bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amyloid‐β plus cholesterol treatment impairs the ability of microglia to efflux excess cholesterol
Authors: Muñoz Oscar M. , Rhodes Christopher H. , Maezawa Izumi , Jin Lee‐Way , Lebrilla Carlito B. , Harvey Danielle J. , Zivkovic Angela M. 
Published: December 2022

AbstractBackgroundMicroglia, specialized phagocytic cells of the brain, play a critical role in the clearance of amyloid beta (Aβ), which is involved in the pathogenesis of Alzheimer’s disease. The ability of microglia to remove Aβ is influenced by their cellular cholesterol clearance capacity. It is not known to what extent Aβ impairs microglial cholesterol efflux capacity, especially in the context of excess cholesterol.MethodHMC3 microglia were treated with Aβ‐oligomer (AβO, 2µM), cholesterol loading (20µg), or AβO + cholesterol in combination, and with or without cholesterol acceptor, high‐density lipoprotein (HDL), at 0.1 mg/mL. Pooled HDL from 18 individuals in a 2‐hour postprandial state and a 36‐hour fasted state were compared. The cellular content of unesterified and esterified cholesterol was measured.ResultsThe addition of cholesterol, AβO, and cholesterol+AβO increased cellular cholesterol content, which was attenuated by the addition of HDL. Importantly, cells treated with cholesterol plus AβO had the highest overall cholesterol content (27.80+/‐2.85µM), and both fasted (20.67+/‐3.04µM, p≥0.05) and postprandial HDL (21.95+/‐3.84µM, p<0.05) were not able to reduce the cellular cholesterol content as well as in the untreated (fasted: 16.17+/‐2.28µM, p<0.05; postprandial: 18.55+/‐2.01µM, p>0.05), cholesterol only (fasted: 17.72+/‐2.17µM, p<0.05; postprandial: 18.14+/‐3.19µM, p<0.05), or AβO only condition (fasted: 16.80+/‐1.40µM, p<0.05; postprandial: 18.42+/‐2.05µM, p>0.05). Fasted HDL more efficiently removed cellular cholesterol in the untreated and in AβO+cholesterol treated cells. Intriguingly, cellular esterified cholesterol content was significantly lowered with fasted HDL but not postprandial HDL in both AβO alone (fasted: 5.73+/‐2.27 µM, p<0.05; postprandial: 10.32+/‐2.70µM, p>0.05) and AβO + cholesterol (fasted: 2.87+/‐2.13µM, p<0.05; postprandial: 9.03+/‐1.74µM, p>0.05).ConclusionThese findings suggest that microglia exposed to a double‐hit of AβO and excess cholesterol experience an impaired ability to efflux excess cholesterol. Additionally, HDL from fasted individuals displayed an enhanced capacity to efflux cholesterol, especially in microglia dually encumbered by AβO + cholesterol. Further studies are needed to examine the impact of this diminished cholesterol efflux capacity and cholesterol accumulation on the phagocytic capacity of microglia.
African‐ancestry based polygenic risk scores improve Alzheimer disease risk prediction in individuals of African Ancestry
Authors: Akgun Bilcag , Hamilton‐Nelson Kara L. , Kushch Nicholas A. , Adams Larry D. , Starks Takiyah D. , Martinez Izri , Laux Renee A. , Whitehead Patrice L. , Kunkle Brian W. ,   Alzheimer’s Disease Genetics Consortium (ADGC), Cuccaro Michael L. , Vance Jeffery M. , Reitz Christiane , Byrd Goldie S. , Haines Jonathan L. , Beecham Gary W. , Pericak‐Vance Margaret A. , Rajabli Farid 
Published: December 2022

