bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of cognitively stimulating activities throughout the lifespan on risk and timing of conversion to dementia
Authors: Lewis Nathan A , Bennett David A , Hofer Scott M 
Published: December 2020

AbstractBackgroundPrevious research suggests that modifiable lifestyle factors, such as engagement in cognitively stimulating activities, contributes to cognitive reserve such that some individuals can tolerate more pathological burden before cognitive symptoms emerge. However, it is unclear whether such benefits persist throughout the lifespan or are limited to certain critical periods. The present study sought to explore if cognitive engagement at various points in the lifespan uniquely contributes to cognitive reserve in late life.MethodData were from 1977 older adults from the Memory and Aging Project without dementia at study onset (M age = 80.10 at baseline). Cognitive assessments were performed annually for an average of 7.42 years until death. Each participant agreed to brain donation for post‐mortem analysis of neuropathologies. Multistate survival modeling was used to examine the influence of lifelong cognitive engagement on risk of transitioning between normal cognition, mild cognitive impairment (MCI), dementia, and death states. Life expectancies for individuals with and without cognitive impairment were then estimated. An additional model was run for participants with available neuropathology data (n = 841), accounting for overall pathological burden.ResultsA total of 560 participants developed dementia during the follow‐up period. Cognitive activity in childhood, young and middle adulthood were included as predictors of risk of transitioning between cognitive states, controlling for age, sex, and education. Only midlife cognitive activity predicted cognitive transitions, with higher activity predicting decreased risk of developing MCI (OR = .82, 95% CI: .71, .95). In the subset of participants with pathology data, cognitive activity in midlife predicted decreased risk of transitioning to MCI (OR = .74, 95% CI: .61, .90) after accounting for pathologic burden. Midlife cognitive activity moderated the effect of pathological burden such that individuals high in pathology and high in cognitive activity were more likely to transition directly from healthy cognition to death without developing impairment.ConclusionWith no known cure for Alzheimer’s Disease, delaying the onset of cognitive decline represents a key target for future dementia research. These findings suggest that cognitive engagement in midlife may help to delay impairment and buffer the effect of brain pathologies on cognition.
Investigating the role of neuronal oxidative stress in early Alzheimer’s disease pathology
Authors: Foret Morgan K. , Do Carmo Sonia , Welikovitch Lindsay A. , Orciani Chiara , Cuello A. Claudio 
Published: December 2020

AbstractBackgroundWhile the amyloid cascade has driven drug development for decades, alternative mechanisms underlying early Alzheimer’s disease (AD) pathogenesis point towards a role of oxidative stress. Cellular responses to oxidative damage are disrupted in AD, additionally, markers of oxidative damage are elevated in the brains of individuals with mild cognitive impairment and AD as well as in AD animal models. However, the earliest role of oxidative stress that coincides with intraneuronal amyloid beta accumulation preceding plaque deposition and cognitive decline has yet to be elucidated. This study aims to investigate oxidative stress related genes as key drivers of disease mechanisms in the early, pre‐plaque AD pathology.MethodsThe McGill‐R‐Thy1‐APP transgenic rat model was utilized to study the role of neuronal oxidative stress responses during the early, pre‐plaque amyloid pathology. Hippocampal neurons from 5‐month‐old pre‐plaque transgenic and non‐transgenic control rats were excised using laser capture microdissection. The expression of 84 genes related to antioxidant response and reactive oxygen species metabolism was investigated by qRT‐PCR. Validation at the protein level was performed using immunofluorescence microscopy and biochemical assays.ResultsAt the mRNA level, genes including superoxide dismutase, DNA repair enzymes, and antioxidants such as glutathione reductase were dysregulated in transgenic hippocampal neurons compared to wild type controls. At the protein level, there were increased amounts of DNA repair enzymes in the subiculum of Tg rats, reinforcing the observations made at the mRNA level. Assessments at the protein level of additional targets as well as their correlation with intraneuronal amyloid beta load are ongoing.ConclusionsThese findings show that genes related to oxidative stress responses are dysregulated specifically in neurons burdened with amyloid peptides during early, pre‐plaque stages of the AD amyloid pathology. This suggests that oxidative stress is an important contributor to the earliest AD pathology.
Apolipoprotein E genotype‐dependent nutrigenetic effects to prebiotic inulin for reducing risk for Alzheimer’s disease in a mouse model
Authors: Chang Ya‐Hsuan , Hoffman Jared D , Yanckello Lucille M , McCulloch Scott D , Lin Penghui , Lane Andrew N , Chlipala George , Green Stefan J , Lin Ai‐Ling 
Published: December 2020

