From Morawetz RB, Crowell RH, DeGirolami U, et al Regional cerebral

blood flow thresholds during cerebral ischemia Fed Proc 1979;38:

2493–2494, with permission.)

This study demonstrated that increased cerebral OEF detected by

PET scanning predicted future stroke in patients with symptomatic

carotid occlusion The study demonstrated that ipsilateral increased

OEF measured by PET is a powerful independent risk factor for

subsequent stroke in patients with symptomatic complete carotid

artery occlusion The ipsilateral ischemic stroke rate at 2 years was

shown to be 5.3% in 42 patients with normal OEF and 26.5% in 39

patients with increased OEF In patients in whom hemispheric

symptoms developed within 120 days, the 2-year ipsilateral stroke

rates were 12% in 27 patients with normal OEF and 50% in 18

patients with increased OEF (159) Previous PET studies have

demonstrated that anastomosis of the superficial temporal artery to

a middle cerebral artery cortical branch can restore OEF to normal

Consequently, a trial of extracranial-to-intracranial arterial bypass

for this group of patients is being conducted in St Louis (159,160)

It should be noted that correlation between different methods

to assess impaired blood flow response to a vasodilatory stimulus

with each other and with methods that assess OEF is quite variable

(155) Vasodilatory hemodynamic stress testing relies on paired

blood flow measurements with the initial measurement obtained at

rest and the second measurement obtained following a cerebral

vasodilatory stimulus (155) A comparison of the reststress

perfu-sion may provide an estimate of cerebrovascular reserve

Acetazo-lamide or inhaling carbon dioxide have been used as vasodilatory

stimuli (155) Acetazolamide is a carbonic anhydrase inhibitor that

increases the carbon dioxide in the brain Each vasodilator stimulus

will result in a significant increase in CBF in normal persons If the

CBF response is muted or absent, pre-existing autoregulatory

cere-bral vasodilatation due to reduced cerecere-bral perfusion pressure is

inferred (155) The blood flow responses to vasodilator stress have

been categorized into several grades of hemodynamic impairment:

(a) reduced augmentation (relative to the contralateral hemisphere

or normal controls); (b) absent augmentation (same as baseline);

and (c) paradoxical reduction in rCBF (“steal” phenomenon)

(155) Although commonly applied, it should be noted that there is

a lack of well-controlled prognostic studies on the use of these

vasodilator rest-stress techniques in patients with cerebrovascular

disease (155,161) However, a recent study measuring OEF

reactiv-ity with acetazolamide found preliminary evidence that positive

OEF reactivity may identify hemodynamic compromise despite

normal baseline OEF (162) Abnormal OEF reactivity may also be

associated with subcortical white matter infarcts (162)

Hemorrhagic Stroke

The importance of ischemia as a secondary mechanism of brain

injury has been addressed in subarachnoid hemorrhage and

intracranial hematoma (139) Multitracer PET studies of patients

with subarachnoid hemorrhage but without vasospasm have shown

a significant reduction in global CMRO2with no significant change

in global OEF, suggesting a primary reduction in CMRO2 in the

absence of vasospasm (163) However, subarachnoid hemorrhage

complicated by vasospasm has been found to be associated with

sig-nificantly increased regional OEF with unchanged CMRO2,

indica-tive of cerebral ischemia without infarction (163) PET studies of

patients with intracerebral intraparenchymal hemorrhage have

shown reduced CBF surrounding the primary bleeding site (164)

PET demonstrated that hematomas exert a primary depression of

metabolism rather than inducing ischemia in the surrounding

tis-sue It also documented the integrity of autoregulation and

pro-vided clinically useful information regarding the safety of bloodpressure reduction after intracranial hematoma (139)

Estimation of Prognosis After Stroke

Functional recovery after focal brain lesions is dependent on theadaptive plasticity of the cerebral cortex and of the nonaffected ele-ments of the functional network (165) Therefore, the degree offunctional recovery after a stroke is related to the location and size

of the lesion, the presence of remaining neurons in the hood of the lesion, and the presence of compensatory mechanisms

neighbor-in functionally connected networks (138) Rather than a completesubstitution of function, the main mechanism underlying recovery

of motor abilities involves enhanced activity in pre-existing works, including the disconnected motor cortex in subcorticalstroke and the infarct rim after cortical stroke (166) Although theregional cerebral metabolic rate of glucose in early ischemia is oftennot coupled to flow or CMRO2 and might even be increased,regional cerebral glucose metabolism is the best indicator of per-manent impairment of tissue function (138) A normal FDG PET

net-or the presence of a mild metabolic abnnet-ormality has been stronglyassociated with good clinical outcome or complete reversal of theneurological dysfunction (167) In contrast, patients with poorclinical outcomes had more severe glucose metabolic deficits (167).The presence of early luxury perfusion in the context of little or

no metabolic alteration may also indicate a favorable prognosis(168) A study comparing early and delayed PET studies in patientswith stroke found that in hyperperfused regions, the acute-stageperfusion, blood volume, and oxygen consumption were signifi-cantly increased, and the OEF was significantly reduced, while allthese variables had significantly returned toward normality in thechronic-stage PET study The ultimately infarcted area did notexhibit significant hyperperfusion in the acute stage (168) Thesedata indicate that early reperfusion into metabolically active tissue

special-is growing more important with the increasing availability of CTand MR perfusion techniques

New Emerging Clinical Applications of PET in Stroke: Neuronal and Hypoxia Imaging

New tracers, such as receptor ligands or hypoxia markers, may ther improve the identification of penumbra tissue in the future(152,169) Clinical application of such techniques may permit theextension of the critical time period for inclusion of patients foraggressive stroke management strategies CBF and FDG PET stud-ies of patients with stroke may not only show the local effectscaused by the primary stroke lesion but also demonstrate remoteeffects because of diaschisis Central benzodiazepine receptor

fur-490 Principles and Practice of PET and PET/CT

LWBK053-3787G-9.01[479-499].qxd 14-08-2008 05:56 PM Page 490 Aptara Inc

ligands, such as [11C]-flumazenil, are markers of neuronal integrity

and therefore may be useful in the differentiation of functionally

and morphologically damaged tissue in stroke [11C]-flumazenil

PET imaging has the potential to depict damaged brain tissue by

directly assessing neuronal loss A study demonstrated the

feasibil-ity of [11C]-flumazenil PET imaging in distinguishing between

irre-versibly damaged and viable penumbra tissue early after acute

stroke (170) In subacute and chronic states after stroke, functional

impairment without morphologic lesions on CT could be

attrib-uted to silent infarctions characterized by significant reduction of

benzodiazepine binding (171)

[18F]-fluoromisonidazole (FMISO) is a PET hypoxia markerthat has been validated to map the penumbra in acute stroke

(172,173) A rat study demonstrated elevated FMISO uptake in the

stroke area only in the early phase of arterial occlusion, but not after

early reperfusion nor when tissue necrosis has developed (174)

FMISO PET may be able to identify true penumbral tissue that

would be amenable to rescue interventions even beyond 12 to 24

hours after stroke onset (173)

EPILEPSY

Epileptic syndromes are classified as generalized and partial types of

seizures Primary generalized epilepsy is associated with diffuse and

bilateral epileptiform discharges on electroencephalogram (EEG)

without evidence of focal brain lesions In contrast, partial epilepsy

is thought to arise from a focal gray matter lesion Partial-onset

seizures may remain partial or may secondarily generalize

Med-ically refractory epilepsy is defined by seizure syndromes that are

not effectively controlled by antiepileptic drugs

The management of medically refractory partial epilepsy has

been revolutionized by neurosurgical techniques aimed at the

resection of the epileptogenic brain focus Therefore, precise seizure

localization is the prime goal of presurgical work-up EEG

moni-toring and structural brain imaging using MRI are part of the

stan-dard work-up of patients with epilepsy undergoing presurgical

evaluation FDG PET can provide additional localizing information

in patients with nonlocalizing surface ictal EEG and can reduce the

number of patients requiring intracranial EEG studies (175) Even

when intracranial EEG is required, FDG PET can be helpful in

guiding placement of subdural grids or depth electrodes prior to

surgical ablative therapy PET imaging should always be performed

before intracranial EEG as prior depth electrode insertion can cause

small hypometabolic regions that may lead to false-positive PET

interpretations (176)

Regional Glucose Hypometabolism as

Interictal Expression of Epileptogenic Foci

Unlike patients with primary generalized epilepsy who have no

interictal abnormalities on CBF or FDG PET studies (177),

interic-tal FDG PET studies can identify epileptogenic foci in patients with

partial epilepsy on the basis of regional cortical glucose

hypome-tabolism (178) It should be noted that FDG PET may show more

widespread hypometabolism than suspected on the basis of the

scalp-recorded EEG (175) The pathophysiology of interictal

corti-cal hypometabolism in partial epilepsy is poorly understood Areas

of interictal hypometabolism in epileptogenic cortex appear to be

partially uncoupled from blood flow with metabolic reductions

being greater relative to flow (179)

Although there are significant correlations between pal volume and inferior mesial and lateral temporal lobe cerebralmetabolic rates in patients with temporal lobe epilepsy (180), stud-ies have failed to find a significant correlation between corticalmetabolism on preoperative FDG PET imaging and neuronal den-sity of resected hippocampi (181) Therefore, hippocampal neu-ronal loss cannot fully account for the regional interictal hypome-tabolism of temporal lobe epilepsy It is possible that synapticmechanisms rather than cell loss may contribute to the observedhypometabolism (182) Children with a new onset of seizures areless likely to have hypometabolism (177) A longer duration of tem-poral lobe epilepsy is associated with greater hippocampal hypome-tabolism, suggesting that epilepsy is a progressive disease (183).Hypometabolism may reflect the effects of persistent epilepsy onthe brain (184)

hippocam-Regional Glucose Hypometabolism in Temporal Lobe Epilepsy

Mesial temporal lobe epilepsy is the most common type of partialepilepsy and is commonly associated with hippocampal sclerosis.FDG PET has high sensitivity in detecting temporal hypometabolicfoci and can be visualized as a region of reduced metabolism, whichwhen compared to the normal temporal lobe may show a significantasymmetry in FDG uptake (185) The severity of glucose hypome-tabolism correlates with the amount of interictal delta activity onEEG (186) It should be noted that false lateralization is rare but mayoccur For example, unrecognized epileptic activity can make thecontralateral temporal lobe appear spuriously depressed (176) Nor-mal right-to-left asymmetry between temporal lobes should not beinterpreted as pathological hypometabolism

Although FDG PET images can be analyzed visually, additionalinformation can be obtained by semiquantitative analysis, such asleft-to-right asymmetry indices Semiquantitative analysis using theasymmetry index is generally considered significant when a differ-ence of 15% or greater exists between the affected and contralateralsides (187) Quantitative asymmetry indices should reduce poten-tial error due to misinterpreting these normal left-to-right varia-tions (188) Registration programs can be used to align structuralMRI and PET for more precise anatomic localization of thehypometabolic area

Although regional hypometabolism is typically present in thetemporal lobe ipsilateral to EEG seizure onset, other brain regionsmay also show patterns of glucose hypometabolism (Fig 9.1.8) Forexample, an FDG PET study of patients with temporal lobe epilepsydemonstrated hypometabolic regions ipsilateral to seizure onsetthat included lateral temporal (in 78% of patients), mesial tempo-ral (70%), thalamic (63%), basal ganglia (41%), frontal (30%),parietal (26%), and occipital (4%) regions (189)

The prevalence of thalamic hypometabolism suggests a physiologic role for the thalamus in initiation or propagation of tem-poral lobe seizures (189) Cerebellar hypometabolism may be ipsilat-eral, contralateral, or bilateral, depending on the distribution andspread of ictal activity and possible effects of phenytoin therapy (Fig.9.1.2) (36,176) Bilateral cerebellar hypometabolism, which is oftenpresent, cannot be fully explained by the effects of phenytoin (36).Unilateral temporal hypometabolism predicts good surgicaloutcome from temporal lobectomy The greater the metabolicasymmetry the greater the chance of becoming seizure free (176).Bilateral temporal hypometabolism may represent a relativeChapter 9.1 • Movement Disorders, Stroke, and Epilepsy 491

patho-contraindication for surgery (176) Similarly, thalamic asymmetry

on FDG PET is a strong predictor of surgical outcome;

hypometab-olism in the thalamus contralateral to the presumed EEG focus

almost invariably predicts poor surgical outcome (190)

Extratem-poral cortical hypometabolism outside the seizure focus, in

partic-ular hypometabolism in the contralateral cerebral cortex, may also

be associated with a poorer postoperative seizure outcome in

tem-poral lobe epilepsy and may represent underlying pathology that is

potentially epileptogenic (191) Preoperative extratemporal

hypome-tabolism of the inferior frontal lobe and thalamus in temporal lobe

epilepsy may be partially reversible after ipsilateral temporal lobe

resection (192)

FDG PET is most useful for those patients with temporal lobe

epilepsy who have equivocal or no structural MRI abnormalities to

provide the necessary lateralization information (180,193)

Although most patients with temporal lobe epilepsy will have the

finding of hippocampal sclerosis on a high resolution MRI, a

signif-icant minority of patients with electroclinically well-lateralized

temporal lobe seizures have no evidence of sclerosis on MRI (194)

A recent study from Australia found that patients with

MRI-nega-tive temporal lobe epilepsy had interictal glucose hypometabolism

that primarily involved the lateral neocortical rather than the

mesiotemporal structures (195) Statistical parametric mapping

analysis may help to distinguish lateral from mesial temporal lobe

epilepsy (196)

Extratemporal Epilepsy

FDG PET may not be as valuable in the evaluation of patients with

extratemporal seizures, such as frontal lobe epilepsy, because of

limited sensitivity (188,197) Areas of hypometabolism in

extratem-poral lobe epilepsy have been found to be focal, regional, or

hemi-spheric (Fig 9.1.9) (198)

Large zones of extrafrontal, particularly temporal,

hypometab-olism are commonly observed ipsilateral to frontal

hypometabo-lism in frontal lobe epilepsies (13) Recent data show that

observer-independent automatic statistical brain mapping techniques may

increase the usefulness of FDG PET in patients with extratemporal

lobe epilepsy (199) For example, a study using an automated brain

mapping method found significantly higher sensitivity in detecting

the epileptogenic focus (67%) than visual analysis (19% to 38%) in

patients with extratemporal epilepsy (200)

Hypometabolic regions in partial epilepsies of neocortical

ori-gin have usually been associated with structural imaori-ging

abnormal-ities (197) Therefore, PET data should always be interpreted in thecontext of high-quality anatomical MRI, providing a structural-functional correlation Interictal hypometabolism may be uncom-mon in the absence of a colocalized structural imaging abnormality

in frontal lobe epilepsy (13) Interictal FDG PET studies will havelimited usefulness in the presence of multiple hypometabolicregions in patients with multifocal brain syndromes, such as in chil-dren with tuberous sclerosis Such children with multifocal lesionsrepresent a special challenge during presurgical evaluation Thegoal of functional imaging in these cases is to identify the epilepto-genic lesions and differentiate them from nonepileptogenic ones Inthis context, ictal rCBF SPECT may have useful clinical applicationsbut may be technically challenging when seizures are short, as isparticularly common in frontal lobe epilepsy and in children whohave infantile spasms that are associated with multifocal corticaldysplasia (201)

Glucose Metabolic PET Studies of Children with Infantile Spasms

Infantile spasms (West syndrome) are age-specific epileptic ena with many underlying etiologies An infantile spasm is an epilep-tic syndrome that begins in early infancy where children have tonic

phenom-492 Principles and Practice of PET and PET/CT

FIGURE 9.1.8 An interictal

fluorodeoxy-glucose PET study of a patient with a left eral and posterior temporal seizure focus.There is an extensive area of hypometabolism

lat-(arrow) in addition to bilateral thalamic and

cerebellar hypometabolic changes

FIGURE 9.1.9 An interictal fluorodeoxyglucose PET study of patient

with partial epilepsy shows a focus of right parietal hypometabolism

(arrow).

LWBK053-3787G-9.01[479-499].qxd 14-08-2008 05:56 PM Page 492 Aptara Inc

and myoclonic seizures, arrhythmia on EEG, and developmental

arrest When the comprehensive evaluation, including MRI scan, fails

to reveal the cause of the spasms and the seizures are refractory to

medical treatment, a PET scan of glucose metabolism should be

per-formed without further delay (202) Glucose metabolism PET studies

in children with intractable cryptogenic infantile spasms have shown

unifocal and, more commonly, multifocal cortical areas of

hypome-tabolism interictally (203) Most infants who are diagnosed with

“cryptogenic” spasms have, in fact, focal or multifocal cortical regions

of decreased (or even occasionally increased) glucose metabolic

activ-ity on PET that are often consistent with areas of cortical dysplasia

missed by MRI (204,205) When a single region of abnormal glucose

hypometabolism is apparent on PET and is congruent with the EEG

findings and the seizures are intractable, surgical removal of the PET

focus results in seizure control and in complete or partial reversal of

the associated developmental delay (201) When the pattern of

glu-cose hypometabolism is generalized and symmetric, a lesional cause

is not likely and neurogenetic or neurometabolic disorders should be

considered when further evaluating the child (201)

Glucose Metabolic PET Studies

in Lennox-Gastaut Syndrome

Lennox-Gastaut syndrome is a childhood epileptic encephalopathy

characterized by an electroclinical triad of 1.0 to 2.5 Hz spike-wave

pattern on EEG, intellectual impairment, and multiple types of

epilep-tic seizures Although the etiology is cryptogenic in about a fourth of

all patients, symptomatic cases are due to diverse cerebral conditions,

which are usually bilateral, diffuse, or multifocal, and involve cerebral

gray matter (206) FDG PET studies have shown that Lennox-Gastaut

syndrome can be classified into four predominant subtypes, each with

a distinct metabolic pattern: normal, unilateral focal

hypometabo-lism, unilateral diffuse hypometabohypometabo-lism, and bilateral diffuse

hypometabolism (207) Patients who have the unilateral focal or

uni-lateral diffuse patterns may be considered for cortical resection (201)

Correlation of FDG PET and EEG studies in the Lennox-Gastaut

syn-drome suggest that an EEG pattern of 1.0 to 2.5 Hz spike-wave

activ-ity (slow spike-wave pattern) is an interictal phenomenon (208)

Interictal H2[15O] Cerebral

Blood Flow PET Studies

It should be noted that interictal H2[15O] CBF PET studies when

compared to FDG PET studies have reduced sensitivity in localizing

epileptogenic zones and sometimes may even be false lateralizing

(209) Furthermore, CBF PET scans are noisier compared to FDG

PET, which may increase partial volume effects and make detection

of a hypoperfused area more difficult Therefore, interictal CBF PET

studies are unreliable markers for epileptic foci and should not be

used in the presurgical evaluation of patients with epilepsy (179)

Ictal PET

Although logistically challenging, FDG PET can also be used for

ictal studies in patients who have frequent seizures (Fig 9.1.10)

(210,211) Chugani et al (210) identified three ictal glucose

meta-bolic patterns in children based on the degree and type of

subcorti-cal involvement Nine children had type I: asymmetric glucose

metabolism of the striatum and thalamus Of these, the seven

old-est children showed unilateral cortical hypermetabolism (always

including frontal cortex) and crossed cerebellar hypermetabolism.Two infants (aged less than 1 year) had a similar ictal PET patternbut no cerebellar asymmetry, presumably owing to immaturity ofcorticopontocerebellar projections Five children had type II: sym-metric metabolic abnormalities of striatum and thalamus This pat-tern was accompanied by hippocampal or insular cortex hyperme-tabolism, diffuse neocortical hypometabolism, and absence of anycerebellar abnormality Four children had type III: hypermetabo-lism restricted to the cerebral cortex

FDG PET may be less accurate for ictal compared to interictalglucose metabolic measurements since seizures may alter the

“lumped constant,” which describes the relationship between FDGand its physiologic substrate glucose (176) Furthermore, a typicalseizure is much shorter than the average 30-minute FDG uptakeperiod Therefore, an “ictal” scan may include interictal, ictal, andpostictal metabolic changes with combinations of hypermetabolicand hypometabolic regions (176) H2[15O] PET imaging has beenused to study quantitative alterations in rCBF accompanyingseizures induced by pentylenetetrazol (212) Patients with general-ized tonic-clonic seizures demonstrated asymmetric flow increases.One patient with a complex partial seizure demonstrated 70% to80% increases in bitemporal flow Thalamic flow increased duringboth complex partial and generalized seizures, indicating the impor-tance of this subcortical structure during ictal activation (212)

Mapping of Cognitive or Language Functions

Changes in the functional activity of the brain (e.g., motor activity,language, or cognitive tasks) are accompanied by increases in rCBFand can be mapped to specific brain regions (3,4) Language-basedPET activation studies have shown good correlation with the Wadalanguage lateralization test (213) More detailed cortical mappingcan be performed to better delineate the motor cortex from theepileptogenic zone Cortical mapping using PET activation studieshave shown comparable results to electrical stimulation mapping ofthe cortex using subdural electrodes (214)

Chapter 9.1 • Movement Disorders, Stroke, and Epilepsy 493

FIGURE 9.1.10 Five-year-old child suffered a left parieto-occipital

stroke caused by left thalamic and intraventricular hemorrhage andsubsequently the onset of seizures An ictal fluorodeoxyglucose PETstudy demonstrates metabolic activation of the left posterior cingu-

loparietal cortex (arrow) adjacent to the stroke lesion.