AbstractBackgroundPolygenic risk scores (PRS) may be a useful approach to predict the risk of the complex disease and to be an important clinical tool for early intervention. PRS studies in Alzheimer Disease (AD) have focused on individuals of European Ancestry resulting in a >75% prediction accuracy. PRS generated from genome wide data in one population often provides reduced predictive accuracy in other populations. This is particularly problematic for underserved groups. In this study, we assessed and compared the PRS prediction accuracy of AD in individuals of African Ancestry (AA) using both AA and non‐Hispanic White (NHW) Genome Wide Association (GWAS) studies.MethodAs part of the Research in African American Alzheimer Disease Initiative (REAAADI) and ADGC, two TOPMED imputed AA datasets were generated (REAAADI:AD=234, cognitively unimpaired (CU)=676 and ADC9: AD cases=109, CU=224). We assessed the PRS using the effect sizes from summary statistics from the NHW (Kunkle et al. 2019) and the AA (Kunkle et al. 2021) studies. To model the effect of APOE we excluded APOE region in PRS constructing and included APOE alleles as separate terms in the prediction model. First, we generated PRS scores on the REAAADI dataset, and validated our model in ADC9 dataset. To assess the PRS performance, we employed the logistic regression modeling (covariates‐only (age, sex, and PC1:3),PRS‐only, and full (PRS+APOE+covariates) model) to construct receiver operator (ROC) curves.ResultEuropean ancestry‐derived PRS has the poor prediction power (AUC=0.53) in the REAAADI dataset whereas the AA‐derived PRS predicts better (AUC= 0.87). Further validation of the AA PRS in ADC9 dataset using covariates‐only, PRS‐only and full modelsvalidated that inclusion of African ancestry derived PRS significantly improves the accuracy of AD prediction in AA individuals (AUCcovariates‐only=0.59; AUCPRS‐only=0.74 and AUCfull=0.81).ConclusionOur results showed that AA‐derived PRS significantly improves AD risk prediction in AA individuals over European ancestry‐derived PRS. Our findings demonstrate the importance of increasing the diversity in genetic studies to improve precision medicine approaches. Moreover, the development of more accurate PRS models that can detect the risk of AD in all in all groups paves the way for more accurate prevention, early detection, and intervention of AD.
Differential associations of amyloid and tau (from PET) with brain volumes (from MRI) by cognitive status
Authors: Woodworth Davis C. , Corrada Maria M. , Kawas Claudia H. , Sajjadi S. Ahmad 
Published: December 2022

AbstractBackgroundAlzheimer’s disease pathology (AD) is an important cause of neurodegeneration and brain atrophy. Non‐AD mechanisms can also cause neurodegeneration alone or in conjunction with AD. Harboring combination of AD and non‐AD pathologies leads to greater cognitive impairment and dementia. Here, we examined the hypothesis that the association of amyloid and tau burden from positron emission tomography (PET) with brain volumes from magnetic resonance imaging (MRI) is weaker in those with dementia compared to those with mild cognitive impairment (MCI) or normal cognition.MethodWe used data from participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who had either florbetapir amyloid PET (N=1320) of flortaucipir tau PET (N=833, 535 of whom had both). We examined the association between volumes of brain structures (FreeSurfer‐v7) and standardized uptake value ratios (SUVr) for amyloid (summary cortical region, normalized to whole cerebellum) and tau (meta‐temporal region, normalized to inferior cerebellar gray matter) separately, using linear regressions adjusting for age, sex, and education. We report results in overall groups and by cognitive status (normal, MCI, dementia). We display semi‐partial correlations (sr, thresholded at Puncorrected<0.05), as measures of effect size.ResultTable‐1 summarizes participant characteristics. The effect of amyloid on brain volumes was modest in the overall cohort, with associations strongest for inferior/middle temporal, inferior parietal, entorhinal, hippocampus, and amygdala regions (sr∼‐0.2, P<0.001 all). In those with dementia, however, there were no distinct associations between amyloid and brain atrophy (Figure‐1). For tau, associations in the overall cohort were similarly strongest for inferior/middle temporal, inferior parietal, entorhinal, hippocampus, and amygdala regions (sr∼‐0.3, P<0.001 all). In those with dementia, associations remained strong for inferior/middle temporal regions (sr∼‐0.3, P<0.001) but tau was not associated with hippocampus volumes (left, sr=‐0.05, P=0.6; right, sr= ‐0.12, P=0.14, Figure‐2); this divergence is further highlighted in select regions (inferior temporal and hippocampus) in Figure‐3.ConclusionWe found that the relationship between amyloid and tau burden and atrophy was stronger in the overall cohort than in participants with dementia. This was particularly the case for medial temporal lobe structures. The effect of non‐AD pathologies on medial temporal lobe atrophy is a potential explanation for the observed results.
Preparation and qualification of soluble amyloid beta oligomers for use in bioanalytic assays supporting Alzheimer’s disease therapeutics
Authors: Cline Erika N. , Vanderstichele Hugo Marcel , Johnson Derrick , Abdeen Sanofar Jainul , McDermott Paul , Cruse James , Viola Kirsten L. , Dean Robert A , Jerecic Jasna 
Published: December 2022

