bluuebunny/crossref_metadata_2025_split huggingface dataset:
Harnessing Chromatin 3D interactions to Understand Ancestry‐Specific Alzheimer Disease (AD) risk
Authors: Wang Liyong , Liu Xiaoxiao , Oron Oded , Xu Wanying , Trittipo Jack , Rajabli Farid , Dykxhoorn Derek M. , Griswold Anthony J. , Pericak‐Vance Margaret A. , Young Juan J , Jin Fulai , Vance Jeffery M. 
Published: December 2022

AbstractBackgroundAncestry‐specific Alzheimer Disease (AD) genetic risk is well recognized. Chromatin 3D interaction map in AD‐relevant cells with different ancestries is lacking but needed to understand the genetic/epigenetic basis for AD in diverse populations. We have shown that the local ancestry (LA) block (∼2Mb in size) surrounding APOE confers differential genetic risk for APOE ε4 carriers in Non‐Hispanic Whites (NHW) and African Americans (AA). Recently, we reported that NHW APOE ε4 carriers have a higher APOE ε4 expression and higher number of astrocytes compared to their AA counterparts in the frontal cortex. We therefore sought to characterize chromatin 3D interactions in astrocytes within different APOE LA.MethodInduced pluripotent stem cells (iPSCs) with African or European LA block (N=2 individuals for each) were differentiated into astrocytes. Chromatin Hi‐C libraries were constructed with 4‐cutter enzyme and sequenced targeting 500 million pair‐end reads per library. Spatial genome structure was examined at compartment, topological associated domain (TAD), and loop levels. To better define enhancer‐promoter interaction (EPI), high‐resolution contact matrices were built using the HiCorr and DeepLoop algorithms.ResultEach library generated over 250 million uniquely mapped, non‐redundant reads for Hi‐C analysis. Compartment and TAD had limited variability among samples (correlation co‐efficiency = 0.62∼0.90 for compartment, 0.84∼0.94 for TAD). Chromatin loop, which usually represents EPI, displays higher variability among samples (correlation co‐efficiency = 0.38∼0.75). In the 5kb‐contact‐matrix analysis, a chromatin interactive event involving APOE was detected, which is supported by Capture‐C data. The higher‐resolution 500bp‐contact‐matrix analysis revealed multiple better‐defined interactions within the event. Of particular interest, an interaction between the 5’end of TOMM40 and CLPTM1 (about 100 kb apart from each other) surrounding APOE is only observed on European but not African LA background.ConclusionChromatin loop displays more inter‐individual variations compared to other spatial genome structures and therefore is more informative in elucidating the epigenetic basis for inter‐ancestry differences in gene expression regulation. While identifying chromatin loop from Hi‐C data at higher resolution is challenging, it has the potential to delimitate EPI and offers insights on the ancestry‐specific AD genetic risk by providing functional mechanisms underlying AD‐associated genetic variants.
Describing biomarkers for Alzheimer’s disease: Localization of amyloid‐β in the retina
Authors: Lee Sieun , Xu Qinyuan (Alis) , Boerkoel Pierre , Hirsch‐Reinshagen Veronica , Mackenzie Ian R , Hsiung Ging‐Yuek Robin , Charm Geoffrey , To Elliot , Liu Alice , Schwab Katerina , Jiang Kailun , Sarunic Marinko , Beg Mirza Faisal , Pham Wellington , Cui Jing , To Eleanor , Matsubara Joanne A 
Published: December 2022

AbstractBackgroundRetinal glial cells, Aβ deposition and their colocalization were examined in post‐mortem retinal cross‐sections of Alzheimer’s disease (AD) donors and age‐matched controls.MethodImmunohistochemistry was performed on paraffin‐embedded cross‐sections of central and mid‐peripheral retinal tissues of AD donors (n = 9) and age‐matched controls (n = 12) to detect Aβ (6F/3D, 12F4, and 6E10) with neuronal profile (TUBB), astrocytes and Muller cells (GFAP), and microglia (IBA‐1). Astrocytes and Muller cells were further distinguished by double‐labelling of GFAP and glutamine synthetase (GS) antibody. The tissues were imaged with a confocal microscope and the degree of immunoreactivity and colocalization were measured layer‐wise and compared (α=.05) between the AD and control groups.ResultThe AD group showed more Aβ load in the mid‐peripheral retina but not central retina. For glial cells, less GFAP immunoreactivity in the central and mid‐peripheral retina and more microglia immunoreactivity in the mid‐peripheral retina were observed in the AD group. In the double‐labelling of GFAP and GS, activated Muller cells (labelled by GFAP and GS) were reduced in the AD group but not astrocytes (labelled only by GFAP). The AD group also showed greater co‐localization of Aβ with neuronal profile but less with microglia.ConclusionThe reduced Muller cell metabolism and increase amount of microglia but with reduced colocalization with Aβ indicate complex glial dysfunction in the AD retina.
