bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of sex and physical and cognitive activities on cognitive reserve in a cohort of ethnically diverse, community‐dwelling older adults
Authors: Pa Judy , Aslayan Vahan , Casaletto Kaitlin B , Rentería Miguel Arce , Harrati Amal , Tom Sarah E , Armstrong Nicole , Rajan Kumar B , Gu Yian , Manly Jennifer J , Brickman Adam M , Zahodne Laura B 
Published: December 2020

AbstractBackgroundPhysical activity and cognitive stimulation may reduce age‐associated cognitive decline, delay dementia onset, and increase cognitive reserve. However, whether the association between these activities and cognitive reserve differs by sex has not been well‐studied. The current study examined interactions between sex and physical or cognitive activities on speed and memory reserve in older adults.MethodResearch participants from the Washington Heights‐Inwood Columbia Aging Project (WHICAP) with normal cognition, mild cognitive impairment, or dementia were included in this study (N=758, age=76.11+6.31, 62% female). Participants were selected based on available measures of 3T brain MRI, physical activity, cognitive activity, and cognition. Speed and memory reserve were calculated as the residuals from regression models partialling out hippocampal volume, total gray matter volume, and white matter hyperintensity volume from speed and memory composite scores, respectively. Physical activity was assessed using the Godin Leisure Time Exercise Questionnaire, converted to metabolic equivalents (METS). Self‐reported cognitive activity (COGACT) was calculated as the sum of three yes/no questions. Sex‐by‐activity (METS or COGACT) interactions and sex‐stratified analyses were conducted using linear regression models. Covariates included age, cohort, education, race/ethnicity, and diagnosis. A secondary analysis considered the effect of APOE4 status based on literature that APOE4 may differentially affect women and men.ResultWomen who reported more physical activity had greater speed reserve, and this effect was not observed for men. Physical activity was not associated with memory reserve. More cognitive activity was associated with greater speed reserve, and this association did not differ by sex. Women, but not men, who reported more cognitive activity had a trend for greater memory reserve. Among women, APOE4 carrier status attenuated relationships between physical activity and speed reserve, and between cognitive activity and speed and memory reserve.ConclusionThe associations between self‐reported physical and cognitive activities and cognitive reserve are more pronounced in women; although women with APOE4 have less benefit from physical or cognitive activity than women without APOE4. Intervention studies that consider sex and APOE4 status are necessary to understand causal effects of physical and cognitive activities on brain and cognitive health.
Diabetes, cognitive decline and mild cognitive impairment among diverse Hispanics/Latinos: Hispanic Community Health Study/Study of Latinos (HCHS‐SOL) investigation of cognitive aging results
Authors: Gonzalez Hector M. , Tarraf Wassim , Gonzalez Kevin A , Fornage Myriam , Zeng Donglin , Gallo Linda , Talavera Gregory A , Daviglus Martha , Lipton Richard B. , Kaplan Robert , Ramos Alberto R , Lamar Melissa , Cai Jianwen , DeCarli Charles , Schneiderman Neil 
Published: December 2020

AbstractBackgroundHispanics/Latinos are the largest ethnic/racial group in the US, have the highest prevalence of diabetes and are at increased risk for neurodegenerative disorders. Additionally, Latinos have the highest prevalence of undiagnosed and untreated diabetes in the United States. Currently, little is known about the relationship between diabetes, cognitive decline and disorders among diverse Hispanics/Latinos. The purpose of this study is to clarify these relationships in diverse middle‐aged and older Hispanics/Latinos.MethodThe Study of Latinos‐Investigation of Neurocognitive Aging (SOL‐INCA) is an ancillary study of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). HCHS/SOL is a multisite (Bronx, NY, Chicago, IL, Miami, FL, San Diego, CA), probability sampled (i.e., representative of targeted populations), and prospective cohort study. Visit 1 baseline enrollment occurred between 2008‐2011. At HCHS/SOL Visit 2 (2016‐2018), SOL‐INCA enrolled diverse Hispanics/Latinos ages 50‐years and older (n=6,377). Global cognitive decline and Mild Cognitive Impairment (MCI) were the primary outcomes. Diabetes status (prevalent, Visit 1 to Visit 2 incident, and no diabetes) was the primary exposure. Associations between the cognitive outcomes and the exposure were examined using survey generalized linear models adjusting for pertinent covariates and confounders.ResultPrevalent diabetes at Visit 1, but not new incident cases of diabetes at Visit 2, was associated with significantly steeper 7‐year global cognitive decline (βGC= ‐0.16; CI= [‐0.25;‐0.07]; p<0.001), domain specific cognitive decline, and higher odds of MCI (OR=1.74; CI=[1.34; 2.26]; p<0.001) compared to persons without diabetes, in age‐ and sex‐adjusted models.ConclusionDiabetes was associated with significant 7‐year cognitive decline and increased MCI prevalence among diverse middle‐aged and older Hispanics/Latinos, but primarily among those with prevalent diabetes at Visit 1. Our findings suggest that significant cognitive decline and MCI may be considered additional disease complications of diabetes among diverse middle‐aged and older Hispanics/Latinos.
