Gray matter lesions in Nasu-Hakola disease: a report on three autopsy cases.

Nasu-Hakola disease is an autosomal recessively inherited disease characterized by lipomembranous polycystic osteodysplasia and sclerosing leukoencephalopathy. While white matter lesions prominent in the brain have been reported in the literature, gray matter lesions have not received particular attention. In this study, we examined three autopsy cases of Nasu-Hakola disease in order to focus specifically on gray matter lesions. The ages at onset of the three cases were 20, 23 and 29 years, and the disease durations were 29, 19 and 8 years, respectively. In addition to characteristic degeneration in the cerebral white matter, such as demyelination with conspicuous fibrillary gliosis and axonal changes, all three cases showed overt pathology in the gray matter. Neuronal loss with gliosis in the thalamus (particularly in the dorsomedial nucleus and anterior nucleus), caudate nucleus, putamen and substantia nigra was prominent in all cases, and the severity corresponded to the disease duration. The cerebral cortices were relatively preserved in all cases. One case showed neuronal loss and gliosis in the gray matter of the hippocampus, possibly due to repeated episodes of epileptic convulsions. These gray matter pathologies are considered to be responsible for some of the clinical manifestations of the disease, including extrapyramidal symptoms.

Distribution of cerebello-olivary degeneration in idiopathic late cortical cerebellar atrophy: clinicopathological study of four autopsy cases.

Late cortical cerebellar atrophy (LCCA) is a neurodegenerative disease which presents with slowly progressive cerebellar ataxia as a prominent symptom and is characterized neuropathologically by a limited main lesion to the cerebellar cortex and inferior olivary nucleus. To elucidate the features of lesions in the cerebellar cortex and inferior olivary nucleus, four autopsy cases suffering from idiopathic LCCA without other cortical cerebellar atrophies, such as alcoholic cerebellar degeneration, phenytoin intoxication, or hereditary cerebellar atrophy including spinocerebellar ataxia type 6, were examined. All affected patients had identical distinct features of cerebellar cortical lesions. In all four cases, the most obvious pathological finding throughout the cerebellum was loss of Purkinje cells, but the rarefaction of granular cell layers was observed only where loss of Purkinje cells was very severe, and thinning of the molecular layer was seen only where the rarefaction of granular cell layers was moderate to severe. Two patients presented with vermis dominant cerebellar cortical lesions, but the other two patients showed hemispheric dominant pathological changes. Neuronal loss of the inferior olivary nucleus was observed in the three autopsy cases. Two of the three cases had a prominent lesion in the dorsal part of the inferior olive and the cerebellar cortical lesion disclosed the vermis dominance, but the other patient, showing prominent neuronal loss in the ventral olivary nucleus, had a cerebellar hemisphere dominant lesion. The patient without neuronal loss in the inferior olivary nucleus had suffered from a shorter period of disease than the others and the rarefaction of granular cell layers and narrowing of the molecular layer of the cerebellar cortex were mild. Therefore, it is obvious that there are two types of cerebellar cortex lesions in idiopathic LCCA; one is vermis dominant and the other is cerebellar hemispheric dominant. The lesion of the inferior olivary nucleus occurs as a secondary degeneration after rarefaction of the granular cell layer and thinning of the molecular layer of the cerebellar cortex progresses. Furthermore, the distribution of the degeneration in the inferior olivary nucleus depends on the distribution of the cerebellar cortex lesions.

[Autopsy case of meningovascular neurosyphilis associated with Fischer's plaques].

We here report an autopsy case of meningovascular neurosyphilis associated with Fischer's plaques, a demyelinating lesion which is typical of the late stage general paresis. A Japanese male who was 59 years old at the time of death, developed personality change and dementia. He was clinically diagnosed as having neurosyphilis by serological tests of the blood and the cerebrospinal fluid. Despite the administration of Penicillin, psychiatric symptoms were unchanged and the patient died of aspiration pneumonia after the clinical course of 18 month. The weight of brain was 1485 g. Postmortem pathological examination of the brain revealed extensive leukocyte infiltration into the meninges, in particular, around the meningeal vessels. Perivascular leukocyte infiltration, though less severe, was also noted in the brain parenchyma in the temporal and frontal cortices. Brain atrophy and neuronal cell loss were absent. The primary pathology of this case was, thus, considered to be meningeal and vascular inflammation consistent with the stage III meningovascular neurosyphilis. However, we also found in the frontal and parietal cortices a few small demyelinating lesions, which were referred to as Fischer's plaques. Fischer's plaque is a hallmark of advanced stage of general paresis where the principal lesion exists in the brain parenchyma. We speculate that, in patients with chronic progressive neurosyphilis, meningovascular and parenchymal lesions coexist during the transitional stage. Attention has to be paid for the occurrence of atypical neurosyphilis in association with increased immuologically compromised hosts and frequent usage of antibiotics.

[An autopsy case of miliary brain metastases].

A 57-year-old man was admitted to our hospital with a diagnosis of psychiatric emergency. His symptoms were similar to encephalitis, metabolic encephalopathy or acute depressive psychosis because of poor focal neurological signs. Laboratory examinations, including routine hematological and biochemical investigations, serum vitamin B1 B12 levels, and cerebrospinal fluid obtained by lumbar puncture, were normal. Brain CT was also normal, therefore it was difficult to make a diagnosis. But, we could clinically diagnose him as having pulmonary adenocarcinoma with numerous metastatic nodules of the brain. Because miliary lesions in the cerebral hemispheres, brainstem and cerebellum were disclosed on brain MRI. Furthermore, chest CT revealed the lung tumor in the left S8 area. In addition, laboratory examination showed a rise of tumor marker and cytologic examination of sputum revealed class V. Fluid-attenuated inversion recovery and contrast-enhanced MR images demonstrated more prominently miliary metastases, in particular lesions in the cerebral cortex, than T1- and T2-weighted images. There was neither edema in the surrounding region of metastatic nodules nor mass effect on all MR images. Spinal MRI showed no metastatic lesions. The patient died of respiratory failure at the age of 58, about eight months after the disease onset. The brain weighed 1,575 g. Neuropathological findings revealed diffuse miliary brain metastases located in all parts of the brain, except for the medulla oblongata. Histological examination disclosed multiple metastases from a well-differentiated adenocarcinoma with a predominant tubular pattern. There was neither edema nor glial reaction in the surrounding area of metastatic lesions. Many pseudorosettes were recognized and carcinoma cells, extending through perivascular spaces into the subarachnoid space, were noticed.

