bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative single‐nucleus multi‐omics analysis prioritizes candidate cis and trans regulatory networks and their target genes in Alzheimer’s disease brains
Authors: Chiba‐Falek Ornit , Gingerich Daniel , Shwab Elliot Keats , Gamache Julia , Garrett Melanie E , Crawford Gregory , Ashley‐Koch Allison 
Published: December 2023

AbstractBackgroundThe genetic underpinnings of late‐onset Alzheimer’s disease (LOAD) are yet to be fully elucidated. Although numerous LOAD‐associated loci have been discovered, the causal variants and their target genes remain largely unknown. Since the brain is composed of heterogenous cell subtypes, it is imperative to study the brain on a cell subtype specific level to explore the biological processes underlying LOAD.MethodsIn this study we performed a parallel single‐nucleus (sn) multi‐omics analysis to simultaneously profile gene expression (snRNA‐seq) and chromatin accessibility (snATAC‐seq) using nuclei from 12 normal and 12 LOAD brains. We developed a pipeline based on integrative analysis of multimodal datasets that utilizes several bioinformatics packages to catalogue cis‐ and trans‐ regulatory network and their target genes.ResultsWe identified cell subtype specific LOAD‐associated differentially expressed genes (DEGs), differentially accessible peaks (DAPs) and cis co‐accessibility networks (CCANs). Integrative analysis defined disease‐relevant CCANs in multiple cell subtypes and discovered LOAD‐associated cell subtype specific candidate cis regulatory elements (cCRE), their candidate target genes, and trans‐interacting transcription factors (TF), some of which were LOAD‐DEG, for example, ELK1 in a specific sub type of excitatory neurons and ATF7 and JUN, found in multiple cell subtypes. Overall, our analysis discovered 53 new candidate LOAD genes and validated 16 gene previously implicated in LOAD. Finally, we focused on a subset of cell subtype‐specific CCANs that overlap known LOAD‐GWAS regions and catalogued putative functional SNPs disrupting TF motifs within LOAD‐cCREs linked to LOAD‐DEGs including, APOE and MYO1E in a specific subtype of microglia.ConclusionsIn this study we identified candidate cis‐ and trans‐ regulatory factors and their target genes that contribute to the pathogenesis of LOAD. To our knowledge, this study represents the most comprehensive systematic interrogation of regulatory networks underlying gene dysregulation in LOAD at an unprecedented cell‐subtype resolution. Collectively, our findings provide a rich dataset for future mechanistic experiments, confirm known LOAD‐GWAS loci while also identifying novel loci, and suggest the disease‐relevant cell types and subtypes for follow‐up validation studies using in vitro and in vivo disease model systems. This information is important for the development of new therapeutic targets and interventions for LOAD.
The complex relationship between anticholinergic medication, frailty, and hospitalization in patients with early‐stage dementia
Authors: Wyman‐Chick Kathryn A , Chrenka Ella A , Miller Michael J , Barrett Matthew J , Sabayan Behnam , Werner Ann M , Rossom Rebecca C 
Published: December 2023

AbstractBackgroundAnticholinergic medications are associated with frailty and hospitalization in patients with dementia. It is unclear if anticholinergic burden mediates the relationship between frailty and hospitalization or if specific dementia syndromes moderate the direct and indirect relationships between these three factors.MethodWe analyzed electronic health record and claims data for member‐patients diagnosed with dementia with Lewy bodies (DLB), Alzheimer’s disease (AD), or vascular dementia (VD) from an integrated healthcare system in the U.S. between October 2015 and August 2022. The Anticholinergic Cognitive Burden Scale (ACB), Claims‐based Frailty Index (frail ≥0.20), and number of hospital admissions were calculated for the 12‐month period prior to dementia diagnosis. Patient demographics, ACB score, frailty status, and hospitalization frequency were compared between dementia syndromes. Baron and Kenny regression‐based method was used to evaluate if ACB is a mediator between frailty and hospitalization. DLB, AD, and VD were included as interactions with ACB and frailty in stratified mediation models to determine if dementia syndrome moderated the relationship. Significant interaction terms indicate a moderating effect of dementia syndrome. All models included patient age and sex as covariates.ResultWe identified 3166 patients (DLB n = 175; AD n = 2478; VD n = 513). Approximately 23% of patients with DLB were prescribed 5+ anticholinergic medications (17.2% with VD; 9.9% with AD; p<.001). Two or more hospitalizations were documented in 12.5% of patients with VD (10.3% with DLB; 5.5% with AD; p<.001). The ACB score was 3.7 greater for patients with frailty compared to those without (3.2, 4.4, p<.001). The relationship between frailty and hospitalization was mediated by ACB (higher ACB was associated with increased utilization; Table 1). A diagnosis of AD or VD moderated the indirect relationship between frailty and hospitalization, but the specific dementia syndrome did not moderate the path between ACB and hospitalization (Table 2; Figure 1).ConclusionIn the year prior to dementia diagnosis, frailty was associated with a higher number of anticholinergic medications, which, in turn, was associated with a greater number of hospitalizations. A diagnosis of VD increased the expected rates of hospitalization for frail patients, while an AD diagnosis decreased the magnitude of the association between frailty and hospitalization.
