bluuebunny/crossref_metadata_2025_split huggingface dataset:
The cardiovascular risk factors, aging and dementia risk score and Australian national university Alzheimer’s disease risk index among Ethiopians
Authors: Gugssa Seid Ali 
Published: December 2023

AbstractIntroductionThe burden of dementia is highest in LMICs, and the dementia prevention potential is greater than in high‐income countries. However, the burden of modifiable dementia risk factors is not determined in Ethiopia. The objective of this study is to determine the need for personalized dementia risk reduction among high risk patients in Ethiopia using the Cardiovascular Risk Factors, Aging and Dementia Risk Score (CAIDE) and Australian National University Alzheimer’s Disease Risk Index (ANU‐ADRI) for midlife and late life.MethodsOf the 381 participants in the Amharic Dementia Tool –Ethiopia, 182 (48%) were at their midlife (40‐64 years of age) and studied for CAIDE, and 200 (52%) were at their late‐life (65‐90 years of age) and studied for ANU‐ADRI. Baseline data was collected on exposure to 6 of the 7 risk factors included in the CAIDE study and to 10 of the 12 risk factors included in the ANU‐ADRI study.ResultsThe mean midlife CAIDE score was 6.97 (SD 2.1), and a quarter of midlife study participants (25.5%) had a score value of 9‐12. The mean late life ANU‐ADRI score was 15.3 (SD 11.9) for males and 14.2 (SD 8.5) for females respectively.ConclusionA quarter of midlife CAIDE study participants of our study have a higher risk of progressing to dementia. The calculated mean ANU‐ADRI score 15.3 (SD 11.9) for our study was lower than the calculated mean ANU‐ADRI score for the Rush Memory and Aging Project 20.3 (SD 11.78), and the Kungsholmen Project 32.38 (SD 7.67), but higher than the calculated mean for the Cardiovascular Health Cognition Study 8.86 (SD 8.77). We strongly propose the need for the establishment of Brain Health Services (BHS) in Ethiopia alongside with the memory clinic to assess risk, risk profiling and communication, and interventions.
Investigating the Associations of Cardiovascular Risk Factors, Conditions, and Interventions with Cerebrovascular Diseases: The 90+ study
Authors: Rajmohan Ravi , Al‐Darsani Zeinah , Ho ChuChing , Wong Joey , Montine Thomas J. , Corrada María M. M. , Kawas Claudia H. 
Published: December 2023

AbstractBackgroundIn the oldest‐old (those >90 years) cerebrovascular diseases are highly prevalent and independently associated with dementia. Although cardiovascular risk factors like hypertension (HTN), hyperlipidemia (HLD), and diabetes mellitus (DM) are thought to be major contributors to the development of cerebrovascular diseases, autopsy studies in the oldest‐old show weak associations with HTN, no association with DM, and HLD remains understudied. We expanded upon existing studies by investigating the associations of cardiovascular risk factors, conditions, interventions, and APOE genotype with the presence of cerebrovascular diseases in participants >90‐years‐old.MethodsParticipants are from The 90+ study, a population‐based epidemiology study of dementia and aging whose participants were survivors of the Leisure World cohort (n = 267). The self‐reported cardiovascular risk factors were DM, HLD, and HTN. Cardiovascular conditions were arrhythmia, coronary artery disease, congestive heart failure (CHF), heart valve disease, myocardial infarction, stroke, and transient ischemic attack. Cardiovascular interventions were coronary artery bypass, pacemaker placement, and statin use. Cerebrovascular diseases were arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy (CAA), and microvascular lesions (MVLs) on autopsy. Neuropathologic evaluation followed NIA‐AA guidelines. We investigated the association between individual cardiovascular risk factors, conditions, interventions, and APOE genotype with individual cerebrovascular pathologies using logistic regressions adjusted for age of death, sex, and education.ResultsParticipants were on average 98.1 years at death and 75% were female (Table 1). None of the cardiovascular features were associated with arteriolosclerosis or atherosclerosis (Figure 1). APOE‐ε4 was positively associated with CAA [OR = 3.62] while DM [OR = 0.23] and statin use [OR = 0.57] were negatively associated (Figure 2). CHF was negatively associated with the likelihood of MVLs [OR = 0.39] (figure 2).ConclusionsCardiovascular risk factors were not associated with cerebrovascular pathologies in our age group, leading to three potential interpretations: 1) they are not risk factors for cerebrovascular pathologies, 2) they have been mitigated through treatment, or 3) they are not associated due to survival bias, as these conditions reduce life expectancy. Associations of APOE‐ε4, DM, and statin use with CAA may relate to β‐amyloid metabolism while CHF’s negative association with MVLs may relate to decreased blood pressure variability. These initial findings on the limited associations warrant further exploration.
1. Validity and reliability of CAMCOG‐DS2 and other cognitive outcomes measures for clinical trials of AD in DS
Authors: Baksh Asaad , Strydom Andre , Tamayo‐Elizalde Miren , Fortea Juan , Benejam Bessy , Zaman Shahid , Beresford‐Webb Jessica , Rebillat Anne‐Sophie , Levin Johannes , Loosli Sandra V. , McCarron Mary , McGlinchey Eimear , Langballe Ellen Melbye , Larsen Frode Kibsgaard , Pape Sarah , Coppus Antonia , Ivain Phoebe , Baldimtsi Eleni 
Published: December 2023