Emerging Clinical Applications of

Benzodiazepine Neuroreceptor and

Serotonin Synthesis Imaging in Epilepsy

The inhibitory neurotransmitter -aminobutyric acid (GABA) has

anticonvulsant properties Benzodiazepine receptor ligands, such as

[11C]-flumazenil (FMZ), have been used to study the regional

cere-bral distribution of benzodiazepine receptor binding sites that are

related to GABAAreceptors The high density of GABAAreceptors

in the normal hippocampus accounts for the high sensitivity of

FMZ PET to detect even mild decreases in binding that are

consis-tent with hippocampal sclerosis in temporal lobe epilepsy FMZ

PET, where available, provides a useful alternative to FDG PET in

the evaluation of patients with epilepsy

A regional decrease in benzodiazepine receptor binding has

been associated with the presence of a possible epileptogenic focus

Unilaterally decreased temporal FMZ binding can also help to

lat-eralize the epileptic focus in patients who have temporal lobe

epilepsy that is associated with bilateral temporal hypometabolism

on FDG PET (201) When compared to FDG studies, FMZ PET

studies have been reported to demonstrate less extensive cortical

involvement For example, a study comparing FDG and FMZ PET

imaging in patients with temporal lobe epilepsy found a wide range

of mesial temporal, lateral temporal, and thalamic glucose

hypome-tabolism ipsilateral to ictal EEG changes as well as extratemporal

hypometabolism In contrast, each patient demonstrated decreased

benzodiazepine receptor binding in the ipsilateral anterior mesial

temporal region, without neocortical changes

Interictal metabolic dysfunction can be variable and usually is

extensive in temporal lobe epilepsy, whereas decreased central

ben-zodiazepine receptor density appears to be more restricted to the

mesial temporal areas (215) Similar benzodiazepine receptor

find-ings have been reported for patients with extratemporal lobe

seizures caused by focal cortical dysplasia (216) Unlike the more

widespread glucose hypometabolic patterns, benzodiazepine

receptor changes may reflect localized neuronal loss that is more

specific to the epileptogenic zone (215) Therefore, FMZ imaging

may be useful in the presurgical evaluation of patients with

epilepsy However, focal increases of benzodiazepine receptor

binding have also been reported in the temporal lobe as well as

extratemporal sites in patients with temporal lobe epilepsy when

statistical brain mapping analysis is performed (217) This may

lead to false-localizing information when attention is only paid to

areas of decreased uptake

A potential clinical application of FMZ PET is the detection of

periventricular increases of FMZ binding, indicating the presence

of heterotopic neurons in patients with temporal lobe epilepsy

(218) The presence of such increases correlates with a poorer

out-come

Another promising direction in the development of PET for

epilepsy is to target serotonergic neurotransmission A novel

tracer,-[11C]-methyl-L-tryptophan (AMT), which accumulates

in epileptic foci in the interictal state, can be a useful approach to

identify epileptogenic sites in children with multifocal brain

lesions (201,219) FMISO PET helps to differentiate between

epileptogenic and nonepileptogenic lesions in a patient with

mul-tifocal lesions Because fluoromisonidazole accumulates in the

vicinity of the seizure focus, PET scanning of this radiotracer

reveals an increased signal in the interictal state compared to

FDG and FMZ, which both reveal decreased uptake (202) This

radiotracer may also be useful in identifying nonresected epilepticcortex in young patients with a previously failed neocorticalepilepsy surgery (220)

CONCLUSION

PET is a method for quantitative and qualitative imaging of regionalphysiological and biochemical parameters With the tomographicprinciple of the PET scanner the quantitative distribution of theadministered isotope can be determined in the brain, and imagescan be provided as well as dynamic information on blood flow,metabolism, and neuroreceptor function Glucose metabolic andblood flow studies have been used for the study of patients withbrain disorders, such as epilepsy, tumor, stroke, or dementia Newtechniques for quantitative image processing and statistical brainmapping analysis using normative databases will aid the clinical util-ity of brain PET Measurement of receptors or neurotransmittermetabolism is a unique ability of PET that has not achieved its fullpotential in the study of patients with neurological disorders PEThas the ability to visualize and quantify key pathophysiologicalprocesses underlying specific brain disorders and may serve as a toolnot only for diagnosis but also for the assessment of effects of thera-peutic interventions

FDG PET imaging can identify specific topographic patternsthat can aid the clinical differential diagnosis of the major atypicalparkinsonian movement disorders (i.e., corticobasal degeneration,multiple system atrophy, and progressive supranuclear palsy).Parkinsonian dementia can be distinguished from Alzheimer dis-ease on the basis of occipital hypometabolism Neurochemicaldopaminergic imaging can identify nigrostriatal denervation seen

in Parkinson disease and may serve as a diagnostic or outcome marker in this disorder Other parkinsonian neurodegenerations,including progressive supranuclear palsy and multiple system atro-phy, also involve nigrostriatal dopaminergic projection losses butare characterized by additional degeneration within the striatumand other subcortical nuclei

bio-Multitracer PET imaging permits the accurate and tive assessment of regional hemodynamics and metabolism instroke that may guide therapeutic decisions and predict the sever-ity of permanent deficits However, PET studies are time con-suming, expensive, and require extensive facilities and technicalsupport Although PET has not been demonstrated to be neces-sary for making patient care decisions in stroke patients, knowl-edge gained from PET regarding acute ischemic stroke andchronic oligemia from arterial occlusive disease is growing moreimportant with the increasing availability of CT and MR perfu-sion techniques A new potential clinical role for PET in strokemay be the application of new hypoxia PET tracers, such asFMISO, that identify true penumbral tissue that would beamenable to rescue interventions even beyond 12 to 24 hoursafter the onset of stroke

quantita-Although the primary imaging modality in the management

of epilepsy is MRI, FDG and benzodiazepine receptor PETimaging often provide complementary information and, inpatients with normal or nonlocalizing MRI, may provide uniquelocalizing information AMT PET has the potential to differenti-ate between epileptogenic and nonepileptogenic lesions in apatient with multifocal lesions, such as in a child with tuberoussclerosis

494 Principles and Practice of PET and PET/CT

LWBK053-3787G-9.01[479-499].qxd 14-08-2008 05:56 PM Page 494 Aptara Inc

1 Siesjo BK Brain energy metabolism New York: Wiley, 1978.

2 Sandor P Nervous control of the cerebrovascular system: doubts and

facts Neurochem Int 1999;35:237–259.

3 Raichle ME Circulatory and metabolic correlates of brain function in

normal humans In: Mountcastle VB, Plum F, eds Handbook of ology The nervous system Bethesda: American Physiological Society,

physi-1987: vol V, 643–674

4 Raichle ME The metabolic requirements of functional activity in the

brain In: Vranic M, Efendie S, Hollenberg CH, eds Fuel homeostasis and the nervous system New York: Plenum Press, 1991:1–4.

5 Buxton RB, Frank LR A model for the coupling between cerebral

blood flow and oxygen metabolism during neural stimulation J Cereb Blood Flow Metab 1997;17:64–72.

6 Vafaee MS, Gjedde A Model of blood–brain transfer of oxygen

explains nonlinear flow-metabolism coupling during stimulation of

visual cortex J Cereb Blood Flow Metab 2000;20:747–754.

7 Mintun MA, Lundstrom BN, Snyder AZ, et al Blood flow and oxygen

delivery to human brain during functional activity: theoretical

model-ing and experimental data Proc Natl Acad Sci U S A 2001;98: 6859–6864.

8 Magistretti PJ Neuron-glia metabolic coupling and plasticity J Exp

Biol 2006;209:2304–2311.

9 Jueptner M, Weiller C Review: does measurement of regional cerebral

blood flow reflect synaptic activity? Implications for PET and fMRI

Neurimage 1995;2:148–156.

10 Magistretti PJ, Pellerin L Cellular mechanisms of brain energy

metab-olism and their relevance to functional brain imaging Philos Trans R Soc Lond B Biol Sci 1999;354:1155–1163.

11 Hoffman EJ, Huang SC, Phelps ME Quantitation in positron emission

computed tomography: 1 Effect of object size J Comput Assist Tomogr

1979;3:299–308

12 Minoshima S, Koeppe RA, Frey KA, et al Stereotactic PET atlas of the

human brain: aid for visual interpretation of functional brain images

J Nucl Med 1994;35:949–954.

13 Henry TR, Mazziotta JC, Engel JJ The functional anatomy of frontal

lobe epilepsy studied with PET Adv Neurol 1992;57:449–463.

14 Perlmutter JS, Powers WJ, Herscovitch P, et al Regional asymmetries

of cerebral blood flow, blood volume, and oxygen utilization and

extraction in normal subjects J Cereb Blood Flow Metab 1987; 7:64–67.

15 Lobaugh NJ, Caldwell CB, Black SE, et al Three brain SPECT

region-of-interest templates in elderly people: normative values, hemispheric

asymmetries, and a comparison of single- and multihead cameras J Nucl Med 2000;41:45–56.

16 Mazziotta JC, Phelps ME, Carson RE, et al Tomographic mapping of

human cerebral metabolism: sensory deprivation Ann Neurol 1982;

12:435–444

17 Loessner A, Alavi A, Lewandrowski KU, et al Regional cerebral

func-tion determined by FDG-PET in healthy volunteers: normal patterns

and changes with age J Nucl Med 1995;36:1141–1149.

18 Ivancevic V, Alavi A, Souder E, et al Regional cerebral glucose

metabo-lism in healthy volunteers determined by fluorodeoxyglucose positronemission tomography: appearance and variance in the transaxial, coro-

nal, and sagittal planes Clin Nucl Med 2000;25:596–602.

19 Takahashi T, Shirane R, Sato S, et al Developmental changes of

cere-bral blood flow and oxygen metabolism in children Am J Neuroradiol

1999;20:917–922

20 Chugani HT, Phelps ME, Mazziotta JC Positron emission tomography

study of human brain functional development Ann Neurol 1987;22:

487–497

21 Kinnala A, Suhonen-Polvi H, Aarimaa T, et al Cerebral metabolic rate

for glucose during the first six months of life: an FDG positron emission

tomography study Arch Dis Child Fetal Neonatal Ed 1996;74: F153–157.

22 Van Bogaert P, Wikler D, Damhaut P, et al Regional changes in glucose

metabolism during brain development from the age of 6 years roimage 1998;8:62–68.

Neu-23 Terry RD, DeTeresa R, Hansen LA Neocortical cell counts in normal

human adult aging Ann Neurol 1987;21:530–539.

24 Schultz SK, O’Leary DS, Boles Ponto LL, et al Age-related changes in

regional cerebral blood flow among young to mid-life adults port 1999;10:2493–2496.

Neurore-25 Martin AJ, Friston KJ, Colebatch JG, et al Decreases in regional

cere-bral blood flow with normal aging J Cereb Blood Flow Metab 1991;

28 Yanase D, Matsunari I, Yajima K, et al Brain FDG PET study of

nor-mal aging in Japanese: effect of atrophy correction Eur J Nucl Med Mol Imaging 2005;32:794–805.

29 Pietrini P, Alexander GE, Furey ML, et al Cerebral metabolic response

to passive audiovisual stimulation in patients with Alzheimer’s disease

and healthy volunteers assessed by PET J Nucl Med 2000;41:575–583.

30 Ishizu K, Nishizawa S, Yonekura Y, et al Effects of hyperglycemia on FDG

uptake in human brain and glioma J Nucl Med 1994;35:1104–1109.

31 Foster NL, VanDerSpek AF, Aldrich MS, et al The effect of diazepamsedation on cerebral glucose metabolism in Alzheimer’s disease as

measured using positron emission tomography J Cereb Blood Flow Metab 1987;7:415–420.

32 Wang GJ, Volkow ND, Overall J, et al Reproducibility of regional brain

metabolic responses to lorazepam J Nucl Med 1996;37:1609–1613.

33 Juengling FD, Kassubek J, Martens-Le Bouar H, et al Cerebral regionalhypometabolism caused by propofol-induced sedation in childrenwith severe myoclonic epilepsy: a study using fluorodeoxyglucosepositron emission tomography and statistical parametric mapping

Neurosci Lett 2002;335:79–82.

34 Gaillard WD, Zeffiro T, Fazilat S, et al Effect of valproate on cerebralmetabolism and blood flow: an 18F-2-deoxyglucose and 15O water

positron emission tomography study Epilepsia 1996;37:515–521.

35 Theodore WH, Bairamian D, Newmark ME, et al Effect of phenytoin

on human cerebral glucose metabolism J Cereb Blood Flow Metab

1986;6:315–320

36 Theodore WH, Fishbein D, Dietz M, et al Complex partial seizures:

cerebellar metabolism Epilepsia 1987;28:319–323.

37 Seitz RJ, Piel S, Arnold S, et al Cerebellar hypometabolism in focal

epilepsy is related to age of onset and drug intoxication Epilepsia

1996;37:1194–1199

38 Joo EY, Tae WS, Hong SB Regional effects of lamotrigine on cerebral

glucose metabolism in idiopathic generalized epilepsy Arch Neurol

43 Baron JC, Marchal G Functional imaging in vascular disorders In:

Mazziotta JC, Toga AW, Frackowiak RSJ, eds Brain mapping: the ders New York: Academic Press, 2000:299–316.

disor-44 Baron JC, Bonsser MG, Comar D, et al Crossed cerebellar diaschisis in

human supratentorial brain infarction Trans Am Neurol Assoc

1980;105:459–461

45 Baron JC, D’Antona R, Pantano P, et al Effects of thalamic stroke onenergy metabolism of the cerebral cortex A positron tomography

study in man Brain 1986;109:1243–1259.

Chapter 9.1 • Movement Disorders, Stroke, and Epilepsy 495

46 Sobesky J, Thiel A, Ghaemi M, et al Crossed cerebellar diaschisis in acute

human stroke: a PET study of serial changes and response to

supratento-rial reperfusion J Cereb Blood Flow Metab 2005;25: 1685–1691.

47 Park CH, Kim SM, Streletz LJ, et al Reverse crossed cerebellar

diaschi-sis in partial complex seizures related to herpes simplex encephalitis

Clin Nucl Med 1992;17:732–735.

48 Brooks DJ Imaging basal ganglia function J Anat 2000;196:543–554.

49 Quinn N Parkinsonism-recognition and differential diagnosis BMJ

52 Hughes AJ, Daniel SE, Blankson S, et al A clinicopathologic study of

100 cases of Parkinson’s disease Arch Neurol 1993;50:140–148.

53 Wolfson LI, Leenders KL, Brown LL, et al Alterations of regional

cere-bral blood flow and oxygen metabolism in Parkinson’s disease

Neu-rology 1985;35:1399–1405.

54 Antonini A, Vontobel P, Psylla M, et al Complementary positron

emis-sion tomographic studies of the striatal dopaminergic system in

Parkinson’s disease Arch Neurol 1995;52:1183–1190.

55 Eidelberg D, Moeller JR, Dhawan V, et al The metabolic topography of

parkinsonism J Cereb Blood Flow Metab 1994;14:783–801.

56 Vander Borght T, Minoshima S, Giordani B, et al Cerebral metabolic

differences in Parkinson’s and Alzheimer’s disease matched for

dementia severity J Nucl Med 1997;38:797–802.

57 Dethy S, Van Blercom N, Damhaut P, et al Asymmetry of basal ganglia

glucose metabolism and dopa responsiveness in parkinsonism Mov

Disord 1998;13:275–280.

58 Zaccai J, McCracken C, Brayne C A systematic review of prevalence

and incidence studies of dementia with Lewy bodies Age Ageing 2005;

34:561–566

59 McKeith IG, Galasko D, Kosaka K, et al Consensus guideline for the

clinical and pathological diagnosis of dementia with Lewy bodies

(LBD): report of the Consortium on DLB International Workshop

Neurology 1996;47:1113–1124.

60 McKeith IG, Dickson DW, Lowe J, et al Diagnosis and management of

dementia with Lewy bodies: third report of the DLB Consortium

Neurology 2005;65:1863–1872.

61 Emre M Dementia associated with Parkinson’s disease Lancet Neurol

2003;2:229–237

62 Ballard C, Ziabreva I, Perry R, et al Differences in neuropathologic

characteristics across the Lewy body dementia spectrum Neurology

2006;67:1931–1934

63 Braak H, Braak E Staging of Alzheimer’s disease-related

neurofibril-lary changes Neurobiol Aging 1995;16:271–284.

64 Friedland RP, Brun A, Budinger TF Pathological and positron emission

tomographic correlations in Alzheimer’s disease Lancet 1985;8422:228.

65 Mielke R, Schroder R, Fink GR, et al Regional cerebral glucose

metab-olism and postmortem pathology in Alzheimer’s disease Acta

Neu-ropathol 1996;91:174–179.

66 Bohnen NI, Minoshima S, Giordani B, et al Motor correlates of

occip-ital glucose hypometabolism in Parkinson’s disease without dementia

Neurology 1999;52:541–546.

67 Steele JC, Richardson JC, Olszewski J Progressive supranuclear palsy: a

heterogeneous degeneration involving the brainstem, basal ganglia, and

cerebellum, with vertical gaze and pseudobulbar palsy Arch Neurol

1964;10:333–359

68 Foster NL, Gilman S, Berent S, et al Cerebral hypometabolism in

pro-gressive supranuclear palsy studied with positron emission

tomogra-phy Ann Neurol 1988;24:399–406.

69 D’Antona R, Baron JC, Samson Y, et al Subcortical dementia Frontal

cortex hypometabolism detected by positron tomography in patients

with progressive supranuclear palsy Brain 1985;108:785–799.

70 Blin J, Baron JC, Dubois B, et al Positron emission tomography study

in progressive supranuclear palsy Brain hypometabolic pattern and

clinicometabolic correlations Arch Neurol 1990;47:747–752.

71 Salmon E, Van der Linden MV, Franck G Anterior cingulate andmotor network metabolic impairment in progressive supranuclear

palsy Neuroimage 1997;5:173–178.

