Eiichi Otomo

Cerebral amyloid angiopathy: A significant cause of cerebellar as well as lobar cerebral hemorrhage in the elderly

We investigated consecutive 1000 autopsied cases (average age 82.9 years) clinicopathologically in order to reveal the significance of cerebral amyloid angiopathy (CAA) as a cause of senile intracranial hemorrhages. We found 101 cases with intracerebral hemorrhages, and CAA accounted for 10.9% of them (31.0% of lobar cerebral hemorrhages, and 14.3% of cerebellar ones). In contrast to hypertensive hemorrhages, CAA-related ones (1) ruptured into the subarachnoid space without exception, (2) often coexisted with dementia of Alzheimers type, and (3) frequently occurred in the night without elevated blood pressure at onset. The cerebrovascular amyloid was strongly immunoreactive with antibody to beta-protein in all of the cases with CAA-related hemorrhages, and less intensively with antibody to cystatin C in 91% of them. Our data indicate that CAA is an important etiological factor of cerebellar hemorrhages, as well as lobar cerebral hemorrhages, in normotensive, aged patients.

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.

Sarpogrelate-Aspirin Comparative Clinical Study for Efficacy and Safety in Secondary Prevention of Cerebral Infarction (S-ACCESS): A randomized, double-blind, aspirin-controlled trial.

Background and Purpose— The antiplatelet agent sarpogrelate is a selective inhibitor of 5-hydroxytryptamine receptors. The purpose of this study was to compare the efficacy and safety of sarpogrelate with those of aspirin in Japanese ischemic stroke patients. Methods— In total, 1510 patients with recent cerebral infarction (1 week to 6 months after onset) were randomly assigned to receive either sarpogrelate (100 mg TID) or aspirin (81 mg/d). Mean follow-up period was 1.59 years. The primary efficacy end point was recurrence of cerebral infarction. Clusters of serious vascular events (stroke, acute coronary syndrome, or vascular event–related death) were selected as secondary end points. The aim of the primary efficacy analysis was to demonstrate the noninferiority of sarpogrelate with respect to aspirin, with the criterion that the upper limit of the 95% CI of the hazard ratio (sarpogrelate vs aspirin) for recurrence of cerebral infarction should not exceed 1.33. Results— Cerebral infarction recurred in 72 patients (6.09%/y) in the sarpogrelate group and in 58 (4.86%/y) in the aspirin group (hazard ratio=1.25; 95% CI, 0.89 to 1.77; P=0.19). A serious vascular event occurred in 90 (7.61%/y) and in 85 (7.12%/y) patients, respectively (hazard ratio=1.07; 95% CI, 0.80 to 1.44; P=0.65). The overall incidences of bleeding events were 89 (11.9%) and 131 (17.3%), respectively (P<0.01). Conclusions— Sarpogrelate was not noninferior to aspirin for prevention of recurrence of cerebral infarction. Bleeding events were significantly fewer with sarpogrelate than aspirin. The effect of aspirin in Japanese patients was similar to that in Western studies.

Prognostic value of high plasma brain natriuretic peptide concentrations in very elderly persons

BACKGROUND Many elderly persons without heart failure have high plasma concentrations of brain natriuretic peptide (BNP). We investigated the prognostic implications and potential causes of these increased levels. METHODS We enrolled 111 persons aged 80 years or older who had no history of hospitalization for cardiac disease, a cardiothoracic ratio < or =55% on chest radiographs, and a serum creatinine level < or =2.0 mg/mL. All subjects had participated in a regular health screening program at our hospital, and were followed for up to 24 months. We studied the correlation of plasma BNP concentration with age, nutritional state, and activities of daily living. Cox proportional hazards models were used to determine the association between BNP levels and clinical outcomes (cardiac hospitalizations, mortality), adjusted for other risk factors. RESULTS During follow-up, 8 subjects (7%) were hospitalized with cardiac disorders, and 21 (19%) died. Each 50-pg/mL increase in the plasma BNP concentration was associated with a 1.6-fold increase in the risk of cardiac events (95% confidence interval [CI]: 1.2 to 2.1) and a 1.4-fold increase in total mortality (95% CI: 1.2 to 1.6). Plasma BNP concentration correlated positively with age (r = 0.31, P = 0.001), serum creatinine level (r = 0.23, P = 0.02), and the activities of daily living (r = 0.36, P = 0.0001). CONCLUSION In very elderly persons, the plasma BNP concentration may be a biochemical marker of an increased risk of cardiac morbidity and total mortality.

