Multiple System Atrophy

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This is an uncommon and heterogeneous group of disorders generally characterized by atypical, relative dopamine-unresponsive parkinsonism with variable degrees of cognitive impairment. MSA includes olivopontocerebellar atrophy (OPCA), striatonigral degeneration, and parkinsonism with orthostatic hypotension and dysautonomia (Shy- Drager syndrome).

Pathogenesis and Pathophysiology. Neuropsychological studies in both sporadic and familial cases of OPCA have demonstrated frontostriatal dysfunction. y A similar profile of frontostriatal impairment occurs in MSA with predominantly striatonigral degeneration features, which is qualitatively different from PD and PSP. 'sal Therefore, it would appear the cognitive impairment in the various forms of MSA results, at least in part, from frontostriatal dysfunction. Cerebellar dysfunction may play an additional role in OPCA.

Epidemiology and Risk Factors. Of five clinical subtypes of OPCA that have been described on both genetic and sporadic bases, mild to moderate decline has been described in types III, IV, and V. y Approximately 60 percent of familial and 35 percent of sporadic cases have accompanying cognitive impairment. y (Also see

Shy- Drager syndrome and striatonigral degeneration.)

Clinical Features and Associated Disorders. Patients with dominantly inherited OPCA (type IV) have frontal lobe-related cognitive impairments, y but the apparent mild intellectual decline in most OPCA may be related more importantly to motor impairment and depression without actual dementia and without evidence of aphasia, agnosia, or apraxia.y Multiple systems atrophy of the Shy- Drager variety has been less studied. Given the clinical similarities to other parkinsonian syndromes, as well as its clinical heterogeneity, mild "subcortical" patterns of cognitive impairment are possible, but it should not presently be regarded as a cause of severe dementia.

Management. Considerations are similar to those discussed for Parkinson's dementia, but successful treatment of psychotic symptoms in OPCA has been reported. Progressive Supranuclear Palsy

Pathogenesis and Pathophysiology. Although the anatomical substrates underlying the parkinsonian and oculomotor disorder are relatively well understood (see Ch.apt.e.L3.4. ), those underlying the cognitive symptoms are not. In addition to mesocorticolimbic dopaminergic alterations (see the section on Parkinson's disease dementia), there is evidence of more pronounced frontal lobe dysfunction than in other subcortical dementias on the basis of neuropsychological tests y , y and PET.y These findings have been attributed to primary striatal damage, which disrupts normal processing in the frontostriatal "cognitive" circuit such that frontal deafferentation occurs.y Striatal damage could also explain disruption in the anterior cingulate attention and lateral-orbitofrontal social affect circuits. y

Rarely, patients with PSP have variable degrees of aphasia, anomia, alexia, apraxia, or hemineglect, and some have had a frank progressive perceptual-motor syndrome similar to CBGD.y Anatomical distribution of degeneration is atypical in such cases and may be maximally present in the parietal cortex. All 10 cases in another report had neocortical tangles and neuropil threads; the density of tangles was highest in Brodmann's area 4. y Pronounced transentorhinal and entorhinal cortical degeneration resulting in hippocampal-isocortex disconnection similar to that occurring in AD has rarely been observed in PSP with severe dementia.

In summary, the typical subcortical pattern of dementia probably reflects substrates that are similar to those found in Parkinson's dementia with greater physiological disruption of frontal lobe function, but atypical cases have presented as definite cortical patterns of dementia due to predominantly cortical patterns of pathology.

Epidemiology and Risk Factors. The incidence of PSP is roughly three new cases per million per year, and the prevalence is 1.5 cases per million, making it about 1 percent as common as PD.y Median survival after symptom onset is approximately 6 to 7 years.y No clear predisposing or genetic factors have been identified to date.

Clinical Features and Associated Disorders. In addition to the extrapyramidal and oculomotor abnormalities that characterize PSP (see ChapteL3,4 ), certain cognitive features occur that led to the characterization of subcortical dementia are discussed in the section on Parkinson's dementia. In addition, there are frontal lobe features that appear to be more prominent than in other types of subcortical dementia. y

Differential Diagnosis. PSP is part of the differential diagnosis of the patient with atypical parkinsonism with dementia (discussed in the Parkinson's disease dementia section) and is usually distinguished clinically on the basis of the oculomotor disturbance and levodopa unresponsiveness.

Evaluation. In addition to the evaluation outline for PD and AD, SPECT and PET may show frontal and basal ganglia hypometabolism.

Management. Severe dementia and psychosis is less common in PSP than in Parkinson's disease dementia, although treatment considerations are otherwise similar for Parkinson's dementia.

Prognosis and Future Perspectives. Disease progression is similar (relentless) to that of other neurodegenerative conditions. Median survival after symptom onset is 6 to 7 years, and patients are typically wheelchair bound at least a year before that.

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