bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of memantine and combination with vitamin D enrichment on body composition in APP/PS1 Alzheimer’s mice following vitamin D deprivation
Authors: Broberg Dana N , Wong Dickson , Doad Jagroop , Umoh Joseph U , Bellyou Miranda , Norley Chris JD , Holdsworth David , Montero‐Odasso Manuel , Beauchet Olivier , Annweiler Cedric , Bartha Robert 
Published: December 2021

AbstractBackgroundVitamin D (vitD) deficiency and changes in body composition are frequently observed in Alzheimer’s disease (AD). The combination of memantine and vitD has been shown to protect cortical axons from glutamate toxicity and beta‐amyloid in AD. Further to these central effects, vitD and memantine may act peripherally to alter metabolism. The purpose of this study was to assess changes in body composition (lean, adipose, and skeletal tissue) in an AD mouse model due to vitD deprivation and subsequent treatment with memantine and memantine combined with high dose vitD supplementation.MethodMale APP/PS1 mice were randomized into four groups. Controls (n=14) received a standard diet throughout. The other three groups started a vitD deficient diet at month 6. At month 9, the VitD‐ group (n=14) remained on this diet, while the Mem&VitD‐ group (n=14) had memantine added, and the Mem&VitD+ group (n=14) had both memantine and 10 IU/g vitD added to their diet. Serum 25(OH)D3 levels were measured at months 6, 9, 12 and 15. Micro‐computed tomography scans were acquired at month 15 and segmented based on signal‐intensity to measure lean, adipose, and skeletal tissue mass and volume.ResultSerum 25(OH)D3 measurements confirmed that mice on vitD‐deficient diets had lower levels (89% decrease), and mice on the vitD‐enriched diet (Mem&VitD+) had higher levels (129% increase), of 25(OH)D3 relative to mice on the standard diet. No differences were observed in adipose or lean tissue mass and volume between the four groups, however, there was a significant increase in skeletal tissue mass (9.3% increase, p<0.05) and volume (9.2% increase, p<0.05), and bone mineral content (8.7% increase, p<0.01) in the Mem&VitD‐ group relative to controls.ConclusionWhile vitD deprivation did not affect body composition in APP/PS1 mice at 15 months, memantine increased absolute skeletal tissue in mice that were vitD‐deficient. However, memantine did not have this effect in mice that were vitD‐enriched. We conclude that combination treatment of memantine and vitD enrichment had no negative effects on body composition in the APP/PS1 mouse model. Future work should clarify whether vitD status impacts the effects of memantine on bone physiology in people with AD.
Effect of vitamin D deprivation and subsequent treatment with memantine and vitamin D enrichment on gait in APP/PS1 Alzheimer’s mice
Authors: Broberg Dana N , Wong Dickson , Bellyou Miranda , Montero‐Odasso Manuel , Beauchet Olivier , Annweiler Cedric , Bartha Robert 
Published: December 2021

AbstractBackgroundAltered gait is a common complication of Alzheimer’s disease (AD) that leads to decreased mobility and quality of life. Additionally, many individuals with AD are vitamin D (vitD) deficient. Combined treatment with memantine and vitD has been shown to protect cortical axons from glutamate toxicity and beta‐amyloid in AD. Therefore, this treatment may mitigate changes in gait associated with AD. The purpose of this study was to assess for the first time in an AD mouse model whether gait is affected by vitD deprivation and whether subsequent treatment with memantine or memantine combined with high dose vitD reverses these effects.MethodMale APP/PS1 mice were randomized into four groups. Controls (n=14) received a standard diet throughout. The other three groups started a vitD deficient diet at month 6. The VitD‐ group (n=14) stayed on this diet, while the remaining two groups began treatment at month 9 with either memantine alone (Mem&VitD‐) or both memantine and 10 IU/g vitD (Mem&VitD+). Serum 25(OH)D3 levels and spatiotemporal parameters of gait (stride length, swing time, swing speed, and front and hind stride widths measured by CatWalk) were assessed at months 6, 9, 12 and 15.ResultMice on vitD‐deficient diets had 7× lower levels of serum 25(OH)D3, and mice on the vitD‐enriched diet (Mem&VitD+) had over 2× higher levels of serum 25(OH)D3, relative to controls. VitD deprivation did not significantly affect stride length, swing time, swing speed, or front stride width, however, it led to a 12% increase in hind stride width by month 15 (Figure 1, VitD‐ vs. Control, p<0.001). Therefore, we examined hind stride width at month 15 in the memantine treatment groups and found that combination treatment with vitD prevented this increase (Figure 2, Mem&VitD+ vs. VitD‐, p<0.05), while memantine alone did not (Mem&VitD‐ vs. VitD‐, p=0.28).ConclusionVitD deprivation led to impaired postural control (hind stride width) in APP/PS1 mice by month 15. Memantine in combination with vitD enrichment, but not memantine alone, was able to prevent this impairment. Therefore, future work should investigate the potential for memantine combined with vitD supplementation to improve gait in people with AD.
Predictors of generalized anxiety during the COVID‐19 pandemic in older African Americans in Detroit
Authors: Hanna Sophie , Bass Dwana , DiCerbo Loraine M. , Shair Sarah , Giordani Bruno , Kavcic Voyko 
Published: December 2021

