Ebook Textbook of clinical neuropsychology (2/E): Part 2

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Cognitive Functions in Adults With Central Nervous System

and Non-Central Nervous System Cancers

Denise D Correa and James C Root

23

Introduction

Cognitive dysfunction is common in many cancer patients

and can be related to the disease and to treatment with

che-motherapy and/or radiotherapy (RT) The

neuropsychologi-cal domains aff ected and the severity of the defi cits may vary

as a result of disease and treatment type, but diffi culties in

executive functions, motor speed, and learning, and retrieval

of information are the most prevalent In a signifi cant

num-ber of cancer patients, changes in cognitive functions

inter-fere with their ability to resume work and social activities at

prediagnosis levels

There has been an increase in the number of studies and

clinical trials that incorporate standardized cognitive

out-come measures for the assessment of patients with cancer

of the central nervous system (CNS; see Correa, 2006;

Taphoorn & Klein, 2004) New developments have been

described in the study of the cognitive side eff ects of

che-motherapy for non-CNS cancers (Correa & Ahles, 2008)

These lines of research have provided valuable information

about the incidence of cognitive dysfunction in patients with

various cancers, and the contribution of treatments involving

diff erent regimens and modalities Studies have also begun

to investigate the underlying mechanisms that may

contrib-ute to the neurotoxicity of RT and chemotherapy (Dietrich,

Han, Yang, Mayer-Proschel, & Noble, 2006; Nordal &

Wong, 2005) and interventions to minimize or prevent both

structural and functional damage associated with these

regi-mens have been proposed (Gehring, Sitskoorn, Aaronson, &

Taphoorn, 2008)

The current chapter reviews studies involving patients

with brain tumors and breast cancer, considering that

most of the research has been conducted in these patient

groups Of note, other emerging areas of study include

cognitive dysfunction associated with androgen ablation

for prostate cancer (Jamadar, Winters, & Maki, 2012;

Nelson, Lee, Gamboa, & Roth, 2008), chemotherapy for

ovarian cancer (Correa & Hess, 2012; Correa et al., 2012;

Correa, Zhou, Thaler, Maziarz, Hurley, & Hensley, 2010),

and high-dose chemotherapy and stem cell

transplanta-tion for hematological cancers (Correa et al., 2013; Syrjala

et al., 2011; Syrjala, Dikmen, Langer, Roth-Roemer, &

Abrams, 2004)

Brain Tumors

Primary brain tumors are classifi ed by their predominant histologic appearance and location; they account for less than 2% of all cancers Gliomas are the most common primary tumors accounting for approximately 40% of all CNS neoplasms (Greenberg, Chandler, & Sandler, 1999) High-grade gliomas (WHO Grade III-IV) include glioblas-toma multiforme, anaplastic astrocytomas, anaplastic oligo-dendrogliomas, and anaplastic mixed gliomas Low-grade gliomas (WHO Grade I-II) include astrocytomas, oligoden-drogliomas, and mixed gliomas Other less frequent brain tumors are primary CNS lymphoma (PCNSL), ependymo-mas, meningiomas, and medulloblastomas (Bondy, El-Zein, Wrench, 2005) Brain metastases are also common intracra-nial tumors in adults (Mehta & Tremont-Lukas, 2004)

Figure 23.1 Coronal and axial MRIs showing a brain tumor

involving cortical and subcortical regions

As eff ective treatment interventions have increased

sur-vival, there has been greater awareness that many brain tumor

patients experience cognitive dysfunction, despite adequate

disease control (Poortmans et al., 2003) This dysfunction

can be related to both the disease and its treatment including

surgery, RT, and chemotherapy The side eff ects of

medica-tions such as corticosteroids and antiepileptics often

contrib-ute to or exacerbate these cognitive diffi culties The relevance

of including cognitive and quality of life (QoL) evaluations

as outcome variables in neuro-oncology research has been

increasingly recognized (Johnson & Wefel, 2013; Meyers &

Brown, 2006) and the National Cancer Institute (NCI) Brain

Tumor Progress Review Group report has recommended that

routine cognitive and QoL assessment become the standard

care for patients with brain tumors (BTPRG, 2000) Meyers

and Brown (2006) published guidelines for the

neuropsycho-logical assessment of patients with brain tumors within the

context of clinical trials The suggested core

neuropsycho-logical test batteries include standardized instruments with

demonstrated sensitivity to the neurotoxic eff ects of cancer

treatment and include tests of attention, executive functions,

learning, and retrieval of new information, and graphomotor

speed (Correa et al., 2004; Wefel, Kayl, & Meyers, 2004) The

feasibility of incorporating a relatively brief cognitive test

battery in multi-institutional clinical trials within the context

of the Radiation Therapy Oncology Group (RTOG) has also

been demonstrated (Meyers et al., 2004; Regine et al., 2004)

Recent longitudinal studies documented that along with

age, histology, and performance status, cognitive functioning

is a sensitive and important factor in clinical trials involving

patients with high-grade tumors (Reardon et al., 2011; Wefel

et al., 2011) Performance on a test of verbal memory was

independently and strongly related to survival after

account-ing for age, performance status, histology, extent of resection,

number of recurrences, and time since diagnosis in patients

with glioblastoma or anaplastic astrocytoma (Meyers, Hess,

Yung, & Levin, 2000) Neuropsychological test performance

predicted survival in patients with metastases and

leptomen-ingeal disease (Meyers et al., 2004), and glioblastomas

(John-son, Sawyer, Meyers, O’Neill, & Wefel, 2012; Klein et al.,

2003) Cognitive decline preceded radiographic evidence of

tumor progression by several weeks in glioma patients

(Arm-strong, Goldstein, Shera, Ledakis, & Tallent, 2003; Brown

et al., 2006; Meyers & Hess, 2003) However, these results are

interpreted with caution considering that some studies had

missing data, lacked a control group, and did not account

for the possible eff ects of medications (Mauer et al., 2007)

Disease and Treatment Effects

Seizures, headaches, increased intracranial pressure, focal

neurological signs, and cognitive impairment are common

presenting symptoms in patients with brain tumors Several

studies documented cognitive impairment at diagnosis and

prior to RT or chemotherapy in patients with high-grade

gliomas (Klein et al., 2001), low-grade gliomas (Klein et al., 2002), and PCNSLs (Correa, DeAngelis, & Shi, 2007) Cog-nitive diffi culties present at the time of diagnosis are often related to the location of the tumor (Klein et al., 2001), but

a diff use pattern of defi cits has also been reported sen, Goldman, Dahlborg, & Neuwelt, 1992) Rate of tumor growth is a predictor of cognitive impairment, as slow-grow-ing tumors (e.g., low-grade gliomas) are often associated with less severe cognitive dysfunction than rapidly growing tumors (e.g., high-grade gliomas) (Anderson, Damasio, & Tranel, 1990; Hom & Reitan, 1984) Tumor type or volume has not been found to predict cognitive performance (Kayl & Meyers, 2003)

Surgical resection can be associated with transient rological and cognitive defi cits due to damage to tumor-surrounding tissue and edema (Bosma et al., 2007; Duff au, 2005), with impairments often consistent with tumor loca-tion (Klein, 2012) Intraoperative stimulation mapping has been used in patients undergoing surgical resection for glio-mas, and a recent meta-analysis (De Witt Hamer, Robles, Zwinderman, Duff au, & Berger, 2012) showed that the pro-cedure was associated with fewer neurological defi cits and allowed for more extensive resections However, the incidence and extent of cognitive dysfunction related to tumor surgi-cal resection is unknown, given the relatively limited number

neu-of studies including pre- and postsurgical cal evaluations In addition, the specifi c contribution of the tumor to cognitive performance is diffi cult to ascertain considering that the majority of patients receive corticoste-roids and antiepileptic medications following diagnosis and perioperatively Steroids may improve cognitive defi cits due

neuropsychologi-to resolution of edema (Klein et al., 2001), but can also be associated with transient mood disturbance and working memory diffi culties (Bosma et al., 2007; Lupien, Gillin, & Hauger, 1999) Antiepileptics can disrupt some aspects of cognitive functions in brain tumor patients, particularly graphomotor speed and executive abilities (van Breemen, Wilms, & Vecht, 2007)

Whole-Brain and Conformal Radiotherapy

MECHANISMS OF CNS INJURY

The pathophysiological mechanisms of radiation injury involve interactions between multiple cell types within the brain including astrocytes, endothelial cells, microglia, neu-rons, and oligodendrocytes (Greene-Schloesser, Moore, & Robbins, 2013; Greene-Schloesser et al., 2012) Suggested mechanisms include depletion of glial progenitor cells and perpetuation of oxidative stress (Tofi lon & Fike, 2000) Radiation may diminish the reproductive capacity of the O-2A progenitors of oligodendrocytes, disrupting the nor-mal turnover of myelin Blood-vessel dilatation and wall thickening with hyalinization, increased blood-brain barrier

(BBB) permeability due to endothelial cell loss and

apopto-sis, and a decrease in vessel density have also been

hypoth-esized to lead to white matter necrosis (Nordal & Wong,

2005; Warrington et al., 2013) The extent to which radiation

damage is due to direct toxicity on cells or secondary to

deleterious eff ects on the vasculature remains to be

eluci-dated (Noble & Dietrich, 2002) Progressive demyelination

may take months to cause symptoms because of the slow

turnover of oligodendrocytes, contributing to the latency in

onset of neurotoxicity and its progressive nature In

addi-tion, RT achieves therapeutic eff ects in part through DNA

damage by introducing interstrand DNA and DNA-protein

crosslinks, single- and double-stranded DNA breaks,

meth-ylation, oxidation, and by increasing formation of

reac-tive oxygen species (ROS) Increased numbers of reacreac-tive

astrocytes and microglia have been shown to produce ROS,

proinfl ammatory cytokines, and growth factors that may

cause progressive infl ammatory injury (Kim, Brown,

Jen-row, & Ryu, 2008) The accumulation of DNA damage in

neuronal cells, when unrepaired, can lead to the

transcrip-tion of defective proteins, apoptosis, and neurodegeneratranscrip-tion

(Fishel, Vasko, & Kelley, 2007) Recent animal and human

studies have documented that RT, chemotherapy, and

corti-costeroids can disrupt hippocampal neurogenesis (Dietrich

et al., 2006; Fike, Rosi, & Limoli, 2009; Monje & Dietrich,

2012; Monje et al., 2007) RT produces elevation of infl

am-matory cytokines in the brain (Lee, Sonntag, Mitschelen,

Yan, & Lee, 2010), and infl ammation surrounding neural

stem cells may contribute to neurogenesis inhibition (Monje,

Toda, & Palmer, 2003) RT-induced apoptosis and a decline

in neurogenesis in the subgranular zone of the dentate gyrus

were associated with defi cits in hippocampal-dependent

tasks in some studies (Madsen, Kristjansen, Bolwig, &

Wortwein, 2003; Raber et al., 2004)

CLINICAL FINDINGS

Radiation encephalopathy has been classifi ed into three

phases according to the time between the administration of

RT and the development of symptoms (DeAngelis & Posner,

2009) These are described as acute, early delayed, and late

delayed Acute encephalopathy develops within days of RT

and the most common symptoms are nausea, headache, and

worsening of neurological signs Disruption of the BBB by

endothelial apoptosis, increased cerebral edema, and

intra-cranial pressure have been suggested as underlying

mecha-nisms Early delayed eff ects occur within a few weeks to six

months following RT and are reversible in most cases

Leth-argy, somnolence, and resurgence of neurological signs, and

a transient decline in cognitive functioning may occur, but

these factors are not predictive of delayed cognitive defi cits

Transient white matter hyperintensity suggesting

demyelin-ation may be seen on magnetic resonance imaging (MRI),

and are thought to be related to BBB disruption or injury to

oligodendrocytes

The late-delayed eff ects of RT become apparent a few months to many years after treatment, and often produce irreversible and progressive damage to the CNS (Sheline, Wara, & Smith, 1980) Risk factors for developing delayed RT-induced brain injury include greater volume of radi-ated tissue, higher total dose of RT (> 2 Gy dose per frac-tion), concomitant administration of chemotherapy, age greater than 60 years, and presence of comorbid vascular risk factors (Behin, 2003; Constine, Konski, Ekholm, McDonald,  & Rubin, 1988; DeAngelis & Posner, 2009) MRI typically shows hyperintensities in periventricular and subcortical white matter, and these changes are often more pronounced in older patients (see Figure 23.2 ) Radiation-induced microbleeds were recently described in patients with gliomas treated with external-beam RT (Bian, Hess, Chang, Nelson, & Lupo, 2013) In a diff usion tensor imaging (DTI) study, there was evidence of early dose-dependent progressive demyelination and axonal degeneration after RT, and subse-quent diff use dose-independent demyelination (Chapman

et al., 2013; Nagesh et al., 2008) Chapman et al (2013) used DTI to study 14 patients with brain metastases before and after whole-brain RT ± chemotherapy The results showed regional variation in white matter changes post-RT, with a signifi cant decrease in fractional anisotropy in the cingulate and fornix A study using positron emission tomography (PET) in a small cohort of brain tumor patients reported dose-dependent reduction in glucose metabolism in brain regions that received greater than 40 Gy at three- and six-month follow-ups; these changes correlated with decreased performance on tests of problem solving and cognitive fl ex-ibility (Hahn et al., 2009)

A substantial number of brain tumor patients treated with

RT experience cognitive dysfunction that varies from mild

to severe, and it is currently considered the most frequent complication among long-term survivors (Behin, 2003) The peak of neurocognitive diffi culties resulting from RT occurs

Figure 23.2 T1-weighted axial MRIs showing periventricular

white matter abnormalities in a 50-year-old man six years post treatment with high-dose chemotherapy and whole-brain radiotherapy

approximately six months to two years after treatment

com-pletion, and its incidence is proportional to the percentage

of patients with disease-free survival (DeAngelis, Yahalom,

Thaler, & Kher, 1992) The variability in the documented

fre-quency of RT-induced cognitive defi cits may be partially

asso-ciated with the insensitivity of the methods of assessment used,

duration of follow-up, retrospective nature of many studies,

inclusion of patients treated with diff erent regimens, and

popu-lation discrepancies In addition, the high incidence of tumor

recurrence and short-term survival in patients with high-grade

malignancies have often been considered confounding variables

that hampered the ability to quantify the frequency, onset, and

course of the delayed cognitive eff ects of RT (Crossen,

Gar-wood, Glatstein, & Neuwelt, 1994) A review of the literature

suggests that the pattern of neuropsychological impairments

associated with the delayed eff ects of whole-brain RT is diff use

(Duff ey, Chari, Cartlidge, & Shaw, 1996), and most consistent

with frontal-subcortical dysfunction with defi cits in attention,

executive functions, learning and retrieval of new information,

and graphomotor speed (Archibald et al., 1994; Crossen et al.,

1994; Salander, Karlsson, Bergenheim, & Henriksson, 1995;

Scheibel, Meyers, & Levin, 1996; Taphoorn & Klein, 2004;

Wefel, Kayl, et al., 2004; Weitzner & Meyers, 1997)

In recent years, conformal RT that includes the area of the

tumor and surrounding margin has supplanted whole-brain

RT in the treatment of gliomas due to equivalent effi cacy and

reduced neurotoxicity (DeGroot, Aldape, & Colman, 2005)

Some studies suggest that conformal RT is associated with

less severe cognitive dysfunction than whole-brain RT (Torres

et al., 2003), but most studies were retrospective and revealed

variable outcomes ranging from no morbidity to marked

cognitive defi cits (Armstrong et al., 2000; Armstrong et al.,

2002; Postma et al., 2002; Surma-aho et al., 2001; Taphoorn

et al., 1994) Recent research reported that radiation dose to

specifi c regions, such as the right temporal lobes and the

hip-pocampi, may be more predictive of cognitive impairment

than total RT dose (Peiff er et al., 2013) Similarly, a

prospec-tive study of patients with low-grade or benign tumors treated

with fractionated stereotactic RT reported a dose-response

relationship, with higher RT doses to the hippocampi

show-ing an association with impairment in word-list delayed recall

(Gondi, Hermann, Mehta, & Tome, 2013)

Chemotherapy Alone or Combined

WithRadiotherapy

The pathophysiological mechanisms of

chemotherapy-induced CNS damage are not well understood Candidate

mechanisms include demyelination, secondary infl ammatory

response, oxidative stress, and DNA damage; immune

dys-regulation; and microvascular injury (Ahles & Saykin, 2007)

There is increasing evidence that chemotherapy has direct

toxic eff ects on progenitor cells, oligodendrocytes, white

mat-ter, gliogenesis, and neurogenesis (Dietrich, 2010) Increased

cell death and decreased cell division in the subventricular

zone and in the dentate gyrus of the hippocampus have been reported in mice (Dietrich et al., 2006; Dietrich, Monje, Wefel, & Meyers, 2008); neural progenitor cells and oligo-dendrocytes are particularly vulnerable

