bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single‐nucleus open chromatin accessibility landscape of Pick’s and Alzheimer’s disease
Authors: Shi Zechuan , Das Sudeshna , Morabito Samuel , Miyoshi Emily , Head Elizabeth , Swarup Vivek 
Published: December 2022

AbstractBackgroundPick’s disease (PiD), a behavioral variant of frontotemporal dementia, is one of the common neurodegenerative dementia that is characterized by tau lesions. Despite the distinct tau aggregation observed in Pick’s disease compared with the tauopathy of Alzheimer’s disease (AD), the similarity in cognitive and behavioral impairments during the progression of the disease make their diagnosis challenging. What determines the differences and similarities between PiD and AD progression, especially at the epigenetic level, are largely unknown. We believe that recent advancement in single‐cell epigenomic profiling methods, Assay for Transposase‐Accessible Chromatin (ATAC) combined with high throughput sequencing, will enable us to map the chromatin‐regulatory landscapes of disease brains at a single‐cell resolution and enable us to understand underlying molecular changes in these diseases.MethodIn the present study, we have isolated single nuclei from the frontal cortex region and performed single‐nucleus ATAC sequencing (snATAC‐seq) of 198,722 nuclei to generate cell‐type specific chromatin accessibility profiles of postmortem brains of PiD and AD patients and to uncover their cellular heterogeneity and similarity. We used cellranger to process the paired‐end FastQ reads of each sample to obtain its chromatin accessibility count matrix. Next, we utilized ArchR and Signac pipelines to generate 501‐bp fixed‐width peak regions and performed downstream differential accessible regions analysis. Quality control was also performed to remove the contribution of low‐quality nuclei.ResultWe constructed chromatin accessibility profiles from 19,690 nuclei from PiD patients, 59,148 nuclei from AD patients, and 119,884 nuclei from healthy controls. We applied UMAP dimensionality reduction and clustered nuclei through open chromatin region to the batch‐corrected epigenomic datasets. We identified seven distinct cell types, including astrocyte, excitatory neurons, inhibitory neurons, microglia, oligodendrocytes, OPC, and pericyte/endothelial cells, and we applied pseudotime trajectory analysis to characterize disease‐associated cell state in both AD and PiD at the epigenomics level.ConclusionOur data identified the cell‐type‐specific open chromatin accessible regions in AD and PiD brains. Although the causative molecular mechanisms of AD and PiD remain unknown, our work helps to identify shared epigenomic changes in AD and PiD, especially in regards to cell‐type‐specific genomic loci with disease risk.
Longitudinal Changes in P3 Event‐related Potential among Older Adults with Preclinical Alzheimer’s Disease: A 1‐year Follow‐Up
Authors: Estes Bradley J , Gustafson Kathleen , Liao Ke , Martin Laura E , Ahmadnezhad Pedram , Kuhlmann Emily , Brooks William M , Mahnken Jonathan D , Burns Jeffrey M. , Devos Hannes 
Published: December 2022

AbstractBackgroundThe third positive peak of the event‐related potential (ERP P3) is understood to reflect neural resource utilization during working memory. We previously showed lower P3 ERP amplitude of the task effect in older adults with preclinical Alzheimer’s disease (AD). The aim of this study was to compare changes from baseline to 1‐year follow‐up in P3 ERP between older adults with and without preclinical AD.MethodCognitively normal, beta‐amyloid positive (CNAβ+, n = 14) participants and beta‐amyloid negative (CNAβ‐, n = 15) controls completed a working memory task (n‐back) with three levels of difficulty (0, 1, 2) at baseline and 1‐year follow‐up. ERP P3 peak amplitude and latency of the task effect (non‐target minus target) were extracted from continuous electroencephalography recording. The frontal midline channel Fz was identified a priori as the main channel of interest. Aβ accumulation was characterized with [18F] Florbetapir positron emission tomography scans. Independent t‐tests, Fisher’s Exact, or Mann‐Whitney U tests were employed to compare baseline characteristics between groups. Linear mixed models with random intercept were used to compare changes in P3 peak amplitude and latency. Group (CNAβ+ vs CNAβ‐), time (baseline, 1‐year), and n‐back (0, 1, 2) were entered as main effects. The main analysis of interest was the interaction between group and time.ResultBaseline age, sex, MOCA scores, and n‐back accuracy and response times did not differ (p>0.11) between CNAβ+ and CNAβ‐ groups [Table 1]. Additionally, no longitudinal changes in MOCA scores or n‐back performance were observed between groups (p>0.41). A significant group by time interaction effect in P3 peak amplitude at Fz was found between CNAβ+ and CNAβ‐ participants (p = 0.049). The P3 peak amplitude increased by 48% in CNAβ+ participants, whereas only a 19% increase was observed in CNAβ‐ participants.ConclusionThe ERP revealed significant changes over time in P3 amplitude for the CNAβ+ participants compared to the CNAβ‐ controls. The greater increase of CNAβ+ task effect amplitude likely represents a growing imbalance in task specific resource allocation. Further investigation of this phenomenon is warranted to evaluate neuronal activity of preclinical AD and the use of P3 ERP as a potential screening tool.
Predictive value of a plasma p‐tau181‐specific assay for amyloid accumulation in asymptomatic Alzheimer’s Disease
Authors: De Meyer Steffi , Vanbrabant Jeroen , Luckett Emma S. , Schaeverbeke Jolien , Stoops Erik , Van Laere Koen , Dupont Patrick , Vanmechelen Eugeen , Poesen Koen , Vandenberghe Rik 
Published: December 2022