AbstractBackgroundThe COVID‐19 pandemic is a health emergency that has forced a change in the daily life of individuals across all nations, races and socioeconomic groups for over a year. Such a crisis has required social isolation, the closing of businesses, schools and many recreational activities. This abrupt change has had negative effects on mental health, especially in the most vulnerable populations.MethodFor this study, 164 community‐dwelling older African Americans (mean age = 75.6, range = 65‐94) were recruited from the Wayne State Institute of Gerontology Healthier Black Elders Center and general Detroit area. Responses were gathered over the phone between July 28, 2020 to January 14, 2021. Generalized anxiety was measured by the GAD‐7. Responses to COVID‐19 were measured by: positive emotions (eg., gratitude, happiness), negative emotion (eg., anger, fear), unmet needs (eg., food, medical care), and personal issues (eg., economic problems, reduced privacy).ResultOf the participants, 12 reported having COVID‐19, with 48% reporting a close family member having the virus, 26% had a death in the family and 67% endorse feelings of isolation. Average anxiety on the GAD‐7 was 6.2 (SD = 5.4, range = 0‐21). Of the 163 participants that completed the scale, 46% reported no anxiety, 28% reported mild anxiety, 17% reported moderate anxiety, and 9 % reported severe anxiety. In a stepwise regression, the following factors were found to predict GAD scores: negative emotions (51% explained variance), positive emotions (3% explained variance) and daily stressors brought on by COVID‐19 (1% explained variance). Further analyses were completed to evaluate additional models to assess the interrelationships between predictors and significant COVID‐related milestones.ConclusionThis current study among older African Americans living in an urban area highlights daily‐life risk factors for anxiety during the time of COVID‐19. Negative emotions as primary predictors are factors which can be specifically addressed with current psychosocial services. More research is needed in order to fully understand the scope and correlates of anxiety predictors during these challenging times.
Modeling cognitive processes with shuffled‐ and fixed‐order multi‐trial wordlist memory tests
Authors: Bock Jason R. , Lee Michael D. , Westfall Holly A. , Hara Junko , Fortier Dennis , Mangrola Tushar , Shankle William R. 
Published: December 2021

AbstractBackgroundMany commonly‐used multi‐trial wordlist memory (WLM) tests present list words in a shuffled order across learning trials, while others maintain a fixed order across trials. The ADAS‐Cog employs shuffling across trials in only one sequence for all assessed subjects. Therefore, to examine the impact of presentation order shuffling on the cognitive processes of learning and memory with a hierarchical Bayesian cognitive processing (HBCP) model, we assessed healthy subjects with a computerized version of the ADAS‐Cog WLM test that randomized wordlist presentation order on each of the three learning trials for each subject (randomized group). We then applied the model with resulting modifications to Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects assessed with the ADAS‐Cog (shuffled group). Finally, we compared results to cognitive processes of patients of a cognitive disorders clinic assessed with the fixed‐order MCI Screen (MCIS; fixed group).MethodRandomized group (n = 89), shuffled group (n = 2,235), and fixed group (n = 3,635) subjects completed respective assessments for university course credit, according to ADNI protocol, or as part of clinical assessment, respectively. The HBCP model uses item response data to estimate cognitive processes of encoding, storage, and retrieval for each wordlist item for each subject (Figure 1), through the probabilities of transferring item episodic memory from one storage state to another on a given trial.ResultAnalysis of randomized group data enabled development of a model extension accounting for observed presentation order. Examination of posterior distributions shows high recall and no serial position curve in the healthy randomized group (Figure 2). Applied to the shuffled group, there is greater interpretability and descriptive adequacy (Figure 3) than there is without the model extension (Figure 4), as can be seen in comparison to fixed group posterior distributions (Figure 5).ConclusionThese findings reveal the impact of presentation order shuffling and demonstrate our model's ability to mitigate it. Shuffling results in loss of information fidelity and the inability to estimate cognitive processing parameters in terms of serial position curves. The greater precision and range of measurement for fixed order presentation tests remains an important consideration for clinical trial design.
Race and sex differences in lifespan glycemic status and midlife cognitive function: The Bogalusa Heart Study
Authors: Newton Robert L , Gwizdala Kathryn L , Bazzano Lydia , Carmichael Owen T 
Published: December 2021