72 Juh R, Pae CU, Kim TS, et al Cerebral glucose metabolism in cobasal degeneration comparison with progressive supranuclear palsy

corti-using statistical mapping analysis Neurosci Lett 2005;383:22–27.

73 Feany MB, Ksiezak-Reding H, Liu WK, et al Epitope expression andhyperphosphorylation of tau protein in corticobasal degeneration:

differentiation from progressive supranuclear palsy Acta Neuropathol (Berl) 1995;90:37–43.

74 Eidelberg D, Dhawan V, Moeller JR, et al The metabolic landscape ofcortico-basal ganglionic degeneration: regional asymmetries studied

with positron emission tomography J Neurol Neurosurg Psychiatry

1991;54:856–862

75 Nagahama Y, Fukuyama H, Turjanski N, et al Cerebral glucose olism in corticobasal degeneration: comparison with progressive

metab-supranuclear palsy and normal controls Mov Disord 1997;12:691–696.

76 Coulier IM, de Vries JJ, Leenders KL Is FDG-PET a useful tool in

clin-ical practice for diagnosing corticobasal ganglionic degeneration? Mov Disord 2003;18:1175–1178.

77 Garraux G, Salmon E, Peigneux P, et al Voxel-based distribution of

metabolic impairment in corticobasal degeneration Mov Disord

2000;15:894–904

78 Hosaka K, Ishii K, Sakamoto S, et al Voxel-based comparison ofregional cerebral glucose metabolism between PSP and corticobasal

degeneration J Neurol Sci 2002;199:67–71.

79 Blin J, Vidailhet MJ, Pillon B, et al Corticobasal degeneration:decreased and asymmetrical glucose consumption as studied with

PET Mov Disord 1992;7:348–354.

80 Lutte I, Laterre C, Bodart JM, et al Contribution of PET studies in

diagnosis of corticobasal degeneration Eur Neurol 2000;44:12–21.

81 Papp MI, Lantos PL The distribution of oligodendroglial inclusions inmultiple system atrophy and its relevance to clinical symptomatology

Brain 1994;117:235–243.

82 Otsuka M, Kuwabara Y, Ichiya Y, et al Differentiating between multiplesystem atrophy and Parkinson’s disease by positron emission tomogra-phy with 18F-dopa and 18F-FDG Ann Nucl Med 1997;11: 251–257.

83 Juh R, Pae CU, Lee CU, et al Voxel based comparison of glucose olism in the differential diagnosis of the multiple system atrophy using

metab-statistical parametric mapping Neurosci Res 2005;52:211–219.

84 Gilman S, Koeppe RA, Junck L, et al Patterns of cerebral glucosemetabolism detected with positron emission tomography differ in

multiple system atrophy and olivopontocerebellar atrophy Ann rol 1994;36:166–175.

Neu-85 Otsuka M, Ichiya Y, Kuwabara Y, et al Glucose metabolism in the tical and subcortical brain structures in multiple system atrophy and

cor-Parkinson’s disease: a positron emission tomographic study J Neurol Sci 1996;144:77–83.

86 Gerstenbrand F, Klingler D, Pfeiffer B Der essentialle Tremor

Phänomenologie und Epidemiologie Nervenarzt 1983;43:46–53.

87 Louis ED, Vonsattel JP, Honig LS, et al Essential tremor associated with

pathologic changes in the cerebellum Arch Neurol 2006;63:1189–1193.

88 Louis ED, Vonsattel JP, Honig LS, et al Neuropathologic findings in

essential tremor Neurology 2006;66:1756–1759.

89 Hallett M, Dubinsky RM Glucose metabolism in the brain of patients

with essential tremor J Neurol Sci 1993;114:45–48.

90 Colebatch JG, Findley LJ, Frackowiak RS, et al Preliminary report:

acti-vation of the cerebellum in essential tremor Lancet 1990;336: 1028–1030.

91 Jenkins IH, Bain PG, Colebatch JG, et al A positron emission raphy study of essential tremor: evidence for overactivity of cerebellar

tomog-connections Ann Neurol 1993;34:82–90.

92 Wills AJ, Jenkins IH, Thompson PD, et al Red nuclear and cerebellarbut no olivary activation associated with essential tremor: a positron

emission tomographic study Ann Neurol 1994;36:636–642.

93 Wills AJ, Jenkins IH, Thompson PD, et al A positron emission raphy study of cerebral activation associated with essential and writ-

tomog-ing tremor Arch Neurol 1995;52:299–305.

496 Principles and Practice of PET and PET/CT

LWBK053-3787G-9.01[479-499].qxd 14-08-2008 05:56 PM Page 496 Aptara Inc

94 Albin RL, Tagle DA Genetics and molecular biology of Huntington’s

disease Trends Neurosci 1995;18:11–14.

95 Huntington’s Disease Collaborative Research Group A novel gene

containing a trinucleotide repeat that is expanded and unstable on

Huntington’s disease chromosomes Cell 1993;72:971–983.

96 Vonsattel J-P, DiFiglia M Huntington’s disease J Neuropathol Exp

Neurol 1998;57:369–384.

97 Bernheimer H, Birkmayer W, Hornykiewicz O, et al Brain dopamine

and the syndromes of Parkinson and Huntington Clinical,

morpho-logical and neurochemical correlations J Neurol Sci 1973;20:415–455.

98 Vonsattel J-P, Meyers R, Stevens T, et al Neuropathological classification

of Huntington’s disease J Neuropathol Exp Neurol 1985;44:559–577.

99 Kuhl DE, Phelps ME, Markham CH, et al Cerebral metabolism and

atrophy in Huntington’s disease determined by 18FDG and computed

tomographic scan Ann Neurol 1982;12:425–434.

100 Kuhl DE, Metter EJ, Riege WH, et al Patterns of cerebral glucose

uti-lization in Parkinson’s disease and Huntington’s disease Ann Neurol

1984;15[Suppl]:S119–S125

101 Maziotta JH, Phelps ME, Pahl JJ, et al Reduced cerebral glucose

metabolism in asymptomatic subjects at risk for Huntington’s disease

N Engl J Med 1987;316:357–362.

102 Feigin A, Leenders KL, Moeller JR, et al Metabolic network

abnor-malities in early Huntington’s disease: an [(18)F]FDG PET study J Nucl Med 2001;42:1591–1595.

103 Hosokawa S, Ichiya Y, Kuwabara Y, et al Positron emission

tomogra-phy in cases of chorea with different underlying diseases J Neurol rosurg Psychiatry 1987;50:1284–1287.

Neu-104 Dubinsky RM, Hallett M, Levey R, et al Regional brain glucose

metab-olism in neuroacanthocytosis Neurology 1989;39:1253–1255.

105 Weindl A, Kuwert T, Leenders KL, et al Increased striatal glucose

con-sumption in Sydenham’s chorea Mov Disord 1993;8:437–444.

106 Bohlega S, Riley W, Powe J, et al Neuroacanthocytosis and

aprebetali-poproteinemia Neurology 1998;50:1912–1914.

107 Sunden-Cullberg J, Tedroff J, Aquilonius SM Reversible chorea in

pri-mary antiphospholipid syndrome Mov Disord 1998;13:147–149.

108 Hsu JL, Wang HC, Hsu WC Hyperglycemia-induced unilateral basal

ganglion lesions with and without hemichorea A PET study J Neurol

2004;251:1486–1490

109 Garnett ES, Firnau G, Chan PKH, et al [18F]fluoro-dopa, an analogue

of dopa, and its use in direct measurement of storage, degeneration,

and turnover of intracerebral dopamine Proc Natl Acad Sci U S A

1978;75:464–467

110 Garnett ES, Firnau G, Nahmias C Dopamine visualized in the basal

ganglia of living man Nature 1983;305:137–138.

111 Frost JJ, Rosier AJ, Reich SG, et al Positron emission tomographic

imag-ing of the dopamine transporter with 11C-WIN35428 reveals marked

declines in mild Parkinson’s disease Ann Neurol 1993;34:423–431.

112 Antonini A, Schwarz J, Oertel WH, et al [11C]raclopride and positron

emission tomography in previously untreated patients with son’s disease: influence of L-dopa and lisuride therapy on striataldopamine D2-receptors Neurology 1994;44:1325–1329.

Parkin-113 Brooks D The early diagnosis of Parkinson’s disease Ann Neurol

1998;44[Suppl 1]:S10–S18

114 Frey KA, Koeppe RA, Kilbourn MR, et al Presynaptic monoaminergic

vesi-cles in Parkinson’s disease and normal aging Ann Neurol 1996;40:873–884.

115 Bohnen NI, Albin RL, Koeppe RA, et al Positron emission

tomogra-phy of monoaminergic vesicular binding in aging and Parkinson

dis-ease J Cereb Blood Flow Metab 2006;26:1198–1212.

116 Eidelberg D, Moeller JR, Dhawan V, et al The metabolic anatomy of

Parkinson’s disease: complementary [18F]fluorodeoxyglucose and[18F]fluorodopa positron emission tomographic studies Mov Dis

1990;5:203–213

117 Morrish PK, Sawle GV, Brooks DJ An [18F]dopa-PET and clinical study

of the rate of progression in Parkinson’s disease Brain 1996;119:585–591.

118 Vingerhoets FJG, Schulzer M, Calne DB, et al Which clinical sign of

Parkinson’s disease best reflects the nigrostriatal lesion? Ann Neurol

1997;41:58–64

119 Freed CR, Greene PE, Breeze RE, et al Transplantation of embryonic

dopamine neurons for severe Parkinson’s disease N Engl J Med

2001;344:710–719

120 Brooks DJ, Ibanez V, Sawle GV, et al Striatal D2receptor status inpatients with Parkinson’s disease, striatonigral degeneration, and pro-gressive supranuclear palsy, measured with 11C-raclopride and

positron emission tomography Ann Neurol 1992;31:184–192.

121 Gilman S, Frey KA, Koeppe RA, et al Decreased striatal gic terminals in olivopontocerebellar atrophy and multiple system

monoaminer-atrophy demonstrated with positron emission tomography Ann rol 1996;40:885–892.

Neu-122 Pirker W, Asenbaum S, Bencsits G, et al [123I]beta-CIT SPECT in tiple system atrophy, progressive supranuclear palsy, and corticobasal

mul-degeneration Mov Disord 2000;15:1158–1167.

123 Sawle GV, Brooks DJ, Marsden CD, et al Corticobasal degeneration Aunique pattern of regional cortical oxygen hypometabolism and stri-atal fluorodopa uptake demonstrated by positron emission tomogra-

monoaminer-sion tomography Ann Neurol 1999;45:769–777.

127 Laureys S, Salmon E, Garraux G, et al Fluorodopa uptake and glucose

metabolism in early stages of corticobasal degeneration J Neurol

1999;246:1151–1158

128 Ilgin N, Zubieta J, Reich SG, et al PET imaging of the dopamine

trans-porter in progressive supranuclear palsy and Parkinson’s disease rology 1999;52:1221–1226.

Neu-129 Rinne UK, Laihinen A, Rinne JO, et al Positron emission tomographydemonstrates dopamine D2receptor supersensitivity in the striatum

of patients with early Parkinson’s disease Mov Disord 1990;5:55–59.

130 Antonini A, Schwarz J, Oertel WH, et al Long-term changes of striataldopamine D2receptors in patients with Parkinson’s disease: a studywith positron emission tomography and [11C]raclopride Mov Disord

1997;12:33–38

131 Nakagawa M, Kuwabara Y, Taniwaki T, et al PET evaluation of therelationship between D2receptor binding and glucose metabolism in

patients with parkinsonism Ann Nucl Med 2005;19:267–275.

132 Walker Z, Costa DC, Walker RW, et al Striatal dopamine transporter

in dementia with Lewy bodies and Parkinson disease: a comparison

Neurology 2004;62:1568–1572.

133 Koeppe RA, Gilman S, Joshi A, et al.11C-DTBZ and 18F-FDG PET

measures in differentiating dementias J Nucl Med 2005;46:936–944.

134 Kidwell CS, Chalela JA, Saver JL, et al Comparison of MRI and CT for

detection of acute intracerebral hemorrhage JAMA 2004;292:

(DEFUSE) study Ann Neurol 2006;60:508–517.

137 Powers WJ Hemodynamics and metabolism in ischemic

cerebrovas-cular disease Neurol Clin 1992;10:31–48.

138 Heiss WD, Herholz K Assessment of pathophysiology of stroke by

positron emission tomography Eur J Nucl Med 1994;21:455–465.

139 Powers WJ, Zazulia AR The use of positron emission tomography in

cerebrovascular disease Neuroimaging Clin North Am 2003;13:741–758.

140 Powers WJ, Raichle ME Positron emission tomography and its application

to the study of cerebrovascular disease in man Stroke 1985;16:361–376.

Chapter 9.1 • Movement Disorders, Stroke, and Epilepsy 497

141 Ter-Pogossian MM, Eichling JO, Davis DO, et al The determination of

regional cerebral blood flow by means of water labeled with

radioac-tive oxygen-15 Radiology 1969;93:31–40.

142 Ter-Pogossian MM, Eichling JO, Davis DO, et al The measure in vivo

of regional cerebral oxygen utilization by means of oxyhemoglobin

labeled with radioactive oxygen-15 J Clin Invest 1970;49:381–391.

143 Jones T, Chesler DA, Ter-Pogossian MM The continuous inhalation of

oxygen-15 for assessing regional oxygen extraction in the brain of

man Br J Radiol 1976;49:339–343.

144 Lenzi GL, Jones T, McKenzie CG, et al Study of regional cerebral

metabolism and blood flow relationships in man using the method of

continuously inhaling oxygen-15 and oxygen-15 labelled carbon

diox-ide J Neurol Neurosurg Psychiatry 1978;41:1–10.

145 Frackowiak RS, Lenzi GL, Jones T, et al Quantitative measurement of

regional cerebral blood flow and oxygen metabolism in man using 15O

and positron emission tomography: theory, procedure, and normal

values J Comput Assist Tomogr 1980;4:727–736.

146 Lammertsma AA, Frackowiak RSJ, Hoffman JM, et al Simultaneous

measurement of regional cerebral blood flow and oxygen metabolism:

a feasibility study J Cereb Blood Flow Metab 1987;7[Suppl 1]:S587.

147 Herscovitch P, Markham J, Raichle ME Brain blood flow measured

with intravenous H215O I Theory and error analysis J Nucl Med

1983;24:782–789

148 Grubb RLJ, Raichle ME, Higgins CS, et al Measurement of regional

cerebral blood volume by emission tomography Ann Neurol

1978;4:322–328

149 Baron JC, Frackowiak RS, Herholz K, et al Use of PET methods for

measurement of cerebral energy metabolism and hemodynamics in

cerebrovascular disease J Cereb Blood Flow Metab 1989;9:723–742.

150 Jones TH, Morawetz RB, Crowell RM, et al Thresholds of focal

cere-bral ischemia in awake monkeys J Neurosurg 1981;54:773–782.

151 Sobesky J, von Kummer R, Frackowiak M, et al Early ischemic edema

on cerebral computed tomography: its relation to diffusion changes

and hypoperfusion within 6 h after human ischemic stroke A

com-parison of CT, MRI and PET Cerebrovasc Dis 2006;21:336–339.

152 Heiss WD Ischemic penumbra: evidence from functional imaging in

man J Cereb Blood Flow Metab 2000;20:1276–1293.

153 Heiss WD, Graf R, Grond M, et al Quantitative neuroimaging for the

evaluation of the effect of stroke treatment Cerebrovasc Dis

1998;8[Suppl 2]:23–29

154 Sobesky J, Zaro Weber O, et al Does the mismatch match the

penum-bra? Magnetic resonance imaging and positron emission tomography

in early ischemic stroke Stroke 2005;36:980–985.

155 Derdeyn CP, Grubb RLJ, Powers WJ Cerebral hemodynamic

impair-ment: methods of measurement and association with stroke risk

Neu-rology 1999;53:251–259.

156 Powers WJ, Press GA, Grubb RLJ, et al The effect of hemodynamically

significant carotid artery disease on the hemodynamic status of the

cerebral circulation Ann Intern Med 1987;106:27–34.

157 Gibbs JM, Wise RJ, Leenders KL, et al Evaluation of cerebral perfusion

reserve in patients with carotid-artery occlusion Lancet

1984;I:310–314

158 Grubb RLJ, Derdeyn CP, Fritsch SM, et al Importance of

hemody-namic factors in the prognosis of symptomatic carotid occlusion

JAMA 1998;280:1055–1060.

159 Grubb RL Jr, Powers WJ, Derdeyn CP, et al The carotid occlusion

surgery study Neurosurg Focus 2003;14:e9.

160 Derdeyn CP, Grubb RL Jr, Powers WJ Indications for cerebral

revas-cularization for patients with atherosclerotic carotid occlusion Skull

Base 2005;15:7–14.

161 Derdeyn CP Is the acetazolamide test valid for quantitative assessment

of maximal cerebral autoregulatory vasodilation? Stroke 2000;31:

2271–2272

162 Nemoto EM, Yonas H, Pindzola RR, et al PET OEF reactivity for

hemodynamic compromise in occlusive vascular disease J

Neuroimag-ing 2007;17:54–60.

163 Carpenter DA, Grubb RLJ, Tempel LW, et al Cerebral oxygen

metabo-lism after aneurysmal subarachnoid hemorrhage J Cereb Blood Flow Metab 1991;11:837–844.

164 Videen TO, Dunford-Shore JE, Diringer MN, et al Correction for tial volume effects in regional blood flow measurements adjacent tohematomas in humans with intracerebral hemorrhage: implementa-

par-tion and validapar-tion J Comput Assist Tomogr 1999;23:248–256.

165 Ward NS Plasticity and the functional reorganization of the human

brain Int J Psychophysiol 2005;58:158–161.

166 Calautti C, Baron JC Functional neuroimaging studies of motor

recovery after stroke in adults: a review Stroke 2003;34:1553–1566.

167 Kushner M, Reivich M, Fieschi C, et al Metabolic and clinical

corre-lates of acute ischemic infarction Neurology 1987;37:1103–1110.

168 Marchal G, Furlan M, Beaudouin V, et al Early spontaneous

hyper-perfusion after stroke A marker of favourable tissue outcome? Brain

1996;119:409–419

169 Kuroda S, Shiga T, Houkin K, et al Cerebral oxygen metabolism andneuronal integrity in patients with impaired vasoreactivity attribut-

able to occlusive carotid artery disease Stroke 2006;37:393–398.

170 Heiss WD, Kracht L, Grond M, et al Early [11C]flumazenil/H2Opositron emission tomography predicts irreversible ischemic cortical

damage in stroke patients receiving acute thrombolytic therapy Stroke

2000;31:366–369

171 Nakagawara J, Sperling B, Lassen NA Incomplete brain infarction of

reper-fused cortex may be quantitated with iomazenil Stroke 1997;28:124–132.

172 Markus R, Donnan G, Kazui S, et al Penumbral topography in human

stroke: methodology and validation of the “Penumbragram.” roimage 2004;21:1252–1259.

Neu-173 Markus R, Reutens DC, Kazui S, et al Hypoxic tissue in ischaemicstroke: persistence and clinical consequences of spontaneous survival

Brain 2004;127:1427–1436.

174 Takasawa M, Beech JS, Fryer TD, et al Imaging of brain hypoxia inpermanent and temporary middle cerebral artery occlusion in the ratusing (18)F-fluoromisonidazole and positron emission tomography: a

pilot study J Cereb Blood Flow Metab 2007;23:679–689.

175 Theodore WH, Newmark ME, Sato S, et al [18F]fluorodeoxyglucosepositron emission tomography in refractory complex partial seizures

Ann Neurol 1983;14:429–437.