Examining the preliminary effect of a randomized control trial of Tele‐Savvy, an online psychoeducation program, on insomnia and sleep quality
Authors: Brewster Glenna S , Higgins Melinda , Yeager Kate , Bliwise Donald , Hepburn Kenneth 
Published: December 2020

AbstractBackgroundSleep disturbance is prevalent among caregivers of persons living with dementia. Tele‐Savvy is an online psychoeducation program that seeks to improve caregivers’ knowledge and skill about their role, and reduce their distress. Caregivers (N=220) were recruited into an NIA‐sponsored trial and randomly assigned to immediate participation in Tele‐Savvy, an attention control condition (Healthy Living), or usual care. This study aims to examine the preliminary impact of Tele‐Savvy on sleep quality (Pittsburgh Sleep Quality Index) and insomnia (Insomnia Severity Index) in the first 20 cohorts of caregivers using data gathered at baseline, 3 and 6 months. Improving sleep quality was not an expected outcome of the study, but we sought to examine whether an active mastery‐focused intervention or an attention condition focused on healthy living might affect this important domain.MethodsMultilevel mixed models were used to test for group, time, and group‐by‐time effects for sleep quality and insomnia.ResultsOn average, caregivers were 64 years old; 72% were White and 23% were African American. At baseline, 50% of the caregivers had poor sleep quality (PSQI > 5). In addition, African Americans had significantly worse insomnia (p=.012; African Americans: Mean (M)‐10.5, standard deviation (SD)‐7.8; Whites: M‐6.2, SD‐5.8;) and sleep quality (p=.006; African Americans: M‐8.0, SD‐4.0; Whites: M‐5.4, SD‐4.1) scores. We found no significant group‐by‐time effect on insomnia (p=.22) or sleep quality (p=.20). For sleep quality, the Tele‐Savvy group reported small decreases over time with the mean remaining above the clinical cut‐off of 5 (7.2 at baseline, 6.6 at 6 months). In contrast, the attention control and waitlist control groups experienced worsening of sleep quality (attention control: 5.9 at baseline to 6.5 at 6 months; waitlist control: 5.6 at baseline to 6.5 at 6 months).ConclusionAt this intermediate point of analysis, that neither the Tele‐Savvy intervention nor the control condition focused on health and well‐being (but not on sleep), were effective at improving caregivers’ sleep quality. It is necessary to develop interventions specific to sleep disturbance or to integrate behavioral or psychoeducational components that target the sleep disturbance into psychoeducational interventions.
Cognitive impairment and risk factors of LATE in the oldest old: The 90+ Study
Authors: Sajjadi S. Ahmad , Phelan Michael , Yan Rui , Scambray Kiana Alexis , Ho Chu‐Ching , Woodworth Davis C. , Corrada Maria M.M. , Kawas Claudia H. 
