Autopsy case of concurrent Huntington's disease and neurofibromatosis type 1.

We report here an autopsy case of concurrent Huntington's disease (HD) and neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease. The patient was a Japanese woman with a significant hereditary burden: seven of her family members within four generations were affected by either NF1 or concurrent HD and NF1. She was diagnosed as having NF1 at age 24. At age 40, she showed signs of irritability, aggressive and childish behaviour, which became progressively worse. At age 48, rigidity and spastic gait were observed. One year later, choreoathetoid involuntary movements became apparent. Diagnosis of HD was made by identification of the abnormally expanded cytosine-adenine-guanine repeats in the Huntington's disease gene. Her condition deteriorated gradually to an apallic state and she died at age 60. Post-mortem examination revealed extensive brain atrophy, which was particularly severe in the frontal and temporal cortices and the striatum. The degree of neurodegenerative change seemed to correspond to grade IV. Polyglutamine positive inclusions were seen frequently in all layers of the cerebral cortex and in the amygdala and hippocampus. Inclusions were also present in the striatum, but there were fewer than in the cortex. Remarkably, neuronal intranuclear inclusions were present in the cerebellum, although they are usually not seen in HD. Features associated with the central nervous system involvement of NF1 were not found in the brain, but HD pathology might have been accelerated by the concurrence of NF1. This is the third report of a case with concurrent HD and NF1 in the world, and the first study in which occurrence of polyglutamine inclusions was confirmed on post-mortem examination.

Vascular complications in dementia with Lewy bodies: a postmortem study.

The effects of cerebrovascular lesions on DLB are not yet fully understood, whereas the development of Alzheimer's disease (AD) is known to be associated with cerebrovascular lesions. In this study, we investigated the frequency of concomitant cerebrovascular pathologies in autopsy-proven DLB cases (n = 25) in comparison with AD cases (n= 63). We also investigated the correlation between cerebrovascular pathologies and the clinical features of DLB cases. On gross inspection, five cases of DLB and seven cases of AD were complicated by cerebral hemorrhages and the difference was significant; most of the lesions in DLB were subdural hemorrhages, possibly related to trauma. Nine cases of DLB and 25 cases of AD had grossly identified infarctions, but no significant difference was observed. Three cases of DLB and four cases of AD had concomitant hemorrhages, while 10 cases of DLB and 43 cases of AD had infarcts on microscopic inspection. There was a significant difference in the frequency of microscopic infarcts between DLB and AD, whereas no significant difference was noted in the frequency of microscopic hemorrhages. In DLB cases without vascular complications, memory disturbance was common as the initial symptom, while parkinsonism was more common in those with vascular complications. However, no significant difference was observed between DLB cases with and without vascular complications with respect to the frequency of individual clinical symptoms over the whole clinical course. These findings suggest that grossly identified hemorrhages are more common in DLB because of trauma, while microinfarcts are less common in DLB than AD, although the reason remains unclear. Such vascular complications might affect the clinical manifestations, in particular, the initial symptom, of DLB.

Depletion of cholinergic neurons in the nucleus of the medial septum and the vertical limb of the diagonal band in dementia with Lewy bodies.

The cholinergic basal forebrain is divided into four subregions (Ch1-4), and cholinergic neuronal loss in the nucleus basalis of Meynert (Ch4) has been correlated with cognitive impairments in both Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). However, the Ch1-2 regions, which provide the major cholinergic innervation to the hippocampus, have not been investigated in DLB. The purpose of this study was to reveal the cholinergic neuronal changes in the medial septum (Ch1) and the nucleus of the vertical limb of the diagonal band (Ch2) of DLB brains. Using choline acetyltransferase (ChAT) immunohistochemistry, we showed that the number of ChAT-immunoreactive neurons in DLB brains was significantly lower than the numbers in AD and non-demented (control) brains. No significant difference in the number of ChAT-immunoreactive neurons was found between the AD and control brains. Moreover, the size of the ChAT-immunoreactive neurons was significantly smaller in the AD and DLB brains than in the control brains. These results show that cholinergic neurons of the Ch1-2 regions are more severely affected in DLB than in AD. Our DLB cases did not fulfill the neuropathologic criteria for definite AD. Furthermore, some Lewy bodies were observed in the Ch1-2 regions. Thus, cholinergic neuronal loss in the Ch1-2 regions might be specific to the pathology of DLB. Taking the distribution of cholinergic fibers in the hippocampus into consideration, this study suggests a possibility that hippocampal cholinergic projection is involved in Lewy-related neurites in the CA2-3 regions, the origin of which remains unclear.

Clinical features of argyrophilic grain disease: a retrospective survey of cases with neuropsychiatric symptoms.

OBJECTIVE: Although argyrophilic grain disease (AGD) appears common in post-mortem series, its clinical features are not widely known. The aim of this study was to explore such clinical features in neuropathologically-confirmed AGD cases. METHODS: After completing a neuropathological assessment of 386 patients, 33 cases (8.5%) were diagnosed as having AGD; 10 were diagnosed as "pure" cases. These subjects had been admitted to geriatric wards of mental hospitals because of behavioral or neuropsychiatric symptoms requiring medical management. Assessment of the clinical features of the pure cases was based on the evaluations in medical records. RESULTS: The average age at onset was 82.2 years. Amnesia was the most common initial symptom; irritability and agitation were also common as initial symptoms. During the course of the illness, irritability was the most frequently observed, followed by delusions (mostly delusions of persecution), dysphoria, and then agitation, and apathy. In contrast to the severity of amnesia, other cognitive functions were relatively spared, and the sensorimotor symptoms were not remarkable. CONCLUSIONS: AGD is a late-onset dementing disorder clinically characterized by amnesia, with other cognitive functions relatively spared, and prominent neuropsychiatric features. These features may correlate with the high level of AGD seen in limbic structures. Future studies are needed to elucidate whether these features are common to all AGD patients or to a clinical subtype with neuropsychiatric symptoms.

Non-uniformity in the regional pattern of Lewy pathology in brains of dementia with Lewy bodies.

We examined the regional pattern of Lewy pathology in brains of dementia with Lewy bodies (DLB) to clarify whether Lewy pathology uniformly progresses or not. Thirty-five autopsied DLB cases were examined using alpha-synuclein-immunohistochemistry, and the regional degree of Lewy pathology in the brainstem, diencephalon and cerebral cortex was quantitatively evaluated. Consequently, we found that the regional pattern of Lewy pathology differed according to the pathological subtype, and was divided into three types: type 1 showed a brainstem-predominant pattern, type 2 was almost equal for the brainstem and cerebral cortex, and type 3 showed a cerebral cortex-predominant pattern. The limbic type/pure and common forms were mainly composed of type 1, whereas the neocortical type/common and Alzheimer's disease (AD) forms were mainly composed of type 3. These findings suggest the possibility that Lewy pathology of the limbic type/pure and common forms mainly progresses from the brainstem to the cerebrum, whereas that of the neocortical type/common and AD forms mainly progresses from the cerebrum to the brainstem. Cases with type 1 Lewy pathology mainly developed parkinsonism, whereas those with type 3 Lewy pathology mainly developed dementia. This corresponded to most of the limbic type/ pure and common forms which developed parkinsonism, whereas most of the neocortical type/common and AD forms developed dementia. Type 1 cases may thus be clinically diagnosed as having Parkinson's disease (PD) with dementia. These findings suggest that PD has clinico-pathological continuity with DLB, and that the regional pattern of Lewy pathology is not uniform.