Association of a polymorphism of the transforming growth factor-beta1 gene with cerebral amyloid angiopathy.

BACKGROUND: A recent study showed that transforming growth factor-beta1 (TGF-beta1) induces amyloid-beta deposition in cerebral blood vessels and meninges of a transgenic mouse model of Alzheimer's disease (AD), and that TGF-beta1 mRNA levels are correlated with cerebral amyloid angiopathy (CAA) in human AD brains. A T/C polymorphism at codon 10 in exon 1 of the TGF-beta1 gene has been reported to be associated with the serum TGF-beta1 concentration. We investigated whether the TGF-beta1 polymorphism is associated with the risk of CAA. METHODS: The association between the severity of CAA and the T/C polymorphism at codon 10 in exon 1 of the TGF-beta1 was investigated in 167 elderly Japanese autopsy cases, including 73 patients with AD. The apolipoprotein E (APOE) genotype was also determined. RESULTS: The genotypes (TT/ TC/ CC) were associated with the severity of CAA significantly in all patients (p = 0.0026), in non-AD patients (p = 0.011), and APOE non-epsilon4 carriers (p = 0.0099), but not in AD patients or APOE epsilon4 carriers. The number of the T alleles positively correlated with the severity of CAA in all patients (p = 0.0011), non-AD patients (p = 0.0026), and APOE non-epsilon4 carriers (p = 0.0028), but not in AD patients or APOE epsilon4 carriers. The polymorphism was not significantly associated with AD. CONCLUSIONS: Our results suggest that the polymorphism in TGF-beta1 is associated with the severity of CAA, especially in non-AD patients and APOE non-epsilon4 carriers.

Association of neprilysin polymorphism with cerebral amyloid angiopathy.

OBJECTIVES: The risk of sporadic cerebral amyloid angiopathy (CAA) may be associated with genetic polymorphisms of molecules related to anabolism or catabolism of amyloid beta protein (Abeta). The authors investigated whether a polymorphism of the gene (NEP) coding for neprilysin, an enzyme catabolising Abeta, is associated with CAA. METHODS: The study analysed the GT repeat polymorphism in the enhancer/promoter region of NEP and severity of CAA in 164 necropsied elderly Japanese subjects. RESULTS: The subjects had NEP polymorphisms with 19 to 23 GT repeats and were classified into nine genotypes. CAA severity was significantly higher in the subjects with up to 40 repeats in total than those with more than 40 repeats (p=0.005). There was a significant correlation between the number of the shorter alleles (19 or 20 repeats) and CAA severity (p=0.024). In addition, there was no interaction between the NEP polymorphism and apolipoprotein E genotype. CONCLUSIONS: These results suggest the association between the NEP polymorphism and the risk of CAA. Further study using more samples from populations with different ethnic backgrounds is necessary.

No association of paraoxonase genotype or atherosclerosis with cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: Both cerebral amyloid angiopathy (CAA) and paraoxonase have been reported to be related to lipid metabolism and atherosclerosis. We investigated whether the paraoxonase gene (PON1) polymorphism and atherosclerosis are associated with risk of CAA. METHODS: Associations of the PON1 polymorphism and atherosclerosis of the aorta and coronary and cerebral arteries with the severity of CAA were investigated in 154 elderly Japanese individuals, including 47 patients with Alzheimer's disease. RESULTS: The PON1 polymorphism or severity of atherosclerosis of the arteries was not associated with the severity of CAA. CONCLUSIONS: The PON1 polymorphism and atherosclerosis would not appear to be associated with risk of CAA in the elderly, although further study with larger samples is necessary for confirmation.

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.

Alpha2-macroglobulin polymorphism is not associated with AD or AD-type neuropathology in the Japanese.

BACKGROUND: alpha2-Macroglobulin (A2M) forms the complex with amyloid beta-protein (Abeta) and is associated with degradation of Abeta. It has been reported that the A2M gene (A2M) exon 18 splice acceptor deletion polymorphism influences the development of AD, regardless of apolipoprotein E-epsilon4 (APOE-epsilon4) 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-epsilon4 status. CONCLUSION: The A2M polymorphism does not affect the development of sporadic AD or formation of AD-type neuropathologic changes.

[Clinical features of late onset dementia with Lewy bodies].

