bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacologic inhibition of astrocyte ApoE release
Authors: Kulas Joshua A , Kovacs Michael A , Milstein Joshua L , Harris Taije H , Ferris Heather A 
Published: June 2023

AbstractBackgroundThe ApoE4 allele is the strongest known genetic risk factor for late onset Alzheimer’s disease. Despite this knowledge, therapeutic strategies seeking to modulate brain ApoE homeostasis remain largely unexplored. Several lines of evidence demonstrate that astrocytes function as the primary producers of ApoE within the brain. In this study, we examine how targeted disruption of astrocyte lipid metabolism and protein prenylation effect the secretion of ApoE from primary astrocyte cultures.MethodPrimary cell cultures of mouse astrocytes were grown from 1‐3 day old pups. Drugs were applied to cells in serum free conditions over a range of timepoints and doses. Astrocyte conditioned media was collected from cultures and ApoE and other proteins of interest were measured by western blot.ResultWe find that inhibiting HMG‐CoA reductase, a rate‐limiting enzyme in the cholesterol synthesis pathway, with simvastatin reduces astrocyte ApoE levels in conditioned media in a dose dependent manner, while secretion of other proteins remain preserved. Inhibition of downstream cholesterol synthesis through blockade of the enzyme FDFT1 with zaragozic acid, however, has no effect on total ApoE secretion. Mice with genetic disruption of brain cholesterol metabolism also have similar levels of ApoE in CSF samples compared to control. These data suggest the effect of HMGCR inhibition on ApoE is not mediated through cholesterol. It is known that HMGCR activity is also required for maintenance of cellular protein prenylation. We tested the prenylation inhibitor FGTI‐2734 and found that it is sufficient to block astrocyte ApoE secretion, suggesting that HMGCR inhibitors may exert their effect on ApoE through this mechanism. Recent work suggests that inflammatory astrocytes exert toxic effects via neurotoxic lipids carried by ApoE and another carrier protein, CLU. We find that inhibiting HMGCR in astrocytes does not prevent cytokine‐induced conversion to an inflammatory phenotype, but remains able to block ApoE releaseConclusionWe conclude that targeted inhibition of prenylation enzymes may provide a therapeutic strategy to modulate ApoE levels in the brain.
Heterogeneous effect of social and behavioral determinants of health on the risk of dementia
Authors: Tang Huilin , Wu Yonghui , Brown Joshua , Anton Stephen , Hernandez Inmaculada , Bian Jiang , Guo Jingchuan 
Published: June 2023

AbstractBackgroundIndividuals experiencing socioeconomic disadvantages are disproportionally affected by dementia. Social and behavioral determinants of health (SBDH) are major contributors to health inequities in dementia risk and outcomes. We aimed to determine the heterogeneous effect of SBDH on dementia risk in older adults.MethodUsing data from the National Alzheimer’s Coordinating Center (NACC) (2005‐2021), we identified adults 65 years and older with ≥2 visits and normal cognition at baseline. Exposures of interest included four SBDH collected at baseline, including alcohol abuse, drug abuse, smoking, and high school education or above. We applied a causal machine learning model and doubly robust learning to estimate the conditional average treatment effects (CATEs) and heterogenous effect of SBDH on the risk of dementia. Following the doubly robust learning framework, we created the models in a two‐step process: a first model that estimates the probability of being exposed (i.e., generating propensity scores), and then a second model that estimates dementia outcome from the exposures of interest, accounting for the probability of being exposed. Hyperparameter optimization and model validation were conducted based on minimal mean square error.ResultsWe included 10,375 participants, with a mean age of 75 (SD: 7) years; 64% were women and 9% (n = 954) developed dementia over a median follow‐up of 5.2 years. In the estimation of CATEs, higher education was associated with a lower risk of dementia (absolute risk deference: ‐0.038; 95%CI, ‐0.065 to ‐0.01), while smoking (‐0.002; ‐0.009 to 0.005), alcohol abuse (‐0.073; ‐0.152 to 0.005), and drug abuse (‐0.024; ‐0.051 to 0.004) were not significantly associated with dementia risk. However, we identified a heterogeneous effect for each of these SBDH (Figure). Over 53%, 68%, and 28% of individuals had an increased risk of dementia with exposure to smoking, alcohol abuse, and drug abuse, respectively.ConclusionWe identified significant heterogeneous effects of SBDH, specifically smoking, alcohol abuse, and drug use, on dementia risk in a group of older adults with normal cognition. Our findings underscore the need to adopt an individualized approach to address dementia disparities. Future studies should examine the mechanisms underlying the heterogenous effects of SBDH on dementia risk.
Dementia increases risk of organ failure and hospital mortality of motorcycle crash‐related hospitalizations in Taiwan: A nationwide population‐based study
Authors: Liu Chih‐Ching 
Published: June 2023

