Journal of Alzheimer's Disease - Volume 71, issue 1

Authors: Hatada, Yutaka | Hashimoto, Mamoru | Shiraishi, Shinya | Ishikawa, Tomohisa | Fukuhara, Ryuji | Yuki, Seiji | Tanaka, Hibiki | Miyagawa, Yusuke | Kitajima, Mika | Uetani, Hiroyuki | Tsunoda, Naoko | Koyama, Asuka | Ikeda, Manabu

Article Type: Research Article

Abstract: Background: Although cerebral microbleeds (CMBs) are commonly observed in patients with Alzheimer’s disease (AD), their clinical relevance for AD remains unclear. Objective: We investigated the significance of CMBs in AD by examining the relationship between CMBs and cerebral blood flow (CBF) in patients with AD. Methods: Thirty-four patients (aged 77.9±7.6 years; 17 men) with probable AD and multiple (≥8) CMBs were selected from 394 consecutive patients. For each lobe of the brain, the correlation between the number of CMBs observed on susceptibility-weighted images and the decrease in CBF observed on single-photon emission computed tomography was assessed. …Results: The number of microbleeds was significantly correlated with the severity of decrease in the occipital lobe (Spearman’s r  = 0.531, p  < 0.001) and temporal lobe (r  = 0.437, p  < 0.001) but not in the frontal lobe (r  = 0.201, p  = 0.101) and parietal lobe (r  = 0.178, p  = 0.146). These results were unchanged in the partial correlational analysis after controlling the effect of other small vessel disease such as lacunars and white matter hyperintensities. Conclusion: Multiple CMBs are associated with cerebral hypoperfusion in AD. The effects of CMBs on CBF differed according to brain location, possibly reflecting different distributions of the underlying cerebral amyloid angiopathy and AD-related histopathology, such as neurofibrillary tangles. Show more

Keywords: Alzheimer’s disease, amyloid angiopathy, cerebral blood flow, cerebral microbleeds

DOI: 10.3233/JAD-190272

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 273-280, 2019

Authors: Osborn, Katie E. | Alverio, Jonathan M. | Dumitrescu, Logan | Pechman, Kimberly R. | Alzheimer’s Disease Neuroimaging Initiative | Gifford, Katherine A. | Hohman, Timothy J. | Blennow, Kaj | Zetterberg, Henrik | Jefferson, Angela L.

Article Type: Research Article

Abstract: Background: Vascular risk factors promote cerebral small vessel disease and neuropathological changes, particularly in white matter where large-caliber axons are located. How Alzheimer’s disease pathology influences the brain’s vulnerability in this regard is not well understood. Objective: Systemic vascular risk was assessed in relation to cerebrospinal fluid concentrations of neurofilament light, a biomarker of large-caliber axonal injury, evaluating for interactions by clinical and protein markers of Alzheimer’s disease. Methods: Among Alzheimer’s Disease Neuroimaging Initiative participants with normal cognition (n  = 117), mild cognitive impairment (n  = 190), and Alzheimer’s disease (n  = 95), linear regression related vascular risk (as …measured by the modified Framingham Stroke Risk Profile) to neurofilament light, adjusting for age, sex, education, and cognitive diagnosis. Interactions were assessed by cognitive diagnosis, and by cerebrospinal fluid markers of Aβ42 , hyperphosphorylated tau, and total tau. Results: Vascular risk and neurofilament light were not related in the main effect model (p  = 0.08). However, interactions emerged for total tau (p  = 0.01) and hyperphosphorylated tau (p  = 0.002) reflecting vascular risk becoming more associated with cerebrospinal fluid neurofilament light in the context of greater concentrations of tau biomarkers. An interaction also emerged for the Alzheimer’s disease biomarker profiles (p  = 0.046) where in comparison to the referent ‘normal’ biomarker group, individuals with abnormal levels of both Aβ42 and total tau showed stronger associations between vascular risk and neurofilament light. Conclusion: Older adults may be more vulnerable to axonal injury in response to higher vascular risk burdens in the context of concomitant Alzheimer’s disease pathology. Show more

