Journal of Alzheimer's Disease - Volume 52, issue 3

Authors: Xing, Yi | Tang, Yi | Zhao, Lina | Wang, Qi | Qin, Wei | Zhang, Jin-Lan | Jia, Jianping

Article Type: Research Article

Abstract: Background: Various evidence demonstrates the influences of ceramides on Alzheimer’s disease (AD) pathogenesis. Furthermore, increased ceramides were also suggested to be related to cognitive decline. However, the association between ceramides and neuropsychiatric symptoms of AD remains unclear. Objective: This study sought to investigate the association between plasma ceramide levels and multiple neuropsychiatric symptoms in AD. Methods: A total of 98 patients and 92 cognitively normal controls participated in this study, including 56 with mild AD and 42 with moderate to severe AD. The Neuropsychiatric Inventory (NPI) was used to assess neuropsychiatric symptoms. Considering the influences …of dementia severity on ceramide levels and neuropsychiatric symptoms, a subgroup analysis was conducted by dementia severity. Results: Except for C24 : 0, all ceramide species were significantly higher in AD patients than in controls. After controlling for confounding factors, the C16 : 0 and C20 : 0 levels were positively associated with delusions, and the quartiles of C22 : 0 and C24 : 0 were positively associated with depression. In the subgroup analysis, association between ceramide species and delusions were only observed in mild AD, and the association between ceramides and depression were prominent in moderate to severe AD. In mild AD, after controlling for age, gender, anti-dementia medications, diabetes status, and ApoE ɛ 4 status, the C16 : 0, C20 : 0, and quartiles of C24 : 1 were associated with delusions. In moderate to severe AD, depression was associated with C22 : 0 and C24 : 0. Conclusion: There were stage-specific associations between ceramides and neuropsychiatric symptoms of AD. The potential mechanisms deserve further investigation. Show more

Keywords: Alzheimer’s disease, ceramides, plasma, psychiatry

DOI: 10.3233/JAD-151158

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1029-1035, 2016

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: Nilsson, Erik D. | Melander, Olle | Elmståhl, Sölve | Lethagen, Eva | Minthon, Lennart | Pihlsgård, Mats | Nägga, Katarina

Article Type: Research Article

Abstract: Background: Copeptin is a reliable surrogate marker for the neurohypophyseal hormone vasopressin. Elevated plasma level of copeptin has been associated with cardiovascular and metabolic disease risk. Objective: To investigate the association between copeptin and risk of dementia. Methods: In all, 18,240 individuals from Malmö, Sweden, were examined between 2002 and 2006 (mean age 69.3 years, 69.8% men). Incident cases of dementia until 31 December 2009 were identified by linkage with the Swedish National Patient Register. To validate the dementia diagnoses, medical records as well as laboratory and neuroimaging data were carefully reviewed. Baseline level of …copeptin was measured in frozen plasma in: (1) all participants who were diagnosed with dementia during follow-up, (2) a random sample of 5100 individuals of the cohort. Results: During a median follow-up of 4.2 years, there were 374 incident dementia cases (age range 60–83 years at baseline): 120 were classified as Alzheimer’s disease (AD), 84 as vascular dementia (VaD), and 102 as mixed dementia. In logistic regressions adjusted for cardiovascular risk factors, baseline level of copeptin predicted incident VaD (Odds ratio (OR) 1.30 per 1 SD increase in log copeptin, 95% CI 1.03–1.64). Copeptin did not predict incidence of all-cause dementia (OR 1.05, 95% CI 0.94–1.18), AD (OR 0.97, 95% CI 0.79–1.18), or mixed dementia (OR 0.85, 95% CI 0.68–1.05). Conclusion: Elevated plasma level of copeptin is a risk marker for incident VaD, but not for incident AD. This suggests that the vasopressin hormonal system might be involved in the development of VaD. Show more

Keywords: Alzheimer’s disease, copeptin, dementia, vascular dementia

DOI: 10.3233/JAD-151118

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1047-1053, 2016

Authors: Ingber, Adam P. | Hassenstab, Jason | Fagan, Anne M. | Benzinger, Tammie L.S. | Grant, Elizabeth A. | Holtzman, David M. | Morris, John C. | Roe, Catherine M.