176 Theodore WH Positron emission tomography in the evaluation of

seizure disorders Neurosci News 1998;1:18–22.

177 Theodore WH Cerebral blood flow and glucose metabolism in

human epilepsy In: Advances in neurology Philadelphia: Lippincott

Williams & Wilkins, 1999: vol 79, 873–881

178 Kuhl DE, Engel J, Phelps ME, et al Epileptic patterns of local cerebralmetabolism and perfusion in humans determined by emission com-puted tomography of18FDG and 13NH3 Ann Neurol 1980;8:348–360.

179 Gaillard WD, Fazilat S, White S, et al Interictal metabolism and bloodflow are uncoupled in temporal lobe cortex of patients with complex

partial epilepsy Neurology 1995;45:1841–1847.

180 Gaillard WD, Bhatia S, Bookheimer SY, et al FDG-PET and

volumet-ric MRI in the evaluation of patients with partial epilepsy Neurology

1995;45:123–126

181 Henry TR, Babb TL, Engel J Jr, et al Hippocampal neuronal loss and

regional hypometabolism in temporal lobe epilepsy Ann Neurol

1994;36:925–927

182 Hajek M, Wieser HG, Khan N, et al Preoperative and postoperativeglucose consumption in mesiobasal and lateral temporal lobe epilepsy

Neurology 1994;44:2125–2132.

183 Theodore WH, Kelley K, Toczek MT, et al Epilepsy duration, febrile

seizures, and cerebral glucose metabolism Epilepsia 2004;45:276–279.

184 Gaillard WD, Kopylev L, Weinstein S, et al Low incidence of abnormal(18)FDG-PET in children with new-onset partial epilepsy: a prospec-

tive study Neurology 2002;58:717–722.

185 Henry TR, Van Heertum RL Positron emission tomography and

sin-gle photon emission computed tomography in epilepsy care Semin Nucl Med 2003;33:88–104.

498 Principles and Practice of PET and PET/CT

LWBK053-3787G-9.01[479-499].qxd 14-08-2008 05:56 PM Page 498 Aptara Inc

186 Erbayat Altay E, Fessler AJ, Gallagher M, et al Correlation of severity

of FDG-PET hypometabolism and interictal regional delta slowing in

temporal lobe epilepsy Epilepsia 2005;46:573–576.

187 Delbeke D, Lawrence SK, Abou-Khalil BW, et al Postsurgical outcome

of patients with uncontrolled complex partial seizures and temporallobe hypometabolism on 18FDG-positron emission tomography

Invest Radiol 1996;31:261–266.

188 Theodore WH, Sato S, Kufta CV, et al FDG-positron emission

tomog-raphy and invasive EEG: seizure focus detection and surgical outcome

Epilepsia 1997;38:81–86.

189 Henry TR, Mazziotta JC, Engel J Interictal metabolic anatomy of

mesial temporal lobe epilepsy Arch Neurol 1993;50:582–589.

190 Newberg AB, Alavi A, Berlin J, et al Ipsilateral and contralateral

thala-mic hypometabolism as a predictor of outcome after temporal

lobec-tomy for seizures J Nucl Med 2000;41:1964–1968.

191 Choi JY, Kim SJ, Hong SB, et al Extratemporal hypometabolism on FDG

PET in temporal lobe epilepsy as a predictor of seizure outcome after

temporal lobectomy Eur J Nucl Med Mol Imaging 2003;30: 581–587.

192 Spanaki MV, Kopylev L, DeCarli C, et al Postoperative changes in

cerebral metabolism in temporal lobe epilepsy Arch Neurol 2000;57:

1447–1452

193 Lamusuo S, Jutila L, Ylinen A, et al [18F]FDG-PET reveals temporal

hypometabolism in patients with temporal lobe epilepsy even whenquantitative MRI and histopathological analysis show only mild hip-

pocampal damage Arch Neurol 2001;58:933–939.

194 Carne RP, O’Brien TJ, Kilpatrick CJ, et al MRI-negative PET-positive

temporal lobe epilepsy: a distinct surgically remediable syndrome

Brain 2004;127:2276–2285.

195 Carne RP, Cook MJ, Macgregor LR, et al “Magnetic resonance

imag-ing negative positron emission tomography positive” temporal lobeepilepsy: FDG-PET pattern differs from mesial temporal lobe epilepsy

Mol Imaging Biol 2007;9:32–42.

196 Kim YK, Lee DS, Lee SK, et al Differential features of metabolic

abnormalities between medial and lateral temporal lobe epilepsy:

quantitative analysis of (18)F-FDG PET using SPM J Nucl Med

2003;44:1006–1012

197 Henry TR, Sutherling WW, Engel J, et al Interictal cerebral

metabo-lism in partial epilepsies of neocortical origin Epilepsy Res

1991;10:174–182

198 Swartz BE, Halgren E, Delgado-Escueta AV, et al Neuroimaging in

patients with seizures of probable frontal lobe origin Epilepsia 1989;

30:547–558

199 Knowlton RC, Lawn ND, Mountz JM, et al Ictal SPECT analysis in

epilepsy: subtraction and statistical parametric mapping techniques

Neurology 2004;63:10–15.

200 Drzezga A, Arnold S, Minoshima S, et al.18F-FDG PET studies in

patients with extratemporal and temporal epilepsy: evaluation of an

observer-independent analysis J Nucl Med 1999;40:737–746.

201 Juhasz C, Chugani HT Imaging the epileptic brain with positron

emis-sion tomography Neuroimag Clin North Am 2003;13:705–716.

202 Sood S, Chugani HT Functional neuroimaging in the preoperative

evaluation of children with drug-resistant epilepsy Childs Nerv Syst

2006;22:810–820

203 Chugani HT, Conti JR Etiologic classification of infantile spasms in

140 cases: role of positron emission tomography J Child Neurol

1996;11:44–48

204 Chugani HT, Shields WD, Shewmon DA, et al Infantile spasms: I PETidentifies focal cortical dysgenesis in cryptogenic cases for surgical

treatment Ann Neurol 1990;27:406–413.

205 Chugani HT, Shewmon DA, Shields WD, et al Surgery for intractable

infantile spasms: neuroimaging perspectives Epilepsia 1993;34:764–771.

206 Markand ON Lennox-Gastaut syndrome (childhood epileptic

encephalopathy) J Clin Neurophysiol 2003;20:426–441.

207 Chugani HT, Mazziotta JC, Engel JJ, et al The Lennox-Gastaut drome: metabolic subtypes determined by 2-deoxy-2[18F]fluoro-D-

syn-glucose positron emission tomography Ann Neurol 1987;21:4–13.

208 Chugani HT, Chugani DC Basic mechanisms of childhood epilepsies:

studies with positron emission tomography.Adv Neurol 1999;79: 883–891.

209 Leiderman DB, Balish M, Sato S, et al Comparison of PET ments of cerebral blood flow and glucose metabolism for the localiza-

measure-tion of human epileptic foci Epilepsy Res 1992;13:153–157.

210 Chugani HT, Rintahaka PJ, Shewmon DA Ictal patterns of cerebral

glu-cose utilization in children with epilepsy Epilepsia 1994;35: 813–822.

211 Meltzer CC, Adelson PD, Brenner RP, et al Planned ictal FDG PET

imaging for localization of extratemporal epileptic foci Epilepsia

interest analysis with the Wada test Ann Neurol 1999;45:662–665.

214 Bookheimer SY, Zeffiro TA, Blaxton T, et al A direct comparison ofPET activation and electrocortical stimulation mapping for language

localization Neurology 1997;48:1056–1065.

215 Henry TR, Frey KA, Sackellares JC, et al In vivo cerebral metabolism

and central benzodiazepine-receptor binding in temporal lobe

epilepsy Neurology 1993;43:1998–2006.

216 Arnold S, Berthele A, Drzezga A, et al Reduction of benzodiazepinereceptor binding is related to the seizure onset zone in extratemporal

focal cortical dysplasia Epilepsia 2000;41:818–824.

217 Koepp MJ, Hammers A, Labbe C, et al.11C-flumazenil PET in patients

with refractory temporal lobe epilepsy and normal MRI Neurology

alpha-ation after failed epilepsy surgery Epilepsia 2004;45:124–130.

221 Morawetz RB, Crowell RH, DeGirolami U, et al Regional cerebral blood

flow thresholds during cerebral ischemia Fed Proc 1979;38:2493–2494.

Chapter 9.1 • Movement Disorders, Stroke, and Epilepsy 499

C H A P T E R

Fluorodeoxyglucose PET Imaging of Dementia:

Principles and Clinical Applications

SATOSHI MINOSHIMA, TAKAHIRO SASAKI, AND ERIC PETRIE

9.2

n many countries, life spans have lengthened considerably

in the past several decades The incidence of dementiaincreases with age, and imaging to detect dementia is ofincreasing importance for both clinical and research applications

(1) Although exact prevalence figures vary across studies, it is

esti-mated that more than 10% of persons over the age of 70 may suffer

from dementia, the most common type, in most populations, being

Alzheimer’s disease (2)

Applications of positron emission tomography (PET) to

imag-ing of dementia date back to the early stages of PET research

devel-opments in the late 1970s and early 1980s In contrast to common

clinical beliefs of the time that global reductions in cerebral

perfu-sion and metabolic activity would be evident in dementia, early

PET imaging demonstrated distinct patterns of regional

hetero-geneity in both hypoperfusion and hypometabolism (3) In 2004,

more than 20 years after the initial application of PET imaging to

dementia, and after considerable experience with

fluorine-18-fluo-rodeoxyglucose (FDG) PET technology, the U.S Center for

Medicare and Medicaid Services announced their final decision to

reimburse for FDG PET imaging for the differentiation of

Alzheimer’s disease and frontotemporal dementia This approval

has ignited renewed clinical and industrial interests in PET imaging

of dementia in parallel to continuing efforts to refine research

applications of these imaging modalities

IMAGING IN THE CLINICAL WORK-UP

to the type of dementing disorder present These diverse symptomsalso imply that dementing disorders may alter neural activity inwidespread brain regions, the effects of which are often reflected onPET imaging

Dementia can be manifested in many medical disorders, some

of which are common differential diagnoses in PET imaging tice Table 9.2.1 describes examples of dementing disorders In thecategory of neurodegenerative diseases, Alzheimer’s disease is themost common form, likely followed by dementia with Lewy bodies

prac-IMAGING IN THE CLINICAL WORK-UP OF

DEMENTING DISORDERS

BRAIN PET AND SINGLE-PHOTON EMISSION

COMPUTED TOMOGRAPHY IMAGING FOR DEMENTIA

DIAGNOSIS

Brain PET Tracer: [18F]-2-fluoro-2-deoxy-D-glucose

PET VERSUS PET/CT

Brain Fluorodeoxyglucose PET Imaging Protocols

Fluorodeoxyglucose PET Image Interpretation Quantification, Pixel Normalization, and StatisticalMapping of Fluorodeoxyglucose PET Images

RADIOTRACERS OTHER THAN FLUORODEOXYGLUCOSE

FOR DEMENTIA PET AND SINGLE-PHOTON EMISSION

COMPUTED TOMOGRAPHY IMAGING

MAGNETIC RESONANCE IMAGING FOR ROUTINE DEMENTIA EVALUATION

METABOLIC PATTERNS OF MAJOR DEMENTING DISORDERS

Alzheimer’s Disease Mild Cognitive Impairment Frontotemporal Dementia Dementia with Lewy Bodies and Parkinson’s Diseasewith Dementia

HEALTH EFFECTS AND COST-BENEFIT CONSIDERATION OF FLUORODEOXYGLUCOSE PET

IN DEMENTIA WORK-UP SUMMARY

ACKNOWLEDGMENTS

I

Vascular dementia includes both microvascular and macrovascular

diseases, but classical multi-infarct dementia is now less commonly

seen in imaging practice, in part due to improved control of risk

factors for vascular diseases Other medical conditions, such as

metabolic disorders and infections, are typically diagnosed during a

standard medical work-up but occasionally are part of the imaging

differential diagnosis

Clinical work-up of dementia patients involves medical,

neuro-logical, and laboratory examinations Table 9.2.2 describes an

exam-ple of the typical diagnostic work-up The goals of the diagnostic

work-up are to (a) confirm the presence of dementia; (b) identify

the potential cause of dementia; and (c) establish a differential

diag-nosis for treatment decision making It is important to note that the

diagnosis of Alzheimer’s disease and other neurodegenerative diseases

is made only after the exclusion of other detectable causes of

demen-tia Structural imaging (computed tomography [CT] and magnetic

resonance imaging [MRI]) is suggested as a part of the work-up

However, the use of structural imaging is primarily to exclude other

causes of dementia, such as brain tumor and vascular disease In

contrast, diagnostic applications of PET and single-photon emission

computed tomography (SPECT) imaging are primarily designed toidentify “positive” markers, such as characteristic changes in cerebralperfusion or glucose metabolism Thus, the goal of PET and SPECT

imaging in the dementia work-up is to identify diagnostic ers of the underlying neurodegenerative disease processes, similar to

biomark-other biomarkers such as cerebrospinal fluid levels of pathologic 

amyloid (i.e., A1–42) and tau protein (5)

BRAIN PET AND SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY IMAGING FOR DEMENTIA DIAGNOSIS

In the current radiology/nuclear medicine practice, both PET andSPECT imaging can be applied to the diagnostic work-up ofdementias As described previously, the current Medicare reim-bursement for FDG PET is limited to the differential diagnosis ofsuspected Alzheimer’s disease versus frontotemporal dementia.However, a large amount of research evidence suggests that FDGPET may also be capable of differentiating other dementing dis-orders SPECT imaging can also be applied more generally in thedementia work-up, but the diagnostic accuracy of brain perfu-sion SPECT may not be as high as FDG PET imaging (6) pre-sumably due to a combination of limited spatial resolution,sensitivity, and the nature of the perfusion tracers typically used

in clinical SPECT imaging For SPECT perfusion imaging, bothtechnetium-99m (99mTc) ethyl cysteinate dimer (ECD) and99mTcHMPAO (hexamethylpropyleneamine oxime) are available inthe United States In Japan, iodine-123 ([123I]) IMP (N-isopropyl- p-iodoamphetamine) is also available for routine clinicalapplications These “perfusion” tracers accumulate in the brainproportional to regional blood flow Since regional neuronalactivity and blood flow are tightly coupled, decreased neuronalactivity due to neurodegenerative processes can be detectedindirectly by SPECT imaging of secondary changes in blood flow

In contrast, FDG PET directly detects changes in regional ronal activity as reflected in rates of neuronal glucose metabolism(Table 9.2.3)

neu-Chapter 9.2 • Fluorodeoxyglucose PET Imaging of Dementia: Principles and Clinical Applications 501

NEURODEGENERATIVE DISEASES

Alzheimer’s disease

Dementia with Lewy bodies

Frontotemporal dementia (including Pick disease)

Parkinson’s disease

Huntington disease

ACQUIRED CEREBRAL DISORDERS

Vascular dementia (micro- and macrovascular)

Brain tumors (frontal lobe)

OTHER MEDICAL CONDITIONS

Metabolic disorder (e.g., chronic drug intoxication,

alcoholism)

Malnutrition (e.g., vitamin B12deficiency),

Infections (e.g., human immunodeficiency virus,

neurosyphilis, tuberculosis, cryptococcosis)

Depression

Interview with patient/family member

Physical examination

Neurological examination

Mini-Mental status examination (MMSE)

Assessment for functional status

Laboratory tests (e.g., complete blood cell count, thyroid, B12)

Neuropsychological examination

Neuroimaging (computed tomography or magnetic resonance

imaging)

Electroencephalogram, lumbar puncture (when required)

Genetic test (e.g., apolipoprotein E) not clinically accepted

Single-photon Emission Computed Tomography for Clinical Dementia Work-up

BRAIN PERFUSION SPECT[99mTc]-ECD, [99mTc]-HMPAO, [123I]-IMPRegional brain uptake determined by:

(1) Blood flow(2) Neuronal (synaptic) activity (coupled to blood flow)BRAIN FDG PET

[18F]-2-fluoro-2-deoxy-D-glucose (FDG)Regional brain uptake determined byNeuronal (synaptic) activity

SPECT, single-photon emission computed tomography; [99mTc],technetium-99m; ECD, ethyl cysteinate dimer; HMPAO,hexamethylpropyleneamine oxime; [123I]-IMP, iodine-123 N-isopropyl-p-iodoamphetamine

Brain PET Tracer:

[18F]-2-fluoro-2-deoxy-D-glucose

The brain uses glucose as a major energy source but does not have

substantial glucose storage capacity Therefore, it requires a

contin-uous supply of glucose from plasma to maintain its functions If

neurons in a certain part of the brain are not functioning normally,

the change can be sensitively reflected by the amount of glucose

uti-lization If a glucose analogue is labeled with a positron emitting

radionuclide and injected intravenously, areas of hypofunctioning

neurons can be depicted as areas of decreased tracer uptake

Sokoloff et al (7) originally developed the glucose analogue,

2-deoxyglucose, for the study of regional brain function

Deoxyglu-cose is transported from plasma to brain cells through the neuronal

membrane glucose transporter Deoxyglucose is then

phosphory-lated by hexokinase to form deoxyglucose-6-phosphate

(deoxy-G6P) However, deoxy-G6P cannot be further metabolized by

enzymes in the glycolytic pathway and therefore accumulates

within neurons When deoxyglucose is labeled with a positron

emitter such as [18F] (8), PET imaging can detect this activity from

outside the brain in three dimensions

Despite more than a decade of research and clinical use of FDG

in brain imaging, the exact microscopic locus of glucose

consump-tion in neurons is still a matter of investigaconsump-tion Sokoloff et al

demonstrated, in dorsal root ganglion neurons, that glucose

con-sumption at synapses increased in proportion to neuronal activity,

while glucose consumption in cell bodies was stable To the degree

that this model applies to the central nervous system, FDG uptake

observed by PET imaging would be expected to preferentially

reflect synaptic activity, possibly coupled with surrounding

astro-cyte uptake (9) This would be consistent with the sensitivity of

FDG PET imaging in detecting regional reductions in cortical

glucose uptake and metabolism in the early stages of Alzheimer’s

disease (10,11), as dysfunction and loss of synapses have been

shown to be very early pathological processes in this disorder

(12,13) This also implies that the degeneration of cortical projection

neurons known to occur in Alzheimer’s disease could result in spatial

discordance between structural imaging measures of neuron loss

and cortical atrophy and FDG PET imaging measures of synaptic

loss and cortical hypometabolism This illustrates the importance

of understanding major pathways of neuronal connectivity in the

brain for correctly interpreting the interrelationship between

regional hypometabolism and atrophy (an example of the more

general phenomenon of diaschisis, which is more commonly

encountered in the interpretation of imaging findings in stroke)

PET VERSUS PET/CT

Combined PET/CT technology is replacing dedicated PET scanners

in many clinical operations Significant advantages of PET/CT for

oncologic work-up are outlined elsewhere in this book Although

dedicated PET scanners can provide sufficient information for

dementia work-up, the use of PET/CT has certain additional

advantages The use of CT for attenuation correction will reduce

overall scanning time This is a clear benefit for imaging elderly and

demented patients who may have difficulty remaining still during

prolonged scans Simultaneous noncontrast CT also allows

screen-ing for gross anatomic abnormalities, such as tumors or subdural

hematomas, which could potentially cause dementia PET/CT

scan-ners that use newer generation PET components can also provide

better image quality that may potentially contribute to better nostic accuracy Because head motion between CT and PET scanscan be substantial in dementia patients, even with reduced scanningtimes, application of quality control measures prior to image recon-struction is critical

diag-Brain Fluorodeoxyglucose PET Imaging Protocols

A protocol for brain FDG PET imaging shares many proceduralsteps with oncologic FDG PET imaging However, there are specificprecautions that need to be taken for brain imaging As an FDG PETscan is capable of detecting very subtle metabolic changes associatedwith dementing disorders, alterations in brain activity produced byenvironmental stimuli during the tracer uptake phase followingintravenous injection of FDG can introduce artifactual metabolicalterations on brain PET images The most noticeable changes occur

in the primary sensory cortices For example, if patients are exposed

to light or visual stimulation, metabolic activity in the visual cortexincreases If auditory stimulation is given during the uptake phase,metabolic activity in the primary auditory cortex increases This issimilar to the muscle uptake occasionally seen in whole-body PETimaging when patients contract their muscles after FDG injection

