bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of diet on cognitive function and gut microbiota
Authors: Solch Rebecca J , Engler‐Chiurazzi Elizabeth , Harper Colin , Wasson Savannah , Ogbonna Sharon , Ouvrier Blake , McDonald Katherine , Wang Hanyun , Biose Ifechukwude Joachim , Bix Gregory J , Maraganore Demetrius M 
Published: December 2022

AbstractBackgroundAlterations in the gut microbiota have been observed in patients with mild cognitive impairment and Alzheimer’s disease. Dietary consumption directly modulates gut microbiota; therefore, the quality of a diet may impact cognitive function and susceptibility to dementia. We hypothesized that consumption of the nutrient dense Mediterranean diet (MeDi) would improve cognitive function through beneficial changes to the gut microbiota as compared to the diet primarily consumed by Americans, the Western diet (WD).MethodTen‐week‐old Sprague Dawley male rats were assigned a MeDi (n = 10) or WD (n = 9). After three months, Morris water maze (MWM) was used to assess spatial reference memory cognition. MWM data were analyzed with two‐way RM ANOVA. Fecal samples were collected prior to the MWM. Microbial composition was determined by 16S rRNA sequencing, and analyses included Mann‐Whitney with false discovery rate.ResultThe MeDi group also spent significantly more time in the target quadrant during probe testing (p = 0.03) and was quicker to reach the platform on reversal testing (p = 0.004), indicative of improved cognitive flexibility. Microbiota α‐diversity indices, Shannon (p = 0.053), Simpson (p = 0.054), and Chao1 (p = 0.056), had a trend to be increased in the MeDi. Microbiota β‐diversity was dissimilar between diets (p<0.001). At the phylum level, Actinobacteria decreased and Patescibacteria increased with consumption of the MeDi as compared to the WD. Actinobacteria relative abundance correlated with MWM time in target quadrant (r = ‐0.58, p = 0.009). Further, relative abundance of Actinobacteria and Patescibacteria correlated with MWM reversal distance to reach platform (Actinobacteria, r = 0.77, p = 0.0001; Patescibacteria, r = ‐0.59, p = 0.007).ConclusionThe MeDi maintained long‐term spatial memory, as measured by the MWM, compared to the WD. Additionally, diet‐modulated gut microbiota at the phylum level and these changes were correlated with cognitive function. Modulation of the gut microbiota through a neuroprotective diet, such as the MeDi, may serve as a method to improve cognitive function.
Effectiveness of a digitally supported care management program for family and other informal dementia caregivers: baseline data from the GAIN randomized controlled trial
Authors: Kilimann Ingo , Klein Olga A. , Thyrian Jochen René , Boekholt Melanie , Teipel Stefan , Hoffmann Wolfgang 
Published: December 2022

AbstractBackgroundAlmost two‐thirds of people with dementia (PwD) living at home receive care from a family or other informal caregiver. For the caregiver this can result in a work load comparable or above a full‐time employment position. Evidence shows that family caregivers have a higher risk for psychiatric and non‐psychiatric diseases like depression, anxiety, and arterial hypertension compared to non‐caregivers. A dyadic approach on disease management and the assessment of unmet needs can help to reduce the burden of care and increase the quality of life of caregivers and PwD. The cluster randomized “Gesund Angehörige Pflegen” (GAIN) trial conducted in general practitioner (GP) practices and memory clinics in Northern Germany aims to evaluate the effectiveness of a digitally supported care management programme to reduce unmet needs of informal caregivers of PwD.MethodThe recruitment for the GAIN trial began in October 2020 and will end in January 2022 with an estimated sample size of n = 200 caregiver. The GAIN baseline assesses the caregiver’s self‐reported unmet needs (Camberwell Assessment of Need for the Elderly, CANE), health‐related quality of life (EQ‐5D‐5L), caregiver burden (Zarit Burden Interview, ZBI), social support (Lubben Social Network Scale, LSNS), the use of medical and non‐medical services and resource utilisation.ResultA blinded interims data quality control analysis (n = 86) documented 10.45 unmet needs on average, 4.55 unmet needs for the caregivers and 5.9 unmet needs connected to the PwD triggering a maxium of 8 suggested interventions per unmet need. These results are higher compared to the previous studies on unmet needs of dementia caregivers. The recruitment for the trial is currently still ongoing. Complete baseline results will be presented at the conference.ConclusionThe use of a tablet‐based expert assessment system in memory clinics or GP praxis to identify unmet needs is well feasible. Caregivers of PwD recruited at GPs or memory clinics for the GAIN trial report a high number of unmet needs indicating the importance of a structured and in‐depth assessment to allow a personalized and dyadic treatment of family caregivers and PwD.
Improved risk prediction of all‐cause dementia, Alzheimer’s disease, and vascular dementia by inflammation‐related biomarkers
Authors: Trares Kira , Schöttker Ben 
Published: December 2022