Keywords: Alzheimer’s disease, cerebrovascular, neurodegeneration, neurofilament light, vascular risk

DOI: 10.3233/JAD-190077

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 281-290, 2019

Authors: Wu, Beibei | Wang, Yujing | Shi, Chenggang | Chen, Yao | Yu, Lexiang | Li, Juan | Li, Weiwei | Wei, Yan | He, Rongqiao

Article Type: Research Article

Abstract: Advanced glycation end products (AGEs) have been implicated in the disease process of diabetes mellitus. They have also been found in senile plaques and neurofibrillary tangles in the brains of Alzheimer’s disease patients. Furthermore, abnormally high levels of D-ribose and D-glucose were found in the urine of patients with type 2 diabetes mellitus, suggesting that diabetic patients suffer from dysmetabolism of not only D-glucose but also D-ribose. In the present study, intravenous tail injections of ribosylated rat serum albumin (RRSA) were found to impair memory in rats, but they did not markedly impair learning, as measured by the Morris water …maze test. Injections of RRSA were found to trigger tau hyperphosphorylation in the rat hippocampus via GSK-3β activation. Tau hyperphosphorylation and GSK-3β activation were also observed in N2a cells in the presence of ribosylation-derived AGEs. Furthermore, the administration of ribosylation-derived AGEs induced the suppression of brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB). Both GSK-3β inhibition and BDNF treatment decreased the levels of phosphorylated tau in N2a cells. In particular, the administration of BDNF could rescue memory failure in ribosylated AGE-injected rats. Ribosylation-derived AGEs downregulated the BDNF-TrkB pathway in rat brains and N2a cells, leading to GSK-3β activation-mediated tau hyperphosphorylation, which was involved in the observed rat memory loss. Targeting ribosylation may be a promising therapeutic strategy to prevent Alzheimer’s disease and diabetic encephalopathies. Show more

Keywords: Advanced glycation end products, brain-derived neurotrophic factor, GSK-3β oxidative stress, ribosylation, tau hyperphosphorylation

DOI: 10.3233/JAD-190158

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 291-305, 2019

Authors: Lennon, Matthew J. | Makkar, Steve R. | Crawford, John D. | Sachdev, Perminder S.

Article Type: Research Article

Abstract: Background: Hypertension is an established risk factor for stroke and vascular dementia but recent meta-analyses examining the association between Alzheimer’s disease (AD) and hypertension have found no significant association. These meta-analyses included short term studies starting in late life which may have obscured the real effect of midlife hypertension. Objective: To examine the association of AD with midlife hypertension, by including only studies with a sufficiently long follow up duration. Methods: Relevant studies were found by searches of MEDLINE, EMBASE, and PubMed. Study outcomes were grouped by measures of blood pressure and definition of hypertension (e.g., …systolic hypertension > 140 mmHg or > 160 mmHg). We assessed pooled effect estimates using random effects models and heterogeneity of pooled estimates through the I2 statistic. Results: Literature search found 3,426 publications of which 7 were eligible studies. There was a significant association between systolic hypertension (>160 mm Hg) and AD (HR 1.25, 95CI 1.06 – 1.47, p  = 0.0065). Similarly, for systolic hypertension > 140 mm Hg, there was a smaller but still significant association (HR 1.18, 95CI 1.02 – 1.35, p  = 0.021). For diastolic hypertension, all four studies found no significant associations between diastolic hypertension and AD, and these data could not be pooled due to heterogeneity in reporting. Conclusions: Our study found that midlife stage 1 and stage 2 systolic hypertension is associated with increased risk of AD by 18 and 25%, respectively, although no association was found for diastolic hypertension. It is likely that assertive control of systolic hypertension starting in midlife is important to preventing AD. Show more

