(American Journal of Pathology. 1998;153:671-676.)
© 1998 American Society for Investigative Pathology
Multiple System Atrophy
Clues from Inclusions
Rudy Castellani, M.D.
From the Division of Neuropathology, Department of Pathology,
University of Maryland, Baltimore, Maryland
 |
Introduction
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Multiple system atrophy (MSA) was added to the list of
neurodegenerative diseases defined by cytoplasmic inclusions when Papp
et al1
demonstrated specific oligodendroglial
inclusions, referred to as glial cytoplasmic inclusions (GCIs), in
brains of patients affected by MSA. Their observation has since allowed
more accurate interpretation of the pathological differential diagnosis
of parkinsonian, cerebellar, and autonomic disorders and has further
supported the concept of MSA as an entity. Moreover, MSA appears unique
among neurodegenerative diseases in that its hallmark inclusion affects
oligodendrocytes, suggesting that glial changes and glial-neuronal
interactions may be early events in neurodegeneration, and emphasizing
the potential importance of myelin metabolism in disease pathogenesis.
In the current issue of this journal, Matsuo and
colleagues2
expand on this finding by providing
evidence that myelin degeneration in patients with MSA is more
widespread than previously recognized.
|
Development of the Multiple System Atrophy Concept: Historical
Perspective
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MSA is a sporadic neurodegenerative disease encompassing three
previously described clinical syndromes—striatonigral degeneration
(SND), olivopontocerebellar atrophy (OPCA), and Shy-Drager syndrome
(SDS)—with a common pathology.3
The current view
of MSA, however, took a number of years to unfold and is probably best
understood from a historical perspective.
In 1900, Déjerine and Thomas introduced the term
olivopontocerebellar atrophy (OPCA) when they described two middle-aged
patients with an ataxic disorder and pathological changes in the
brainstem and cerebellum. The striatum and substantia nigra were not
examined, or at least not commented on.4
Déjerine and
Thomas, and later Loew5
under the tutelage of
Déjerine himself, recognized OPCA cases as "atypical" when
they had a hereditary component or, interestingly, when there were
associated CNS lesions, but their concept of "atypical OPCA" fell
quickly into disuse.6
Nevertheless, OPCA as
described by Déjerine and Thomas persisted as an entity and was
the subject of a number of studies in the middle part of the 20th
century7,8
despite the fact that the distinction
between familial and sporadic OPCA (see below) and the frequency of
associated lesions were not fully appreciated.
In 1960, Shy and Drager described a
neurological syndrome with autonomic failure and parkinsonism,
SDS,9
in which striking orthostatic hypotension
was the common clinical feature. Previously described cases of
orthostatic hypotension, in retrospect, may have represented
SDS,10-12
but these were not as well
characterized. Shy and Drager noted degeneration of the
intermediolateral cell columns of the spinal cord (later recognized as
the anatomical substrate of autonomic failure), in addition to neuronal
loss and/or gliosis at many other sites including the caudate nuclei,
substantia nigra, cerebellar Purkinje's cells, and inferior olivary
nuclei. Lewy bodies were noted in a minority of the early SDS cases,
raising the possibility of "transitional" forms between SDS and
Parkinson's disease,13
although it should be
noted that examination of the striatum and (now) the presence of GCIs
will usually permit distinction between these two apparently separate
processes. It is also important to remember that the description of SDS
(as well as SND) preceded the availability of levodopa for diagnosis
and treatment of parkinsonism.14
The year before, van der Eecken et al had presented
"Striopallidal-nigral degeneration: An hitherto undescribed lesion in
paralysis agitans" to the American Association of Neuropathologists.
Their account was published in 1960 and then described in more detail
in 1961 and 1964 under the designation "striatonigral degeneration"
(SND).15-17
SND patients typically exhibited
parkinsonism and the major foci of neuronal loss were in the striatum
and the substantia nigra. Lewy bodies were not a constant feature in
SND, being present in the substantia nigra in only one of four cases.