Article Type: Research Article

Abstract: Background: The influence of reserve variables and Alzheimer’s disease (AD) biomarkers on cognitive test performance has been fairly well-characterized. However, less is known about the influence of these factors on “non-cognitive” outcomes, including functional abilities and mood. Objective: We examined whether cognitive and brain reserve variables mediate how AD biomarker levels in cognitively normal persons predict future changes in function, mood, and neuropsychiatric behavior. Methods: Non-cognitive outcomes were examined in 328 individuals 50 years and older enrolled in ongoing studies of aging and dementia at the Knight Alzheimer Disease Research Center (ADRC). All participants were …cognitively normal at baseline (Clinical Dementia Rating [CDR] 0), completed cerebrospinal fluid (CSF) and structural neuroimaging studies within one year of baseline, and were followed for an average of 4.6 annual visits. Linear mixed effects models explored how cognitive reserve and brain reserve variables mediate the relationships between AD biomarker levels and changes in function, mood, and neuropsychiatric behavior in cognitively normal participants. Results: Education levels did not have a significant effect on predicting non-cognitive decline. However, participants with smaller brain volumes exhibited the worst outcomes on measures of mood, functional abilities, and behavioral disturbance. This effect was most pronounced in individuals who also had abnormal CSF biomarkers. Conclusions: The findings suggest that brain reserve plays a stronger, or earlier, role than cognitive reserve in protecting against non-cognitive impairment in AD. Show more

Keywords: Alzheimer’s disease, biomarkers, cognitive reserve, dementia

DOI: 10.3233/JAD-150478

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1055-1064, 2016

Authors: Henneges, Carsten | Reed, Catherine | Chen, Yun-Fei | Dell’Agnello, Grazia | Lebrec, Jeremie

Article Type: Research Article

Abstract: Background: Improved understanding of the pattern of cognitive decline in Alzheimer’s disease (AD) would be useful to assist primary care physicians in explaining AD progression to patients and caregivers. Objective: To identify the sequence in which cognitive abilities decline in community-dwelling patients with AD. Methods: Baseline data were analyzed from 1,495 patients diagnosed with probable AD and a Mini-Mental State Examination (MMSE) score ≤ 26 enrolled in the 18-month observational GERAS study. Proportional odds logistic regression models were applied to model MMSE subscores (orientation, registration, attention and concentration, recall, language, and drawing) and the corresponding …subscores of the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog), using MMSE total score as the index of disease progression. Probabilities of impairment start and full impairment were estimated at each MMSE total score level. Results: From the estimated probabilities for each MMSE subscore as a function of the MMSE total score, the first aspect of cognition to start being impaired was recall, followed by orientation in time, attention and concentration, orientation in place, language, drawing, and registration. For full impairment in subscores, the sequence was recall, drawing, attention and concentration, orientation in time, orientation in place, registration, and language. The sequence of cognitive decline for the corresponding ADAS-cog subscores was remarkably consistent with this pattern. Conclusion: The sequence of cognitive decline in AD can be visualized in an animation using probability estimates for key aspects of cognition. This might be useful for clinicians to set expectations on disease progression for patients and caregivers. Show more

Keywords: Alzheimer’s disease, cognition, disease progression, observational study

DOI: 10.3233/JAD-150852

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1065-1080, 2016

Authors: Liu, Cheng-Hui | Bu, Xian-Le | Wang, Jun | Zhang, Tao | Xiang, Yang | Shen, Lin-Lin | Wang, Qing-Hua | Deng, Bo | Wang, Xin | Zhu, Chi | Yao, Xiu-Qing | Zhang, Meng | Zhou, Hua-Dong | Wang, Yan-Jiang

