Authors: Hattori, Yorito | Maki, Takakuni | Saito, Satoshi | Yamamoto, Yumi | Nagatsuka, Kazuyuki | Ihara, Masafumi
Article Type: Research Article
Abstract: Accumulation of amyloid-β peptide (Aβ) in the brain is one of the most important features of Alzheimer’s dementia (AD). Cerebral amyloid angiopathy (CAA) is characterized by Aβ accumulation in the walls of cerebral arteries and capillaries, and is present in over 90% of patients with AD. Several novel agents for AD/CAA developed around the amyloid hypothesis have shown positive signs in animal studies but have failed in clinical trials due to adverse events and/or lack of efficiency. As CAA is presumably caused by a failure in Aβ clearance, drugs that promote Aβ clearance may hold promise in the treatment of …CAA and possibly AD. With this in mind, cilostazol, an anti-platelet drug with vasodilating action, has been found to promote Aβ clearance along perivascular drainage pathway, reduce Aβ accumulation in the brain, and restore memory impairment in Tg-SwDI mice, an animal model of CAA. We therefore tested whether the most common anti-platelet agent, aspirin, also reduced Aβ and rescued cognitive impairment in Tg-SwDI mice, and also whether aspirin affected hemorrhagic complications that can occur in Tg-SwDI mice. Mice aged 4 months were assigned into vehicle-treated and low-dose aspirin-treated groups. Low-dose aspirin for 8 months did not increase hemorrhagic lesions, nor increase resting cerebral blood flow or cerebral vascular reserve in response to hypercapnia or acetylcholine. Subsequently, aspirin did not restore cognitive dysfunction. These results suggest that low-dose aspirin does not have a direct influence on cerebrovascular Aβ metabolism nor aggravate hemorrhagic complications in CAA. Show more
Keywords: Alzheimer’s dementia, amyloid β, aspirin, cerebral amyloid angiopathy
DOI: 10.3233/JAD-160013
Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1037-1045, 2016
Authors: Manousopoulou, Antigoni | Saito, Satoshi | Yamamoto, Yumi | Al-Daghri, Nasser M. | Ihara, Masafumi | Carare, Roxana O. | Garbis, Spiros D.
Article Type: Short Communication
Abstract: The aim of this study was to examine hemisphere asymmetry of response to pharmacologic treatment in an Alzheimer’s disease mouse model using cilostazol as a chemical stimulus. Eight-month-old mice were assigned to vehicle or cilostazol treatment for three months and hemispheres were analyzed using quantitative proteomics. Bioinformatics interpretation showed that following treatment, aggregation of blood platelets significantly decreased in the right hemisphere whereas neurodegeneration significantly decreased and synaptic transmission increased in the left hemisphere only. Our study provides novel evidence on cerebral laterality of pharmacologic activity, with important implications in deciphering regional pharmacodynamic effects of existing drugs thus uncovering novel …hemisphere-specific therapeutic targets. Show more
Keywords: Alzheimer’s disease, cilostazol, hemisphere asymmetry, mass spectrometry pharmacology, pharmacodynamics, pharmacoproteomics
DOI: 10.3233/JAD-151078
Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 333-338, 2016
Authors: Saito, Satoshi | Yamashiro, Takayuki | Yamauchi, Miho | Yamamoto, Yumi | Noguchi, Michio | Tomita, Tsutomu | Kawakami, Daisuke | Shikata, Masamitsu | Tanaka, Tomotaka | Ihara, Masafumi
Article Type: Research Article