AbstractBackgroundPlasma phosphorylated tau‐181 (p‐tau181) is one of the most reliable blood‐based biomarkers for Alzheimer’s Disease (AD), yet has been consistently quantified with assays employing an antibody cross‐reacting with p‐tau175. We investigated the ability of a novel phospho‐specific plasma p‐tau181 assay to predict longitudinal amyloid accumulation in cognitively unimpaired (CU) elderly.MethodsPlasma p‐tau181 was quantified with a novel Simoa‐based assay using a p‐tau181 specific antibody (ADx252) in a prospective longitudinal cohort of 78 CU elderly (baseline age[mean] = 70 years, 47% female, 51% APOE‐ε4 carriers). Plasma sampling, amyloid‐β (Aβ)‐PET ([18F]flutemetamol or [11C]PiB) and episodic memory tests (average Buschke Selective Reminding total retention /12) were performed at baseline and Aβ‐PET was repeated on average 5 years later (SD: 2, range 1‐10 years). Longitudinal amyloid accumulation was modelled through calculation of Aβ‐PET rate of change by dividing the difference between baseline and follow‐up tracer uptake (in Centiloids) by the time interval between scans (in years). A Spearman correlation matrix between longitudinal amyloid accumulation, plasma p‐tau181, baseline amyloid load, age and baseline episodic memory was calculated. Z‐scores of all variables were entered into a hierarchical regression analysis in a stepwise manner based on correlation strength and finally sex and APOE were added.ResultsBaseline plasma p‐tau181 correlated with longitudinal amyloid accumulation (ρ = 0.28, Figure 1A) as well as age (ρ = 0.31, Figure 1B). A negative correlation was found between age and baseline episodic memory scores (ρ = ‐0.33), and between p‐tau181 and baseline episodic memory scores (ρ = ‐0.19), although the latter did not reach significance. Apart from plasma p‐tau181, none of the other baseline variables correlated significantly with longitudinal amyloid accumulation (Figure 2). Hence, plasma p‐tau181 was entered into the base regression model. This base model (F(1,76) = 7.78, p = 0.007) explained 27% of the variance (R2) in longitudinal amyloid accumulation. Including additional predictors like demographics, clinical data or baseline amyloid load, did not further improve the model.ConclusionPlasma p‐tau181 measured with the novel phospho‐specific Simoa assay best reflects longitudinal amyloid accumulation in asymptomatic Alzheimer’s Disease with no additional predictive value of the other baseline factors included.
Risk of all‐cause dementia, Alzheimer’s disease, and vascular dementia among breast cancer survivors: Evidence from Swedish population data
Authors: Wennberg Alexandra MV , Ding Mozhu , Talbäck Mats , Feychting Maria , Modig Karin 
Published: December 2022