To reduce metabolic variations due to external stimuli, a patientshould be kept in a dimly lit room with low ambient noise levelsboth before and after FDG injection An intravenous injection lineshould be established at least 10 minutes before FDG injection, sothat brain activation due to intravenous line placement can subsideprior to imaging The patient should be instructed not to speak,read, listen to music, or watch television in the injection room Atmany institutions, and recommended in several protocols, FDGinjection is typically performed with the patient’s eyes open It isimportant to minimize interaction with the patient during at leastthe first 20 minutes after FDG injection, during the period of maxi-mal brain tracer uptake With respect to tracer dosing, 300 to 600MBq (typically 370 MBq) and 125 to 250 MBq (typically 150 MBq)

of FDG are recommended for two-dimensional and sional image acquisition protocols, respectively (14)

three-dimen-The patient should fast for at least 4 to 6 hours prior to FDGPET imaging It is desirable if the patient can avoid caffeine, alco-hol, and other substances or drugs that may affect brain chemistryand function If plasma glucose levels are more than 160 to 200mg/dL, many institutions recommend rescheduling the study, since

a high plasma glucose level will degrade image quality as a result ofcompetitive inhibition of neuronal FDG uptake by high levels ofendogenous, unlabeled, plasma glucose

Image acquisition can be started after allowing at least 20 utes of tracer uptake following the intravenous injection of FDG Abrain FDG PET emission scan is typically acquired in three-dimen-sional data acquisition mode for 5 to 20 minutes As mentionedpreviously, a shorter scanning time is desirable for elderly anddementia patients Images can be reconstructed by either filteredback-projection or iterative image reconstruction methods

min-Fluorodeoxyglucose PET Image Interpretation

Many neurodegenerative diseases are known to affect certain parts

of the brain both pathologically and metabolically The differentialdiagnosis of dementia on FDG PET relies on identification of thesecharacteristic patterns of altered cerebral metabolic activity

502 Principles and Practice of PET and PET/CT

Owing to widespread availability of high-speed computer

workstations, interpretation of FDG PET images is typically

per-formed on a computer monitor using image display software In

this setting, image features such as the color scale and the

inten-sity/contrast can be changed interactively by the interpreter This

helps the interpreter identify subtle metabolic changes and confirm

the consistency of findings across different display modes (Fig

9.2.1) Image interpretation based solely on printed films is not a

desirable method of image interpretation Also, it is often helpful to

view all images in a multislice display, instead of scrolling through

single slices, to better understand the overall distribution of

hypometabolism in the brain In addition to transverse images,

reformatted sagittal and coronal images provide better structural

definition in certain structures, such as temporal lobe, subcortical

structures, and midline structures Coronal images are also useful

for comparison of metabolic asymmetry when the head position is

tilted To achieve consistent structural identification, it is desirable

to reslice reconstructed images parallel to the line passing through

anterior and posterior commissures (AC-PC line) The AC-PC line

defines the standard stereotactic coordinate system for human

brains (15) and allows consistent localization of cortical and

sub-cortical structures Since the anterior and posterior commissures

cannot be appreciated on brain PET images, the AC-PC line can be

approximated by a line passing through anterior and posterior

poles of the brain (Fig 9.2.2)

Structures that provide diagnostic clues for dementing ders include frontal, parietal, temporal, and occipital associationcortices; posterior and anterior cingulate cortices; primary sensori-motor and visual cortices; thalamus; striatum; pons; and cerebel-lum These structures need to be identified on PET images to allowidentification of regional metabolic alterations (Table 9.2.4) Mod-ern PET and PET/CT scanners have sufficient spatial resolution todepict cortical gyri and subcortical structures (Fig 9.2.3) However,the resolution is typically not sufficient to resolve individual gyrifacing each other at a sulcus As a result, in a normal brain, FDGuptake often appears accentuated at the sulcus In contrast, if there

disor-is atrophy present and a sulcus disor-is widened, the two gyri facing thesulcus can be seen separately

In normal subjects, brain FDG uptake is greatest in the primaryvisual cortex, especially if the eyes are open during the uptakeperiod Other primary cortices, such as sensorimotor and primaryauditory cortex, also show relatively high uptake The posterior cin-gulate cortex often shows very high uptake as well, almost equiva-lent to that of the primary visual cortex (11) Within the associationcortices, the frontal lobe should have general FDG uptake compara-ble to or greater than that of parietal or temporal association cor-tices (hyperfrontality) This hyperfrontality can be lost in manyconditions In the aging brain, FDG uptake in the frontal lobe, inparticular the medial frontal cortex, tends to decrease more thanother parts of the brain (16) This decrease is often associated with

Chapter 9.2 • Fluorodeoxyglucose PET Imaging of Dementia: Principles and Clinical Applications 503

FIGURE 9.2.1 Effects of different color scales on brain PET image interpretation—Alzheimer disease The right

four images represent white background with different lower cutoff thresholds Different color scales give ent impressions for the degree of hypometabolism Color scales tend to be more sensitive for subtle changes thanblack and white scales Applying different color scales and cutoff thresholds when interpreting PET images on aworkstation can confirm consistency of the findings

differ-FIGURE 9.2.2 Effects of slice orientation on brain PET image interpretation—Alzheimer disease Top row (A):

transverse slices when images are obtained when the neck is extended Bottom row (B): transverse slices when

images are realigned parallel to the line passing through the anterior and posterior commissures (AC-PC) Arrows

indicate locations of the primary sensorimotor cortex In (A), relatively preserved fluorodeoxyglucose (FDG)

uptake in the primary sensorimotor cortex is localized posteriorly in the superior part of the brain and creates animpression that FDG uptake in the parietal association cortex would be relatively preserved in contrast to

decreased frontal uptake In (B), the primary sensorimotor cortex is localized in between frontal and parietal lobes

in the stereotactic orientation FDG uptake in frontal and parietal association cortices is clearly diminished incomparison to that of the primary sensorimotor cortex, a diagnostic feature of Alzheimer disease

a widened interhemispheric fissure in the medial frontal lobe that

can be appreciated on PET images Decreases in glucose

metabo-lism may also extend to the lateral frontal cortex and anterior

peri-sylvian regions in advanced age populations (Fig 9.2.4)

Quantification, Pixel Normalization, and

Statistical Mapping of Fluorodeoxyglucose

PET Images

Using FDG PET imaging data, absolute regional glucose metabolic

rates can be quantified by mathematical tracer kinetic modeling The

tracer kinetic modeling typically requires a plasma input function

of tracer concentration, which can be measured by arterial sampling,

arterialized venous sampling (warming of the arm to increase rial-venous shunting), or image-based region of interest analysis ofarterial activity on dynamic PET images Early PET investigationswith absolute glucose metabolic quantification demonstratedglobal metabolic reductions in Alzheimer’s disease as well as othertypes of dementias in addition to focally and differentially accentu-ated hypometabolism (17,18) Due to the requirement for arterialinput function measurement, absolute quantification of glucosemetabolism by FDG PET is not practical in many clinical settings.Clinical interpretation of FDG PET imaging for dementia is there-

arte-fore typically based on the relative distribution of FDG uptake in the brain (In this chapter, the terms FDG uptake and glucose metab- olism are used interchangeably for convenience.)

Despite administration of a similar dose of FDG, the level ofFDG uptake in the brain can vary significantly and is influenced byseveral factors, including endogenous plasma glucose levels and thedistribution of FDG within the body The standard uptake value,which is often used for semiquantitative analysis in oncologic imageinterpretation, is not commonly used for brain PET image interpre-tation due to limited quantitative accuracy Instead, pixel values ofFDG PET images can be normalized to FDG uptake in a referenceregion that is known not to be, or at least is expected not to be, sig-nificantly affected by the disease processes under study (i.e., brainpixel values/averaged pixel values within the reference region) Tra-ditionally, the thalamus and the cerebellum have been used for thispurpose in Alzheimer’s disease Minoshima et al (19) previouslycompared normalized FDG uptake by different reference regions,including thalamus, cerebellum, primary sensorimotor cortex,whole brain, and pons, in comparison to absolute glucose metabolicrates measured using an arterial input function in the same Alzheimer’sdisease subjects and found that pixel normalization using thepons produced the most accurate and precise estimates of absoluteglucose metabolism It is important to note that normalization

504 Principles and Practice of PET and PET/CT

Images for Dementia Diagnosis

CORTICAL STRUCTURES

Frontal association cortex

Parietal association cortex

Temporal association cortex

Occipital association cortex

Posterior and anterior cingulate cortices

Primary visual cortex, primary sensorimotor cortex

Watershed areas (anterior-middle, middle-posterior cerebral

FIGURE 9.2.3 Normal

fluorode-oxyglucose PET images Cortical andsubcortical structures are clearlydepicted by the current generation of

a PET scanner

by averaged whole-brain activity, as is often used in brain mapping

analyses, can underestimate the degree and extent of

hypometabo-lism in dementias as these disorders often affect relatively large areas

of the brain and the averaged whole-brain activity is therefore

affected by the disease processes Also, particularly when global

nor-malization is used, artifactual relatively increased regional FDG

uptake may be observed A caution should be exercised not to

inter-pret this finding as increased regional glucose metabolism, as it often

represents regionally less severe hypometabolism

Owing to significant advancements in PET brain activation

studies and mapping technology developed in late 1980s and early

1990s (20–24), modern interpretations of brain PET images are

often performed statistically in the standard stereotactic coordinate

system (15) In these analyses, brain PET images are resliced to

match with the standard coordinate system, and individual

differ-ences in regional brain shape are minimized by computer

algo-rithms that perform nonlinear warping Once brain image data sets

are standardized, image sets from different subjects can be

com-pared on a pixel-by-pixel basis for various statistical assessments To

objectively and quantitatively estimate regional metabolic changes

in dementias, we developed a brain mapping method in which

indi-vidual brain PET data sets can be compared to a normative data set

(often called a normal database) that is created from scans of

mul-tiple normal control subjects (25) For each pixel, a Z score, defined

as [(individual pixel value minus normal control mean)/normal

control standard deviation], can be calculated and displayed for

image interpretation (Fig 9.2.5) In this analysis, areas of

hypome-tabolism can be detected as higher Z scores This significantly

improves the diagnostic accuracy of Alzheimer’s disease using brain

PET images (26) The concept of this image analysis is similar to

that used in cardiac image interpretation (bull’s eye) Statistical

brain mapping analyses of FDG PET and perfusion SPECT are now

used extensively for research investigations of dementia (16,27–32),

and similar brain mapping software is now commercially available

for routine clinical applications

RADIOTRACERS OTHER THAN FLUORODEOXYGLUCOSE FOR DEMENTIA PET AND SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY IMAGING

Numerous radiotracers have been developed and used for PET and

SPECT investigations of dementing disorders These include tracers

for assessment of (a) oxygen metabolism ([15O]-O2); (b) blood flow

([15O]-water,123I-IMP,99mTc-HMPAO,99mTc-ECD); (c) cholinergic

system (carbon-11 [11C]-scopolamine, [11C]-TRB, [11C]-NMPB,

[123I]-IBVM, [123I]-QNB, [11C]-PMP, [11C]-BMP); (d)

dopaminer-gic system ([18F]-dopa, [11C]-nomifensine, [11C]-raclopride, [11

C]-DTBZ, [123I]-IBZP, [123I]-IBF, [123I]-IBZM; (d) serotonergic system([18F]-setoperone); (e) central and peripheral benzodiazepinereceptors ([11C]-FMZ, [123I]-IMZ, [11C]-PK11195); and (f) amyloid([11C]-PIB, [18F]-FDDNP, [11C]-SB-13) (abbreviations found inMEDLINE) Significant efforts have been directed toward imaging

of the cholinergic system in Alzheimer’s disease (33–42) owing tothe cholinergic hypothesis (43) and the widespread availability ofcholinergic treatments for Alzheimer’s disease Beyond traditionalperfusion, metabolic, and neurotransmitter receptor imaging, recentPET investigations have also been directed at characterizing immuneactivity in Alzheimer’s brain using [11C]-PK11195 and amyloiddeposition using tracers such as [11C]-PIB, [18F]-FDDNP, and[11C]-SB-13 Some of these tracers are described elsewhere in thisbook

Chapter 9.2 • Fluorodeoxyglucose PET Imaging of Dementia: Principles and Clinical Applications 505

FIGURE 9.2.4 Normal

fluorodeo-xyglucose (FDG) PET images

obtained in an elderly subject Mildly

decreased FDG uptake and widened

interhemispheric fissure in the

medial frontal lobe are common for

an elderly subject

FIGURE 9.2.5 Statistical mapping of brain PET images for image

interpretation Original images are first standardized in the stereotacticcoordinate system (stereotactic reorientation parallel to the anteriorand posterior line and anatomic standardization to minimize individ-ual anatomic variances), and gray matter activity is extracted into threedimensions (3D-stereotatic surface projections [3D-SSP]) (25) Datafrom multiple normal subjects constitute normal database (mean andstandard deviation for each pixel) When patient data in question areprocessed in the same way, each pixel value of the patient data is com-pared to the mean value of the normal database relative to the standarddeviation and generates a Z score to indicate the degree of deviationfrom the normal mean This forms Z-score maps indicating areas ofdecreased FDG uptake in the patient in comparison to the normaldatabase Z-score maps significantly improve diagnostic accuracy ofbrain FDG PET for dementia (26)

MAGNETIC RESONANCE IMAGING FOR

ROUTINE DEMENTIA EVALUATION

Structural imaging is often employed to exclude disorders such as

stroke, frontal lobe tumor, and subdural hematoma in dementia

patients The cost-effectiveness of CT and MRI in dementia care has

been debated For clinical interpretation of FDG PET images,

com-parison with MRI is often useful for the evaluation of white matter

changes, such as microvascular disease, which can affect cortical

meta-bolic activity For a typical dementia work-up, a noncontrast MRI can

be obtained with pulse sequences including T1-weighted images,

T2-weighted images, and fluid-attenuated inversion recovery (FLAIR)

images (Fig 9.2.6) T2-weighted and FLAIR images are useful for the

evaluation of white matter abnormalities that cannot be appreciated

by FDG PET imaging T2-weighted images can also be used to

evalu-ate a large vessel flow void T1-weighted images provide detailed

infor-mation regarding anatomy It is important to note that

neurodegener-ative diseases can coexist with vascular disease (mixed dementia) (44).

These patients can present with clinical symptoms that are not typical

for each condition and are diagnostically challenging Documentation

of ischemic changes on MRI and neurodegenerative features on FDG

PET help to establish the diagnosis of mixed dementia

Significant efforts have been made in the field of MRI research to

generate markers of neurodegenerative diseases In addition to

tradi-tional hippocampal volume measurements, structural measurement

can now be done for cortical gray matter using voxel-based analysis

Quantitative MR perfusion imaging has also been used for dementia

evaluation In addition, diffusion tensor imaging has been used to

evaluate white matter tract abnormalities in Alzheimer’s disease

Spectroscopic analysis of neurodegenerative disorders is another

example More recently, the feasibility of imaging amyloid in animals

using fluorine-19-labeled tracer (45) as well as without tracer (46)

have both been demonstrated Although a detailed review of these

technologies is outside the scope of this chapter, they may

signifi-cantly enhance in vivo investigations and represent possible future

advances in clinical approaches to imaging of dementing disorders

METABOLIC PATTERNS OF MAJOR

DEMENTING DISORDERS

One goal of FDG PET evaluation is to differentiate dementias with

treatment options (e.g., symptomatic treatments for Alzheimer’s

disease, dementia with Lewy bodies, treatment and risk management

for cerebrovascular disease) from nontreatable dementias Differentdementing disorders are often associated with unique metabolicfeatures (47) In the clinical setting, a systematic approach to imageinterpretation contributes to diagnostic accuracy An example of asystematic image interpretation is shown in Fig 9.2.7 Major neu-rodegenerative disorders are described below

Alzheimer’s Disease

Alzheimer’s disease is considered to be the most common cause ofdementia The disease was first described by Dr Alzheimer’s in

1906 (48) Clinical diagnostic criteria for probable Alzheimer’s

dis-ease defined by National Institute of Neurological and nicative Disorders and Stroke/Alzheimer’s Disease and RelatedDisorders Association (NINCDS-ADRDA) (49) include: (a)dementia established by clinical examination and neuropsycholog-ical tests (e.g., Mini-Mental State Examination); (b) deficits in two

Commu-or mCommu-ore areas of cognition; (c) progressive wCommu-orsening of memCommu-oryand other cognitive functions; (d) no disturbance of conscious-ness; (e) onset between ages 40 and 90, most often after age 65; and(f) absence of systemic disorders or other brain diseases that in and

of themselves could account for the progressive deficits in memory

506 Principles and Practice of PET and PET/CT

FIGURE 9.2.6 Magnetic resonance

imaging for routine clinical

evalua-tion T1-weighted (left), T2-weighted (middle), and fluid-attenuated inver- sion recovery (FLAIR) (right) images

are routinely obtained for dementiawork-up

FIGURE 9.2.7 An example of a systematic interpretation of

fluo-rodeoxyglucose PET images The interpretation starts with a question

if the scan is normal, then evaluate Alzheimer changes, frontotemporalchanges, and then atypical changes AD, Alzheimer disease; DLB,dementia with Lewy bodies; VC, visual cortex; FTD, frontotemporaldementia; HD, Huntington’s disease; CJD, Creutzfeldt-Jakob’s disease

and cognition Confirmatory neuropathologic changes include

senile plaques containing A1-42fibrils and neurofibrillary tangles

made up of hyperphosphorylated tau isoforms Several causative

gene abnormalities (e.g., mutations in amyloid precursor protein

[APP], presenilin-1 [PS-1], presenilin-2 [PS-2]) as well as genes

that carry risk factors for earlier age of onset (e.g., apolipoprotein

E [APOE] genotype) have been identified, but common genetic

abnormalities for the majority of sporadic cases are yet to be

eluci-dated Mechanisms of amyloid deposition have been extensively

investigated, and the involvement of APP processing by -secretase

and other enzymes has been unveiled There have been numerous

publications to date concerning both research and clinical

applica-tions of PET imaging in Alzheimer’s disease, and the role of PET

imaging agents for amyloid is discussed in Chapter 9.1 in this

book

Metabolic features of Alzheimer’s disease seen on FDG PET

images vary depending on the stage of the disease In mild

demen-tia, FDG uptake in the parietotemporal association cortices as well

as posterior cingulate cortex and precuneus is typically decreased

FDG uptake in the frontal association cortex varies, but mild

reduc-tions may be present in patients with mild dementia In contrast,

FDG uptake in the primary sensorimotor cortex, primary visual

cortex, thalamus, putamen, pons, and cerebellum is relatively

preserved (Fig 9.2.8) It is important to note that this contrast

between areas relatively affected and areas relatively preserved gives a

diagnostic clue to Alzheimer’s disease If FDG uptake is decreased in

areas supposed to be relatively preserved in Alzheimer’s disease,

despite the presence of parietotemporal hypometabolism, these

findings might indicate either non-Alzheimer’s disease or

coexist-ing diseases such as ischemic vascular changes When the disease

progresses, FDG uptake in all of the association cortices, including

frontal lobe, decreases However, FDG uptake in primary cortices

and subcortical structures remains relatively preserved, even in

advanced disease (Fig 9.2.9)

Positive and negative predictive values of the aforementioned

FDG PET findings are influenced by the pretest probability of the

disease Risk factors for Alzheimer’s disease include advanced age;

gender (women greater than men); family history; previous head

trauma; and APOE e4 allele status (50) The association with APOEe4 allele status has prompted consideration of combining informa-tion on genetic risk factors and PET findings to improve the diag-nostic accuracy of Alzheimer’s disease (51)

In a meta-analysis, the diagnostic accuracy of FDG PET, based

on DSM-III-R or NINCDS-ADRDA clinical diagnostic criteria for

Alzheimer’s disease, was approximately 80% sensitivity and 70%specificity (averaged over data from three class I articles) (52–54),although these values varied somewhat depending on clinical set-tings, physician expertise, and patient populations In contrast, theFDG PET diagnostic accuracy for Alzheimer’s disease in compari-son to autopsy results was approximately 90% sensitivity and 76%specificity (averaged over two class II articles) (47,55) These datademonstrate that the accuracy of an FDG PET diagnosis ofAlzheimer’s disease is comparable to, or even better than, that of aclinical diagnosis In addition, FDG PET can produce objectivediagnostic imaging findings in a single laboratory visit withoutnecessitating a follow-up office visit to confirm progression of cog-nitive decline

There are certain “normal variants” of the classic pattern ofregional metabolic hypometabolism associated with Alzheimer’s dis-

ease Alzheimer’s findings are commonly described as bilateral, but

a certain degree of hemispheric asymmetry is also common In somecases, only one hemisphere shows substantial abnormalities, andabnormalities in the other hemisphere could be subtle (Fig 9.2.10).The FDG PET diagnosis for Alzheimer’s disease should be based on

confirmation of areas typically affected and preserved in each

hemi-sphere as described above Metabolic asymmetry often correlateswith clinical symptoms (i.e., more prominent visuospatial dysfunc-tion with right hemisphere dominant hypometabolism, moreprominent language problem with left hemispheric hypometabo-lism (56)

Minoshima et al (57,58) previously described significanthypometabolism in the posterior cingulate cortex and precuneus inAlzheimer’s disease Hypometabolism in the posterior cingulatecortex is difficult to appreciate on transverse slices and it is bestvisualized by sagittal slices or by the use of statistical mapping tech-niques However, some fraction of patients may not demonstrateChapter 9.2 • Fluorodeoxyglucose PET Imaging of Dementia: Principles and Clinical Applications 507

FIGURE 9.2.8 Mild Alzheimer disease Mild metabolic reductions involving parietotemporal association cortices

bilaterally Fluorodeoxyglucose uptake in the primary sensorimotor cortex (top row), primary visual cortex (middle row), striatum and thalamus (middle row), and cerebellum (bottom row) is relatively preserved.