Neurotoxicity has been reported after high-dose regimens with procarbazine, lomustine, and vincristine (PCV) chemo-therapy (Postma et al., 1998), and after high-dose methotrex-ate (HD-MTX) and high-dose cytarabine, particularly if RT

is administered before or during chemotherapy (DeAngelis & Shapiro, 1991; see Figure 23.2 ) Chemotherapy administered intrathecally is more likely to cause CNS toxicity than when

it is applied systemically Combined treatment with RT and chemotherapy may have a synergistic eff ect (Keime-Guibert, Napolitano, & Delattre, 1998), as chemotherapy agents may interfere with the same cellular structures as radiation and may act as a radiosensitizer Radiation may alter the distri-bution kinetics of chemotherapeutic agents in the CNS by increasing the permeability of the BBB, aff ecting the abil-ity of arachnoid granulations or choroid plexus to clear the drug, or interrupting the ependymal barrier to allow drugs in the cerebrospinal fl uid to enter the white matter Finally, RT-induced cellular changes may allow greater amounts of the drug to enter nontumor cells or less of it to exit The interac-tions between RT and HD-MTX are the most clearly dem-onstrated (Keime-Guibert et al., 1998), and nonenhancing, confl uent lesions in the periventricular and subcortical white matter have been documented on MRI studies (Correa et al., 2004; Keime-Guibert et al., 1998) Decrease in white matter density in the corpus callosum, hippocampal cell death, and memory impairments were reported in rats treated with HD-MTX (Seigers et al., 2009) Carmustine, cyclophosphamide, cisplatin, cytarabine, thiotepa, and methotrexate were found

to be associated with neurotoxicity, with changes in cortical and subcortical brain regions (Rzeski et al., 2004) Defi cits

in spatial and nonspatial memory have been described after administration of methotrexate and 5-fl uorouracil in mice (Winocur, Vardy, Binns, Kerr, & Tannock, 2006) However, the cognitive side-eff ects of chemotherapy are often diffi cult

to determine in brain tumor patients as most also receive RT

in the course of their treatment

Variation in genetic polymorphisms may increase the susceptibility to cognitive dysfunction following RT ± che-motherapy In a recent cross-sectional study (Correa, et al., 2013), brain tumor patients with at least one Apolipoprotein

E (APOE) є-4 allele had signifi cantly lower scores in verbal learning and delayed recall, and marginally signifi cant lower scores in executive function, in comparison to non-carriers

symp-neurological signs (Greenberg et al., 1999) The majority of

patients undergo surgical tumor resection and receive a

com-bined modality regimen of RT and chemotherapy; recent

trials involving glioblastoma patients have also included

anti-angiogenic therapy with bevacizumab (Gilbert et al., 2014)

The median survival time is less than two years for patients

with glioblastomas, and two to three years for anaplastic

astrocytomas (Carson, Grossman, Fisher, & Shaw, 2007;

Stupp et al., 2005) Cognitive impairment in patients with

high-grade gliomas is multifactorial and includes the tumor

and the adverse eff ects of treatment Disease recurrence and

short-term survival have been considered confounding

vari-ables that limit the ability to quantify the frequency, onset,

and course of the delayed cognitive eff ects of RT and

che-motherapy Several studies have suggested that tumor

pro-gression contributes signifi cantly to cognitive decline, and

that relatively stable performance is seen in patients without

recurrent disease (Brown et al., 2006)

Klein et al (2001) studied cognitive functioning in 61

patients with high-grade gliomas following surgery or biopsy,

and included comparison groups of 50 patients with lung

cancer and age-matched healthy controls As compared to

healthy controls, cognitive impairment (i.e., attention and

executive functions) was evident in all glioma patients and

52% of lung cancer patients The use of antiepileptic

medica-tion was associated with working memory defi cits Patients

with tumors in the right hemisphere had greater diffi culties in

visuospatial tests, and patients with left hemisphere tumors

showed greater susceptibility to interference and slower

visual scanning Bosma et al (2007) assessed cognitive

func-tions at eight- and 16-month intervals after RT in 32 and 18

high-grade glioma patients, respectively Patients with tumor

progression had a more pronounced cognitive decline (i.e.,

psychomotor speed, executive functions) than patients who

remained stable; however, the decline was also considered

to be in part related to the side eff ects of antiepileptics and

corticosteroids However, in a recent study of patients with

high-grade tumors (de Groot et al., 2013) treated with

leve-tiracetam ( n = 35), valproic acid or phenytoin ( n = 38), or no

antiepileptics ( n = 44), there were no signifi cant diff erences

on cognitive test performance between patients on newer

compared to older antiepileptics and patients receiving no

medication six weeks postsurgery; there was a benefi cial

eff ect of both antiepileptics on verbal memory

Hilverda et al (2010) studied 13 patients with

glioblas-toma multiforme treated with RT and temozolomide with

no evidence of disease progression Neurocognitive

evalu-ations were performed after surgery, six weeks post-RT

and concomitant temozolomide, and after three cycles of

adjuvant temozolomide in progression-free patients The

results showed that at baseline, 11 patients had impaired

attention, information processing speed, and executive

functions in comparison to healthy controls At the fi rst

follow-up, four patients improved, four deteriorated, and the

others were relatively stable At the last follow-up, cognitive

performance remained stable in all domains for 11 patients, with one patient improving and one patient declining in the interim The authors concluded that cognitive functions are likely to be relatively stable in the absence of disease pro-gression Froklage and colleagues (2013) assessed cognitive functions and radiological abnormalities in patients with newly diagnosed high-grade gliomas treated with chemo-radiation followed by adjuvant temozolomide Neuropsy-chological assessments were conducted before treatment

and prior to adjuvant temozolomide ( n = 33), during and after temozolomide ( n = 25 and 17, respectively), and three and seven months post treatment completion ( n = 9 and 5,

respectively); patient dropout was primarily due to disease progression In comparison to matched healthy controls, 63% of patients had defi cits in executive functions, process-ing speed and working memory at baseline Approximately 70% of the patients remained stable during the follow-up period, and most of the patients who declined had tumor progression Cerebral atrophy and white matter hyperintensi-ties developed or worsened in approximately 45% of patients during follow-up

Brown et al (2006) reported the results of prospective Mini-Mental Status Examinations (MMSE) in 1, 244 high-grade tumor patients who participated in the North Central Cancer Treatment Group treatment trials, which used radia-tion and nitrosurea-based chemotherapy The proportion of patients without tumor progression who had signifi cant cog-nitive deterioration ranged from 13% to 18%, and remained stable over the 24-month follow-up period; a decline in MMSE scores was a predictor of more rapid time to tumor progression and preceded radiographic changes Corn et al (2009) examined QoL and mental status in 203 patients with glioblastoma multiforme within the context of a Phase I/

II study of the RTOG to assess the impact of dose tion conformal RT Patients were administered the MMSE

escala-at the start and escala-at the end of radiescala-ation, and escala-at four-month intervals subsequently The results showed a decline in the MMSE over the follow-up period, and this was considered

to be at least in part related to RT However, considering the demonstrated low sensitivity of cognitive screening measures (e.g., MMSE) to detect cognitive dysfunction in brain tumor patients (Meyers & Wefel, 2003), the fi ndings of these two large studies may represent an underestimation

A Phase II trial evaluated cognitive functioning in 167 patients with recurrent glioblastoma treated with bevaci-zumab-based therapy (Wefel et al., 2011) Patients with objective response to treatment or progression free survival greater than six months had stable median cognitive test scores across the 24-month follow-up, but patients with evi-dence of progressive disease exhibited cognitive decline In a prospective study of newly diagnosed glioblastoma patients treated with temozolomide, hypofractionated stereotactic

RT and bevacizumab, 37 patients underwent longitudinal neuropsychological evaluations (Correa et al., 2011) Lin-ear mixed model analyses showed a signifi cant decline in

set-shifting and verbal learning ( p < 0.05) from baseline to

the four-month follow-up, and performance remained stable

or improved slightly at subsequent intervals Visuospatial

memory was stable at four months, but showed a trend

toward a decline at subsequent follow-ups The decline in

executive functions and memory in the early phase of

treat-ment was thought to be related to the acute eff ects of RT

In a recent, large clinical trial for patients with newly

diag-nosed glioblastoma comparing the effi cacy of standard

chemo-radiation, maintenance temozolomide, and placebo

or bevacizumab, cognitive evaluations were performed

lon-gitudinally in patients without disease progression (Gilbert

et al., 2014) The initial results suggested that patients

ran-domized to bevacizumab, compared to placebo, experienced

greater decline over time in executive functions and

informa-tion processing speed, suggesting either bevacizumab-related

neurotoxicity or unrecognized tumor progression In a recent

study of long-term survivors of anaplastic

oligodendroglio-mas treated with RT versus RT and procarbazine, lomustine

and vincristine (Habets et al., 2014), a variable pattern of

cognitive impairment was seen in 75% of patients who were

progression free, regardless of initial treatment type

Low-Grade Tumors

Low-grade gliomas are slow-growing infi ltrative tumors most

common in young and middle-aged adults, and the majority

of patients present with seizures and headaches (Greenberg

et al., 1999) The median survival ranges from fi ve to ten

years, and these tumors invariably progress to more

aggres-sive high-grade gliomas (Shaw et al., 2002) Treatment

inter-ventions remain controversial regarding the optimal timing

of surgical intervention, RT, and chemotherapy (Cairncross,

2000; Kiebert et al., 1998; Shaw et al., 2002; Soffi etti et al.,

2010) Several studies that documented cognitive

dysfunc-tion in low-grade glioma patients found that the tumor itself,

rather than RT, was the primary contributing factor (Laack

et al., 2003; Taphoorn et al., 1994; Torres et al., 2003)

How-ever, studies including long-term survivors reported that

both partial and whole-brain RT was associated with

cog-nitive dysfunction several years after treatment completion

(Douw et al., 2009), and a decline in nonverbal memory was

evident in some studies Tumor-related epilepsy and the side

eff ects of antiepileptic medications also contribute to

cog-nitive dysfunction in these patients (Klein, 2012)

Method-ological problems including diff erences in the sensitivity of

the neuropsychological measures administered, retrospective

designs, and the inclusion of patients with high- and

low-grade tumors, and patients treated with partial and

whole-brain RT (Imperato, Paleologos, & Vick, 1990; Kleinberg,

Wallner, & Malkin, 1993; Torres et al., 2003) may account

for some of the variability of the fi ndings in the literature

A recent report by the Response Assessment in

Neuro-Oncology group (RANO), recommended that standardized

assessments of cognitive functions and QoL be incorporated

in clinical trials involving low-grade glioma patients (van den Bent et al., 2011) The characterization of tumor- and treatment-related cognitive dysfunction in patients with low-grade tumors is particularly relevant given the relatively prolonged survival and the controversy in the eff ectiveness

of early treatment

A cross-sectional study assessed cognitive outcome in 195 low-grade glioma patients (104 treated with RT 1–22 years prior to enrollment) compared to 100 low-grade hematologi-cal cancer patients, and 194 healthy controls (Taphoorn et al., 1994) Glioma patients completed the cognitive evaluation

at a mean of six years after diagnosis, and obtained lower test scores than the cancer control group on psychomotor speed, visual memory, and executive functions Although the authors concluded that the tumor had the most detrimental eff ects on cognition, decreased verbal and visual memory was evident in patients who received RT in daily fractions exceeding 2 Gy, and some of the cognitive test scores declined over time only among those treated with RT Antiepileptic treatment was associated with more pronounced cognitive dysfunction A follow-up study (Douw et al., 2009) included

65 of these patients who underwent a neuropsychological re-evaluation at a mean of 12 years (range 6–28 years) after the initial assessment Patients who received RT showed a decline in attention, executive function, and information processing speed, regardless of fraction dose White matter hyperintensities and cortical atrophy correlated with worse cognitive test performance Surma-aho et al.(2001) assessed cognitive functioning in low-grade glioma patients approxi-

mately seven years post-RT ± chemotherapy ( n = 28) or gical resection alone ( n = 23); 19 patients had whole-brain

sur-RT and nine had focal sur-RT The results showed that patients treated with RT had signifi cantly lower scores in percent retention of visual materials and estimated Performance IQ, and more extensive periventricular white matter abnormali-ties on MRI, in comparison to patients who did not receive

RT The authors concluded that RT increased the risk for cognitive impairment and leukoencephalopathy in patients with low-grade tumors

Correa et al (2007) studied cognitive functions in 40 patients with low-grade gliomas: 24 patients had surgery only, and 16 had conformal RT ± chemotherapy Patients treated with RT ± chemotherapy had lower scores in atten-tion and executive functions, psychomotor speed, verbal and nonverbal memory, and naming than untreated patients

In addition, patients who completed treatment at intervals greater than three years had signifi cantly lower scores in non-verbal memory Antiepileptic polytherapy, treatment history, and disease duration contributed to reduced psychomotor speed; 62% of treated patients had white matter disease on MRI, whereas only 10% of the untreated patients had such changes In a subsequent study (Correa et al., 2008), 25 of these patients completed additional cognitive follow-ups The results showed a mild decline in nonverbal memory

12 months after the initial evaluation regardless of treatment

status; scores remained one standard deviation below

norma-tive values in other cogninorma-tive domains Among the 16 patients

who completed a subsequent evaluation (12–27 months later),

there was improvement in untreated patients, but a decline in

some aspects of executive function in patients treated with RT

± chemotherapy Disease duration and treatment history were

thought to contribute to the pattern of fi ndings

Armstrong et al (2000) assessed cognitive functions

prospectively in 20 patients with low-grade tumors treated

with conformal RT A decrement in verbal memory retrieval

was evident during the early delayed period following RT

with improvement at longer intervals The long-term eff ects

of RT on cognition were examined in a subsequent study

involving 26 patients with low-grade tumors (Armstrong,

Stern, & Corn, 2001) A selective decline in learning and

recall of visual information fi ve years post-RT was detected

despite continued improvement up to that point Long-term

improvements were noted on tests of attention, executive

functions, and verbal recall The authors concluded that

partial RT was not associated with signifi cant delayed

cog-nitive impairments in this population In a recent study

(Gondi et al., 2013), 18 patients with low-grade or benign

tumors treated with fractionated stereotactic RT completed

a neuropsychological evaluation at baseline and 18 months

following treatment The results suggested that RT dose

greater than 7.3 Gy to 40% of the bilateral hippocampi was

associated with impairment on a list-learning delayed recall

test Alterations in functional connectivity using

magnetoen-cephalography have also been described recently in patients

with low-grade gliomas (Bosma et al., 2008)

Primary Central Nervous System

Lymphoma (PCNSL)

PCNSL is a rare infi ltrative tumor that develops most

fre-quently in the subcortical periventricular white matter, with

single lesions occurring in 60%–70% of patients and

multi-focal lesions in 30%–40% It is a disease of middle and late

adult life with a mean age at diagnosis of 60 years, and it is

slightly more common in men Focal neurological signs are

the most common presentation followed by psychiatric

symp-toms, headaches, and seizures (Batchelor et al., 2012;

Ruben-stein, Ferreri, & Pittaluga, 2008) The standard treatment for

PCNSL often includes HD-MTX regimens and whole-brain

RT Although this treatment approach is eff ective, with a

median survival of 30 to 60 months (DeAngelis et al., 2002),

it is associated with delayed neurotoxicity in most patients

(Correa et al., 2012; Poortmans et al., 2003; Thiel et al.,

2010) Delayed treatment-related cognitive dysfunction has

been recognized as a frequent complication among long-term

survivors, and may interfere with QoL (Correa et al., 2007)

Recent studies suggest that HD-MTX without RT can be

effi cacious in the treatment of PCNSL and diminish the risk

for delayed neurotoxicity (Juergens et al., 2010; Rubenstein

et al., 2013; Thiel et al., 2010) However, since disease relapse

is relatively common and some patients require salvage therapy, the optimal induction and consolidative therapy for PCNSL remains controversial The importance of assessing the incidence and extent of cognitive dysfunction associated with HD-MTX regimens with and without WBRT has been recognized by the International Primary CNS Lymphoma Collaborative Group (IPCG; (Abrey et al., 2005; Ferreri, Zucca, Armitage, Cavalli, & Batchelor, 2013) and guidelines for standardized cognitive assessments to be incorporated in clinical trials have been developed (Correa et al., 2007) A literature review indicated that cognitive function was evalu-ated systematically in a relatively limited number of studies, and methodological problems limited the understanding of the contribution of disease and treatments (Correa et al., 2007)