AbstractBackgroundPrior studies showed dementia is associated with the increased risk of injuries in motorcycle crashes, especially in young onset dementia. However, little is known about the effect of young onset dementia on the risk of organ failure and hospital mortality of motorcycle crash‐related hospitalizations. This study describes the prevalence of organ failure and hospital mortality of motorcycle crash‐related hospitalizations among patients with and without dementia and assesses whether dementia is at higher risk of organ failure and hospital mortality of motorcycle crash‐related hospitalizations.MethodIn this population‐based cohort study, we compared patients with dementia aged 40‐64 years and its age‐ and sex‐ matched participants without dementia when they had the first hospitalization for motor vehicle accident injury (MVAI). Data in this study were obtained from the Taiwan National Health Insurance Research Database entries and Taiwan Police‐reported Traffic Accident Registry between 2006 and 2015. Major outcomes were development of organ failure and hospital mortality in motorcycle crash‐related hospitalizations. Logistic regression with generalized estimating equations were performed to account for hospital clustering effect.ResultIn patients with dementia, the prevalence rates of organ failure and hospital mortality was 6.88% and 4.44%, respectively, which were higher than participants without dementia (3.08% and 2.07%). After adjustment of potential confounders, patients with dementia had a 91% higher risk (95%CI 1.45‐2.51) of organ failure of motorcycle crash‐related hospitalizations than patients without dementia, especially those with respiratory organ failure (adjusted odds ratio [OR]1.96, 95%CI 1.46‐2.63). Similarity, patients with dementia were related with increased risk of hospital mortality (adjusted OR 1.39, 95%CI 1.01‐1.93).ConclusionIn motorcycle crash‐related hospitalizations, the presence of dementia may rise the risk of organ failure and hospital mortality, which warrants the concerns of healthcare providers.
Sex differences of APOE neuropathology‐based scores in brain aging
Authors: Adluru Nagesh , Deming Yuetiva , Nair Veena A. , Prabhakaran Vivek , Bolaños Alfredo D , Lose Sarah R , Alexander Andrew L , Okonkwo Ozioma C. , Bendlin Barbara B 
Published: June 2023

AbstractBackgroundBy reinterpreting the difference between a model prediction and calendar age, machine learning algorithms allow for estimation of “brain age” using MRI. There is growing evidence for sex differences in the influence of APOE genotype (evaluated as APOE ε4 carrier status) on Alzheimer’s disease (AD) endophenotypes at various stages of disease. The purpose of this study is to examine the influence of an APOE neuropathology‐based score (APOE npscore) on the brain aging estimated from deep learning.MethodsBrain age from 274 participants (Fig. 1) in the Wisconsin‐ADRC was estimated from T1w‐MRI using a publicly available deep learning model called two‐stage‐age‐network (TSAN) that was pre‐trained on over four thousand scans from OASIS, ADNI‐I and PAC‐2019. TSAN uses a novel rank‐based loss along with mean squared loss and makes predictions in two steps which does not require a posteriori bias correction. This is a significant improvement from prior deep learning models in reducing the “regression‐to‐mean bias” typically present in brain age models. APOE genotypes (ε2ε2, ε2ε3, ε3ε3, ε2ε4, ε3ε4, ε4ε4) were weighted by the log(odds‐ratio) from a large study of autopsy‐confirmed AD cases/controls, providing a variable representing the relative amount of risk across APOE genotypes. Mood’s median test was used to examine the sex differences between the excess brain aging (EBA) as a function of the APOE npscore.Results
Fig. 2 shows the brain age predictions. Fig. 3 shows that there are significant differences between females and males in the EBA for the APOE npscore <0. Median EBA for both males and females is <0 when APOE npscore <0 suggesting protective effects of ε2 on brain aging. The median EBA >0 for both the sexes when APOE npscore ≥0.ConclusionWe report sex differences in the influence of APOE genotype on brain aging. There is heterogeneity in the differences within the ε4+ (APOE npscore >0) and ε4‐ (APOE npscore ≤0) groups. These sex differences may not be observed when using just ε4 carrier status instead of the APOE npscore. This provides evidence for a shift in paradigm for the way we analyze APOE genotype because of latent nuances of the ε4‐status influence on AD outcomes.
Comparing characteristics among ADRC cohorts stratified by percentage of autopsied cases that were normal versus demented at visit prior to death
Authors: Gauthreaux Kathryn , Nelson Peter T , Mock Charles , Kukull Walter A. 
Published: June 2023

