Enkephaenkepha-lin immunoreactivity is derived from the striatopallidal projection of the indirect pathway as well as neurons that are intrinsic to GPe that also express GABA and enkepha
Trang 27.2.3.1.1 4 Serot onin
Serotonergic innervation to GPe is less intense than GPi
(Lavoie and Parent, 1990) and 5-HT levels are lower in
GPe in MPTP models of PD (Pifl et al., 1991)
7.2.3.1.1 5 Acet ylcholine
The G Pe rece ives a small cholinergic i nput from P PN
(Garcia-Rill, 1991) The significan ce of c holine rgic i npu t
in the re gulation o f G Pe n euron s remains to b e exp lo red
7.2.3.1.2 Neu ropeptid e of GPe afferents
7.2.3.1.2 1 En kephali n
The GPe is characterized by the presence of dense
immunoreactivity to enkephalin The level of
enkepha-lin in GPe is second only to that of striatum Enkephaenkepha-lin
immunoreactivity is derived from the striatopallidal
projection of the indirect pathway as well as neurons
that are intrinsic to GPe that also express GABA and
enkephalin (Hoover and Marshall, 1999) In MPTP
models of primate PD, along with an increased release
of GABA, the level of enkephalin in GPe is also
increased (Betarbet and Greenamyre, 2004)
7.2.3.2 Neur ochemis try of GPe neurons
Neu rons intri nsic to GPe are of two type s: those n
eu-rons that contain GABA and parvalbu min and project
to STN, GPi and nigra and thos e that express GAB A
and PPE A (enkep halin) that project to the parva
lbu-min contain ing intern euron s of the striatum ( Bevan
et al., 1998; Hoov er and Marshal l, 1999 ) Dopamine
dener vation by either 6-O HDA lesioning of nigra o r
by administ ration of D2-ant agonists but not D 1
-antago-nists incr eases GAD 67 mRNA levels in bo th types of
GPe neurons and this increas e is reve rsed by STN
lesioning (Billi ngs and Marshall, 2004 ) In PD, GAB A
levels are increas ed in GPe ( Kish et al., 1986 )
In control brains, the GPe neuro ns do not express
mRN A for neuro tensin Dopamine denervat ion wi th
6-OHDA , however , resu lts in the expre ssion of im mu-noreactivi ty for neuroten sin in neuro ns of GP in rats (Mar torana et al., 2003 )
Th e SP/dyno rphi n-containi ng axons of the direct pathway traverse through GPe, but neurons of GPe
do not no rmally expre ss mRN A for SP or for SP receptors After 6-OHDA destruc tion of SN in rats, several neuro ns in GP in rats express immuno reactiv-ity for SP ( Mar torana et al., 2003 )
7.2.3.3 Neurochem istry of GPe rece ptors 7.2.3.3.1 Neurot ransmitter recepto rs 7.2.3.3.1 1 Dopa mine receptors D1 mRNA as well as D 1 -receptor pr otein from affer-ent terminals is expr essed in the ne urons and neuro-phil of GPe The level of expression of D1 mRNA
in control and PD is not altered ( Hurl ey et al.,
2001) D2 -receptors are densely distributed in both type s of GPe ne uron and possibly in t he ni gr opallidal terminals and play a significant role in the regulat ion
of GAD67 in both types o f p allidal n euron ( Hoover and Marshall, 2004) In GPe, imm u noreact ivity for
bo th D2 S and D2 L forms ha s been observed, but the immunoreacti ve pattern of D2 L f or m s h o w s a hi gh e r intensity t han the D2 S form (Khan et al., 1998) The striatal neurons e xpress t he D2 L form more i ntensely than the D2 S form (Khan et al , 1998) Ter mina ls o f the dense projections from the medium spiny neurons
of the indirect pathway to GPe may be the source of the D2L immunoreactivity in GPe GPe also receives
a small but significant projection from SNpc, which expresses mainly the D2S form in their soma and axons, thereby suggesting that the nigropallidal pro-jections may be the source of D2S immunoreactivity observed in GP D3-receptor binding is low in both pallidal segments but it is upregulated after MPTP (Morissette et al., 1998)
Fig 7.1 For f ul l color figure, se e plate section Diagrammatic representation o f n eurochemi cal change s in P D ( Se e se ction
7 6 2 ) T h e r e d do t / d a s he d l i n e r e p r e s e nt s t he d e g e n e r a t i n g d op amine rgic ni g rostriatal, mesos triatal and mesolimbic inp ut The blue dashed line represents the degeneration of the ascending serotoninergic projections from the oral raphe to the basal ganglia and the cerebral cortex The red dotted line represents the degenerating ascending norepinephrinergic projections from locus ceruleus to the cerebral cortex Note that the basal ganglia receive very little direct norepinephrinergic projec-tion from locus ceruleus The solid orange line represents an increased histaminergic input to the basal ganglia and the cor-tex The descending purple dotted line represents the degeneration of the norepinephrinergic input from the locus ceruleus and A2/C2 to the spinal cord The blue dashed line depicts the degeneration of serotoninergic input to the spinal cord from caudal raphe pallidus The descending dopaminergic projection to the spinal cord from the hypothalamic A11 group of TH-positive neurons, shown as a solid red line, does not degenerate in PD The pattern of loss of cholinergic neurons is not shown in the figure The text boxes show that the pattern of loss of various neurotransmitters varies at different levels of the PD brain
