bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Precision β‐Amyloid 1‐40, β‐Amyloid 1‐42, and Ptau181 Plasma Assay Performance in NCRAD Biomarker Assay Laboratory
Authors: Russ Kristen A. , Smith Emily , Kostadinova Ralitsa V. , Gao Sujuan , Brown Steve , Apostolova Liana G. , Risacher Shannon L , Saykin Andrew J. , Foroud Tatiana M. , Dage Jeff L. 
Published: December 2023

AbstractBackgroundTo achieve the robust and reliable implementation of assays in the National Centralized Repository for Alzheimer’s Disease and related Dementias (NCRAD), new assays and platforms must be assessed for performance characteristics. The goal of this study is to assess the [Fujirebio Lumipulse] G1200 performance in comparison to existing platformsMethodPlasma samples utilized for assay precision measurements were collected from healthy control subjects and patients with Alzheimer’s disease (AD) by the Indiana Biobank. Five samples were chosen to span the assay range and were assayed on two separate days. Clinical utility was assessed with plasma samples (N = 179) collected by the Indiana Alzheimer’s Disease Research Center (IADRC). A subset (N = 92) of these samples were also assayed on the Neurology 4‐Plex E Advantage Kit on the [Quanterix] Simoa‐HDx platform. All samples were assayed on the [Fujirebio Lumipulse] G β‐Amyloid 1‐40, β‐Amyloid 1‐42, and Ptau181 plasma assays.Result[Fujirebio Lumipulse] G β‐Amyloid 1‐40, β‐Amyloid 1‐42, and Ptau181 plasma assays had an average inter‐assay coefficient of variation of 2.6%, 2%, and 2% respectively (Figure 1). In samples with both [Fujirebio Lumipulse] and Simoa‐HDx pTau181 data, linear regression showed an R^2 of 0.80 and slope of 1.67. Bland‐Altman analysis showed a consistent bias of 54%. Once results were standardized by Z‐score, slope was near one, y‐intercept near zero, demonstrating comparability of results. Area Under Receiver Operating Characteristic curve (AUC) for IADRC samples with PET data was 0.84 for Aβ 42/40 ratio alone and 0.87 including age, sex and APOE status. AUC for Ptau181 alone was 0.83 and 0.89 including age, sex and APOE status. Assays were able to detect differences in clinical diagnosis or amyloid status (Figure 2A and B).ConclusionThe [Fujirebio Lumipulse] assays exhibited high precision. When standardized by Z‐score, the [Fujirebio Lumipulse] Ptau181 assay was comparable to the Simoa‐HDx Ptau181v2 assay allowing comparison of data between assay platforms. AUCs for amyloid PET were higher when considering age, sex and APOE status in the model. The assays were able to differentiate between clinical diagnoses and amyloid status suggesting suitability for implementation.
Detection of subclinical epileptiform discharges in Alzheimer’s disease using long‐term out‐patient EEG monitoring
Authors: Musaeus Christian Sandøe , Frederiksen Kristian Steen , Bo Andersen Birgitte , Høgh Peter , Kidmose Preben , Fabricius Martin , Hribljan Melita Cacic , Hemmsen Martin Christian , Rank Mike Lind , Waldemar Gunhild , Kjaer Troels Wesenberg 
Published: December 2023

AbstractBackgroundIn patients with Alzheimer’s disease (AD) without clinical seizures, up to half have epileptiform discharges in long‐term in‐patient electroencephalography (EEG) recordings. Long‐term in‐patient monitoring is obtrusive, and expensive as compared to out‐patient monitoring. No studies have so far investigated if long‐term out‐patient EEG monitoring is able to identify epileptiform discharges in AD. To investigate if epileptiform discharges as measured with ear‐EEG are more common in patients with AD compared to healthy elderly controls (HC). To understand the association with AD, we investigated the variability across multiple recordings.MethodIn this longitudinal observational study, 24 patients with mild to moderate AD and 15 age‐matched HC were included in the analysis. Patients with AD underwent up to three ear‐EEG recordings, each lasting up to two days, within 6 months. The first recording was defined as the baseline recording.ResultAt baseline, epileptiform discharges were detected in 75.0% of patients with AD and in 46.7% of HC (p‐value = 0.073). The spike frequency (spikes or sharp waves/24 hours) was significantly higher in patients with AD as compared to HC with a risk ratio of 2.90 (CI: 1.77‐5.01, p<0.001). Most patients with AD (91.7%) showed epileptiform discharges when combining all ear‐EEG recordings.ConclusionLong‐term ear‐EEG monitoring detects epileptiform discharges in most patients with AD with a three‐fold increased spike frequency compared to HC, which most likely originates from the temporal lobes. Since most patients showed epileptiform discharges with multiple recordings, elevated spike frequency should be considered a marker of hyperexcitability in AD.