Detecting early Alzheimer’s disease using neuropsychological assessment and structural neuroimaging
Authors: Quek Yi‐En , Fung Yi Leng , Bourgeat Pierrick , Vogrin Simon J , Collins Steven J , Bowden Stephen C 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) can be challenging to diagnose early as cognitive changes are mild. Neuropsychological assessment, in contrast to cognitive screening or isolated cognitive tests, are more sensitive to the mild cognitive changes in early AD. Magnetic resonance imaging (MRI) can detect early structural brain changes in AD, particularly entorhinal cortex, transentorhinal cortex, and hippocampal atrophy. Combining neuropsychological assessment with MRI examination may yield improved ability to detect early AD. The current study examined combining neuropsychological and MRI measures to detect patients with mild cognitive impairment (MCI) in a memory clinic sample.MethodNeuropsychological assessment and entorhinal cortex, transentorhinal cortex, and hippocampal volume measurement were conducted in memory clinic patients, including 38 with memory symptoms, 16 with MCI, and 16 with dementia due to AD, and in 40 healthy controls. Backward stepwise multinomial logistic regression was used to compare the neuropsychological measures and MRI measures.ResultAmong the neuropsychological measures, memory and processing speed were the most important measures that contributed to group membership prediction. All MRI measures contributed to group membership prediction. The neuropsychological measures were more accurate than the MRI measures at detecting patients with MCI. Combining the MRI measures with the neuropsychological measures did not improve group membership prediction.ConclusionNeuropsychological assessment is an important tool to support MCI diagnosis. MRI measures contribute little diagnostic value over and above neuropsychological assessment. Further advancement in deriving MRI‐based measurements is required to achieve clinical utility.
Passive logging of smartphone interactions as a feasible and reliable measure to monitor everyday cognition in Alzheimer’s Disease
Authors: Keijzer Matthijs J. , Glind Marie‐Christine M.A.B.J Van De , Twose James , de Kloet Sybren F. , Redeman Erwin G.M. , Meijer Kim A. , van der Flier Wiesje M. , Sikkes Sietske A.M. 
Published: December 2023

AbstractBackgroundAs cognitive assessments can be burdensome to patients, new approaches are emerging to assess symptomatic changes in Alzheimer’s Disease (AD). Since typing on smartphones requires a variety of cognitive functions, passively and remotely collected typing behaviour has the potential to provide day‐to‐day insights into cognitive decline in AD. We investigated therefore the feasibility and reliability of a keyboard application for smartphones (Neurokeys) that passively collects keystroke dynamics (KD) to monitor cognition in people with preclinical and clinical AD.MethodParticipants with preclinical AD (N = 8) and patients with a clinical AD diagnosis (N = 8, Table 1) were included from the Amsterdam Dementia Cohort. Participants used Neurokeys for 28 consecutive days in the context of the ‘A Personalized Medicine Approach for Alzheimer’s Disease’ (ABOARD)‐project. The retention rate (active users on day 28) and the average number of daily keystrokes were calculated to determine feasibility. KD were aggregated into two commonly investigated features: time between keystrokes (flight‐time) and duration of a keystroke (hold‐time), which were standardized into z‐scores. Intra‐class correlations (ICC) between first and last 14 days of data collection for both features were determined to assess reliability. Finally, KD features were correlated to scores on the Mini‐Mental State Examination (MMSE) to explore the association between KD and global cognition.ResultsThe retention rate was 93.75% for all participants (Figure 1). Participants with preclinical AD used the keyboard for 26.25±2.12 days with 653.67±305.61 keystrokes each day, and clinical AD patients used the keyboard for 22.63±4.10 days with 409.44±288.73 daily keystrokes. For all participants, the ICC for flight‐time and hold‐time are 0.85 and 0.89 respectively. MMSE is negatively correlated with flight‐time (r = ‐0.68, p = 0.003), but not with hold‐time (r = ‐0.20, p = 0.45, Figure 2).ConclusionThe number of daily keystrokes is sufficient to obtain reliable KD features in preclinical and clinical AD. The results show that people with better global cognition type faster, indicating that passive logging of keystrokes can be a feasible measure for cognition in AD. To elaborate on these first findings, a larger validation study can further explore the utility of smartphone interactions and aid the development of digital biomarkers in AD.