Published: December 2020

AbstractBackgroundLimbic predominant age related TDP‐43 encephalopathy (LATE) is a newly proposed term to denote the contribution of TDP‐43 pathology to dementia at older age. The aim of this work was to study the role of LATE in cognitive impairment and its risk factors in the oldest old.Method240 participants of The 90+ Study with comprehensive clinical, neuropsychology, and neuropathology data were included. Dementia status, clinical syndrome, and impaired cognitive domains were determined at multi‐disciplinary post‐mortem case conferences blind to autopsy data. Alzheimer’s disease neuropathology (ADNP) was defined as CERAD neuritic plaque score≥2 and Braak neurofibrillary tangle stage≥5. We defined LATE as those with at least amygdala and hippocampal TDP‐43 pathology (stage>2). We explored the association of LATE and ADNP with cognition measures as outcome by logistic regression analyses adjusting for age, sex, and education. We separately explored the association between medical histories (as potential risk factors) and LATE and ADNP as outcomes adjusting for the above covariates.Result52% of the participants (N=125) died with dementia and of those, 33% were LATE positive (Table 1). There was no association between LATE and sex, age at death, or education. Compared with ADNP, LATE was as important a predictor of dementia and clinical diagnosis of Alzheimer’s at death (Table 2). Both pathologies were associated with impaired memory, language, visuospatial ability, and orientation. Only ADNP, but not TDP‐43, was associated with impaired executive function. Lower likelihood of LATE was associated with histories of hypertension (but not hypertension medications), cataract, alcohol use (median 1 drink/day), and macular degeneration (trended toward significant association). History of COPD was significantly associated and history of autoimmune conditions (thyroid or rheumatological diseases) trended towards an association with a higher likelihood of LATE (Figure). None of the above relationships were seen for ADNP.ConclusionLATE is an important degenerative pathology in the oldest old comparable to ADNP in its relation to dementia and clinical diagnosis of Alzheimer’s. The intriguing associations of LATE with other health conditions warrant further investigation of the potential effect of autoimmunity, reduced brain perfusion, and chronic hypoxia in its development.
The in silico search for endogenous anti‐Alzheimer's compounds
Authors: Weaver Donald F , Barden Christopher , Gupta Mayuri , Meek Autumn , Reed Mark , Wang Yanfei , Wu Fan 
Published: December 2020

AbstractBackgroundSince many peptide and proteins are susceptible to oligomerization analogous to Aβ and tau, there is evolutionary pressure to inhibit deleterious protein misfolding; likewise, the immunoinflammatory cascade triggered by such misfolding is also subject to homeostatic regulation. Accordingly, it is reasonable to postulate the existence of endogenous molecules within the human brain that could modulate or even interrupt the neurotoxic cascade of AD by blocking both the proteopathy and immunopathy of Alzheimer's disease (AD). Such compounds would constitute platforms for future drug development.MethodWe sought to identify a single anti‐proteopathic and anti‐immunopathic agent endogenous to the human central nervous system; to find this compound, we created a comprehensive library of 1,376 molecules (molecular weight < 600 Da) naturally occurring within the human brain and employed an in silico screening assay. Using computer‐aided screening with a molecular mechanics force field, we docked these endogenous molecules against computer models of in Aβ(HHQK16LVFF), tau(KKAK144), IL‐1R1(HKEK80), IL‐1β(KLRK76), C1qA(KKGH225), IFN‐gamma(KKKR112) and RANTES(RKNR70). Additional molecular dynamics simulations were done to refine the docking. Finally, multiple in vitro assays were done, verifying that the in silico hits had correctly predicted the ability to block oligomerization and to bind to multiple immunopeptides.ResultSeveral zwitterionic and aromatic‐anionic compounds capable of binding to these multiple amyloid, tau and immunoprotein targets were identified. Strong in silico hits included 2‐aminoethanesulfonic acid, L‐phosphoserine, 5‐hydroxytryptamine and 3‐hydroxyanthranilic acid. These predictions were verified using in vitro assays, including the kinetic Thioflavin T [ThT] aggregation assay.ConclusionSearching for an “endogenous anti‐AD compound” represents an unexplored concept. Our in silico and in vitro studies suggest that compounds endogenous to the human brain can inhibit pathological both the proteopathic and immunopathic pathogeneses of AD. The value of a novel in silico screening assay to identify such endogenous agent capable of "one‐drug‐multiple‐targets" has also been demonstrated.