AbstractBackgroundDown syndrome (DS) is an important population to include in clinical trials aiming to prevent or delay Alzheimer’s disease (AD). This talk will summarise previous work in trajectory modelling to identify the earliest ages of change in cognition and the optimal sample sizes needed for clinical trials in DS. It will present validate data on the new version of the Cambridge Cognitive Examination–Down syndrome version II (CAMCOG‐DS‐II) alongside established cognitive tests. The CAMCOG‐DS‐II has been developed to assess cognitive impairments associated with dementia in people with DS.MethodThis was an observational, multicentre, longitudinal study (n = 174) across seven existing cohorts in six different European languages to validate cognitive tests in adults with DS aged 25 years and older. It assessed the relationships between tests of cognition, behaviour, function, and health. Cognitive assessments included the CAMCOG‐DS‐II, the CANTAB Paired Associates Learning (PAL) Task, the modified Cued Recall Test (mCRT) and the Purdue Pegboard Test. We examined correlations between tests, group differences between those with and without dementia and explored test‐retest reliability of the CAMCOG‐DS‐II.ResultOur results showed that completion rates for the CAMCOG‐DS‐II were high, and floor and ceiling effects were low. The CAMCOG‐DS‐II memory sub‐score correlated significantly with the mCRT total recall score (Spearman’s ∼0.5), and the praxis sub‐score significantly correlated with the Purdue Pegboard total score (Spearman’s >0.7).ConclusionThere is currently a critical lack of suitable diagnostic and outcome measures that can be used in clinical trials. These results show that the CAMCOG‐DS‐II is a feasible test of cognition and will help to provide sensitive cognitive endpoints for clinical trials which are seeking to find suitable treatments for AD in adults with DS. Future analysis will include trajectories of change from baseline to one year of follow up for each primary outcome measure.
Examining the interplay between AD pathology and intracellular/extracellular properties of cortical tissue in preclinical AD
Authors: Hosseini Hadi , Avelar‐Pereira Bárbara , Gozdas Elveda 
Published: December 2023

AbstractBackgroundAD pathology affects neuronal microstructural decades before clinical manifestation of the disease. Amyloid plaques and tau tangles are key contributors to alterations in brain microstructural properties such as neurite morphology and axonal transport and packing, among others. It takes many years for these microstructural changes to build up and be reliably detected using volumetric MRI measures of neurodegeneration. Here, we examined the utility of neurite imaging – a biologically inspired model for examining cortical microstructure – to examine the impact of amyloid and tau pathology on intra‐ and extra‐cellular properties of cortical tissue and to further improve our mechanistic understanding of AD development.MethodWe utilized multimodal imaging data collected as part of ADNI‐3 including structural, multi‐shell diffusion MRI, and amyloid (18F‐florbetapir) and tau (18F‐flortaucipir) PET. The sample included 90 cognitively normal older adults (CN:23/67 amyloid‐positive/negative, age = 72.0(8.8) years) and 65 older adults with mild cognitive impairment (MCI: 36/29 amyloid‐positive/negative, 73.3(7.2) years). Neurite orientation dispersion and density imaging (NODDI) measures including intracellular volume fraction (ICVF), neurite orientation and dispersion index (ODI) in gray matter, standardized uptake value ratio (SUVR) for amyloid/tau PET and cortical thickness were extracted for 360 regions defined by surface‐based HCP atlas. We performed mediation analyses to examine the interplay between AD pathology and intracellular/extracellular properties of brain tissue and also compared the clinical utility of cortical neurite measures against volumetric MRI in detecting brain changes associated with AD pathology (tau burden) in preclinical AD.ResultMediation analyses showed that tau burden mediates the impact of amyloid on intracellular properties of brain tissue (ICVF) in medial and lateral temporal structures (Fig.1A) whereas ODI is a significant mediator of the effect of extracellular amyloid accumulation on intra‐cellular tau burden in entorhinal cortex (Fig.1B) in amyloid‐positive older adults. Further, among the regions with highest tau burden in amyloid‐positive CN group, ICVF changes in lateral temporal cortex successfully distinguished preclinical AD from amyloid‐negative CN and was associated with tau pathology.ConclusionOverall, these preliminary results suggest that accumulation of amyloid plaques results in reduction of neurite complexity while build‐up of tau reduces the intracellular volume fraction in preclinical stage of AD.
Unraveling the transcriptomic landscape of healthy aging
Authors: Girdhar Kiran , Bendl Jaroslav , Hoffman Gabriel E , Lee Donghoon , M Prashant N , Bennett David A. A , Haroutunian Vahram , Fullard John F , Roussos Panos 
Published: December 2023