Identification of rare coding variants associated with Alzheimer’s disease.
Authors: Khurshid Zainab , Farrer Lindsay A. , Zhang Xiaoling , Martin Eden R. , Kuzma Amanda B , Farrell John , Tong Tong , Zhu Congcong , Naj Adam C. , Cantwell Laura B , Valladares Otto , Wang Li‐San , Lunetta Kathryn L. , Schellenberg Gerald D. , Haines Jonathan L. , Leung Yuk Yee , Pericak‐Vance Margaret A. 
Published: December 2023

AbstractBackgroundPrevious whole exome sequencing (WES) studies of Alzheimer’s disease (AD) have identified genome‐wide significant associations with rare variants in several novel genes and highlighted the need for investigations in larger samples. We combined WES and whole genome sequencing (WGS) data assembled by the Alzheimer Disease Sequencing Project (ADSP) to increase the power for detecting associations of AD with rare variants in gene coding regions.MethodWe developed an efficient computational pipeline to perform both pre‐merging and post‐merging genotype, variant and sample‐level quality control (QC) on WGS data containing 16,905 individuals and WES data for 20,504 individuals. The resultant sample included participants from European (EA, 11,279 AD cases, 8,924 controls), African American (AA, 2,757 AD cases, 4,336 controls), and Caribbean Hispanic (CH 1,438 AD cases, 3,256 controls) ancestries. We employed GENESIS to test association of AD with 250,465 bi‐allelic QC’d variants using a logistic model including covariates for age, sex, exome capture kit, read length, and ancestry principal components (PCs).ResultIn the total sample, variants from APOE and other known AD genes including SORL1 (P = 5.30×10‐7), NECTIN2 (P = 6.94×10‐7), and TREM2 R47H (P = 2.34×10‐13) crossed or neared the study‐wide significance (SWS) threshold of P = 2.00×10‐7 (0.05/250,465). SWS or borderline significant associations were also found with variants in several novel loci including TKTL2 (P = 2.35×10‐8), D2HGDH, (P = 1.09×10‐7), CECR1 (P = 4.02×10‐7), PDHA2 (P = 2.76×10‐7), GOLGA1 (P = 1.72×10‐7), CYLD (P = 1.84×10‐7), and RP11‐243M5.4 (P = 1.37×10‐7). PSEN1 missense mutation G206A (rs63750082) previously associated with early onset AD in the CH group, was significantly associated with late onset AD in the same population (P = 1.58×10‐13). SWS association of AD with APOE was observed in all groups. Significant associations were also observed with variants in SERPINB8 (P = 3.77×10‐9) and FAM171A (P = 7.20×10‐7) in EAs and TLR4 (P = 4.58×10‐7) in CH. Associations with several top‐ranked variants were replicated in the Alzheimer’s Disease Genetics Consortium GWAS dataset that were imputed using the TOPMed reference panel and ADSP 5K WGS dataset.ConclusionWe demonstrated that merging WGS and WES datasets can increase power to detect associations with rare coding variants in genes including ones previously implicated in AD (CYLD and TLR4) and early‐onset stroke (CECR1).