OPCA was also described in one case but, as in SDS, only in retrospect
was OPCA found to be an important component of the underlying disease.
It also seems surprising that striatal pathology in patients with
parkinsonism was not described until the early 1960s. In fact,
pathological accounts of typical SND were described earlier, but were
included under the label of Parkinson's
disease.18
Given that approximately 10% of
patients with parkinsonism have MSA, it is indeed likely that many such
cases "have swelled the ranks of Parkinson's disease
clinics"14
unrecognized as a separate disease.
Finally, in a 1969 paper titled "Orthostatic Hypotension and Nicotine
sensitivity in a Case of Multiple System Atrophy," Graham and
Oppenheimer reported the case of a 60-year-old man who presented with
clinical features of SDS as well as cerebellar ataxia exacerbated by
cigarette smoking.19
Progressive clinical
deterioration ensued and he died about 2 1/2 years later.
Neuropathological examination disclosed degeneration of the striatum,
substantia nigra, pons, inferior olivary nucleus, cerebellar
Purkinje's cells, and intermediolateral cell column of the spinal
cord. From careful examination of this single case and review of
pertinent literature, Graham and Oppenheimer made the observation that
SDS, SND, and OPCA often co-existed clinically and pathologically and
were likely different expressions of one underlying disease. For better
or worse, they introduced the term "multiple system atrophy" for
this group of diseases to avoid "unnecessary confusion caused by
inventing new names."
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Clinical Neuropathology and Patterns of Degeneration
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According to current understanding, almost all MSA patients
develop parkinsonism or cerebellar signs. Thus, about 80% of patients
are parkinson-predominant (SND-predominant) and 20% are
cerebellar-predominant (OPCA-predominant).20
Pure
SND is relatively common clinically, whereas pure OPCA is unusual.
Onset of autonomic dysfunction (SDS) in MSA is variable but is usually
present at some point during the disease course. Patients with severe
autonomic dysfunction tend to be younger and to have a shorter
survival.20
As alluded to previously, the
frequent occurrence of parkinsonism emphasizes the often difficult
distinction between MSA and disorders such as Parkinson's disease and
progressive supranuclear palsy (Steele-Richardson-Oslewski syndrome).
Descriptions in recent studies of patterns of pathological involvement
of gray matter are generally an extension of the original accounts,
noting neuronal loss and gliosis in the striatum (more in the putamen
than in the caudate nucleus), substantia nigra, locus ceruleus,
inferior olivary nucleus, pontine nuclei, cerebellar Purkinje's
cells, intermediolateral cell column in the thoracic spinal cord,
and Onuf's nucleus in the sacral spinal cord. Other
populations variably affected include the external pallidum, thalamus,
vestibular nuclei, dorsal motor nucleus of the vagus, and corticospinal
tracts.20-22
The degree of involvement tends to
follow clinical signs, with the striatonigral system severely affected
in parkinson-predominant and pure SND cases, and the
olivopontocerebellar system severely affected in cerebellar-predominant
cases.20
Pathological changes in the
olivopontocerebellar system may be subtle or nonexistent in pure SND
cases, but because pure OPCA is unusual, striatal and nigral pathology
is present in the majority of MSA cases. Autonomic dysfunction in MSA
is related to degeneration of the intermediolateral cell column and
Onuf's nucleus.13
Dementia, on the other hand,
is not a major presenting problem, although some cortical deficits
emerge with psychometric testing23
and subtle
pathological abnormalities affecting the cerebral cortex are
described.24,25
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Absence of Well-Defined Genetic Etiology
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MSA is a largely sporadic condition and there have been few
studies investigating potential genetic etiologies. In a recent study
of 80 well-characterized MSA patients, Bandmann et
al26
found no alterations in either the SCA-1 or
SCA-3 gene, indicating that MSA is likely distinct from autosomal
dominant ataxias associated with unstable trinucleotide
repeats.27
Gotoda et al28
identified a mutation in the gene for 
-tocopherol transfer protein
in one patient with adult-onset spinocerebellar dysfunction,
substantiating the notion that altered vitamin E metabolism leads to
spinocerebellar pathology; however, the patient's neurological
disorder more closely resembled Friedreich's ataxia than MSA. In a
case-controlled study, Nee et al29
found that