AbstractBackgroundAging leads to physiological deterioration and structural changes in the human brain that might lead to cognitive decline. Also, aging in the brain has been associated with a decrease in the number of neurons and synapses. Additionally, the risk of developing neurodegenerative diseases such as Alzheimer’s and Parkinson’s increases with age. This close relationship between aging and neurodegenerative diseases suggests the existence of common molecular mechanisms that regulate gene expression in specific cell types in the brain. It has been challenging to identify these cell specific changes using current gene expression data, as it tends to be confounded by cellular heterogeneity.MethodHere we generate and analyze single‐nucleus RNA libraries from prefrontal cortex of n = 269 postmortem controls of age ranging from 2.5‐100 years from various ethnic groups (n = 153 Caucasian, n = 93 Afro‐American, n = 19 Hispanic, n = 4 Asian). Based on age, we stratified the samples into 5 stages ranging from 1) 2.5‐12 years, 2)13‐39 years, 3) 40‐59 years, 4) 60‐80 years and 5) >80 years to compare the transcriptomic changes.ResultWe compared changes in gene expression in different cell types across 5 stages and identified genes that changed as a function of age. We also looked at sex‐specific transcriptomic changes across these stages. After that, we used age specific genes to predict the biological age of samples across all cell types. Finally, we used a method called WGCNA (weighted gene co‐expression network analysis) to investigate specific molecular mechanisms that are unique to each stage.ConclusionOur study provides the comprehensive view of changes in specific cell types that underlies the aging process. Also, provides a cell‐specific list of biomarkers for every stage that can predict normal age that has no effect of disease and is independent of chronological age.
Estimation of Long‐term Care Utilization and Lifetime Distribution of Medical Cost for Dementia in Korea
Authors: Lee Jun Hong 
Published: December 2023

AbstractBackgroundTo investigate the current status of long‐term care services for patients with dementia and lifetime medical costs for dementia in South Korea.MethodThis study utilized the National Health Insurance Service‐National Health Information Database (NHIS‐NHID) from January 2017 to December 2021. The prevalence and incidence of dementia was estimated by extracting people who were diagnosed and treated with dementia (age ?45 years) from the database. The use of long‐term care services for the elderly with newly diagnosed dementia was also investigated. Additionally, the lifetime medical expenses for dementia were estimated using data on single year’s medical costs, population data, and a life table from Statistics Korea.ResultThe prevalence of dementia increased over three years from 2015 to 2017, while the incidence of dementia gradually decreased. Among the patients with newly diagnosed dementia, approximately 30% used the long‐term care services, while 4th graders accounted for the highest proportion every year. The older the age and the lower the income quartile, the shorter the time it took to apply for long‐term care services after diagnosis of dementia. The total medical expenses per capita increased steadily every year, and the lifetime medical expenses were higher for females than males. Half of the lifetime medical costs of dementia occurred after 67 years of age for males and 83 years for females.ConclusionThis study suggests that medical, social, and political measures are needed to effectively manage long‐term care service recipients and prepare for rising medical costs for dementia.
A human stem cell model of development and pathology of basal forebrain cholinergic neurons
Authors: Martinez Jose , Xu Ke , Bhattacharyya Anita 
Published: December 2023