AbstractBackgroundThe association between early‐life glycemic control (during adolescence and young‐adulthood) and both cognition and risk of AD is not well understood. Furthermore, African Americans (AA) are underrepresented in aging research and disproportionally at higher risk for diseases related to glycemic control (Chow et al., 2012). This study assessed race and sex differences in the association between early‐life glycemic control and midlife cognitive function in a biracial, semi‐rural, Deep Southern population‐based epidemiological cohort.MethodThe Bogalusa Heart Study has followed participants from childhood to adulthood since 1973. Glycemic control measures including fasting insulin and glucose, and HOMA‐IR, were collected at roughly biannual visits from 1973 to today and cognitive measures were collected between 2013‐2016. Cognitive measures (n = 1295) included memory, executive function (EF), and global cognition. Glycemic control variables were averaged within specific age epochs (<20 (adolescent), 21‐40 (early adulthood) and >40 (adulthood). Linear regression models had metabolic measures as predictors and cognitive measures as outcomes. Models were run within age and race specific subgroups including sex, race, and education as covariates.ResultAmong women, greater levels of each glycemic predictor within adolescent and early‐adulthood epochs were associated with poorer memory and EF (Average Est. ‐0.018, p ≤ 0.037), and greater fasting glucose within the adolescent epoch was associated with poorer global cognition (Average Est. ‐0.061, p = 0.021). Greater HOMA‐IR and insulin levels within the adolescent epoch were associated with greater memory among men (Average Est. 0.040, p ≤ 0.020). Among AA, greater fasting glucose was associated with lesser EF performance within each epoch (Average Est. ‐0.006, p ≤ 0.037). Greater HOMA‐IR and insulin levels within early‐adulthood and >40 epochs were associated with greater memory for AA, and greater EF among whites (Average Est. 0.013, p ≤ 0.040 (AA), 0.029, p ≤ 0.025 (white)).ConclusionPoorer early to mid‐life glycemic control is associated with poorer EF and memory for women, better memory for men and AA, poorer EF for AA, and better EF for whites. Race and sex differences in the relationship between lifespan glycemic exposures and cognition decades later are pronounced and could reflect disparities in health‐related exposures throughout the lifespan.
Using digital twins to reduce sample sizes while maintaining power and statistical accuracy
Authors: Walsh David , Schuler Alejandro M , Hall Diana , Walsh Jonathan R. , Fisher Charles K. 
Published: December 2021