patients with MSA had significantly more potential exposures to metal,
dusts, fumes, plastic monomers and additives, organic solvents, and
pesticides than the control population. The authors concluded that MSA
develops as a result of a genetically determined selective
vulnerability in the nervous system, although the nature of the
selective vulnerability was not elucidated and no disease-associated
genetic locus was identified. It should also be emphasized here that,
aside from one report of GCIs in SCA-1
pathology,30
GCIs continue to represent a
specific hallmark of sporadic MSA and are generally not a component of
the inherited ataxias. Therefore, the available data indicate that MSA
is an acquired condition distinct from CNS diseases with well-defined
genetic causes. In this regard it is interesting to note that increased
amounts of iron are consistently found in the striatum of MSA patients
both neuropathologically and on
neuroimaging.31,32
Fe(II) as a potent catalyst of
reactive oxygen species has been implicated in the
pathogenesis of common neurodegenerative
diseases.33,34
At present, evidence for oxidative
stress in MSA remains circumstantial.
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Glial Cytoplasmic Inclusions as the Pathological Hallmark of
Multiple System Atrophy: Characteristics, Distribution, and Pathogenic
Implications
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In their original study in 1989, Papp et al documented the
important finding of argyrophilic oligodendroglial inclusions in the
brains of patients with MSA.1
The GCIs were first
noted by Gallyas silver impregnation, used to demonstrate Alzheimer's
neurofibrillary pathology; they were localized largely to the white
matter and to cells with morphological features of oligodendrocytes in
all 11 cases. Neuronal inclusions with similar characteristics to GCIs
were also reported,35
but these are now
considered insufficient in density or specificity to be a reliable
feature of MSA.36
No GCIs were seen in any of the
age-matched normal controls and GCIs were absent from a variety of
other neurodegenerative diseases. Subsequent studies have verified the
presence of GCIs in MSA as well as the conclusion of Papp et al that
GCIs are sensitive and specific hallmarks of
MSA.37-42
The relevance of GCIs, not only
to characterizing a nosological entity but also in terms of enhancing
neuropathological interpretation of parkinsonian, ataxic, and autonomic
disorders, is self-evident.
By routine light microscopy, GCIs are faint eosinophilic inclusions
that eccentrically displace the nucleus. The Gallyas silver
technique produces selective dark staining of inclusions with a
clean background, making it more useful in demonstrating GCIs than
Bodian or Bielschowsky techniques, which have more background and less
pronounced staining of the inclusion. The various silver techniques
show GCIs are sickle-shaped to flame-shaped to ovoid, sometimes
superficially resembling neurofibrillary tangles. The fact that GCIs
were not detected earlier, though somewhat surprising, may reflect
their less intense staining with commonly used silver impregnations and
the fact that GCIs are essentially negative with other common stains,
including phosphotungstic acid hematoxylin, periodic acid-Schiff,
Masson trichrome, Alcian blue, thioflavine S, Congo red, oil red O, or
Sudan black B.3,36
On ultrastructural
examination, GCIs are comprised of loosely aggregated filaments with
cross-sectional diameters of 20 to 30 nm. The filaments often entrap
cytoplasmic organelles such as mitochondria and secretory vesicles,
have no limiting membrane, and are reported to have tubular profiles
and electron-dense granules along much of their
length.36,39
By immunocytochemistry, GCIs are
consistently positive for ubiquitin and -B crystallin, and less
intensely positive for - and ß-tubulins.3,36
Ubiquitin and -B crystallin positivity is not surprising, as both
proteins accumulate in a variety of poorly soluble inclusions as
a general indicator of cellular stress. MAP5 positivity is also
reported.38,39
GCIs are negative for
neurofilaments, glial fibrillary acidic protein, myelin basic protein,
vimentin, actin, desmin, myosin, and cytokeratin. The variable
literature on tau immunocytochemistry may reflect the phosphorylation
state of the tau epitope, as GCIs are generally negative for
phosphate-dependent tau antibodies and positive for normal adult
tau;43
this is in contrast to the neurofibrillary
pathology of Alzheimer's disease. The apparent absence of
phosphorylated tau further distinguishes GCIs from glial lesions in
corticobasal degeneration and progressive supranuclear palsy (eg,
tufted astrocytes, coiled bodies, astrocytic
plaques).36,43
The regional distribution of GCIs within the brain is complex.
