bluuebunny/crossref_metadata_2025_split huggingface dataset:
Physiological Confounders of Blood‐Based Alzheimer’s Disease Biomarkers in Middle‐Aged Asymptomatic Individuals
Authors: Tristão‐Pereira Catarina , Fuster Valentin , Sanchez‐Gonzalez Javier , Ibañez Borja , Zetterberg Henrik , Blennow Kaj , Gispert Juan Domingo , Cortes‐Canteli Marta 
Published: December 2023

AbstractBackgroundBlood‐based biomarkers represent a promising tool for Alzheimer’s disease (AD) clinical diagnosis and patient management. However, the identification of physiological factors that may influence their concentration levels in plasma is fundamental to warrant their clinical use, but more data is needed on whether such possible confounders result in clinically relevant changes. Here, we aim to identify physiological confounders of blood‐based AD biomarkers in a middle‐aged asymptomatic population.MethodThe Progression of Early Subclinical Atherosclerosis (PESA) study is a longitudinal study following >4000 asymptomatic middle‐aged individuals. This study included 537 PESA participants, 370 of them with follow‐up data 4.7±0.6 years later. The concentrations of Aβ40, Aβ42, p‐tau181, GFAP and NFL in plasma were quantified using the Simoa pTau‐181 V2 and Neurology 4‐Plex E Advantage Kits. Potential confounders were also measured and included body mass index (BMI), as a proxy of blood volume; creatinine, as of kidney function; and aspartate (AST) and alanine aminotransferase (ALT), as of liver function. Stepwise regression was used to determine which confounders (predictors) are associated with plasma biomarkers (outcomes), adjusting for age, sex and APOE, both cross‐sectionally and in annual change rates (p<0.05). Participants were classified into normal and abnormal, based on standard cut‐off values for all potential confounders. Between‐group differences in plasma biomarkers were sought, and the abnormal group’s fold‐change was calculated.ResultThe studied sample had a mean age of 50.4±4.3 years, 441 were males and 88 APOE‐ε4 carriers (Figure 1). All blood‐based biomarkers but Aβ42/40 were negatively correlated with BMI and positively correlated with creatinine (Figure 2). ALT and AST were associated with Aβ40, Aβ42 and p‐tau181 but with opposite effects. Increases in BMI were associated with a decline in NFL and GFAP, while an increase in AST with a decline in amyloid and tau accumulation in plasma. Abnormally high BMI was associated with lower biomarker plasma concentrations, except for in Aβ42/40, with a maximum fold‐change of ‐12% for GFAP (Figure 3).ConclusionBMI, kidney and liver function are associated with plasma brain biomarkers levels in asymptomatic middle‐aged individuals. However, the magnitude of their effect is minor, with limited impact for their clinical applicability in individual patients.
Brains in focus: Uncovering protein aggregate changes across Alzheimer’s disease with single‐molecule imaging
Authors: English Lizzie A , Boeken Dorothea , Cheetham Matthew R , Danial John SH , Klenerman David 
Published: December 2023