Abstract: Background: Cerebral amyloid angiopathy is a cerebrovascular disease directly implicated in Alzheimer’s disease pathogenesis through amyloid-β deposition. Growing evidence has shown a pivotal role of chronic neuroinflammation both in cerebral amyloid angiopathy and Alzheimer’s disease. Objective: The aim of this study was to investigate whether circulating levels of the complement 3, a crucial component of the innate immune system, are increased in patients with cerebral amyloid angiopathy. Methods: Serum complement 3 levels were retrospectively measured by a sandwich enzyme-linked immunosorbent assay in a single-center cohort of patients with mild cognitive impairment. The diagnosis of cerebral amyloid angiopathy was based on …the modified Boston criteria. Logistic regression analysis was performed to identify the predictive factors for cerebral amyloid angiopathy. Results: We analyzed 55 mild cognitive impairment patients (mean age [standard deviation]: 76.3 [6.8] years; 33 [60% ] men). Complement 3 levels were significantly increased in cerebral amyloid angiopathy patients (n = 16) compared with those without cerebral amyloid angiopathy (n = 39) (median [interquartile range]: 0.43 [0.34–0.65] versus 0.35 [0.25–0.45], respectively; p = 0.040). Univariate and multivariate logistic regression analysis revealed that increased complement 3 levels were significantly associated with cerebral amyloid angiopathy. After selection of the best predictive model using stepwise selection, complement 3 was preserved as a significant independent predictive factor for cerebral amyloid angiopathy (odds ratio per 0.1 unit/mL increase [95% confidence interval]: 1.407 [1.042–1.899]; p = 0.026). Conclusion: Complement activation may play a pivotal role in cerebral amyloid angiopathy. Complement 3 may be a novel diagnostic biomarker for cerebral amyloid angiopathy. Show more
Keywords: Alzheimer’s disease, biomarkers, cerebral amyloid angiopathy, complement 3, inflammation
DOI: 10.3233/JAD-220494
Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 381-387, 2022
Authors: Takahashi, Yukako | Saito, Satoshi | Yamamoto, Yumi | Uehara, Toshiyuki | Yokota, Chiaki | Sakai, Go | Nishida, Norifumi | Takahashi, Ryosuke | Kalaria, Raj N. | Toyoda, Kazunori | Nagatsuka, Kazuyuki | Ihara, Masafumi
Article Type: Research Article
Abstract: Background: Time and resource limitations prevent cognitive assessment in acute-to-subacute settings, even in comprehensive stroke centers. Objective: To assess cognitive function in acute stroke patients undergoing routine clinical, laboratory, and radiological investigations, with a view to improving post-stroke care and treatment. Methods: Sixty-nine patients (72.6±11.1 years; 65% male) were prospectively enrolled within 14 days of acute ischemic stroke. Patients with altered consciousness, aphasia, or dysarthria were excluded. Clinical features including modified Rankin and NIH stroke scales, and vascular risk factors were assessed, as well as neuroimaging parameters by semi-quantitative evaluation of medial temporal lobe atrophy (MTLA) using MRA source images, …FLAIR images for white matter changes (Fazekas scores), and T2∗ images for cerebral microbleeds. Neuropsychological screening was conducted using the Montreal Cognitive Assessment (MoCA) test. Univariate and multivariate analyses were used to evaluate the influence of variables on MoCA total and subscale scores. Results: Lower MoCA scores of 22 or less were associated with MTLA [OR (95% CI), 5.3 (1.0–27.5); p = 0.045], education years [OR (95% CI), 0.71 (0.55–0.91); p = 0.007], and modified Rankin scale at discharge [OR (95% CI), 2.4 (1.3–4.5); p = 0.007]. The delayed recall MoCA score was correlated with MTLA (r = – 0.452, p < 0.001), periventricular (r = – 0.273, p = 0.024), and deep (r = – 0.242, p = 0.046), white matter changes. Conclusions: MTLA, together with lower educational history, are quick indicators of amnestic cognitive impairment after stroke. The association between cognitive impairment and physical disability at discharge may signify the importance of earlier cognitive assessment. Show more
Keywords: Comprehensive stroke center, dementia, medial temporal lobe atrophy, Montreal Cognitive Assessment, post-stroke dementia, stroke
DOI: 10.3233/JAD-180976
Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 621-629, 2019