Significant numbers of GCIs have consistently been found in the
putamen, pallidum, lateral caudate nucleus, basis pontis, spinal cord
intermediate gray matter, internal capsule, and middle cerebellar
peduncle,36
indicating a general tendency for
GCIs to accumulate in and around degenerated brain regions. Not
surprisingly, some have viewed this as evidence that GCI formation is a
secondary phenomenon. On the other hand, Papp and Lantos found from
their distribution study that GCIs preferentially involve
suprasegmental motor systems, supraspinal autonomic systems, and their
targets, while sparing primary sensory areas and cortical and
subcortical limbic structures, suggesting a "system-bound"
oligodendroglial degeneration.35
Moreover, the
presence of GCIs in such areas as motor cortex, cerebral white matter,
subthalamic nucleus, and brainstem reticular formation (structures that
do not typically degenerate in MSA) and their relative absence in the
substantia nigra, locus ceruleus, and inferior olivary nucleus suggest
that GCI formation cannot be attributed solely to a reaction to
neuronal damage.35
Inoue et
al40
also found a general relationship between
the density of GCIs and the severity of white matter tract involvement,
although again GCIs were more widespread than neuronal loss and the
density of GCIs in the cerebellar white matter in relation to severity
of pathology was more complex. Few GCIs were found in cerebellar white
matter with severe OPCA, whereas numerous GCIs were sometimes found
with little or no OPCA, furthering the argument that GCIs may be an
early lesion and not necessarily a reaction to neuronal injury.
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The Oligodendrocyte and Myelin as Potential Primary Targets
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GCIs consistently localize to cells with oligodendroglial
characteristics. By immunocytochemistry, GCI-containing cells are
immunoreactive with antibodies against Leu-7, carbonic anhydrase enzyme
II, and transferrin.39,42
Ultrastructural
characteristics of GCI-containing cells are also consistent with
oligodendroglial origin.1,37,39,42
As mentioned,
oligodendroglial inclusions are rarely encountered in other
neurodegenerative diseases; only in MSA does the oligodendrocyte
represent the predominant inclusion-bearing cell. It is somewhat
paradoxical that MSA rather eloquently affects selected gray matter
"systems" whereas its hallmark inclusion-bearing cell produces
myelin. Implicating the oligodendrocyte as the primary target,
therefore, means providing a mechanism for region-specific
oligodendrocyte dysfunction or a mechanism whereby oligodendrocyte
dysfunction leads to pronounced destruction of selected vulnerable
neuronal populations. To date there is little evidence that
oligodendrocytes may be subtyped according to the neuronal populations
they subserve. Older classifications of Mori and
LeBlond44
and Stensaas and
Stensaas45
subtyped oligodendrocytes based on
fine structural features of the oligodendrocyte nucleus and processes
and myelin sheaths, respectively, providing indirect evidence
for functional specialization, but no conclusive evidence for tract
specificity. More recently, oligodendrocyte development has been
characterized by immunophenotype, shedding some light on the
development of macroglia, but likewise has not progressed to the point
of tract or functional specificity.46
Additionally, single oligodendrocytes have been shown to myelinate
axons of different anatomical tracts, casting some doubt on the
possibility that oligodendrocytes may be classified based on the
functional properties of corresponding
axons.47,48
In MSA, GCIs are reported to involve
so-called perivascular, perifascicular, and perineuronal
oligodendrocytes without further qualification as to subtype. In
essence, then, GCIs involve all morphological types of oligodendrocytes
with varying frequency in various anatomical
regions.3,35
It therefore appears that
oligodendroglial disturbance in MSA, whether or not it occurs
primarily, tends to be more generalized and would likely have to occur
in conjunction with intrinsic vulnerability of selected neuronal
populations, the nature of which remains to be determined.
