Naomi Suematsu

Immune Reactions Associated With Cerebral Amyloid Angiopathy

BACKGROUND AND PURPOSE Cerebral amyloid angiopathy (CAA) occasionally coexists with cerebral vasculitis. An immune system may influence deposition or degradation of the amyloid in cerebral blood vessels. The purpose of this study was to elucidate immune reactions associated with CAA. METHODS In 11 elderly patients with sporadic CAA, 2 patients with Icelandic familial CAA, and 2 patients with CAA and granulomatous angiitis, the cerebrovascular amyloid proteins and infiltrating inflammatory cells were analyzed immunohistochemically. RESULTS In both sporadic CAA (beta-protein amyloid angiopathy) and Icelandic familial CAA (cystatin C amyloid angiopathy), leptomeningeal and cortical vessels were associated with an increase or activation of monocyte/macrophage lineage cells. In the cases of CAA with granulomatous angiitis, the vascular amyloid was of beta-protein and associated with infiltration of many monocyte/macrophage lineage cells, which included multinucleated giant cells containing the amyloid in the cytoplasm as well as T cells composed of CD4+ and CD8+ subsets. Amyloid P component, which was reported to be a common component of amyloid deposits and to prevent phagocytic proteolysis of amyloid fibrils of beta-protein, was negative for the vascular amyloid in a case of CAA with granulomatous angiitis but positive in the others. CONCLUSIONS In both the beta-protein and cystatin C amyloid angiopathies, cerebrovascular amyloid deposition was associated with an increase or activation of monocyte/macrophage lineage cells. Prominent reactions of monocyte/macrophage lineage cells admixed with CD4+ and CD8+ T cells (granulomatous angiitis) were occasionally associated with beta-protein angiopathy. In some of these cases, the absence of amyloid P component might be related to pathogenesis of the granulomatous reaction.

An immunohistochemical study of centenarian brains: a comparison

To evaluate the pathology of centenarian brains, which would reflect the ultimate stage of the aging process, 13 centenarians (M:F=1:12; mean+/-SD, 101.5+/-1.5 years) from the consecutive autopsy series were studied. None had severe dementia compatible with Alzheimers disease (AD). As younger controls, 20 nondemented (ND) individuals (79.8+/-3.2 years) and 20 AD patients (80.8+/-3.0 years) were selected. In addition to the routine examination including methenamine-Bodian staining, an immunohistochemical study was performed, using antibodies to amyloid beta protein, tau, ubiquitin, glial fibrillary acidic protein (GFAP), synaptophysin, and Ki-MIP (a marker of the microglial and perivascular cells). No centenarian subjects satisfied the neuropathological criteria for definite AD. The densities of senile plaques and neurofibrillary tangles (NFTs) were significantly lower in almost all examined subdivisions than the AD patients, and tended to be higher than the ND subjects. Cerebral amyloid angiopathy of the centenarian was less severe than the AD patients, as well as the proliterations of GFAP-positive astrocytes and Ki-MIP-positive microglial cells, and the loss of synaptic terminal density. The relative mildness of the age-related morphological changes in the centenarians compared with the AD patients supports the idea that AD would not be the ultimate condition of the aging process, but would develop through the switching to the pathological process.

Dementia of the Alzheimer type and related dementias in the aged: DAT subgroups and senile dementia of the neurofibrillary tangle type