Early screening for Alzheimer’s disease (AD) in subjects with age‐related macular degeneration: Associated risk factors and impact on their quality of life
Authors: Martinez Luis E , Martinez Sara Carolina , Baracaldo Gabriela 
Published: December 2023

AbstractBackgroundAge‐associated macular degeneration (AMD) is one of the main causes of central vision loss in one or both eyes, Multiple studies have shown that AMD and Alzheimer’s disease (AD) have risk factors and histopathological changes in common, such as the constitution of protein deposits.MethodCase‐control type analysis study, On a sample of 236 subjects, of whom 118 present AMD (cases) from the Colombian Ophthalmology Center in the city of Bogotá and 118 non‐DMR (controls) an analytical study of biomarkers for Alzheimer’s disease (ApoE) is performed to establish the degree of association between AMD and AD. After performing anamnesis and risk factors questionnaire, the fundus of the eye is studied by means of a Topcon TRV‐50VT type non midritic camera confirming the AMD, and Neuropsychological evaluation for cognitive impairment (MMSE, MOCA, MOCA BASICA and MOCA BLIND) for detection of MCI or AD and QOLIE quality of life questionnaire.ResultStudy in progress, in the phase of recruitment of subjects to participate, in the ophthalmological center in Bogotá. Visual abnormalities are prominent in AD and are believed to develop before cognitive decline, with our study we proposed the hypothesis of correlation for biomarkers (+) especially for ApoE 4 in blood for subjects with AMD and AD/MCI. On the other hand, we propose Correlation of ApoE2 or ApoE3 for biomarkers in the control group. In addition, we hope to correct the risk factors in both pathologies, we also plan a significant impact on quality of life for subjects with AMD and AD/MCI compared to the other groups.ConclusionMany of the protein accumulations associated with druses have been identified as responsible for the pathogenesis of other diseases such as AD, arteriosclerosis and amyloidosis, opening the possibility of common origins. Apo E is a cholesterol‐carrying protein that is present in hard and soft druses, in the brain one of the functions of Apo E is to regulate cholesterol during the process of neuronal remodeling. The apolipoprotein E allele inheritance is involved in the pathogenesis of arteriosclerosis and AD but with a decreased risk of exudative AMD.
Design of a Phase 2, Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Group Study to Assess the Efficacy, Safety, and Tolerability of BIIB080 in Subjects with Mild Cognitive Impairment Due to Alzheimer’s Disease or Mild Alzheimer’s Disease Dementia
Authors: Ziogas Nick , Mummery Catherine J. , Rovira Mercè Boada , Cummings Jeffrey L. , Fox Nick C , Hansson Oskar , Iwata Atsushi , Salloway Stephen , Schneider Anja , Unwin Anne , Huang Ellen , Edwards Amanda , Tien Irene , Wu Shuang , Lin Lin , Shulman Melanie , Landen Jaren , Haeberlein Samantha Budd 
Published: December 2023

AbstractBackgroundBIIB080 (formerly IONIS MAPT‐RX) is an antisense oligonucleotide (ASO) designed to bind to MAPT pre‐mRNA, promote its degradation, and prevent translation of all forms of tau protein. BIIB080 is, to our knowledge, the first tau targeting ASO to enter human clinical trials in Alzheimer’s disease (AD).BIIB080 was evaluated in Study ISIS 814907‐CS1 (NCT03186989) a Phase 1b, placebo‐controlled, double blind, multiple ascending dose clinical trial with 13‐week treatment period and 23‐week follow‐up period followed by an open‐label long term extension in patients with mild Alzheimer’s disease. BIIB080 was generally well tolerated. Importantly, robust, time‐dependent and dose‐dependent decreases in CSF total and phosphorylated tau were observed. Additionally, BIIB080 impacted aggregated tau pathology as measured by tau PET as early as 25 weeks.Based on the Phase 1b results, Biogen is conducting a Phase 2 study, Study 247AD201 (NCT05399888) that will evaluate the efficacy, safety, and