bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulating amyloid‐beta proteostasis in the brain of 5xFAD mice by selective expression of angiotensin converting enzyme in microglia
Authors: Gomez Andrew , Wu Shaogen , Byun Hyae Ran , Muro Alek , Muhammad AKM Ghulam , Li Lin , Tourtellotte Warren G 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease (AD) is a common and progressive neurodegenerative disease characterized by abnormalities in amyloid‐beta (Ab) proteostasis in the brain. Abnormal cleavage of Ab and aggregation into extracellular amyloid‐containing plaques is widely believed to contribute to neuroinflammation, synapse loss and neurotoxicity in AD. Microglia are brain‐resident myeloid‐lineage cells that mediate synapse homeostasis and the immune response to Ab deposition in the brain, and many Genome‐Wide Association Studies (GWAS) have identified late‐onset AD (LOAD) risk‐associated genes that are primarily expressed in microglia, suggesting their important role in disease pathogenesis (Kunkle et al., 2019, Wightman et al. 2021). Identifying signaling pathways in microglia that modulate Ab proteostasis may provide important targets for disease therapy.MethodThe gene encoding for Angiotensin Converting Enzyme (ACE) has been identified as an AD risk‐associated gene (Kunkle et al., 2019, Wightman et al, 2021), and ACE modulates the function of myeloid‐lineage cells, such as neutrophils and macrophages. ACE expression in macrophages appears to modulate their ability to decrease Ab plaque load in the brain and reverse cognitive abnormalities in AD model mice. Here, we developed a novel mouse model to express ACE specifically in microglia (RACE). We mated RACE mice to 5xFAD mice and examined the role of ACE expression in microglia using molecular, physiologic and behavioral techniques. Single nucleus RNA sequencing (10x Genomics) and digital spatial profiling on tissues sections (Nanostring GeoMx) was used to identify gene expression modulated by ACE in microglia.ResultWe find that ACE expression in microglia in 5xFAD mice increases amyloid phagocytosis, reduces plaque burden, rescues synapse and neuron loss, enhances microglial recruitment to plaques, rescues learning and memory deficits, and modulates gene expression associated with injury and autophagy in plaque‐associated microglia. Single‐nucleus RNA sequencing, proteomic profiling, synaptic plasticity, and pharmacological studies are in process to interrogate the molecular basis of ACE function in microglia.ConclusionACE expression in microglia has the remarkable capacity to restore Ab proteostasis, rescue synapse and neuron loss, and learning and memory abnormalities in 5xFAD mice. Signaling pathways and gene expression modulated by ACE in microglia may be targets for novel disease therapy.
APOE4 Carriers with Perivascular Spaces Exhibit Altered Cerebral Blood Flow
Authors: Kapoor Arunima , Dutt Shubir , Alitin John Paul M , Jang Jung Yun , Gaubert Aimée , Nguyen Amy , Sible Isabel J , Marshall Anisa J , Shenasa Fatemah , Engstrom Allie , Bradford David , Rodgers Kathleen E. , Shao Xingfeng , Wang Danny J.J. , Nation Daniel A. 
Published: December 2023

AbstractBackgroundPerivascular spaces (PVS) are fluid‐filled spaces surrounding arterioles, capillaries and venules in the brain, which support metabolic waste clearance. Enlarged PVS are associated with increased dementia risk. Changes in arterial pulsatility are hypothesized to be associated with accumulation of toxic solutes and PVS widening. However, few prior studies have examined whether cerebral blood flow (CBF) is linked to PVS.MethodIndependently living older adults (N = 60, mean age = 68.1 years; SD = 7.5; age range 55‐88 years; 30.0% male) free of dementia or clinical stroke were recruited from the community and underwent brain MRI and venipuncture. Pseudo‐continuous arterial spin labeling was utilized to determine CBF in gray matter CBF (mL/100g tissue/min). Regional mean values were determined for regions of interest. PVS were qualitatively scored in the basal ganglia (BG), and centrum semiovale (CS). APOE genotyping was conducted on the blood cell pellet fraction.ResultAfter accounting for age and sex, multiple linear regression analysis revealed a significant negative association between BG‐PVS and CBF in the left inferior occipital gyrus (B = ‐.07, 95% CI (‐.13, ‐.01), p = .022), right inferior occipital gyrus (B = ‐.06, 95% CI (‐.12, ‐.001), p = .048), left middle occipital gyrus (B = ‐.05, 95% CI (‐.10, ‐.001), p = .047), right middle occipital gyrus (B = ‐.08, 95% CI (‐.13, ‐.02), p = .007), and right inferior temporal gyrus (B = ‐.05, 95% CI (‐.09, ‐.01), p = .025) as well as a positive association in the left precuneus (B = .05, 95% CI (.01, .08), p = .022). When stratified by APOE4 status, all associations were significant only in APOE4 carriers. CS‐PVS were not associated with CBF.ConclusionThese findings indicate altered CBF in older adults with BG‐PVS but not CS‐PVS. Resting CBF was altered in specific brain regions, predominantly in APOE4 carriers. APOE4 is known to convey both vascular risk and risk for Alzheimer’s disease (AD). Additional longitudinal studies are warranted to explore the association between PVS and CBF in individuals at risk for dementia to further understand vascular contributions to the development of AD and other dementias.