In the current issue of this journal, Matsuo and
colleagues2
document extensive myelin
degeneration in MSA brains by demonstrating widespread white matter
(but not GCI) immunopositivity with anti-EP antisera and monoclonal
antibody QD-9. Both antibodies recognize synthetic peptide QDENPVV
(corresponding to human myelin basic protein residues 82–88) and were
previously shown to immunolabel degenerated myelin in multiple
sclerosis and infarcted brains, but not myelin in normal
brain.49
The presence of unusual myelin basic
protein epitopes in MSA, in both affected and unaffected brain regions,
substantiates the notion of widespread oligodendroglial dysfunction in
MSA and highlights white matter disease as an integral component.
Nevertheless, the question of how oligodendrocyte degeneration might
lead to neuronal loss, to the extent encountered in MSA, remains. It is
noteworthy in this regard that axonal damage is known to occur in
otherwise classical demyelinating
conditions.50,51
Furthermore, the critical
trophic influences that are described between oligodendrocytes and
axons52
indicate that oligodendroglial pathology
would likely affect neuronal function. Oligodendrocyte pathology in the
form of (presumably chronic) inclusions, on the other hand, causing
selective and severe gray matter damage, would be unusual. It is safe
to conclude that despite the compelling evidence presented so far, more
studies are needed before GCIs or degenerated myelin epitopes may be
interpreted as primary lesions in the neurodegenerative process of MSA.
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Inclusions: Etiology Versus Epiphenomenon
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The difficulty in establishing a direct association between
inclusions and etiology is not unique to MSA. While inclusions provide
empirical pathological hallmarks for a number of neurodegenerative
diseases and are particularly strategic for studying disease
pathogenesis,53,54
a direct association between
inclusion and etiology (as opposed to epiphenomenon) remains unproven
for most neurodegenerative disorders. This includes neurofibrillary
pathology of Alzheimer disease and progressive supranuclear palsy, Lewy
bodies of Parkinson's disease and diffuse Lewy body disease, Pick's
bodies of Pick's disease, the various tau pathologies of corticobasal
degeneration, and Rosenthal fibers of Alexander's disease. On the
other hand, recent reports demonstrating tau gene mutation in familial
multiple system tauopathy,55
and the
immunolocalization of -synuclein, a protein mutated in chromosome
4-linked familial Parkinson's disease,56
to Lewy
bodies of idiopathic Parkinson's disease,57
provide direct links between genetic lesions and abnormal gene products
accumulating in hallmark inclusions. Therefore, as the biochemical
composition of GCIs and associated myelin abnormalities continue to be
elucidated, rigorous study of the pathological lesions of MSA, with the
hope of determining etiology and treatment strategies, appears
warranted. This is particularly true in light of the lack of a genetic
basis for the disease.
|
Conclusions
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After nearly a century of study MSA is now known to be a specific,
albeit heterogeneous, neurodegenerative disease encompassing
olivopontocerebellar atrophy, striatonigral degeneration, and
Shy-Drager syndrome. It was through thoughtful case examination,
detailed neuropathological study, and advances in molecular genetics
that the entity of MSA was fully realized. The relatively recent
identification of unique cytoplasmic inclusions and widespread white
matter abnormalities have broadened the scope of the neurodegenerative
process, and have challenged traditional views of MSA as a disease
primarily of gray matter. While studies on GCIs and oligodendroglial
dysfunction will continue to provide insight into the pathophysiology
and perhaps etiology of MSA, the progress already made will continue to
be an important lesson in neurodegenerative disease pathogenesis and
careful clinicopathological observation.
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Acknowledgements
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I am grateful to Dr. Mark A. Smith for critical review of this
commentary and helpful suggestions, and to Philippe Pary for valuable
assistance.