AbstractBackgroundCancer incidence and survival rates are increasing, and, as of 2020, two‐thirds of cancer survivors are over the age of 65; however, there is a paucity of evidence investigating their long‐term health. Cancer survivors may be at increased risk of cognitive impairment, even at younger ages. This risk may be associated with both the cancer and the cancer treatment, though very little research has been done using population datasets.MethodIn this matched cohort study, we examined risk of dementia among breast cancer survivors (n = 34900) compared to age‐matched comparison subjects (n = 290063). Women born 1935‐1975 registered in the Swedish Total Population Register between January 1st, 1991 and December 31st, 2015 were eligible for inclusion in the study. Survivors were women with a first breast cancer diagnosis between 1991 and 2005 who survived for at least 5 years after their initial diagnosis. All‐cause dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) were assessed using ICD codes in the National Patient Register. Date of death was determined by record linkage to the National Cause of Death Registry until December 31st, 2015.ResultIn subdistribution hazard models accounting for competing risk of death and adjusted for age, among all individuals in the analyses, there was no association between breast cancer survivorship and risk of all‐cause dementia, AD, or VaD. However, when stratified by age of cancer diagnosis, there was a higher risk of all‐cause dementia (subdistribution hazard ratio (SHR) = 1.28, 95% CI 1.05, 1.57) and VaD (SHR = 1.68, 95% CI 1.15, 2.45) among those diagnosed with breast cancer after age 65. Examining AD risk, the point estimate indicated an elevated risk, but the result was not statistically significant (SHR = 1.31, 95% CI 0.98, 1.76).ConclusionOur findings suggest that breast cancer survivors who were diagnosed with cancer after age 65 are at higher risk of developing dementia compared to women without a history of cancer. This suggests that late‐life but not mid‐life breast cancer may be a risk factor for dementia. However, more work needs to be done to further investigate potential differences between types of dementia and mediating effects.
Diabetes and hypertension are associated with elevated beta‐amyloid burden: evidence from the prospective population‐based Rotterdam Study
Authors: van Arendonk Joyce , Neitzel Julia , Steketee Rebecca M.E. , van Assema Daniëlle , Segbers Marcel , Ikram M. Arfan , Vernooij Meike W. 
Published: December 2022

AbstractBackgroundHigher vascular risk increases the likelihood of developing dementia. Better understanding the association between vascular risk and Alzheimer’s disease (AD) pathology at the pre‐dementia stage is critical for developing effective strategies to delay cognitive decline. In this work, we estimated the impact of vascular risk on the presence and severity of in‐vivo measured brain beta‐amyloid (Aβ) plaques in participants from the population‐based Rotterdam Study.MethodsVascular risk factors (hypertension, hypercholesterolemia, diabetes, obesity, physical inactivity, and smoking) were assessed twelve and seven years prior to 18F‐florbetaben positron emission tomography (PET) in 506 dementia‐free participants. Vascualr risk factors were associated with binary amyloid PET status or continuous PET readouts (SUVr values) using logistic and linear regression models respectively, adjusted for age, sex, education, APOE4 risk allele count, and time between vascular risk and PET assessment.ResultsParticipants’ mean age at time of amyloid PET was 68 years (range: 60‐90), 262 (51.8%) were women and 158 (31.2%) carried at least one APOE4 risk allele (Figure 1). The adjusted prevalence estimates of an amyloid‐positive PET status markedly increased with age (12% in 60‐69y vs. 45.5% in 80‐89y age‐groups) and APOE4 allele count (8.3% in non‐carriers vs. 34.8 to 58.8% in carriers of one or two risk allele(s); Figure 2). A diagnosis of diabetes seven years prior to PET assessment was associated with a higher risk of a positive amyloid status (OR[95%CI]=4.07[1.66–9.71], P=0.002; Figure 3) and higher SUVr values, indicating more severe Aβ pathology (standardized beta=0.478[0.205–0.750], P=0.001; Figure 4). We found evidence for an association between hypertension and higher SUVr values in APOE4 carriers, but not in non‐carriers (interaction: standardized beta=0.425[0.092–0.758], P=0.013; Figure 5). Hypercholesterolemia, obesity, physical inactivity and smoking were not related to amyloid PET measures.ConclusionThe current findings suggest a contribution of diabetes and hypertension to the pathophysiology of AD. Since both conditions respond well to lifestyle modification and drug treatment, further research should be conducted to examine the preventative effect of early risk management on the development of AD neuropathology.
Investigating neurodegenerative heterogeneity in cognitively unimpaired A4 pre‐randomization cohort
Authors: Shand Cameron , Donohue Michael C. , Oxtoby Neil P 
Published: December 2022