AbstractBackgroundSoluble amyloid beta oligomers (sAβOs) accumulate early in Alzheimer’s disease (AD) and trigger AD‐related neuropathologies and impairments in memory. sAβO structures contributing to the neurotoxic effects remain ill‐defined due to their low concentration, instability, and heterogeneity, impeding the effective design and use of sAβO reference standards in bioanalytic assays for use in clinical trials. At present, no assays for sAβOs are available with proven robustness and clinical performance, due to absence of well‐characterized critical raw materials (antibodies, reference materials for preparation of sAβO calibrators) and quality control specimens.MethodWe have used amyloid‐derived diffusible ligands (ADDLs), a synthetic model preparation commonly used in the literature (Stine et al. 2003), as a sAβO standard integrated into different assays designs developed on the Mesoscale Discovery (MSD) technology. As proof‐of‐concept, we have utilized these ADDL assays to study the specificity and selectivity of antibodies targeted against sAβOs.ResultOptimization of ADDL coating, stabilization of coated materials, and long‐term plate stability indicated that ADDL‐coated plates provided a suitable platform to assess the performance of sAβO‐targeting antibodies.Prior to coating, ADDL preparations were tested for reproducible SDS‐stable size distribution and immunoreactivity using SDS‐PAGE with silver stain and Western immunoblotting. The native size distribution (SEC) and globular conformation (AFM) of ADDLs and their ability to bind neuronal synapses in culture (ICC) and subsequently elicit AD‐related pathologies has been well reported in the literature. ADDLs were coated onto 96‐well MSD plates and the ADDL‐coated plates were stored at 4 °C for long‐term use; plate stability was confirmed up to one year. Biotinylated and non‐biotinylated sAβO‐targeting antibodies with variable selectivity towards monomeric or oligomeric Aβ species were used for comparative binding analysis. Additional sAβO preparations, including low concentration ADDL preparations and commercially available sAβOs were used to further understand the selectivity and specificity of the panel of sAβO‐targeting antibodies.ConclusionQualified sAβO preparations (ADDLs) can be used as tools for coating plates to determine specificity and selectivity of sAβO‐targeting antibodies. Other expected uses are: (i) calibrator in immunoassays; or (ii) to screen for the presence of sAβO auto‐antibodies in biological fluids.
Improving movement confidence of people with dementia using gaming
Authors: Astell Arlene J. , Dove Erica 
Published: December 2022

AbstractBackgroundPeople living with dementia face increased risk of falls due to balance impairment and falling‐related psychological factors, such as fear of falling and lack of confidence. Improving movement confidence could improve balance and impact fall risk. This study set out to examine movement confidence of people living with dementia while playing a digital bowling game.MethodSixty‐six people (34F/32M) with dementia (mean MoCA 12.7/30), completed a formal balance measure (mini‐BEST or Sharpened Romberg) before and after participating in a 20‐session (2x per week) digital bowling game. Samples of video recordings of the bowling sessions were analysed by two raters, using a coding scheme developed to examine movement confidence.ResultFormal balance measures confirmed that the majority of participants were substantially impaired in several domains, including reactive postural control (mini‐BEST) and balance with eyes open (Sharpened Romberg). By contrast movement confidence during game play started at a high level in several domains such as optimal walking and fluency of motion and remained high throughout.ConclusionMovement confidence can be observed when people with dementia are playing a physical game and contrasts with their performance on formal measures. This may be due to game playing focusing attention onto the game activity, whereas formal assessment focuses on completing the specific movements under assessment. The results highlight the potential of exergames to improve movement confidence and target balance to reduce fall risk of people living with dementia.
Alzheimer‐like biomarker heterogeneity in a preclinical elderly birth cohort: Insight46
Authors: Garcia Mar Estarellas , Young Alexandra L. , Keuss Sarah E , Alexander Daniel C. , Schott Jonathan M 
Published: December 2022