AbstractBackgroundBasal forebrain cholinergic neurons (BFCNs) in the nucleus basalis regulate attention, memory, learning and processing of information related to cognitive function throughout the lifespan. Degeneration of BFCNs is strongly correlated with cognitive function and degeneration of the BFCN projection system is an early event in Alzheimer’s disease (AD) pathogenesis and in Down syndrome (DS, trisomy 21) that is characterized by intellectual impairment at birth and AD pathology in middle age. Understanding the vulnerability of BFCN neurons will help us understand the underlying mechanisms of neurodegeneration in both AD and DS.MethodWe generated BFCNs from trisomy 21 induced pluripotent stem cells (iPSCs) and isogenic controls through addition of morphogens and growth factors following developmental principles. The efficiency of the protocol was assessed through immunofluorescence for choline acetyl transferase (ChAT).ResultWe established a protocol to generate BFCNs from control and trisomy 21 iPSCs through a stepwise process of 1) ventralization of neural progenitors with SHH or SHH agonist, 2) regulation of LHX8 expression with NGF and, 3) regulation of ISLET1 expression and BFCN survival with BMP9. The protocol generated approximately 60% BFCNs from both trisomy 21 and control iPSCs.ConclusionFew differentiation protocols have been established to derive BFCNs from iPSCs. Our iPSC model enables analysis of pathological markers, identification of disrupted molecular pathways, manipulation of conditions to affect neurodegeneration and screening of potential therapeutics in human BFCNs.
Visceral Abdominal Adipose Tissue and Insulin Resistance Respectively Influence Alzheimer Disease Amyloid Pathology and Neurodegeneration in Midlife
Authors: Dolatshahi Mahsa , Commean Paul K. , Nguyen Caitlyn , Ippolito Joseph , Benzinger Tammie L.S. , Raji Cyrus A. 
Published: December 2023

AbstractBackgroundObesity and adiposity at midlife, evidenced by high body mass index (BMI), are increasingly understood as a risk factor for Alzheimer’s disease (AD). Importantly, visceral fat is known to be associated with insulin resistance and proinflammatory state, the mechanisms involved in AD pathology. Herein, we aimed to assess the association between brain MRI volumes as well as amyloid and tau uptake with obesity, insulin resistance, and abdominal adipose tissue in cognitively normal midlife population.MethodA total of 34 middle‐aged (age: 51.27 ± 6.12 years, BMI: 32.28 ± 6.39 kg/m2), cognitively normal participants, underwent bloodwork, brain and abdominal MRI, as well as amyloid and tau PET scan. Homeostatic Model Assessment for Insulin Resistance (HOMAIR) > 1.9 was used as a measure of insulin resistance. Visceral and subcutaneous adipose tissue (VAT, SAT) were semi‐automatically segmented using VOXel Analysis Suite (Voxa). FreeSurfer 7.1.1 was used for automatic segmentation of cortical and subcortical brain regions using a probabilistic atlas. Dynamic amyloid imaging was performed with a bolus injection of ∼15 mCi of [11C]PiB, followed by a 60‐min scan. A single intravenous bolus of between 7.2‐10.8 mCi of AV‐1451 was administered. Data from the 30‐60 minute, and 80‐100 minute post‐injection window for PiB and AV‐1451 were used for the analysis, respectively. The association of brain volumes and PiB and AV‐1451 SUVRs within the default mode network areas with BMI and VAT/SAT ratio were assessed using linear regression models.ResultWe observed lower right entorhinal white matter volumes in obese participants with insulin resistance compared to metabolically normal non‐obese group (p = 0.004), without any significant difference in PiB or AV‐1451 SUVRs. Regression models with sex, age and education as covariates showed a significant positive association between VAT/SAT ratio and left precuneus white matter PiB SUVRs (R2 = 0.31, p = 0.005), but no significant associations with AV‐1451 SUVRs.ConclusionIn our midlife obese sample with insulin resistance, there were lower right entorhinal white matter volume, which is involved in relaying information to the hippocampus. We also demonstrate higher early amyloid pathology in AD‐signature areas such as the precuneus in mid‐life persons with high VAT/SAT ratio, a marker of visceral obesity.
Loss of tubulin tyrosine ligase, a novel feature of sporadic and familial AD, is an enhancer of tau phosphorylation
Authors: Parato Julie , Qu Xiaoyi , Sproul Andrew , Pero Maria Elena , Bartolini Francesca 
Published: December 2023