[An autopsy case of dementia lacking distinctive histology showing semantic dementia].

We report an autopsy case of dementia lacking distinctive histology (DLDH) showing semantic dementia. At age 47, a Japanese man developed aspontaneity, followed by semantic dementia a few months after the onset. Thereafter he developed disinhibition and the language disturbance, which progressed transcortical sensory aphasia and terminally mixed transcortical aphasia. At age 48, about 10 months after the disease onset, neurological examination revealed frontal signs and hyperreflexia in the four extremities and 4 months later, the patient presented with mild rigidity in the right upper and lower extremities. At age 49, 1 year and 8 months after the onset of the disease, he could not walk by himself. At age 50, 2 years and 8 months after the onset, he died of pneumonia. The brain weighed 1350 g. Macroscopically, atrophy of the frontal lobes and temporal lobes, predominant in the left, was evident. The caudate nucleus was severely atrophic, in addition to the depigmentation of the substantia nigra. Neuronal loss and astrocytosis was obvious in the cerebral cortex, prominently in the frontotemporal lobes, amygdala, caudate nucleus, putamen, pallidum, thalamus, and substantia nigra. In the caudate nucleus, prominent neuronal loss with fibrillary gliosis was obvious. Senile plaques, neurofibrillary tangles, Pick bodies, astrocytic plaques, and tufted astrocytes were not found by Gallyas and tau staining. Ubiquitin-immunoreactive intracytoplasmic inclusions were not encountered in the hippocampal dentate gyrus and superficial layers in the frontotemporal cortex. On the basis of meticulous perusal of the literature, we believe that our case is the first autopsy case of DLDH reported in Japan.

A novel L266V mutation of the tau gene causes frontotemporal dementia with a unique tau pathology.

We report a novel mutation of tau (L266V missense mutation in exon 9) which may cause a type of familial frontotemporal dementia. The brain of a patient showed Pick body-like inclusions and unique tau-positive, argyrophilic astrocytes with stout filaments and naked, round, or irregular argyrophilic inclusions with deposits of both three-repeat and four-repeat tau. Recombinant tau with a L266V mutation showed a reduced ability to promote microtubule assembly, which may be the primary effect of the mutation.

Contrasting genotypes of the tau gene in two phenotypically distinct patients with P301L mutation of frontotemporal dementia and parkinsonism linked to chromosome 17.

Association between clinical characteristics and types of the tau gene mutation has been observed in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). P301L mutation seldom causes parkinsonism as a leading symptom; instead it usually causes personality changes with aggressiveness and disinhibition. We experienced two patients of FTDP-17 from separate families (designated as patient 1 from family 1 and patient 2 from family 2). They had P301L mutation in common. However, their phenotypes were distinct from each other. Aggressive behaviors and disinhibition were the main symptoms in patient 1, whereas parkinsonism was the most prominent feature in patient 2. Their genotypes of the tau gene were different at three sites, i. e. in exon 6, in intron segment before exon 10, and in exon 13, though they do not bring amino acid change. Patient 1 had more prevalent C/C, C/C, and rare T/C respectively. Patient 2 had less prevalent T/T, A/A, and more prevalent T/T respectively. These findings suggest two things. Firstly, they do not share a common founder for P301L mutation. Secondly, either of the two less prevalent genotypes observed in patient 2 may be the factor to modify the phenotype of P301L mutation into those unusual clinical features with prominent parkinsonism. Accumulation of information as to phenotype-genotype association will settle this hypothesis.

Parkinson's disease mimicking senile dementia of the Alzheimer type: a clinicopathological study of four autopsy cases.

This report concerns four Japanese autopsy cases of Parkinson's disease (PD) mimicking senile dementia of the Alzheimer type. Three patients with a clinical diagnosis of senile dementia of the Alzheimer type developed memory disturbance as the initial sign, and a patient with a clinical diagnosis of atypical senile dementia presented with hallucination and delusion as the initial sign. Dementia was evident in all four patients, and slight parkinsonism appeared in the middle to late stages of the disease in two patients. Macroscopical examination of the brain disclosed slight depigmentation of the substantia nigra and prominent depigmentation of the locus ceruleus in all four cases. Histological examination of the four patients showed neuronal loss with astrocytosis and the appearance of Lewy bodies in the substantia nigra, locus ceruleus, and dorsal vagal nucleus. The nucleus basalis of Meynert was involved in three cases, in which this structure was examined. The total Lewy body scores of the four cases were 1 in three cases and 0 in the other, compatible with PD. Massive appearance of senile plaques, consistent with Braak stage C, was found in one case, and the slight appearance of senile plaques, consistent with Braak stage A, was evident in two cases. One case had no evidence of senile plaques. In all four cases, slight neurofibrillary changes were present in the limbic areas, compatible with Braak stages II to III. Based on these clinicopathological findings and a review of the literature, we concluded that PD simulating Alzheimer's disease without overt parkinsonism rarely exists. Furthermore, we postulate that the clinical features of PD are more widespread than previously believed.