AbstractBackgroundApolipoprotein E ε4 (APOE4) allele is the strongest genetic risk factor for Alzheimer’s disease (AD). Cognitively normal APOE4 carriers show an early decline in brain metabolic functions and gut microbiome dysbiosis before the onset of AD compared to APOE3 carriers. Our laboratory previously found that inulin, a prebiotic, is effective to restore metabolic functions and gut microbiome balance, and thus reduce risk for AD in an ApoE4 mouse model (Hoffman et al., 2019). However, whether the responses to the inulin diet are APOE allele‐dependent remains unknown. Therefore, our objective was to identify whether inulin would differently contribute to metabolic and gut microbiome changes due to APOE genotype.MethodWe fed 3‐month‐old asymptomatic ApoE3 (E3FAD) and ApoE4 (E4FAD) mice a prebiotic inulin diet or a control diet containing cellulose for 4 months (N=15/group; Male:Female=1:1). After 4 months, we used magnetic resonance spectroscopy to measure in vivo brain scyllo‐inositol level, a compound that has been demonstrated to inhibit amyloid β aggregation (Fenili, Brown, Rappaport, & McLaurin, 2007). We collected the fecal samples for gut microbiome sequencing, and cecal and blood samples for metabolomic profiling.ResultInulin induced scyllo‐inositol in hippocampus of the brain with a higher level in E4FAD mice. Inulin increased blood metabolites in tryptophan and tyrosine metabolic pathways that enhance nervous system in E3FAD mice. It increased blood metabolites in pentose phosphate pathway and citric acid cycle that support nucleotides and nucleic acids biosynthesis and energy production in E4FAD mice. These alterations in hippocampus and blood showed inulin’s impacts on systemic metabolism depending on mouse ApoE genotypes. Inulin enhanced short chain fatty acids in cecum with a greater increase in E3FAD mice. E3FAD mice showed more distinct gut microbiome patterns between inulin and control groups compared to E4FAD mice.ConclusionInulin‐induced systemic metabolism and gut microbiome changes are APOE genotype‐dependent. Our study contributes to the gut‐brain axis research and potential AD prevention. Future studies can design human interventions that facilitate the guide of personalized nutrition in APOE3 and APOE4 population to prevent AD.
Grip strength and gait speed as early biomarkers of brain amyloid and tau deposition
Authors: Jacob Mini Elizabeth , Terbojevich Tommaso , O’Donnell Adrienne , Gonzales Mitzi , Satizabal Claudia L , Beiser Alexa S , Johnson Keith A , Seshadri Sudha 
Published: December 2020