Keywords: Alzheimer’s disease, dementia, hypertension, meta-analysis, midlife

DOI: 10.3233/JAD-190474

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 307-316, 2019

Authors: Kleipool, Emma E.F. | Trappenburg, Marijke C. | Rhodius-Meester, Hannke F.M. | Lemstra, Afina W. | van der Flier, Wiesje M. | Peters, Mike J.L. | Muller, Majon

Article Type: Research Article

Abstract: Background: Orthostatic hypotension (OH) has been cross-sectionally and longitudinally related to dementia in the general population. Whether OH contributes to clinical progression to mild cognitive impairment (MCI) or dementia is less certain. Also, differences in risk of progression between patients with early OH (EOH) versus delayed and/or prolonged OH (DPOH) are unclear. Objective: Assess the prevalence of EOH and DPOH, investigate the longitudinal association between EOH and DPOH and either incident MCI or dementia. Methods: 1,882 patients from the Amsterdam Dementia Cohort [64±8 years; 43% female; n  = 500 with subjective cognitive decline (SCD), n  = 341 MCI, …n  = 758 Alzheimer’s disease (AD), n  = 49 vascular dementia (VaD), n  = 146 frontotemporal dementia (FTD), n  = 88 Lewy body dementia (DLB)]. Definition OH: systolic blood pressure (BP) drop≥20 mmHg and/or a diastolic BP drop≥10 mmHg at 1 and/or 3 minutes after standing. EOH: OH only at 1 minute, DPOH: OH at (1 and) 3 minutes. Results: Prevalence OH: 19% SCD, 28% MCI, 41% dementia. Compared to SCD, odds of having OH were highest in patients with VaD and DLB; ORs (95% CI) were 2.6 (1.4–4.7) and 5.1 (3.1–8.4), respectively. After a mean (SD) follow-up of 2.2 (1.4) years, 105 (22%) of SCD or MCI patients showed clinical progression. Compared to patients without OH, those with DPOH had an increased risk of progression; hazard ratio (95% CI) was 1.7 (1.1–2.7), and those with EOH did not; 0.8 (0.3–1.9). Conclusion: Compared to SCD, prevalence of OH was higher in MCI and highest in dementia, particularly in VaD and DLB. DPOH, more likely associated with autonomic dysfunction, is a risk factor for incident MCI or dementia. Show more

Keywords: Blood pressure, clinical progression, dementia, orthostatic hypotension

DOI: 10.3233/JAD-190402

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 317-325, 2019

Authors: Feng, Tian | Yamashita, Toru | Shang, Jingwei | Shi, Xiaowen | Nakano, Yumiko | Morihara, Ryuta | Tsunoda, Keiichiro | Nomura, Emi | Sasaki, Ryo | Tadokoro, Koh | Matsumoto, Namiko | Hishikawa, Nozomi | Ohta, Yasuyuki | Abe, Koji

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) and chronic cerebral hypoperfusion (CCH) often coexist in dementia patients in aging societies. The hallmarks of AD including amyloid-β (Aβ)/phosphorylated tau (pTau) and pathology-related events such as neural oxidative stress and neuroinflammation play critical roles in pathogenesis of AD with CCH. A large number of lessons from failures of drugs targeting a single target or pathway on this so complicated disease indicate that disease-modifying therapies targeting multiple key pathways hold potent potential in therapy of the disease. In the present study, we used a novel mouse model of AD with CCH to investigate a potential therapeutic effect …of a free radical scavenger, Edaravone (EDA) on AD with CCH via examining motor and cognitive capacity, AD hallmarks, neural oxidative stress, and neuroinflammation. Compared with AD with CCH mice at 12 months of age, EDA significantly improved motor and cognitive deficits, attenuated neuronal loss, reduced Aβ/pTau accumulation, and alleviated neural oxidative stress and neuroinflammation. These findings suggest that EDA possesses clinical and pathological benefits for AD with CCH in the present mouse model and has a potential as a therapeutic agent for AD with CCH via targeting multiple key pathways of the disease pathogenesis. Show more

Keywords: Alzheimer’s disease, chronic cerebral hypoperfusion, edaravone, neural oxidative stress, neuronal loss, neuroinflammation