RT AND CHEMOTHERAPY REGIMENS

Studies involving patients treated with whole-brain RT and HD-MTX, or with whole-brain RT and chemotherapy with BBB disruption reported signifi cant cognitive impairment The pattern of cognitive defi cits was diff use and the domains disrupted included attention and executive functions, psy-chomotor speed, and learning and retrieval of new infor-mation Harder et al (2004) studied cognitive functions in

19 PCNSL patients at a mean of 23 months after treatment with HD-MTX followed by whole-brain RT In comparison

to a non-CNS-cancer control group, PCNSL patients had lower scores on verbal and nonverbal memory, attention, executive function, and motor speed Correa et al (2012) studied 50 PCNSL treated with whole-brain RT and HD-

MTX ( n = 24), or HD-MTX alone ( n = 26) between three and

54 months posttreatment Patients treated with whole-brain

RT and HD-MTX had impairments in selective attention and executive functions, verbal memory, and graphomo-tor speed across most cognitive domains; these were of suffi cient severity to interfere with QoL as more than 50% were not working due to their illness Patients treated with HD-MTX alone had signifi cantly higher scores on tests of selective attention and memory than patients treated with the combined modality regimen Patients with more exten-sive white matter disease on MRIs had lower scores on tests

of set-shifting and memory Thirty-three patients completed

an additional follow-up cognitive evaluation at a mean of 14–16 months after the initial visit The results suggested

no signifi cant changes on any of the cognitive tests among patients treated with whole-brain RT and HD-MTX, but patients who received HD-MTX alone obtained a signifi -cantly higher score on auditory attention Doolittle, Korfel,

et al (2013) studied neuropsychological functions and roimaging outcomes in 80patients with PCNSL evaluated at

neu-a medineu-an of 5.5 yeneu-ars (rneu-ange: 2 to 26 yeneu-ars) neu-after dineu-agnosis

Treatment modalities included: MTX ( n = 32), MTX (intra-arterial) in conjunction with BBB disruption ( n

HD-= 25), HD-MTX followed by high-dose chemotherapy and

autologous stem cell transplant (ASCT) (n = 8), and

HD-MTX followed by whole-brain RT ( n = 15); fi ve of these

patients also received high-dose chemotherapy and ASCT

prior to whole-brain RT Patients treated with HD-MTX

and whole-brain RT had signifi cantly lower mean scores in

attention, executive function, and motor speed than patients

treated with HD-MTX in conjunction with BBB disruption,

and all patients treated without WBRT combined Among

patients treated with BBB disruption chemotherapy, there

was a signifi cant improvement in executive functions and no

evidence of decline in other domains (Doolittle, Dosa, et al.,

2013) White matter abnormalities were more extensive in

the patients treated with RT The fi ndings were consistent

with other studies, suggesting increased risk for delayed

neu-rotoxicity following combined modality regimens However,

the retrospective nature of these studies limited the ability

to examine the specifi c contributions of the tumor and the

delayed eff ects of treatment

In a recent prospective study (Correa et al., 2009; Morris et

al., 2013), PCNSL patients treated with induction rituximab,

methotrexate, procarbazine, and vincristine (R-MPV)

fol-lowed by consolidation reduced-dose whole-brain RT (23.4

Gy) and cytarabine underwent cognitive evaluations prior to

treatment and up to four years after treatment completion

At baseline, impairments in selective attention, memory, and

motor speed were evident After induction chemotherapy,

there was a signifi cant improvement in executive function

and memory There was no evidence of signifi cant cognitive

decline during the follow-up period, except for motor speed

The preliminary fi ndings were interpreted as evidence that

cognitive dysfunction was primarily related to the disease,

and that the new treatment approach with low-dose RT may

not be associated with progressive cognitive decline

CHEMOTHERAPY REGIMENS

The studies that reported cognitive outcome in PCNSL

patients treated with HD-MTX alone or with BBB

disrup-tion chemotherapy without RT were mostly prospective

(Correa et al., 2007) Several studies documented cognitive

impairment prior to therapy in attention, executive functions,

memory, graphomotor speed, and language Posttreatment

follow-up intervals were variable across studies, but several

reported either stable or improved cognitive performance

Methodological problems in several of these studies,

how-ever, limited the ability to discern the specifi c contributions

of the disease and chemotherapy alone regimens to cognitive

dysfunction

Pels et al (2003) performed cognitive evaluations in 22

patients between four and 82 months after completion of

treatment with HD-MTX There was no evidence of decline

in attention, verbal memory, visual memory, word fl uency,

or visual-construction abilities in patients who had either a

partial or a complete response to treatment Fliessbach et

al (2005) assessed cognitive functions in 23 patients prior

to and up to a median of 44 months after treatment with HD-MTX (all patients were in disease remission) At the pretreatment baseline, impairments were evident in atten-tion and executive functions, verbal and nonverbal memory,

and word fl uency; these were classifi ed as mild ( z ≤ −1.5) in three patients, moderate ( z ≤ −2 and > −3) in ten, and severe ( z ≤ −3) in six patients At the last follow-up, impairment

(in at least one domain) was mild in fi ve patients, ate in fi ve, and severe in one; 12 patients had no defi cits Twenty-one patients improved, but scores remained in the low average range on tests of attention, non-verbal memory, and word fl uency The authors concluded that the cognitive defi cits were associated primarily with tumor and there was

moder-no treatment-related cognitive decline The most sensitive domains were attention, executive functions, and memory McAllister et al (2000) studied a cohort of 23 prior to and post BBB disruption chemotherapy (mean =16.5 months, SD

= 10.9) The results showed signifi cantly improved cognitive

functioning posttreatment (summary z -score) When

exam-ining individual tests, there was evidence of improvement

in intellectual functioning, learning, memory, attention, and visuospatial skills, with a nonsignifi cant trend demon-strated for executive functioning; seven patients had cogni-tive decline, mostly in motor speed Neuwelt et al (1991) studied 15patients before and one year after BBB disruption chemotherapy; nine patients were also seen for long-term follow-up (mean of 3.5 years after diagnosis) Focus of data

analysis was on the summary z -score, which ranged at

base-line from −2.59 to 0.46 with a mean of −1.1 (SD = 1.1) At the end of treatment, the summary score ranged from −1.45

to 0.26 with a mean of 0.35 (SD = 0.52), suggesting a nifi cant improvement in cognitive functioning from baseline

sig-As reported recently by Doolittle, Dosa, et al (2013), term follow-up of PCNSL patients at a median of 12years after BBB disruption chemotherapy indicated either stable

long-or improved cognitive functions

Metastatic Brain Tumors

Brain metastases are common and develop most often in patients with lung cancer (50%), followed by breast cancer (15%–20%) and melanoma (10%), and less frequently in other cancers (e.g., colorectal, kidney) (Lassman & DeAn-gelis, 2003) Patients may present with headaches, focal weakness, altered mental status, and seizures Standard treatment has involved surgical resection and external beam whole-brain RT; the median survival is four to six months (Lassman & DeAngelis, 2003) Recent randomized trials comparing stereotactic radiosurgery plus whole-brain RT versus whole-brain RT alone reported improvement in sur-vival with the addition of radiosurgery in patients with soli-tary metastases (Andrews et al., 2004; Ayoma et al., 2006) Temozolomide and radiosensitizers have also been added to the regimen recently (Abrey et al., 2001) Although whole-brain RT has been shown to improve tumor control across

several studies (Brown, Asher, & Farace, 2008) and to reduce

the development of subsequent metastases (Kocher et al.,

2011), the neurotoxicity of whole-brain RT, including

cog-nitive dysfunction, has been a concern A recent report by

RANO supports the inclusion of standardized assessments

of cognitive functions and QoL in clinical trials involving

patients with brain metastases (Lin et al., 2013)

Defi cits in memory and motor speed have been

docu-mented in patients with newly diagnosed or recurrent

metastases evaluated either during or after whole-brain RT

(Herman et al., 2003; Platta, Khuntia, Mehta, & Suh, 2010)

Several studies also documented cognitive dysfunction prior

to therapy, and Meyers et al (2004) reported that baseline

cognitive performance predicted survival in patients with

brain metastases A pilot study including 15 patients treated

with stereotactic radiosurgery alone (Chang et al., 2007)

doc-umented impaired executive function, manual dexterity, and

memory at baseline; 13 patients declined on one or more tests

at the one-month follow-up, and the fi ve long-term survivors

had stable or improved cognitive performance Welzel et al

(2008) studied memory functions prospectively in 44 patients

treated with prophylactic RT for small-cell lung cancer and

in patients with brain metastases treated with whole-brain

RT At baseline, lung cancer patients had lower memory

scores than patients with brain metastasis Verbal memory

decline was evident during RT in patients with metastases

only, but at the eight-week post-RT follow-up both groups

had memory impairment

Meyers et al (2004) studied cognitive outcome in the

con-text of a Phase II randomized trial involving 400 patients

with brain metastases treated with whole-brain RT alone

or in combination with motexafi n gadolinium At baseline,

91% of patients had impairment in one or more cognitive

domains, and 42% had impairment in four of eight tests

Optimal tumor control following treatment correlated with

preservation of cognitive function, and in a small group of

long-term survivors there was stable or improved

perfor-mance In a Phase III trial involving 554 patients with brain

metastasis (Mehta et al., 2009), the interval to neurocognitive

decline was prolonged in the group treated with whole-brain

RT and motexafi n gadolinium Serial neurocognitive

assess-ments were performed in the context of a randomized trial

involving patients with one to three brain metastases treated

with radiosurgery ( n = 30) versus radiosurgery plus

whole-brain-RT ( n = 28) (Chang et al., 2009) Patients treated with

radiosurgery plus whole-brain RT were signifi cantly more

likely to show a decline in verbal learning at four months

posttreatment than patients treated with radiosurgery alone

In a study of 208 brain metastases patients treated with

whole-brain RT (30 Gy) (Li, Bentzen, Renschler, & Mehta,

2007), the median time to decline in executive and motor

functions was longer in patients with a poor response to

treat-ment (i.e., less tumor shrinkage) In patients surviving more

than 15 months, reduced tumor size was correlated with

pre-served executive and motor functions, but not with memory

performance; a signifi cant decline in memory at four months posttreatment was noted In addition, the risk of delayed leukoencephalopathy was found to be signifi cantly higher for patients with brain metastases treated with radiosurgery and whole-brain RT relative to patients who had radiosurgery alone (Monaco et al., 2013) A recent review of randomized controlled studies involving patients treated with prophy-lactic RT, radiosurgery, and radiosurgery and whole-brain

RT suggested that whole-brain RT, particularly high-dose regimens (36 vs 25 Gy), was associated with a deleterious eff ect in memory, executive functions, and processing speed (McDuff et al., 2013)

Preventive or Treatment Interventions

There are no established preventive or therapeutic tions for cancer-treatment-related cognitive dysfunction Ghia et al (2007) developed a hippocampal-sparing inten-sity-modulated approach to whole-brain RT that limits the radiation dose to the hippocampus with the intent of reduc-ing the neurocognitive sequelae of RT Preliminary results from a clinical trial involving 113 patients with brain metas-tases (Gondi et al., 2013) showed that sparing the subgranu-lar zone of the hippocampus during whole-brain RT was associated with more preserved memory function at the four- and six-month posttreatment follow-ups, in comparison to historical controls treated with standard whole-brain RT; however, only 28 patients were available for the six-month assessment (Brown et al., 2013) In a randomized study, the potential protective eff ects of memantine versus placebo on cognitive function were evaluated in 508 patients with brain metastases receiving whole-brain RT (Brown et al., 2013) The results showed that patients treated with memantine had signifi cantly longer time to cognitive decline, and a reduced rate of decline in memory, executive function, and process-ing speed compared to placebo; however, attrition may have limited statistical power as only 29% of patients completed the 24-week assessment

Treatments that target the vascular mechanism of RT damage including hyperbaric oxygenation, anticoagulation, and aspirin have been attempted, but without clear benefi ts (DeAngelis & Posner, 2009) There is preliminary evidence suggesting that bevacizumab may reduce abnormal enhance-ment associated with necrosis, possibly through the removal

of VEGF-induced reactive vascularization (Torcuator et al., 2009) In a placebo-controlled, randomized study of bevacizumab for the treatment of RT necrosis in 14 brain tumor patients (Levin et al., 2011), there was a decrease in MRI enhancement and improvement in neurological symp-toms in all patients treated with bevacizumab A decrease in radiation necrosis on MRI following bevacizumab was also reported in 11 patients with brain metastases treated with stereotactic radiosurgery (Boothe et al., 2013) However, a recent review of the use of bevacizumab for the treatment of

RT necrosis suggested that although most studies reported

a reduction in radiographic volume of necrosis-associated

edema, a high rate of serious complications raised concerns

about this treatment approach (Lubelski, Abdullah, Weil, &

Marko, 2013)

Pharmacological treatments for RT-induced cognitive

dysfunction have been based primarily on therapies used for

other neurological disorders that cause similar symptoms

(Kim et al., 2008) Agents such as psychostimulants and

ace-tylcholinesterase inhibitors have been used to treat cognitive

dysfunction in patients with brain tumors Comprehensive

reviews of studies on interventions for this clinical

popula-tion indicated that there are several completed and ongoing

trials using these and other medications, as well as cognitive

rehabilitation and behavioral interventions (Gehring,

Aaron-son, Taphoorn, & Sitskoorn, 2010; Wefel, Kayl, et al., 2004)

A prospective open-label Phase II study was conducted to

assess the effi cacy of donepezil in the treatment of cognitive

dysfunction in 24 patients with primary brain tumors (Shaw

et al., 2006) After 24 weeks of treatment there was evidence

of improvement in attention, verbal and visual memory, in

mood, and QoL A recent open-label randomized pilot study

examined the effi cacy of four weeks of methylphenidate and

modafanil in 24 brain tumor patients either during or

fol-lowing treatment with RT or chemotherapy (Gehring et al.,

2012) The results showed a benefi cial eff ect of stimulant

treatment in speed of processing and executive functions

requiring divided attention, and on patient-reported fatigue

and QoL, regardless of the medication used However, the

results were interpreted with caution give the small sample

size and large proportion of dropouts A recent multicenter

double-blind placebo-controlled study including 37 patients

with primary brain tumors treated with modafi nil for six

weeks showed no benefi cial eff ects on cognitive function,

fatigue, or mood in comparison to placebo (Boele et al.,

2013)

The small number of studies using cognitive

rehabilita-tion in brain tumor patients suggests some benefi cial eff ects,

but problems with accrual and attrition and methodological

problems limit the evaluation of its effi cacy (Gehring et al.,

2010) In a study involving 13 brain tumor patients (Sherer,

Meyers, & Bergloff , 1997), there was a signifi cant increase

in functional independence in approximately half of the

patients following three to 12 weeks of training in the use

of compensatory strategies Locke et al (2008) compared

the feasibility of memory and problem solving training in

dyads of primary brain tumor patients and caregivers

ver-sus a no-intervention control group At the three-month

follow-up 50% of patients reported using the strategies,

but there was no signifi cant intervention eff ect on QoL and

functional capacity and not enough patients completed the

neuropsychological assessment Gehring et al (2008)

con-ducted a randomized controlled trial to assess the effi cacy of

computer-based attention training and compensatory skills

training in 140 patients with gliomas; patients were randomly

assigned to the intervention group or to a wait list control

group There was a signifi cant improvement in self-reported cognitive function but not on neuropsychological test per-formance immediately after completion of the seven-week program Conversely, at the six-month follow-up patients showed an improvement in attention and verbal memory, but not on self-reported cognitive function The prevention of cognitive defi cits with agents that may protect neurons from treatment-induced damage is an area of growing interest (Kim et al., 2008), and the potential neuroprotective eff ects

of lithium and other agents are under investigation (Gehring

et al., 2010; Khasraw, Ashley, Wheeler, & Berk, 2012; Wefel, Kayl, et al., 2004)

Non-CNS Cancers

Beyond the eff ects of primary CNS cancers on cognition, non-CNS cancer diagnosis and treatment has also been found to be associated with cognitive dysfunction Among primary cancers, breast cancer is relatively common, with approximately 124 per 100,000 new cases diagnosed each year, and a prevalence of approximately 2.8 million women currently diagnosed in the United States alone (http://seer.cancer.gov/statfacts/html/breast.html), with 89% survival rates of fi ve years or more Given its prevalence and survival rates, cognitive changes associated with breast cancer diag-nosis and treatment have been most widely studied In this section we review cross-sectional and longitudinal studies assessing neuropsychological outcome and self-reported cog-nitive dysfunction in individuals diagnosed with breast can-cer Contributions of structural and functional imaging that may help to clarify the underlying changes in brain structure and function following treatment are then discussed, fol-lowed by potential mechanisms by which treatments may exert an eff ect on the brain and cognition