AbstractBackgroundThe heterogeneous nature of Alzheimer’s disease and uncertainty of determining disease severity and subtype can confound treatment effects in clinical trials. Computational methods for subtyping can assist in trial enrichment. This study investigates the latent heterogeneity and severity (including absence) of neurodegeneration in the cognitively unimpaired A4 cohort enriched for elevated amyloid.MethodBaseline 3T T1‐weighted MRI data from ADNI (N=687) and A4 pre‐randomization (N=1240, all Aβ+ [Sperling et al. 2020, DOI:10.1001/jamaneurol.2020.0387]) studies were included. FreeSurfer was used to estimate regional brain volumes, of which 13 features were input to SuStaIn (Young et al., 2018, DOI:10.1038/s41467‐018‐05892‐0) to train two cohort‐specific models of neurodegeneration subtypes. Volumes were first adjusted for age, sex, education, and intracranial volume, and z‐scored relative to controls (Aβ– in A4; cognitively normal in ADNI). For each feature, z‐score events of z=1 (subtle abnormality) and z=2 (atrophy) were used. The number of subtypes was determined using cross‐validation.ResultFigure 1 shows our SuStaIn model for ADNI, replicating the three‐subtype finding of Young et al. (2018). Figure 2 shows our SuStaIn model for A4, which estimated a similar three‐subtype model: typical, cortical, subcortical (named for the earliest atrophy events). Notable differences between the models are in the subtle abnormality (z=1) events in A4 that might, or might not, develop into more prominent atrophy (z=2), such as with the caudate which stalls at z=1 (Figure 2, top‐left). Our results indicate the presence of AD‐like heterogeneity in the A4 cohort. Figure 3 shows boxplots of amyloid PET SUVr — there are no statistically significant differences between subtypes (Mann‐Whitney U test), suggesting amyloid PET screening is insufficient to detect neurodegeneration heterogeneity. There were no statistically significant subtype differences in cognitive measures nor demographics (Table 1).ConclusionOur results show that neurodegeneration heterogeneity exists in the A4 cohort, despite amyloid PET screening. This heterogeneity could have ramifications on the potential success of the A4 trial, particularly if it correlates with different rates of cognitive decline and confounds anti‐amyloid therapeutic effects on trial endpoints. Our results support the use of more holistic, multimodal, data‐driven screening for clinical trials in Alzheimer’s disease to reduce cohort heterogeneity.
High anticholinergic burden in patients referred from primary care to a tertiary memory care.
Authors: Castilhos Raphael Machado , Formoso Carolina Rodrigues , Strelow Matheus Zschornack , Borelli Wyllians Vendramini , Chaves Marcia L Fagundes 
Published: December 2022

AbstractBackgroundThe anticholinergic burden (ACB) quantifies the cumulative anticholinergic drug exposure. Although a high ACB is associated with a greater risk of functional/cognitive decline, its usage is frequent in clinical practice. We aim to quantify the ACB and polypharmacy in referrals to a dementia tertiary outpatient clinic.MethodA retrospective analysis was performed including medical records of referrals from primary care to the tertiary outpatient dementia clinic of the Hospital de Clínicas de Porto Alegre from 2014 to 2021. All medications were evaluated and ACB was measured with the Brazilian Anticholinergic Activity Drug (BAAD) score. It classified drugs according to its central anticholinergic activity from 1 to 3, with higher values indicating greater anticholinergic activity. BAAD score is the sum of anticholinergic activity of each drug, with scores above 3 meaning high ACB. Polypharmacy was defined as the use of > 3 drugs. A logist regression was performed using age, sex, dementia etiology, and Mini Mental State Examination (MMSE) as covariates.ResultAmong 398 referrals, 238 had a diagnosis of dementia: Alzheimer’s disease (AD) (34.4%), mixed type dementia (10.9%), vascular dementia (VD) (9.6%) and others (Frontotemporal, Lewy bodies, alcohol and others 26.9%). A total of 43 (18%) individuals had severe dementia, named unspecified dementia. Polypharmacy was frequent (277, 74.5%) and VD presented an increased number of medications when compared with other groups (7.2+‐3.1, p<0.002 for all). A third of patients with dementia were classified as high ACB (119, 32%), though dementia etiologies were not associated with BAAD (p = 0.13). In the regression analysis BAAD were associated with VD (OR 3.6, IC 95%: 1.34‐9.9) and other types of dementia (OR 2.4, IC 95%: 1.19‐5). BAAD had a significant correlation with Geriatric Depression Scale (GDS) (r = 0.23, p = 0.0002), but not MMSE (p = 0.07).ConclusionMost patients presented polypharmacy at arrival to a tertiary memory clinic, and a third presented a high ACB. VD was a predictor of ACB score, and they may be at a greater risk of cognitive and functional worsening.
Investigation of relationship between tau PET SUVR and an indicator of post‐translational modification of tau in human blood plasma using electrochemical assay
Authors: Yoon Hyosang , Kwon SunSang , Jeong Seongeun , Hwang Bo Song , Seo Sang Won , Lee Soo Hyun 
Published: December 2022