AbstractBackgroundOligomers are increasingly implicated in Alzheimer’s disease (AD)1. The characteristics of these protein aggregates remain largely unknown due to their low biological concentration, solubility, small size and structural heterogeneity. This study aims to better classify the diverse protein aggregates found in human brains across AD onset and progression.MethodsPost‐mortem flash‐frozen brain samples (n = 28) spanning the full range of AD stages (Braak 0‐VI) were obtained from London Neurodegenerative Diseases Brain Bank: two brain regions, middle temporal gyrus (MTG) and primary somatosensory cortex (SOM), were obtained from 14 donors. The post‐mortem tissues were homogenised to extract proteins into liquid fractions for single‐molecule studies. Antibodies, including 6E10, HT7, AT8 and SC‐12767, were selected to bind aggregates of amyloid‐β, tau, phosphorylated tau and α‐synuclein respectively. Ultra‐sensitive single‐molecule array (Simoa®) assays measured protein aggregate quantities in the homogenates. Single‐molecule pull‐down (SiMPull) assays, imaged by super‐resolution fluorescence microscopy, measured aggregate size and shape within the homogenates. BCA assays quantified the total protein content of the homogenates for normalisation.ResultsMorphological differences in tau aggregates were observed between disease stages with super‐resolution microscopy. Quantities of phosphorylated and total tau aggregates tend to increase significantly in the MTG and SOM from mid‐stage AD onwards according to Simoa® assays. In comparison to tau, aggregate quantities of amyloid‐β and α‐synuclein displayed less variation between non‐diseased controls and different AD stages.ConclusionsSingle‐molecule techniques can sensitively detect a broad range of protein aggregates from human brains. Novel differences in the morphologies and quantities of aggregates have been identified across AD stages. There is strong potential for uncovering the specific protein aggregates responsible for AD with these methods. This could facilitate earlier disease detection and more effective treatment targeting.
1 Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353‐356 (2002).
Analysis of the screening process in the Brazilian Subjective Cognitive Decline Cohort
Authors: Souza Victória Tizeli , da Mota Simone Sieben , De Marchi Bruno De Oliveira , Formoso Carolina Rodrigues , Rivas Gabriela Raquel Paz , Carvalho Guilherme Da Silva , De Souza Haniel Bispo , Beltrami Lucas Bastos , Suwa Samuel Masao , Slaviero Wesley , Santos Rhaná Carolina , Carnevalli Sarah Vitoria Bristot , de Albuquerque Ana Letícia Amorim , Giordani Manuella Edler Zandoná , Strelow Matheus Zschornack , Borelli Wyllians Vendramini , Carello‐Collar Giovanna , Chaves Marcia L Fagundes , Zimmer Eduardo R , Castilhos Raphael Machado 
Published: December 2023

AbstractBackgroundSubjective Cognitive Decline (SCD) is conceptualized as cognitive complaints in cognitively unimpaired (CU) individuals and is associated with progressive cognitive decline. Recruiting these individuals can be challenging, especially due to the low education levels and limited access to information by a portion of the Brazilian population.ObjectiveWe aimed to analyze the profile of the screened individuals during the recruitment process in the ongoing Brazilian Subjective Cognitive Decline (BRASCODE) Cohort at the Hospital de Clínicas de Porto Alegre (HCPA), Southern Brazil.MethodsWe analyzed the sociodemographic characteristics of the screened individuals recruited predominantly through social media and newspaper invitation. This study evaluated CU individuals aged 65+ years‐old with cognitive complaints. Exclusion criteria were the presence of uncontrolled psychiatric/clinical illness, cerebrovascular disease, and the use of psychotropic drugs. The recruitment was carried out exclusively by phone calls in two phases. In the first one, the exclusion criteria were applied and, in the second, the following scales were performed: Modified Telephone Interview for Cognitive Status (TICS‐M); Generalized Anxiety Disorder Assessment (GAD‐2); Geriatric Depression Scale; and the Subjective Cognitive Decline Scale.ResultsFrom February to December 2022, 406 individuals were recruited. Most were women (74.6%; n = 303), with a median (SD) age of 71.6 (5.8) years‐old and 11 (5.2) years of formal education. The main reasons for exclusion in phone call 1 were clinical illness (39.9%; n = 59) and cerebrovascular disease (10.1%; n = 15). In those individuals evaluated in the phone call 2 (62.3%; n = 256), most were excluded because presented TICS‐M score below cut‐off (31.6%; n = 80), absence of cognitive complaints (29.6%; n = 75), and GAD‐2 (7%; n = 18) and GDS (3.5%; n = 9) scores above the cut‐off (Figure 1). Only 74 (18.2%) individuals were included in the cohort.ConclusionThe high screening failure seen in our study and the predominance of women with high educational level reveal the difficulty in screening SCD individuals and indicate the need for alternative recruitment methods, especially in a setting with low education.
TREM2 Burden associates solely with Alzheimer’s Disease, and decreases the Chance to become a Centenarian
Authors: Dijkstra Janna I.R. , Vermunt Lisa , Biessels Geert Jan , Braber Anouk , Claassen Jurgen A.H.R. , De Deyn Peter Paul , Ghanbari Mohsen , Huisman Martijn , Hulsman Marc , Ramakers Inez H.G.B. , Reinders Marcel J. T. , Seelaar Harro , Tesi Niccoló , Visser Pieter Jelle , van der Flier Wiesje M. , Teunissen Charlotte E. , Holstege Henne , Van Der Lee Sven J 
Published: December 2023