AbstractBackgroundScreening biomarkers, accessible and measurable at a primary care clinic, may hold the key to risk stratification and prevention efforts in Alzheimer’s and related dementias. Among potential candidates that could fulfill this role, gait speed and grip strength have garnered strong evidence as early predictive factors. The pathophysiologic basis for this association is not clear; it is possible that functional performance is impaired by early tau/amyloid deposition. To test this, we examined the cross‐sectional relationship between gait speed and grip strength measures with amyloid and tau PET in middle‐aged Generation 3 participants in the Framingham Heart Study.MethodAmong 190 participants, examined in 2016‐2019, average age was 55.1 (SD 7.7), and 44% were women. Fast walk speed was measured over 4 meters, and grip strength was assessed using a hand‐held Jamar dynamometer. PET amyloid imaging was done using [11C]PiB tracer and tau using [18F]AV‐1451. We tested associations between fast walk speed (FWS) and grip strength (GS) with amyloid in the frontal and lateral retrosplenial (FLR) regions and tau in parahippocampal, entorhinal, inferior temporal regions. Linear regression models were performed with adjustment for sex, time from exam to PET scan, total cholesterol, diabetes, cardiovascular disease, smoking status, systolic blood pressure, waist‐hip ratio, APOEe4 status and physical activity. We also tested interactions between FWS/GS and APOE status /gender.ResultFWS and GS did not demonstrate independent associations with tau or amyloid PET imaging in the full sample, however significant interactions were noted between FWS/GS and both gender and APOE. In the APOE status stratified analysis, higher FWS was associated with higher parahippocampal tau levels among e4 negative, while higher GS was associated with lower parahippocampal tau among e4 positive individuals. Additionally, higher GS was associated with lower parahippocampal Tau in men, but not in women.ConclusionGrip strength and gait speed may be early markers of tau deposition in cognitively normal middle‐aged individuals. Further studies with larger samples are required to confirm the relationship and identify sub‐groups who may benefit from screening and preventive interventions.
Dementia: Vitamin D deficiency is associated with lower Mini‐Mental State Exam (MMSE) scores
Authors: Komatsu Caroline , Komatsu Ricardo S , Belem Dinah , Ariosa Rodrigo Hara , David Caroline Casolari Araújo Mansur , Garcia Isabelle Belmonte 
Published: December 2020

AbstractBackgroundPatients with Alzheimer's disease (AD) have a high prevalence of vitamin D deficiency, which is also associated with impaired cognitive performance in older adults. According to the systematic review and meta‐analysis conducted by Anweiler et al. (2013), AD cases had lower serum vitamin D concentrations than matched controls. The quality assessment of systematic reviews of vitamin D, cognition and dementia conducted by Aghajafari et al. (2018) also corroborated the potential link between low serum vitamin D concentrations and dementia.Method40 outpatients with the diagnostic of AD according to criteria proposed by NINCDS‐ADRDA (2011), followed – up at a public university hospital, had their vitamin D levels assessed and MMSE scores evaluated.Results9 patients (22,5%) presented vitamin D normal range (vitamin D level ≥ 30 ng/mL) and 31 patients (77,5%) presented vitamin D deficiency (vitamin D level < 30 ng/mL). From the vitamin D normal range group 5 patients (55,56%) presented moderate cognitive impairment (MMSE = 10 – 20) and 4 (44,44%) patients presented mild cognitive impairment (MMSE > 20). From the vitamin D deficiency group 4 patients (12,90%) presented severe cognitive impairment (MMSE < 10), 10 patients (32,27%) presented moderate cognitive impairment and 17 patients (54,83%) presented mild cognitive impairment. Both groups, vitamin D normal range and vitamin D deficiency, had on average the same educational level: 2,89 and 3,19 years respectively.ConclusionIn this sample of patients with AD, vitamin D deficiency is associated with lower MMSE scores when compared to vitamin D normal range.
Different patterns of β‐amyloid pathology in the cerebellum of early‐onset Alzheimer’s disease individuals
Authors: de Luca e Tuma Raphael , Rodriguez Roberta Diehl , Brucki Sonia Maria Dozzi , Suemoto Claudia Kimie , Leite Renata Elaine Paraizo , Ferretti‐Rebustini Renata Eloah de Lucena , Jacob‐Filho Wilson , Pasquallucci Carlos Augusto , Grinberg Lea Tenenholz , Nitrini Ricardo 
Published: December 2020

