Neurodiagnostic Studies
CT and MRI scans in patients with OPCA typically show pancerebellar
and brain stem atrophy, enlarged 4th ventricle and cerebellopontine angle
cisterns, and demyelination of transverse pontine fibers on T2-weighted MRl
images.{4} PET scans show reduced metabolic rate in the brain stem and
cerebellum.{36} In one study, 73% of brain stem auditory evoked responses
were abnormal.{104}
Neuropathology and Neurochemistry
Pathologic studies show a wide variation of neuronal damage. The
fundamental pathologic change in OPCA is loss of Purkinje cells in the
cerebellar cortex, particularly in the vermis.{56} In addition to cerebellar
atrophy, substantia nigra degeneration and depigmentation, neuronal loss
in other brain stem nuclei, and demyelination of corticospinal tracts and
posterior columns are seen.{62} Recently clear, argyrophilic,
introcytoplasmic structures that react with antitubulin antibodies were
demonstrated in nearly all patients with OPCA.{58,82,87} These glial
cytoplasmic inclusions are located prominently in the white matter of the
putamen, internal capsule, cerebral peduncles, and substantia nigra. They
were found in the brains of all 11 patients diagnosed with MSA but not in
any of the other 284 brains from patients with different neurologic
diseases.{87} All of Nakazato et al's {82} six patients with sporadic OPCA
were found to have 'oligodendroglial cytoplasmic inclusions', whereas
one of two brains with the hereditary forms showed similar lesions. The
concurrent cellular and myelin destruction was suggested to be caused by
generation of oligodendroglial cytoplasmic inclusions in affected cells
triggering a complement activated secondary demyelinating response.{4} The
observation of oligodendroglial cytoplasmic inclusions in nearly all cases
of MSA suggest the possibility that the three forms of MSA are related and
that the disease process originates in the myelin or axons.
Detailed morphometric and biochemical studies correlated reductions in
aspartic and glutamic acid with Purkinje cell loss in the cerebellar cortex
and with neuronal cell loss in the inferior olives (aspartic acid).{1} In
addition, quisqualate receptors appear to be decreased, whereas quinolinic
acid metabolism is increased.{61,73} The increased quinolinic acid
phosphoribosyl-transferase activity in OPCA was interpreted as a
compensatory mechanism designed to protect quinolinic acid-sensitive
granule cells.{61} In addition, low glutamate dehydrogenase activity was
found in most but not all studies; however, this defect probably is not
disease-specific.{4,65} Recently mitochondrial DNA abnormalities were
postulated to be important in the pathogenesis of OPCA in some
patients.{112}
CORTICOBASAL GANGLIONIC DEGENERATION
Clinical Aspects
ln 1968, Rebeiz et al {96} reported three patients of Irish decent with
parkinsonism, myoclonus, supranuclear palsy, and apraxia who were found
at autopsy to have 'corticodentatonigral degeneration with neuronal
achromasia', Recently this complex neurobehavioral disorder has become
increasingly recognized. Its most striking features include marked asymmetry
of involvement. apraxia. and parkinsonism. In their review of 15 patients,
Riley et al {97} categorized the typical
features of what is now termed 'corticobasal ganglionic degeneration' into
movement disorders (akinesia, rigidity, p&~stural instability, limb
dystonia, cortical myoclonus, and postural/intention tremor), cortical
sensory loss, apraxias (ideational and ideomotor), and the 'alien limb'
phenomenon. Dementia is a late feature of CBGD. In our experience,
limb contractures, often preceded by the alien hand phenomenon, are more
common in this condition than in any other parkinsonism plus syndrome.{17}
Neurologic examination often reveals hyperreflexia, Babinski signs, ocular
motility disturbance, and bulbar impairment but no ataxia. Of the 15
patients reported by Riley et al,{97} the age at onset ranged from 51 to 71
years, and men were more commonly affected than women (3:2). Two patients
died 7 and 10 years after disease onset.