Article Type: Research Article

Abstract: Background: Capsaicin-rich diets are common worldwide. Capsaicin has been shown to have favorable effects on various diseases including atherosclerosis, cardiovascular diseases, stroke, obesity, hypertension, cancer, and gastrointestinal and inflammatory diseases. The impact of capsaicin on Alzheimer’s disease (AD), which is the most common form of dementia in the elderly, remains unknown. Objective: To investigate the correlations of capsaicin intake with cognition and blood markers of AD. Methods: A total of 338 participants aged 40 years or older were enrolled from communities. Dietary habits regarding chili pepper consumption were collected using a Food Frequency Questionnaire (FFQ). …Cognitive function was measured using the Chinese version of the Mini-Mental State Examination (MMSE). Blood amyloid-β (Aβ)40 and Aβ42 were measured with ELISA kits. Results: In univariate analysis, MMSE scores (r  = 0.209, p  < 0.001), serum Aβ40 levels (r  = –0.149, p  = 0.006), the ratio of Aβ42 /Aβ40 (r  = 0.11, p  = 0.043) and total serum Aβ levels (r  = –0.097, p  = 0.075), but not serum Aβ42 levels (r  = 0.17, p  = 0.757), were significantly correlated with total capsaicin diet scores. In multivariate analysis, total capsaicin diet scores were positively associated with MMSE scores and inversely associated with serum Aβ40 levels, and total serum Aβ levels, but not serum Aβ42 levels and the ratio of Aβ42 /Aβ40 , after adjustment for age, gender, educational level, smoking history, alcohol consumption, body mass index (BMI) and comorbidities. Conclusion: These findings suggest that a capsaicin-rich diet may exert favorable effects on AD blood biomarkers and cognitive function in middle-aged and elderly adults. Show more

Keywords: Alzheimer’s disease, amyloid-beta, capsaicin, cognitive function

DOI: 10.3233/JAD-151079

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1081-1088, 2016

Authors: Wang, Wei | Lu, Lu | Wu, Qiao-qi | Jia, Jian-ping

Article Type: Research Article

Abstract: Amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, and neuroinflammation are major pathophysiological events in Alzheimer’s disease (AD). However, the relationships among these processes and which first exerts an effect are unknown. In the present study, we investigated age-dependent behavioral changes and the sequential pathological progression from the brain to the periphery in AD transgenic (PS1V97L -Tg) mice and their wild-type littermates. We discovered that the brain Aβ significantly increased at 6 months old, the increased brain Aβ caused memory dysfunction, and the ability of Aβ to induce tau hyperphosphorylation might be due to oxidative stress and neuroinflammatory reactions. The levels …of Aβ42 , total tau (t-tau), oxidative stress parameters, and proinflammatory cytokines in plasma can be used to differentiate between PS1V97L -Tg mice and their wild-type littermates at different time points. Collectively, our findings support the hypothesis that Aβ is a trigger among these pathophysiological processions and show that plasma biomarkers can reflect the condition of the AD brain. Show more

Keywords: Alzheimer’s disease, amyloid-β, oxidative stress, proinflammatory cytokines, PS1V97L-Tg mouse, tau

DOI: 10.3233/JAD-160004

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1089-1099, 2016

Authors: Kim, Hee-Jin | Im, Hyung Kyun | Kim, Juhan | Han, Jee-young | de Leon, Mony | Deshpande, Anup | Moon, Won-Jin