AbstractBackgroundDementia‐enriched research studies and normal control‐enriched research studies have different recruitment models and thus may differ in clinical and demographic characteristics. These distinctions can contribute to different study findings and perspectives. We generated a novel operationalization for cohort status in NIA‐funded Alzheimer’s Disease Research Centers (ADRC), based on the proportion of research participants that were normal, or demented, prior to death. Based on that operationalization, we compared differences in the rates of several clinical features among participants who came to autopsy.MethodData were obtained from the National Alzheimer’s Coordinating Center (NACC). Eligibility criteria included participants with autopsy data available and ADRCs with > = 30 eligible participants. 31 different ADRC autopsy cohorts were thus included, and the total number of individual research participants was 6,722. The first 3 digits of participant zip codes were included in the study. ADRCs were assigned to two groups based on the proportion of participants with normal cognition to participants with dementia. The “more non‐demented “(MN; n = 18) group included ADRCs with >10% ratio of normal to dementia participants, while the “more dementia” (MD; n = 13) group included ADRCs with <10% ratio of normal to dementia participants. Clinical features and diagnoses were compared between the two groups using Pearson’s chi‐square for the categorical variables and two‐sample t‐tests for the continuous variables.ResultThe overall cohort sizes were similar between groups and clinical Alzheimer’s disease (AD) was diagnosed at similar rates in both MN and MD ADRCs. MD ADRCs had more frontotemporal lobar degeneration (FTLD) and Lewy body disease (LBD) diagnoses than MN centers, while MN centers had more cerebrovascular disease and participants were on average older at death than those in MD ADRCs. Other trends identified were that MN ADRCs had lower rates of APOEɛ4 and MD ADRCs tended to include cases from a larger number of different zip codes.ConclusionIn this sample, we found differences in clinical features between MD and MN ADRCs that probably reflect study designs related to recruitment practices. Future research examining additional features may yield further elaborate discrepancies found between these types of autopsy cohorts.
Novel mathematical modeling approach finds Fortasyn Connect affects memory through reducing hippocampal atrophy in the LipiDiDiet trial
Authors: Hartmann Tobias , van Oudenhoven Floor M , Solomon Alina , Visser Pieter Jelle , Blennow Kaj , Kivipelto Miia , Soininen Hilkka 
Published: June 2023