The Relationship between All‐cause Dementia and Acute Diabetes Complications among American Indian and Alaska Native Peoples
Authors: Niu Xiaoyi , Chang Jenny , Corrada Maria M. , Bullock Ann , Manson Spero , O'Connell Joan , Jiang Luohua 
Published: December 2022

AbstractBackgroundAmerican Indian and Alaska Native people (AI/ANs) bear a disproportionate burden of diabetes. Growing evidence has shown significant associations between several acute diabetes complications and dementia among diabetes patients in the general population. However, little is known about these relationships among AI/ANs.MethodsThis cross‐sectional study extracted patient registration and health service utilization data from the Indian Health Service’s National Data Warehouse and related administrative databases. A total of 29,337 AI/AN adults with diabetes who were 45+ years old and used IHS or tribal health services during fiscal year 2013 were included. All‐cause dementia and acute diabetes complications were identified using ICD‐9 diagnostic codes in the utilization data. Negative binomial regression models were used to evaluate the associations of interest after adjusting for potential confounders.ResultsNearly 3% (n = 843) of AI/AN diabetes patients had a dementia diagnosis. Among AI/ANs with diabetes, similar proportions of patients had a history of hospitalization or ED visits for hypoglycemia only (3.6%) or hyperglycemia only (4.1%). About 0.8% had both types of acute diabetes complications. As shown in Fig1, after controlling for demographics, health care coverage, and comorbidities, dementia diagnosis was associated with 94% higher rate of severe hypoglycemia (Incidence Rate Ratio [IRR = 1.94, 95% CI:1.50‐2.51), 52% higher rate of severe hyperglycemia (IRR = 1.52, 95% CI, 1.11‐2.08), and 92% higher rate of any acute complication (IRR = 1.92, 95% CI:1.53‐2.41). Dementia was not significantly associated with diabetic ketoacidosis (DKA) in the adjusted model (IRR = 1.82, 95% CI:0.83‐4.01). Further adjustments on clinical measurements and medications did not substantially change the estimated IRRs for hypoglycemia and hyperglycemia.ConclusionsAI/AN diabetes patients with dementia suffered from considerably higher rates of severe hypoglycemia and hyperglycemia than their counterparts without dementia. Clinical management of patients with comorbid diabetes and dementia is particularly challenging and requires individualized treatment approaches.
Event‐related‐potentials are sensitive and reliable EEG biomarkers for mild cognitive impairment: A longitudinal study
Authors: Meghdadi Amir H. , Mcconnell Marissa , Richard Christian , Hamilton Joanne M , Boeve Bradley F. , St Erik K , Salat David H , Berka Chris 
Published: December 2022

AbstractBackgroundEvent‐related‐potentials (ERPs) during cognitive tasks are sensitive measures of cognitive decline [1]‐[2] and could quantitatively measure the trajectory of disease progression or response to clinical interventions. In this longitudinal study, we aimed to compare ERPs between individuals with mild cognitive impairment (MCI) and controls, and to demonstrate the test‐retest reliability of ERP measures to assess their potential utility for future observational studies and treatment trials.MethodsParticipants included individuals with mild cognitive impairment (MCI, n=31) and healthy controls stratified by age: HC2 (n=46, 40‐60 yrs.), HC3 (n=56, 60‐90 yrs.). ERPs during attention, image recognition, and verbal memory tasks were recorded using a wireless EEG to determine amplitudes and latencies of the P200 and late positive potential (LPP) ERP components in response to target (memorized) and non‐target (novel) stimuli. Differences between MCI and HC3 groups were characterized at the initial visit, and longitudinal changes in ERP components were determined at 1‐year follow‐up for both groups. Reliability of ERP measures was demonstrated by computing intraclass correlation coefficient (ICC) measures of test‐retest variability in all healthy controls (HC2 and HC3) from initial visit to 1‐year follow‐up.ResultsAt the initial visit, the MCI group demonstrated reduced LPP amplitude (Hedges‐g=0.8, p=10‐3) and delayed P200‐latency (Hedges‐g=0.89, p=10‐4) when compared to HC3. Reliability in healthy controls was high for LPP (0.85 and 0.75 for target and non‐target stimuli, respectively) and moderate for P200‐latency (0.67 and 0.53 for target and non‐target stimuli, respectively), without longitudinal changes after 1‐year follow‐up. Individuals with MCI demonstrated increased P200‐latency (Hedges‐g= 1.05, p=0.02, df=8).ConclusionsIndividuals with MCI demonstrated quantifiable memory ERP deficits at baseline with detectable change in the P200 component at 1‐year follow‐up, demonstrating that ERPs are sensitive measures for quantifying mild cognitive impairment. Test‐retest reliability of these measures was good or moderate after 1‐year, supporting their feasibility for longitudinal monitoring of patients during disease progression or quantifying the cognitive impact of potential interventions.