ApoB‐related Sulcal depth Patterns Contributed to Executive Function and Plasma Biomarkers of Alzheimer’s disease
Authors: Wang Ziqi , Wang Jiayu 
Published: December 2023

AbstractBackgroundAs the cerebral cortex is an important indicator of the pathological changes of AD, ApoB, ApoA1, ApoB/ApoA1 and blood Alzheimer’s biomarkers have been proved to be important markers of AD.MethodWe analyzed data from 21 patients with SCD enrolled in the 500 nm light therapy cohort who filled a battery of neuropsychological tests and had apolipoproteins, plasma Alzheimer’s biomarkers, and gene levels assessed at the time of their baseline 3T MRI scans. The sulcal depth and cortical thickness were obtained using the vertex‐based approach with the CAT12 toolbox (in SPM12).ResultAt corrected thresholds (p < 0.05, FWE‐corrected), there were significant positive correlations between ApoB and sulcal depth in the lateral occipital cortex, and between ApoB/ApoA1 and sulcal depth in the left lateral occipital cortex. In addition, we found a significant negative correlation between shape trails test part B (STT‐B) time and sulcal depth in the left lateral occipital cortex (β = ‐0.502, p = 0.040). Moreover, the plasma Aβ42 was positively related to sulcal depth (β = 0.493, p = 0.044) and plasma p‐tau181 was negatively related to the sulcal depth (β = ‐0.592, p = 0.012) in the left lateral occipital cortex. There was no relationship between cortical thickness and apolipoproteins or any of the biomarkers.ConclusionApoB and ApoB/ApoA1 influence sulcal depth in the left lateral occipital cortex where the sulcal depth may relate to the executive function and plasma Alzheimer’s biomarkers in SCD.
Estimating the Prevalence of Dementia in a sample of Australian Prisoners: The Cohort Study Design, Results and Implications for Public Health and Prison Sectors
Authors: Modini Ella L , Nixon Margaret , Fullam Rachael , Macfarlane Stephen 
Published: December 2023

AbstractBackgroundThe number of older prisoners within our prison system is increasing. The health challenges faced by prisoners in general contribute to prisoners being considered ‘old’ within the prison system once they reach the age of 50. The prison lifestyle, combined with the risk factor profiles of those incarcerated (higher rates of low educational attainment, smoking, substance use, head injury, psychiatric illness, unmet chronic health needs) suggests that older prisoners are likely to be at significantly higher risk of developing dementia than those of similar ages in the general population.Surprisingly, however, we know very little about the prevalence of dementia within prison systems both internationally and locally, with no Australian data being available. This study aimed to estimate the prevalence of dementia among older prisoners within prisons in Victoria, Australia. Cognitive screening was conducted on a large sample of older prisoners housed within 3 correctional facilities in Victoria, such that the overall prevalence of dementia within this vulnerable group could be ascertained, as a first step towards appropriate service planning.MethodDementia assessments of over 100 prisoners aged over 50 years, were conducted across three prison sites in Victoria, Australia. Each assessment included a demographic interview to capture the presence of risk factors and an Addenbrooke’s Cognitive Examination 3rd edition. All assessment data were reviewed by a psychogeriatrician for quality and to identify false positive dementia screens.ResultThe total sample of prisoners 114 reported higher rates of risk factors than those seen in the general population. Conservative dementia prevalence rates based on psychogeriatrician review of self‐reported medical history and patterns of responding on the ACE‐III suggest that dementia is more prevalent in prison populations than in the Australian general population. The overall sample of 95 included assessments suggested prisoners were up to eight times more likely to have dementia than population estimates of 1.1%.ConclusionDementia is likely to be more prevalent in prison systems due to increased risk factors profiles. This poses a significant challenge for corrective services as the ageing prisoner population continues to increase. This study provides rationale for review of planning and service provision to older prisoners.