DOI: 10.3233/JAD-190369

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 327-339, 2019

Authors: Wong, Mark Yu Zheng | Tan, Chuen Seng | Venketasubramanian, Narayanaswamy | Chen, Christopher | Ikram, M.K. | Cheng, Ching-Yu | Hilal, Saima

Article Type: Research Article

Abstract: Background: Dementia is the leading cause of dependency and disability among older persons worldwide. There remains, however, limited studies on dementia rates within the Asia-Pacific region, with little data on differences across major Asian ethnic groups. Objective: To study the prevalence of cognitive impairment (CI) and dementia in community-dwelling Indians from Singapore and to examine interethnic differences among Chinese, Malays, and Indians. Methods: Participants (>60 years) drawn from the Indian component of the multiethnic Epidemiology of Dementia in Singapore (EDIS) study were screened using the locally validated Abbreviated Mental Test and Progressive Forgetfulness Questionnaire. Screen-positive participants …underwent further detailed neuropsychological assessments. CI was classified into Cognitive impairment no dementia (CIND)-mild, CIND-moderate, and dementia. Results: Of 961 Indian adults, 120 (12.5%) had CIND-mild, 101 (10.5%) CIND-moderate, and 12 (1.2%) dementia. The overall age-standardized prevalence of any CI was 24.6%. The prevalence of any CI increased with age (15.7% in ages 60–64 years to 30.1% in ages≥80 years), and was higher in women than men. Multivariate analysis showed that age, lower education, and hypertension were independently associated with CI. Even after demographic and cardiovascular risk factor adjustment, Indians were more likely to be cognitively impaired compared to Chinese (odds ratio [OR], 95% CI:1.37 [1.01–1.86 ]) but not Malays (0.89 [0.72–1.10]). Conclusions: Among elderly Indians, the overall prevalence of any CI was 24.6%. Despite similar assessment protocols and risk factor adjustments, the prevalence of CI was higher in Indians compared to Chinese but similar to Malays. Further research is needed to unravel other factors that may underlie these ethnic differences. Show more

Keywords: Cognitive impairment, dementia, epidemiology, Indian, prevalence, population-based, risk factors

DOI: 10.3233/JAD-190610

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 341-351, 2019

Authors: Kostev, Karel | Bohlken, Jens | Jacob, Louis

Article Type: Research Article

Abstract: Background: Most previous studies focusing on the migraine headache-dementia relationship have failed to simultaneously adjust for several common comorbidities. Objective: The goal of this retrospective cohort study was to investigate the association between migraine headaches and dementia in general practices in the UK. Methods: The current study sample included patients who received a migraine diagnosis in one of 67 general practices in the UK between January 1997 and December 2016 (index date). Patients without migraine diagnoses were matched 1 : 1 to patients with migraine diagnoses based on propensity scores using a greedy algorithm and derived from the …logistic regression using age, sex, index year, and co-diagnoses. The main outcome of the study was the association between migraine headaches and the incidence of dementia within 10 years of the index date. Results: This study included 7,454 individuals with or without migraine diagnoses. Mean age was 67.7 years (SD = 5.8 years), and 72.9% of patients were women. Within 10 years of the index date, 5.2% of participants with and 3.7% of those without migraine headaches were diagnosed with dementia (log-rank p  < 0.001). The respective figures were 5.8% and 3.6% in women (log-rank p  < 0.001) and 4.5% and 3.4% in men (log-rank p  = 0.722). We observed a positive association between migraine diagnoses and all-cause dementia (hazard ratio [HR] = 1.43) as well as Alzheimer’s disease (HR = 1.87). Sensitivity analyses further revealed that these associations were only significant in women (all-cause dementia: HR = 1.65; Alzheimer’s disease: HR = 2.27). Conclusion: Migraine diagnoses were positively associated with all-cause dementia and Alzheimer’s disease in women. Show more

Keywords: Dementia, migraine, retrospective cohort study, sex differences, United Kingdom

DOI: 10.3233/JAD-190581

Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 353-360, 2019