Statistical mapping (see Fig 9.2.17) shows additional metabolic reductions in the posterior cingulate cortex andprecuneus A contrast between areas affected and areas preserved (selective vulnerability) is the diagnostic feature

of Alzheimer disease Both hemispheres are often affected, but asymmetry is also common (Fig 9.2.10)

significant abnormalities in the posterior cingulate cortex (59).

Early onset patients (younger than 65 years old) are known to

demonstrate more marked metabolic abnormalities compared to

late onset patients (60) This translates to clinical implications that,

if a suspected dementia patient with age below 65 years old does not

show convincing metabolic abnormalities, this patient probably

does not have Alzheimer’s disease Mixed dementia is also common

and can have somewhat atypical metabolic features, such as

decreased and asymmetric FDG uptake in subcortical structures If

FDG PET images show major metabolic findings of Alzheimer’s

disease, such as parietotemporal hypometabolism, but also

asym-metric reduction in FDG uptake in subcortical structures (e.g.,

thalamus, cerebellum) and/or watershed areas, coexisting micro- or

macrovascular disease becomes a consideration Crossed-cerebellar

diaschisis associated with abnormalities in the contralateral

hemi-sphere is commonly seen in stroke and other pathologic conditions,

but is not prominently seen in Alzheimer’s disease The presence of

apparent crossed-cerebellar diaschisis should raise the possibility of

non-Alzheimer’s changes or coexisting non-Alzheimer’s pathology

Mild Cognitive Impairment

Progressive neurodegenerative processes, particularly Alzheimer’s

disease, have been shown to have a long prodromal phase

Signifi-cant neuronal loss has occurred by the time clinical symptoms of

dementia become evident Currently, no therapies are available that

directly target the underlying neurodegenerative processes in this

disorder Several classes of drugs, such as HMG-CoA reductaseinhibitors (statins), nonsteroidal anti-inflammatory drugs, hormonereplacement therapy in women, and antioxidants (e.g., vitamin Eand vitamin C) have shown promise for preventing or delaying the

onset of Alzheimer’s disease in vivo or in epidemiological studies,

but have not proven effective when tested in controlled clinical trials

A possible explanation for these discordant findings is that theseagents act to prevent or delay the underlying neurodegenerativeprocesses in Alzheimer’s disease but are unable to reverse neuronaldamage once it has occurred and therefore are not effective in thetreatment of the disease once it has progressed to the point of clinicalsigns and symptoms This being the case, the identification ofpatients still in the early, presymptomatic, stage of the disease wouldfacilitate efforts at disease modification or prevention

To help identify patients with early stage dementia who may

derive greater benefit from treatment, the concept of mild cognitive impairment (MCI) has been developed (61,62) MCI patients are

identified based on diagnostic criteria including (a) complaint ofmemory impairment; (b) normal activities of daily living; (c) nor-mal general cognitive function; (d) abnormal memory function forage, and (e) absence of dementia In some studies, approximately10% to 15% of MCI patients convert to Alzheimer’s disease everyyear Subsequent research has identified other subgroups of MCIpatients who present with cognitive deficits in domains other than,

or in addition to, short-term memory (e.g., language, visuospatialskills, executive function [planning, sequencing, abstract reason-ing]) and determined that multiple etiologic factors other than, or

508 Principles and Practice of PET and PET/CT

FIGURE 9.2.9 Severe Alzheimer

disease Fluorodeoxyglucose (FDG)uptake in the parietotemporal as well

as frontal association cortices isseverely decreased (the right hemi-sphere more severe than the left).Even at this late stage of the disease,FDG uptake in the primary sensori-motor and visual cortices, striatum,thalamus, and cerebellum is rela-tively preserved

FIGURE 9.2.10 Alzheimer disease.

Hemispheric asymmetry Right etotemporal cortices show decreasedfluorodeoxyglucose (FDG) uptake.FDG uptake in the right primarysensorimotor cortex is relatively pre-

pari-served (top row) The patient’s head

was tilted in the scanner, whichwould give impressions of asymmet-ric striatal and thalamic uptake

in addition to, incipient Alzheimer’s disease may be present (i.e.,

degenerative, vascular, metabolic, traumatic, psychiatric disorders)

(63,64)

Metabolic features of MCI are, for the most part, consistent

with those seen in Alzheimer’s disease, but of milder degree (11)

Metabolic reduction in the posterior cingulate cortex is a relatively

consistent finding Identification of Alzheimer-type metabolic

changes in MCI patients is highly predictive of subsequent

cogni-tive decline and development of frank dementia (31) In a clinical

setting, however, mild metabolic changes associated with very early

Alzheimer’s disease in MCI patients may not be easily identified on

FDG PET images (Fig 9.2.11) However, application of statistical

mapping techniques can clearly improve diagnostic accuracy of

FDG PET imaging in these circumstances (see Fig 9.2.17) (26)

Another approach is to combine imaging findings and other

bio-markers such as risk genotypes to improve diagnostic accuracy

(51) Combination of multiple diagnostic biomarkers is one of the

directions of current research in Alzheimer’s disease

The extreme sensitivity of FDG PET in detecting very early

changes in dementia is further demonstrated by findings of subtle

Alzheimer’s changes in cognitively normal middle-aged APOE e4

homozygotes (65) and in normal elderly subjects who later

devel-oped cognitive decline (66) It remains to be determined just how

early in the course of Alzheimer’s disease altered glucose metabolic

activity can be demonstrated and whether this occurs earlier or

later than detectable changes in other Alzheimer’s disease

biomark-ers, such as amyloid PET tracer uptake or alterations in cerebral

spinal fluid -amyloid and tau levels.

Frontotemporal Dementia

In contrast to Alzheimer’s disease, frontotemporal dementia is

more common among younger patients (onset under 65 years of

age), and more prevalent in men (67) In the United States, the first

government approval for dementia work-up by FDG PET was the

differential diagnosis of Alzheimer’s disease versus frontotemporaldementia It is important to note that the pathological and clinicalcharacterization and classification of frontotemporal dementia is

an evolving field of research A spectrum of neurodegenerative orders that affects predominantly frontal and temporal lobes isincluded in the category of frontotemporal dementia Mutations ofthe tau gene on chromosome 17 cause some forms of familial fron-totemporal dementia (68) Mutations in progranulin genes haverecently been associated with other familial forms of frontotempo-ral dementia (69) Other cases of frontotemporal dementia areassociated with amyotrophic lateral sclerosis (70,71) Both the clin-ical presentations and pathologic features of frontotemporaldementia are similarly heterogeneous (72) and also do not neces-sarily show one-to-one correspondence (Table 9.2.5)

dis-Chapter 9.2 • Fluorodeoxyglucose PET Imaging of Dementia: Principles and Clinical Applications 509

FIGURE 9.2.11 Very early Alzheimer disease identified in a patient with mild cognitive impairment (MCI) Very

mild metabolic reductions in the left lateral parietal association cortex (top row), but it may not be difficult to

appreciate such changes by visual inspection Mildly accentuated fluorodeoxyglucose uptake in the region of the

primary sensorimotor cortex bilaterally (top row) is often a sign of mild metabolic reductions in adjacent

associ-ation cortices Statistical mapping of this patient (Fig 9.2.17) clearly demonstrates mild metabolic reductions inthe parietotemporal association cortices, frontal association cortices, and posterior cingulate cortex and pre-cuneus, bilaterally (the left hemisphere more severe than the right), but relative preservation of primary sensori-motor and visual cortices, findings consistent with very mild Alzheimer disease

Dementia

PATHOLOGYClassic Pick’s disease (PiD)Corticobasal degeneration (CBD)Progressive supranuclear palsy (PSP)Frontotemporal lobar degeneration with motor neurondisease or motor neuron disease-type inclusions (FTLD-MND/MNI)

Neurofibrillary tangle dementia (NFTD)Dementia lacking distinctive histopathologic features (DLDH)CLINICAL PRESENTATIONS

Frontal lobe dementiaPrimary progressive aphasiaCorticobasal degeneration syndromeProgressive supranuclear palsyAmyotrophic lateral sclerosis

Reflecting the pathologic and clinical heterogeneities of

fron-totemporal dementia, the metabolic features of these disorders are

also variable Classical lobar hypometabolism affecting

predomi-nantly frontal lobe may be seen in Pick’s disease (Fig 9.2.12)

Although frontal and temporal lobes are often involved bilaterally,

hypometabolism can be significantly asymmetric (Fig 9.2.13) In

addition to the frontal hypometabolism, the caudate nucleus and

anterior temporal lobe often show hypometabolism Similar to

Alzheimer’s disease, FDG uptake in the primary sensorimotor cortex

(as well as other primary cortices such as primary visual cortex) is

relatively preserved When the disease progresses, areas of

hypome-tabolism extend to the parietal and temporal association cortices

(73) This progressive pattern is an important contrast to that of

Alzheimer’s disease in which parietotemporal association cortices

are initially involved, and the frontal association cortex is affected in

more severe cases These metabolic features provide differential

diagnostic clues for Alzheimer’s disease versus frontotemporal

dementia However, other types of frontotemporal dementia

demonstrate more variable metabolic features Progressive

supranuclear palsy shows milder superior frontal hypometabolism

as well as subcortical hypometabolism (74–76) (Fig 9.2.14)

Fron-totemporal dementia resulting from mutations of the tau gene on

chromosome 17 can show more temporal lobe-dominant

meta-bolic reductions with milder frontal hypometabolism (Fig 9.2.15)

It is sometimes difficult to distinguish temporal-dominant

510 Principles and Practice of PET and PET/CT

hypometabolism in frontotemporal dementia from those seen inAlzheimer’s disease Other biomarkers such as amyloid PET imag-ing may be helpful to better differentiate these conditions.Many other medical and psychiatric conditions are known toaffect metabolic activity in the frontal lobe (Table 9.2.6) Amongthese, vascular disease, alcoholism, and depression can be seenrelatively frequently in patients referred for imaging studies Corre-lation with medical history as well as structural MRI becomesessential for accurate differential diagnosis especially when FDGPET findings are somewhat atypical

Dementia with Lewy Bodies and Parkinson’s Disease with Dementia

A pathologic hallmark for Parkinson’s disease is the presence ofLewy bodies in the brainstem (77) (Fig 9.2.16) In the 1970s,demented patients were described who had numerous corticalLewy bodies (78) Owing to the development of antiubiquitinimmunocytochemistry (79,80), cortical Lewy bodies were subse-quently described in larger numbers of patients presenting withdementia After decades of debate and various proposals for taxon-omy, a consensus of pathologic and clinical diagnostic criteria fordementia with Lewy bodies were established in 1996 (81) Dementiawith Lewy bodies is now considered to be the second most commoncause of dementia (81,82), following Alzheimer’s disease, and

FIGURE 9.2.12 Frontotemporal

dementia Classical case of frontallobar hypometabolism (bilateral).Additional metabolic reductions areseen in the anterior temporal lobeand caudate Fluorodeoxyglucoseuptake in the primary sensorimotorcortex and occipital cortex is rela-tively preserved

FIGURE 9.2.13 Frontotemporal

dementia Hemispheric asymmetry.The left frontal lobe, caudate, andanterior temporal lobe are moreseverely involved than the righthemisphere These asymmetric find-ings are seen often in frontotemporaldementia as well as in Alzheimer dis-ease Fluorodeoxyglucose uptake inthe primary sensorimotor cortex isrelatively preserved in both hemi-spheres

Chapter 9.2 • Fluorodeoxyglucose PET Imaging of Dementia: Principles and Clinical Applications 511

followed by vascular dementia and frontotemporal dementia Three

distinctive clinical features are (a) spontaneous motor features of

parkinsonism occurring early in the course of the disease; (b)

marked fluctuations in cognitive function; and (c) persistent

well-formed visual hallucinations However, these symptoms are not

necessarily consistent among patients, and clinical diagnosis

remains challenging Patients with dementia with Lewy bodies are

sensitive to the side effects of neuroleptics, and adverse events can

be severe and fatal (83), requiring careful selection of agent and

dosage Also, response to cholinesterase treatment can be more

favorable in comparison to Alzheimer’s disease (81) Because of

these therapeutic implications, differential diagnosis of Alzheimer’s

disease versus dementia with Lewy bodies is critical

Albin et al (84) reported the first FDG PET findings of

autopsy-proven cases of dementia with Lewy bodies, which was

fol-lowed by a larger number of autopsy confirmed cases of both

dementia with Lewy bodies and Alzheimer’s disease (55) Dementia

with Lewy bodies showed metabolic changes nearly identical to

Alzheimer’s disease in the cerebral cortex, but additional significant

hypometabolism was observed in the occipital lobe, including the

primary visual cortex (which is typically relatively preserved in

Alzheimer’s disease) Such occipital hypometabolism was seen in

dementia with Lewy bodies with and without coexisting

Alzheimer’s changes When using occipital hypometabolism as a

marker of dementia with Lewy bodies, the sensitivity and specificity

to distinguish dementia with Lewy bodies from Alzheimer’s disease

were 90% and 80%, respectively (autopsy-confirmed cases) These

findings have been confirmed by other investigators (85,86) and arenow considered to be a supportive feature of dementia with Lewybodies in the most recent consensus diagnostic criteria (87) It isinteresting to note that, despite the diagnostic value of the occipitalhypometabolism in dementia with Lewy bodies, Lewy bodies arenot prominent in the occipital lobe at autopsy The pathophysiolog-ical mechanisms of occipital hypometabolism in dementia withLewy bodies have yet to be elucidated

More than half of Parkinson’s disease patients eventuallydevelop dementia Many of these patients exhibit cortical Lewybodies identical to dementia with Lewy bodies Despite differences

in the temporal sequences of symptoms (motor symptoms first inParkinson’s disease with dementia, dementia first in dementia withLewy bodies), both diseases share similar pathological findings—abnormal neuronal -synuclein inclusions forming Lewy bodies(88) Treatment responses to cholinesterase inhibitors are also sim-ilar in the two disorders (89) Reflecting close similarities betweenParkinson’s disease with dementia and dementia with Lewy bodies,FDG PET findings are also similar in these two disorders Parkin-son’s disease with dementia is characterized by hypometabolism inthe parietotemporal association cortices and additional hypome-tabolism in the occipital cortex including the primary visual cortex(30) When compared to Alzheimer’s disease, metabolic reductions

in the medial temporal cortex are relatively mild

Imaging biomarkers other than FDG PET for dementia withLewy bodies have been investigated Consistent with the fact thatdementia with Lewy bodies and Parkinson’s disease with dementia

FIGURE 9.2.14 Progressive

supra-nuclear palsy Mild metabolic

reduc-tions are seen in the superior frontal

cortex (more prominent in the

medial frontal cortex), the left

hemi-sphere more severely involved than

the right (top row) Mild metabolic

reduction is also seen in the left

cau-date (middle row).

