Journal of Alzheimer's Disease - Volume 71, issue 3

Authors: Yang, Alex J.T. | Frendo-Cumbo, Scott | MacPherson, Rebecca E.K.

Article Type: Research Article

Abstract: Background: Obesity, insulin resistance, and type 2 diabetes are established risk factors for the development of Alzheimer’s disease (AD). Given this connection, two drugs, metformin (MET) and resveratrol (RESV), are considered for the clearance of amyloid-β peptides through AMPK-mediated activation of autophagy. However, overactivation of AMPK observed in late-stage AD brains and relationships between AMPK and neurogenesis (through mTORC1 inhibition), questions treatment with these drugs. Objective: To examine if MET and/or RESV supplementation activates brain AMPK, regulates markers of autophagy, and affects markers of neuronal health/neurogenesis. Methods: 8-week-old male C57BL/6J mice were fed a low (N = 12; …10% kcal fat; LFD) or high fat diet (N = 40; 60% kcal fat; HFD) for 9 weeks to induce insulin resistance and obesity. HFD mice were then treated with/without MET (250 mg/kg/day), RESV (100 mg/kg/day), or COMBO (MET: 250 mg/kg/day, RESV: 100 mg/kg/day) for 5 weeks. Hippocampus and prefrontal cortex were extracted for western blotting analysis. Results: Cortex AMPK (T172) and raptor (S792, the regulatory subunit of mTORC1) phosphorylation were upregulated following RESV, COMBO treatments. mTOR (S2448) and ULK1 (S555) activation was seen following MET, COMBO and RESV, COMBO treatments, respectively, in the cortex and hippocampus. p62 content was decreased following RESV, COMBO, with LC3 content being increased following RESV treatment in the cortex. Brain derived neurotropic factor (BDNF) was significantly decreased following RESV, COMBO, and synaptophysin following all treatment in the cortex. Conclusion: These results demonstrate that while treatments upregulated markers of autophagy in the prefrontal cortex, reductions in neuronal health markers question the efficacy of AMPK as a therapy for AD. Show more

Keywords: Autophagy, BDNF, metformin, resveratrol, synaptophysin

DOI: 10.3233/JAD-190123

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 945-956, 2019

Authors: Kulshreshtha, Ambar | Goetz, Margarethe | Alonso, Alvaro | Shah, Amit J. | Bremner, J. Douglas | Goldberg, Jack | Vaccarino, Viola

Article Type: Research Article

Abstract: Background/Objective: The 2020 Strategic Impact Goal introduced by the American Heart Association (AHA) aims at improving cardiovascular health (CVH) of all Americans by 20%. AHA defined ideal CVH across seven established modifiable risk factors for cardiovascular diseases. Prior studies have indicated that ideal CVH also benefits brain health and cognitive aging, but it is possible that this association is explained by familial factors. Methods: We examined 272 male monozygotic and dizygotic twin pairs (total 544 subjects) free of overt cardiovascular disease and dementia from the Vietnam Era Twin Registry. Memory and learning were measured by Trail Making tests …and Wechsler Memory Scale (Immediate and Delayed Memory tests and Visual Reproductive Test). Each of the seven CVH components (smoking, body mass index, physical activity, diet, total cholesterol, blood pressure, and blood glucose) was scored per established criterion. Results: The mean age of the twins was 55 years, 96% were whites, and 61% monozygotic. When considering twins as individuals, for every unit increase in CVH score (indicating better cardiovascular health), twins demonstrated faster cognitive processing speed (Trail B: – 5.6 s, 95% CI – 10.3, – 0.9; p  = 0.03) and better story recall, both immediate (0.35, 95% CI 0.06, 0.62; p  = 0.02) and delayed (0.39, 95% CI 0.08, 0.70; p  = 0.01). Conclusions: Better CVH is associated with better cognitive health in several domains. As suggested by within-pair analysis, this association is largely explained by familial factors, implying that early life exposures are shared determinants of both brain health and cardiovascular health. Show more

Keywords: Epidemiology, prevention, risk factors

DOI: 10.3233/JAD-190217

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 957-968, 2019

Authors: Petersen, Maria Skaalum | Restorff, Marjun | Stórá, Tórmóður | Waldemar, Gunhild | Joensen, Sofus