tolerability of BIIB080 in participants with mild cognitive impairment (MCI) due to Alzheimer’s disease or mild Alzheimer’s disease dementia.MethodRandomized, double‐blind, placebo‐controlled, parallel‐group Phase 2 study (CELIA), is enrolling approximately 735 individuals aged 50‐80 years, with MCI due to Alzheimer’s disease or mild Alzheimer’s disease dementia, Clinical Dementia Rating (CDR) global score 0.5‐1, Mini Mental State Examination (MMSE) score 22‐30, objective evidence of cognitive impairment at Screening, and evidence of amyloid pathology as measured by PET or cerebrospinal fluid (CSF) sampling.The Phase 2 study will randomize participants to receive 1 of 3 different dose regimens of intrathecal (IT) BIIB080 or placebo every 12 or 24 weeks during the 76‐week placebo‐controlled period. The primary endpoint will assess the dose‐response in change from Baseline to Week 76 on the CDR‐SB.The study includes a tau PET substudy to assess the effect of BIIB080 on tau aggregates with 18F‐MK6240.ResultThe Ph2 CELIA study is currently recruiting participants.ConclusionThe ongoing Ph2 CELIA trial will assess the efficacy, safety and tolerability of BIIB080, compared to placebo in subjects with MCI due to Alzheimer’s disease or mild Alzheimer’s disease dementia.
Effect of long‐term treatment with carbonic anhydrase inhibitors on the brain microcirculation in Tg‐SwDI mice
Authors: Gutiérrez‐Jiménez Eugenio , Rasmussen Peter Mondrup , Mikkelsen Irene Klærke , Kura Sreekanth , Fruekilde Signe Kirk , Bordoni Luca , Boas David , Fossati Silvia , Østergaard Leif 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) shares many risk factors with cardiovascular diseases, and much evidence shows that AD involves a cerebrovascular component. AD patients display disturbances in brain hemodynamics characterized by decreased cerebral blood flow (CBF) during steady‐state conditions. It has been suggested that capillary stalls heavily impact the CBF of AD animal models. Increased stalling time may impair capillary flow patterns, reducing oxygen availability to the brain tissue. Previous studies have shown that capillary stalling is induced by leukocyte plugging due to damage to the capillary endothelium and adhesion molecules' expression. Carbonic anhydrase inhibitors (CAIs), potent vasodilators, have been shown to reduce amyloid β (Aβ) neurovascular toxicity. We examined capillary hemodynamics in the Tg‐SwDI mouse model after long‐term treatment with CAIs.MethodFour months old Tg‐SwDI mice were fed for 140 – 150 days with a diet supplemented with acetazolamide (ATZ), methazolamide (MTZ), or no medication (Tg‐Ctrl). A control group of wild‐type (WT) mice was also included. We performed imaging in awake head‐restrained Tg‐SwDI and WT mice through a cranial window placed onto the barrel cortex’s somatosensory area. Capillary stalls were quantified using time‐series OCT‐angiography. We examined capillary hemodynamics, morphometrics, and amyloid load using two‐photon microscopy. The distribution of flow dynamics was estimated as the coefficient of variance (CVs) of capillary scans. Amyloid load and ICAM‐1 expression were measured in the brain cortex and hippocampus using ELISA.ResultWe included 62 mice (mean 16 ± 3 per group). Both treated groups showed a decreased stalling time compared to the Tg‐Ctrl group (p < 0.05). Mice treated with MTZ showed larger capillary diameters correlated to increased cell flux and velocity (p ≤ 0.01). We observed a similar in mice treated with ATZ. Cell velocity and diameter CVs were much smaller in mice treated with ATZ than in non‐treated mice (p < 0.01), indicating more homogenous capillary flow patterns. We observed a similar tendency in the MTZ group. Hemodynamic changes were associated with decreased Ab‐42 and ICAM‐1.ConclusionTreatment with CAIs improves capillary flow hemodynamics and distribution, preventing amyloid accumulation in brain tissue. Improvement of capillary flow patterns is associated with better oxygen diffusion.