AbstractBackgroundDementia risk prediction models, such as the widely used Cardiovascular Risk Factors, Aging and Dementia (CAIDE) model, combining factors from the fields of demographic, cognition, physical and health, have proven themselves. However, it is of interest whether inflammatory biomarkers additionally improve such dementia risk prediction models.MethodsThe Olink Target 96 Inflammation panel was assessed in serum samples of a large German, population‐based cohort study. In a nested case‐cohort design (n=1688), the CAIDE model was used for dementia risk prediction and aimed to improve by adding 72 inflammation‐related biomarkers of the Olink panel. Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression and bootstrapping were utilized to select relevant biomarkers and determine areas under the curve (AUCs) for all‐cause dementia, Alzheimer’s disease (AD) and vascular dementia (VD) in the total cohort, as well as in mid‐life and late‐life sub‐samples.ResultsOver 17 years of follow‐up, 440 participants developed dementia. Of those, 147 were diagnosed with AD and 195 with VD. The prediction model including APOE ε4 carrier status (CAIDE model 2) had a better discriminative ability for all‐cause dementia, AD, and VD than the model without APOE ε4 (CAIDE model 1) with AUCs of 0.751, 0.767, and 0.725, respectively. Adding 16 inflammation‐related biomarkers selected by LASSO regression to the CAIDE model significantly increased the AUC for all‐cause dementia risk prediction by 0.025 (95%CI: 0.001–0.045). The AUC increases for AD (0.024) and VD (0.019) were of similar magnitude but not statistically significant due to lower case numbers. Moreover, the CAIDE model generally performed better in mid‐life (50‐64 years) than in late‐life (65‐75 years) sub‐samples, and all increases in the AUC caused by inflammation‐related biomarkers were larger in the mid‐life sub‐sample.ConclusionInflammation‐related biomarkers significantly improved the CAIDE model for all‐cause dementia prediction. Especially the predictive abilities of these blood‐based biomarkers in mid‐life are of clinical relevance to guide early preventive measures.
Value of plasma biomarkers to predict memory change in cognitively unimpaired individuals
Authors: den Braber Anouk , Verberk Inge M.W. , Tomassen Jori , Coomans Emma M , van der Landen Sophie M , Boonkamp Lynn , Dage Jeffrey L. , Stoops Erik , Willemsen Gonneke , Nivard Michel G. , van Berckel Bart NM , Scheltens Philip , Visser Pieter Jelle , de Geus Eco J.C. , Teunissen Charlotte E. 
Published: December 2022