AbstractBackgroundRare TREM2 variants are major risk factors for Alzheimer’s disease (AD), but TREM2 variants may also confer a higher risk for other neurodegenerative diseases and a lower probability for cognitively healthy aging. We studied the TREM2 burden associated with different types of dementia and cognitively healthy centenarians (CHCs).MethodWe included participants of the 100‐Plus Study, Amsterdam Dementia Cohort, Longitudinal Aging Study Amsterdam and various Dutch memory clinics. TREM2 variants (R47H, R62H, Q33X, R62C, T96K) were genotyped with a high density array or imputed using standard methods (TOPMED reference panel). To avoid family bias and ethnic differences, related individuals and those of non‐European ancestry were excluded. Frequencies of individual variants and the burden of TREM2 variants were compared in AD dementia, dementia with Lewy Bodies (DLB), frontotemporal dementia (FTD), cognitively normal controls and CHCs (correcting for 5 principal components).ResultWe identified 242 carriers of TREM2 mutations and 6,683 controls without a TREM2 mutation with a mean age of 69 years (SD ±14 years), 50% female (Table 1). TREM2 variants were significantly associated with AD dementia (OR 1.4, 95%CI 1.1‐1.8, p = 0.01) (Table 2). R47H conferred the highest risk for AD (OR 2.8, 95%CI 1.4‐5.6, p = 0.004), compared to 1.3‐fold increased risk of R62H (95%CI 0.9‐1.7, p = 0.11). The carrier frequency was not increased in DLB (OR 1.4, 95%CI 0.7‐2.6, p = 0.34) and was not increased in FTD compared to controls (OR 0.59, 95%CI 0.3‐1.3, p = 0.18). Of interest, the allele frequency of TREM2 variants in centenarians is half of the expected frequency (OR = 0.46, 95%CI 0.1‐1.1, p = 0.10), and only concerns R62H.ConclusionWe replicate the association of TREM2 with increased risk of AD. In contrast to previous reports no association was observed with DLB or FTD. Cognitively healthy centenarians show a negative trend for TREM2 allele frequency suggesting that carrying a TREM2 variant decreases chances of survival to extreme age.
The frequency of psychotropic drug use in early‐onset Alzheimer’s disease ‐ experience from the Center for Memory Disorders in Serbia
Authors: Šarčević Maksim , Stojkovic Tanja , Stojmenovic Gorana Mandic , Obradovic Dragan , Stefanova Elka 
Published: December 2023

AbstractBackgroundNeuropsychiatric symptoms (NPS) occur frequently in patients with young onset Alzheimer’s Disease (YOAD). However, studies on psychotropic drug use (PDU) mainly focus on elderly patients with dementia. It is important to know the prevalence of PDU in patients with YOAD in order to reduce excess use of these medications in this group. Our study aim is to investigate the frequency of PDU among patients with YOAD.MethodThis is a retrospective study on 135 patientsfrom Memory Centre of Neurology Clinic, Clinical Centre of Serbia, with clinical diagnosis of YOAD. We included outpatients that had first visit to our clinic from 01.04.2012. to 01.04.2017. The data on psychotropic drug use werecollected from medical records. Statistical analyses were done using SPSS20.ResultMean age of our patients at inclusion was 60.07±5.27 and mean disease duration was 3.42±1.53. 85.18% patients received PT drugs. Antidepressants were prescribed most frequently, in 63.7% of patients, while antipsychotics were used by 45.93% of patients, and benzodiazepines by 61.5%. The earliest prescribed PTs were antidepressants, 3.66 years from the first symptoms and 1.45 years after diagnosis and antidepressants were used the longest in our group, 3.15 years.ConclusionThe frequency pf PDU in our cohort is high and comes close to PDU in patients in nursing homes in other European countries. The reason might be the high frequency of NPS in YOAD but also prescribing practice in the absence of systematic non pharmacological measures and that is something we have to take notice of.
Amyloid‐beta immunotherapy induces novel methylomic changes in Alzheimer’s disease brain
Authors: MacBean Lachlan Ford , Smith Adam R. , Boche Delphine , Lunnon Katie 
Published: December 2023