AbstractBackgroundAlzheimer’s Disease (AD) trials are challenging due to their size, length and costs. Bayesian designs can reduce the required sample sizes by using external data sources to construct prior distributions for treatment effects, so that the same effect sizes can be detected with fewer trial participants. We apply a Bayesian approach based on digital twins ‐ longitudinal, patient‐level placebo records with baseline characteristics matched to those of actual subjects in AD trials. These records are generated by a machine learning model of AD progression that we have trained on data from placebo arms of past clinical trials and from observational studies.MethodWe re‐analyzed a Phase II, double‐blind, placebo‐controlled trial of Resveratol in 119 patients with mild‐to‐moderate AD ‐ Mini‐Mental State Examination (MMSE) scores between 14‐26 ‐ using a method we call PROCOVA+. We focused on the Alzheimer's Disease Assessment Scale ‐ Cognitive (ADAS‐Cog11, primary endpoint), the Clinical Dementia Rating ‐ Sum of Boxes (CDR‐SB) and MMSE.PROCOVA+ leverages the digital twins’ outcomes in two ways: as covariate information on the actual trial participants, and to construct prior distributions for the expected placebo outcomes for each endpoint. These prior distributions are centered on the mean outcomes of all digital twins, with dispersions that reflect how accurately digital twins match actual subjects on similar clinical trials. We determined the necessary sample sizes for PROCOVA+ to achieve the same power as the original study, while fixing a 2:1 randomization ratio between the active treatment and placebo arms. We randomly sampled that number of subjects from the original study and computed estimates and credible intervals for each endpoint.ResultThe total sample size across the two arms was reduced by 17%. The estimates of the treatment effects agreed closely with those of the original study for all three endpoints, with credible intervals which were no wider than the original confidence intervals.ConclusionDigital twins present an opportunity to design and analyze AD trials in a way that maintains statistical accuracy, while reducing the required sample sizes and hence the time and cost associated with recruiting and treating extra subjects.
Identification of small molecule drugs that target apolipoprotein E4‐catalyzed amyloid‐β fibrillization: A new therapeutic approach to Alzheimer’s disease
Authors: Johnson Noah R , Wang Athena Ching‐Jung , Coughlan Christina M , Sillau Stefan H , Lucero Esteban M , Viltz Lisa , Markham Neil , Allen Cody , Dhanasekaran A. Ranjitha , Chial Heidi J , Potter Huntington 
Published: December 2021

AbstractBackgroundCarrying the ε4 allele of the apolipoprotein E (APOE) gene is the strongest risk factor for Alzheimer’s disease (AD) besides age itself. Having one copy of APOE4 triples the risk for AD, whereas being homozygous for APOE4 increases the risk by greater than 12‐fold. As one potential mechanism, apoE, and especially apoE4, acts as a catalyst to accelerate the polymerization rate of amyloid‐β (Aβ) into neurotoxic oligomers and filaments. Thus, inhibiting this catalytic process is a promising therapeutic approach to preventing AD. Repurposing a known drug to inhibit the apoE4‐Aβ interaction would have numerous benefits such as faster, less expensive testing in clinical trials, and a greater chance of making it to market.MethodWe developed an apoE4‐Aβ fibrillization assay and screened two small molecule drug repurposing libraries containing more than 3,000 compounds with a history of use in human clinical trials. The cytotoxicity and efficacy of hit compounds were evaluated in transgenic mouse and rat primary neurons. We also modeled changes in cognition using MMSE scores and clinical diagnoses of National Alzheimer’s Coordinating Center (NACC) participants using time slopes and Cox proportional hazards, respectively, and adjusted for age and sex.ResultOur high‐throughput screen identified 31 hit compounds that inhibited apoE4‐catalyzed Aβ fibrillization in a dose‐dependent manner. Five of those hit compounds were non‐toxic, blood‐brain barrier permeable, and reduced apoE4‐induced Aβ and tau neuropathology in AD cell culture models. One hit compound was the anti‐depressant imipramine, which, when taken by AD patients, was associated with improved cognition (P=0.0490) and increased incidence of receiving an improved clinical diagnosis (P<0.0001), compared to all other anti‐depressants. Another hit compound was the anti‐psychotic olanzapine, which, when taken by AD patients who were APOE4 carriers, was associated with improved cognition (P=0.0235) and improved clinical diagnosis (P=0.0435), compared to all other anti‐psychotics.ConclusionWe identified five novel inhibitors of the apoE4‐Aβ interaction, two of which were associated with clinical improvements when prescribed to AD patients for their normal indications. These findings validate an apoE‐centric approach to developing new AD therapeutics. This set of small molecules may be useful for preventing or reversing AD, particularly in APOE4 carriers.
The first MultiTEP‐based conjugated vaccine targeting pyroglutamated pE3‐Aβ is immunogenic and effective in a 5xFAD animal model
Authors: Zagorski Karen , King Olga , Hovakimyan Armine , Antonyan Tatevik , Petrushina Irina , Chadarevian Jean Paul , Danhash Emma , Cribbs David H. , Davtyan Hayk , Blurton‐Jones Mathew , Agadjanyan Michael G , Ghochikyan Anahit 
Published: December 2021