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Footnotes
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Address reprint requests to Rudy Castellani, M.D., Division of Neuropathology, Department of Pathology, University of Maryland, Baltimore, 22 South Greene St., Baltimore, MD 21201.
Accepted for publication July 20, 1998.
|
References
|
|---|
-
Papp MI, Kahn JE, Lantos PL: Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 1989, 94:79-100[Medline]
-
Matsuo A, Akiguchi I, Lee GC, McGeer EG, McGeer PL, Kimura J: Myelin degeneration in multiple system atrophy detected by unique antibodies. Am J Pathol 1998, 153:735-744[Abstract/Free Full Text]
-
Lantos PL, Papp MI: Cellular pathology of multiple system atrophy: a review. J Neurol Neurosurg Psychiatry 1994, 57:129-133[Medline]
-
Déjerine J, Thomas AA: L'atrophie olivo-ponto-cérébelleuse: Nouv Iconog Salpatriere 1900, 13:330–370
-
Loew P: L'atrophie olivo-ponto-cérébelleuse, Thesis, 1903–1904: University of Paris
-
Berciano J: Olivopontocerebellar atrophy. J Neurol Sci 1982, 53:253-272[Medline]
-
Critchley M, Greenfield JC: Olivo-ponto-cerebellar atrophy. Brain 1948, 71:343-364
-
Greenfield JG: The spino-cerebellar degenerations. Blackwell Scientific Publications, Oxford, 1954
-
Shy GM, Drager GA: A neurological syndrome associated with orthostatic hypotension: a clinical-pathological study. Arch Neurol 1960, 2:511-527
-
Bradbury S, Eggleston C: Postural hypotension: a report of three cases. Am Heart J 1925, 1:73-86
-
Langston W: Orthostatic hypotension: report of a case. Ann Intern Med 1936, 10:688-695
-
Young RH: Association of postural hypotension with sympathetic nervous system dysfunction: case report with review of neurological features associated with postural hypotension. Ann Intern Med 1944, 15:910-916
-
Bannister R, Oppenheimer DR: Degenerative diseases of the nervous system associated with autonomic failure. Brain 1972, 95:457-474[Free Full Text]
-
Quinn N: Multiple system atrophy: the nature of the beast. J Neurol Neurosurg Psychiatry 1989, suppl:78-89
-
van der Eecken H, Adams RD, van Bogaert L: Striopallidal-nigral degeneration. An hitherto undescribed lesion in paralysis agitans. J Neuropathol Exp Neurol 1960, 19:159-161
-
Adams RD, van Bogaert L, van der Eecken H: Dégénérescences nigro-striées et cerebello-nigro-striées. Psychiat Neurol 1961, 142:219-259
-
Adams RD, van Bogaert L, van der Eecken H: Striato-nigral degeneration. J Neuropathol Exp Neurol 1964, 23:584-608
-
Messing Z: Atrophie olivo-ponto-cerebelleuse dans un cas de maladie de Parkinson. Rev Neurol (Paris) 1930, 60:498-499
-
Graham JG, Oppenheimer DR: Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy. J Neurol Neurosurg Psychiatry 1969, 32:28-34[Medline]
-
Wenning GK, Ben Shlomo Y, Magalhães M, Daniel SE, Quinn NP: Clinical features and natural history of multiple system atrophy: an analysis of 100 cases. Brain 1995, 117:835-845[Abstract/Free Full Text]
-
Wenning GK, Ben-Shlomo Y, Magalhães M, Daniel SE, Quinn NP: Clinicopathological study of 35 cases of multiple system atrophy. J Neurol Neurosurg Psychiatry 1995, 58:160-166[Abstract]
-
Wenning GK, Tison F, Ben Shlomo Y, Daniel SE, Quinn NP: Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord 1997, 12:133-147[Medline]
-
Robbins TW, James M, Lange KW, Owen AM, Quinn NP, Marsden CD: Cognitive performance in multiple system atrophy. Brain 1992, 115:271-291[Abstract/Free Full Text]
