Huntingtons Disease

Pathogenesis and Pathophysiology. The cognitive impairment in HD, like other subcortical dementias, primarily

reflects frontostriatal dysfunction, and there is pathological evidence of both subcortical and cortical pathology. Grossly, the cortical gyri appear normal to slightly atrophic. Coronal sections reveal striking caudate greater than putamen and pallidum atrophy. Neuronal loss and gliosis follow the same regional distribution. The medium-sized spiny type I striatal neurons are preferentially affected, whereas the aspiny type I neurons that contain somatostatin and neuropeptide Y are unaffected. Several neurotransmitters are decreased in the striatum, most notably GABA and acetylcholine. Glutamic acid decarboxylase and choline acetyltransferase are also diminished.

Milder degenerative changes occur in the neocortex and thalamus. Cross-sectional areas within the frontal, temporal, and parietal lobes were decreased compared with controls, with atrophy in HD being greater than in PSP. y Quantitative analysis in HD patients compared with that of controls has revealed moderate to severe neuronal loss in the cortex and striatum, which was differentially distributed in the cortical laminae in primary sensory and association cortices. y Ubiquitin-reactive dystophic neurites were identified in all cortical but no subcortical areas, y and these neurites have been hypothesized by some to correlate with dementia. Evidence exists for excitotoxic damage and mitochondrial DNA mutations and oxidative stressy in the pathogenesis of cortical pathology in HD.

Clinical Features and Associated Disorders. Lieberman and associates found that 90 percent of patients were demented by a mean age of 48.3 years, and that dementia preceded the onset of chorea in 24 percent.y There are discrepant studies with regard to the existence of preclinical cognitive abnormalities, although preclinical metabolic abnormalities are detectable with PET. y Whether or not it is the critical determinant of cognitive decline, cognitive decline correlates pathologically and radiologically with degree of caudate atrophy y and hypometabolism.y Three areas of particular interest in the dementia of HD are frontal lobe-related or frontostriatal-related neuropsychiatric deficits, declarative memory impairment, and motor learning difficulties. Visuospatial disturbances have been demonstrated in some studies. With regard to frontostriatal neuropsychiatric deficits, patients may present initially with either primarily psychiatric or cognitive disturbances, although both may occur together. Regarding cognitive disturbances, prospective study of cognitive decline in early cases has shown that psychomotor slowing is a characteristic early feature, y and memory impairment, although present early on, does not deteriorate as rapidly, or correlate as well with caudate atrophy, as does psychomotor speed.y Patients with HD have greater perseveration and less initiation than AD patients, and they have greater problems with concentration and sustained attention. The overall pattern of frontal lobe-related deficits nonetheless appears qualitatively distinct from purely frontal cortical damage and has instead been attributed to frontostriatal dysfunction.

Regarding declarative memory impairment, much work has focused on the qualitative differences between HD and amnesic patients, including both AD and Korsakoff's patients. HD causes memory loss, but it appears to be less severe compared with that of AD at matched stages of dementia severity, although this factor has been more consistent at milder stages of dementia. Most studies have found that patients with HD have greater difficulty learning a task (such as a list of words), but they benefit more greatly by cued recall or recognition compared with free or unassisted recall. This has been thought to reflect greater impairment of retrieval than storage mechanisms, and it affects remote memory retrieval as well as more recently learned material. y There are many similarities in the memory disturbance between HD and PD, suggesting similarities between the subcortical dementia illnesses, but overlap is imperfect. For example, patients with HD have greater impairment of learning and free recall, better recognition memory, and more perseveration than PD patients. y

In contrast to the mild impairments of verbal learning, motor learning is severely impaired. There is a "double dissociation" between the performance of AD and HD patients on tests of these two memory systems: AD patients do poorly on verbal and well on motor learning, and HD patients do well on verbal and poor on motor learning.y Demented PD patients perform poorly on both,y which is interesting to consider in light of known overlap with AD pathology in a large subset of these patients. The most likely anatomical substrates, supported by the overlap with PD, are the basal ganglia, their frontal lobe connections, and related motor structures.

Differential Diagnosis. see Chapter 34 . In the absence of chorea, the family history is critical in reaching a diagnosis. In the absence of both chorea and a family history, the differential diagnosis is that of other subcortical dementias and chronic progressive encephalopathies.

Evaluation. The clinical examination may provide compelling evidence for HD, which can be confirmed genetically. Ancillary tests include MRI or CT to ascertain caudate atrophy, and (optionally) SPECT or PET to ascertain caudate hypometabolism. Neuropsychological assessment is useful to document the nature and severity of cognitive decline, particularly in mild to moderate stages of the illness. Other causes of chorea should be sought, as discussed in the Movement Disorders section.

Management. see Chapter 34 . Pharmacological management of dementia and chorea often involves dopaminergic antagonists including neuroleptic drugs but is far from adequate.

Prognosis and Future Perspectives. Death occurs within 10 to 20 years after onset, although suicide is more prevalent in at-risk and early-onset HD patients. Aspiration and inanition result from severe dysphagia, as well as from an apparent increased metabolic demand in patients with HD. See also Movement Disorders section.

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