The aims of this study are to elucidate variations in the neuropathology of dementia of the Alzheimers type (DAT) and related dementias in the elderly, and to delineate a senile dementia characterized by abundant neurofibrillary tangles (NFT) in the hippocampal region and by a scarcity of senile plaques (SP) throghout the brain (senile dementia of the NFT type; SD‐NFT) in comparison with usual DAT cases. One hundred and five autopsied patients who developed dementia at age 70–100 years were investigated. The autopsy series included 57 cases of DAT, five of diffuse Lewy body disease (DLBD) with Alzheimer‐tyupe neuropathological changes, and five of SD‐NFT. The 57 DAT patients were classified into three subgroups depending onthe severity of the neocotical neuronal degeneration (NFT and neuronal loss): the diffuse, severe type (DAT‐DS, extensive and severe involvement of the neocortex; n= 18); the diffuse, mild type (DAT‐DM, mild involvement of the neocortex; n= 29); and the localized type (DAT‐L, neuronal degeneration almost localized to the hippocampal region; DAT without neocortical NFT; n= 10). The frequencies of the DAT subgroups, DLBD, and SD‐NFT in each age group at the onset were DAT‐DS (41%) > DAT‐DM (38%) > DLBD (16%) > DAT‐L (6%) of patients in their 70s, DAT‐DM (52%) > DAT‐L (24%) > DAT‐DS (16%) > SD‐NFT (8%) of those in their 80s, and DAT‐DS (40%) > SD‐NFT (30%) > DAT‐L (20%) > DAT‐DS (10%) of those in their 90s and older. In a morphometric comparison with age‐mathced DAT cases, the SD‐NFT showed a significantly higher density of hippocampal NFT and a significant scarcity of SP and cerebral amyloid angiopathy in the brain. Analysis of genotypes of apolipoprotein E gene revealed that no patient with the SD‐NFT had ε4 allele which was shown to be frequently associated with DAT. Our results have indicated (i) that the later onset of DAT and related dementias is linked with the milder neuronal degeneration in the neocortex, and (ii) that the SD‐NFT is a common neuropathological condition that causes dementia in the very aged, in which the pathogenetic process may be different from that in DAT.

Senile Dementia of the Neurofibrillary Tangle Type: A Comparison with Alzheimer’s Disease

A subset of senile dementia, ‘senile dementia (SD) of the neurofibrillary tangle (NFT) type’ (SD-NFT), is characterized by numerous NFTs in the hippocampal region and absence or scarcity of senile plaques throughout the brain. To elucidate the pathogenesis of SD-NFT in comparison with Alzheimer’s disease (AD), we investigated the hippocampal lesions and analyzed the tau gene. The hippocampal regions from 5 patients with SD-NFT were neuropathologically evaluated in comparison with AD and nondemented control subjects. The tau gene was analyzed in 3 patients with SD-NFT. The densities of NFTs in the CA1/subiculum and entorhinal cortex of SD-NFT were significantly higher than those in AD. However, hippocampal atrophy, neuronal and synaptic loss, and astrocytic and microglial proliferation in SD-NFT were significantly mild compared with AD. There was no significant difference between SD-NFT and AD in the immunoreactivities of NFTs with different anti-tau antibodies. No mutation was found in the tau gene from the SD-NFT patients. Our results indicate that the neurodegenerative process with NFT formation of the hippocampal region in SD-NFT would be different from that in AD.

Association of Presenilin-1 Polymorphism With Cerebral Amyloid Angiopathy in the Elderly

BACKGROUND AND PURPOSE An intronic polymorphism of presenilin-1 (PS-1), a gene responsible for early-onset familial Alzheimers disease, has been reported to be associated with late-onset sporadic Alzheimers disease. In a search for a genetic risk factor of sporadic cerebral amyloid angiopathy (CAA), we investigated the association of the polymorphism of PS-1 with CAA. METHODS The association between the severity of CAA and genotypes of a polymorphism in intron 8 of PS-1 was investigated in 137 autopsy cases of the elderly. RESULTS A significant decrease of PS-1 2/2 genotype frequency was associated with severe or moderate CAA. CONCLUSIONS Our results suggest that PS-1 intronic polymorphism may be associated with the severity of CAA in the elderly.

No association of paraoxonase gene polymorphism with atherosclerosis or Alzheimer's disease.