Interrogating CD33 exon‐2 skipping in iPSC‐derived microglia
Authors: Murchison Angela , Schmid Benjamin , Liu Jihua , Covarrubias Stephanie , Holst Bjørn , Cribbs David H. , Poon Wayne W. 
Published: December 2023

AbstractBackgroundAD Genome‐wide association studies (AD‐GWAS) of late‐onset AD (LOAD) have identified single nucleotide polymorphisms (SNPs) within genes predominantly expressed in microglia (TREM2, TYROBP, CD33, CR1, PILRA, PLCG2, INPP5D, BIN1, MS4 gene family) or upregulated in microglia in association with disease (APOE, TREM2); these risk SNPs can either confer increased or decreased AD risk and implicate microglia function and neuroimmune mechanisms in disease etiology. One identified AD GWAS risk SNP is closely associated with the CD33 gene, confers protection, but is in linkage disequilibrium with rs12459419. The rs12459419 SNP is located at the 5′ intron‐exon junction of CD33 exon 2 and promotes exon skipping during CD33 pre‐mRNA splicing in microglia. Exon 2 skipping removes the immunoglobulin domain from full‐length CD33 (CD33M) leading to a truncated isoform (CD33‐D2).MethodHere, we generated exon‐2 deleted iPSCs (CD33Delta2/Delta2) from three patient iPSCs (CD33C/C) in order to investigate the impact of exon‐2 skipping on microglia function. These iPSC lines were differentiated to microglia in order to determine the mechanistic impact of exon‐2 skipping on microglia function.ResultExon‐2 skipping results in a microglia signature identified in the ex vivo brain.ConclusionThe interferon microglia signature may be indicative of a protective microglia phenotype that mitigates AD risk
Non‐imaging measures to predict variability in white matter changes relevant to VCID
Authors: Raghavan Sheelakumari , Przybelski Scott A. , Lesnick Timothy G. , Reid Robert I. , Fought Angela J. , Gebre Robel K , Algeciras‐Schimnich Alicia , Machulda Mary M. , Vassilaki Maria , Knopman David S. , Jack Clifford R. , Petersen Ron , Graff‐Radford Jonathan , Vemuri Prashanthi 
Published: December 2023

AbstractBackgroundSmall vessel disease (SVD) is a common vascular contributor to cognitive impairment and dementia. In this work, we evaluated and compared non‐imaging measures that can predict variability in SVD related white matter (WM) damage in a population‐based sample.MethodWe identified 752 participants in the population‐based sample of Mayo Clinic Study of Aging (≥50 years of age), who had at least 2 diffusion tensor imaging (DTI) scans and white matter hyperintensity (WMH) assessments along with baseline demographics, systemic vascular health, lifestyle, motor impairment, behavioral symptoms, and plasma markers (Summarized in Figure 1). We computed the WM markers of SVD: fractional anisotropy of genu of the corpus callosum (Genu‐FA) representative of early WM changes, WMH representative of late WM changes, and Vascular WM score (combination of Genu‐FA and WMH). Using all available data, we fit linear mixed effect models and evaluated predictors of WM markers by considering each category of features independently (with demographics) as well as by combining all categories of featuresResultPlasma, gait, systemic vascular, and life‐style measures were significant predictors of all three WM markers of SVD (Figure 2). The predictors of early and late WM slightly differed such that there were no additional significant contributions from behavioral and plasma measures to Genu‐FA. In the final composite models shown in Table 1, higher gait speed, lower number of cardiovascular and metabolic conditions (CMC) and lower Unified Parkinson’s disease rating scale scores were associated with better Genu‐FA whereas higher CMC, Beck Anxiety Inventory scores (BAI), and glial acidic protein (GFAP) levels were associated with higher burden of WMH.ConclusionOur observations evaluated the non‐imaging markers of greater WM damage that are relevant to vascular contributions to cognitive impairment to dementia (VCID). We found that in addition to higher vascular risk, worse plasma GFAP, gait measures, and BAI scores were predictors of greater WM damage. Some non‐imaging markers were more associated with early WM changes and others with late WM changes.