We conducted a retrospective study to elucidate clinical features of late onset dementia with Lewy bodies (DLB). Nineteen patients with DLB of neocortical category were neuropathologically diagnosed out of 500 consecutive autopsies at Yokufukai Hospital by using the pathological criteria of the consortium on DLB International Workshop. Medical history and clinical signs and symptoms were reviewed from the medical records. The age at onset was 55-88 years (mean 75.9 years), the age at death was 62-91 years, and duration of illness was 1-14 years. The initial symptoms were memory disturbance (10 cases), delirium (6 cases), gait disturbance (3 cases), visual hallucination (3 cases). We divided nineteen cases of DLB into two group: the age of onset was under 75 years (9 cases) and over 76 years (10 cases). The early onset group showed parkinsonism (67%), and visual hallucination (55%). The sensitivity of the clinical diagnosis of probable DLB based on DLB international workshop consensus criteria was 67%. On the other hand, the late onset group (10cases) presented with delirium (70%), parkinsonism (20%), and visual hallucination (30%). The sensitivity of a clinical diagnosis of probable DLB was 30%. Our results indicated considerable difficulty of the diagnosis of late onset DLB cases by the consensus criteria, requiring more sensitive criteria and diagnostic tests for DLB.

Cilostazol stroke prevention study: A placebo-controlled double-blind trial for secondary prevention of cerebral infarction.

Cilostazol, an antiplatelet drug that increases the cyclic adenosine monophosphate (AMP) levels in platelets via inhibition of cyclic AMP phosphodiesterase, has been used in chronic arterial occlusive disease. The purpose of the present study was to examine the effects of cilostazol on the recurrence of cerebral infarction using a multicenter, randomized, placebo-controlled, double-blind clinical trial method. Patients who suffered from cerebral infarction at 1 to 6 months before the trial were enrolled between April 1992 and March 1996. Oral administration of cilostazol (100 mg twice daily) or placebo was randomly assigned to the patients and continued until February 1997. The primary endpoint was the recurrence of cerebral infarction. In total, 1,095 patients were enrolled. An analysis based on 1,052 eligible patients (526 given cilostazol and 526 given placebo) showed that the cilostazol treatment achieved a significant relative-risk reduction (41.7%; confidence interval [CI], 9.2% to 62.5%) in the recurrence of cerebral infarction as compared with the placebo treatment (P=.0150). Intention-to-treat analysis of 1,067 patients also showed a significant relative-risk reduction (42.3%; CI, 10.3% to 62.9%, P=.0127). No clinically significant adverse drug reactions of cilostazol were encountered. Long-term administration of cilostazol was effective and safe in the secondary prevention of cerebral infarction.

A deletion polymorphism of alpha(2)-macroglobulin gene and cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: alpha(2)-Macroglobulin may be implicated in amyloid beta protein deposition. A deletion in the exon 18 splice acceptor of the alpha(2)-macroglobulin gene (A2M) has been reported to be associated with risk for Alzheimer's disease (AD). In search of genetic risk factors for cerebral amyloid angiopathy (CAA), we investigated association of the A2M deletion polymorphism with CAA. METHODS: The association between the severity of CAA and A2M deletion polymorphism was investigated in 178 autopsy cases of the elderly including 68 patients with AD. RESULTS: There was no significant difference in the severity of CAA between individuals with the A2M deletion allele and those without in the AD, non-AD, or total cases. Status for the epsilon4 allele of the apolipoprotein E gene did not influence the results. CONCLUSIONS: Our results suggest that the A2M deletion polymorphism may not be a definitive risk factor of CAA in the elderly, although further study with larger samples is necessary to confirm this.

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

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.

An inherited prion disease with a PrP P105L mutation: clinicopathologic and PrP heterogeneity.