Article Type: Research Article

Abstract: Background: Dementia has become an important public health, economic, and social issue. Knowledge about prevalence, incidence, and trends of dementia in a country is of crucial importance. However, no studies of incidence or prevalence of dementia have been undertaken in the Faroe Islands. Objectives: The aim was to estimate the overall and trend in incidence and prevalence of dementia among individuals ≥60 years in the Faroe Islands from 2010-2017. Methods: Population-based register study where all individuals ≥60 years with a dementia diagnosis from January 2010 to December 2017 were identified. The overall crude and age-and-sex-specific incidence …and prevalence was assessed. Results: The overall crude incidence among individuals ≥60 years from 2010 to 2017 was 5.1 per 1000 individuals and the prevalence 22.5 per 1000 individuals. The age-and sex-standardized annual incidence of dementia fluctuated between 4.8 and 6.7 per 1000, with no clear secular trend while the age-and sex-standardized prevalence increased steadily from 14.5 in 2010 to 30.8 per 1000 individuals in 2017. Conclusion: The age-standardized incidence or prevalence estimates in the Faroes seem to be lower than in other countries. The incidence was relatively stable in the period while the prevalence of dementia simultaneously increased. Show more

Keywords: Dementia, Faroe Islands, incidence study, nationwide study, prevalence study, trend in incidence and prevalence

DOI: 10.3233/JAD-190341

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 969-978, 2019

Authors: Huseby, Carol J. | Hoffman, Claire N. | Cooper, Grace L. | Cocuron, Jean-Christophe | Alonso, Ana P. | Thomas, Stefani N. | Yang, Austin J. | Kuret, Jeff

Article Type: Research Article

Abstract: Tau is a microtubule-associated protein that normally interacts in monomeric form with the neuronal cytoskeleton. In Alzheimer’s disease, however, it aggregates to form the structural component of neurofibrillary lesions. The transformation is controlled in part by age- and disease-associated post-translational modifications. Recently we reported that tau isolated from cognitively normal human brain was methylated on lysine residues, and that high-stoichiometry methylation depressed tau aggregation propensity in vitro . However, whether methylation stoichiometry reached levels needed to influence aggregation propensity in human brain was unknown. Here we address this problem using liquid chromatography–tandem mass spectrometry approaches and human-derived tau samples. Results …revealed that lysine methylation was present in soluble tau isolated from cognitively normal elderly cases at multiple sites that only partially overlapped with the distributions reported for cognitively normal middle aged and AD cohorts, and that the quality of methylation shifted from predominantly dimethyl-lysine to monomethyl-lysine with aging and disease. However, bulk mol methylation/mol tau stoichiometries never exceeded 1 mol methyl group/mol tau protein. We conclude that lysine methylation is a physiological post-translational modification of tau protein that changes qualitatively with aging and disease, and that pharmacological elevation of tau methylation may provide a means for protecting against pathological tau aggregation. Show more

Keywords: Aging, Alzheimer’s disease, mass spectrometry, methylation, phosphorylation, post-translational modification, tau protein

DOI: 10.3233/JAD-190604

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 979-991, 2019

Authors: Wiest, Isabella | Wiemers, Tim | Kraus, Max-Joseph | Neeb, Heiko | Strasser, Erwin F. | Hausner, Lucrezia | Frölich, Lutz | Bugert, Peter