Neurodiagnostic Studies
CT scans were abnormal in 14 of the 15 patients in one series; eight
had asymmetrical parietal lobe atrophy corresponding to the most affected
side, and six had bilateral parielal atrophy.{97} PET scanning reveals
reduced fluorodopa uptake in the caudate and putamen and cortical
hypometabolism especially in the superior temporal and inferior parietal
lobe.{100}
Neuropathology and Neurochemistry
Pathologic features in this disease include neuronal degeneration in the
precentral and postcentral cortical areas with achromatic neural inclusions
seen not only in the cortex, but also in the thalamus, subthalamic nucleus,
red nucleus, and substantia nigra.{31,69} Dopamine concentration throughout
the striatum and substantia nigra was reduced when compared with age-matched
controls.{97} To date, no effective treatment has been found, although the
dystonia may improve with botulinun' toxin.
ALZHEIMER'S DISEASE WITH PARKINSONISM
Clinical Aspects
Dementia occurs in approximately 20% of patients with Parkinson's disease,
but this usually develops later in the course of the illness.{91} Cognitive
decline seems to be more prominent in patients with the PIGD form of
Parkinson's disease as compared with the more typical tremor variety.{25,54}
Alternatively extrapyramidal signs were reported in about one third of
patients with Alzheimer's disease.{77} Diffuse Lewy body disease (DLBD),
considered by some a variant of Alzheimer's disease or at' overlap between
Alzheimer's disease and l2arkinson's disease, is now well recognized, but
its clinical and pathologic criteria have not yet been fully defined.{11,13}
Differentiation of Alzheimer's disease and DLBD on clinical findings alone
may he difficult. Crystal et al {13} reviewed the course of six DLBD, three
Alzheimer's disease and one Parkinson's disease patient with autopsy-
confirmed diagnosis and found that patients with DLBD were more likely to
have gait impairment, rigidity, and resting tremor early in the course of
the illness. In another study of 30 patients with DLBD, psychosis and
dementia were often found to precede parkinsonism.{11} Agitation,
hallucinations, delusions, and abnormal electroencephalograms were more
common in patients with DLBD than in the patients with Alzheimer's
disease.{11} No differences were found with respect to age, gender, or
disease progression between autopsy-proved cases of Alzheimer's disease
and DLBD.{30} On neurologic examination, rigidity, bradykinesia, and action
tremor were more frequent in the patients with DLBD, whereas impairment
of up-gaze was surprisingly more common in the Alzheimer's disease group.
The differentiation between DLBD and the other parkinsonism plus
syndromes, particularly PSP, can be particularly difficult when a patient
with parkinsonism and dementia is also found to have oculomotor disturbance,
as noted in some patients with DLBD.{68}
Neurodiagnostlc Studies
There are no diagnostic studies that call reliably differentiate between
Parkinson's dementia, Alzheimer's disease, and DLBD. PET scanning showed
no differences between Alzheimer's disease and DLBD.{113} In one series of
37 patients with Alzheimer's disease, however, concentrations of
cerebrospinal fluid homovanillic acid and biopterin were noted to be
significantly lower in the patients with Alzheimer's disease with
extrapyramidal signs as compared with the group without extrapyramidal signs
matched for age and dementia severity.{59}
Neuropathology and Neurochemistry
About one third of patients with Alzheimer's disease have Lewy bodies at
autopsy, but patients with DLBD, seem to have a greater neuronal loss in
the substantia nigra, substantia inominata, and locus ceruleus and have
lower cortical choline acetyltransferase levels than the patients with
Alzheimer's disease.{30} Besides diffuse distribution of Lewy bodies
throughout the basal forebrain, brain stem and hypothalamus, a paucity
of neurofibrillary tangles in DLBD helps to diffrentiate DLBD from
Alzheimer's disease.{11,30} Although Gibb et al {30} found no Lewy bodies