Trang 37.2.3.1.1 4 Serot onin
Serotonergic innervation to GPe is less intense than GPi
(Lavoie and Parent, 1990) and 5-HT levels are lower in
GPe in MPTP models of PD (Pifl et al., 1991)
7.2.3.1.1 5 Acet ylcholine
The G Pe rece ives a small cholinergic i nput from P PN
(Garcia-Rill, 1991) The significan ce of c holine rgic i npu t
in the re gulation o f G Pe n euron s remains to b e exp lo red
7.2.3.1.2 Neu ropeptid e of GPe afferents
7.2.3.1.2 1 En kephali n
The GPe is characterized by the presence of dense
immunoreactivity to enkephalin The level of
enkepha-lin in GPe is second only to that of striatum Enkephaenkepha-lin
immunoreactivity is derived from the striatopallidal
projection of the indirect pathway as well as neurons
that are intrinsic to GPe that also express GABA and
enkephalin (Hoover and Marshall, 1999) In MPTP
models of primate PD, along with an increased release
of GABA, the level of enkephalin in GPe is also
increased (Betarbet and Greenamyre, 2004)
7.2.3.2 Neur ochemis try of GPe neurons
Neu rons intri nsic to GPe are of two type s: those n
eu-rons that contain GABA and parvalbu min and project
to STN, GPi and nigra and thos e that express GAB A
and PPE A (enkep halin) that project to the parva
lbu-min contain ing intern euron s of the striatum ( Bevan
et al., 1998; Hoov er and Marshal l, 1999 ) Dopamine
dener vation by either 6-O HDA lesioning of nigra o r
by administ ration of D2-ant agonists but not D 1
-antago-nists incr eases GAD 67 mRNA levels in bo th types of
GPe neurons and this increas e is reve rsed by STN
lesioning (Billi ngs and Marshall, 2004 ) In PD, GAB A
levels are increas ed in GPe ( Kish et al., 1986 )
In control brains, the GPe neuro ns do not express
mRN A for neuro tensin Dopamine denervat ion wi th
6-OHDA , however , resu lts in the expre ssion of im mu-noreactivi ty for neuroten sin in neuro ns of GP in rats (Mar torana et al., 2003 )
Th e SP/dyno rphi n-containi ng axons of the direct pathway traverse through GPe, but neurons of GPe
do not no rmally expre ss mRN A for SP or for SP receptors After 6-OHDA destruc tion of SN in rats, several neuro ns in GP in rats express immuno reactiv-ity for SP ( Mar torana et al., 2003 )
7.2.3.3 Neurochem istry of GPe rece ptors 7.2.3.3.1 Neurot ransmitter recepto rs 7.2.3.3.1 1 Dopa mine receptors D1 mRNA as well as D 1 -receptor pr otein from affer-ent terminals is expr essed in the ne urons and neuro-phil of GPe The level of expression of D1 mRNA
in control and PD is not altered ( Hurl ey et al.,
2001) D2 -receptors are densely distributed in both type s of GPe ne uron and possibly in t he ni gr opallidal terminals and play a significant role in the regulat ion
of GAD67 in both types o f p allidal n euron ( Hoover and Marshall, 2004) In GPe, imm u noreact ivity for
bo th D2 S and D2 L forms ha s been observed, but the immunoreacti ve pattern of D2 L f or m s h o w s a hi gh e r intensity t han the D2 S form (Khan et al., 1998) The striatal neurons e xpress t he D2 L form more i ntensely than the D2 S form (Khan et al , 1998) Ter mina ls o f the dense projections from the medium spiny neurons
of the indirect pathway to GPe may be the source of the D2L immunoreactivity in GPe GPe also receives
a small but significant projection from SNpc, which expresses mainly the D2S form in their soma and axons, thereby suggesting that the nigropallidal pro-jections may be the source of D2S immunoreactivity observed in GP D3-receptor binding is low in both pallidal segments but it is upregulated after MPTP (Morissette et al., 1998)
Fig 7.1 For f ul l color figure, se e plate section Diagrammatic representation o f n eurochemi cal change s in P D ( Se e se ction