Article Type: Research Article

Abstract: Background: Rapid eye movement sleep behavior disorder (RBD) may present as an early manifestation of an evolving neurodegenerative disorder with alpha-synucleinopathy. Objective: We investigated that dementia with RBD might show distinctive cortical atrophic patterns. Methods: A total of 31 patients with idiopathic Parkinson’s disease (IPD), 23 with clinically probable Alzheimer’s disease (AD), and 36 healthy controls participated in this study. Patients with AD and IPD were divided into two groups according to results of polysomnography and rated with a validated Korean version of the RBD screening questionnaire (RBDSQ-K), which covers the clinical features of RBD. …Voxel-based morphometry was adapted for detection of regional brain atrophy among groups of subjects. Results: Scores on RBDSQ-K were higher in the IPD group (3.54 ± 2.8) than in any other group (AD, 2.94 ± 2.4; healthy controls, 2.31 ± 1.9). Atrophic changes according to RBDSQ-K scores were characteristically in the posterior part of the brain and brain stem, including the hypothalamus and posterior temporal region including the hippocampus and bilateral occipital lobe. AD patients with RBD showed more specialized atrophic patterns distributed in the posterior and inferior parts of the brain including the bilateral temporal and occipital cortices compared to groups without RBD. The IPD group with RBD showed right temporal cortical atrophic changes. Conclusion: The group of patients with neurodegenerative diseases and RBD showed distinctive brain atrophy patterns, especially in the posterior and inferior cortices. These results suggest that patients diagnosed with clinically probable AD or IPD might have mixed pathologies including α -synucleinopathy. Show more

Keywords: Brain atrophy, dementia, RBD screening questionnaire, REM sleep disorder, voxel-based morphometry

DOI: 10.3233/JAD-151197

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1101-1109, 2016

Authors: Mulder, Cornelis K. | Dong, Yun | Brugghe, Humphrey F. | Timmermans, Hans A.M. | Tilstra, Wichard | Westdijk, Janny | van Riet, Elly | van Steeg, Harry | Hoogerhout, Peter | Eisel, Ulrich L.M.

Article Type: Research Article

Abstract: Background: Soluble oligomeric (misfolded) species of amyloid-β (Aβ) are the main mediators of toxicity in Alzheimer’s disease (AD). These oligomers subsequently form aggregates of insoluble fibrils that precipitate as extracellular and perivascular plaques in the brain. Active immunization against Aβ is a promising disease modifying strategy. However, eliciting an immune response against Aβ in general may interfere with its biological function and was shown to cause unwanted side-effects. Therefore, we have developed a novel experimental vaccine based on conformational neo-epitopes that are exposed in the misfolded oligomeric Aβ, inducing a specific antibody response. Objective: Here we investigate …the protective effects of the experimental vaccine against oligomeric Aβ1-42 -induced neuronal fiber loss in vivo . Methods: C57BL/6 mice were immunized or mock-immunized. Antibody responses were measured by enzyme-linked immunosorbent assay. Next, mice received a stereotactic injection of oligomeric Aβ1-42 into the nucleus basalis of Meynert (NBM) on one side of the brain (lesion side), and scrambled Aβ1-42 peptide in the contralateral NBM (control side). The densities of choline acetyltransferase-stained cholinergic fibers origination from the NBM were measured in the parietal neocortex postmortem. The percentage of fiber loss in the lesion side was determined relative to the control side of the brain. Results: Immunized responders (79%) showed 23% less cholinergic fiber loss (p  = 0.01) relative to mock-immunized mice. Moreover, fiber loss in immunized responders correlated negatively with the measured antibody responses (R2  = 0.29, p  = 0.02). Conclusion: These results may provide a lead towards a (prophylactic) vaccine to prevent or at least attenuate (early onset) AD symptoms. Show more

Keywords: Alzheimer’s disease, amyloid-β protein (1–42), cholinergic fibers, cyclopeptides, immunization, mice, nucleus basalis of Meynert, stereotactic injection

DOI: 10.3233/JAD-151136

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1111-1123, 2016

Authors: Cretin, Benjamin | Sellal, François | Philippi, Nathalie | Bousiges, Olivier | Di Bitonto, Laure | Martin-Hunyadi, Catherine | Blanc, Frederic