in the hippocampus or cortex, Burkhardt et al {11}reported 'Lewy-like'
bodies in the limbic system and neocortex. Others report different
antigenic coniponents of the Lewy body in DLBD and Parkinson's disease,
with tau protein being present only in the dementing disorder.{22}
Pathologic changes in Alzheimer's disease have been well characterized:
Neuritic plaques containing beta-amyloid protein were demonstrated in
both sporadic and familial Alzheimer's disease, and neurofibrillary tangles
(NFTs) consist of the paired helical filament tau. The abnormal phosphate
substitution is thought to interfere with normal neurotubule formation.{64}
In patients with Alzheimer's disease, NFTs are found predominantly in the
hippocampus, but extrapyramidal signs are more likely associated with
increased NFTs in the substantia nigra.{32} Tabaton et at{110} report
antigenic similarities between the NFTs of PSP and Alzheimer's disease
when derived from neurons of similar populations and postulated that
anatomic location rather than disease specificity is the deterinining factor
for antigenicity. In a study contrasting Parkinson's dementia and
Alzheimer's disease, de Ia Monte et al{80} found similar reductions in the
cross sectional areas of the globus pallidus-putamen; greater cell loss
was noted in the amygdala of Parkinson's dementia brains, however,
whereas Alzheimer's disease was associated with prominent cortical
atrophy. The relative frequencies of Lewy bodies, neuritic plaques,
and NFTs, however, were not discussed.
PARKINSONISM-DEMENTIA COMPLEX OF GUAM (PDCG)
Clinical Aspects
The combination of parkinsonisn, dementia, and motor neuron disease
was first noted in a population of Guam.{44} In a review of 363 Chammoro and
three Filipino immigrants with this disease, men were affected twice as
frequently as women, but no differences in age of onset (57 years) or death
(62
years) were seen between the genders.{115} Besides parkinsonism.
supranuclear ocular motility disorder was reported in all 37 patients in
one series.{67} Patients with parkinsonism usually present later than those
with amytrophic lateral sclerosis, possibly because patients presenting with
motor neuron disease do not survive long enough to develop extrapyramidal
symptoms.{114} Furthermore basal ganglia signs may be masked by the motor
neuron disease.
Neurodiagnostic Studies
PET scanning in patients with the parkinsonian form of this disease reveals
decreased presynaptic l8F-6-fluorodopa uptake similar to patients with
Parkinson's disease, whereas those with amyotrophic lateral sclerosis have
an intermediate picture between Parkinson's disease and control
populations, suggesting a preclinical lesion.{105}
Neuropathology and Neurochemistry
The finding of increased frequencies of this neurodegenerative disorder on
the island of Guam suggest a possible environmental etiology.{44} The
neurotoxin beta-N-methylamino-L-alanine (BMAA), a compound found in the
cycad plant and believed to be in high concentrations in flour made from
this plant, produces a similar spectrum of neurologic decline in
monkeys.{106} An analysis of the BMAA content of cycad flour, however,
suggests that the quantities of BMAA normally consumed by the inhabitants
of the endemic areas were not sufficient to produce neurologic toxicity.{20}
Other hypotheses concerning abnormalities in mineral metabolism and
hypomagnesemia or hypocalcemia also have been suggested, but supporting
evidence is lacking.{27}
Pathologically this condition resembles Alzheimer's disease more than
Parkinson's disease; tau-containing NFTs are present particularly in the
hippocampus{35,101} and other brain and spinal cord areas.{75}
Immunohistochemical studies of autopsied brains of patients with PDCG
showed marked reduction in the number of dopaminergic neurons in both the
lateral and the medial substantia nigra.{39} Despite marked reduction of
nigrostriatal dopamine concentration, the striatal output system was well
preserved and glutamate, gamma-aminobutyric acid (GABA), choline
acetyltransferase, and serotonin were spared.
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