AbstractBackgroundLipiDiDiet is a 6‐year, randomized, double‐blind, placebo‐controlled intervention in 311 individuals with prodromal Alzheimer’s disease (AD)/mild cognitive impairment receiving the specific multinutrient combination Fortasyn Connect (Souvenaid) or a calorie‐matched placebo control once daily.1 AD is characterized by neurodegeneration including significant synapse loss, and the hippocampal formation is particularly vulnerable in the early stages of AD. Results over the first 2 and 3 years of intervention showed that Fortasyn Connect reduced hippocampal atrophy and slowed decline on clinical and other measures related to cognition, function, and disease progression.2,3 Here, possible mechanistic pathways through which the intervention may affect the risk of disease progression are being explored post‐hoc.MethodA new type of multivariate joint model was applied to the 3‐year LipiDiDiet clinical trial data in which the longitudinal outcomes MRI hippocampal volume (HCV) and neuropsychological test battery (NTB)‐memory are allowed to be associated with disease progression and dropout, and affect each other directly. Specifically, for each longitudinal outcome a linear mixed‐effects model is used to estimate its trajectory, where, for the second longitudinal outcome, the linear predictor of the first outcome is included as time‐varying covariate. Results are compared for both pathways (HCV and NTB‐memory and vice versa), and with results of existing multivariate joint models that have the form of so‐called parallel mediator models (i.e. longitudinal outcomes are merely allowed to be correlated but not to influence each other causally).ResultComparing the models, we observed a strong association between changes in NTB‐memory and disease progression and no direct treatment effect on NTB‐memory. Notably, there was a strong direct treatment effect for HCV changes, together with a direct effect of HCV on disease progression. Moreover, indirect effects of HCV changes on disease progression were mediated through NTB‐memory.ConclusionThis new multivariate joint model is useful in modeling possible mechanistic pathways. Overall results from application to the 3‐year data suggest that the observed intervention effects of Fortasyn Connect are partly mediated through reduction of hippocampal atrophy both directly and indirectly via NTB‐memory, in addition to yet to be defined other/complementary pathways.
1
Funding includes EU‐JPND.
2Lancet Neurol. 2017;16:965‐975.
3Alz & Dementia. 2021;17:29‐40.
Associations between repetitive negative thinking and segregation of the anterior salience network amongst healthy middle‐aged adults
Authors: Solé‐Padullés Cristina , Cattaneo Gabriele , Marchant Natalie L , Cabello‐Toscano María , Mulet‐Pons Lídia , Sánchez Javier Solana , Tormos‐Muñoz Josep Mª , Pascual‐Leone Alvaro , Bartrés‐Faz David 
Published: June 2023

AbstractBackgroundRepetitive Negative Thinking (RNT) includes negative thoughts about the future (worry) and past (rumination), and has been associated with AD physiopathology (Marchant et al. Alzh&Dement 2020;16:1054). Prefrontal and anterior cingulate cortices play a major role in RNT (Demnitz‐King et al., Psychiatry Res Neuroimaging. 2021;316:111353). Nonetheless, RNT involves several brain regions within large‐scale networks (Makovac et al., Psychiatry Res Neuroimaging. 2020;295:111020), the efficiency of which depends on their ability to remain segregated (Tononi et al., PNAS, 1994;91:11). We investigated associations between RNT and system segregation (SyS) of the Anterior Salience Network (ASN), Default Mode Network (DMN) and Executive Control Network (ECN) in middle‐aged adults.Method248 healthy controls (mean age: 59.17 (SD 4.79), 50.61% women) from the Barcelona Brain Health Initiative (Cattaneo et al. Front Aging Neurosci. 2018;10:321) underwent resting‐state functional magnetic resonance imaging to compute SyS using a node‐based approach with the Shirer atlas (Shirer et al., Cereb Cortex. 2012;22:1). RNT was estimated from questionnaires as previously (Schlosser et al., BMC Psychiatry, 2020;20:1), and a global RNT score was computed. Regression analyses investigated associations between RNT and SyS of ASN, DMN and ECN, including age, depression and stress ratings, emotional stability and cognitive complaints.ResultRNT was positively predicted by cognitive complaints (t = 3.18, p = 0.002) and depression (t = 6.55, p<0.0001), and negatively by emotional stability (t = ‐4.77, p<0.0001). Likewise, RNT was negatively associated with SyS_ASN (t = ‐2.57, p = 0.011; Fig1). Post‐hoc analyses revealed increased connectivity between ASN and ventral DMN (vDMN, t = 2.57, p = 0.01) and the reverse for ASN‐dorsal DMN (dDMN, t = ‐2.03, p = 0.04; Fig2).ConclusionHigher levels of RNT amongst middle‐aged subjects were related to less segregation of the ASN. Results are of importance considering that declining brain segregation predicts dementia severity (Chan et al. Nat Aging 2021;1:1053). Specifically, the ASN presented higher coupling with the vDMN (medial temporal lobe and precuneus), linked to self‐processing and autobiographical processes (Bayley et al., J Neurosci. 2006;26:51), and lower coupling with the dDMN (medial prefrontal regions) associated with cognitive control (Piguet et al., Biol Psychol. 2014;103:195). This dissociative connectivity may partially explain poorer cognitive control and increased self‐referential processes characteristic of RNT (Piguet et al., Biol Psychol. 2014;103:195).
Examining factors that influence African‐Americans and Blacks’ participation in Alzheimer’s biomarker research
Authors: Wang Sophia , Van Heiden Sarah , Saykin Andrew J. , Eliacin Johanne 
Published: June 2023