FIGURE 9.2.15 Frontotemporal

dementia Temporal-dominant

hy-pometabolism Fluorodeoxyglucose

uptake is decreased in the anterior

temporal lobe bilaterally Additional

metabolic reductions are seen in the

medial frontal cortex bilaterally and

caudate nucleus

exhibit neuropathological overlap with Parkinson’s disease, PET

and SPECT imaging of dopamine systems demonstrate decreased

dopaminergic markers in all three of these conditions (87,90,91) In

contrast, Alzheimer’s disease is associated with only mild decrease

in dopaminergic markers Decreased dopamine uptake in the

stria-tum is considered to be a suggestive feature of dementia with Lewy

bodies in the current consensus diagnostic criteria (87) More

recently, loss of cardiac sympathetic innervation in dementia with

Lewy bodies was found using metaiodobenzylguanidine SPECT

imaging (92,93) Decreased metaiodobenzylguanidine uptake in

the heart can help distinguish dementia with Lewy bodies from

Alzheimer’s disease (94–96) Expanded commercial availability of

these imaging biomarkers will likely further improve the ability to

differentiate dementia with Lewy bodies, Alzheimer’s disease, and

related disorders in clinical settings

HEALTH EFFECTS AND

COST-BENEFIT CONSIDERATION

OF FLUORODEOXYGLUCOSE PET

IN DEMENTIA WORK-UP

Despite the government approval of reimbursement for FDG PET

concerning differential diagnosis of Alzheimer’s versus

frontotem-poral dementia in the United States, there is limited evidence

con-cerning the cost effectiveness of FDG PET diagnosis in dementia care

in comparison to that without PET diagnosis Due to logistic ties in obtaining such evidence (i.e., the time required for final[pathologic] diagnostic confirmation; limited outcome variables;limited funding to conduct large-scale, prospective studies), attemptshave been made to utilize statistical models to estimate the effective-ness of PET imaging in the diagnosis of dementia (the Agency forHealthcare Research and Quality, Contract No 290-97-0014, TaskOrder 7, December 14, 2001) This analysis evaluated costs per life-years saved and quality-adjusted life years resulting from institutingcholinesterase inhibitor treatment in three clinical scenarios (mild tomoderate dementia, mild cognitive impairment, and subjects at riskfor dementia) with treatment based on presence or absence of PETimaging findings and concluded that “treatment without testing” inall three groups was the best outcome However, the conclusions ofthis analysis have been criticized on several grounds, including lim-ited outcome measures and limited input data for patients with mildcognitive impairment and subjects at risk for dementia, and there arestill ongoing efforts to generate more evidence to assess the size ofhealth effects in a prospectively designed research protocol Oneexample is a Center for Medicare and Medicaid Services supportedstudy of FDG PET in the diagnosis of questionable dementia.Cost-benefit considerations become an important factor in theimplementation and widespread use of FDG PET imaging fordementia work-up The literature evidence concerning cost ofdementia care with and without FDG PET imaging is also limited.One study estimated that the use of FDG PET could result in greaternumbers of patients being accurately diagnosed for the same level

difficul-of financial expenditure over a wide range difficul-of tested values for PETdiagnostic accuracy, costs of PET imaging, and long-term carecosts, as well as varying degrees of use of structural neuroimaging(97) Another study argued that the use of functional imaging stud-ies for the diagnosis of Alzheimer’s disease is not cost effective inlight of the effectiveness of currently available treatments (98).Given the impending implementation of new, potentially disease-modifying treatments (i.e.,-secretase inhibitors, -amyloid anti-

bodies) and improving imaging technologies such as amyloid PET imaging, further cost-benefit analyses of PET imaging for

512 Principles and Practice of PET and PET/CT

FIGURE 9.2.16 Dementia with Lewy bodies Hypometabolism in the parietotemporal association cortices (the

left hemisphere more severe than the right) similar to Alzheimer disease is seen When compared to Alzheimer ease (Fig 9.2.8), fluorodeoxyglucose (FDG) uptake in the primary visual cortex and occipital cortex is decreased,metabolic features of dementia with Lewy bodies Typically, FDG uptake in the primary visual cortex is compara-ble to that of the thalamus This case clearly shows metabolic reductions in the visual cortex in comparison to

dis-those in the thalamus (middle row).

Alzheimer’s disease and other dementing illnesses are likely to be

initiated to allow informed and cost-effective diagnostic and

treat-ment decisions in clinical settings

SUMMARY

In this chapter PET imaging of dementia, with a particular

empha-sis on FDG PET, has been reviewed The clinical work-up of

demen-tia, common fluorodeoxyglucose PET imaging protocols, principles

of image interpretation, metabolic features of major

neurodegener-ative disorders, and cost-benefit relationships have been

summa-rized Extensive research and clinical applications of FDG PET in

dementia have been published by numerous investigators Given

the increasing availability of PET imaging in routine clinical

settings and ongoing developments of imaging technology, PETimaging can be expected to improve the diagnosis and management

of patients with dementia in the future

ACKNOWLEDGMENTS

The authors thank Yoshimi Anzai, MD, and Donna Cross, PhD, fortheir expert input Data presented in this article are in part sup-ported by NIH/NINDS RO1-NS045254

REFERENCES

1 Kukull WA, Higdon R, Bowen JD, et al Dementia and Alzheimer

dis-ease incidence: a prospective cohort study Arch Neurol 2002;59:

sup-oxygen-15 and positron tomography Brain 1981;104:753–778.

4 Diagnostic and statistical manual of mental disorders (DSM-IV)

Wash-ington, DC: American Psychiatric Association, 1994

5 Fagan AM, Csernansky CA, Morris JC, et al The search for antecedent

biomarkers of Alzheimer’s disease J Alzheimers Dis 2005;8:347–358.

6 Ishii K, Minoshima S PET is better than perfusion SPECT for early

diagnosis of Alzheimer’s disease Eur J Nucl Med Mol Imaging

2005;32:1463–1465

7 Sokoloff L, Reivich M, Kennedy C, et al The [14C]deoxyglucosemethod for the measurement of local cerebral glucose utilization: the-ory, procedure, and normal values in the conscious and anesthetized

albino rat J Neurochem 1977;28:897–916.

8 Reivich M, Kuhl D, Wolf A, et al Measurement of local cerebral glucosemetabolism in man with 18F-2-fluoro-2-deoxy-d-glucose Acta Neurol Scand Suppl 1977;64:190–191.

9 Magistretti PJ, Pellerin L Cellular bases of brain energy metabolismand their relevance to functional brain imaging: evidence for a promi-

nent role of astrocytes Cerebral Cortex 1996;6:50–61.

10 Reiman EM, Caselli RJ, Yun LS, et al Preclinical evidence of Alzheimer’sdisease in persons homozygous for the epsilon 4 allele for apolipopro-

tein E N Engl J Med 1996;334:752–758.

11 Minoshima S, Giordani B, Berent S, et al Metabolic reduction in the

posterior cingulate cortex in very early Alzheimer’s disease Ann Neurol

1997;42:85–94

12 Masliah E, Mallory M, Hansen L, et al Synaptic and neuritic alterations

during the progression of Alzheimer’s disease Neurosci Lett 1994;174:

67–72

13 Masliah E, Terry RD, Alford M, et al Cortical and subcortical patterns

of synaptophysinlike immunoreactivity in Alzheimer’s disease Am J Pathol 1991;138:235–246.

14 Bartenstein P, Asenbaum S, Catafau A, et al European Association ofNuclear Medicine procedure guidelines for brain imaging using[(18)F]FDG Eur J Nucl Med Mol Imaging 2002;29:BP43–48.

15 Talairach J, Tournoux P Co-planar stereotaxic atlas of the human brain.

New York: Thieme, 1988

16 Petit-Taboue MC, Landeau B, Desson JF, et al Effects of healthy aging

on the regional cerebral metabolic rate of glucose assessed with

statisti-cal parametric mapping Neuroimage 1998;7:176–184.

17 Benson DF, Kuhl DE, Hawkins RA, et al The fluorodeoxyglucose 18F

scan in Alzheimer’s disease and multi-infarct dementia Arch Neurol

1983;40:711–714

18 Kuhl DE, Metter EJ, Riege WH Patterns of local cerebral glucose lization determined in Parkinson’s disease by the [18F]fluorodeoxyglu-

uti-cose method Ann Neurol 1984;15:419–424.

Chapter 9.2 • Fluorodeoxyglucose PET Imaging of Dementia: Principles and Clinical Applications 513

FIGURE 9.2.17 Sample Z-score maps of fluorodeoxyglucose PET

images presented in this chapter Anatomic reference images at the top

(REF) Right lateral (RT.LAT), left lateral (LT.LAT), right medial

(RT.MED), and left medial (LT.MED) hemispheres are demonstrated

in 3D-SSP format Color images represent Z scores that indicate the

degree of regional hypometabolism relative to the normal database

Normal (Fig 9.2.3); mild Alzheimer disease (Fig 9.2.8); severe

Alzheimer’s disease (Fig 9.2.9); asymmetric Alzheimer disease (Fig

9.2.10); mild cognitive impairment (very mild Alzheimer disease)

(Fig 9.2.11); frontotemporal dementia (frontal lobar

hypometabo-lism) (Fig 9.2.12); asymmetric frontotemporal dementia (Fig 9.2.13);

and frontotemporal dementia, temporal dominant (Fig 9.2.15)

19 Minoshima S, Frey KA, Foster NL, et al Preserved pontine glucose

metabolism in Alzheimer disease: a reference region for functional

brain image (PET) analysis J Comput Assist Tomogr 1995;19:

541–547

20 Fox PT, Perlmutter JS, Raichle ME A stereotactic method of

anatomi-cal loanatomi-calization for positron emission tomography J Comput Assist

Tomogr 1985;9:141–153.

21 Friston KJ, Passingham RE, Nutt JG, et al Localisation in PET images:

direct fitting of the intercommissural (AC-PC) line J Cereb Blood Flow

Metab 1989;9:690–695.

22 Minoshima S, Koeppe RA, Mintun MA, et al Automated detection of

the intercommissural line for stereotactic localization of functional

brain images J Nucl Med 1993;34:322–329.

23 Woods RP Modeling for intergroup comparisons of imaging data

Neu-roimage 1996;4:S84–S94.

24 Friston KJ, Frith CD, Liddle PF, et al The relationship between global

and local changes in PET scans J Cereb Blood Flow Metab 1990;10:

458–466

25 Minoshima S, Frey KA, Koeppe RA, et al A diagnostic approach in

Alzheimer’s disease using three-dimensional stereotactic surface

pro-jections of fluorine-18-FDG PET J Nucl Med 1995;36:1238–1248.

26 Burdette JH, Minoshima S, Vander Borght T, et al Alzheimer disease:

improved visual interpretation of PET images by using

three-dimen-sional stereotaxic surface projections Radiology 1996;198:837–843.

27 Ishii K, Sasaki M, Yamaji S, et al Demonstration of decreased posterior

cingulate perfusion in mild Alzheimer’s disease by means of H215O

positron emission tomography Eur J Nucl Med 1997;24:670–673.

28 Signorini M, Paulesu E, Friston K, et al Rapid assessment of regional

cerebral metabolic abnormalities in single subjects with quantitative

and nonquantitative [18F]FDG PET: a clinical validation of statistical

parametric mapping Neuroimage 1999;9:63–80.

29 Bartenstein P, Minoshima S, Hirsch C, et al Quantitative assessment of

cerebral blood flow in patients with Alzheimer’s disease by SPECT

J Nucl Med 1997;38:1095–1101.

30 Vander Borght T, Minoshima S, Giordani B, et al Cerebral metabolic

differences in Parkinson’s and Alzheimer’s diseases matched for

demen-tia severity J Nucl Med 1997;38:797–802.

31 Drzezga A, Lautenschlager N, Siebner H, et al Cerebral metabolic

changes accompanying conversion of mild cognitive impairment into

Alzheimer’s disease: a PET follow-up study Eur J Nucl Med Mol

Imag-ing 2003;30:1104–1113.

32 Nobili F, Koulibaly M, Vitali P, et al Brain perfusion follow-up in

Alzheimer’s patients during treatment with acetylcholinesterase

inhibitors J Nucl Med 2002;43:983–990.

33 Holman BL, Gibson RE, Hill TC, et al Muscarinic acetylcholine

recep-tors in Alzheimer’s disease In vivo imaging with iodine 123-labeled

3-quinuclidinyl-4-iodobenzilate and emission tomography JAMA

1985;254:3063–3066

34 Weinberger DR, Mann U, Gibson RE, et al Cerebral muscarinic

recep-tors in primary degenerative dementia as evaluated by SPECT with

iodine-123-labeled QNB Adv Neurol 1990;51:147–150.

35 Kuhl DE, Koeppe RA, Fessler JA, et al In vivo mapping of cholinergic

neurons in the human brain using SPECT and IBVM J Nucl Med

1994;35:405–410

36 Kuhl DE, Minoshima S, Fessler JA, et al In vivo mapping of cholinergic

terminals in normal aging, Alzheimer’s disease, and Parkinson’s disease

Ann Neurol 1996;40:399–410.

37 Kuhl DE, Koeppe RA, Minoshima S, et al In vivo mapping of cerebral

acetylcholinesterase activity in aging and Alzheimer’s disease Neurology

1999;52:691–699

38 Kuhl DE, Minoshima S, Frey KA, et al Limited donepezil inhibition of

acetylcholinesterase measured with positron emission tomography in

living Alzheimer cerebral cortex Ann Neurol 2000;48:391–395.

39 Kuhl DE, Koeppe RA, Snyder SE, et al In vivo butyrylcholinesterase

activity is not increased in Alzheimer’s disease synapses Ann Neurol

2006;59:13–20

40 Namba H, Irie T, Fukushi K, et al In vivo measurement of

acetyl-cholinesterase activity in the brain with a radioactive acetylcholine

ana-log Brain Res 1994;667:278–282.

41 Irie T, Fukushi K, Namba H, et al Brain acetylcholinesterase activity:

validation of a PET tracer in a rat model of Alzheimer’s disease J Nucl Med 1996;37:649–655.

42 Iyo M, Namba H, Fukushi K, et al Measurement of acetylcholinesterase

by positron emission tomography in the brains of healthy controls and

patients with Alzheimer’s disease Lancet 1997;349:1805–1809.

43 Bartus RT, Dean RLd, Beer B, et al The cholinergic hypothesis of

geri-atric memory dysfunction Science 1982;217:408–414.

44 Rockwood K, Macknight C, Wentzel C, et al The diagnosis of “mixed”dementia in the Consortium for the Investigation of Vascular Impair-

ment of Cognition (CIVIC) Ann N Y Acad Sci 2000;903:522–528.

45 Higuchi M, Iwata N, Matsuba Y, et al.19F and 1H MRI detection of

amy-loid beta plaques in vivo Nat Neurosci 2005;8:527–533.

46 Jack CR Jr, Garwood M, Wengenack TM, et al In vivo visualization of

Alzheimer’s amyloid plaques by magnetic resonance imaging in

trans-genic mice without a contrast agent Magn Reson Med 2004;52:1263–1271.

47 Silverman DH, Small GW, Chang CY, et al Positron emission phy in evaluation of dementia: regional brain metabolism and long-

tomogra-term outcome JAMA 2001;286:2120–2127.

48 Alzheimer A Uber einen eigenartigen schweren Erkrankungsprozeb

der Hirnrinde Neurologisches Centralblatt Neurologisches Centralblatt

1906;23:1129–1136

49 Tierney MC, Fisher RH, Lewis AJ, et al The NINCDS-ADRDA WorkGroup criteria for the clinical diagnosis of probable Alzheimer’s disease:

a clinicopathologic study of 57 cases Neurology 1988;38:359–364.

50 Corder EH, Saunders AM, Strittmatter WJ, et al Gene dose ofapolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late

onset families Science 1993;261:921–923.

51 Drzezga A, Grimmer T, Riemenschneider M, et al Prediction of vidual clinical outcome in MCI by means of genetic assessment and(18)F-FDG PET J Nucl Med 2005;46:1625–1632.

indi-52 Holmes C, Cairns N, Lantos P, et al Validity of current clinical criteriafor Alzheimer’s disease, vascular dementia and dementia with Lewy

bodies Br J Psychiatry 1999;174:45–50.

53 Jobst KA, Barnetson LP, Shepstone BJ Accurate prediction of cally confirmed Alzheimer’s disease and the differential diagnosis of

histologi-dementia: the use of NINCDS-ADRDA and DSM-III-R criteria, SPECT,

x-ray CT, and APO E4 in medial temporal lobe dementias Oxford

Pro-ject to Investigate Memory and Aging Int Psychogeriatr 1998;10:271–302.

54 Lim A, Tsuang D, Kukull W, et al Clinico-neuropathological correlation

of Alzheimer’s disease in a community-based case series J Am Geriatr Soc 1999;47:564–569.

55 Minoshima S, Foster NL, Sima AA, et al Alzheimer’s disease versusdementia with Lewy bodies: cerebral metabolic distinction with

autopsy confirmation Ann Neurol 2001;50:358–365.

56 Foster NL, Chase TN, Fedio P, et al Alzheimer’s disease: focal cortical

changes shown by positron emission tomography Neurology 1983;33:

961–965

57 Minoshima S, Foster NL, Kuhl DE Posterior cingulate cortex in

Alzheimer’s disease Lancet 1994;344:895.

58 Minoshima S, Foster NL, Frey KA, et al Metabolic differences inAlzheimer’s disease with and without cortical Lewy bodies as revealed

by PET J Cereb Blood Flow Metab 1997;17:S437.

59 Bonte FJ, Harris TS, Roney CA, et al Differential diagnosis betweenAlzheimer’s and frontotemporal disease by the posterior cingulate sign

J Nucl Med 2004;45:771–774.

60 Ichimiya A, Herholz K, Mielke R, et al Difference of regional cerebralmetabolic pattern between presenile and senile dementia of the

Alzheimer type: a factor analytic study J Neurol Sci 1994;123:11–17.

61 Petersen RC Normal aging, mild cognitive impairment, and early

Alzheimer’s disease Neurologist 1995;1:326–344.

62 Petersen RC, Smith GE, Waring SC, et al Aging, memory, and mild

cog-nitive impairment Int Psychogeriatr 1997;9:65–69.

514 Principles and Practice of PET and PET/CT

63 Petersen RC, Doody R, Kurz A, et al Current concepts in mild cognitive

impairment Arch Neurol 2001;58:1985–1992.

64 Petersen RC, Stevens JC, Ganguli M, et al Practice parameter: early

detection of dementia: mild cognitive impairment (an evidence-based

review) Report of the Quality Standards Subcommittee of the

Ameri-can Academy of Neurology Neurology 2001;56:1133–1142.

65 Reiman EM, Caselli RJ, Yun LS, et al Preclinical evidence of Alzheimer’s

disease in persons homozygous for the epsilon 4 allele for

apolipopro-tein E N Engl J Med 1996;334:752–758.

66 de Leon MJ, Convit A, Wolf OT, et al Prediction of cognitive decline in

normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/

poitron-emission tomography (FDG/PET) Proc Natl Acad Sci U S A

2001;98:10966–10971

67 Ratnavalli E, Brayne C, Dawson K, et al The prevalence of

frontotem-poral dementia Neurology 2002;58:1615–1621.

68 Poorkaj P, Bird TD, Wijsman E, et al Tau is a candidate gene for

chromosome 17 frontotemporal dementia Ann Neurol 1998;43:

815–825

69 Baker M, Mackenzie IR, Pickering-Brown SM, et al Mutations in

pro-granulin cause tau-negative frontotemporal dementia linked to

chro-mosome 17 Nature 2006;442:916–919.

70 Lomen-Hoerth C, Anderson T, Miller B The overlap of amyotrophic

lateral sclerosis and frontotemporal dementia Neurology 2002;59:

1077–1079

71 Ringholz GM, Greene SR The relationship between amyotrophic

lat-eral sclerosis and frontotemporal dementia Curr Neurol Neurosci Rep

2006;6:387–392

72 Mott RT, Dickson DW, Trojanowski JQ, et al Neuropathologic,

bio-chemical, and molecular characterization of the frontotemporal

dementias J Neuropathol Exp Neurol 2005;64:420–428.

73 Diehl-Schmid J, Grimmer T, Drzezga A, et al Decline of cerebral

glu-cose metabolism in frontotemporal dementia: a longitudinal 18

F-FDG-PET-study Neurobiol Aging 2007;28:42–50.

74 Foster NL, Gilman S, Berent S, et al Progressive subcortical gliosis and

progressive supranuclear palsy can have similar clinical and PET

abnor-malities J Neurol Neurosurg Psychiatry 1992;55:707–713.

75 Karbe H, Grond M, Huber M, et al Subcortical damage and cortical

dysfunction in progressive supranuclear palsy demonstrated by

positron emission tomography J Neurol 1992;239:98–102.

76 Foster NL, Minoshima S, Johanns J, et al PET measures of

benzodi-azepine receptors in progressive supranuclear palsy Neurology 2000;54:

79 Kuzuhara S, Mori H, Izumiyama N, et al Lewy bodies are

ubiquiti-nated A light and electron microscopic immunocytochemical study

Acta Neuropathol (Berl) 1988;75:345–353.

80 Lennox G, Lowe J, Morrell K, et al Anti-ubiquitin

immunocytochem-istry is more sensitive than conventional techniques in the detection of

diffuse Lewy body disease J Neurol Neurosurg Psychiatry 1989;52:67–71.

81 McKeith LG, Galasko D, Kosaka K, et al Consensus guidelines for the

clinical and pathologic diagnosis of dementia with Lewy bodies (DLB):

report of the consortium on DLB international workshop Neurology

83 McKeith I, Fairbairn A, Perry R, et al Neuroleptic sensitivity in patients

with senile dementia of Lewy body type BMJ 1992;305:673–678.