AbstractBackgroundPost‐mortem neuropathological examinations following the first active immunotherapy strategy (AN‐1792, Elan Pharmaceuticals, 2000) for Alzheimer’s disease (AD) have evidenced amyloid‐β (Aβ) plaque clearance and increased microglial phagocytic activity in immunised individuals. This study characterises the epigenetic profiles of individuals who underwent Aβ immunotherapy with the aim of discovering novel therapeutic targets and biomarkers.MethodDNA was isolated from post‐mortem prefrontal cortex tissue of 16 immunised AD cases who received varying doses (ug) and number of doses during the trial period, including placebos. DNA methylation was quantified using methylation arrays and the raw intensity values processed and normalised for subsequent statistical analysis to identify differentially methylated positions (DMPs) across the genome associated with Aβ immunotherapy. Additional analyses included regions of enrichment analysis for identification of differentially methylated regions (DMRs) and weighted gene co‐expression network analysis to identify gene clusters with highly correlated methylation levels.ResultAfter correcting for known (age, sex, cell type composition) and unknown variables, a DMP located within Chromosome 19 Open Reading Frame 12 (C19Orf12) at the genome‐wide significance level (P < 9.00E−08) was associated with Aβ immunisation. 10 DMRs were further associated with immunisation, with three regions consisting of ≥ 3 CpG sites and having a Sidak‐corrected P < 0.05. These regions were located within the CRISP2 (chr6; 49681178:49681391 [8 probes], Sidak‐corrected P = 8.29E‐05), CTTNA1 (chr5; 138210906:138211184 [8 probes], Sidak‐corrected P = 5.96E‐06), and RNF39 (chr6; 30038859:30039025 [12 probes], Sidak‐Corrected P = 2.60E‐05) genes.ConclusionIndicating better inflammatory markers can help inform of effective preventative care strategies for elders. This study provides evidence for altered epigenetic processes in the pathophysiology of AD and identifies novel processes specific to Aβ immunotherapy. The next step for this project includes analysing RNA sequencing data, to determine if observed methylomic changes correlate with gene expression, and genotyping array data.
Reframing dementia: can a human rights approach bring hope?
Authors: McGettrick Grainne 
Published: December 2023

AbstractDementia discourse is largely medicalized and the voice of the person with dementia is not often heard in public or policy discourse. Dementia still remains stigmatized and hidden, and in many societies, is often associated with shame due to its social construction. As a result, people living with dementia and their carers retreat, live lesser lives and largely exist on the margins of our society. However, if we were to reframe dementia as a human rights issue (as set out the United Nations Convention on the Human Rights of Persons with Disabilities) and use the rights model of disability to begin to tackle the societal, attitudinal and physical barriers that limit participation, then perhaps there is hope that people living with dementia continue to be valued and respected a central part of our families, communities and society after diagnosis.A Human Rights Based Approach (HRBA) would ensure that the person’s agency is recognized, they are treated as equal and active citizens with rights, and make certain they are involved in all the decisions that impact their lives in multiple spheres, including policy, public discourse, research, services, civic life and advocacy. This reframing of the discourse requires the broad range of actors to engage and change their practice. From a policy and systems perspective, it would demand a significant shift in the current approach and an adopting of the PANEL principles (Participation, Accountability, Non‐discrimination and Equality, Empowerment and Legality) in how we develop policy and service responses. A HRBA requires a move from the traditional ‘doing for’ to a model of enablement, active engagement and working together. By challenging the medical model and the current status quo, can we reduce stigma, bring people with dementia and their families in from the margins and offer hope for a better life living with dementia using a human rights lens?
Voxel‐level of abnormal β‐amyloid accumulation and spatiotemporal distribution patterns in Alzheimer’s Disease
Authors: Sun Pan , Cai Yue , Li Anqi , Zhu Yalin , Ma Shaohua , Guo Tengfei ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