While terms such as chemo-brain and chemo-fog would

indicate a primary role for chemotherapy, recent research has questioned whether chemotherapy exposure alone is either necessary or suffi cient for cognitive decline follow-ing treatment (Hurria, Somlo, & Ahles, 2007) Treatment varies with stage of disease but includes surgical resection potentially in combination with radiation treatment to the breast, adjuvant chemotherapy in later stages, and endocrine therapies depending on receptor characteristics of tumor cells Surgical resection alone (lumpectomy or mastectomy) may be performed in early stage disease in cases in which the tumor is relatively small and there is no evidence of extended disease either to the lymph nodes or other anatomical sites Adjuvant chemotherapy treatment, in which chemotherapy drugs are delivered following surgical resection, may be used

to prevent recurrence or in cases in which the disease is found

to extend, i.e., to have metastasized, beyond the primary site Radiation may be used to reduce the size of a tumor prior to resection, and to prevent recurrence following resection, as well as in later stages of the disease Hormonal therapies may

be used following primary treatment on an extended basis

in cases in which tumor cells are found to have a high

recep-tor count for either progesterone or estrogen; these therapies

work by reducing availability of estrogen and so lower the

promotion of tumor cells

Self-Reported Cognitive Changes

Following Treatment

Changes in cognitive function following treatment,

includ-ing slowinclud-ing, inattention, distraction, forgetfulness, diffi

cul-ties in multitasking, and language function, are commonly

reported by cancer survivors Early research found that

approximately half of cancer patients reported some change

in cognition at one point in their treatment (Cull, Stewart, &

Altman, 1995) Six or more months following treatment,

30% of lymphoma patients reported concentration diffi

-culties and 52% reported forgetfulness (Cull et al., 1996)

Schagen et al (1999) described persistent self-reported

diffi culties in concentration (31%) and memory (21%) in

breast cancer survivors at longer intervals Ahles et al

(2002) described self-reported diffi culties in concentration

and complex attention in survivors of breast cancer and

lymphoma up to ten years after chemotherapy Incidence

of self-reported cognitive dysfunction at similar intervals

was found in other studies surveying the eff ects of

treat-ment of diverse cancers on cognition (Castellon et al., 2004;

Downie, Mar Fan, Houede-Tchen, Yi, & Tannock, 2006;

Hermelink et al., 2007; Jansen, Dodd, Miaskowski,

Dowl-ing, & Kramer, 2008; Mehnert et al., 2007; Poppelreuter

et al., 2004; Schagen et al., 2008; Shilling & Jenkins, 2007;

van Dam et al., 1998)

Cross-Sectional Neuropsychological

Studies—Posttreatment

The fi rst studies to examine cognitive eff ects of treatment

were generally cross-sectional, comparing cancer patients

and healthy control groups, or comparing cancer patients

stratifi ed by treatment regimen In an early study

compar-ing high-dose chemotherapy, low-dose chemotherapy, and

healthy control groups two years after completion of

treat-ment, individuals treated with high-dose chemotherapy

performed signifi cantly worse in measures of attention,

psychomotor speed, visual memory, and motor function

than healthy controls, while the high-dose group performed

signifi cantly worse than the low-dose group only on a

mea-sure of reaction time (van Dam et al., 1998) In a study

examining breast cancer survivors approximately two years

following completion of cyclophosphamide, methotrexate,

and 5-fl uorouracil (CMF) chemotherapy treatment

com-pared with survivors treated with surgery and radiation

only, signifi cantly greater impairment was found in the

chemotherapy group in domains of psychomotor speed,

motor function, attention, mental fl exibility, and visual

memory (Schagen et al., 1999) Evidence for cognitive

eff ects at longer intervals was found by Ahles et al (2002)

at approximately fi ve years postdiagnosis, between therapy and no-chemotherapy groups in the domains of verbal memory and psychomotor speed While other stud-ies found similar diff erences between treatment groups and healthy controls (Yamada, Denburg, Beglinger, & Schultz, 2010), a subset found signifi cant diff erences only between cancer-diagnosed (regardless of treatment) and healthy control groups or normative data (Jim et al., 2009; Scher-wath et al., 2006), while a minority failed to fi nd any diff er-ence between treatments or health status (Donovan et al., 2005; Inagaki et al., 2007; Yoshikawa et al., 2005) The most

chemo-recent and largest study ( N = 196) of long-term eff ects of

chemotherapy exposure (mean = 20 years) found signifi cantly lower performance on measures of immediate and delayed verbal memory, psychomotor speed, and executive functioning in chemotherapy-treated subjects compared to healthy controls (Koppelmans et al., 2012)

The interpretation of these crosssectional studies and later ones is limited due to the absence of a pretreatment, base-line time point This is a signifi cant limitation since work following initial cross-sectional studies suggests that sig-nifi cant cognitive diff erences exist prior to treatment Wefel

et al (2004) found that 35% of women exhibited cognitive impairment prior to cancer treatment, specifi cally in verbal learning (18%) and memory function (25%) Ahles et al (2008) investigated pretreatment cognitive ability in healthy controls, and patients diagnosed with invasive (Stages 1–3) and noninvasive (Stage 0) breast cancer, and found signifi -cantly slowed reaction time in the invasive group compared

to healthy controls, and lower overall performance in the invasive group compared to the healthy and noninvasive patient groups While pretreatment, baseline diff erences remain poorly understood in regard to mechanism or etiol-ogy, that diff erences are present prior to treatment between groups requires that longitudinal assessments be conducted

to delineate specifi c treatment-related contributions to tive dysfunction

Longitudinal Neuropsychological Studies:

Pre- and Posttreatment

Given the potential for pretreatment cognitive dysfunction, longitudinal studies generally fi nd more modest declines in cognitive dysfunction than cross-sectional, posttreatment studies have reported These studies have generally found that a subset of patients are aff ected following treatment within a larger cohort of unaff ected individuals; as a result, rates of impairment or decline are more useful in assessing putative eff ects of treatment than reliance on group mean diff erences, since group means will tend to obscure subgroup diff erences Also problematic are widely varying assessment batteries and screening instruments, making aggregation of numerous studies in systematic reviews or meta-analyses diffi cult Despite these issues, available data do suggest

signifi cant treatment related eff ects found in longitudinal

studies, although a subset of studies have reported null

results

In an early longitudinal study using published

norma-tive data for comparison, Wefel et al (2004) found that

61% of chemotherapy treated patients exhibited a decline

in one or more cognitive domains, mainly consisting of

psychomotor speed, attention, and learning three weeks

following completion of treatment Shilling, Jenkins,

Mor-ris, Deutsch, and Bloomfi eld (2005) found signifi cant

reli-able change (declines on at least two or more measures)

from pretreatment baseline to six months posttreatment

compared to healthy controls in 34% of patients (18.6% in

healthy controls); they also found signifi cant declines (time

X group interactions) in the patient group as compared to

controls were found in selective attention, working memory,

and delayed verbal memory measures Schagen et al (2006)

found a greater proportion of high-dose chemotherapy

patients declined from baseline to six-months posttreatment

time points (25%) compared with healthy control subjects

(6.7%), while standard-dose and cancer-diagnosed subjects

not treated with chemotherapy did not exhibit any signifi

-cant diff erence Stewart et al (2008) found a greater

propor-tion of chemotherapy-treated patients exhibited a reliable

decline (31%) than patients not treated with chemotherapy

(12%) with working memory the most aff ected Collins

et al (2009) found signifi cant declines in working memory

and visual memory for chemotherapy treated patients

from baseline to six months posttreatment compared to

patients treated with hormonal therapies Quesnel, Savard,

and Ivers (2009) compared groups treated with

combina-tion chemotherapy/RT to RT alone and to healthy controls

before and after treatment, and three months

posttreat-ment; signifi cant pretreatment attentional diff erences were

noted in the patient group compared to healthy controls,

with signifi cant posttreatment verbal memory declines in

both patient groups and signifi cantly greater verbal fl uency

decline in the chemotherapy treated group Vearncombe

et al (2009) compared groups treated with chemotherapy

with or without hormonal and RT to a group not treated

with adjuvant therapies at baseline and four weeks

follow-ing completion of treatment: 16.9% of the chemotherapy

group exhibited decline in verbal learning and memory,

abstract reasoning, and motor function following

treat-ment, with an association of decreased hemoglobin and

increased anxiety to impairment

Ahles et al (2010) compared performance of patients

treated with chemotherapy, patients not treated with

che-motherapy, and healthy controls at baseline, one month,

and six months following treatment The chemotherapy

group failed to improve in verbal ability at the one-month

time point compared to the other groups, and a signifi

-cant contribution of age and baseline cognitive reserve to

chemotherapy-related cognitive decline in processing speed

was found; performance in the chemotherapy group was

similar to no-chemotherapy and healthy controls at the six-month time point Wefel et al (2010) examined perfor-mance in a single group of chemotherapy-treated patients

at pretreatment, during treatment, and approximately one month following completion of treatment: 21% exhibited dysfunction predominantly in learning and memory, execu-tive function, and psychomotor speed at the pretreatment time point; 65% of patients exhibited signifi cant decline

in the same domains during or shortly after treatment compared to baseline Hedayati, Alinaghizadeh, Schedin, Nyman, and Albertsson (2012) compared chemotherapy, hormone therapy, no therapy, and healthy controls prior to surgery, prior to adjuvant treatment, six months after start

of adjuvant treatment, and three months after completion

of treatment; results indicated signifi cantly worse memory performance for breast cancer diagnosed subjects regard-less of treatment, and lower memory and processing speed performance following chemotherapy treatment compared with the pretreatment time point Jansen, Cooper, Dodd, and Miaskowski (2011) examined cognitive changes in patients treated with doxorubicin and cyclophosphamide

combination (referred to as AC ) therapy alone and AC

therapy followed by taxane before treatment, one week and six months following completion of treatment Prior

to therapy, 23% of patients exhibited cognitive impairment with signifi cant declines in visuospatial ability, attention, and delayed memory immediately following treatment, and general improvement after six months Biglia et al (2012) examined cognitive functioning in a single group of women diagnosed with breast cancer before and immediately after completion of chemotherapy treatment, and reported a signifi cant decline in attention Collins, Mackenzie, Tasca, Scherling, and Smith (2013b) compared chemotherapy and healthy control groups shortly after completion of treatment and one year following completion of treatment: Results suggested signifi cantly improved global cognition perfor-mance at one year with a specifi c improvement in work-ing memory; however, approximately one-third of patients exhibited persistent cognitive dysfunction at the one-year time point In a novel study examining dose-response in chemotherapy treatment, Collins, MacKenzie, Tasca, Scherling, and Smith (2013a) conducted serial assessments

in women undergoing active treatment with chemotherapy and compared these to seven yoked time points in a healthy control group; declines in global cognitive performance as well as specifi c declines in working memory, psychomotor speed, verbal and visual memory performance were exhib-ited with increasing frequency over the seven assessment points (chemotherapy group impairment time 1 = 11.7% and at time 7 = 37%; control group impairment time 1 = 10% and at time 7 = 15.2%)

Other studies examining cognitive abilities at short vals following treatment have failed to fi nd signifi cant eff ects Jenkins et al (2006) found no signifi cant diff erences between groups treated with chemotherapy, endocrine/RT, and

inter-healthy controls from pretreatment baseline to six months

posttreatment, but did fi nd a potential eff ect of

treatment-related menopause initiation on attention and memory

measures Hermelink et al (2007) assessed a single group of

patients before and toward the end of active treatment and

found mean performance before treatment to be signifi cantly

below normative values in fi ve out of 12

neuropsychologi-cal measures At the second time point, approximately equal

proportions of patients exhibited reliable improvement (28%)

or decline (27%) from pretreatment performance, although

interpretation is limited given that no control group was

available for comparison Mehlsen, Pedersen, Jensen, and

Zachariae (2009) compared patients treated with

chemo-therapy, cardiac patients, and healthy controls, but failed to

fi nd any increased rate of impairment or decline in the

che-motherapy group Debess, Riis, Pedersen, and Ewertz (2009)

compared chemotherapy, chemotherapy and hormonal

ther-apy, no-chemotherther-apy, and healthy control groups and found

no signifi cant diff erences six months following completion

of treatment in any cognitive domain Tager et al (2010)

compared chemotherapy and no-chemotherapy groups at

baseline and at six months and one year following treatment;

while no signifi cant cognitive eff ect was exhibited, women

not treated with chemotherapy improved in motor

function-ing compared to those treated with chemotherapy, which was

interpreted as being potentially related to improvement in

treatment-related peripheral neuropathy

Several studies have examined longer-term cognitive eff ects

of treatment at one-year time points and beyond At one

year posttreatment, Wefel et al (2004) found improvement in

approximately 50% of aff ected patients, and persistent

dys-function was evident in the remaining half of the sample

In a study with baseline assessment during active treatment,

one-year, and two-year time points, Mar Fan et al (2008)

found 16% of patients on active treatment exhibited

moder-ate to severe impairment on the High Sensitivity Cognitive

Screen (compared with 5% in the healthy control group)

These eff ects appeared to decline in severity at one- and

two-year time points, with 4.4% exhibiting moderate to severe

dysfunction in the chemotherapy group at one year (3.6% in

healthy controls), and 3.8% at two years (0% in healthy

con-trols), although signifi cant practice eff ects for this screening

measure are implicated In a single group of

chemotherapy-treated patients using normative data as comparison, Wefel

et al (2010) found that 61% of patients exhibited either new

or persistent decline at one year posttreatment with most

fre-quent decline in learning and memory In contrast, in a study

with pretreatment, six-month, and one-year time points,

Col-lins et al (2009) found no diff erence in impairment in

che-motherapy-treated and hormone-treated patients (11% and

10% respectively) at one year, although, signifi cantly, those

patients treated with chemotherapy and on active hormonal

treatments at one year exhibited decreased psychomotor

speed and verbal memory Similarly, Ahles et al (2010) found

no signifi cant diff erence in performance for chemotherapy,

no-chemotherapy, and healthy control groups at one year following treatment

Summary of Neuropsychological Findings

Based on the literature reviewed, cognitive dysfunction lowing diagnosis and treatment of breast cancer is a sig-nifi cant concern in the immediate to intermediate periods following active treatment, with a subset of studies fi nding persistent cognitive dysfunction at one year and greater time points, and even at 20 years posttreatment Contex-tualization of these fi ndings is important as several factors infl uence interpretation of these results First, estimates of self-reported dysfunction would suggest much higher rates

fol-of cognitive diffi culties (up to 50%) than are found in either cross-sectional or longitudinal studies employing objective measures Disagreement between self-report and objective assessment is a well-known and typical fi nding in several other neurocognitive syndromes (Reid & Maclullich, 2006) Sources of disagreement that lead to overestimates of cogni-tive dysfunction include emotional factors that lead to nega-tive perceptions of functioning, and priming as a result of knowledge of potential eff ects of treatment (Schagen, Das, & van Dam, 2009) Factors that potentially lead to underesti-mates of cognitive dysfunction following treatment include insensitivity of objective measures to subtle cognitive dys-function, assessment of performance in the rarefi ed envi-ronment of the consulting offi ce that limits distraction and competing demands, and potentially poor ecological valid-ity of objective measures resulting in poor approximation of real-world cognitive demands