Longitudinal analysis in an Alzheimer’s murine model reveals sex‐specific inflammatory response
Authors: Barber Alicia J , del Genio Carmen L , Pizzi Elizabeth , Swain Anna Beth , Tapiavala Vedant N , Watson Sarah C , Mah'moud Mirelle M , Zanazzi George J , Gaur Arti B 
Published: December 2023

AbstractBackgroundStriking sex‐related differences are observed in individuals with Alzheimer’s disease (AD). Females with AD largely present with more severe neuropathology, yet surprisingly, males with AD have an increased risk of mortality. To elucidate this dichotomy, we conducted a longitudinal study in an AD mouse model, aimed at identifying cellular and molecular based drivers of sex‐specific disease trajectories.MethodTissues were collected from 3xTg‐AD and control mice of both sexes across the lifespan (3‐24 months) and stained with H&E (liver, spleen, heart, lungs, kidney) or beta‐amyloid, phospho‐tau, and total tau antibodies (brain). Brain tissue was also used for RNA‐sequencing. Sex‐specific differential gene expression and ingenuity pathway analyses were conducted between age‐matched 3xTg‐AD and control brain tissue samples, in addition to clinical AD and control brain tissue samples obtained from the AD Knowledge Portal RNAseq Harmonization Study.ResultOver the course of our longitudinal study, we confirmed that female 3xTg‐AD mice exhibit more severe Alzheimer’s related neuropathology than males. Surprisingly, 3xTg‐AD males do not develop amyloid plaque pathology within their lifespan, however, they do experience significantly worse splenomegaly, myocardial injury, and liver inflammation in old age, resulting in higher mortality, compared to females. Changes observed in gene expression across the lifespan of both sexes show significant upregulation of various inflammatory pathways in the brain, including the complement system. However, in line with pathological findings, aged female 3xTg‐AD mice exhibit sex‐specific dysregulation of synaptic and endocrine pathways in the brain, while male 3xTg‐AD mice exhibit sex‐specific dysregulation of TREM1 signaling, hepatic dysfunction, and additional immune‐related pathways. Many canonical pathways disrupted in 3xTg‐AD mice were also detected in clinical AD samples, including pathogen induced cytokine storm signaling, S100 family signaling, and hepatic fibrosis/hepatic stellate cell activation.ConclusionOur results show widespread inflammatory responses in the 3xTg‐AD model, that are exacerbated in male mice, suggesting a systemic impact of Alzheimer’s disease involving liver dysfunction. Furthermore, neuroinflammation is not correlated with amyloid plaque deposition in 3xTg‐AD mice, raising important questions surrounding the protein’s role in disease progression. Our analyses of clinical AD RNA‐sequencing data further validate the gene expression changes observed in 3xTg‐AD mice.