Mitochondrial DNA copy number predicts dementia risk with early mobility impairment
Authors: Tian Qu , Zweibaum David , Qian Yong , Pilling Luke , Casanova Francesco , Atkins Janice L , Melzer David , Ding Jun , Ferrucci Luigi 
Published: December 2023

AbstractBackgroundMobility impairment precedes Alzheimer’s disease (AD) and dementia. Potential mechanisms may involve mitochondrial dysfunction which is a hallmark of aging and links to both mobility impairment and brain health. In this study, we aimed to determine whether mitochondrial DNA copy number (mtDNA‐CN), a blood‐based marker related to mitochondrial function, would predict future dementia with and without the presence of early mobility impairment.MethodIn the UK Biobank, we estimated mtDNA‐CN using fastMitoCalc from complete Whole Genome Sequencing data at study entry. Dementia diagnoses were ascertained from medical records, including AD and non‐AD dementia. Early mobility impairment was defined as having slow walking pace by self‐report at study entry. The absence of mobility impairment was defined as having steady average or brisk walking pace. In participants who were free of dementia at study entry, we examined the association between mtDNA‐CN and future dementia with and without early mobility impairment using cox proportional hazard models, adjusted for age, sex, ethnicity, body mass index, apolipoprotein ε4 carrier status, assessment center, and technical covariates related to mtDNA‐CN.ResultAmong 188,706 participants (mean age = 56±8 years, 55% women, 94% White), 13,821 reported slow walking pace at study entry and 2,564 developed dementia (1,085 AD, 1,479 non‐AD dementia) over a mean follow‐up of 12.5 years. After covariate adjustment, each standard deviation higher mtDNA‐CN (i.e. 16) was marginally associated with a lower risk of any dementia (HR = 0.96, 95%CI: 0.91‐1.00, p = 0.063). Among those who reported slow walking pace at study entry, each standard deviation higher mtDNA‐CN was associated with a 12% lower risk of developing any dementia (HR = 0.88, 95%CI: 0.783‐0.991, p = 0.034). There was a trend toward significance for non‐AD dementia (HR = 0.87, 95%CI: 0.754‐1.01, p = 0.065), and not for AD dementia (HR = 0.89, 95% CI: 0.727‐1.09, p = 0.245). Among those without early mobility impairment, mtDNA‐CN was not significantly associated with dementia (HR = 0.97, 95%CI: 0.92‐1.02, p = 0.176).ConclusionIn a large sample of community‐dwelling adults, higher mtDNA‐CN is associated with a lower risk of developing dementia especially accompanied by early mobility impairment. Maintaining mitochondrial function in aging may protect against dementia that is preceded by mobility impairment.