Article Type: Research Article

Abstract: Background: Early diagnosis of Alzheimer’s disease (AD) is challenging, and easily accessible biomarkers are an unmet need. Blood platelets frequently serve as peripheral model for studying AD pathogenesis and might represent a reasonable biomarker source. Objective: In the present study, we investigated the potential to differentiate AD patients from healthy controls (HC) based on blood count, platelet morphology, and function as well as molecular markers at the time of first clinical diagnosis. Methods: Blood samples from 40 AD patients and 29 age-matched HC were included for determination of 78 parameter by blood counting, platelet morphometry, aggregometry, …flow cytometry (CD62P, CD63, activated fibrinogen receptor), protein quantification of nicotinic acetylcholine receptor α 7 (nAChRα 7) and caveolin-1 (CAV-1), and miRNA quantification (miR-26b, miR-199a, miR-335). Group comparison between patients and controls was performed in univariate and multivariate statistical analyses. Results: AD patients showed significantly lower aggregation response to ADP and arachidonic acid and significantly decreased CD62P and CD63 surface expression induced by ADP and U46619 compared to HC. Relative nAChRα 7 and CAV-1 expression was significantly higher AD platelets than in HC. Multivariate analysis of 63 parameter revealed significant differences between AD patients and healthy controls. The best performing feature model revealed a sensitivity of 96.6%, a specificity of 80.0%, and a positive predictive value of 89.3%. No grouping could be achieved by using single parameter groups. Conclusion: Significant differences between platelet characteristics from AD patients and HC at the time of first clinical diagnosis were observed. The best performing parameter can be used as a blood-based biomarker for AD diagnosis in a multivariate model in addition to the standardized mental tests. Show more

Keywords: Aggregometry, Alzheimer’s disease, blood-based biomarker, platelet morphology

DOI: 10.3233/JAD-190574

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 993-1004, 2019

Authors: Puthusseryppady, Vaisakh | Coughlan, Gillian | Patel, Martyn | Hornberger, Michael

Article Type: Research Article

Abstract: Background: Dementia-related missing incidents are highly prevalent but still poorly understood. This is particularly true for environmental/geospatial risk factors, which might contribute to these missing incidents. Objective: The study aimed to conduct a retrospective, observational analysis on a large sample of missing dementia patient case records provided by the police (n  = 210), covering dates from January 2014 to December 2017. In particular, we wanted to explore 1) whether there were any hotspot regions of missing incidents and 2) the relationship between outdoor landmark density and missing incidents. Methods: Global spatial autocorrelation (Moran’s I) was used to …identify the potential hotspot regions for missing incidents. Meanwhile, spatial buffer and regression modelling were used to determine the relationship between outdoor landmark density and missing incidents. Results: Our demographics measures replicated and extended previous studies of dementia-related missing incidents. Meanwhile, no hotspot regions for missing incidents were identified, while higher outdoor landmark density led to increased missing incidents. Conclusion: Our results highlight that missing incidents do not occur in isolated hotspots of regions but instead are endemic in patients regardless of location. Higher outdoor landmark density emerges as a significant geospatial factor for missing incidents in dementia, which crucially informs future safeguarding/intervention studies. Show more

Keywords: Dementia, risk factors, spatial navigation, spatial analysis

DOI: 10.3233/JAD-190244

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 1005-1013, 2019

Authors: Shaffer, Rachel M. | Sheppard, Lianne | Peskind, Elaine R. | Zhang, Jing | Adar, Sara D. | Li, Ge

Article Type: Research Article

Abstract: Background: Cerebrovascular diseases play an important role in dementia. Air pollution is associated with cardiovascular disease, with growing links to neurodegeneration. Prior studies demonstrate associations between fine particulate matter (PM2.5 ) and biomarkers of endothelial injury in the blood; however, no studies have evaluated these biomarkers in cerebrospinal fluid (CSF). Objective: We evaluate associations between short-term and long-term PM2.5 exposure with CSF vascular cell adhesion molecule-1 (VCAM-1) and e-selectin in cognitively normal and mild cognitive impairment (MCI)/Alzheimer’s disease (AD) individuals. Methods: We collected CSF from 133 community volunteers at VA Puget Sound between 2001–2012. …We assigned short-term PM2.5 from central monitors and long-term PM2.5 based on annual average exposure predictions linked to participant addresses. We performed analyses stratified by cognitive status and adjusted for key covariates with tiered models. Our primary exposure windows for the short-term and long-term analyses were 7-day and 1-year averages, respectively. Results: Among cognitively normal individuals, a 5 μg/m3 increase in 7-day and 1-year average PM2.5 was associated with elevated VCAM-1 (7-day: 35.4 (9.7, 61.1) ng/ml; 1-year: 51.8 (6.5, 97.1) ng/ml). A 5 μg/m3 increase in 1-year average PM2.5 , but not 7-day average, was associated with elevated e-selectin (53.3 (11.0, 95.5) pg/ml). We found no consistent associations among MCI/AD individuals. Conclusions: We report associations between short-term and long term PM2.5 and CSF biomarkers of vascular damage in cognitively normal adults. These results are aligned with prior research linking PM2.5 to vascular damage in other biofluids as well as emerging evidence of the role of PM2.5 in neurodegeneration. Show more