7 6 2 ) T h e r e d do t / d a s he d l i n e r e p r e s e nt s t he d e g e n e r a t i n g d op amine rgic ni g rostriatal, mesos triatal and mesolimbic inp ut The blue dashed line represents the degeneration of the ascending serotoninergic projections from the oral raphe to the basal ganglia and the cerebral cortex The red dotted line represents the degenerating ascending norepinephrinergic projections from locus ceruleus to the cerebral cortex Note that the basal ganglia receive very little direct norepinephrinergic projec-tion from locus ceruleus The solid orange line represents an increased histaminergic input to the basal ganglia and the cor-tex The descending purple dotted line represents the degeneration of the norepinephrinergic input from the locus ceruleus and A2/C2 to the spinal cord The blue dashed line depicts the degeneration of serotoninergic input to the spinal cord from caudal raphe pallidus The descending dopaminergic projection to the spinal cord from the hypothalamic A11 group of TH-positive neurons, shown as a solid red line, does not degenerate in PD The pattern of loss of cholinergic neurons is not shown in the figure The text boxes show that the pattern of loss of various neurotransmitters varies at different levels of the PD brain
Trang 4Table 7.2
Changes in the levels of neurotransmitters and neuropeptides in PD
SN Striatum Gpe STN Gpi Hypothalamus Spinal cord Cerebellum Cerebral cortex Neurotransmitters
Histamine "" "" """ ""
Acetylcholine #
Glutamate Unchanged "" Unchanged " Unchanged
GABA Unchanged "" "" Unchanged ""
Neuropeptides
Enkephalin Unchanged " - "" " """
Dynorphin Unchanged ""
Cholecystokinin - 8 Undetectable "
Neurotensin "" "
NPY "
References in text.
Neurotransmitter changes in MPTP model of PD are similar ( Pifl and Hornykiewicz, 1998 ).
Trang 5Chapter 8
The neuropathology of parkinsonism
DANIEL P PERL*
Mount Sinai School of Medicine, New York, NY, USA
8.1 Introduction
A variety of disorders of the nervous system result in
parkinsonian symptoms Virtually all involve damage
to various components of the basal ganglia Some of
these conditions are rather common whereas others are
exceedingly rare Here, the neuropathologic features of
many of these conditions will be summarized First
and foremost will be a discussion of the neuropathologic
finding in cases of Parkinson’s disease, the prototype
condition Some of the other, better-characterized forms
of parkinsonism will then be reviewed
8.2 Parkinson’s disease (paralysis agitans)
James Parkinson’s 1817 classic monographAn Essay
on the Shaking Palsy is well known for its elegant
description of the clinical features of the disorder
that would ultimately bear his name (Parkinson, 1955,
originally published 1817) However, it also includes
Parkinson’s comment that he was reluctant to speculate
on the nature and cause of the disease he was describing
This hesitation was caused by the fact that, as he noted,
he was hampered ‘not having had the advantage, in a
single case, of that light which anatomical examination
yields’ At the time little neuropathologic expertise
was available and it would be almost 100 years until
some of the underlying anatomical features would
first be identified Indeed, in the later portion of the
19th century, Jean-Martin Charcot failed to find a
char-acteristic abnormality in the brains of patients who
had suffered from Parkinson’s disease Based on his
inability to recognize an identifiable neuropathologic
lesion, Charcot began to lecture that Parkinson’s disease
might be functional in nature It was not until 1912
that Frederick Lewy first described the diagnostic
intranuclear inclusion body associated with Parkinson’s disease (Lewy, 1912) Interestingly, Lewy’s descrip-tions of the inclusions that bear his name were first seen
in neurons of the substantia innominata and the dorsal motor nucleus of the vagus but in his original report he failed to recognize their presence in the substantia nigra pars compacta It was not until 1919, in Tre´tiakoff’s the-sis at the University of Paris (Tre´tiakoff, 1919), that the importance of involvement of the substantia nigra pars compacta in cases of Parkinson’s disease, especially with involvement by Lewy bodies, first became recognized It would be many decades until the neuroanatomic and neu-rochemical details of basal ganglia structure and function would eventually become clarified, ultimately leading to the introduction of the primary form of therapy for the disease, levodopa, and then to other secondary forms of treatment that are currently in use
8.2.1 Gross morphologic abnormalities
In patients with Parkinson’s disease the gross external appearance of the brain does not reveal any distinguish-ing features However, on further dissection of the speci-men, the cut surface of the midbrain reveals a loss of pigmentation of the substantia nigra that is readily appar-ent (Fig 8.1) This loss of pigmentation may be complete