AbstractBackgroundMany ongoing studies for AD immunotherapy are focused on the immunodominant N‐terminus of Aβ. This region is often truncated and post‐translationally modified in amyloid. The pyroglutamate modified variant of Aβ40/42 (pE3‐Aβ) is more neurotoxic and aggregation‐prone and is thought to play an important role in disease onset. We have previously demonstrated that our proprietary vaccine platform MultiTEP is extremely immunogenic in various mammals, including disease models of AD and aged monkeys, and can be used to generate a robust immune response towards various targets. Based on these we developed a MutiTEP‐based vaccine targeting pE3‐Aβ.MethodA genetically engineered variant of MultiTEP was generated to enable chemoselective bioconjugation of synthetic peptides under mild aqueous conditions. The peptide‐protein stoichiometry was selected at 3:1 based on previous data. C57Bl6 and 5xFAD mice were monthly immunized with pE3‐Aβ‐MultiTEP adjuvanted vaccine, AV‐1986R. Antibody titers were tested via ELISA on plates coated with pE3‐Aβ42 and unmodified Aβ42 as control. The reduction of brain pathology in 5xFAD was assessed via biochemical assessment (MSD ELISA) as well as IHC and confocal microscopy using various commercial antibodies. The binding of immune sera to brain sections from non‐AD, MCI, and AD cases was examined.ResultThe AV‐1986R generates a robust immune response in transgenic and WT mice after two immunizations. The generated antibodies exhibit three orders of magnitude higher affinity (one to a million avg endpoint titer) to the pE3‐Aβ compared to Aβ42 and recognized Aβ plaques in brain tissue slices from both transgenic animals and AD cases. Importantly, vaccination significantly reduced AD‐like pathology in 5xFAD mice.ConclusionAV‐1986R is immunogenic and effective. A recent report from Elly‐Lilly about the pE3‐Aβ specific monoclonal antibody donanemab shows that treatment slows down the cognitive decline in humans. While this is promising and re‐affirms the selection of pE3‐Aβ as a therapeutic target, the regular injections of monoclonal antibodies are extremely expensive and have low patient compliance due to the frequent and invasive nature of the treatment. We suggest using active vaccine as a feasible alternative, allowing the maintenance of a constant level of therapeutic antibodies with minimal costs and infrequent vaccine injections.
The role of inflammation on the association between apathy and motoric‐cognitive outcomes
Authors: Ceide Mirnova E. 
Published: December 2021

AbstractBackgroundRecent literature indicates that apathy is associated with poor cognitive outcomes in community dwelling older adults, including motoric cognitive risk syndrome (MCR), a predementia syndrome defined by subjective cognitive complaints and slow gait. The role of biological markers in the association between apathy and motoric‐cognitive outcomes has not been established. The objectives of this study were to 1) examine the association between inflammation and apathy and 2) to evaluate the moderating effect of inflammation on the association between apathy and motoric‐cognitive outcomes.MethodWe measured apathy in 347 community dwelling older adults enrolled in the Central Control of Mobility in Aging study using an apathy scale score derived from confirmatory factory analysis of the Geriatric Depression Scale Long Form. We conducted cross‐sectional analyses of the following: the association between IL‐6 and CRP with apathy and the moderating effect of IL‐6 on the association between apathy and MCR and slow gait, using logistic regression and linear regression models, respectively. Linear associations were reported using β‐coefficients, while logistic associations were reported using odds ratio (OR) with 95% confidence intervals (CI), adjusting for age, gender, general health status and depression scale score.ResultlogIL‐6 but not logCRP was associated with apathy, in adjusted models (β=.037, 95% CI: .002‐.072, p=.04). Apathy was not significantly associated with MCR at cross‐section (OR: 0.48, 95% CI: .08‐2.97, p=.43), but apathy was significantly associated with gait velocity (β=‐14.45, 95% CI: ‐24.89 ‐ 4.01, p=.01). IL‐6 was associated with gait velocity (β=‐4.48, 95% CI: ‐7.42 ‐ 1.53, p=.003) and moderated the association between apathy and gait velocity by a change in β of 14.5%.ConclusionWe found that IL‐6, but not CRP was associated with apathy in a cohort of community dwelling older adults. Furthermore, IL‐6 moderated the association between apathy and gait velocity, a risk factor for dementia. Apathy was not associated with MCR at cross‐section, despite being associated with incident MCR in prior studies, suggesting that apathy is an early predictor of motoric‐cognitive decline.