There are several forms of primary degenerative parkinsonism, including idiopathic (or sporadic) PD, sporadic PD with superimposed pathological features of AD, familial PD (or parkinsonian syndromes), and Parkinson's-ALS- dementia complex of Guam. Pathological substrates differ among these conditions, as do the frequency of cognitive disturbances. In patients with pathological evidence of AD, dementia is usually (but not invariably) present. In familial cases, genetic defects and pathological changes differ between kindreds, so it is difficult to generalize to sporadic PD. In each case of PD, however, when dementia is described, it is most consistent with a "subcortical pattern" to distinguish it from typical Alzheimer-type dementia.
Pathogenesis and Pathophysiology. Memory performance in nondemented and demented patients with PD is qualitatively different, y , y suggesting that cognitive impairment in nondemented and demented PD patients reflects
different anatomical or neurochemical systems,^] or separate pathogenetic processes.y Histological components of the Parkinson's dementia picture include both Parkinson's and Alzheimer-type pathology. Therefore, one must consider the roles of cortical Lewy bodies, concomitant AD pathology, and cholinergic deficiency in the pathogenesis of dementia in PD (see the section on diffuse Lewy body disease). Recent studies using ubiquitin staining in previous pathologically diagnosed PD demonstrate that 76 percent of cases have neocortical Lewy bodies compared with only 32 percent of cases studied only with routine hematoxylineosin stains. y Concomitant AD changes meeting diagnostic criteria for AD diagnosis have been found in up to 50 percent of patients with PD dementia.
PD is characterized by nigral degeneration with Lewy bodies in the pigmented brain stem nuclei, but the contribution of medial substantia nigra neuronal loss, the most consistent pathological finding in PD, to dementia is unclear. The basal ganglia interfaces with the limbic system through a subset of structures collectively referred to as the ventral striatum and ventral pallidum. Cortical input to the ventral striatum is from the hippocampal formation through the precommissural fornix, and dopaminergic input comes from the ventral tegmental area (part of the mesocorticolimbic dopaminergic system). Analogous to the concept that the dorsal or neostriatum and its neocortical targets are part of a so-called motor loop, so, too, have the ventral striatum and its allocortical or paralimbic targets been termed a cognitive loop.y However, the role of the cognitive loop remains speculative, and it is unknown whether any cognitive alterations in PD or dementia reflect this loop.
Epidemiology and Risk Factors. Considering the heterogeneity of parkinsonian syndromes, potential co-occurrence of AD, and the cognitive side effects of antiparkinsonian treatment, estimates of dementia prevalence in PD vary considerably. Most range between 20 and 30 percent. y Based upon autopsy studies, about half of demented parkinsonian patients have coincident AD pathology. y
Clinical Features and Associated Disorders. Although PSP was the original model for subcortical dementia, this model is applicable to PD, which is much more common than PSP. The concept was intended to distinguish subcortical dementia from the cortical dementia of AD. Subcortical dementia-related memory impairment is benefited more by cuing than the memory disturbance of cortical dementia. Patients have equal or greater difficulty learning new material but have relatively less difficulty retrieving it, possibly due to disturbed frontal or frontostriatal function involved in attending to and organizing the memory task. Subcortical dementia is not usually accompanied by aphasia, apraxia, and agnosia. However, it is accompanied by psychomotor slowing, an early feature of Parkinson's dementia. y , y Patients perform disproportionately poorly on timed tests whether the tests use motor responses (such as the digit symbol substitution subtest of the Wechsler Adult Intelligence Scale-Revised [WAIS-R]), or whether they are purely cognitive (such as the controlled oral word association test). PD results in disproportionately poor performances on visuospatial tasks, although this aspect does not seem to be a major source of clinical disability, and the cause is debated. Depression is more common in PD with or without dementia than in AD. Finally, the noncognitive (motor) parkinsonian features make distinction from AD and related cortical degenerative syndromes generally possible. The distinction has clinical value, despite overlap with cortical dementia on both clinical and pathological grounds that blur nosological boundaries. For example, a subset of patients with Alzheimer's disease have mild extrapyramidal features, y and there is important subcortical pathology in the basal forebrain of AD. The coincidence of Alzheimer's pathology in patients with Parkinson's disease with so-called subcortical dementia has already been alluded to earlier. There are certain kindreds in which a parkinsonian syndrome is invariably accompanied by severe dementia. Nondegenerative quasiparkinsonian syndromes in which cognitive impairment is present can have many etiologies including multi-infarct dementia, normal pressure hydrocephalus, and post-encephalitic parkinsonism, and are discussed elsewhere.
Differential Diagnosis. The main question in patients presenting with parkinsonism and dementia is whether the entire picture is explained by PD and whether it will respond to levodopa therapy. The differential diagnosis of PD is extensive, and dementia can occur in many of the conditions discussed in the section on PD. Some of the differential diagnoses that are of particular note that are also degenerative include PSP, multiple systems atrophy (MSA), DLBD, and CBGD. Occasionally, frontal lobe disorders may be mistaken for parkinsonian syndromes with dementia, including both degenerative etiologies, such as Pick's disease, and nondegenerative etiologies, such as frontal lobe meningiomas. Other progressive, nondegenerative diseases that have loosely fitting parkinsonian features include multi-infarct dementia and normal pressure hydrocephalus. Occasionally, parkinsonian features occur in patients with AD (see AD and DLBD sections).
Evaluation. MRI is generally preferable to CT, in part because of the multifocal areas of increased T2 signal (often missed or poorly defined by CT) in periventricular, basal ganglia, and other locations that may signify a small vessel multi-infarct state. Evaluation is similar to that described for AD save that response to therapy offers additional diagnostic information (see later).
Management. Dopaminergic therapy is discussed in the section on PD, but certain special considerations apply here. First, dopaminergic therapy is more likely to cause hallucinations and delusions in parkinsonian patients with dementia, as well as in patients with related parkinsonian syndromes, than in those with uncomplicated PD. Second, neuroleptic therapy is more likely to cause an exacerbation of parkinsonian symptoms. Third, so-called on-off motor fluctuations may be accompanied by mild fluctuations in cognitive status as well. There are no perfect solutions, and antipsychotic therapy with atypical agents such as risperadone and clozapine, which produce fewer parkinsonian side effects than standard agents, will need to be tried cautiously if absolutely required. Tacrine, although not generally recommended, could be considered given the frequency of Alzheimer-type pathology, including cholinergic deficiency, although again there is at least the theoretical risk that increasing central cholinergic tone could mildly exacerbate the parkinsonian syndrome.
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