OBJECTIVE: To clarify a clinical and neuropathologic phenotype of an inherited prion disease associated with a missense mutation at codon 105 in the prion protein (PrP) gene that was originally described as a variant of Gerstmann-Sträussler-Scheinker disease demonstrating spastic paraparesis. METHODS: Two siblings from a Japanese family are described. PrP gene analyses, neuropathologic studies with immunohistochemistry, and Western blot analysis of the PrP were performed. RESULTS: Both patients showed a missense (proline-->leucine) mutation at codon 105 and a methionine/valine polymorphism at codon 129 of the PrP gene. Clinically, Patient 1 presented with progressive spastic paraparesis, ataxia, and dementia. Patient 2, the sister of Patient 1, showed prominent action myoclonus and dementia. Neuropathologically, multiple PrP-positive amyloid plaques and diffuse PrP deposition in the deep cortical layers were found in the cerebral cortex with primarily frontal dominant atrophy in both patients. Tau-positive pathologic structures including neurofibrillary tangles, neuropil threads, and dystrophic neurites around the plaques were abundant in the brain of Patient 2. In contrast, the tau pathology was scarce in Patient 1. Western blot analysis of the brain showed different patterns of detergent-insoluble PrP fragments between the patients. CONCLUSIONS: Despite the identical codon 105 mutation and codon 129 polymorphism of the PrP gene, remarkable clinical and neuropathologic differences, and PrP heterogeneity were present between the affected siblings. The phenotypic variability might be related to PrP heterogeneity.

Lack of genetic associations of alpha-1-antichymotrypsin polymorphism with alzheimer-type neuropathological changes or sporadic Alzheimer's disease.

To elucidate the influence of the alpha1-antichymotrypsin (ACT) polymorphism on Alzheimer-type neuropathological changes and the development of sporadic Alzheimer's disease (AD), we studied the relationship between the ACT polymorphism and the severity of Alzheimer-type neuropathological changes in the brains from AD patients and nondemented subjects. There was no association of the ACT polymorphism with Alzheimer-type neuropathological changes in AD or nondemented individuals. ACT polymorphism was not associated with the development of AD. These results remained nonsignificant when the ACT genotype groups were divided into subgroups according to the apolipoprotein E (ApoE) epsiolon4 status. Our study shows that the ACT polymorphism has no effect on Alzheimer-type neuropathological changes or the development of AD, either alone or in combination with ApoE epsiolon4.

Involvement of the spinal posterior horn in Gerstmann-Sträussler-Scheinker disease (PrP P102L).

OBJECTIVE: The authors studied the pathomechanisms of the characteristics associated with Gerstmann-Sträussler-Scheinker disease (GSS). BACKGROUND: GSS, associated with a missense mutation at codon 102 of the prion protein (PrP) gene (GSS102), is a hereditary disorder that presents with progressive ataxia and dementia, and is characterized by the loss of deep tendon reflexes and painful dysesthesias of the legs in its early stage. METHODS: The authors conducted immunohistochemical studies of the spinal cord and peripheral nervous system in one of two patients from a Japanese family with GSS102 in comparison with patients with GSS105. RESULTS: The authors found intense PrP immunoreactivities mainly in the posterior horn of the spinal cord, but not in the dorsal root ganglia or peripheral nerves. In addition to PrP amyloid plaques, synaptic-type, fine granular PrP deposits were distributed in the spinal posterior horns. In contrast to the GSS102 patient, the spinal cords of the GSS105 patients showed no granular PrP deposits. CONCLUSIONS: The PrP abnormalities in synaptic structures of the spinal posterior horn may cause synaptic dysfunction that leads to loss of deep tendon reflexes and painful dysesthesias in patients with GSS102.

Butyrylcholinesterase K variant and cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: Cholinesterases are found histochemically in the vessels affected with cerebral amyloid angiopathy (CAA). A gene for the K variant of butyrylcholinesterase (BCHE-K) may be associated with late-onset Alzheimer's disease (AD). In search of genetic risk factors for CAA, we investigated the association of BCHE-K with CAA. METHODS: The association between the severity of CAA and BCHE-K was investigated in 155 autopsy cases of the elderly, including 48 patients with AD. RESULTS: There was no significant association of BCHE-K with the severity of CAA in the total, AD, or non-AD cases. Status of the epsilon4 allele of apolipoprotein E gene did not influence the results. CONCLUSIONS: Our results may suggest that BCHE-K is not a definitive risk factor for CAA in the elderly, although further study with larger samples is necessary to confirm this.

Association of alpha1-antichymotrypsin polymorphism with cerebral amyloid angiopathy.

In search of genetic risk factors of sporadic cerebral amyloid angiopathy (CAA), we investigated the association of a polymorphism in the signal peptide sequence of alpha1-antichymotrypsin (ACT) with the severity of CAA in 155 autopsy cases of the elderly, including 48 patients with Alzheimer's disease. In the total cases, there was no significant association of the ACT genotypes (AA, AT, and TT) with the severity of CAA. Within the Alzheimer's disease group, however, a significant correlation was found between the ACT A allele frequency and the severity of CAA.