Evaluation of COVID on cognitive performance using a mobile application (DANA)
Authors: Hwang Phillip H , Leibel Daniel , Popp Zachary T , Drane James , Lee Marissa , Prabhu Meha , Kohli Anisha , Chen Herbert , Kumar Anupama , Lathan Corinna , Au Rhoda , Vannorsdall Tracy D 
Published: December 2022

AbstractBackgroundThe neurocognitive impact of having COVID is receiving greater awareness, with greater COVID severity potentially conferring risk of more negative cognitive outcomes. Current cognitive assessment methods are limited by factors, such as time and location, which can be mitigated by the use of mobile applications. We aimed to assess the relationship between COVID severity and cognitive performance at baseline and over time using a mobile cognitive assessment.MethodParticipants in the analytic sample included 27 COVID‐positive (COVID+) Johns Hopkins Post‐acute Covid Team patients who received care in the intensive care unit (COVID+/ICU+; n = 6) or in other units (COVID+/ICU‐; n = 21). Another 23 participants from a separate study investigating the use of mobile cognitive applications in older adults were included as non‐COVID controls (COVID‐). Cognition was assessed via cognitive efficiency (CE) scores, a derived measure of speed and accuracy, for the Procedural Reaction Time (PRT) task of the Digital Automated Neurobehavioral Assessment (DANA) mobile application. Participants with missing or unavailable PRT assessment data were excluded from the analytic sample. PRT CE scores between COVID‐, COVID+/ICU‐, and COVID+/ICU+ participants were analyzed at baseline using ANOVA, as well as longitudinally over a six‐week period.Result
Table 1 presents demographic characteristics. At baseline, average PRT CE scores were highest among the COVID‐ group (mean = 86.55; standard deviation = 17.06), followed by the COVID+/ICU+ group (mean = 80.41; standard deviation = 15.83), and then the COVID+/ICU‐ group (mean = 76.93; standard deviation = 14.03). There was no significant difference in average baseline PRT CE scores between the three groups (p = 0.135). Those in the COVID‐ group and COVID+/ICU‐ group appeared to achieve higher PRT CE scores over the six‐week assessment period, while those in the COVID+/ICU+ group did not improve relative to their baseline (Figure 1a&b).ConclusionWe observed qualitative differences in the rate of recovery for cognitive performance between participants with COVID who did and did not require ICU admission. Given the limited sample size and other potential confounding factors, further analyses with additional data collected are needed in order to more rigorously compare cognitive performance cross‐sectionally and longitudinally between COVID groups.
Protecting cognitive function and delaying dementia: preliminary evidence from Lebanon
Authors: Darwish Hala J 
Published: December 2022

AbstractBackgroundIn Lebanon, it is projected that dementia will become a health crisis within the next 20 years. Therefore, the protection and management of cognitive impairment in older adults are of great significance for the aging population. We will present findings from research examining the role cognitive reserve factors and vitamin D play in cognitive impairment among older adults.MethodsIn the first study, we investigated the cognitive function and cognitive reserve factors of 508 community‐based Lebanese older adults aged 65 years using secondary data analysis. In a second cross‐sectional study, we explored the cognitive performance and serum vitamin D levels in 254 older (>60 years) as well as younger (30‐60 years) adults.ResultsStudy 1. Older adults with dementia had lower education levels and attained lower occupational complexity. High education, complex occupation attainment, and leisure activity significantly predicted better global cognitive function. An older adult who gained high education levels or high complexity level occupation was 7.1 or 4.6 times more likely to have better global cognitive function than another who attained lower education or complexity level occupation, respectively. Study 2. Pearson’s correlation and stepwise linear regression analyses showed that a low serum 25 dihydroxy vitamin D (<30ng/ml) level was associated with a higher risk of cognitive impairment in older as well as younger adults (30 years).ConclusionThese results suggest that cognitive reserve factors should be taken into consideration clinically during dementia diagnosis and when initiating community‐based preventive strategies in Arab populations. These findings also suggest that vitamin D correction needs to be explored as an intervention to prevent cognitive impairment. Other evidence supporting lifestyle changes and cognitive rehabilitation for the prevention and treatment of cognitive impairment should also be considered. Such interventions may reduce the risk of cognitive impairment and Alzheimer’s disease in older adults.