Article Type: Research Article

Abstract: Background: Aside from rare case reports, only one study, with 12 patients, has addressed the phenotypic presentation of epilepsy in clinically defined amnestic mild cognitive impairment (aMCI, presumed to correspond to the AD prodromal stage): the authors highlighted a pharmacosensitive non-convulsive partial epileptic syndrome most probably related to the temporal or temporo-frontal cortices. Objective: The objective of this study was to verify the existence and the syndromic features of epileptic prodromal AD in a tertiary Memory Clinic. Methods: We conducted a retrospective, single-center study of the electro-radio-clinical features of 13 cases of epileptic prodromal AD …patients (3.1% of a cohort of MCI, n  = 430 subjects), selected on both clinical criteria and CSF biomarkers. Results: In our patients, a pharmacosensitive temporal lobe epilepsy syndrome, inaugurating prodromal AD, started at a mean age of 63 years (±12.8 years) and preceded MCI diagnosis by 4 to 7 years. At the stage of aMCI, median MMSE score was 26 and imaging showed mild hippocampal atrophy. After almost one year under treatment, cognitive complaints were not relieved but the MMSE score remained stable at 26 for 11 patients (2 patients were excluded from analysis because of the onset of aphasic or neurovisual symptoms altering MMSE scoring). Conclusion: Our data, in conjunction with those of the 12 previously described subjects, suggest the existence of a currently unrecognized inaugural epilepsy syndrome of sporadic AD. Such a syndrome could be called the epileptic variant of AD because seizures are its sole feature for more than 2.5 years. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, partial seizures, temporal lobe epilepsy

DOI: 10.3233/JAD-150096

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1125-1133, 2016

Authors: Meng, Xiangbao | Luo, Yun | Liang, Tian | Wang, Mengxia | Zhao, Jingyu | Sun, Guibo | Sun, Xiaobo

Article Type: Research Article

Abstract: A strategy for activating transcription factor EB (TFEB) to restore autophagy flux may provide neuroprotection against Alzheimer’s disease. Our previous study reported that gypenoside XVII (GP-17), which is a major saponin abundant in ginseng and Panax notoginseng , ameliorated amyloid-β (Aβ)25-35 -induced apoptosis in PC12 cells by regulating autophagy. In the present study, we aimed to determine whether GP-17 has neuroprotective effects on PC12 cells expressing the Swedish mutant of APP695 (APP695swe) and APP/PS1 mice. We also investigated the underlying mechanism. We found that GP-17 could significantly increase Atg5 expression and the conversion of LC3-I to LC3-II in APP695 cells, …which was associated with a reduction in p62 expression. GP-17 also elevated the number of LC3 puncta in APP695 cells transduced with pCMV-GFP-LC3. GP-17 promoted the autophagy-based elimination of AβPP, Aβ40 , and Aβ42 in APP695swe cells and prevented the formation of Aβ plaques in the hippocampus and cortex of APP/PS1 mice. Furthermore, spatial learning and memory deficits were cured. Atg5 knockdown could abrogate the GP-17-mediated removal of AβPP, Aβ40 , and Aβ42 in APP695swe cells. GP-17 upregulated LAMP-1, increased LysoTracker staining, and augmented LAMP-1/LC3-II co-localization. GP-17 could release TFEB from TFEB/14-3-3 complexes, which led to TFEB nuclear translocation and the induction of autophagy and lysosome biogenesis and resulted in the amelioration of autophagy flux. The knockdown of TFEB could abolish these effects of GP-17. In summary, these results demonstrated that GP-17 conferred protective effects to the cellular and rodent models of Alzheimer’s disease by activating TFEB. Show more

Keywords: APP/PS1 mice, autophagy flux, lysosome biogenesis, transcription factor EB

DOI: 10.3233/JAD-160096

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1135-1150, 2016

Article Type: Other

DOI: 10.3233/JAD-160313

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1151-1155, 2016