Article abstract Both AD and paraoxonase (PON) have been reported to be related to lipids and atherosclerosis, suggesting that the PON gene (PON) is a possible genetic risk factor for AD. We found no association of PON polymorphism with severity of atherosclerosis, densities of AD-type, neuropathologic change, or development of AD in 47 AD and 90 nondemented patients. Our study suggests that PON polymorphism does not play a causal role in the development of atherosclerosis or AD.

Panencephalopathic type of Creutzfeldt-Jakob disease associated with cadaveric dura mater graft

A 52 year old man with Creutzfeldt-Jakob disease who received a cadaveric dura mater graft 99 months before the onset is reported. The prion protein gene was homozygous for methionine at the polymorphic codon 129. Neuropathological examination disclosed a panencephalopathic type of Creutzfeldt-Jakob disease which was characterised by severe involvement of the cerebral white matter and cerebellum, as well as of the cerebral cortical and deep grey matter. Thus the panencephalopathic type of Creutzfeldt-Jakob disease may occur in association with cadaveric dura mater grafts.

Vascular Variant of Alzheimer's Disease Characterized by Severe Plaque-Like β Protein Angiopathy

In the neuropathological investigations of 32 demented patients with severe cerebral amyloid angiopathy (CAA), we found an unusual case, a 90-year-old woman, presenting with the pathology of atypical Alzheimers disease (AD). The case showed severe plaque-like angiopathy, in which all the senile plaques except for some diffuse plaques were formed around amyloid beta (/A4) protein-laden vessels. Analysis of the amyloid beta protein precursor gene from the patient revealed no mutation. Our results have indicated that, among demented patients with severe CAA, there is the vascular variant of AD characterized by severe plaque-like beta protein angiopathy.

α2-Macroglobulin polymorphism is not associated with AD or AD-type neuropathology in the Japanese

Background: α2-Macroglobulin (A2M) forms the complex with amyloid β-protein (Aβ) and is associated with degradation of Aβ. It has been reported that the A2M gene (A2M) exon 18 splice acceptor deletion polymorphism influences the development of AD, regardless of apolipoprotein E-ε4 (APOE-ε4) status. Objective: To determine the effect of A2M polymorphism on the development of AD and AD-type neuropathologic changes. Methods: The authors examined the A2M and APOE genotypes, the densities of the senile plaques (SPs), SPs with dystrophic neurites (NPs), and neurofibrillary tangles (NFTs) in the brains of 62 postmortem-confirmed sporadic AD and 90 nondemented patients from an autopsy series of elderly Japanese subjects. Results: There was no association of the A2M polymorphism with AD, age at onset, or duration of illness in AD. The A2M polymorphism was not associated with the SPs, NPs, or NFTs in AD or nondemented patients. The results remained insignificant, even when the A2M genotype groups were divided into subgroups by APOE-ε4 status. Conclusion: The A2M polymorphism does not affect the development of sporadic AD or formation of AD-type neuropathologic changes.

Influence of Apolipoprotein E Genotype on Cerebral Amyloid Angiopathy in the Elderly

BACKGROUND AND PURPOSE The inheritance of the epsilon 4 allele of the apolipoprotein E gene (APOE) is associated with increased risk of developing dementia of the Alzheimer type (DAT). We have investigated whether the APOE genotype influences the severity of cerebral amyloid angiopathy (CAA) in elderly individuals with or without DAT. METHODS From a consecutive autopsy series, we studied 88 patients (85.2 +/- 8.1 years) without degenerative disorders other than DAT. The percentages of amyloid-laden vessels in the occipital lobes were calculated and compared between APOE genotypes. RESULTS For epsilon 3/3 and epsilon 3/4 genotypes, there was a trend toward increased CAA in epsilon 3/4 individuals for non-DAT and conversely in epsilon 3/3 individuals for DAT patients, but these did not achieve significance. CONCLUSIONS The present study suggests that the epsilon 4 allele is not a strong risk factor for CAA in elderly people.