Examining the measurement equivalence of Alzheimer’s Disease Centre Neuropsychological Test Battery (Version 3) across two distinct cultures
Authors: Tay Sze Yan , Koay Way Inn , Liew Tau Ming 
Published: December 2023

AbstractBackgroundNeuropsychological assessments are important in clinical diagnostic process for dementia as it help early detection of cognitive difficulties. Prior to using neuropsychological test batteries across different populations, it is critical to standardize the battery to ensure consistency in the assessment process, as well as valid and comparable results across different settings. The Alzheimer’s Disease Centre Neuropsychological Test Battery (Version 3) (ADCNTB3) is a widely used battery that had shown sensitivity in detecting cognitive decline in MCI and early dementia, with minimal test repetition effects (Boccardi et. al., 2022). While norms are available in America, harmonization efforts are currently in place to adapt ADCNTB3 for European populations.MethodThis study examined whether ADCNTB3 could be adapted to Singapore (multi‐ethic Asian population), a culture distinctly different from America, and whether ADCNTB3 demonstrates measurement equivalence when adapted to the Singapore population. Following the qualitative process of cultural adaptation, the ADCNTB3 was administered to 266 community‐dwelling older persons with normal cognition in Singapore. Scores from these participants were then compared with 1064 random samples with normal cognition from National Alzheimer’s Coordinating Centre (NACC) to evaluate whether the ADCNTB3 has equivalent scores across the two distinct populations. Score‐difference between the 2 populations was computed using multiple linear regression (adjusted for age, education, gender, family history of dementia, cardiovascular conditions, psychiatric and neurological history, smoking, untreated hearing loss, obesity, MoCA total score, CDR sum of boxes, NPI‐Q total score) and equivalence scores are considered to be present if the 90% confidence interval of the adjusted score‐difference fall within the equivalence margin. A priori, we defined the equivalence margin as 0.5 Standard Deviation of tests from ADCNTB3, as this often defines the minimally important clinical significance (Sloan et al., 2005).ResultOther than working and delayed memory tasks, all other tests from the ADCNTB3 are not directly equivalent. Notably, Asians performed better in visuospatial task, but consistently performed poorer in most other tasks.ConclusionOther than working and delayed memory tasks, all other tests from the ADCNTB3 are not directly equivalent. Notably, Asians performed better in visuospatial task, but consistently performed poorer in most other tasks.
Associations between Anxious‐Depression and Cognitive Change, Function, and Impairment: Results from the Hispanic Community Healthy Study/Study of Latinos‐Investigations of Neurocognitive Aging
Authors: Gonzalez‐Prado Roberto , Paredes Alejandra Morlett , Tarraf Wassim , Stickel Ariana M , Kuwayama Sayaka , Zeng Donglin , Gallo Linda C , Testai Fenando D , Daviglus Martha L , Penedo Frank J , González Hector M 
Published: December 2023

AbstractBackgroundAnxiety and depression often co‐occur and both are risk factors for Alzheimer’s disease and related dementias (ADRD). This study sought to examine associations between anxiety and depressive symptoms with cognitive change, function and impairment among middle‐aged and older Hispanics/Latinos.MethodData included 6,162 middle‐aged and older Hispanic/Latinos adults (Age M = 63.4 years, SD = ±8.2 years; 55% female) enrolled in the Study of Latinos‐Investigation of Neurocognitive Aging study (SOL‐INCA), an ancillary study to the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Participants completed the Spielberger State‐Trait Anxiety Inventory 10‐item (STAI‐10) and Center for Epidemiology Scale for Depression 10‐item (CESD‐10) at HCHS/SOL Visit 1 (2008‐2011). Outcomes of interest include cognitive function at Visit 2, change in cognition from Visit 1 to 2 (approximately 7‐years later in SOL‐INCA), and mild cognitive impairment status (MCI; NIA‐AA diagnostic criteria) at Visit 2. Latent class analysis (LCA) was used to derive phenotypes of