AbstractBackgroundThe cerebellum has not been extensively studied in the setting of Alzheimer’s disease (AD). As the disease progresses, the cerebellum is one of the last brain regions to accumulate β‐amyloid (βA) deposits usually as diffuse plaques. However, distinct morphologies are described in the cerebellum in early‐onset Alzheimer’s disease (EOAD).MethodTo investigate the presence of βA deposits in the cerebellum, we analyzed brain sections immunostained with βA antibody (4G8) of 46 individuals with cognitive impairment and neuropathological diagnosis of AD. Of them, cerebellum sections of 19 individuals with Thal phase 5 were evaluated regarding the distribution and morphology of the βA deposits. All cases are from the Biobank for Aging studies of the University of São Paulo. AD‐type pathology was scored using the Braak and Braak staging, CERAD criteria and the Thal phase system. Diagnosis of AD required at least intermediate AD neuropathological changes. Presence of cognitive impairment (CI) was evaluated according to the Clinical Dementia Rating Scale (CDR>0,5).ResultCerebellar βA pathology was found in 19 cases (41%). Higher frequency of amyloid pathology was observed in the group of individuals who developed CI before 65 years of age (87%). In this group of individuals, focal deposits such as compact plaques were more frequently observed than the typical diffuse deposits often seen in molecular layer. Additionally, EOAD individuals had more involvement of Purkinje cell, and granular cell layers than in the molecular layer. Amyloid angiopathy with capillary involvement was observed in the cerebellum of 3 individuals. Of them, only one had EOAD, but all had two APOE ε4 genes.ConclusionThe βA cerebellar involvement can be influenced by the patient’s age, particularly in EOAD cases. These changes observed in the cerebellum may reflect a different vulnerability pattern of βA pathology in individuals with early‐onset AD.
Enriching early‐life activities and cognition in later life: Results from the Health and Retirement Study (HRS)
Authors: Crane Breanna M , Carlson Michelle C 
Published: December 2020

AbstractBackgroundThe positive association between engagement in mid‐ and late‐life enrichment activities and cognitive function in late‐life has been presented in many studies. However, the effect of enriching early‐life activities (EELAs) on cognition in late‐life has been relatively unexplored. Recently, we have found that greater enrichment in early‐life was linked to positive late‐life cognition and brain biomarkers (i.e., larger amygdala and hippocampal volumes, etc.). In this study, we examined the relationship between EELAs and late‐life cognition using the 2017 Life History Mail Survey (LHMS) and additional cognitive and demographic variables, all of which came from the Health and Retirement Study (HRS).MethodA complete‐case analysis was conducted from a subset of respondents in the HRS aged 50+ (N = 1,872, M = 66.5, SD = 10.1) who completed cognitive testing during 2010 and completed the ten‐item retrospective survey in the LHMS on enriching activities performed during adolescence. Univariate and multivariate linear regression models were used to assess the relationship between EELAs in adolescence and cognition in later‐life.ResultEngaging in EELAs was positively associated with late‐life cognition after adjusting for age, gender, race, mother's and father’s education, birth cohort, income, and various health behaviors (e.g., smoking, diabetes, hypertension). After incorporating one’s level of education into the model, this association was no longer significant.ConclusionThese results suggest that engaging in enriching activities in adolescence may be protective against cognitive decline in later‐life. Providing programs that promote EELAs (e.g., after‐school programs, extracurricular activities, etc.) during adolescence may be a key modifiable factor to buffer the effects of cognitive decline in later‐life. Future studies should incorporate additional in‐depth questions about EELAs to further investigate the relationship between these activities in early‐life and cognition in later‐life.
ICA‐derived sources of synaptic density PET ([11C]UCB‐J) relate to cognitive impairment severity in Alzheimer’s disease
Authors: Fang Xiaotian T. , Mecca Adam P. , Naganawa Mika , O'Dell Ryan S. , Chen Ming‐Kai , van Dyck Christopher H. , Carson Richard E. 
Published: December 2020