Racial disparities in predictors of dementia in a population‐based cohort
Authors: Borelli Wyllians Vendramini , Ferreira Pamela C.L. , Formoso Carolina Rodrigues , Pascoal Tharick A , Castilhos Raphael Machado , Zimmer Eduardo R 
Published: December 2022

AbstractBackgroundIdentifying predictors of dementia may reduce its burden across the globe. Herein, we aimed at investigating predictors of probable dementia in different race groups of a middle‐income country.MethodThe ELSI‐Brazil cohort consists of 9412 individuals (63.55+‐10.14 years of age). This cohort comprises individuals at/ or above 50 years of age from across the country. Complex sampling warrants nationwide representativity for diseases with low prevalence. Probable dementia was defined as a brief cognitive screening (using category fluency test) score below normative data for age and education, associated with a Katz scale score below 6. Multivariate logistic regression models were performed to measure predictors of dementia in Black, Brown, White and Indigenous individuals. Asian ancestry individuals were excluded from this analysis due to the small sample size (n = 90).ResultThe frequency of individuals with probable dementia was statistically similar between groups, especifically 8.7% (n = 74/887) in black individuals, 7.8% (n = 17/220) in indigenous individuals, 7.5% (n = 301/4283) in Brown individuals, and 7.2% (n = 245/3590) in White individuals (p = 0.51). Indigenous individuals with probable dementia were significantly younger than other groups (59.1 years, p<0.001). Predictors of dementia differ significantly between groups, except for depression, which was the only predictor universally present. In Brown individuals, stroke and myocardial infarction were associated with predictors of dementia (OR: 2.34 [1.5 ‐ 3.5] and OR: 2.57 [1.69 ‐ 3.84] respectively), while the feeling of loneliness (OR: 1.69 [1.20 ‐ 2.42]) and being economically inactive (OR: 2.89 [1.68 ‐ 4.80]) were associated with dementia in White individuals. In Black individuals, recent hospitalization was a strong predictor (OR: 2.86 [1.47 ‐ 5.42]), while in Indigenous individuals, only depression was a predictor (OR: 19.22 [3.74 ‐ 352]), potentially associated with its small sample.ConclusionDistinct profile of predictors for probable dementia should be accounted for when evaluating distinct races groups. While depression was a predictor for all races, Brown individuals presented a clinical profile more vulnerable to cardiovascular events.