anxious‐depression using both STAI‐10 and CESD‐10 items. The phenotypes were used as exposures in survey generalized linear regression models for cognitive function, change, and MCI. Covariables included age, sex, education, income, heritage, center, and antianxiety/antidepressant medication use.ResultLCA results demonstrated 3 classes of anxious‐depression (Low; 62%, Moderate; 30%, and High; 8%). We found consistent negative associations between the Moderate and High group with cognitive function, from baseline. Participants in the High group had more pronounced associations (p<.001) than the Moderate group (p<.01) vs. the Low group, after covariate adjustments. We found consistent negative associations with MCI whereby both Moderate (OR = 1.62, CI = [1.12; 2.33], p<.05) and High (OR = 1.64, CI = [1.25; 2.16], p<.001) groups were associated with higher odds ratios for MCI. However, there were no associations with cognitive change.ConclusionThis study demonstrated the utility of the anxious‐depression construct when investigating the relationships between co‐occurring anxiety and depressive symptoms with cognitive aging among Hispanics/Latinos. Anxious‐depression was negatively associated with cognitive function and MCI status, demonstrating unique effects of co‐occurring anxiety and depressive symptoms among older Hispanic/Latinos. However, further replications are required to evaluate the longitudinal effects of anxious‐depression on cognitive outcomes.
NLRP3‐inflammasome inhibition by Leishmania‐derived factors in the neuropathogenesis of Alzheimer’s Disease (AD): assessing the molecular and therapeutic role
Authors: La Rosa Francesca , Varotto Ilaria , Epis Sara , Cattaneo Giulia , Saresella Marina , Marventano Ivana , Hernis Ambra , Bandi Claudio , Clerici Mario 
Published: December 2023

AbstractBackgroundThe hygiene hypothesis suggests that certain aspects of modern life are linked to lower rates of exposure to pathogens and lower immune‐system stimulation, being in turn positively related to Alzheimer’s‐disease (AD) risk. Amazonian tribes exhibit an exceptionally high prevalence of infections in individuals of all ages resulting in a better‐regulated degree of inflammation and improved cognitive functions after infection with the high parasite like Leishmanias (L). These findings suggest that a highly pathogenic environment and chronic infections might be favorable to shaping ever‐lasting immune responses, including against neurodegenerative conditions. Typical parasitic infections among indigenous included spp, protozoan parasites recognized by the same receptors that sense misfolded‐Aß in microglia; it is followed by subsequent regulation of the NLRP3, a cytosolic multiprotein complex mainly expressed in myeloid cells and composed of the Nod‐like receptor (NLR), the adaptor apoptosis‐associated speck‐like protein (ASC), and the pro‐caspase1, leading to the cleavage of bioactive IL1ß and IL18. Herein we investigated a possible connection between L tarantulae, nonpathogenic for humans, isolated from the lizards Tarentolae annularis and Tarentolae mauritanica to reduce IL1ß, IL18, Caspase1 release and ASC‐speck formation.Methodin vitro model of THP1 wild‐type and ASC‐knockout derived‐Macrophage were cultured in unstimulated or Lypolisaccaride and Aß treatment post L tarantulae (Lt‐p10)(10 parasites/cell) infection. L phagocytosis were quantified by confocal mycroscopy, cytokines production by ELLA and ASC‐speck formation and NLRP3 by AMNIS FlowSight.ResultASC‐speck formation as well as IL18 and caspase1 were significant (p<0.05)downregulated in LPS+Aß macrophages wild‐type post L‐infection compare to unstimulated cells; no significant differences were found for: i)IL1ß production on supernatants of cells; and ii)NLRP3 florecent‐mean between cell wild‐type and ASC‐knockout.ConclusionL is able to modulate the immune response in vertebrates, suppressing the inflammatory response, and allowing the parasites to survive and replicate in phagocytic cells of our immune system, such as in macrophages. Given this ability, one can imagine exploiting this effect of damping immune response to ameliorate or cure those diseases in which inflammation plays a key role or it is one of the major drivers, such as AD.