AbstractBackgroundWe have recently shown that loss of tubulin tyrosine ligase (TTL) and subsequent disruption of a‐tubulin retyrosination is a feature of AD and a promoter of synaptic loss by inhibiting microtubule entries into dendritic spines. TTL+/‐ mice have cognitive deficits, altered LTP, synapse loss and increased levels of detyrosinated and D2 tubulin, two tubulin modifications that accumulate on non‐dynamic microtubules. We also found that low levels of phospho‐tau correlated with higher levels of detyrosinated and D2 tubulin in pyramidal neurons residing in the anterior hippocampal formation of human AD brains, raising the question of whether improper microtubule longevity drives early stages of tau hyperphosphorylation in AD. Here, we demonstrate that loss of TTL enhances both AMPK activation and tau phosphorylation in cultured rat hippocampal and human cortical neurons, and present preliminary evidence on the mechanisms by which this regulation may occur and contribute to TTL‐loss dependent synaptic dysfunction.MethodHuman cortical neurons derived from iPSC lines in which the London familial APP mutation V717I was knocked into one allele of the IMR90 control using CRISPR/Cas9, were used as a cellular model of familial AD. Lentiviral infection with shRNA against TTL was used to silence TTL expression. Microtubule dynamics were measured by confocal time‐lapse microscopy in neurons expressing EB3‐EGFP, a protein that tracks the growing plus ends of microtubules. Immunoblotting was performed to measure both unmodified and modified levels of TLL, tubulins, AMPK subunits, total tau, p262 and AT8 phospho‐tau.ResultIn the APP neurons, we found that a reduction in TTL levels correlated with an increase in p262/AT8 phospho‐tau variants and phospho‐AMPK, the active state of one of the kinases that phosphorylates serine 262, a key residue in the binding of tau to microtubules. Knockdown of TTL was sufficient to reduce microtubule dynamics and increase both active AMPK levels and phospho‐tau.ConclusionOur results indicate that loss of TTL alone reduces dynamic microtubules, triggers tau kinase activation, and results in hyperphosphorylated tau. Together with our previously published data, these findings suggest that reduced levels of TTL act as one of the early drivers of tau hyperphosphorylation in AD.
Deep learning based normative models identify structures that become abnormal with Alzheimer’s disease
Authors: Jaramillo Camilo , Trujillo Maria , Bernal Jose 
Published: December 2023

AbstractBackgroundImproving dementia diagnosis is a major global concern, given that up to 20% of subjects are misdiagnosed. Normative modelling, which quantifies how far individuals deviate from healthy controls (HC), may help to better situate subjects along the spectrum. To determine whether this is the case, we implemented a deep learning based normative model and tested it on structural neuroimaging data from subjects with HC, mild cognitive impairment (MCI), and Alzheimer’s disease (AD).MethodWe developed an adversarial autoencoder (AAE) (Figure 1) leveraging FreeSurfer features, namely cortical surface area of 68 cortical subregions (34 by hemisphere; Desikan‐Killiany atlas) and volumes of 33 neuroanatomical structures (Aseg atlas). Our model not only returns individual “deviation” scores—divergence from HC—but also identifies regions of interest that contribute to said score, facilitating interpretability. We retrieved T1‐weighted MRI scans (n = 204) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (HC/MCI/AD 105/29/60; Table 1). We trained our AAE on 71 HC samples (n = 71) and tested it on the rest (n = 133). We used bootstrapping to compute confidence intervals (CI) for each point estimate and examined regions where scores differed for the considered groups [1].ResultDeviation scores were lowest for HC (mean 0.74 [95%‐CI 0.63–0.88]), highest for AD (mean 1.21 [95%‐CI 1.03–1.50]), and intermediate for MCI (mean 1.04 [95%‐CI 0.88–1.27]), implying subjects indeed fell along the AD spectrum (Figure 2A). Said scores also enabled classifying subjects into HC, MCI, and AD with a mean area under the curve (AUC) of 75% (Figure 2B‐C; HC vs. MCI: 0.75 [95%‐CI 0.62–0.85]; HC vs. AD: 0.76 [95%‐CI 0.64–0.82]). According to the AAE, the hippocampus, parahippocampal cortex, ventricles, and inferior parietal lobe contributed to such differences (Figure 2D‐E).ConclusionNormative models can identify structures that become abnormal as the brain undergoes ageing and AD, in line with the literature. Further testing on a larger and more heterogeneous sample will reveal the potential of this tool and its potential deployment in clinics.
References
:[1] W. H. L. Pinaya et al., “Using normative modelling to detect disease progression in mild cognitive impairment and Alzheimer’s disease in a cross‐sectional multi‐cohort study”, Scientific reports, vol. 11 1, p. 15746, 2021.