Second, cross-sectional objective studies would also gest higher rates of cognitive dysfunction than similar lon-gitudinal studies As discussed in the previous section, this may be due to preexisting cognitive dysfunction in patients prior to treatment as has been found in a subset of studies

sug-It is important to note that “pretreatment” in this case is before adjuvant chemotherapy treatment but not necessarily before surgical resection In the study by Ahles et al (2008), all patients were postsurgery at baseline, and in Wefel et al (2004) 50% of patients had already undergone either lumpec-tomy or mastectomy at baseline Underscoring the impor-tance of this observation, Wefel et al reported that patients who underwent surgical resection were approximately twice

as likely to have cognitive impairment compared to biopsy

alone ( p = 0.03), although this did not meet the a priori nifi cance level specifi ed by the authors ( p = 0.01) Another

sig-potential infl uence on cognitive function prior to apy treatment is the stress related to cancer diagnosis and treatment In general, in those studies that formally assessed mood symptoms, cognitive performance was not associated with self-reported anxiety, although direct eff ects of chronic stress and hypothalamic-pituitary-adrenal axis (HPA) dys-regulation may be one promising future research direction that so far had been only minimally studied Regardless of

chemother-etiology, eff ects of other variables—e.g., stress of diagnosis

and treatment, surgical stress and potential infl ammatory

dysregulation, and anesthetic exposure, all of which precede

chemotherapy treatment—may play a role in addition to

spe-cifi c eff ects of adjuvant therapies that follow

Finally, longitudinal studies suggest that cognitive

dysfunc-tion following treatment may be subtle and exhibited in only

a subset of patients Several potential mechanisms and risk

factors for posttreatment cognitive dysfunction have been

proposed (Ahles, Root, & Ryan, 2012; Ahles & Saykin, 2007)

that may predispose individuals to decline Age and cognitive

reserve have been found to be associated with signifi cantly

greater declines in processing speed from pre- to

posttreat-ment in older individuals with lower cognitive reserve (Ahles

et al., 2010) Genetic contributions have also been identifi ed,

including interaction of the COMT-Val (Val+; Val/Val; Val/

Met) genotype with treatment regimen on cognition (Small

et al., 2011), as well as the APOE-e4 genotype (Ahles et al.,

2003) To the extent that diagnosis and treatment may

inter-act with specifi c risk finter-actors prior to treatment, averaging

cognitive test performance within a given treatment group

may obscure signifi cant patient subgroups in whom risk for

cognitive dysfunction may be heightened In addition to

clarifying the longitudinal course of cognitive dysfunction

in survivors following treatment, potential mechanisms of

cognitive dysfunction have received increasing attention

Principal among these has been research investigating

under-lying brain structure and function and potential changes due

to cancer diagnosis and treatment

Structural and Functional Imaging Studies

Imaging studies investigating potential eff ects of cancer and

treatment on brain structure and function have accumulated

in recent years, and multiple reviews are available

summariz-ing these fi ndsummariz-ings (Ahles et al., 2012; de Ruiter & Schagen,

2013; Deprez, Billiet, Sunaert, & Leemans, 2013; McDonald &

Saykin, 2013; Reuter-Lorenz & Cimprich, 2013; see also

Tables 23.1 and 23.2 ) Following a similar trajectory as in

neuropsychological studies, early structural and functional

research focused on cross-sectional designs posttreatment,

limiting the interpretability of results given no pretreatment

baseline comparisons Cross-sectional, posttreatment studies

using MRI (Abraham et al., 2008; Dale, Fischl, & Sereno,

1999; de Ruiter, Reneman, Boogerd, Veltman, Caan, et al.,

2011; Deprez et al., 2011; Inagaki et al., 2007) have

docu-mented reductions in gray matter, primarily in frontal cortex

and the hippocampus, and white matter integrity in cancer

survivors treated with chemotherapy, although negative

results have also been reported In the most recent study

uti-lizing DTI methods, while no group diff erence was reported,

signifi cant associations of white matter integrity with time

since treatment were found within a breast cancer cohort at

mean interval of 20 years since treatment (Koppelmans

et al., 2014)

Longitudinal studies have reported similar results: First, decreased gray matter density in bilateral frontal, temporal (including hippocampus), and cerebellar regions and right thalamus at one month postchemotherapy, with only partial recovery at one year postchemotherapy in several structures, compared with no signifi cant changes in gray matter over time in the no-chemotherapy cancer group or the healthy controls (McDonald et al., 2010); and second, decreased frontal, parietal, and occipital white matter integrity in chemotherapy-exposed patients, with no changes in the no-chemotherapy group or healthy controls posttreatment (Deprez et al., 2012) Gray matter density alterations were replicated by McDonald, Conroy, Smith, West, and Saykin (2013), who found reduced gray matter density one month after completion of treatment, which was associated with greater self-reported executive dysfunction

Cross-sectional studies of cancer survivors using tional imaging techniques, including functional MRI (fMRI) (de Ruiter, Reneman, Boogerd, Veltman, van Dam, et al., 2011; Ferguson, McDonald, Saykin, & Ahles, 2007; Kesler

func-et al., 2009; Kesler func-et al., 2011) and functional positron sion tomography (fPET) (Silverman et al., 2007), have dem-onstrated areas of increased and decreased activation during performance, primarily in working memory and executive functioning tasks, in survivors exposed to chemotherapy, as compared with controls, in areas similar to the structural diff erences described McDonald et al (2012) conducted a longitudinal study using fMRI and found frontal lobe hyper-activation to support a working memory task before treat-ment, decreased activation one month postchemotherapy, and a return to pretreatment hyperactivation at one year posttreatment Interestingly, two other studies reported hyperactivation during a memory task before treatment in patients with cancer compared with healthy controls, con-sistent with the reports of neuropsychological defi cits at pre-treatment (Cimprich et al., 2010; Scherling et al., 2011) One interpretation is that pretreatment hyperactivation represents

emis-an attempt to compensate for preexisting defi cits; however, over years, patients lose the ability for compensatory activa-tion as a result of exposure to cancer treatments and/or age-associated changes in the brain More recent work has found associations of functional recruitment with verbal working memory (Lopez Zunini et al., 2013) In a novel pilot-study, reductions in functional connectivity shortly after treatment were found in the dorsal attention network and default mode network, with partial resolution in the dorsal attention net-work at one year but persistent reduced connectivity in the default mode network (Dumas et al., 2013)

The most recent imaging work has investigated putative mechanisms of structural and functional alterations follow-ing treatment A potential role of proinfl ammatory cytokines

is suggested by recent work fi nding an association of infl matory biomarkers (IL-1ra; sTNF-RI) with regional brain metabolism (Pomykala et al., 2013) utilizing fPET Similarly, hippocampal volumes and verbal memory performance have

am-Table 23.1 Structural imaging studies

Modality

Assessment schedule

Participants Outcomes

Yoshikawa et al

(2005)

Cross-sectional MRI

t1: 12 months post-tx

CTX+: n = 44 CTX−: n = 31

No diff erence in hippocampal volume or memory performance between CTX+ and CTX− at 12 months posttreatment.

Inagaki et al (2007) Cross-sectional

MRI

t1: > 12 months post-tx

CTX+: n = 51 CTX−: n = 54 HC: n =55

Smaller gray and white matter in prefrontal, parahippocampal, cingulate, and precuneus in CTX+ compared to CTX− at

12 months posttreatment.

Inagaki et al (2007) Cross-sectional

MRI

t1: > 36 months post-tx

CTX+: n = 73 CTX−: n = 59 HC: n =37

No diff erence between CTX+ and CTX− at 36 months posttreatment.

Abraham et al

(2008)

Cross-sectional DTI

t1: 22 months post-tx

CTX+: n = 10 HC: n =9

Lower FA in genu and slower processing speed in CTX+ compared with healthy controls at 22 months posttreatment.

McDonald, Conroy,

Ahles, West, and

Saykin (2010)

Longitudinal MRI

t1: pre-tx t2: one month post-tx t3: 12 months post-tx

CTX+: n = 17 CTX−: n = 12 HC: n = 18

Decreased gray matter density in both CTX+ and CTX− compared with healthy controls at one month posttreatment Decreased frontal, temporal, thalamic, and cerebellar gray matter density in CTX+ at one month posttreatment compared with pretreatment Gray matter density recovered in the CTX+ group with areas of reduced density remaining at one year posttreatment.

Koppelmans et al

(2011)

Cross-sectional MRI

t1: 21 years post-tx

CTX+: n = 184 HC: n = 368

Smaller total brain volume and gray matter volume

in CTX+ compared with health controls at 21 years posttreatment.

Deprez et al (2011) Cross-sectional

MRI DTI

t1: 80–160 days post-tx

CTX+ n = 18

CTX− n = 10

HC n = 18

Decreased frontal and temporal FA and increased frontal

MD in CTX+ compared to CTX− and healthy controls 80–160 days posttreatment.

Deprez et al (2012) Longitudinal

MRI, DTI

t1: pre-tx t2: 3–4 months post-tx

CTX+ n =34 CTX− n =16

HC n =19

Decreased frontal, parietal, and occipital FA in CTX+ with

no changes in either CTX− or healthy controls at three to four months —posttreatment.

de Ruiter and

Schagen (2013)

Cross-sectional MRI, DTI, MRS

t1: > 9 years post-tx

CTX+: n = 17 CTX−: n = 15

Reduced white matter integrity in CTX+ compared with CTX− > 9 years −posttreatment Reduced N−

acetylasparate/creatine in left centrum semiovale in CTX+ compared with CTX− > 9 years −posttreatment Smaller posterior parietal volume in CTX+ compared with CTX− >

9 years —posttreatment McDonald et al

(2013)

Longitudinal MRI

t1: pre-tx t2: 1 month post-tx

CTX+ n = 27 CTX− n = 28

CTX+ n = 42

HC n = 35

Left hippocampal volume reduced in chemotherapy treated group IL-6 and TNFa increased in chemotherapy group Hippocampal volume positively correlated with TNFa and negatively correlated with IL-6.

Conroy et al (2013) Cross-sectional

MRI

t1: average 6 years post-tx

CTX+ n = 24

HC n = 23

CTX+ group exhibited regional reductions in gray matter density compared to HC Time since treatment was associated with greater gray matter density in CTX+ group Oxidative DNA damage was negatively correlated with gray matter density.

Koppelmans et al

(2014)

Cross sectional DTI

t1: average 20 years post-tx

CTX+ n = 187

HC n = 374

No signifi cant diff erence in global or regional white matter integrity Time since treatment was associated with declining white matter integrity.

Notes: CTX+ = chemotherapy; CTX− = no chemotherapy; MRS = magnetic resonance spectroscopy; HC = healthy controls; FA = fractional anisotropy;

MD = mean diff usivity

Table 23.2 Functional imaging studies

Authors Design/

Modality

Assessment Schedule

Participants In-Scanner Task Outcomes Pretreatment

Cimprich et al

(2010)

sectional fMRI

Cross-t1: pre-tx only

BC: n = 10 HC: n = 9

Verbal working memory

Greater bilateral activation during verbal working memory task in breast cancer diagnosed subjects compared to healthy controls pretreatment.

Cross-t1: pre-tx only

BC: n = 23 HC: n = 23

Visual N-back Greater inferior frontal gyrus, insula, thalamus and

midbrain activations during working memory task

in breast cancer diagnosed subjects compared with healthy controls pretreatment.

Posttreatment

Ferguson et al

(2007)

sectional MRI; fMRI

Cross-t1: 22 months post-tx

CTX+: n = 1 HC: n = 1

Auditory N-back Greater WM hyperintensities and greater spatial

extent of frontal activation during working memory

in the CTX+ case compared with twin healthy control case.

Silverman et al

(2007)

sectional PET

Cross-t1: 5–10 years post-tx

CTX+: n = 5 CTX+Tam: n =7 CTX−: n = 5 HC: n = 3

Paired word memory task 10-minute delay, 1-day delay

Lower inferior frontal gyrus metabolism in CTX+ compared to CTX- and healthy controls 5to 10years posttreatment Lower basal ganglia metabolism

in CTX+Tam treated subjects compared to CTX+, CTX−, and healthy controls 5to 10years posttreatment.

Kesler, Bennett,

Mahaff ey, and

Spiegel (2009)

sectional fMRI

Cross-t1: 3 years post-tx

CTX+: n = 14 HC: n = 14

Verbal declarative encoding

Verbal declarative recognition

Lower prefrontal cortex activation during encoding

in CTX+ compared to healthy controls 3years posttreatment Greater regional activations during recall in CTX+ compared to healthy controls 3years posttreatment.

Kesler, Kent, and

O’Hara (2011)

sectional fMRI

Cross-t1: 5 years post-tx

CTX+: n = 25 CTX−: n = 19

Card sorting task Lower left middle dorsolateral prefrontal cortex

activation and premotor cortex activation in breast cancer diagnosed subjects compared to healthy controls Lower left caudal lateral prefrontal cortex activation in CTX+ compared with CTX− and healthy controls 5years posttreatment.

de Ruiter et al

(2011)

sectional fMRI

Cross-t1: 10 years post-tx

CTX+: n = 19 CTX−: n = 15

Tower of London, Paired Associates

Lower dorsolateral prefrontal cortex activity during Tower of London task, lower parahippocampal gyrus activity during paired associates task in CTX+ compared to CTX− 10 years posttreatment McDonald et al

(2012)

Longitudinal fMRI

t1: pre-tx t2: 1 month post-tx t3: 1 year post-tx

CTX+: n = 16 CTX−: n = 12 HC: n = 15

N-Back Task Greater frontal activation and lower parietal

activation at baseline in BC diagnosed patients relative to controls Lower frontal activation in BC-diagnosed patients relative to healthy controls immediately following treatment Greater frontal activation in BC diagnosed patients relative to healthy controls one year following treatment Lopez Zunini

et al (2013)

Longitudinal fMRI

t1: pre-tx t2: 1 month post-tx

CTX+: n =21 HC: n = 21

Verbal recall task At pre-tx, CTX+ exhibited reduced recruitment in

anterior cingulated compared to controls At one month post-tx, CTX+ exhibited reduced recruitment

in bilateral insula, left inferior orbitofrontal cortex and left middle temporal gyrus compared to controls Fatigue, depression, and anxiety were associated with

a subset of diff erence in recruitment.

Dumas et al

(2013)

Longitudinal fMRI

T1: pre-tx T2: 1 month post-tx T3: 1 year post-tx

CTX+ n =9 Resting state

functional connectivity

Reductions in functional connectivity shortly after treatment were found in the dorsal attention network and default mode network, with partial resolution in the dorsal attention network at one year but persistent reduced connectivity in the default mode network Pomykala et al

(2013)

Longitudinal PET

T1: post-tx T2: 1 year post-tx

CTX+ n = 23 CTX− n = 10

Resting FDG PET

Association of infl ammatory biomarkers (IL-1ra; sTNF-RI) with regional brain metabolism utilizing PET.

Key: Ctx+ = chemotherapy; Ctx- = no chemotherapy; fMRI = functional magnetic resonance imaging

been found to be associated with serum infl ammatory

cyto-kines (TNFa; IL6) following treatment (Kesler, Janelsins,

et al., 2013) A potential role of DNA damage and its

asso-ciation with cortical gray matter was recently suggested in

a study by Conroy et al (2013) that found higher oxidative

DNA damage in a sample of breast cancer survivors than in

healthy controls and associations of oxidative DNA damage

with gray matter density

Treatment Interventions

Treatment of cognitive dysfunction in breast cancer patients

is a challenging clinical need and newly expanding area of

research One particularly challenging aspect with regard to

rehabilitation in this cohort is the often signifi cant but subtle

cognitive dysfunction exhibited in these patients In contrast

to rehabilitation programs in traumatic brain injury or

pri-mary CNS tumors, the target of cognitive rehabilitation in

non-CNS cancers may be diffi cult to discern, and multiple

diff use processes may be aff ected Treatment has generally

taken the form of both compensatory and direct (restitutive)

rehabilitation, as well as cognitive behavioral therapy, and

pharmacologic treatment Although it is not the focus of this

brief review, mindfulness-based programs and exercise

regi-mens have also been considered either as alternatives to

cog-nitive rehabilitation programs or as parts of a multitreatment

strategy Generally, outcomes of treatment are promising but

the research on which they are based is still in the early stage

of development and no defi nitive conclusions can be drawn

from the handful of studies that have been conducted

In an early, single-arm study to address treatment

strate-gies for cognitive dysfunction following treatment (Ferguson,

Ahles, et al., 2007), a program of Memory and Attention

Adaptation Training (MAAT) was tested that included (a)

education on memory and attention; (b) self-awareness

training; (c) self-regulation via relaxation training; and (d)

compensatory strategy training Improved self-reported and

objective cognitive function was found, along with adequate

feasibility and patient satisfaction, although no comparison

arm is available for assessing placebo and practice eff ects In

a later, two-arm trial (Ferguson et al., 2012), patients were

randomized to receive either MAAT or assigned to a wait-list

control group Patients treated with MAAT exhibited signifi

-cantly improved verbal memory as compared to the wait list

control group, as well as signifi cantly improved self-reported

“spiritual well-being,” although no signifi cant eff ect was

found for other cognitive domains or for other self-reported

cognitive outcomes Poppelreuter, Weis, and Bartsch (2009)

compared the eff ectiveness of computer-based training, and

a rehabilitation program to a control group at baseline, at

end of rehabilitation, and at six months, although no specifi c

eff ect of intervention was found, with all groups

improv-ing over time on measures of cognitive function Von Ah

et al (2012) studied eff ects of memory or processing speed

training versus a wait list control group at baseline, shortly

following training, and two months after completion of the intervention, with signifi cant eff ects for processing speed at both the immediate and two month follow-up evaluation, and signifi cant memory eff ects at the two month follow-up evaluation; interpretation of delayed eff ects are complicated

by no signifi cant eff ect immediately following training rier et al (2013) examined the eff ectiveness of a compensa-tory and mindfulness rehabilitation program versus control