Antiplatelet Cilostazol Is Beneficial in Diabetic and/or Hypertensive Ischemic Stroke Patients

Background and Purpose: Although antiplatelets are known to be effective for secondary prevention of cerebral infarction, the number needed to treat is rather large and the effects in stroke patients with complications such as hypertension or diabetes are inadequately defined. This study was conducted to examine the effect of such complications on recurrence of cerebral infarction, and to assess the effect of cilostazol, an antiplatelet agent, in these high-risk subjects. Methods: A post hoc subgroup analysis of the already reported Cilostazol Stroke Prevention Study, which was a placebo-controlled double-blind trial, has been carried out to clarify the influence of various complications on recurrence in the placebo group and the effects of cilostazol in 1,095 patients with noncardioembolic ischemic cerebrovascular disease. Treatment continued for an average of 1.8 ± 1.3 years (maximum 4.8 years). Results: The recurrence rate of the diabetic stroke patients was significantly higher compared with the nondiabetics in the placebo group (9.4 vs. 4.7%/year, p = 0.01). Furthermore, our study showed that the relative risk reduction (RRR) for recurrence of infarction was 41.7% with cilostazol. This treatment provided a significant benefit in patients with lacunar infarction (RRR 43.4%, p = 0.04), with diabetes (RRR 64.4%, p = 0.008), or with hypertension (RRR 58.0%, p = 0.003). Conclusions: Diabetic patients are particularly at risk for recurrence of cerebral infarction. Cilostazol is useful for the prevention of the recurrence of vascular events in patients with lacunar infarction, and is probably effective in high-risk patients with diabetes and/or hypertension.

Subarachnoid haemorrhage in the elderly: a necropsy study of the association with cerebral amyloid angiopathy.

To clarify the contribution of cerebral amyloid angiopathy (CAA) to subarachnoid haemorrhage (SAH) in the elderly, relationships between SAH and CAA were investigated in 997 necropsy cases aged 60 years or older. Primary SAH (bleeding from subarachnoid vessels) was found in 15 cases (1.5%). There was no case in which primary SAH was clearly attributed to CAA. Secondary SAH [secondary rupture of intracerebral haemorrhage (ICH) through the cortex to the subarachnoid space] was found in 23 patients (2.3%). In 11 (48%) of them, ICH with secondary SAH was associated with CAA. The results indicated that primary SAH is rarely related to CAA, however, CAA is the most frequent cause of ICH accompanying secondary SAH in the elderly.

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 association of neprilysin polymorphism with Alzheimer's disease and Alzheimer's disease-type neuropathological changes

Sporadic Alzheimers disease is a polygenic disease and the relation between many genetic risk factors and the development of Alzheimers disease has been controversial. Accumulation of amyloid β-protein (Aβ) in the brain is the neuropathological hallmark and thought to be a key event in the upstream stage of pathological cascade of the disease. Although increased production of Aβ is established in the pathogenesis of familial Alzheimers disease due to mutations in presenilin 1, 2, and amyloid β-protein precursor genes, there is no evidence of up regulated synthesis of Aβ in the brains of patients with sporadic Alzheimers disease. In addition, aging is the most major risk factor for the disease. These findings suggest the possibility that reduction of the catabolic system of Aβ due to aging causes the formation of senile plaques in sporadic disease. Therefore, proteolytic enzymes of Aβ might be related to the development of sporadic Alzheimers disease. One of the enzymes responsible for the degradation of Aβ is neprilysin (NEP).1 This is a membrane bound metallopeptidase which is widely expressed in many tissues including the CNS. It cleaves Aβ 1–42 between amino acids 9 and 10 and between amino acids 37 and 38.2 Reduced mRNA and protein concentrations of NEP in the brain from patients with Alzheimers disease were reported, suggesting that low concentrations of NEP contributed to the accumulation of Aβ.3 Recent investigation showed that NEP inhibitor infusion into the brain resulted in increased deposition of Aβ, indicating that NEP regulates proteolytic catabolism of Aβ in vivo.2 There is a dinucleotide repeat polymorphism in the 5′ region of the NEP gene. A lower molecular weight allele of NEP gene polymorphism is associated …

A quantitative Golgi study of basal dendrites of hippocampal CA1 pyramidal cells in senile dementia of Alzheimer type.

Basal dendrites of hippocampal CA1 pyramidal cells in senile dementia of Alzheimer type (SDAT) were studied quantitatively by the Golgi impregnation method. The present data suggested that basal dendrites of the pyramidal cells were decreased in number in SDAT, and that the dendritic decrease was associated with a decrease in size of their cell bodies.

Electroencephalography in old age: Dominant alpha pattern

Abstract EEGs of 1007 subjects and patients 60 years and over were analyzed with special reference to the pattern of the dominant alpha waves. 1. 1. The difference in mean value of the frequencies of the dominant alpha waves in normal subjects (9.47 ± 1.73 c/sec) and in neurological patients (8.65 ± 1.64 c/sec) was statistically significant. 2. 2. The mean values of frequencies of the dominant alpha waves tend to decrease significantly with increasing decade, after the 7th decade. 3. 3. No significant difference in mean values and in the distribution curves of the frequencies of the dominant alpha waves were noted in the normotensive and in the hypertensive subjects.