Keywords: Alzheimer’s disease, biomarkers, cellular adhesion molecules, cerebrospinal fluid, cerebrovascular disorders, dementia, particulate matter

DOI: 10.3233/JAD-190563

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 1015-1025, 2019

Authors: Ezzati, Ali | Zammit, Andrea R. | Harvey, Danielle J. | Habeck, Christian | Hall, Charles B. | Lipton, Richard B. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Predicting clinical course of cognitive decline can boost clinical trials’ power and improve our clinical decision-making. Machine learning (ML) algorithms are specifically designed for the purpose of prediction; however. identifying optimal features or algorithms is still a challenge. Objective: To investigate the accuracy of different ML methods and different features to classify cognitively normal (CN) individuals from Alzheimer’s disease (AD) and to predict longitudinal outcome in participants with mild cognitive impairment (MCI). Methods: A total of 1,329 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included: 424 CN, 656 MCI, and 249 AD individuals. …Four feature-sets at baseline (hippocampal volume and volume of 47 cortical and subcortical regions with and without demographics and APOE4 ) and six machine learning methods (decision trees, support vector machines, K-nearest neighbor, ensemble linear discriminant, boosted trees, and random forests) were used to classify participants with normal cognition from participants with AD. Subsequently the model with best classification performance was used for predicting clinical outcome of MCI participants. Results: Ensemble linear discriminant models using demographics and all volumetric magnetic resonance imaging measures as feature-set showed the best performance in classification of CN versus AD participants (accuracy = 92.8%, sensitivity = 95.8%, and specificity = 88.3%). Prediction accuracy of future conversion from MCI to AD for this ensemble linear discriminant at 6, 12, 24, 36, and 48 months was 63.8% (sensitivity = 74.4, specificity = 63.1), 68.9% (sensitivity = 75.9, specificity = 67.8), 74.9% (sensitivity = 71.5, specificity = 76.3), 75.3%, (sensitivity = 65.2, specificity = 79.7), and 77.0% (sensitivity = 59.6, specificity = 86.1), respectively. Conclusions: Machine learning models trained for classification of CN versus AD can improve our prediction ability of MCI conversion to AD. Show more

Keywords: Alzheimer’s disease, classification, early diagnosis, machine learning, magnetic resonance imaging, mild cognitive impairment, predictive analytics

DOI: 10.3233/JAD-190262

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 1027-1036, 2019

Authors: Charil, Arnaud | Shcherbinin, Sergey | Southekal, Sudeepti | Devous, Michael D. | Mintun, Mark | Murray, Melissa E. | Miller, Bradley B. | Schwarz, Adam J.

Article Type: Research Article

Abstract: At autopsy, individuals with Alzheimer’s disease (AD) exhibit heterogeneity in the distribution of neurofibrillary tangles in neocortical and hippocampal regions. Subtypes of AD, defined using an algorithm based on the relative number of tangle counts in these regions, have been proposed—hippocampal sparing (relative sparing of the hippocampus but high cortical load), limbic predominant (high hippocampal load but lower load in association cortices), and typical (balanced neurofibrillary tangles counts in the hippocampus and association cortices) AD—and shown to be associated with distinct antemortem clinical phenotypes. The ability to distinguish these AD subtypes from the more typical tau signature in vivo …could have important implications for clinical research. Flortaucipir positron emission tomography (PET) images acquired from 45 amyloid-positive participants, defined clinically as mild cognitive impairment or AD, aged 50–92 years, 56% female, and estimated to be Braak V-VI based on their PET pattern of tau pathology, were studied. By translating the neuropathologic algorithm to flortaucipir PET scans, patterns of tau pathology consistent with autopsy findings, and with a similar prevalence, were identified in vivo . 6/45 (13%) participants were identified as hippocampal sparing and 6/45 (13%) as limbic predominant AD subtypes. Hippocampal sparing participants were significantly younger than those assigned to the other two subtypes. Worse performance on delayed recall was associated with increased hippocampal tau signal, and worse performance on the trail making test B-A was associated with lower values of the hippocampus to cortex ratio. Prospective studies can further validate the flortaucipir SUVR cut-points and the phenotype of the corresponding AD subtypes. Show more