Effect of antihypertensive treatment Lisinopril on central arterial stiffness and cognitive functions in Dahl‐S rat model of vascular dementia
Authors: Fedorova Olga V. , Fenner Rachel C. , Grigorova Yulia N. , McDevitt Ross , Juhasz Ondrej , Ajamu Samuel , Wei Wen , Zernetkina Valentina I. , Petrashevskaya Natalia , Long Jeffrey M. , Rapp Peter R. , Lakatta Edward G. 
Published: December 2020

AbstractBackgroundDahl salt‐sensitive rats (DSS) represent a model of vascular dementia, because they demonstrate an age‐associated increase in blood pressure (BP) and central arterial stiffness (CAS) accompanied by cognitive decline independent of a high salt intake. We hypothesized that treatment with an anti‐hypertensive drug ACE inhibitor Lisinopril will lower CAS and improve cognitive function in the adult hypertensive DSS.MethodMale DSS were kept on a normal salt diet for 12 months. Six‐month old rats received vehicle (control; DSS‐C; n = 20) or Lisinopril (15 mg/kg/day; DSS‐LIS; n = 20) for 6‐mo. Systolic BP (SBP), pulse wave velocity (PWV), a marker of CAS (by Doppler echocardiography), open field test (OFT) to assess anxiety‐like behavior and locomotion, and cued reaction time task (CRTT) to assess executive functioning were performed at BL (before treatment), after 3 and 6‐mo of treatment. Morris Water maze (MWM) test was performed to assess hippocampal spatial memory. Aortae were stained for elastin and collagen (immunohistochemistry). Statistical analysis: 2‐way ANOVA repeated measures and t‐test; data presented as mean ± SEM.ResultAll non‐treated DSS were hypertensive. DSS‐LIS have lower SBP vs. BL and vs. age‐matched DSS‐C. PWV was lower in 12‐mo DSS‐LIS vs. BL and vs. age‐matched DSS‐C (Table). In MWM, DSS‐LIS had a higher path efficiency and traveled shorter distance to find the invisible platform vs. DSS‐C. In CRTT, DSS‐LIS had less premature responses than DSS‐C 3‐mo post treatment (Table). There was no change in total distance and distance traveled in the center in OFT at all time points in DSS‐LIS vs. DSS‐C (Table). 12‐mo old DSS‐LIS had lower heart and aortic weight, less aortic medial wall collagen and greater elastin/collagen ratio vs. DSS‐C (Table).ConclusionChronic treatment with Lisinopril effectively lowered SBP, CAS and reduced aortic collagen in aged hypertensive DSS rats. Lisinopril resulted in improved hippocampal spatial memory and reduced impulsive behavior demonstrating a beneficial cognitive effect in the DSS model of vascular dementia. Further studies will need to elucidate the effect of Lisinopril on cerebral blood vessels and whether ACE inhibitor has a direct effect of the brain in addition to its effect on CAS. Supported by the Intramural Research Program of the NIA/NIH.