84 Albin RL, Minoshima S, D’Amato CJ, et al Fluoro-deoxyglucose

positron emission tomography in diffuse Lewy body disease Neurology

1996;47:462–466

85 Ishii K, Imamura T, Sasaki M, et al Regional cerebral glucose

metabo-lism in dementia with Lewy bodies and Alzheimer’s disease Neurology

1998;51:125–130

86 Okamura N, Arai H, Higuchi M, et al [18F]FDG-PET study in

demen-tia with Lewy bodies and Alzheimer’s disease Prog macol Biol Psychiatry 2001;25:447–456.

Neuropsychophar-87 McKeith IG, Dickson DW, Lowe J, et al Diagnosis and management of

dementia with Lewy bodies: third report of the DLB Consortium rology 2005;65:1863–1872.

Neu-88 Lippa CF, Duda JE, Grossman M, et al DLB and PDD boundary issues:

diagnosis, treatment, molecular pathology, and biomarkers Neurology

2007;68:812–819

89 Thomas AJ, Burn DJ, Rowan EN, et al A comparison of the efficacy ofdonepezil in Parkinson’s disease with dementia and dementia with

Lewy bodies Int J Geriatr Psychiatry 2005;20:938–944.

90 Hu XS, Okamura N, Arai H, et al.18F-fluorodopa PET study of striataldopamine uptake in the diagnosis of dementia with Lewy bodies

Neurology 2000;55:1575–1577.

91 Walker Z, Costa DC, Janssen AG, et al Dementia with Lewy bodies:

a study of post-synaptic dopaminergic receptors with iodine-123

iodobenzamide single-photon emission tomography Eur J Nucl Med

)I-meta-iodobenzyl-with Alzheimer’s disease J Neurol Neurosurg Psychiatry 2001;70:781–783.

94 Hanyu H, Shimizu S, Hirao K, et al Comparative value of brain sion SPECT and [(123)I]MIBG myocardial scintigraphy in distinguish-

perfu-ing between dementia with Lewy bodies and Alzheimer’s disease Eur J Nucl Med Mol Imaging 2006;33:248–253.

95 Jindahra P, Vejjajiva A, Witoonpanich R, et al Differentiation of tia with Lewy bodies, Alzheimer’s disease and vascular dementia by car-diac 131I-meta-iodobenzylguanidine (MIBG) uptake (preliminary

demen-report) J Med Assoc Thai 2004;87:1176–1181.

96 Kitagawa Y Usefulness of [123I] MIBG myocardial scintigraphy for ferential diagnosis of Alzheimer’s disease and dementia with Lewy bod-

dif-ies Intern Med 2003;42:917–918.

97 Silverman DH, Gambhir SS, Huang HW, et al Evaluating early tia with and without assessment of regional cerebral metabolism by

demen-PET: a comparison of predicted costs and benefits J Nucl Med 2002;43:

253–266

98 McMahon PM, Araki SS, Neumann PJ, et al Cost-effectiveness of

func-tional imaging tests in the diagnosis of Alzheimer disease Radiology

2000;217:58–68

Chapter 9.2 • Fluorodeoxyglucose PET Imaging of Dementia: Principles and Clinical Applications 515

C H A P T E R

Psychiatric Disorders MARC LARUELLE AND ANISSA ABI-DARGHAM

10

sychiatric conditions were once qualified as “functional”

illnesses, that is, disorders in which no major abnormalities

of brain integrity such as tumors, inflammation, or infectioncould be detected by neuropathological examination Indeed, follow-

ing a century of postmortem studies, only subtle abnormalities have

been found at autopsy in brains of patients who suffered from major

psychiatric illnesses, and few of these have been consistently

repli-cated These observations led to the impression that these illnesses

were due to functional rather than structural brain abnormalities.

Computed tomography (CT) and magnetic resonance imaging

(MRI) studies have consistently observed abnormalities in brain

regional volumes in many of these conditions, but these

abnormali-ties remain for the most part within the limits of normal variability

None of them is pathognomonic or diagnostic Therefore, the advent

of molecular imaging with positron emission tomography (PET) and

single-photon emission computed tomography (SPECT) held

enor-mous promises for the field of psychiatry because, for the first time,

living brain functions were directly accessible to clinical investigation

Using PET and SPECT, a large body of studies has documented

that psychiatric disorders are associated with regional alterations in

flow and metabolism under both resting and activation conditions

In this regard, PET and SPECT have played a major role in

unravel-ing alterations in brain function associated with these conditions

Today these techniques have largely been replaced by functional

MRI (fMRI), which offers clear advantages in terms of spatial and

temporal resolution, not to mention the lack of radiation exposure

Therefore, it is foreseeable that the role of PET and SPECT studies

of flow and, to some extent, metabolism in psychiatry research may

be greatly reduced in the future

On the other hand, the ability of nuclear medicine techniques to

image specific biomolecules is unmatched by any other method

cur-rently available to clinical investigators Studies of receptors,

trans-porters, enzymes, and other processes such as transmitter release

clearly constitute the uniqueness of PET for current and future

psy-chiatric research These techniques have already yielded a number of

fundamental observations So far none of these findings has led toclinical applications useful in the diagnosis or treatment of these dis-orders in individual patients However, it is anticipated that suchapplications may surface from this line of research in the near future.The aim of this chapter is to describe the major findings stem-ming from this line of research and their implications for our under-standing of the pathophysiology and treatment of major psychiatricillnesses For the reasons discussed above, the chapter will focus onimaging studies of specific biomolecules as opposed to the study offlow and metabolism Nonetheless, important flow and metabolismstudies will be discussed, particularly when molecular imaging stud-ies provide clues to the pathophysiology underlying their observa-tions The chapter will include both PET and SPECT studies, as itwould not be feasible to provide a comprehensive review of this fieldwithout describing the important contributions of SPECT.Technical considerations critical to the discussion of the find-ings will be included when appropriate, but, for an overview of thetechnical background of these studies, the reader is referred toChapters 1–3, and 5 in this book In line with the clinical orienta-tion of this chapter, the studies will be reviewed by disorder (schiz-ophrenia, mood, anxiety, personality, conduct, and substance abusedisorders) rather than by transmitter system

The main neurotransmitter systems that have been studied withPET or SPECT in relation to psychiatric disorders and their treat-ment include dopamine (DA), serotonin (5-HT),-aminobutyricacid (GABA), and opiate systems Radiotracers most frequentlyused include those for the DA D2/3receptor: carbon-11 [11C]-N-

methylspiperone, [11C]-raclopride, iodine-123 [123I]-IBZM (benzamide

derivative (S)-3-[123

l]-iodo-N-[(1-ethyl-2-pyrrolidinyl)])-methyl-2-hydroxy-6-methoxybenzamide), [123I]-epidipride, fluorine-18[18F]-fallypride, [11C]-FLB457, [11C]-PHNO (11)C]()-PHNO([(11)C]()-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b] [1,4]oxazin-9-ol; D1receptors: [11C]-SCH23390, [11C]-NNC112;

DA transporters: [11C]-cocaine, [11C]-methylphenidate, [123I]-

-CIT (123I-labeled 2--carbomethoxy-3--(4-iodophenyl)-tropane),

SCHIZOPHRENIA

Dopamine Transmission Serotonin Transmission Gamma-aminobutyric Acid Secretion Transmission Antipsychotic Drug Occupancy Studies

PERSONALITY DISORDERS CONDUCT DISORDER SUBSTANCE ABUSE

Cocaine Methamphetamine Ecstasy

Heroin Nicotine Alcohol

CONCLUSION

P

[11C]/[18F]-CFT (2--carbomethoxy-3--(4-fluorophenyl) tropane),

technetium-99m [99mTc]-TRODAT-1; dopa decarboxylase:

[18F]/[11C]-DOPA; monoamine oxydase: [11C]-deprenyl and [11

C]-clorgyline; 5-HT2 receptors: [18F]-altanserin, [18F]-setoperone,

[11C]-MDL100907; 5-HT1A receptors: [11C]-WAY100635; 5-HT

transporters: [123I]--CIT, [11C]-McN5652, [11C]-DASB;

benzodi-azepine receptors: [123I]-iomazenil, [11C]-flumazenil; and mu

opi-ate receptors: [11C]-carfentanil, [18F]-cyclofoxy

SCHIZOPHRENIA

Dopamine Transmission

The classical DA hypothesis, formulated over 40 years ago, proposed

that schizophrenia is associated with hyperactivity of dopaminergic

neurotransmission (1,2) This hypothesis was essentially based on

the observation that all effective antipsychotic drugs provided at

least some degree of D2receptor blockade (3,4), an observation that

is still true today As D2receptor blockade is most effective against

positive symptoms (delusions and hallucinations), the DA

hyperac-tivity model appeared to be most relevant to the pathophysiology of

these symptoms This idea was further supported by the fact that

sustained exposure to DA agonists such as amphetamine can induce

a psychotic state characterized by some features of schizophrenic

positive symptomatology (emergence of paranoid delusions and

hallucinations in the context of a clear sensorium) (5,6) These

phar-macological effects suggest, but do not establish, a dysregulation of

DA systems in schizophrenia

On the other hand, negative and cognitive symptoms are

gen-erally resistant to treatment by antipsychotic drugs Functional

brain imaging studies have suggested that these symptoms are

asso-ciated with prefrontal cortex (PFC) dysfunction (7) Studies in

non-human primates have demonstrated that deficits in DA

transmis-sion in the PFC produce cognitive impairments reminiscent of

those observed in schizophrenic patients (8), suggesting that a

deficit in DA transmission in the PFC may be implicated in the

cog-nitive impairments associated with schizophrenia (9,10)

Thus, a contemporary view of the role of DA in schizophrenia

is that subcortical mesolimbic DA projections may be hyperactive

(resulting in positive symptoms) and that the mesocortical DA

pro-jections to the PFC may be hypoactive (resulting in negative

symp-toms and cognitive impairment) Furthermore, these two

abnor-malities may be related, as the cortical DA system generally exerts an

inhibitory action on subcortical DA systems (11,12) The advent in

the early 1980s of techniques based on PET and SPECT to measure

indices of DA activity in the living human brain opened the

possi-bility of direct investigation of these hypotheses

Subcortical Dopamine Transmission

Studies of striatal DA transmission in schizophrenia examined both

postsynaptic (D2 receptors and D1 receptors) and presynaptic

([DOPA] decarboxylase activity, stimulant-induced DA release,

baseline DA release, and dopamine transporter [DAT]) functions

Striatal Dopamine Receptors

Striatal D2receptor density in schizophrenia has been extensively

studied with PET and SPECT imaging (unless specified otherwise,

the term D2receptor is used in this chapter to designate both D2and

D3receptors) A meta-analysis (13) of these studies identified 17

studies comparing D receptor parameters in patients with

schizo-phrenia (included a total of 245 patients, 112 neuroleptic naive, and

133 neuroleptic free), and controls (n  231), matched for age andsex (14–30) Radiotracers included butyrophenones ([11C]-N-

methyl-spiperone, [11C]-NMSP, n  4 studies, and bromine-76[76Br]-bromospiperone, n  3 studies), benzamides ([11C]-raclo-pride, n  3 studies, and [123I]-IBZM, n  5 studies) or the ergotderivative [76Br]-lisuride, n  2 studies) Only 2 of 17 studiesdetected a significant elevation of D2receptor density parameters.However, meta-analysis revealed a small (12%) but significant ele-vation of striatal D2receptors in patients with schizophrenia Noclinical correlates of increased D2receptor binding parameters havebeen reliably identified Studies performed with butyrophenones (n  7) show an effect size of 0.96  1.05, significantly larger thanthe effect size observed with other ligands (benzamides and lisuride,

n  10; 0.20 ± 0.26; P  04) This difference has been attributed to

differences in vulnerability of the binding of these tracers, to tition by endogenous DA, and to elevation of endogenous DA inschizophrenia (31,32) Interestingly, a recent study in unaffectedmonozygotic twins of patients with schizophrenia suggested that amodest elevation of D2receptors in the caudate might be associatedwith genetic vulnerability to schizophrenia (33)

compe-Regarding striatal D1receptors, several imaging studies haveconfirmed the results of postmortem studies of unaltered levels ofthese receptors in the striatum of patients with schizophrenia(20,34,35)

Several lines of evidence suggest that D3receptors might play animportant role in the pathophysiology and treatment of schizophre-nia (36) An increase in the concentration of D3receptors has beenreported in postmortem brains of patients with schizophrenia (37)

In addition to their role in schizophrenia, D3 receptors are alsobelieved to play an important role in drug addiction (38) Untilrecently, imaging D3 receptor was not feasible: PET radiotracerscommonly used to study D2and D3receptors exhibit similar affini-ties for both receptors and the concentration of D3receptors in thehuman striatum is lower than that of D2receptors The recent dis-covery that [11C]-PHNO is a D3preferring imaging agent might

open a window to the in vivo study of this important target (39).

Striatal DOPA Decarboxylase ActivitySeveral studies have reported rates of activity of DOPA decarboxy-lase in patients with schizophrenia, using [18F]-DOPA (40–45) or[11C]-DOPA (46) The majority of these studies reported increasedaccumulation of DOPA in the striatum of patients with schizophre-

nia, and the combined analysis yielded a significant effect size (P.01) (13) Together, these studies provide the strongest evidence forthe existence of a dysregulation of DA function in the striatum ofuntreated patients with schizophrenia In addition, several of thesestudies reported that high DOPA accumulation was more pro-nounced in psychotic paranoid patients, while low accumulationwas observed in patients with negative or depressive symptoms andcatatonia Although the relationship between DOPA decarboxylaseand the rate of DA synthesis is unclear (DOPA decarboxylase is notthe rate-limiting step of DA synthesis), these observations are com-patible with higher DA synthesis activity of DA neurons in schizo-phrenia, at least in subjects experiencing psychotic symptoms.Striatal Amphetamine-induced Dopamine Release

D2receptor imaging, combined with pharmacological tion of DA release, enables more direct evaluation of DA presynap-tic activity Numerous groups have demonstrated that an acute

manipula-Chapter 10 • Psychiatric Disorders 517

increase in synaptic DA concentration is associated with decreased

in vivo binding of benzamide radioligands, such as [11

C]-raclo-pride, [18F]-fallypride, or [123I]-IBZM These interactions have been

demonstrated in rodents, nonhuman primates, and humans, using

a variety of methods to increase synaptic DA (for review of this

abundant literature, see Laruelle [47]) It has also been consistently

observed that the in vivo binding of spiperone and other

buty-rophenones is not as affected by acute fluctuations in endogenous

DA levels, as is the binding of benzamides (47)

The decrease in [11C]-raclopride and [123I]-IBZM in vivo

bind-ing followbind-ing acute amphetamine challenge has been well validated

as a measure of the change in D2receptor stimulation by DA due to

amphetamine-induced DA release Manipulations that are known

to inhibit amphetamine-induced DA release, such as pretreatment

with the DA synthesis inhibitor -methyl-para-tyrosine (MPT) or

with the DAT blocker GR12909, also inhibit the

amphetamine-induced decrease in [123I]-IBZM or [11C]-raclopride binding

(48,49) The effect of methamphetamine on [11C]-raclopride in

vivo binding is also significantly blunted in patients with Parkinson

disease (50) Combined microdialysis and imaging experiments in

primates demonstrated that the magnitude of the decrease in ligand

binding was correlated with the magnitude of the increase in

extra-cellular DA induced by the challenge (26,49), suggesting that this

noninvasive technique provides an appropriate measure of the

changes in synaptic DA levels

Three of three studies demonstrated that the

amphetamine-induced decrease in [11C]-raclopride or [123I]-IBZM binding was

elevated in untreated patients with schizophrenia compared to

well-matched controls (24,26,27) A significant relationship was

observed between the magnitude of DA release and the transient

induction or deterioration of positive symptoms The increased

amphetamine-induced DA release was observed in both first

episode/drug-naive patients and patients previously treated with

antipsychotic drugs (51) Patients who were experiencing an

episode of illness exacerbation (or a first episode of illness) at the

time of the scan showed elevated amphetamine-induced DA

release, while patients in remission showed DA release values not

different from controls (51), suggesting that the dysregulation of

the DA system revealed by this challenge might represent a state

rather than a trait factor This exaggerated response of the DA

sys-tem to amphetamine exposure did not appear to be a nonspecific

effect of stress, as elevated anxiety before the experiment was not

associated with a larger amphetamine effect Furthermore,

nonpsy-chotic subjects with unipolar depression, who reported levels of

anxiety similar to the schizophrenic patients at the time of the scan,

showed normal amphetamine-induced displacement of [123

I]-IBZM (52)

These findings were generally interpreted as reflecting a larger DA

release following amphetamine in the schizophrenic group Another

interpretation of these observations would be that schizophrenia is

associated with increased affinity of D2receptors for DA Over the past

few years, several D2receptor radiolabeled agonists such as [11C]-NPA

([11C]N-propyl-norapomorphine) and [11C]-PHNO have been

successfully developed, and studies using these agents in patients

with schizophrenia are needed to solve this issue (39,53–57)

Striatal Baseline Dopamine Activity

A limitation of the amphetamine challenge of imaging studies is that

they measure changes in synaptic DA transmission following a

non-physiological challenge (i.e., amphetamine) and do not provide any

information about synaptic DA levels at baseline (i.e., in the lenged state) Several laboratories have reported that, in rodents,acute depletion of synaptic DA is associated with an acute increase in

unchal-the in vivo binding of [11C]-raclopride or [123I]-IBZM to D2tors (for review, see Laruelle [47]) The increased binding was

recep-observed in vivo but not in vitro, indicating that it was not due to

receptor up-regulation (58), but to removal of endogenous DA andunmasking of D2receptors previously occupied by DA The acute

DA depletion technique was developed in humans using MPT, toassess the degree of occupancy of D2receptors by DA (58–61) Usingthis technique, higher occupancy of D2 receptors by DA wasreported in patients with schizophrenia experiencing an episode ofillness exacerbation, compared to healthy controls (28) Again,assuming normal affinity of D2receptors for DA, the data are consis-tent with higher DA synaptic levels in patients with schizophrenia.Increased D2receptor stimulation by DA at intake, as measured withthe MPT paradigm, was predictive of rapid clinical response toantipsychotic drugs (28) This finding illustrates the potential ofmolecular imaging to predict treatment response (Fig 10.1).Striatal Dopamine Transporters

The data reviewed above are consistent with higher DA output inthe striatum of patients with schizophrenia, which could beexplained by increased density of DA terminals Since striatal DATare exclusively localized on DA terminals, this question was investi-gated by measuring binding of [123I]--CIT (62) or [18F]-CFT (63)

in patients with schizophrenia Both studies reported no differences

in DAT binding between patients and controls In addition, Laruelle

et al (62) reported no association between amphetamine-induced

DA release and DAT density Thus, the increased presynaptic output

518 Principles and Practice of PET and PET/CT

FIGURE 10.1 Imaging dopamine transmission and prediction of

therapeutic response in schizophrenia Relationship between dopaminesynaptic levels at intake, as estimated by the -methyl-para-tyrosine

I]-IBZM binding potential (BP), and the decrease

in positive symptoms measured after 6 weeks of antipsychotic ments Patients with high DA synaptic levels showed a larger decrease

treat-in positive symptoms followtreat-ing treatment than patients with DA levelssimilar to controls (effect ofMPT on [123

I]-IBZM BP in control jects was 9%  7%) (From Abi-Dargham A, Rodenhiser J, Printz D, et al.Increased baseline occupancy of D2 receptors by dopamine in schizo-

sub-phrenia Proc Natl Acad Sci U S A 2000;97(14):8104–8109, with

permission.)