or, more commonly, partial When some visible pigmen-tation remains in the substantia nigra aside from a lessen-ing of the black coloration, there is typically some blurring of its edges In such cases the observer may be forced to compare this appearance to that of a normal brain in order to verify the presence of pigmentary loss The locus ceruleus is similarly depigmented in almost all cases Importantly, the gross appearance of the globus pallidus, caudate nucleus and putamen remains intact and these important basal ganglia structures are
*Correspondence to: Daniel P Perl, MD, Professor of Pathology (Neuropathology), Mount Sinai School of Medicine, One Gustave
L Levy Place, Box 1134, New Y or k, NY 10029, USA E-mail: daniel.perl@mssm.edu, Tel: þ 1- 212-241-7371, Fax: þ 1-212-996-1343
Parkinson’s disease and related disorders, Part I
W.C Koller, E Melamed, Editors
# 2007 Elsevier B.V All rights reserved
Trang 6Chapter 9
Genetic aspects of Parkinson’s disease YOSHIKUNI MIZUNO *, NOBUTAKA HATTORI AND HIDEKI MOCHIZUKI
Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
9.1 Genetics of familial forms of Parkinson’s
disease
To date, 13 forms of famili al Parkinson ’s disease (PD )
have been map ped to certain loci on chromos omes and
they are designat ed as PARK 1, PARK 2, and so on
( Table 9.1 ) PARK1 , PARK 4, PARK 5, PARK 8 and
PARK 11 are auto somal-dom inant forms and PAR K2,
PARK 6, PARK 7 and PARK 9 are autosom al-recess ive
forms The causa tive genes have been iden tified in
seven forms ( a-synucl ein, parkin, ubiqu itin carbox
y-terminal hydrol ase L1 (UCH-L 1), DJ-1, PIN K1,
leucine -rich repea t kinase 2 (LRRK 2), and ATP1 31A
as the order of discover y) Th ese discover ies cont ributed
grea tly to the understand ing of molecu lar mechanism of
nigral neuro nal death in spora dic PD Re cent progr ess in
famili al forms of PD will be review ed belo w
9.1.1 Aut osomal- dominant fam ilial Parkins on’s
dise ase due to a -synuclein mutation s (PARK1)
9.1.1.1 Clini cal features of PARK1
PARK 1 is an auto somal-dom inant fam ilial PD caused
by mutation s of the a-synu clein gene Clinica l featur es
were first described by Golbe et al (1990) , who
reporte d two large, proba bly relat ed, k indreds with
auto psy-confirm ed PD The mode o f inhe ritance was
auto somal dominan t The rese archers found 41 affected
indivi duals in two kindr eds Both kindr eds immigr ated
to the New Jersey/ New Yor k area betwee n 1890 and
1920 from Con tursi, a village in the hills of Salerno
province in south ern Italy ( Golbe et al., 1990 ) Both
kindreds had their common ori gin in a sing le small
town in sout hern Italy, suggesting the com mon orig in
of the two kindreds, and in fact this common origin was later confirmed The average age of onset was 46.5 10.8 years (range 28–68, n ¼ 33) Death occurred
at the age of 53.5 9.2 years (range 42–74, n ¼ 31) Tremor was not a predominant feature: 2 out of 41 affected patients examined had prominent tremor and only 8 had tremor at all Otherwise, clinical features were typical of idiopathic PD Dementia was said to be unu-sual, mild or late Those patients treated with levodopa showed improvement in their parkinsonism and some
of them developed motor fluctuations Thus the age of onset in these kindreds was younger than that of sporadic
PD and the disease duration was shorter The causes of death were usually complications from PD Golbe et al reported 2 autopsied patients who showed severe neuro-nal loss in the substantia nigra with Lewy bodies in remaining neurons and in cell ghosts Gliosis was marked The locus ceruleus and dorsal motor nucleus
of the vagus also showed mild to moderate cell loss with Lewy bodies The substantia innominata revealed mild cell loss, moderate gliosis and numerous Lewy bodies
In 1996, Golbe et al reported follow-up of this family They were able to detect a total of 60 patients with average age of onset at 45.6 13.5 years (range 20–85 years) A mean course to death was 9.2 4.9 years (range 2–20 years) A segregation ratio was 40.1% for kindred members aged 50 years and older The authors found a highly variable degree of dementia in many of the affected members
Markopoulou et al (1995)reported a Greek-American kindred with clinically typical PD in 16 individuals in three generations Clinical features were similar to those
of the Contursi family with mean onset age in the 40s and mean survival time of 9 years.Golbe et al (1996)
*Correspondence to: Yoshikuni Mizuno, MD, Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan E-mail: y_mizuno@med.juntendo.ac.jp, Tel: þ 3-3813-3111, Ext 3807; Fax: þ3-5800-0547
Parkinson’s disease and related disorders, Part I
W.C Koller, E Melamed, Editors
# 2007 Elsevier B.V All rights reserved