Cher-at baseline and following training and found improvement

on self-reported cognitive function as well as in objective attention functioning In a cognitive-training rehabilitation study, Kesler et al (2013) utilized online training software

to examine remediation of executive functioning skills and found signifi cant improvements on the Wisconsin Card Sorting Test, Symbol Search, and letter fl uency in the active treatment group versus controls, together with improved self-reported cognitive functioning in the active treatment group

In addition to direct and compensatory rehabilitation grams, pharmacologic treatments have also been investigated including modafanil and dexymethylphenidate Results are mixed regarding effi cacy of dexymethylphenidate, with a subset of studies fi nding signifi cant improvement in fatigue and cognition (Lower et al., 2009) while others fi nd no ben-

pro-efi cial eff ect (Mar Fan et al., 2008) Modafi nil has received increasing attention for its effi cacy in treating cognitive dys-function following treatment, again specifi cally with regard

to treatment of attentional dysfunction and fatigue, with promising results (Kohli et al., 2009; Lundorff , Jonsson, & Sjogren, 2009)

Conclusion

The recent literature suggests that both brain tumor and the adverse eff ects of treatment contribute to cognitive dysfunc-tion in a signifi cant number of brain tumor patients The studies reviewed indicated that whole-brain RT alone or in combination with chemotherapy result in more pronounced cognitive dysfunction than either partial RT or chemo-therapy alone Antiepileptics and corticosteroids, often used

in the treatment of these patients, may also further disrupt cognitive functioning The cognitive domains suggested to

be particularly sensitive to treatment-induced cognitive function include several aspects of attention and executive functions, learning and retrieval of new information, and graphomotor speed

Advancements in the fi eld include the development of guidelines for the use of standardized neuropsychological tests in the context of clinical trials, and the inclusion of cognitive outcome measures in several recent and ongoing multi-center studies and clinical trials in neuro-oncology The fi ndings from such studies would improve our under-standing of the toxicity of various treatment modalities, and enable both physicians and patients to make decisions regarding treatment based not only on survival rates and time to disease progression, but also on QoL

In non-CNS cancers, the body of literature on

self-reported cognitive dysfunction, cross-sectional and

lon-gitudinal objective cognitive assessments before and after

treatment, and structural and functional imaging fi ndings

strongly support the occurrence of neuropsychological

dysfunction associated with diagnosis and treatment for

breast cancer Cognitive changes may appear early in the

posttreatment course but may become more apparent after

physical/medical factors and concerns have resolved or

when patients attempt to return to prediagnosis

respon-sibilities (school, work, household demands) Currently,

long-term eff ects are poorly understood, with the

major-ity of studies suggesting persistent cognitive problems and

another subset suggesting relative resolution of diffi culties

over time

Recent studies have begun to describe the

pathophysi-ological mechanisms that may underline the adverse eff ects

of RT and chemotherapy, and additional research is

nec-essary to identify contributing factors for the development

of treatment-related cognitive dysfunction (e.g., genetic

sus-ceptibility) The effi cacy of pharmacological and behavioral

interventions to improve cognitive function is increasingly

being investigated in studies involving patients with brain

tumors and non-CNS cancers

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Toxins in the Central Nervous System

Marc W Haut, Jennifer Wiener Hartzell, and Maria T Moran

24

Introduction

In this chapter, we review a variety of substances that are

toxic to the brain It is beyond the scope of this chapter

to cover all toxins; thus, we focus on the most common,

most well-studied, and those which we believe are the

most interesting We refer readers to more

comprehen-sive reviews when greater depth is warranted We begin

with toxins occurring most commonly in the workplace,

including heavy metals and solvents, and then discuss

car-bon monoxide poisoning, which may occur at work or at

home We then discuss substances of abuse and complete

our review with a description of the neurotoxic eff ects

of chemotherapy for non–central nervous system (CNS)

cancers Although chemotherapy is not typically discussed

in chapters related to toxic exposure, it is a toxin to both

cancerous and healthy cells, and there is a growing body

of literature highlighting the cognitive, neuroanatomical,

and functional changes that substantiate the phenomenon

of “chemo-brain.” For each toxin, we address common

neuropsychological defi cits, relevant emotional and

behav-ioral changes, and structural magnetic resonance imaging

(MRI) fi ndings Less frequently, we incorporate functional

imaging fi ndings to illustrate particular points related to

toxic exposure

There are a few themes to keep in mind while reading The

vast majority of studies in this area are cross-sectional When

longitudinal data are available, they are generally collected

after the onset of abuse or exposure and then during the

course of continued abuse, exposure, abstinence, or

cessa-tion Cross-sectional data create quite a “chicken or the egg”

problem: Are cognitive and structural brain diff erences in

exposed individuals the direct consequence of abuse or

expo-sure or, instead, do they represent preexisting diff erences that

render individuals vulnerable to the eff ects of toxic exposure

or substance abuse? For example, in one study comparing

stimulant-dependent subjects to their stimulant-naive

sib-lings and normal controls, the sibling pairs demonstrated the

same abnormalities in fronto-striatal brain systems relative

to controls (Ersche et al., 2012) Of course, cognitive and

structural defi cits observed with toxic exposure may

repre-sent a combination of preexisting and predisposing defi cits,

as well as the direct consequences of exposure or abuse

There are some exceptions in studies that are prospective in nature that we will highlight

There are two other common limitations inherent to the majority of studies on toxic exposure First, data regard-ing exposure or abuse are frequently based on self-report Thus, there are limitations in establishing a dose-response eff ect Second, many individuals are poly-substance abusers

or exposed to multiple toxins, which makes it challenging

to obtain a clean or homogenous sample to investigate the

specifi c eff ects of neurotoxins These issues impact the

qual-ity of the data at hand

With specifi c regard to substance abuse, there are sions when the available data do not fully support a long-term toxic eff ect of certain substances; however, we believe it is reasonable to assume that there are consequences of chronic substance abuse on brain structure and function Substances are abused to begin with because they alter how individuals feel or experience the world, which occurs through neural processes While it is reasonable to assume that, at a certain level of exposure, toxins will produce permanent changes to the CNS, the science must catch up to prove this assumption true Regardless of whether the defi cits associated with toxic exposure are a cause or eff ect of the exposure, such defi cits impact one’s ability to participate in and benefi t from avail-able treatment options This concept, in particular, is of great importance when considering the societal eff ects

Heavy Metals

The impact of heavy metals on the human brain has been recognized and studied for centuries, dating as far back as the second century B.C (Needleman, 2004) Loosely, the term

heavy metals refers to a subset of naturally occurring

ele-ments with metallic properties that exert a toxic eff ect on the environment and living organisms (Duruibe, Ogwuegbu, & Egwurugwu, 2007) Industry and the environment constitute the primary mechanisms of neurotoxic exposure

Lead

The neurotoxic eff ects of lead were recognized as far back

as antiquity among metal workers and wine drinkers turies ago, the use of lead in wine making was banned, but

Cen-industry remained a viable source of toxicity (Needleman,

2004; Sandstead, 1986) By the early 1900s, leaded paints and

gasoline became major sources of environmental pollution

In 1970s, the U.S government banned residential and public

use of lead-based paints and began phasing out leaded

gaso-line because of scientifi c studies demonstrating neurotoxic

eff ects on children (Ibrahim, Froberg, Wolf, & Rusyniak,

2006; Needleman, 1975)

Lead permeates the blood-brain barrier and alters neural

activity (Khalil et al., 2009) Children are especially susceptible

to lead toxicity during fetal and early development as lead is

more easily absorbed by the developing CNS Lead may be

transmitted from mother to child through the umbilical cord

and breast milk (Needleman, 2004; Sanders, Liu, Buchner, &

Tchounwou, 2009) Prenatal lead exposure has been liked with

developmental, cognitive, and neurobehavioral eff ects Elevated

lead levels were found in children with encephalopathy, mental

retardation, learning disabilities, and hyperactivity (Moore,

Meredith, & Goldberg, 1977; Marlowe et al., 1982;

Needle-man, 2004) Relative to children with low lead concentrations,

children with high levels of lead were found to have lower

intelli-gence (Landrigan et al., 1975; Needleman, Gunnoe, Leviton, &

Peresie, 1978; Needleman, Geiger, & Frank, 1985)

There is a clear dose-response eff ect, but adverse eff ects

are observed in children with low levels of lead exposure

(Needleman, 2009; Needleman et al., 1979) Studies

con-ducted by Herbert Needleman in the late 1970s and 1980s

demonstrated intellectual and cognitive defi cits in children

who did not show overt clinical signs of lead intoxication

(Ibrahim et al., 2006; Needleman, 2004; Needleman et al.,

1978; Needleman et al., 1979) Specifi c defi cits in overall

intelligence, verbal abilities, attention, reaction time, and

behavior were identifi ed (Needleman et al., 1979) In a

fol-low-up 11 years later, the same cognitive defi cits persisted

and higher childhood lead levels were associated with worse

academic performance and increased absenteeism in high

school (Needleman, Schell, Bellinger, Leviton, & Allred,

1990) This signifi cant and persistent inverse relationship

between childhood lead exposure and intellectual

function-ing has been well-replicated (Bellfunction-inger, Stiles, & Needleman,

1992; Lanphear et al., 2005; Mazumdar et al., 2011;

Needle-man et al., 1985; NeedleNeedle-man & Landrigan, 1981; Tong,

Baghurst, McMichael, Sawyer, & Mudge, 1996)

Childhood lead exposure has also been linked with signifi

-cant social and behavioral problems, including aggression,

hyperactivity, impulsivity, delinquency, conduct problems,

and antisocial behavior (Dietrich, Ris, Succop, Berger, &

Bornshein, 2001; Carpenter, 2001; Marcus, Fulton, & Clarke,

2010; Needleman et al., 1996) A meta-analysis found that

lead burden was associated with attention defi cit/hyperactivity

disorder (ADHD) symptoms; the eff ect size was similar to

the eff ect sizes between lead and intelligence, as well as lead

and conduct problems (Goodlad, Marcus, & Fulton, 2013)

Occupational lead exposure represents the most

com-mon route of lead poisoning in adults There is a high risk

of occupational toxicity among miners, welders, smelters, battery plant workers, painters, and construction workers (Ibrahim et al., 2006) Neurologic symptoms of acute lead toxicity include headache, fatigue, emotional lability, tremor, neuropathy, ataxia, and, rarely, encephalopathy (Ibrahim

et al., 2006; Järup, 2003; Kim & Kim, 2012) The bilateral wrist drop is a pathognomonic sign (Ibrahim et al., 2006) Behaviorally, lead-exposed workers display increased rates

of depression, anxiety, irritability, anger, and hallucinations (Baker, Feldman, White, & Harley, 1983; Flora, Gupta, & Tiwari, 2012; Jeyaratnam, Boey, Ong, Chia, & Phoon, 1986) Workers exposed to lead demonstrate signifi cant and long-term defi cits in general intellect, spatial ability, memory, motor speed, and reaction time relative to controls (Baker

et al., 1983; Hogstedt, Hane, Agrell, & Bodin, 1983; nam et al., 1986; Khalil et al., 2009)

There is mounting evidence that cognitive defi cits ated with lead toxicity progress over time In old age, for-mer lead-exposed workers demonstrate poorer performance

associ-on measures of visuospatial ability, learning and memory, executive functions, and manual dexterity (Needleman, 2004; Schwartz et al., 2000; Shih et al., 2006) Some researchers assert that lead plays a role in the development of neurode-generative disorders, such as Alzheimer’s disease and amyo-trophic lateral sclerosis (ALS), although a direct causal link has not been identifi ed (Johnson & Atchison, 2009; Liu, Hao, Zeng, Dai, & Gu, 2013; Vinceti, Bottecchi, Fan, Finkselstein, & Mandrioll, 2012; Weiss, 2011)

On structural neuroimaging, adults exposed to lead ing childhood or early adulthood demonstrate white mat-ter lesions, total brain atrophy, and region-specifi c declines

dur-in gray matter volume, particularly dur-in the frontal lobes (Brubaker, Dietrich, Lanphear, & Cecil, 2010; Cecil et al., 2008;Schwartz et al., 2010; Stewart et al., 2006) There is evidence of a longitudinal association between cumulative lead dose and cognitive dysfunction, white matter lesions, and brain volume loss (Schwartz et al., 2010) Similarly, dif-fusion tensor imaging (DTI) studies illustrate that childhood lead exposure alters early brain myelination and produces long-term, persistent defi cits in axonal integrity (Brubaker

et al., 2009)

Unfortunately, the toxic eff ects of lead are nearly sible to treat or reverse Although chelation therapy suc-cessfully lowers blood lead levels through accelerating the excretion of heavy metals, it does not reduce lead-related morbidity and mortality in children or adults (Dietrich et al., 2004; Kosnett, 2010; Rogan et al., 2001) Other than simply terminating the exposure, eff orts are geared toward primary prevention (Flora & Pachauri, 2010; Needleman, 2004)

treat animal skins and produce felt for hats The saying “mad

as a hatter” comes from the observed toxic eff ects among

hat makers The main feature of Mad Hatter’s disease, as

the condition was labeled, was erethism : a behavioral

pre-sentation characterized by shyness, social anxiety, paranoia,

irritability, and mood lability Accompanying fatigue, tremor,

ataxia, and cognitive changes were also reported (Haut et al.,

1999; O’Carroll, Masterton, Dougall, Ebmeier, &

Good-wing, 1995)

In the 1950s, the neurotoxic eff ects of mercury gained

more serious global attention A Japanese chemical plant

discharged methyl mercury and contaminated the water

and aquatic life of Minamata Bay The fi rst outbreak of

Minamata disease, as mercury poisoning came to be called,

occurred in 1953 and has aff ected thousands since then,

pri-marily through consumption of contaminated fi sh (Ekino,

Susa, Ninomiya, Imamura, & Kitamura, 2007; O’Carroll et al.,

1995)

Accidental and occupational mercury exposure still occurs

today by way of inhalation of mercury vapor, oral ingestion

of liquid mercury (e.g., quicksilver), or cutaneous exposure

(Haut et al., 1999; Ibrahim et al., 2006) The most common

routes of modern exposure include fi sh consumption,

den-tal amalgams, and vaccines (Clarkson, Magos, & Myers,

2003; Risher, Murray, & Prince, 2002) Mercury crosses the

blood-brain barrier and concentrates within neurons, thus

interfering with normal cell function (Ibrahim et al., 2006)

Neuropathological studies indicate that occipital and

cer-ebellar neurons are prime targets of mercury-related

degen-eration (Clarkson et al., 2003; Davidson, Myers, & Weiss,

2004; Ekino et al., 2007)

Prenatal mercury exposure has been correlated with

devel-opmental delays and widespread cognitive defi cits

(David-son et al., 2004; Grandjean et al., 1997) Beginning in the

1990s, the U.S Food and Drug Administration (FDA) began

issuing advisories on limiting fi sh consumption during

preg-nancy (Counter & Buchanan, 2004) Studies conducted in

the Faroe Islands, where whale meat was heavily consumed,

found long-term defi cits aff ecting motor functions, attention,

visuospatial skills, language, and memory among prenatally

exposed children (Counter & Buchanan, 2004; Davidson

et al., 2004; Grandjean et al., 1997) The Seychelles Child

Development Study investigated the eff ects of lower levels of

prenatal mercury exposure from consuming fi sh and did not

fi nd cognitive defi cits (Davidson et al., 2004; Davidson et al.,

2010; Davidson, Myers, Weiss, Shamlaye, & Cox, 2006)

Among adults, acute mercury poisoning is associated with

an array of clinical symptoms Cerebellar dysfunction is

com-mon with gait ataxia, tremor, dysmetria, dysarthria, or gaze

nystagmus Primary visual disturbance is refl ected through

constriction of the visual fi elds Hearing impairment,

olfac-tory and gustaolfac-tory disturbances, and somatosensory

dys-function are also observed Behaviorally, erethism remains

characteristic of mercury intoxication Personality change

may manifest as disinhibition, emotional lability, emotional

hypersensitivity, paranoia, or social anxiety (Ekino et al., 2007; Haut et al., 1999; Kim & Kim, 2012) Clinical symp-toms of acute toxicity may present within hours of exposure Although symptoms of chronic, lower-level mercury poison-ing develop more gradually, the same domains are aff ected (Haut et al., 1999; Ibrahim et al., 2006; Järup, 2003; Risher

et al., 2002) The timing of onset, rate of progression, and overall severity of symptoms are contingent upon the level

of exposure (Ibrahim et al., 2006)