AbstractBackgroundPlasma levels of amyloid‐β1‐42/1‐40, phosphorylated‐tau (P‐tau) and glial fibrillary acidic protein (GFAP) can be used to predict amyloid‐β pathology in elderly cognitively unimpaired individuals, but their prognostic value in early Alzheimer’s Disease (AD) stages in the normal aging population needs further study. We aimed to investigate the value of these plasma biomarkers for predicting memory change in cognitively unimpaired individuals in a population‐based cohort.MethodFrom the EMIF‐AD PreclinAD study we selected 188 individuals with normal cognition, who had plasma samples, amyloid‐β status and at least one cognitive follow‐up available (total follow‐up years (mean(SD) = 4.3(.42)) (Table 1). Amyloid‐β status was defined using visual read of dynamic [18F]flutemetamol‐PET images or CSF amyloid‐β1‐42/1‐40<0.066 (Euroimmun). Simoa assays were used to measure plasma amyloid‐β1‐42/1‐40 (AMYBLOOD), P‐tau181 (Eli Lilly) and GFAP (Quanterix) levels. Linear mixed models, adjusted for age, sex and years of education, were applied to test associations of baseline plasma biomarker levels with subsequent change in memory (plasma*time), and its interaction with amyloid‐β status (plasma*time*amyloid‐β status).ResultFrom the total cohort tested, 31 subjects (16.5%) were amyloid‐positive. These individuals were older, showed worse baseline memory performance, lower plasma amyloid‐β1‐42/1‐40, and higher plasma P‐tau181 and GFAP levels compared to amyloid‐negative individuals (Table 1). Higher plasma GFAP levels at baseline were significantly associated with worse memory performance over time (GFAP*time: β=‐.03, p=.01). Interestingly, this relation was significantly stronger in amyloid‐positive compared to amyloid‐negative individuals (GFAP*time*amyloid‐β status: β=‐.07, p=.001) (Table 2, Figure 1). No significant associations were observed for baseline plasma amyloid‐β1‐42/1‐40 and P‐tau181 levels with change in memory over time (P‐tau181*time: β=‐.02, p=.07; amyloid‐β1‐42/1‐40
*time: β=.02, p=.12) (Table 2).ConclusionOur data suggest plasma GFAP can be used as a predictor of future memory decline in cognitively unimpaired, amyloid‐positive, individuals in the normal aging population. This supports the use of plasma GFAP as a prognostic marker for disease and treatment‐effect monitoring in the early stages of AD development.
Allowing “rescue therapy” in preclinical Alzheimer’s trials
Authors: Donohue Michael C. , Insel Philip S. , Aisen Paul , Delmar Paul , Giacobino Caroline , Ostrowitzki Susanne , Fontoura Paulo , Doody Rachelle S. 
Published: December 2022

AbstractBackgroundAduhelm’s recent approval, and the potential approval of additional effective therapies in early (prodromal‐to‐mild) Alzheimer’s disease (AD), will impact the conduct of clinical trials, including trials designed to delay or prevent cognitively unimpaired participants from progressing to mild cognitive impairment (MCI) or AD dementia. Allowing “rescue therapy” with these approved therapies during preclinical AD trials (“treatment policy design”) is expected to increase participation and improve adherence in these very large and long clinical trials. Our goal was to evaluate the impact of allowing “rescue therapy” on the study power using simulation.MethodIn the simulated study, cognitively unimpaired elderly adults with elevated levels of beta‐amyloid were randomized 1:1 to the control arm (starting on placebo and initiating “rescue therapy” upon progression to Clinical Dementia Rating [CDR] scale score > 0) or to the experimental arm (same experimental treatment throughout the study).Key simulation parameters (placebo decline and variance) were based on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and other cohort data. The continuous endpoint was Preclinical Alzheimer’s Cognitive Composite (PACC) scores. The triggering event to allow the start of “rescue therapy” was progression to CDR > 0. A range of different study design parameters (study duration, magnitude and timing of treatment effect, and continuous outcome vs time to event) were explored.ResultPreliminary simulation results indicated that allowing “rescue therapy” had limited impact on the study power/sample size. They also suggested that continuous endpoints provided more power compared with a time‐to‐event endpoint in this setting.ConclusionThis initial simulation study suggests that clinical trials of subjects in preclinical or at‐risk stages of AD that allow rescue medications during the trial may retain adequate power, with a limited impact on sample size, when analyzed with a primary treatment policy estimand. The potential benefit of the “treatment policy” approach in terms of recruitment and adherence/engagement cannot yet be quantified but could be substantial.
An examination of the usability of the Mayo Test Drive remote cognitive testing platform in older adults with and without cognitive impairment
Authors: Patel Jay S , Christianson Teresa J. , Karstens Aimee J , Stricker John L , Kremers Walter K. , Jack Clifford R. , Knopman David S. , Mielke Michelle M. , Petersen Ronald C. , Stricker Nikki H. 
Published: December 2022

AbstractBackgroundMayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform for self‐administered assessment for novel (Stricker Learning Span) and open access (Symbols Test) cognitive measures with previously demonstrated validity and reliability. Our study aim was to examine the usability of MTD, defined as the extent to which MTD was used to achieve the desired study goal of completing a testing session among participants willing to engage in an all‐remote study.Methods248 Mayo Clinic Study of Aging and Mayo Alzheimer’s Disease Research Center participants were invited to participate in this ancillary, uncompensated remote pilot study via email. To examine 1) willingness to participate in a remote cognitive assessment study and 2) usability of MTD, the initiation and completion rates of MTD were examined by cognitively unimpaired (CU; n = 142) and cognitively impaired (CI; n = 106) groups (see Figure 1). These rates and other factors associated with MTD feasibility were further explored across age in CU (i.e., 50–69, 70–79, and 80+ years) and specific diagnostic groups in CI (i.e., individuals with dementia, mild cognitive impairment (MCI), and possible MCI).ResultsSession completion rate (usability) was 98% across all participants who chose to participate, and, surprisingly, completion rates did not vary by age or diagnostic groups (p = .69; see Table 1). As expected, more individuals chose to participate in the CU (77%) versus CI (52%) group (p < .001). In terms of feasibility, individuals over 80 and with CI were more likely to have some contact with the study coordinator. Use of smartphones decreased with age, with most CU individuals over 70 using a personal computer (69‐73%; Table 2).ConclusionsThough the CI group was less likely to choose to participate than the CU group, out of those that did choose to participate the rate of completion was 98%. This demonstrates high usability of MTD. Study coordinator support and a flexible testing platform is critical for facilitating participation in remote testing across the aging population, and more supports and incentives may be needed for individuals with cognitive impairment to improve participation rates.
Spatially resolved transcriptomics in the APPSWE [Tg2576] mouse model of Alzheimer’s disease
Authors: Uytingco Cedric R , Chew Jennifer , Hartnett Andrej D , Weisenfeld Neil , Williams Stephen R , Ziraldo Solongo B , Meschi Francesca , Miller Kelly , Yin Yifeng 
Published: December 2022

AbstractBackgroundAlzheimer's and other neurodegenerative diseases remain pervasive, impacting patients and their families as the disease progresses. Despite the continual expansion of our understanding of these conditions, the detailed molecular mechanisms and progression of pathology throughout the brain remain elusive and complex. Using genomic and RNA‐seq approaches, identification of individual cells and their genetic makeup provide an added perspective on their roles in how the central nervous system (CNS) function in both healthy and diseased states. Here we demonstrate the characterization of spatial transcriptomic patterns in the APPSWE [Tg2576] mouse model of familial Alzheimer’s Disease using the Visium Spatial Gene Expression Solution.MethodSerial sections of fresh‐frozen transgenic APPSWE [Tg2576] and littermate control mouse brains were placed onto Visium Spatial Gene Expression slides. The slides consist of ∼5,000 spot arrays with uniquely barcoded probes allowing for the capture of native mRNA. The samples were H&E or immunostained and then permeabilized, allowing for the capture of transcripts and library generation. The resulting libraries were then sequenced on an Illumina NovaSeq. Then, using the 10x Genomics Space Ranger analysis pipeline and the Loupe Browser desktop software, the RNA‐seq data were merged with stained tissue images to align reads, perform clustering, and gene expression analysis.ResultWith the generated data, we demonstrated an improved version of the spotted oligo array technology that increases tissue coverage and spatial resolution with reduced spot size, and increased spot number and packing density. We captured spatial patterns of gene expression and mapped the information back to H&E and immunostained images with regional annotations. Performing differential analysis on the resulting spatial gene expression data, we observed elevated expression of the Pmch (pro‐melanin concentrating hormone) gene within the hypothalamic region of APPSWE [Tg2576] transgenic mice compared to the littermate controls. By immunofluorescence staining, we confirmed the gene expression patterns and utilized this approach to identify the cells and refine the gene expression characterization.ConclusionTogether, this confluence of imaging and sequencing is a valuable tool for understanding the relationships between CNS cell types in healthy and diseased samples with an unbiased anatomical and gene expression‐driven method.
Deep plasma proteomics reveal age‐related molecular pathways modulated by GRF6019 treatment in Alzheimer’s disease patients
Authors: Nanasi Tibor , Feng Mia , Braithwaite Steven P , Lehallier Benoit 
Published: December 2022