AbstractBackgroundHuman tau protein is a well‐known biomarker to predict and diagnose the progress of Alzheimer’s disease [1]. The tau protein undergoes various post‐translational modificiation (PTM) of tau such as phosphorylation, O‐glycosylation, nitration, and glycation. Recently, abnormal phosphorylation of tau protein is observed in AD patients, while the level of O‐GlcNAcylation on tau protein is relatively elevated in brains of normal controls [2]. Reference: [1] L.M. Ittner et al. Nature Reviews Neuroscience, 12 (2011) 67. [2] C. Alquezar et al. Frontiers in Neurology, 11 (2021) 595532:Method(Figure 1) To investigate tau protein in human blood plasma and its PTM, a novel type of electrochemical sensor demonstrated and obtained Taumeter, an indicator as relative impedance changes of phosphorylated tau and O‐glycosylated tau, using secondary antibodies Finally, the as‐obtained Taumeter and PET SUVR were investigated for a relationship.ResultWe investigated the clinical relationship between Taumeters for AT8 and AT270 and tau PET SUVR, respectively, obtained from human blood plasma from normal control (NC, n=9), mild cognitive impairment (MCI, n=14), and Alzheimer’s disease (AD, n=13). In the case of AT8, it was observed that average Taumeters in MCI and AD were 2.86 and 4.73 times higher than those in NC (p=0.078 between NC and AD) (Figure 2a). In the case of AT270, average Taumeters in MCI and AD were 1.84 and 4.24 times higher than those in NC (p=0.057 between NC and AD) (Figure 2b). In further study, Taumeters for AT8 and AT270 correlated with tau PET SUVR (r=0.151, p=0.384 and r=0.575, p<0.001) (Figure 2c‐d).ConclusionIn this study, we investigated Taumeter reflecting PTM of tau proteins using secondary antibodies (O‐GlcNAc antibody, AT8, and AT270) in human blood and tau PET scan to investigate the relationship of Taumeter and tau PET SUVR in NC, MCI, and AD. As a result, it can be carefully implied that Taumeter has the relationship with the progress of AD.
A longitudinal study on quality of life along the spectrum of Alzheimer’s disease
Authors: Mank Arenda , Rijnhart Judith J.M. , van Maurik Ingrid S. , Jönsson Linus , Handels Ron , Bakker Els D. , Teunissen Charlotte E. , van Berckel Bart NM , van Harten Argonde C. , Berkhof Johannes , van der Flier Wiesje M. 
Published: December 2022

AbstractBackgroundQuality of life (QoL) is an important outcome from the perspective of patients and their caregivers, in both dementia and pre‐dementia stages.1 Yet, little is known about the long‐term changes in QoL over time.2 We aimed to compare the trajectories of the QoL between amyloid‐positive and amyloid‐negative patients along the Alzheimer’s disease (AD) continuum of cognitively normal to dementia.MethodIn this longitudinal study, we included n = 447 (age 61.6±6.6, n(40%)F, Mini Mental State Examination (MMSE) 29(27‐29), 23% amyloid‐positive) patients with Subjective Cognitive Decline (SCD), n = 276 (age 64.6±7.0, n(33%F), MMSE 27(25‐28), 52% amyloid‐positive) patients with Mild Cognitive Impairment (MCI) and n = 417 (age 64.4±7.0, n(51%F), MMSE 23 (19‐25), all amyloid‐positive) with AD dementia from the Amsterdam Dementia Cohort. We used linear mixed‐effect models (LMM) to compare QoL trajectories of the European Quality of Life‐5 Dimensions (EQ‐5D‐3L and EQ‐5D‐5L) and Visual Analogue Scale (VAS) between 1) amyloid‐positive and amyloid‐negative SCD or MCI patients and 2) amyloid‐positive SCD, MCI, and dementia patients. The models were adjusted for age, sex, Charlson Comorbidity Index (CCI), education and EQ‐5D scale (3 or 5 level).ResultIn SCD, amyloid‐positive participants had a higher VAS at baseline, but showed a steeper decline over time in EQ‐5D and VAS than amyloid‐negative participants (figure 1). Also in MCI, amyloid‐positive patients had higher QoL at baseline, but subsequently showed a steeper decline in QoL over time compared to amyloid‐negative patients. When we compared amyloid‐positive patients along the Alzheimer continuum, we found no difference between SCD, MCI or dementia in baseline QoL, but QoL decreased at a faster rate in the dementia stage compared with the pre‐dementia stages of SCD and MCI (figure 2). When we additionally adjusted for covariates in model 2, the effects remained.ConclusionQoL decreased at a faster rate over time in amyloid‐positive SCD or MCI patients than amyloid‐negative patients. QoL decreases over time along the entire continuum of AD of SCD, MCI and dementia, with the strongest decrease in dementia patients.