AbstractBackgroundAfrican Americans and Blacks in the US are less likely to engage in Alzheimer’s disease (AD) research studies, despite having two to three times higher risks of developing AD compared to Whites. Understanding the various factors influencing African Americans and Blacks’ participation in AD research, especially studies that involve biomarkers, is important for increasing equity in AD research, and advancing AD diagnosis and treatment for diverse populations.MethodStudy participants included 164 community‐dwelling African Americans and Blacks in the Indianapolis metropolitan area, aged 55 and older, and who had no prior participation in AD research. Participants were administered a 24‐item survey to examine their knowledge of AD, willingness to participate in biomarker research procedures (genetic testing, brain MRI, and PET Scan), and views of incentives for participation.ResultMost participants were female (68%) and had less than 16 years of education (71%). About half were 65 years old or older. Most participants (84%) reported that they did not know what caused AD or how to manage it, and only 43% were aware that “Black people are at higher risk of developing dementia, including Alzheimer’s disease, compared to Whites.” Most participants were willing to do or consider participating in biomarker procedures common in AD research studies (90% genetic testing, 86% MRI, and 82% PET scan).The majority (85%) were agreeable to future contact for research participation. Most participants viewed return of test results, particularly from cognitive testing (81%) and brain scans (82%), and information about brain health (72%) as incentives to participate in research.ConclusionOur findings revealed that older African‐American and Black participants are willing to engage in Alzheimer’s disease biomarker research study procedures. They also viewed knowledge (in the form of return of results and information about brain health) as a major incentive for participation. Our findings suggest that future outreach and recruitment strategies tailored towards African Americans and Blacks may benefit from focusing on the value of knowledge these studies can provide to participants. We also identified opportunities to educate African Americans and Blacks about their increased risk for AD and the causes and prevention of AD.
Adiposity and the risk of dementia: A population‐based study
Authors: de Crom Tosca O.E. , Mooldijk Sanne S. , Ikram M. Arfan , Ikram M. Kamran , Voortman Trudy 
Published: June 2023

AbstractBackgroundA higher body mass during mid‐life is a well‐established risk factor for dementia, while a higher body mass during late‐life has been linked to a decreased dementia risk. Yet, body mass may be an inaccurate measure of adiposity, especially in elderly. We therefore differentiated between body mass, fat mass, fat free mass, android fat mass and gynoid fat mass and examined the association between these measures and the risk of dementia. We also determined trajectories of body composition before the diagnosis of dementia.MethodIn the population‐based Rotterdam Study, body composition was measured using dual X‐ray absorptiometry every 4‐5 years between 2002‐2016. Incident dementia was recorded until 2020. We assessed the association between the first body composition measure and the risk of dementia using Cox models, adjusted for sex, age, height, education, smoking, alcohol intake, physical activity, depressive symptoms, and APOE ε4 status. Trajectories of body composition for patients before dementia diagnoses were constructed using linear mixed models and for dementia‐free participants, matched on birth year and sex. All analyses were done for men and women separately.ResultOf the 3,408 men (mean age 66.4 years) and 4,563 women (mean age 66.5 years) with at least one body composition measure available, 293 men and 526 women developed dementia during a mean follow‐up of 10.3 years. Higher body mass, fat mass, android fat mass and gynoid fat mass, but not fat free mass, tended to associate with a decreased risk of dementia in both men and women (Figure 1). After excluding the first five years of follow‐up only the association of gynoid fat mass in women remained statistically significant (hazard ratio [95% confidence interval]: 0.85 [0.75‐0.97]). No major differences in trajectories of body composition were observed, although a slight trend of a decrease in total, android and gynoid fat mass was observed in women up to 2 years before diagnosis.ConclusionA higher body mass, fat mass, android fat mass and gynoid fat mass were associated with a decreased risk of dementia. These results may be explained by reverse causality or competing risks, although a protective effect of adiposity cannot be excluded.