AbstractBackgroundTwo main complexities of Alzheimer’s Disease (AD) arise from pathological changes (such as amyloid accumulation) occurring a decade or more before symptom onset, and AD being a highly heterogeneous disease with various clinical subtypes. Subtype and Stage Inference (SuStaIn), a data‐driven modelling technique, has been previously applied to ADNI to better understand AD. Here we apply SuStaIn to Insight46, a sub‐study of the British 1946 Birth Cohort to detect different trajectories of preclinical neurodegeneration.MethodSuStaIn was applied to cross‐sectional MRI, amyloid PET, plasma biomarkers, and cognition (Preclinical Alzheimer Cognitive Composite [PACC]) from 466 study members (Table 1). 376 Amyloid‐negative individuals (computed as Lane et al. 2019) were designated as controls. SuStaIn subtypes were also estimated in ADNI (N=789; Tables 1 and 2) for comparison. T‐tests and Chi‐squared tests were used to assess subtype differences in baseline APOE, amyloid status, white matter hyperintensity volume (WMHV), and rates of change in whole brain, ventricular and hippocampal volume calculated using the boundary shift integral.ResultFigure 1 shows three subtypes uncovered by SuStaIn: ‘Typical’, ‘Subcortical’ and ‘Cortical’. The ‘Typical’ subtype appears to reflect a typical AD progression pattern, with early involvement of Aβ40/42 ratio and Neurofilament light (NFL), followed by the PACC and finally, plasma tau. MRI volumetric changes appear later. Both ‘Subcortical’ and ‘Cortical’ subtypes are characterised by earlier abnormality in MRI volumes.Figure 2 shows that subjects assigned to the ‘Cortical’ subtype had significantly higher WMHV than the other two subtypes (p‐value < 0.002). No other significant differences in baseline characteristics were found.Figure 3 shows ‘Typical’ subtype has significantly higher rates of ventricular expansion and whole brain atrophy compared with ‘Subcortical’ subtype (p‐values = 0.001).ConclusionThis study reveals three different subtypes (‘Typical’, ‘Subcortical’ and ‘Cortical’) of presumed neurodegeneration in an elderly, preclinical cohort; these are consistent with those found in AD patient cohorts, e.g. ADNI, meaning that these methods may have utility in population based cohorts. These results suggest that SuStaIn may be helpful in determining different subtypes of neurodegeneration at a very early stage with implications for recruitment to, and powering of, clinical trials.
Progranulin upregulation by antisense oligonucleotides targeting regRNAs for treatment of FTD‐GRN
Authors: Aydemir Yeliz Yuva , Abdullatif Ali Al , Ramaswami Gokul , Golczer Gabriel , Akerberg Brynn , Weinstein Jenna , Nishi Yuichi , Pai Rutuja , Cohick Evan , Matthews Bryan , Liu Yuting , Giagtzoglou Nikolaos , Bumcrot David , Sehgal Alfica 
Published: December 2022

AbstractBackgroundHeterozygous mutations in progranulin (GRN) gene leading to progranulin protein (PGRN) haploinsufficieny are the major genetic cause of GRN‐related frontotemporal dementia (FTD‐GRN)1, 2 and 3. Decreased levels of PGRN disrupt lysosome homeostasis, cause aberrant microglia activation and neuronal cell death resulting in progressive behavioral changes, language deficits and memory impairment4. We hypothesize that upregulation of PGRN in both neuronal cells and microglia would be effective for treating FTD‐GRN patients.MethodRegulatory RNAs (regRNAs) are a class of noncoding RNAs that modulate gene transcription. We have developed an RNA Actuating Platform (RAPTM) that identified regRNAs and enables tunable upregulation of genes by specific targeting of regRNAs with antisense oligonucleotides (ASOs).ResultOur platform identified shared GRN regRNAs in human iPSC‐derived neuron and microglia like cells (iMGLs). ASOs targeting shared regRNAs were screened in a human neuroblastoma cell line to identify lead ASOs that upregulate GRN at least 2‐fold. We showed that the lead ASOs upregulate GRN in both human iPSC‐derived neurons and iMGL cells. Moreover, this level of GRN upregulation was sufficient to rescue staurosporine‐induced toxicity in FTD‐GRN patient iPSC‐derived neurons.Furthermore, we identified mouse Grn regRNA‐targeting ASOs that upregulate Grn transcription 2.5‐fold in mouse neuroblastoma cell lines and primary neurons. We tested these ASOs for efficacy in an FTD‐GRN mouse model (Grn+/tm1.1Far
)5 by intracerebroventricular injection. Grn upregulation is observed across disease‐relevant brain regions, including cortex in the Grn haploinsufficient mice.ConclusionHere, we describe the development of oligonucleotide drug candidates that target regRNAs to upregulate GRN expression as a therapeutic approach for FTD‐GRN. We believe that our strategy will restore secreted and lysosomal PGRN levels in both microglia and neurons thereby decreasing neuroinflammation and neurotoxicity. We are developing these oligonucleotides as a disease modifying treatment for patients with FTD‐GRN.
Ante mortem imaging of cortical microstructure relates to post mortem locus coeruleus hypopigmentation in autopsy‐confirmed Alzheimer’s disease
Authors: Torso Mario , Ridgway Gerard R , Hardingham Ian , Chance Steven A ,   National Alzheimer’s Coordinating Center,   for The Alzhemer's Disease Neuroimaging Initiative
Published: December 2022