Neuropsychological defi cits associated with mercury icity are widespread and nonspecifi c, but executive dysfunc-tion is a strong theme Cognitive defi cits aff ecting motor functions, attention and concentration, processing speed, verbal memory, cognitive fl exibility, and abstraction have been documented in cases of acute and chronic mercury exposure (Haut et al., 1999; Neghab, Norouzi, Choobineh, Kardaniyan, & Zadeh, 2012; O’Carroll et al., 1995) The severity of cognitive defi cits, however, is relatively mild In

tox-a mettox-a-tox-antox-alysis extox-amining the eff ects of occuptox-ationtox-al cury exposure on neuropsychological function, a mild eff ect size was found, there was no dose-response relationship, and cessation of exposure led to cognitive recovery (Rohling & Demakis, 2006)

Mercury intoxication causes changes to the cerebrum and cerebellum At autopsy, atrophy of the cerebellar vermis and hemispheres, calcarine cortex, precentral gyrus, postcentral gyrus, and transverse temporal gyri are noted (Eto, 1997) These structural fi ndings correlate with the cerebellar, visual, motor, and various sensory changes observed clinically In patients with known mercury poisoning, atrophy of the cal-carine and cerebellar cortices are most striking on computed tomography (CT) and MRI, and decreased cerebellar blood

fl ow has been demonstrated with single photon emission computed tomography (SPECT) (Eto, 1997; Eto, 2000; Eto, Marumoto, & Takeya, 2010; Farina, Avila, da Rocha, & Aschner, 2012; Itoh et al., 2001; Kim & Kim, 2012; Korogi, Takahashi, Okajima & Eto, 1998) Functional imaging stud-ies suggest a dose-response eff ect In one study conducted with the prenatally exposed Faroe Islanders, higher mercury exposure correlated with more widespread brain activation

on visual and motor tasks (White et al., 2011)

Theories about the pathogenic role of mercury in degenerative diseases, such as Alzheimer’s disease, have also been put forth Although mercury and other heavy metals may contribute to the onset or progression of neurodegen-erative conditions, we emphasize that no causal link has been identifi ed (Carpenter, 2001; Johnson & Atchison, 2009; Mutter, Naumann, Sadaghiani, Schneider, & Walach, 2004; Weiss, 2011)

As with lead toxicity, prevention of mercury intoxication

is superior to treatment Modern preventative eff orts include removing amalgam fi llings and avoiding high intake of cer-tain fi sh, such as shark, tuna, and swordfi sh (Järup, 2003) Antioxidants show promise as potential therapeutic agents, but their effi cacy remains unclear Chelating therapies may

partially remove mercury from the body, but cannot reverse

CNS damage (Clarkson et al., 2003; Farina et al., 2012)

Ultimately, mercury exerts an enduring toxic eff ect upon

liv-ing organisms

Organic Solvents

Organic solvents are used in a wide range of industries

in manufacturing and cleaning processes Exposure may

occur through inhalation, dermal absorption, oral routes,

or through a combination of these Acute eff ects of solvent

exposure are similar to the acute eff ects of alcohol (which is

also a solvent), such as feelings of intoxication, dizziness,

dis-coordination, and headache There is an ever-growing body

of research on the eff ects of chronic exposure to solvents

The reader is referred to prior reviews for details, but the

cognitive defi cits typically observed after solvent exposure

aff ect attention, memory, motor skills, and visual

percep-tion Processing speed, working memory, and other

execu-tive functions may also be impaired (Baker, 1994; Jin et al.,

2004; Morrow, Muldoon, & Sandstrom, 2001; van Valen et al.,

2012; White & Proctor, 1993) Some studies do not report

cognitive defi cits following exposure and there has been

speculation that chronic low-level exposure does not result in

permanent defi cits (Dick et al., 2010); however, several

well-controlled studies, including a twin study and prospective

studies, have documented defi cits (Hanninen, Antti-Poika,

Juntunen, Koskenvuo, 1991; Morrow, Steinhauer, Condray,

& Hodgson, 1997) A meta-analysis of solvent-exposed

individuals compared to nonexposed controls reported

sig-nifi cant eff ect sizes Measures of attention, processing speed,

and response inhibition showed particularly strong eff ects It

should be noted that the meta-analysis failed to document

a dose-response relationship, which the authors attributed

to the incomplete descriptions of exposure in the studies

examined Individual studies, however, have reported

dose-response relationships, such that a greater severity and

lon-ger duration of exposure is associated with a greater degree

of cognitive defi cit (Morrow et al., 2001; Nilson, Bäckman,

Sällsten, Hagberg, Barregård, 2003) Indeed, despite the

well-demonstrated cognitive eff ects of solvent exposure,

variability in study methodology and individual exposure

factors do exist and result in inconsistent fi ndings In

addi-tion, the precise amount and duration of exposure necessary

to produce symptoms has not been determined and there

is no specifi c biologic marker that is critical to document

exposure Individuals are also frequently exposed to more

than one substance

The long-term outcome of cognitive defi cits following

solvent exposure is also debated Defi cits are reversible in

some individuals (Morrow et al., 1997), while other studies

suggest that aging may exacerbate cognitive defi cits (Nilson

et al., 2003) It has been hypothesized that solvent-exposed

individuals are at increased risk of dementia, but this is not

consistently supported in the literature (Berr et al., 2010;

Dick et al., 2010) Cognitive reserve may also play a role in the expression of cognitive defi cits following solvent expo-sure, as lower educational attainment was associated with greater cognitive dysfunction in solvent-exposed workers (Sabbath et al., 2012)

Emotional changes are also common, with high rates of depression, anxiety, and personality disturbance in those exposed to solvents (Condray, Morrow, Steinhauer, Hodg-son, & Kelley, 2000; Morrow et al., 2000; Visser et al., 2011)

Up to 71% of a solvent-exposed sample may meet criteria for an active Axis I condition (Morrow et al., 2000) A posi-tive association has been demonstrated between psychiatric symptoms and the severity and duration of exposure (Con-dray et al., 2000; Morrow et al., 2000); however, emotional symptoms do not fully account for resultant cognitive defi -cits (Perrson, Osterberg, Karlson, & Orbaek, 2000; Morrow

et al., 2001)

Neuroimaging studies have provided some elucidation of the underlying structural eff ects of solvent-related cognitive defi cits but there are few studies, thus limiting conclusions There is evidence of white matter change based on proton magnetic resonance spectroscopy (MRS), DTI, and volumet-ric measurement of the corpus callosum, with an association between degree of white matter change and severity of expo-sure (Alkan et al., 2004; Haut et al., 2006; Visser et al., 2008) The lipophilic properties of organic solvents are thought to account for their affi nity for white matter, as myelin has a high fat content Changes to gray matter may be expected as well, but have been less thoroughly examined There is evi-dence of brain atrophy based on readings of individual clini-cal scans (Keski-Santti, Mantyla, Lamminen, Hyvarinen, & Sainio, 2009) Functional imaging studies using positron emission tomography (PET) and functional magnetic reso-nance imaging (fMRI) have documented alterations in fron-tal lobe activation during working memory tasks (Haut et al., 2000; Tang et al., 2011)

Carbon Monoxide

Carbon monoxide (CO) is a colorless, odorless gas, produced

by incomplete combustion of carbons The affi nity of CO for hemoglobin is more than 200 times that of oxygen, displac-ing oxygen from hemoglobin Carboxyhemoglobin is formed and interferes with the transport of oxygen to tissue, lead-ing to hypoxia Common mechanisms of exposure include motor vehicle exhaust, heating units, and generators Poi-soning may be intentional (suicide attempt) or unintentional (fi re or faulty heating) There are increases in unintentional exposures with cold temperatures in the winter months and with incorrect use of generators during power outages from natural disasters (CDC, 2009; Iqbal et al., 2012) CO is the most common cause of death by poisoning in the United States (Prockop & Chichkova, 2007) In 2007 alone, there were more than 21,000 visits to emergency departments and 2,300 hospitalizations from confi rmed cases of CO

poisoning (Iqbal et al., 2012) Because of the nonspecifi c

nature of symptoms, exposures may go unnoticed and,

there-fore, rates may be underestimated The literature regarding

CO exposure focuses primarily on acute CO poisoning, as it

is more readily identifi ed and more frequently comes to

clini-cal attention The rate of chronic, long-term CO exposure

is unknown and its eff ects are poorly understood Unless

otherwise stated, the fi ndings discussed in this section refer

to acute CO poisoning

The symptoms of exposure range from fl u-like symptoms

of headache, dizziness, weakness, and nausea to more severe

symptoms of syncope, coma, and death Cardiac symptoms,

such as angina and arrhythmias, may occur Individuals in

the same CO exposure event may display diff erent clinical

presentations, and the severity of exposure can diff er between

individuals in the same location (Prockop, 2005) There may

be complicating factors of substance intoxication with both

accidental exposure and suicide attempts

CO poisoning is associated with impairments in memory,

attention, processing speed, visual-spatial skills, executive

functions, and intellect (Chambers, Hopkins, Weaver, &

Key, 2008; Gale et al., 1999; Kesler et al., 2001; Parkinson

et al., 2002; Porter, Hopkins, Weaver, Bigler, & Blatter, 2002;

Prockop, 2005) There is wide individual variability in

cog-nitive defi cits and long-term outcome following acute CO

exposure (Hopkins & Woon, 2006) This variability may be

explained by severity of exposure, but not consistently so

For example, Chambers and colleagues (2008) prospectively

examined the neuropsychological performance of 256

indi-viduals with CO poisoning, stratifi ed by severity of exposure

(55 less severe, 201 more severe), at serial intervals following

the initial exposure The two groups did not diff er in

preva-lence of cognitive defi cits at six weeks, six months, or 12

months postexposure At six weeks, rates of exposure were

39% and 35% for the less and more severe groups respectively

Behavioral and emotional symptoms following CO

poisoning include depression, anxiety, and mood lability

(Chambers et al., 2008; Gale et al., 1999; Jasper, Hopkins,

Duker, Waver, 2005) Psychiatric disturbance may predate

CO exposure (i.e., depression in individuals with CO

poi-soning from suicide attempts) and may persist In general,

individuals with CO poisoning due to suicide attempts show

higher rates of depression and anxiety relative to individuals

who were accidentally exposed (Jasper et al., 2005)

Interest-ingly, depression and anxiety may actually be more common

in less-severely poisoned patients early in the course of

recov-ery (Chambers et al., 2008) There are also rare case reports

of new-onset obsessive-compulsive disorder (OCD) and

symptoms associated with Kluver-Bucy syndrome (Hopkins &

Woon, 2006) While behavioral and emotional symptoms

may infl uence cognitive defi cits, they do not fully account for

cognitive dysfunction in individuals exposed to CO (Porter

et al., 2002)

Some individuals experience a delayed-onset

neuropsy-chiatric syndrome with symptoms emerging 7–14 days after

exposure, and after an apparent recovery from acute toms The syndrome is typically characterized by parkinso-nian symptoms including bradykinesia, masked facies, and gait disturbance Prevalence estimates range from 0.06% to 40% of CO-exposed individuals (Hopkins & Woon, 2006), and there may be increased risk of the delayed syndrome with increasing age, longer duration of coma, and prolonged anoxia (Min, 1986) The structural neuroimaging fi ndings and clinical symptoms associated with the delayed syndrome may or may not resolve (Choi, 2002; Cocito et al., 2005; Min, 1986; Sohn, Jeong, Kim, Im, & Kim, 2000)

Neuroimaging fi ndings have revealed atrophy in the brains

of individuals who have been exposed to CO In addition to whole-brain atrophy, regional atrophic changes may aff ect the fornix, hippocampus, corpus callosum, and basal gan-glia (Gale et al., 1999; Kesler et al., 2001; Porter et al., 2002; Pulsipher, Hopkins, & Weaver, 2006) Atrophy of the corpus callosum was identifi ed in 80% of patients within six months

of exposure (Porter et al., 2002), but there was no tion with cognitive performance Infarcts in the bilateral hip-pocampi have been reported and associated with amnesia (Bourgeois, 2000; Gottfried & Chatterjee, 2001) Voxel-based morphometry reveals lower gray matter volumes in the basal ganglia, claustrum, amygdala, hippocampus, and frontal and parietal regions, as well as a correlation between lower gray matter volume and slower psychomotor speed (Chen, Chen

correla-et al., 2013)

Basal ganglia structures, particularly the globus pallidus, have known susceptibility to CO exposure; however, basal ganglia lesions are not universally identifi ed and may even

be absent in the presence of parkinsonian symptoms (Cocito

et al., 2005; O’Donnell, Buxton, Pitkin, & Jarvis, 2000; Prockop, 2005) For example, following the same exposure event, one individual experienced parkinsonian symptoms without a lesion in the globus pallidus, while another indi-vidual had pallidal lesions without parkinsonian symptoms (Sohn et al., 2000) Reliance on individual case reports of observable lesions may be misleading, as other neuroimaging methods have revealed structural compromise in the absence

of observable lesions Pulsipher and colleagues (2006) found decreased basal ganglia volume in 28% of a prospective sam-ple of patients with CO at six months postexposure, with an observable lesion in only one individual

Damage to white matter, particularly in periventricular regions, is commonly reported following CO exposure and white matter may be more sensitive than gray matter in the acute phases of exposure (Prockop & Chichkova, 2007; Sener, 2003) White matter hyperintensities on MRI have remained stable at six-month follow-up (Parkinson et  al., 2002) Using diff usion-weighted imaging, Chen, Huang and colleagues (2013) documented elevations in apparent dif-fusion coeffi cient (ADC, a marker of tissue injury) in the globus pallidus and corpus callosum acutely (< two weeks), subacutely (two weeks to six months), and chronically (> one year) following CO exposure ADC values correlated

with cognitive performance The delayed neuropsychiatric

syndrome that may follow CO exposure has also been

asso-ciated with changes in gray and white matter (Chu et al.,

2004; Cocito et al., 2005; Lo et al., 2007) DTI studies have

revealed white matter disruption in normal appearing white

matter that correlates with cognitive performance and

per-sists after hyperbaric oxygen treatment (Lin et al., 2009; Lo

et al., 2007)

Treatment of CO poisoning involves administration of

oxygen Guidelines typically suggest normobaric treatment

for lower levels of exposure and less severe symptoms, while

hyperbaric treatment is generally utilized in more severe

exposures; however, it can be diffi cult to initially determine

the exposure severity (Prockop & Chichkova, 2007) There is

also some debate about whether hyperbaric treatment yields

a better outcome than normobaric treatment (Stoller, 2007;

Weaver et al., 2002; Wolf, Levonas, Sloan, & Jagoda, 2008)

Substances of Abuse

Cannabis

Cannabis use has increased in recent years across the United

States This trend may be, in part, due to the legalization of

marijuana’s medicinal use in 20 states and recreational use in

two states While there are clear, acute aff ects of cannabis use

on cognition, hence its propensity for use, there are very few

prospective studies examining the long-term cognitive eff ects

of cannabis use One study conducted through the Dunedin

Multidisciplinary Health and Development Study seems to

provide strong evidence for long-term eff ects of cannabis on

intellect and cognition, at least at fi rst glance (Meier et al.,

2012) In this study, a cohort of 1037 individuals was followed

from birth to age 38, with cannabis use documented at ages

18, 21, 26, 32, and 38 years Participants were evaluated at

age 13, before cannabis use began, and then again at age 38

Intelligence was reassessed at multiple time points, but more

comprehensive neuropsychological evaluations occurred at

age 38 only; therefore, true prospective longitudinal data are

available only for intelligence Results illustrated a decline in

intelligence in cannabis users, as well as a pattern of

increas-ing intellectual decline with increasincreas-ing use The eff ect was

general and impacted all aspects of intelligence, including all

four Wechsler Adult Intelligence Scale–IV (WAIS-IV)

indi-ces (Verbal Comprehension, Perceptual Reasoning, Working

Memory, and Processing Speed) Cognitive defi cits were

asso-ciated with adolescent-onset use, but less so with adult-onset

use, and cessation of cannabis use did not fully reverse the

cognitive eff ects Despite the strengths of this study, including

the prospective design and large sample size, there are several

potential confounds, such as personality and socioeconomic

status, that may account for intellectual changes independent

of cannabis use (Daly, 2013; Rogeberg, 2013)

If one carefully examines the Meier study (Meier et al.,

2012) and other studies, there are indications that cannabis

exerts a long-term impact on variety of cal functions The most common defi cits observed aff ect learning and memory and secondary defi cits involve work-ing memory, reasoning/judgment, and inhibitory control (Crane et al., 2013; Gonzalez, 2007) Neurodevelopment factors and sex diff erences are also important variables to consider Adolescent-onset cannabis use appears to have a more detrimental impact on cognition relative to adult-onset use Additionally, males appear to have more problems with reasoning/judgment, whereas females have more problems with memory (Crane et al., 2013)

