Masaaki Iijima

FTDP-17 mutations N279K and S305N in tau produce increased splicing of exon 10

Missense mutations and intronic mutations in the tau gene cause frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP‐17). Known missense mutations reduce the ability of tau to promote microtubule assembly. Intronic mutations lead to increased mRNA splicing of the alternatively spliced exon 10, resulting in an overproduction of tau isoforms with four microtubule‐binding repeats. We show here that the recently identified FTDP‐17 missense mutations N279K and S305N do not reduce the ability of tau to promote microtubule assembly. Instead they lead to increased splicing of exon 10, like the intronic mutations. The N279K and S305N mutations define a class of missense mutations in tau whose primary effects are at the RNA level.

A distinct familial presenile dementia with a novel missense mutation in the tau gene

We report a Japanese family with early onset hereditary frontotemporal dementia and a novel missense mutation (Ser305Asn) in the tau gene. The patients presented with personality changes followed by impaired cognition and memory as well as disorientation, but minimal Parkinsonism. Imaging studies showed fronto-temporal atrophy with ventricular dilatation more on the left, and postmortem examination of the brain revealed numerous neurofibrillary tangles (NFTs) with an unusual morphology and distribution. Silver-stained sections showed ring-shaped NFTs partially surrounding the nucleus that were most prominent in frontal, temporal, insular and postcentral cortices, as well as in dentate gyrus. Cortical NFTs were restricted primarily to layer II, and were composed of straight tubules. Numerous glial cells containing coiled bodies and abundant neuropil threads were detected in cerebral white matter, hippocampus, basal ganglia, diencephalon and brain stem, but no senile plaques or other diagnostic lesions were seen. Both the glial and neuronal tangles were stained by antibodies to phosphorylation-independent and phosphorylation-dependent epitopes in tau. Thus, this novel mutation causes a distinct familial tauopathy.

An Autopsy Case of Binswanger's Disease without Hypertension and Associated with Cerebral Infarction in the Terminal Stage

Abstract: We report here an autopsy case of Binswangers disease (BD) without hypertension and associated with cerebral infarction in the terminal stage. The female patient, who was 74 years old at the time of death, had initially demonstrated manic‐depressive disorder‐like mental disorder, followed by dementia and neurological deficits. A brain CT scan showed white matter low attenuation bilaterally and symmetrically. BD was clinically diagnosed despite the lack of hypertension. In the terminal stage, she suffered an infarction in the left anterior cerebral artery region, and died of pneumonia. Neuropathologically, we found the infarction of the left anterior cerebral artery region, demyelination, fibrillary gliosis, lacunae and arteriosclerosis of the small arteries and arterioles in the white matter.

Relative frequencies of dementia of the Alzheimer type and vascular dementia in Japanese nursing homes.

Abstract: We have studied neuropathologically 200 aged nursing home residents (101 men and 99 women) autopsied between 1976 and 1985. Seventy‐three of the 200 showed dementia during life, that is, 27% and 55% of the residents in nursing homes and special nursing homes, respectively. The relative frequencies of SDAT and VD in nursing homes as a whole were the same (34%). The relative frequencies of SDAT and VD in special nursing homes, where usually high concentrations of VD have been noted, were 21% and 52%, respectively. A comparison of the results of our special nursing homes (SDAT‐.VD = 1:2.5) and nursing homes as a whole (SDAT:VD = 1:1) with those of Barnes and Raskind (SDAT:VD = 2:1) and Rovner et al. (SDAT:VD = 3:1) showed that the frequencies of VD in Japanese nursing homes are considerably higher than those in their American counterparts.

An Autopsy Case of Alzheimer Disease with Myoclonus and Periodic Spikes on EEG

This is a case of Alzheimer disease with myoclonus and periodic spikes on EEG. A 56‐year‐old man developed progressive dementia and, 3 years later, generalized convulsions. Eight years later, he showed myoclonus and periodic spikes on EEG. Cranial CT showed cortical atrophy and ventricular dilatation. He became apallic and died of pneumonia at the age of 65,9 years after the onset of the disease. The brain weighed 1,050 g. Neuropathologically, diffuse neuronal loss, abundant neurofibrillary tangles and senile plaques, particularly diffuse plaques, were found extensively in the cerebral cortex. The white matter was preserved. In the Ammons horn, abundant neurofibrillary tangles and senile plaques were observed. Grumose degeneration of the cerebellar dentate nucleus, Kuru plaques or prions were not found. Numerous diffuse plaques of the cerebral cortex have rarely been reported in autopsy cases of Alzheimer disease with myoclonus and periodic spikes on EEG.

An Autopsy Case of PSP with Astrocytic Inclusions

Abstract: Argyrophilic glial cytoplasmic inclusions were observed in astrocytes (Astrocytic Inclusions) in a case of progressive supranuclear palsy (PSP). The inclusions were predominantly distributed in the lenticular nucleus and midbrain, but not in the cerebral cortex, white matter nor in the thalamus. When examined by double staining with Gallyas silver and GFAP, they resembled the neurofibrillary tangles (NFT) and were tau positive. The distribution of these inclusions was not related to that of NFT. These inclusions indicate that astrocytes were involved in the same pathological changes as NFT. Argyrophilic inclusions were also observed in oligodendroglias on Gallyas silver staining. They appeared coiled and located mainly in the cerebral and cerebellar white matter.

Clinicopathological study of dementia in the elderly who died at home: A comparison of SDAT and non-demented subjects with SDAT changes

Forty‐eight elderly persons who resided and died at home are reported. Eight of the subjects (17%) were nondemented but had pathological changes of senile dementia of the Alzheimer type (SDAT). Each of these subjects showed numerous hippocampal neurofibrillary tangles (NFT). Five of the eight subjects demonstrated neocortical senile plaques (SP), such as typical plaques and primitive plaques with diffuse plaques, and one had NFT. The other three subjects did not have SP. The density of SP in hippocampal CA2, midbrain, pons, and cerebellum in SDAT were significantly higher than that of non‐demented subjects with SDAT changes. The density of SP and NFT in SDAT did not exceed that in non‐demented subjects with SDAT changes in the other areas. The distribution of SP in the hippocampal CA2, brainstem, and cerebellum will be useful for the histopathologic diagnosis of SDAT.

Vascular dementia clinically resembling Creutzfeldt-Jakob disease

An autopsy case of vascular dementia, clinically resembling Creutzfeldt‐Jakob disease, is reported. A 74‐year‐old woman showed progressive dementia, transient myoclonus of the right upper arm, diffuse periodic synchronous discharges on electroencephalography, and brain atrophy on computed tomography. The duration of the illness was 17 months. Neuropathologic findings were numerous small necrotic foci in the middle and lower layers of the cerebral cortex, myelin pallor of the cerebral white matter, and fibrous thickening of the arterial and arteriolar walls in the cerebrum and cerebellum (both cortex and white matter). Vascular dementia was diagnosed. On the basis of these features, it is considered that such neuropathologic changes caused Creutzfeldt‐Jakob‐like symptoms, such as dementia and periodic synchronous discharges.