AbstractBackgroundSeveral lines of evidence indicate that Locus Coeruleus (LC) abnormalities occur early in Alzheimer’s disease and are linked to tau pathology. However, the mechanisms underlying alterations in LC structure and function, and their contributions to pathogenesis and disease progression remain unclear. We investigate ante mortem cortical microstructural changes in patients with autopsy‐confirmed Alzheimer’s disease neuropathological changes (ADNC), stratified by Locus Coeruleus hypopigmentation (LCh).MethodParticipants with intermediate or severe ADNC and ante mortem MRI were obtained from the National Alzheimer's Coordinating Center (NACC; n=29) and the Alzheimer's Disease Neuroimaging Initiative (ADNI; n=6). Participants were grouped by LCh severity (15 with none/mild and 20 moderate/severe).Structural and diffusion MRI (dMRI) were used to calculate cortical mean diffusivity and three novel cortical diffusivity measures, at whole‐brain and regional levels: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+).Clinical, demographic and MRI data were used to characterize groups. Group differences in diffusion metrics were tested with a linear model, adjusting for age, interval between scan and date of death, site‐ID, number of dMRI images, and diffusion b‐value, with false discovery rate correction (pFDR<0.05).ResultThe more severe LCh group was significantly younger; no significant differences were detected for cortical or hippocampal volumes, cortical thickness, CDR or MMSE. At whole‐brain level, more severe LCh exhibited significantly higher PerpPD and ParlPD. The regional investigation revealed a widespread pattern of higher PerpPD, while ParlPD showed significantly higher values mainly in parieto‐occipital regions (Figure1).ConclusionTogether, these findings suggest that LCh severity might contribute to different patterns of cortical microstructural changes in individuals with the same ADNC severity. The more severe LCh group was significantly younger, consistent with the idea that noradrenergic hyperactivity in a more impaired LC might accelerate the spreading of AD neuropathology due to an influence of noradrenergic projections (Weinshenker, 2018). Cortical microstructural measures from dMRI could help stratify patients in clinical trials based on patterns linked to noradrenergic dysfunction, supporting pharmacological treatment focused on hyperactivities of the noradrenergic system.
Cardiac function and neuropathological substrates on MRI across age span: A Cross‐Cohort Collaboration (CCC)
Authors: Yaqub Amber , Wolters Frank J. , Collaboration Cross‐Cohort 
Published: December 2022

AbstractBackgroundCardiac dysfunction has been linked to an increased risk of dementia. However, the underlying pathophysiological substrates remain largely unspecified due to considerable heterogeneity in prior studies. We aggregated data from seven community‐based studies within the Cross‐Cohort Collaboration, to study the association between cardiac function and brain health.MethodsParticipants from all cohorts underwent echocardiography to assess systolic function (left ventricular ejection fraction (LVEF)) and diastolic function (EA‐ratio, deceleration time (DT)). High‐resolution brain MRI was performed to compute volumes of total brain (TBV), gray matter, white matter, hippocampus, and white matter hyperintensities (WMH). We used multivariable linear regression models to determine the association of echocardiographic measures and clinical heart failure with brain volumes, pooling the results using random‐effects meta‐analysis.ResultsAmong 10,307 individuals (median age: 62.5 years [54.7 – 70.5]; 54.9% women), moderate to severe systolic function was associated with lower total brain volume (beta per 1‐SD decrease: ‐0.18; 95%CI [‐0.32 ‐ ‐0.04], I2=36%), most profound for white matter and hippocampal volumes. Impaired relaxation in the diastolic phase was associated with smaller total brain volumes (‐0.10; 95%CI [‐0.16 ‐ ‐0.04], I2=2%), again driven by white matter and the hippocampi. Restrictive diastolic function similarly predisposed to lower hippocampal volume (‐0.16; 95%CI [‐0.31 ‐ ‐0.01], I2=0%). Diastolic dysfunction, but not systolic function, was associated with higher volume of WMH (0.03; 95%CI [0.01‐0.05]; I2=0% for DT). Of 8055 participants with clinical data, 277 (3.4%) had heart failure, which was related to all lower brain volumes. These results were consistent across cohorts. In stratified analyses, higher LVEF was associated with higher TBV, from age 50‐59 years onwards up until the oldest age category (80+ years), including larger hippocampi (0.04; 95%CI [0.00‐0.08]; I2=0%) for those aged between 50‐59 years.ConclusionCardiac dysfunction is associated with brain imaging markers of neurodegeneration in community‐dwelling individuals from midlife to late‐life. Preservation of cardiac function may be an additional target to promote cognitively healthy ageing.