In terms of the structural underpinnings of related cognitive defi cits, the evidence points to changes in the prefrontal cortex, subcortical striatal structures, and the limbic system (Mata et al., 2010; Smith et al., 2013; Yucel

cannabis-et al., 2008) There is some evidence that heavy use is not associated with diff erences in brain volume between users and controls although, within users, the volumes of the amygdala and hippocampus varied negatively with use (Cousijn et al., 2012) One particular study of interest examined memory performance using the California Verbal Learning Test-II (CVLT-II) in adolescents who were abstinent for at least six months and correlated their performance with hippocam-pal volume (Ashtari et al., 2011) Performance was lower in users relative to controls, and correlated with smaller right hippocampal volumes This structure-function correlation is important, but does not provide defi nitive evidence linking cannabis use to impaired learning and memory as a result of changes in the hippocampus

Along the same lines, there is evidence of an association between cannabis use and reduced medial orbital frontal volume, as well as correlation between volume reductions and decision-making defi cits (Churchwell, Lopez-Larson, & Yurgelun-Todd, 2010) These fi ndings were accompanied by

a dose-response eff ect Smith and colleagues (2013) found diff erences in striatal and thalamic shape among cannabis users, and these diff erences in brain structure shape corre-lated with working memory defi cits

Amphetamines and MDMA

Both amphetamines and MDMA amphetamine) have high rates of abuse and, in particular, heavy use on college campuses This brief review will focus most on MDMA Other amphetamines (speed and meth-amphetamine) are associated with cognitive defi cits aff ect-ing attention, inhibition, executive functions, visual spatial skills, and learning and memory (Ersche & Sahakian, 2007; Scott et al., 2007) Methamphetamine abuse is hypothesized

(3,4-Methylenedioxymeth-to impact fron(3,4-Methylenedioxymeth-to-striatal systems, in particular (Scott et al., 2007) Changes are noted in the frontal gray and white mat-ter (Daumann et al., 2011; Koester et al., 2012; Nakam et al., 2011; Tobia et al., 2010), and there is some suggestion that frontal lobe defi cits may predate abuse and then worsen secondary to abuse (Winhusen et al., 2013) Questions also

remain about the permanency of the defi cits, thus it is

impor-tant to consider moderator variables with individual cases

(Dean, Groman, Morales, & London, 2013) Additionally,

there are some data to support a causal link between

absti-nence and improved cognition (Iudicello et al., 2010) It has

also been shown that abstinent users are dopamine-defi cient

and experience memory defi cits that are associated with

striatal dopamine reductions (McCann et al., 2008)

We chose to focus on MDMA in this review because of

its cultural popularity among young adults and the

avail-ability of prospective data In one prospective study of 188

MDMA-naive users who had a high likelihood of use, de

Win and colleagues (2008) employed a variety of structural

(MRS, DTI) and functional imaging techniques (SPECT

to study serotonin transporters and perfusion-weighted

imaging to study blood volume) Changes were observed in

blood fl ow in the putamen and globus pallidus and fractional

anisotropy in the fronto-parietal white matter and thalamus,

with no changes observed in the serotonin system or brain

metabolites measured by MRS These changes occurred after

an average use of six tablets Unfortunately, cognitive data

were not provided A recent review suggests that, while not all

aspects of cognition are aff ected by MDMA abuse, memory

and executive functions are most commonly aff ected

(Par-rot, 2013) Indeed, some studies report minimal diff erences

between users and controls (Halpern et al., 2010), but there

are prospective cognitive data to support memory

impair-ment in MDMA users (Wagner, Becker, Koester,

Gouzoulis-Mayfrank, & Daumann, 2012)

Opiates

Opiate use has resurged in recent years with abuse of

pre-scription-based opiate pain medications, which is a particular

problem here in Appalachia, and with heroin use and

celeb-rity overdoses making national news Neuropsychological

defi cits in longterm opiate users include visual spatial defi

-cits, impaired attention and memory, and more prominent

frontal lobe dysfunction (Gruber, Silveri, & Yurgelun-Todd,

2007) Some of these defi cits may be related to

personal-ity characteristics that actually lead individuals to become

users in the fi rst place (Prosser et al., 2008) It is of particular

interest that the treatments used for opiate addiction, namely

methadone and buprenorphine, are opiates themselves and

thus may also have a negative impact on cognition (Prosser

et al., 2006; Rapeli, Fabritius, Kalska, & Alho, 2009, 2011)

Some data suggest that the eff ect of methadone is greater

(van Holst & Schilt, 2011), but such fi ndings are tentative

due to methodological limitations

Neuroimaging studies suggest that changes in gray matter

volume are present immediately after abstinence and that,

while some areas may improve over time (i.e., superior

fron-tal gyrus), diff erences between users and controls remain in

the middle frontal gyrus and cingulate (Wang et al., 2012)

White matter changes are also present using DTI, with

fractional anisotropy (FA) reductions observed in the hippocampus correlating with memory performance and FA reductions in the orbital frontal white matter correlating with performance on the Iowa Gambling Task (Lin et al., 2012; Qiu et al., 2013)

Alcohol

From a neuropsychological perspective, alcohol is the most widely and thoroughly studied substance of abuse There are many excellent reviews (e.g., Parsons, 1994; Parsons, 1998; Parsons & Nixon, 1998; Rourke and Loberg, 1993), so we will just briefl y summarize the knowledge as we understand

it Cognitive defi cits occur in a wide range of areas, ing memory, attention, processing, visual spatial skills and frontal lobe/executive functions Some defi cits may improve with abstinence, but some individuals with a suffi ciently long duration and intensity of abuse experience persistent defi cits Cognitive defi cits can be mild, and in some cases reversible, but may also rise to the level of a dementia syndrome In those cases, some level of residual cognitive impairment is likely even with prolonged abstinence Mild cognitive defi -cits can be detected in social drinkers or those with alcohol dependence (Parsons, 1998) Of course, Korsakoff ’s amnesia may also present in individuals who abuse alcohol and have concurrent nutritional defi cits We refer readers to a recent

includ-series of review articles on this subject published in

Neuro-psychology Review (2012, Volume 22)

Neuroimaging defi cits associated with alcohol abuse and dependence aff ect a wide range of brain structures, including both gray and white matter MRI demonstrates reduction in the volume of frontal gray and white matter, as well as the cerebellum (Rosenbloom & Pfeff erbaum, 2008) As with cog-nitive defi cits, structural brain changes may at least partially reverse with abstinence, and improvements in brain structure are related to improvements in brain function (Sullivan, Har-ris, & Pfeff erbaum, 2010) Consistent with other substances

of abuse, there is evidence of preexisting, genetically linked structural defi cits that may predispose certain individuals

to alcohol abuse (Gierski et al., 2013) In addition, use and abuse during adolescence, when the brain is exceedingly vulnerable to insult, may have particularly negative eff ects

on brain structure (Lisdahl, Gilbart, Wright, Shollenbarger, 2013) There are also some prospective data noting declines

in white matter integrity in adolescents who use both alcohol and cannabis, but not in those who use alcohol alone (Jaco-bus, Squeglia, Bava, & Taper, 2013)

Chemotherapy

Alkylating agents were fi rst introduced as anticancer pies following World War II The cytotoxic eff ects of nitrogen mustards became evident secondary to chemical warfare and, thereafter, mustine or “HN2” became the fi rst chemotherapy drug Although toxic eff ects to human tissue were recognized

thera-early in the introduction of nitrogen mustard therapy, it was

presumed that anticancer agents did not cross the

blood-brain barrier and that any cognitive changes occurring in the

context of non-CNS tumors were secondary to other factors

(Ahles & Saykin, 2007a; Goodman et al., 1946; Karnofsky,

1958; Rhoads, 1946; Silberfarb, Philibert, & Levine, 1980)

The neurotoxic eff ects of chemotherapy were not discussed

until the 1980s, when researchers at Dartmouth put forth

that cognitive impairment in chemotherapy-treated cancer

patients was independent of aff ective disturbance (Nelson &

Suls, 2013; Oxman & Silberfarb, 1980; Silberfarb, 1983;

Sil-berfarb et al., 1980) In the late 1990s, chemotherapy-related

cognitive impairment gained more substantial scientifi c

attention and the phenomenon of “chemo-brain” was born

(Ahles, 2012; Ahles & Whedon, 1999; van Dam et al., 1998)

Chemo-brain, alternatively known as “chemo-fog” and

“chemotherapy-related cognitive impairment,” refers to

cog-nitive changes caused by chemotherapy itself (Raff a et al.,

2006; Hodgson, Hutchinson, Wilson, & Nettelbeck, 2013)

Although high-dose chemotherapy exerts a more potent

eff ect on cognition than standard-dose chemotherapy, both

are suffi cient to produce cognitive defi cits (van Dam et al.,

1998) The bulk of research on chemo-brain has been derived

from studies of patients having undergone standard-dose

chemotherapy for breast cancer, lymphoma, and other

non-CNS cancers (Abrey, 2012; Saykin, Ahles, & McDonald,

2003) The precise mechanisms underlying

chemotherapy-induced neurotoxicity are not well understood, although the

integrity of the blood-brain barrier and oxidative stress are

believed to play a role (Saykin et al., 2003; Seigers, Schagen,

Tellingen, & Dietrich, 2013)

Between 15% and 75% of cancer patients report at least

mild cognitive impairment at some point during or after

treatment, while up to 61% may experience persistent

post-treatment cognitive defi cits (Ahles, 2012; Ahles & Saykin,

2007b; Janelsins et al., 2011; Wefel, Lenzi, Theriault, Davis, &

Meyers, 2004) Cognitive defi cits in attention, concentration,

processing speed, verbal and visual memory, and

multitask-ing are commonly reported followmultitask-ing treatment (Ahles &

Saykin, 2002; Wefel et al., 2004) A recent meta-analysis of

chemotherapy-related cognitive impairment found that the

domains of memory and executive function are most

consis-tently aff ected on neuropsychological testing (Hodgson et al.,

2013) Although some cancer patients experience resolution

of cognitive symptoms following treatment, others face more

persistent cognitive diffi culties for up to 20 years following

treatment (de Ruiter et al., 2011; Koppelmans et al., 2012)

Mood disturbance is common among cancer patients and

may at least partially fuel subjective cognitive complaints

(Koppelmans et al., 2012) The prevalence of major

depres-sion in cancer survivors has been estimated at between 10%

and 25% (Fann et al., 2008), which is fairly consistent with

recent estimates from the U.S adult population (9% as

reported by CDC, 2010) Most cancer survivors do not meet

clinical criteria for major depression and actually experience

fewer depression symptoms relative to normal controls (Koppelmans et al., 2012) There is also evidence that cancer patients experience clinical depression and anxiety prior to cancer treatment (Linden, Vodermaier, MacKenzie, & Greig, 2012) Thus, it does not appear that chemotherapy triggers mood disturbance in the same way that it leads to cognitive defi cits, but rather that preexisting depression and anxiety and treatment eff ects, such as fatigue, contribute to the cogni-tive sequelae known as chemo-brain

Some propose that the eff ects of chemo-brain cannot

be fully captured through neuropsychological measures (Reuter-Lorenz & Cimprich, 2013) When cognitive com-plaints exceed objective defi cits, clinicians frequently write the discrepancy off to stress, fatigue, or mood disturbance (Scherling & Smith, 2013) Neuroimaging off ers an alterna-tive mechanism to explore the eff ect of chemotherapy on cognition and the brain

Structural imaging studies applying tensor-based and voxel-based morphometry demonstrate reductions in total brain volume and gray matter volume in chemotherapy-exposed patients relative to healthy controls (Conroy et al., 2013; Inagaki et al., 2007; Koppelmans et al., 2012; McDon-ald, Conroy, Ahles, West, & Saykin, 2010) These changes have been documented shortly after treatment and at long-term follow-up, mainly in cross-sectional designs and at least one prospective study (McDonald et al., 2010)

Signifi cant reductions in white matter integrity are tently reported in DTI studies of patients receiving chemo-therapy (Abraham et al., 2008; Deprez, Billiet, Sunaert, & Leemans, 2013; Deprez et al., 2011; Deprez et al., 2012) Decreased FA in various white matter tracts has been found

consis-to correlate with neuropsychological performance on sures of processing speed, attention and short-term memory (Abraham et al., 2008; Deprez et al., 2011; Deprez et al., 2012)

Functional imaging studies suggest that chemotherapy infl uences the way cancer patients use their brains during cognitive tasks (Haut, Wiener, Marano, & Abraham, 2013)

As early as one month after chemotherapy, patients onstrate decreased frontal activation on working memory tasks relative to healthy controls (de Ruiter & Schagen, 2013; McDonald et al., 2012) Some report a return to neurofunctional baseline at one year after treatment, while others report persistent changes in brain activation In an fMRI study conducted ten years after chemotherapy, breast cancer survivors showed task-specifi c hyporesponsiveness

dem-of the dorsolateral prefrontal cortex and parahippocampal gyrus, in addition to generalized hyporesponsivenss of the bilateral posterior parietal cortex (de Ruiter et al., 2011) Other follow-up studies suggest similar activation patterns and a correlation between frontal activation and cognitive performance (Conroy et al., 2013; Kesler, Kent, & O’Hara, 2011; Simó, Rifa-Ros, Rodriguez-Fornells, & Bruna, 2013) Functional imaging studies have also documented signifi -cantly increased cortical activation in chemotherapy-treated

cancer patients relative to healthy controls (Kesler, Bennett,

Mahaff ey, & Spiegel, 2009) In one study comparing two

monozygotic twins, only one of whom received

chemo-therapy for breast cancer, the chemochemo-therapy-treated twin

demonstrated a wider extent of spatial activation during an

n-back working memory task, but no diff erence in

perfor-mance (Ferguson, McDonald, Saykin, & Ahles, 2007)

Simi-larly, one study using 18 fl uorodeoxygluose-PET found lower

resting metabolism in the inferior frontal cortex of patients

treated with chemotherapy 5–10 years earlier relative to

con-trols, but then increased frontal activation during a memory

task (Silverman et al., 2007) These fi ndings may stem from

decreased cognitive effi ciency or some sort of compensatory

mechanism

Although cognitive defi cits resulting from standard-dose

systemic chemotherapy are usually mild, the eff ect on quality

of life may be more substantial (Saykin et al., 2003)

Cogni-tive complaints have been associated with poorer functional

outcome (Reid-Arndt et al., 2010) Chemo-brain can infl

u-ence basic functioning, self-esteem, social relationships,

edu-cational goals, and career decisions (Ahles & Saykin, 2001;

Ahles & Whedon, 1999; Voh Ah et al., 2013) Social

sup-port and fatigue are also imsup-portant predictors of quality of

life (Reid-Arndt, Hsieh, & Perry, 2010) Thus, preventative

eff orts or treatment are important

In the last few years, cognitive-behavioral

interven-tions targeting chemo-brain have been developed and

researched Preliminary fi ndings from two recent

random-ized controlled trials suggest that brief cognitive

behav-ioral therapy (CBT) or cognitive rehabilitation improves

cognitive performance and overall life satisfaction in

chemotherapy-treated cancer patients relative to

no-treat-ment controls (Cherrier et al., 2013; Ferguson et al., 2012)

These results are very promising Other treatment options

include pharmacological interventions targeting attention/

alertness, sleep, mood, diet, and physical activity, which

mitigate chemotherapy-induced cognitive defi cits The

util-ity of cholinesterase inhibitors and herbal supplements,

such as Ginkgo biloba, is unknown (Fardell, Vardy,

John-ston, & Winocur, 2011)

Assessment and Other Issues

Although cognitive symptoms vary depending upon the

toxin, attention and executive functions are almost

univer-sally aff ected and should be assessed thoroughly as part of

a neuropsychological examination In cases of occupational

toxic exposure, issues of secondary gain and

malinger-ing must be considered A substantial portion of patients

with suspected chronic toxic encephalopathy demonstrates

suboptimal eff ort on cognitive tests (Greve et al., 2006; van

Hout, Schmand, Wekking, & Deelman, 2006; van Hout,

Schmand, Wekking, Hageman, & Deelman, 2003) and,

therefore, inclusion of performance/symptom validity

mea-sures is recommended

Conclusions

There is clearly individual variability in the eff ects and sequelae associated with exposure to CNS toxins From a cognitive perspective, executive dysfunction is a common theme across the toxins discussed in this chapter Hand-in-hand with this, emotional lability is a frequent behavioral consequence Apart from alcohol, the threshold for neu-rotoxicity is poorly understood across toxins Addition-ally, because longitudinal data are lacking, the persistence

of resultant symptoms is unclear and it is challenging to determine if the defi cits observed are, in fact, a consequence

of toxic exposure, or a predisposition There is increasing evidence of structural brain predispositions to substance abuse, in particular Further research that takes into account genetic and structural vulnerabilities to the eff ects of toxins

is necessary to elucidate threshold and permanency issues

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