AbstractBackgroundBlood has been widely investigated to discover biomarkers and gain insights into the biology of aging and age‐related diseases. Its protein composition provides information about complex biological processes, as proteins are often direct regulators of cellular pathways. Using recent methodological developments allowing the measurement of thousands of proteins with very high sensitivity and specificity, we sought to understand comprehensive proteomic changes in two AD clinical trials.MethodPhase 2 clinical trials (GRF6019‐201 n=40 and GRF6019‐202 n=26) testing the safety, tolerability, and feasibility of repeated infusions of the plasma fraction GRF6019 in Alzheimer's disease (AD) were used as the source to measure more than 7000 proteins in plasma using the SOMAscan and Olink assays. To evaluate the relevance of the proteomics changes induced by GRF6019, we compared these changes to those observed in a healthy aging cohort (∼5000 proteins measured in 370 subjects).ResultStandard statistical analysis at the protein levels lacked power due to the small sample size in phase 2 clinical trials. By analyzing trajectories of groups of proteins, clinical proteomics revealed multiple clusters of proteins responding to GRF6019. Remarkably, several pathways modulated by GRF6019 were particularly relevant for the biology of aging and AD – including the complement/coagulation cascades and neuronal pathways (q<0.05).ConclusionAltogether, our results suggest that the treatment of AD patients with a complex plasma fraction modulates biological pathways that are relevant to aging and AD. Our results establish deep proteomics as a powerful tool to study human response to treatment in clinical trials.
Role of ABCA7 in Neural Lipid Metabolism and Its Association with Alzheimer's Disease Neuropathology
Authors: Garliyev Viktor , Wiener Joel P. , Pratico Domenico , Lyssenko Nicholas N. 
Published: December 2022

AbstractBackgroundStrong genetic evidence supports involvement of adenosine triphosphate binding‐cassette transporter subfamily A member 7 (ABCA7) in Alzheimer’s disease (AD) pathogenesis. ABCA7 closely resembles ABCA1, a cholesterol transporter, in structure. However, molecular specificity of ABCA7‐mediated lipid transport and the role of this protein in AD pathophysiology are understood incompletely. We advance the hypothesis that ABCA7 protects against AD development by removing neurodegenerative lipid from the brain.MethodA validated monoclonal antibody was used to measure ABCA7 protein in a cohort of 104 individuals represented by the hippocampus and a different cohort of 119 individuals represented by the parietal cortex. Both cohorts included individuals with Braak stages 0‐V. Changes in ABCA7 level in response to treatment with lipid metabolism modulators were investigated in human microglial C20 and HMC3 and human astrocytic A172 cell lines.ResultTo match for age, the cohorts were subdivided into 63‐78 and 79‐94 age‐at‐death brackets. There was no significant correlation between ABCA7 protein levels and Braak stages. However, individuals with Braak stages II‐V as a group had significantly lower ABCA7 levels than individuals with Braak stages 0/I as a group in the 63‐78 age bracket of both cohorts (Mann‐Whitney p<0.0001 and p=0.003, respectively) and in the 79‐94 bracket of the parietal cortex cohort (p=0.037) but not in the hippocampus cohort (p=0.33). One of the reasons for this difference between the hippocampus and parietal cortex was that ABCA7 levels decreased significantly with age in the Braak stage 0/I group in the hippocampus but not the parietal cortex (p=0.02 vs p=0.77 for ABCA7 levels in the 63‐78 vs 79‐94 age bracket, respectively). An analysis of lipid metabolism using pharmacological modulators revealed that ABCA7 expression in microglial and astrocytic cells does not respond to the intracellular cholesterol level or regulators of intracellular cholesterol metabolism.ConclusionThese results are in line with the hypothesis that ABCA7 prevents AD neuropathogenesis, i.e., loss of ABCA7 protein occurs sharply and early between Braak stages I and II. There also appear to be brain region‐specific changes in ABCA7 expression with age. The neurodegenerative lipid that ABCA7 removes from the brain remains to be identified.