Keywords: Hippocampal sparing, limbic predominant, subtype, tau

DOI: 10.3233/JAD-190264

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 1037-1048, 2019

Authors: Aguirre, Naiara | Costumero, Víctor | Marin-Marin, Lidón | Escudero, Joaquín | Belloch, Vicente | Parcet, María Antonia | Ávila, César

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) has been associated with memory impairment due to alterations in the medial temporal lobe (MTL) and the precuneus. Therefore, the goal of this study was to investigate the effects of AD on the brain networks associated with the hippocampus and precuneus during an encoding memory task. 68 mild cognitive impairment patients (MCI), 21 AD patients, and 20 healthy controls (HC) were included. Participants were instructed to memorize landscapes while undergoing fMRI scanning, followed by a recognition test. MCI were followed up clinically for 18 months to track conversion status. Independent component analysis (ICA) was performed to investigate …AD effects on precuneus and MTL networks during memory encoding. Behavioral analyses indicate that HC had a better performance than MCI converters (MCIc) and AD. ICA showed that MCIc had significantly higher activation in the MTL-associated network than MCI non converters (MCIn) and AD, including bilateral hippocampus, parahippocampus, and fusiform gyrus. Furthermore, the precuneus-associated network fitted the default mode network, showing a negative correlation with behavioral performance. These findings indicate that the hyperactivation of the hippocampal network displayed by MCIc has potential discrimination capacity to distinguish them of MCIn, and could be interpreted as a compensatory mechanism. Show more

Keywords: Alzheimer’s disease, hippocampus, independent component analysis, memory, precuneus

DOI: 10.3233/JAD-190421

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 1049-1061, 2019

Authors: Tadokoro, Koh | Morihara, Ryuta | Ohta, Yasuyuki | Hishikawa, Nozomi | Kawano, Satoko | Sasaki, Ryo | Matsumoto, Namiko | Nomura, Emi | Nakano, Yumiko | Takahashi, Yoshiaki | Takemoto, Mami | Yamashita, Toru | Ueno, Setsuko | Wakutani, Yosuke | Takao, Yoshiki | Morimoto, Nobutoshi | Kutoku, Yumiko | Sunada, Yoshihide | Taomoto, Katsushi | Manabe, Yasuhiro | Deguchi, Kentaro | Higashi, Yasuto | Inufusa, Haruhiko | You, Fukka | Yoshikawa, Toshikazu | von Greiffenclau, Markus Matuschka | Abe, Koji

Article Type: Research Article

Abstract: Oxidative stress is part of the entire pathological process that underlies the development of Alzheimer’s disease (AD), including the mild cognitive impairment (MCI) stage. Twendee X (TwX) is a supplement containing a strong antioxidative mix of eight antioxidants, which has been shown to have a clinical and therapeutic benefit in AD model mice. Here, we conducted a multicenter, randomized, double-blind, and placebo-controlled prospective interventional study to evaluate the efficacy of TwX in mitigating MCI. The primary outcomes were differences in Mini-Mental State Examination (MMSE) and Hasegawa Dementia Scale-revised (HDS-R) scores between baseline and six months for placebo and TwX groups. …Seventy-eight subjects with MCI were randomized into placebo (n  = 37) and TwX (n  = 41) groups. MMSE scores at six months differed significantly between the TwX and placebo groups (p  = 0.018), and HDS-R scores for the TwX group exhibited a significant improvement at six months relative to baseline (p  = 0.025). The TwX group did not show any change in affective or activities of daily living scores at six months. The present study indicates that strong antioxidative supplement TwX is clinical beneficial for cognitive function in subjects with MCI. Show more

Keywords: Dementia, dietary supplement, mild cognitive impairment, oxidative stress, randomized controlled trial

DOI: 10.3233/JAD-190644

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 1063-1069, 2019