Cognitive stimulation for people with dementia in nursing homes: results of a feasibility study examining a new 24/7 approach (CogStim24)
Authors: Seven Ümran Sema , Folkerts Ann‐Kristin , Guicheteau Julie , Dichter Martin , Köpke Sascha , Kalbe Elke 
Published: December 2023

AbstractBackgroundCognitive stimulation is known to be effective to enhance global cognition and quality of life in PwD, so far there is a clear undersupply with this intervention which is typically provided in guided small groups.AimTo assess the feasibility of a new continuous 24/7 cognitive stimulation program (CogStim24) based on a process evaluation and to examine possible effects of CogStim24 on the primary outcome global cognition in people with dementia (PwD) and secondary outcomes including quality of life, behavioral and psychiatric symptoms in PwD as well as work‐related quality of life and stress experiences of nursing and care staff.MethodsThe CogStim24 program is a complex intervention which was developed to be conducted as an everyday intervention during routine care, and includes cognitively stimulating techniques, e.g., based on reminiscence therapy, multisensory stimulation, and physical activity. In four nursing homes, N = 20 nursing and care staff took part in the 11‐week CogStim24 training program. The intervention was conducted to N = 40 PwD. (Neuro)Psychological assessments was conducted pre‐ and after‐staff training, as well as after a 6‐week implementation phase. A process evaluation will be performed.ResultsThe staff training and the intervention were demonstrated to be feasible in the context of a nursing home. Currently, the implementation process is evaluated and an efficacy analysis is performed.DiscussionThe study has the potential to serve as a basis for a large multicenter cluster randomized controlled trial. The interdisciplinarity and the mixed‐methods approach will help to generate detailed information on practicability and mechanisms of impact. This is important for the further development of the intervention as well as for facilitating the implementation of the intervention. PwD and nursing home staff are involved in all relevant steps of program development and evaluation. The CogStim24 24/7 approach has the potential to reach many more PwD, including those who are bedridden.
Cross‐scale functional connectivity patterns of the aging brain learned from the multi‐cohort iSTAGing study
Authors: Zhou Zhen , Li Hongming , Tran Chau B , Ma Yuncong , Srinivasan Dhivya , Abdulkadir Ahmed , Wen Junhao , Erus Guray , Mamourian Elizabeth , Nasrallah Ilya M. , Bryan Nick , Wolk David A. , Beason‐Held Lori L , Resnick Susan M. , Shou Haochang , Davatzikos Christos , Fan Yong 
Published: December 2023

AbstractBackgroundBrain functional connectivity (FC) measures derived from resting‐state fMRI (rsfMRI) data have advanced our understanding of the brain organization. However, most existing studies investigate the brain functional networks (FNs) at a specific scale, ignoring potentially complementary FC information at different levels of spatial granularity as well as the cross‐scale information. Given that the brain is a multi‐scale, hierarchical system, FCs between FNs at different spatial scales may provide complementary information to those measured within‐scales for characterizing the aging brain.MethodWe computed multiscale FNs to capture their FC measures across multiple scales and investigated the associations between cross‐scale FCs and the brain aging based on rsfMRI data of a diverse cohort (n = 4186, aged 22 to 97 years) from seven sites of the iSTAGING study [1]. For each subject, we computed the FNs at seven scales, yielding seven sets of k (k = 17, 25, 50, 75, 100, 125 and 150) FNs, same as our previous study [2‐3]. We estimated FC measures between the 542 FNs using Pearson’s correlation, yielding the cross‐scale FC matrices that were harmonized across sites in the tangent space using ComBat‐GAM [4] with sex and age as covariates. The harmonized FC measures were used as features to build an age prediction model using Ridge regression as illustrated in Figure 1. The brain age prediction model was compared with that built on harmonized FC measures between FNs of the same scales, with the performance estimated with a nested five‐fold cross‐validation.ResultThe cross‐scale FC measures performed significantly better than the within‐scale FC measures for the brain age prediction, as summarized in Table 1. Figure 2 shows the most informative FC measures for the brain age prediction. Specifically, FC measures computed both cross‐ and within‐scales between the visual, somatomotor, and frontoparietal networks provided relatively more useful information for the brain age prediction than FC measures between other FNs.ConclusionOur study demonstrated that the cross‐scale FC measures provided complementary information to the within‐scale FC measures for predicting the brain age, facilitating enhanced understanding of aging related changes of the brain functional organization.