-
Fujita T, Doi M, Ogata T, Kanazawa I, Mizusawa H: Cerebral cortical pathology of sporadic olivopontocerebellar atrophy. J Neurol Sci 1993, 116:41-46[Medline]
-
Arai N, Papp MI, Lantos PL: New observations on ubiquitinated neurons in the cerebral cortex of multiple system atrophy (MSA). Neurosci Lett 1994, 182:197-200[Medline]
-
Bandmann O, Sweeney MG, Daniel SE, Wenning GK, Quinn N, Marsden CD, Wood NW: Multiple-system atrophy is genetically distinct from identified inherited causes of spinocerebellar degeneration. Neurology 1997, 49:1598-1604[Abstract/Free Full Text]
-
Koeppen AH: The hereditary ataxias. J Neuropathol Exp Neurol 1998, 57:531-543[Medline]
-
Gotoda T, Arita M, Arai H, Inoue K, Yokota T, Fukuo Y, Yazaki Y, Yamada N: Adult-onset spinocerebellar dysfunction caused by a mutation in the gene for the -tocopherol-transfer protein. N Engl J Med 1995, 333:1313-1318[Abstract/Free Full Text]
-
Nee LE, Gomez MR, Dambrosia J, Bale S, Eldridge R, Polinsky RJ: Environmental-occupational risk factors and familial associations in multiple system atrophy: a preliminary investigation. Clin Auton Res 1991, 1:9-13[Medline]
-
Gilman S, Sima AA, Junck L, Kluin KJ, Koeppe RA, Lohman ME, Little R: Spinocerebellar ataxia type 1 with multiple system degeneration and glial cytoplasmic inclusions. Ann Neurol 1996, 39:241-255[Medline]
-
Martin WR, Roberts TE, Ye FQ, Allen PS: Increased basal ganglia iron in striatonigral degeneration: in vivo estimation with magnetic resonance. Can J Neurol Sci 1998, 25:44-47[Medline]
-
Schwarz J, Weis S, Kraft E, Tatsch K, Bandmann O, Mehraein P, Vogl T, Oertel WH: Signal changes on MRI and increases in reactive microgliosis, astrogliosis, and iron in the putamen of two patients with multiple system atrophy. J Neurol Neurosurg Psychiatry 1996, 60:98-101[Abstract]
-
Smith MA, Wehr K, Harris PLR, Siedlak SL, Connor JR, Perry G: Abnormal localization of iron regulatory protein in Alzheimer's disease. Brain Res 1998, 788:232-236[Medline]
-
Smith MA, Harris PLR, Sayre LM, Perry G: Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci USA 1997, 94:9866-9868[Abstract/Free Full Text]
-
Papp MI, Lantos PL: The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to clinical symptomatology. Brain 1994, 117:235-243[Abstract/Free Full Text]
-
Chin SS-M, Goldman JE: Glial inclusions in CNS degenerative diseases. J Neuropathol Exp Neurol 1996, 55:499-508[Medline]
-
Yagishita S, Amano N, Iwabuchi K, Hasegawa K, Kowa K: Argyrophilic glial intracytoplasmic inclusions in multiple system atrophy: immunocytochemical and ultrastructural study. Acta Neuropathol 1992, 84:273-277[Medline]
-
Arai N, Nishimura M, Oda M, Morimatsu Y, Ohe R, Nagatomo H: Immunohistochemical expression of microtubule-associated protein 5 (MAP5) in glial cells of multiple system atrophy. J Neurol 1992, 109:102-106
-
Arima K, Murayama S, Murayama M, Inose T: Immunocytochemical and ultrastructural studies of neuronal and oligodendroglial cytoplasmic inclusions in multiple system atrophy 1. Neuronal cytoplasmic inclusions. Acta Neuropathol 1992, 83:453-460[Medline]
-
Inoue M, Yagashita S, Ryo M, Hasegawa K, Amano M, Matsushita M: The distribution and dynamic density of oligodendroglial cytoplasmic inclusions (GCIs) in multiple system atrophy: a correlation between the density of GCIs and the degree of involvement of striatonigral degeneration and olivopontocerebellar systems. Acta Neuropathol 1997, 93:585-591[Medline]