AbstractBackgroundThe spatial patterns of β‐amyloid (Aβ) accumulation are critical for early diagnosis and clinical trials of Alzheimer’s Disease (AD). In this study, we explored a new voxel‐level Aβ index and investigated spatial patterns of voxels with abnormal Aβ deposition in different stages of AD.MethodWe identified 944 ADNI participants with Aβ 18F‐florbetapir positron emission tomography (PET) image. All Aβ PET images were co‐registered with their corresponding magnetic resonance imaging (MRI) scans, intensity‐normalized to the whole cerebellum, and spatial‐normalized to the Montreal Neurological Institute (MNI) space. We defined the threshold of each voxel as the mean+2SD of 18F‐florbetapir PET images of 51 participants who were Aβ PET negative (A‐), CSF p‐Tau181 negative (T‐), hippocampal atrophy negative (N‐), and cognitively unimpaired (CU) at both baseline and follow‐up. The positive voxel number (NoVoxel+) was counted based on the threshold of each voxel. The cross‐sectional and longitudinal correlations between NoVoxel+ and cortical summary Aβ standard uptake value ratio (SUVR) were determined in A‐ and Aβ‐positive (A+) separately. We compared baseline NoVoxel+ among different stages of AD, as well as how it related to longitudinal changes of Aβ SUVR, CSF p‐Tau181, residual hippocampal volume (rHCV), temporal meta‐ROI cortical thickness, and preclinical Alzheimer cognitive composite (PACC) score, and follow‐up tau PET levels, controlling for age, sex and APOE4. Finally, we investigated the spatial patterns of NoVoxel+ in different stages of AD.ResultThe new Aβ index NoVoxel+ was strongly correlated with the cortical summary Aβ SUVR cross‐sectionally and longitudinally regardless of Aβ positivity (Figure 1). Cognitively impaired (MCI and dementia) individuals showed larger (p<0.001) NoVoxel+ than the CU individuals, A+ group had greater NoVoxel+ than the A‐ group (Figure 2). NoVoxel+ was related to faster rates of increases in Aβ SUVR and CSF p‐Tau, decreases in rHCV, temporal meta‐ROI cortical thickness, and PACC. Abnormal Aβ voxels were primarily located in precuneus, medial orbital frontal and anterior/posterior cingulate regions in A‐/CU group (Figure 3).ConclusionThe proposed voxel‐level Aβ deposition NoVoxel+ may be useful to investigate the spatial and temporal patterns of Aβ accumulation in AD, particularly in early amyloidosis stage.
MR1/MAIT cell axis in the temporal development of Alzheimer’s disease pathology
Authors: Johnson Season Kealyn , Kersey Holly N , Codocedo Juan F , Newell Kathy L , Landreth Gary E , Lamb Bruce T , Oblak Adrian L , Brutkiewicz Randy R 
Published: December 2023

AbstractBackgroundNeuroinflammation is a hallmark feature of Alzheimer’s disease (AD). A major producer of inflammation is mucosal‐associated invariant T (MAIT) cells, a novel subpopulation of innate‐like T cells that recognize unique antigens presented by the MR1 molecule. This study aims to determine the contributions of the MR1/MAIT cell axis in humans and animal models of AD.MethodBrain tissue from various ages of 5XFAD mice and those that are MR1‐deficient (MR1KO), and from AD and non‐AD individuals, was analyzed for correlative relationships between MR1 and Aβ expression, and the presence of MAIT cells. qPCR was used to determine transcriptional changes in Mr1. Immunofluorescent microscopic analysis of MR1 expression and MAIT cell numbers in the brain was performed with antibodies against MR1, microglia, Aβ, and MR1 tetramers for MAIT cells. The activation state of brain MAIT cells was analyzed by flow cytometry with antibodies against CD69 and CD25.ResultIn brain sections from AD patients and 5XFAD mice, MR1 expression was substantially elevated in microglia surrounding plaques versus those further away (human AD: P < 0.05; 5XFAD: P < 0.001). In 5XFAD/MR1KO mice, the development of amyloid‐beta plaque pathology occurred at a significantly slower rate than in normal 5XFAD mice. Furthermore, there was a temporal increase in MAIT cell numbers (P < 0.01) in the brains of 5XFAD mice. These MAIT cells were highly activated, with elevated expression of both CD69 (P < 0.05) and the interleukin‐2 receptor alpha chain (CD25) (P < 0.05); such was not the case with brain‐resident classical T cells.ConclusionThe MR1/MAIT cell axis augments the temporal development of Aβ plaques. Thus, our data indicate a potential detrimental role for MR1 and/or MAIT cells in AD pathology. Understanding the contribution of this innate immune axis could provide novel clues as to the overall role of innate immunity in AD, leading to its identification as a potential therapeutic target in AD.