Fenchol ameliorates Alzheimer’s disease like phenotypes by modulating microbiome/proteolysis/senescence axis
Authors: Razazan Atefeh , Karunakar Prashantha , Mishra Sidharth P. , Sharma Shailesh , Yadav Hariom 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is progressive debilitating public health problem, with no successful preventive and therapeutic strategy. Emerging evidence indicate that the gut microbiome and its metabolites like short chain fatty acids (SCFAs; such as acetate, propionate, butyrate) contribute in AD pathology. SCFAs function as gut microbiome sensors on distinct cell types including neurons through activating G‐couple protein receptors like free fatty acid receptor 2/3 (FFAR2/3). Therefore, targeting this signaling can be a novel strategy to ameliorate AD pathology.MethodUpon screening of >144,000 natural compounds library with human FFAR2 docking patterns, and selected 14 compounds were further studied for FFAR2 signaling agonism by measuring phosph‐ERK1/2, cAMP and calcium levels in SK‐N‐SH cells that express FFAR2. In addition, selected compound (Fenchol) investigated for its beneficial effects on life‐span, Aβ accumulation, neurodegeneration and cognitive functions in Caenorhabditis (C.) elegans and cells.ResultWe demonstrated that FFAR2 expressed in neuronal cells, and its inhibition aggravates Aβ‐induced neuronal cell death. We screened >144,000 natural compound library with human FFAR2 docking patterns, and selected 14 compounds, based on higher binding energy. Further, among them, Fenchol shows highest FFAR2 signaling activation in terms of phospho‐ERK1/2, inhibition in cAMP and increase in intracellular calcium in SK‐N‐SH cells. Interestingly, Fenchol enhanced longevity in wild‐type (N2), and human Aβ42 over‐expressing CL2600 Caenorhabditis (C.) elegans strains. Fenchol also reduced Aβ aggregates, neurodegeneration induced paralysis and cognitive memory (by chemotaxis assay) in C. elegans. In addition, Fenchol induced reduction in Aβ aggregates are linked with significantly increased proteolysis and reduced senescence (β‐galactosidase staining) in C. elegans and neuronal cells.ConclusionOverall, results demonstrate that Fenchol (a microbiome sensor through FFAR2 agonist) ameliorates Aβ aggregation in neuronal cells through activation of proteolysis and reduces senescence which ultimately can ameliorate AD pathology.
Genetically predicted telomere length and Alzheimer’s disease endophenotypes: A Mendelian randomization study
Authors: Vilor‐Tejedor Natalia , Rodríguez‐Fernández Blanca , Milà‐Alomà Marta , Arenaza‐Urquijo Eider M , Suárez‐Calvet Marc , Sanchez‐Benavides Gonzalo , Grau‐Rivera Oriol , Minguillón Carolina , Fauria Karine , Zetterberg Henrik , Blennow Kaj , Kollmorgen Gwendlyn , Eichenlaub Udo , Gispert Juan Domingo , DeVivo Immaculata , Sala‐Vila Aleix , Molinuevo Jose Luis , Crous‐Bou Marta ,   ALFA Study
Published: December 2020

AbstractBackgroundTelomere length (TL) is a putative biomarker of biological aging and aging‐related outcomes. Observational studies are limited to conclude whether TL is causally associated with AD or a marker of an underlying pathological process. Mendelian randomization (MR) was developed for assessing causality using genetic variants in epidemiological research. Our main objective was to test the potential causal role of TL in cognitive performance, brain vulnerability and AD core biomarkers through an MR analysis.MethodsOur analysis was conducted in the context of the ALFA (ALzheimer and FAmilies) study. We created episodic memory, executive function and global cognitive composites. We calculated an AD signature as a composite measure reflecting cortical thickness of specific AD vulnerable regions. We measured cerebrospinal fluid (CSF) levels of amyloid‐β(Aβ)42, Aβ40, p‐tau, t‐tau and neurofilament light (NfL) using NeuroToolKit and Elecsys® immunoassays (Roche Diagnostics). Genome‐wide genotyping was performed. MR analyses using 3 Single Nucleotide Polymorphisms (SNPs) (rs2736100, rs9420907, rs755017) associated with TL identified in Genome‐wide Association studies (GWAS) were used as instrumental variables to determine the predicted effect of TL on AD endophenotypes: cognitive performance, AD signature, and AD biomarkers. Causal effects of TL were estimated using the inverse‐variance weighted method. Stratified analyses by APOE‐ɛ4 status were conducted.ResultsMR analysis revealed a significant association between SNPs predicting shorter TL and increased levels of NfL, supporting a potential causal role of TL on biomarkers of neuronal injury (Table 1; Figure 1). Additionally, we observed suggestive evidence of causality between shorter TL and worse episodic memory, and reduced cortical thickness in the AD signature (Table 1). Effect modification by APOE‐ɛ4 genotype was also suggested: associations between SNPs predicting short TL and worse cognitive performance, reduced thickness in the AD signature, and increased levels of NfL were only observed among APOE‐ɛ4 non‐carriers (Table 2).ConclusionsPreliminary results of our MR analysis showed an association between SNPs predicting shorter TL and AD endophenotypes, suggesting a potential causal role of telomeres in AD vulnerability, specifically in individuals not at increased genetic risk of AD. Further observational and genetic analyses in larger datasets are warranted to better understand these associations.