AbstractBackgroundSynaptic loss is a primary pathology in Alzheimer's disease (AD) and correlates best with cognitive impairment as found in postmortem studies. Previously, we observed in vivo synaptic density loss with [11C]UCB‐J PET (radiotracer for synaptic vesicle protein 2A, SV2A) in hippocampus and throughout the cortex. Here, we used independent component analysis (ICA), a data‐driven method that identifies independent sources (networks) by linearly unmixing the observed signal into maximally independent components. The aim is to apply ICA, which does not use subject group information, to synaptic density PET data to identify brain networks associated with cognitive deficits in AD.Method[11C]PIB PET was performed to determine brain amyloid status. A structural T1‐weighted MR was acquired to exclude structural abnormalities and for PET co‐registration and analysis. [11C]UCB‐J binding to SV2A was measured in 38 AD (24 dementia, 14 mild cognitive impairment) and 19 cognitively normal (CN) participants. [11C]UCB‐J distribution volume ratio values were calculated using SRTM2 (population‐fixed k2') with whole cerebellum as reference, registered into MNI space and smoothed (8‐mm Gaussian). Based on previous SV2A ICA, 18 independent components (IC) were extracted. Subject loadings per IC were compared between groups using unpaired t‐tests. Pearson's correlations were used to assess relationships between loading weights and cognitive measures: logical memory II (LMII), Rey auditory verbal learning test (RAVLT‐delay), clinical dementia rating sum of boxes (CDR‐sob), mini‐mental state examination (MMSE).ResultFor 8 ICs, we observed significant differences in loading weights between CN and AD groups, including a component (IC01) located in hippocampus and temporal lobe (Figure 1). Within the AD/MCI group, loading weights for IC02, located in the right parietal‐temporal lobe (Figure 2), correlated with LMII (R2: 0.13, p=0.025), and RAVTL‐delay (R2: 0.13, p=0.027). For IC03, located in the left parietal hemisphere (Figure 3), loading weights correlated with CDR‐sob (R2: 0.23, p=0.0028) and MMSE (R2: 0.13, p=0.024).ConclusionWe demonstrated that ICA could define coherent spatial patterns of synaptic density. Furthermore, commonly used cognitive measures correlate significantly with loading weights for two of such networks within only the AD/MCI group. Further studies will explore whether ICA‐based networks might be more sensitive than conventional ROI‐based analysis.
Web‐based assessment of cardiovascular risk factors and cognition in older adults: Findings from the Brain eHealth feasibility study
Authors: Yaffe Kristine , Kaup Allison R , Bahorik Amber L , Butcher Xochitl , Attarha Mouna , Marcus Gregory M , Pletcher Mark J , Olgin Jeffrey E 
Published: December 2020

AbstractBackgroundCardiovascular risk factors (CVRFs) are linked to cognitive aging. Most studies rely on lengthy in‐person assessments, and it is unclear if web‐based platforms can be used to detect the contribution of risk factors, including CVRFs, to cognitive aging offering a more pragmatic and low cost approach.MethodWe recruited 239 adults who were enrolled in the Health eHeart project in order to conduct the Brain eHealth study, a mobile health feasibility study of web‐based measurement tools in adults age ≥50. CVRFs were identified based on health surveys from the Health eHeart study using the Eureka Research platform between March 2013, and February 2019, and included hypertension, high cholesterol, diabetes, and atrial fibrillation. After an average of 3 years participants completed a web‐based cognitive assessment with the BrainHQ platform (POSIT Science) that assessed 3 cognitive domains: episodic memory, working memory, and executive function. We used linear regression models to examine the association between CVRFs and cognitive function.ResultAmong the 239 participants (mean age, 62.7±8.8, 43% female, 89% white), CVRF prevalence was 54% for high cholesterol, 44% for hypertension, 12% for atrial fibrillation, and 7% for diabetes. In multivariable models adjusted for age, race/ethnicity, and sex, atrial fibrillation was associated with poor working memory (β = ‐0.52, 95%CI ‐0.92,‐0.11) and worse episodic memory (β = ‐0.26, 95%CI ‐0.42,‐0.08), and hypertension was associated with worse episodic memory (β = ‐0.25, 95%CI ‐0.42, ‐0.08). There was no association for diabetes or high cholesterol. In a sensitivity analysis, we further adjusted for motor speed processing, which led to similar results.ConclusionResults of this feasibility study suggest that web‐based tools may be used to detect the contribution of CVRFs, especially atrial fibrillation and hypertension to cognitive function in older adults. The potential of these mobile measurement tools to track the relationship between older adults’ cardiovascular health and cognitive aging should be further investigated in a larger study.