Stable Isotope Labelling Kinetics: Models and methods to evaluate APP production rates with Posiphen treatment in the DISCOVER clinical trial
Authors: Elbert Donald L , Galasko Douglas R. , Farlow Martin R. , Aslanyan Vahan , Pa Judy , Lucey Brendan , Honig Lawrence S. , Moghekar Abhay , Bateman Randall J. , Momper Jeremiah , Rissman Robert A , Balasubramanian Archana , Maccecchini Maria L. , Feldman Howard H. ,   ADCS DISCOVER Study Group
Published: December 2023

AbstractBackgroundPosiphen has been reported to decrease translation of beta amyloid precursor protein (APP) mRNA, resulting in decreased production of Aβ.1 The pharmacodynamics of Posiphen require further clarification to better assess its therapeutic potential.MethodThe DISCOVER phase 1b placebo controlled RCT enrolled patients with MCI or mild AD dementia (age 55‐89, MMSE 17‐30, CDR = 0.5‐1.0, CSF Aβ42/40 < 0.131 by mass spectrometry) at five centers.2,3 Patients were randomized to sequential dose cohorts of oral Posiphen (60 mg; once (QD), twice (BID) or three times (TID) per day for 21 days) or placebo. SILK studies were performed during a confinement on day 22. Lumbar and venous catheters were placed and 13C6‐leucine infused for 9 hours with dosing of placebo or Posiphen according to assigned study arm. CSF and venous blood were collected every two hours over 36 hours. Pharmacodynamics of APP were evaluated via a recently described mathematical model of APP and Aβ kinetics.4
ResultAPP production rate was calculated for a total of 14 subjects (less than study design due to COVID) by the model in Figure 1. Nonparametric analysis of group differences was not significant (p = 0.08) with n = 1‐5 per group (Figure 2A). A trend towards lower CSF Aβ40 concentrations (indicative of lower intrinsic APP production rates) prior to drug exposure was noted in the higher dose groups (Figure 2B). The calculated APP production rate was thus controlled for pre‐drug CSF Aβ40 concentrations, which showed a downward trend with increasing dose (95%CI:(‐2209.58, 147.79, p = 0.08; Figure 3) but was not significant.ConclusionThis study provides preliminary evidence that the rate of production of APP may be measured by the SILK method in Aβ lowering drug trials. Variability in APP productions rates in the population suggest that CSF Aβ concentration should be considered as part of study randomization.
Associations between NTproBNP and 10‐year cognitive decline in The Irish Longitudinal Study on Ageing (TILDA)
Authors: De Looze Celine , Feeney Joanne , Fitzpatrick Annette L. , Kenny Rose Anne , O’Halloran Aisling M ,   The Irish Longitudinal Study on Ageing
Published: December 2023

AbstractBackgroundNT‐proB‐type Natriuretic Peptide (NTproBNP) is a hormone released in response to changes in pressure inside the heart often related to heart failure and other cardiac problems. Early evidence shows significant correlations between brain structure and markers of heart failure including ejection fraction and NTproBNP. We sought to investigate if levels of this biomarker are related to cognitive decline over 10 years in older adults participating in the Irish Longitudinal Study on Ageing (TILDA), a nationally representative cohort of adults aged 50 years and older residing across Ireland.MethodLevels of NTproBNP were measured in 4,105 participants, mean age 61.5 years and 53.8% women, from blood drawn at baseline (Wave 1: 2009‐2011). Verbal memory (10‐word immediate and delayed recall) and verbal fluency/ executive function (animal naming) were measured every two‐years over a 10‐year follow‐up (Wave 1 – 6) and were used to create a composite score at each wave which served as a measure of global cognitive function. Linear mixed effect models with adjustment for covariates were performed. Model 1 included age, age^2, sex, education; Model 2 included Model 1 + cardiovascular diseases (heart failure, heart attack, stroke, tia, hypertension, diabetes), lifestyle factors (smoking, alcohol, physical activity, waist‐hip ratio) and depression.ResultNTproBNP was significantly and negatively associated with cognitive function at Wave 3 (B = ‐0.13, 95%CI = ‐0.20, ‐0.05), Wave 4 (B = ‐0.24, 95%CI = ‐0.31, ‐0.16), Wave 5 (B = ‐0.25, 95%CI = ‐0.32, ‐0.17) and Wave 6 (B = ‐0.26, 95%CI = ‐0.34, ‐0.17) (p<.001) (Figure 1). After further adjustment, the associations remained significant.ConclusionThese results suggest that NTproBNP may be useful as an early indicator of cognitive decline in older adults for those with and without current cardiovascular diseases.