The effect of physical activity on CSF biomarkers of Alzheimer’s disease differs between men and women
Authors: Milà‐Alomà Marta , Salvadó Gemma , Gispert Juan Domingo , Vilor‐Tejedor Natalia , Grau‐Rivera Oriol , Sala‐Vila Aleix , Sanchez‐Benavides Gonzalo , Arenaza‐Urquijo Eider M , Crous‐Bou Marta , González‐de‐Echávarri José Maria , Minguillón Carolina , Fauria Karine , Simon Maryline , Kollmorgen Gwendlyn , Rodríguez‐Lantero Juan , Ashton Nicholas J , Zetterberg Henrik , Blennow Kaj , Molinuevo Jose Luis , Suárez‐Calvet Marc ,   ALFA study
Published: December 2020

AbstractBackgroundIncreasing evidence suggests that sex influences several aspects of Alzheimer’s disease (AD). Cardiovascular risk factors are associated with AD, and men and women differ in the prevalence of these risk factors. We aimed at determining whether (1) sex and cardiovascular risk factors have an effect on CSF biomarkers; (2) sex modifies the association between cardiovascular risk factors and CSF biomarkers in middle aged cognitively unimpaired individuals of the ALFA+ study.MethodWe measured CSF Ab42, Ab40, p‐tau, t‐tau, neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, S100, IL6, sVCAM1, sICAM1, MCP1 and α‐synuclein in 381 participants of the ALFA+ study (34.4% Ab‐positive, 65.6% Ab‐negative; Ab42/40 cutoff = 0.071). Biomarker measurements were performed using MSD, Roche NeuroToolKit and Elecsys® immunoassays. The following cardiovascular risk variables were studied: hypertension, smoking, dyslipidaemia, physical activity, LDL and HDL cholesterol, glucose, Hb1Ac, triglycerides, BMI and systolic and diastolic blood pressure. ANCOVA was performed to test the effect of sex on each biomarker and potential interaction effects between sex and cardiovascular variables.ResultWe found that CSF NfL, GFAP, IL6, sVCAM1 and MCP1 were higher in men, while CSF neurogranin and YKL40 were higher in women. These differences were still significant after adjusting for Ab pathology. Regarding cardiovascular variables, men had higher diastolic blood pressure, glucose and triglycerides, while women had higher total, LDL and HDL cholesterol. After adjusting for these cardiovascular variables, sex differences in CSF NfL were still significant, suggesting that they were not confounded by cardiovascular factors (Table 1). In the whole cohort, we observed that sex modifies the association with physical activity levels and CSF NfL (interaction ‘sex x physical activity’: p=0.019). After stratifying by Ab status, we observed that higher physical activity was associated with lower CSF NfL only in Ab positive men (Figure 1).ConclusionSex affects CSF biomarkers and modifies their association with cardiovascular risk factors. Specifically, physical activity is associated with lower NfL in middle aged men in the preclinical stage of the Alzheimer’s continuum, but not in women. Our results suggest that the impact of cardiovascular risk factors on neurodegeneration differs between men and women.