Whole genome sequence association analysis of Brain MRI measures
Authors: Shade Lincoln MP , Satizabal Claudia L , Glahn David C , Mosley Thomas H , Heckbert Susan R. , Launer Lenore J. , Yanek Lisa R , Bis Joshua C , Smith Jennifer A , DeCarli Charles S. , Arnett Donna K , Psaty Bruce M. , Nyquist Paul A , Mathias Rasika A , Rotter Jerome I , Rich Stephen S , Blangero John , DeStefano Anita L. , Fardo David W. , Fornage Myriam , Seshadri Sudha , Sarnowski Chloé ,   TOPMed Neurocognitive working group
Published: December 2022

AbstractBackgroundGenome‐wide association studies (GWAS) of brain volumes have identified common genetic variants with modest effect sizes that lie mainly in non‐coding regions. We sought to identify low frequency and rare variants influencing brain volumes by performing association analyses using whole‐genome sequence data from the Trans‐Omics for Precision Medicine (TOPMed) Program.MethodWe analyzed up to 7,607 participants (57% women; 62% European ancestry, 21% African‐Americans, 15% Hispanic/Latino, 2% Chinese‐American), mean age of 60.5 (16.2), from eight TOPMed population‐ or family‐based studies (FHS, GENESTAR, CHS, GENOA, ARIC, CARDIA, MESA, and SAFS). We excluded participants with dementia, stroke, presence of large brain infarcts, tumor or low‐quality scans. We tested the association of hippocampal (HV), total brain (TBV), lateral ventricular (LVV) and intracranial (ICV) volumes to individual genetic variants with minor allele counts ≥ 15 using mixed‐effect linear regression models adjusted for age, age2, sex, study and the first 10 principal components. Models for HV, TBV and log(LVV) were adjusted for ICV. We accounted for relatedness using an empirical kinship matrix and trait variance variability by using a random effect for study.ResultWe detected one novel region with low frequency variants associated with HV (13q14, P = 5.8×10−9). The top 13q14 variant for HV (rs115674829) minor allele frequency (MAF) was 2% in our pooled sample but was more common in the pan‐African 1000 Genomes population (MAF = 14%). This variant lies in LINC00598 at 237kb from FOXO1, a member of the forkhead family of transcription factors that has been linked to Alzheimer’s Disease. Additionally, we detected new suggestive associations (P≤10−7) for TBV (16p11) and LVV (1q25, 2q22, 3q13, 5q14, and 10q23), including common variants. Finally, we confirmed the association of common variants in GWAS loci for all traits.ConclusionOur whole genome sequence analyses revealed intriguing new loci of low‐frequency and common variants, and replicated loci previously associated with brain volumes. Future work will include ancestry‐specific and conditional analyses, as well as gene‐based and scan tests.Supported by: AG058589, AG052409, AG054076, NO1‐HC‐25195, HHSN268201500001I and 75N92019D00031, R01HL131136, P30 AG066546, and K99AG066849.
Leukocyte Surface Biomarkers Implicate Deficits of Innate Immunity in Late‐onset Alzheimer’s Disease
Authors: Li Yihan , Huang Xin , Fowler Christopher , Doecke James D , Trounson Brett , Pertile Kelly , Rumble Rebecca , Lim Yen Ying , Maruff Paul , Mintzer Jacobo E. , Dore Vincent , Rowe Christopher , Fripp Jurgen , Wiley James S , Masters Colin L. , Gu Ben J 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is characterized by amyloid‐β (Aβ) plaques, neurofibrillary tangles, reactive astrogliosis, and microgliosis. Aberrant Aβ accumulation starts 20–30 years before clinical onset, so biomarker test is essential to diagnose people living with early AD. PET imaging and CSF measurements allow the diagnosis of preclinical and prodromal AD in research and clinical trials, but their invasiveness and costliness might limit their application in hospital setting. Therefore, developing non‐invasive population screening tests is necessary for the early diagnosis of AD. Recent genetic findings strongly implicate the role of innate and adaptive immunity in AD and suggest that a systemic failure of cell‐mediated Aβ clearance contributes to AD onset and progression. Our research question was to develop an immune‐related blood‐based biomarker test to facilitate the diagnosis and prognosis of AD. It was hypothesized that the pattern of immune‐related receptors and molecules expressed on peripheral leukocytes could differentiate people living with AD from healthy population.MethodWe recruited 180 and 200 participants from AIBL in two discovery phases and validated our findings by an independent cohort of 112 participants from AIBL. A total of 34 innate and adaptive immunity‐related leukocyte antigens on peripheral lymphocytes, monocytes, and neutrophils were examined by flow cytometry immunophenotyping. Data was analysed by logistic regression and ROC analyses.ResultWe identified upregulated CD35, CD59, CD91, RAGE, and Scara‐1 expressions and downregulated CD11c, CD18, CD36, CD163, MerTK, and P2X7 expressions on leukocytes of MCI/AD patients. Significant correlation between them and Aβ burden, episodic memory, and PACC score was observed, such as CD59 and CD91. Pathway analysis revealed upregulation of complement inhibition and downregulation of cargo receptor activity and Aβ clearance in AD. We proposed a marker panel including CD11c, CD59, CD91 and CD163 and this panel predicted patients’ PET Aβ status with AUC of 0.93 (0.88 to 0.97), which was repeated in validation cohort. Regarding adaptive immunity, we did not see significant results.ConclusionOur study suggested deficits in innate immunity in AD, which is consistent with genomic studies. Our proposed leukocyte‐based biomarker panel might be sensitive and practical for AD screening and diagnosis.