-
Kato S, Nakamura H, Hirano A, Ito H, Llena JF, Yen S-H: Argyrophilic ubiquitinated inclusions of Leu-7-positive glial cells in olivopontocerebellar atrophy (multiple system atrophy). Acta Neuropathol 1991, 82:488-493[Medline]
-
Murayama S, Arima K, Nakazato Y, Satoh J, Oda M, Inose T: Immunocytochemical and ultrastructural studies of neuronal and oligodendroglial cytoplasmic inclusions in multiple system atrophy 2. Oligodendroglial inclusions. Acta Neuropathol 1992, 84:32-38[Medline]
-
Cairns NJ, Atkinson PF, Hanger DP, Anderton BH, Daniel DE, Lantos PL: Tau protein in the glial cytoplasmic inclusions of multiple system atrophy can be distinguished from abnormal tau in Alzheimer's disease. Neurosci Lett 1997, 230:49-52[Medline]
-
Mori S, Leblond CP: Electron microscopic identification of three classes of oligodendrocytes and a preliminary study of their proliferative activity in the corpus callosum of young rats. J Comp Neurol 1970, 139:1-30[Medline]
-
Stensaas LJ, Stensaas SS: Astrocytic neuroglial cells, oligodendrocytes and microgliacytes in the spinal cord of the toad. I. Light microscopy. Z Zellforsch 1968, 84:473-489[Medline]
-
Ludwin SK: The pathobiology of oligodendrocytes. J Neuropathol Exp Neurol 1997, 56:111-124[Medline]
-
Bleichenki PV, Celio MR: Relationship between oligodendrocytes and axons. Neuroreport 1997, 8:3965-3967[Medline]
-
Sternberger NH, Itoyama Y, Kies MW, Webster H deF: Immunocytochemical method to identify basic protein in myelin-forming oligodendrocytes of newborn rat C.N.S. J Neurocytol 1978, 7:251-263[Medline]
-
Matsuo A, Lee GC, Terai K, Takami K, Hickey WF, McGeer EG, McGeer PL: Unmasking of an unusual myelin basic protein epitope during the process of myelin degeneration in humans: a potential mechanism for the generation of autoantigens. Am J Pathol 1997, 150:1253-1266[Abstract]
-
Griffin JW, Li CY, Ho TW, Tian M, Gao CY, Zue P, Mishu B, Cornblath DR, Macko C, McKhann GM, Asbury AK: Pathology of motor-sensory axonal Guillain-Barre syndrome. Ann Neurol 1996, 39:17-28[Medline]
-
Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L: Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998, 338:278-285[Abstract/Free Full Text]
-
Kaplan MR, Meyer-Franke A, Lambert S, Bennett V, Duncan ID, Levinson SR, Barres BA: Induction of sodium channel clustering by oligodendrocytes. Nature 1997, 386:724-728[Medline]
-
Castellani R, Perry G, Harris PLR, Cohen M, Sayre L, Salomon RG, Smith MA: Advanced lipid peroxidation end products in Alexander's disease. Brain Res 1998, 787:15-18[Medline]
-
Castellani R, Smith MA, Richey P, Perry G: Glycoxidation and oxidative stress in Parkinson disease and diffuse lewy body disease. Brain Res 1996, 737:195-200[Medline]
-
Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M: -synuclein in filamentous inclusions of lewy bodies from Parkinson's disease and dementia with lewy bodies. Proc Natl Acad Sci USA 1998, 95:6469-6473[Abstract/Free Full Text]
-
Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL: Mutation in the -synuclein gene identified in families with Parkinson's disease. Science 1997, 276:2045-2047[Abstract/Free Full Text]
-
Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B: Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci USA 1998, 95:7737-7741[Abstract/Free Full Text]
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Introduction
Development of the Multiple...