Can we use machine learning to predict cognitive performance from actigraphy data? Preliminary results from the UK Biobank Study
Authors: Falck Ryan S , Liu‐Ambrose Teresa , Galea Liisa A , Tam Roger 
Published: December 2023

AbstractBackgroundCircadian rhythms (i.e., the ∼24‐hour biological clock) are critical to the maintenance of the sleep‐wake cycle, and sleep‐wake disturbances are common in people at risk for cognitive decline and dementia. Several studies have identified circadian factors associated with cognitive decline using actigraphy (a common field measure for indexing the sleep‐wake cycle). However, there are currently untapped opportunities to use the power of artificial intelligence, specifically machine learning (ML), to improve our ability to identify signs of cognitive decline from actigraphy data. As a first step towards this goal, we examined the utility of two supervised ML models for predicting cognitive performance using data from the UK Biobank study.MethodA cross‐sectional analysis of participants in the UK Biobank study (40‐69 years at entry) with valid actigraphy data and complete cognitive data (N = 49,469). Participants completed computerized versions of Trail Making Test B‐A (TMT) and Digit Symbol Substitution Test (DSST). Actigraphy data were collected over 7 days, with average hourly movement being indexed. Along with 24‐hour actigraphy data, we included the following features in each model: age, biological sex, household income, educational attainment, smoking and alcohol intake, ethnicity, body mass index, and Townsend Deprivation Index. Seventy percent of participants were randomized to the training set, with the remaining 30% held out as a test set. We developed two separate ML models to predict cognitive performance: 1) a linear regression approach; and 2) a 3‐hidden layer (40 hidden units per layer) neural network. Model accuracy was compared using the coefficient of determination (R2).ResultMean age was 55 years (SD = 8 years) and 56% of participants were female. Average TMT time was 27.22 seconds (SD = 20.10 seconds), and mean DSST score was 20.06 (SD = 5.04). Our supervised linear regression had modest predictive ability of TMT (R2 = 8%) and DSST performance (R2 = 21%); the 3‐hidden layer neural network had similar predictive capability for both TMT (R2 = 8%) and DSST (R2 = 21%).ConclusionML approaches for predicting cognitive performance using actigraphy data show modest capability. Further work is needed to identify how ML can be used to predict cognitive function from biometric data.
A comparison of the original ADAS‐cognitive subscale and a novel extended version in mild cognitive impairment and Alzheimer’s disease.
Authors: Roller Hunter R , Chaulagain Suchana , McGinity Sean , Botchway Albert , Conner Drew C , Zec Ronald F , Ala Tom , Hascup Erin R. , Trivedi Mehul Alkesh 
Published: December 2023

AbstractBackgroundThe Original Alzheimer’s disease Assessment Scale‐cognitive subscale (oADAS) is the gold standard for assessing cognition in Alzheimer’s disease (AD) medication clinical trials. One criticism is that this measure is not sensitive to pre‐dementia syndromes such as mild cognitive impairment (MCI), possibly due to ceiling effects for many of the subtests in the original ADAS‐cog (oADAS). In this study, we examined group differences between individuals with MCI, AD, and normal controls (NC) on the oADAS and a novel extended version of the ADAS (eADAS). We hypothesized the eADAS would be more sensitive than the oADAS at detecting differences between the groups after controlling for age, education, and sex.MethodThe oADAS was administered using standardized methods. The eADAS included short‐delay recall and recognition trials for the first wordlist, a short‐delay true‐false word recognition trial for the second word‐list, a letter‐digit timed psychomotor test, supermarket fluency, spontaneous clock drawing, three additional items to the object naming subtest, three additional figures to copy, and a similarities test. MCI and possible AD were diagnosed using established diagnostic criteria. The NC group was significantly younger and more educated than the MCI and AD groups. A 3×2 ANCOVA model with group as the between subject factor and ADAS type as the within subject factor was used. Total error scores from the oADAS and eADAS were converted to z‐scores.ResultThere was no main effect of ADAS type or ADAS type X education or ADAS type X group interactions. There were ADAS type x age and ADAS type x gender interactions (p’s = 0.01). Pairwise comparisons demonstrated that the NC group had lower total error scores compared to the MCI and AD groups and the MCI group had lower total error scores compared to the AD group for both the oADAS and eADAS (p’s<0.001).ConclusionThe results of the current study indicate that oADAS and eADAS are sensitive to group differences between MCI and AD, which was contrary to our hypothesis. We suggest more rigorous diagnostic criteria for MCI in the present study may explain some of the conflicting findings in the literature.