bluuebunny/crossref_metadata_2025_split huggingface dataset:
Utility of CSF biomarkers in assessing neurodegeneration in Early‐Onset Alzheimer’s disease
Authors: Eldaief Mark C. , Touroutoglou Alexandra , Brickhouse Michael , Katsumi Yuta , Eloyan Ani , Nudelman Kelly N. , Foroud Tatiana M. , Carrillo Maria C. , Rabinovici Gil D. , Apostolova Liana G. , Schindler Suzanne E. , Herries Elizabeth M. , Henson Rachel L. , Dage Jeffrey L. , Dickerson Bradford C. 
Published: January 2025

AbstractBackgroundThere is a significant need for biomarkers of neurodegenerative burden in Early‐onset Alzheimer’s disease (EOAD). Evidence suggests that levels of specific CSF biomarkers (e.g., Neurofilament light (NfL), Synaptosomal‐Associated Protein (SNAP‐25), neurogranin, Visinin‐like protein 1 (VILIP‐1), Aß 42/40, phospho‐tau and total tau) index the extent of neurodegeneration in dementing illnesses. However, it remains unclear whether these biomarkers correlate to cortical atrophy patterns in EOAD. Based on prior work demonstrating correlations between NfL, SNAP‐25, neurogranin and Aß 42/40 CSF levels and cognitive impairment in EOAD (Dage et al. 2023), we hypothesized that these biomarkers (and not VILIP‐1, phospho‐tau or total tau) would variably predict cortical atrophy within our recently described EOAD signature (Touroutoglou et al. 2023).MethodWe recruited 92 EOAD patients. In each patient, atrophy within the EOAD cortical signature were calculated as W‐scores (i.e., Z‐scores adjusted for age and sex relative to a sample of healthy controls). We first ran a simple regression analysis of each of the 7 CSF biomarkers and W‐scores in the EOAD signature across EOAD patients. We then entered the biomarkers with significant correlations to the EOAD signature into a stepwise regression analysis with backward elimination to ascertain the most parsimonious model predicting atrophy in the EOAD signature. As a control region not expected to be related to these biomarkers, we assessed correlations to calcarine fissure cortical atrophy.ResultAs predicted, we observed a significant correlation between CSF levels of NfL, SNAP‐25, neurogranin and Aß 42/40 and atrophy within the EOAD signature. After entering these four biomarkers into the stepwise regression analysis, the most parsimonious model identified complementary contributions of NfL, SNAP‐25, and Aß 42/40, in predicting atrophy in the EOAD signature. There were no correlations between any biomarker and calcarine atrophy.ConclusionSelected CSF biomarkers in EOAD patients predict the degree of atrophy within the EOAD cortical signature. Ongoing work includes correlating these biomarkers with topographical atrophy patterns on the whole‐brain voxel‐wise level. Our results suggest that certain CSF biomarkers could assess neurodegenerative burden within EOAD individuals. This would provide valuable information regarding disease progression for clinical care and clinical trials involving disease‐modifying therapies.
Investigating the ATN (Amyloid, Tau, Neurodegeneration) framework in Alzheimer’s Disease and its causal genetic‐drivers using Digital‐Twins
Authors: Sanjay Apoorva Bharthur , Sun Li , Shokeen Deepanshi , Isacson Ole , Shin So‐Youn , Latourelle Jeanne 
Published: January 2025

AbstractBackgroundAmyloid, Tau and neurodegeneration (ATN), the hallmark pathologies of Alzheimer’s Disease (AD) translating to measurable biomarkers are important for disease modifying therapeutics.MethodAD Digital‐Twins were built using AITIA’s patented A.I. platform REFSTM [aitiabio.com], based on a Bayesian network model of ADNI data which reverse‐engineered the connectivity of ∼59K multi‐modal variables and AD‐related outcomes profiled from 317 subjects (Control: MCI: Dementia=97:191:29). The average causal effect of each upstream‐downstream variables was estimated through in‐silico counterfactual experiments to evaluate the temporal relationship between the ATN outcomes, to identify the causal gene‐drivers (at blood RNA‐expression level) of “ATN” outcomes, and to investigate the known AD genotypic variants strongly driving ATN gene‐drivers. Age‐gene interaction was additionally explored through “double‐intervention” experiments, to evaluate age‐specific effects of gene‐drivers on ATN outcomes.ResultAD Digital‐Twins evaluated the ATN temporal relationship, and recapitulated some known relationships such that CSF‐abeta and Tau measures drive neurodegeneration measures, although it also showed CSF‐Tau measures to be upstream of amyloid PET, suggesting Tau changes may interact with other outcome changes more dynamically over the course of disease progression (Figure 1). Next, in‐silico experiments identified a total of 228 ATN gene‐drivers, including 8 common to all outcome‐categories, which affect cognitive outcomes as well (Figure 2) and are strongly related to immune‐response and inflammation pathways. Many of these genes were causally driven by multiple AD‐associated genotypic variants reported in GWAS, especially in the “NECTIN2” and “APOE” region. Furthermore, in‐silico experiments showed some Tau‐driving genes are likely to be causally driven by Amyloid and Neurodegeneration driving genes. Lastly, age‐specific effects were observed for a portion of each A‐, T‐ and N‐ gene‐drivers, especially with Tau‐driving genes having a stronger effect with opposite directionality for younger vs older age groups (Figure 3).ConclusionTau related abnormalities are likely early events in AD progression and more strongly linked to disease pathophysiology. Aitia’s AI platform allows powerful and systematic evaluation of multiple modalities and outcomes, accelerating precision medicine efforts in AD.
Using a blood‐based biomarker panel for Alzheimer’s disease to determine eligibility for disease modifying treatment in a memory clinic setting: three scenarios
Authors: Vigneswaran Sinthujah , Verberk Inge M.W. , Gouda Mariam , van de Giessen Elsmarieke , Wilson David H , Vijverberg Everard G.B. , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , Teunissen Charlotte , van Harten Argonde C. 
Published: January 2025

AbstractBackgroundBlood‐based biomarkers (BBM) for Alzheimer’s disease (AD) may be able to identify individuals eligible for emerging anti‐amyloid treatments (DMT). We aimed to evaluate how to use BBM as (pre‐) selection tools for DMTs by simulating different triaging scenarios in a memory clinic setting.MethodsWe included 1199 participants from the Amsterdam Dementia Cohort with measured BBM (plasma pTau181, GFAP and NfL) and used a predefined Youden‐index based cut point for amyloid positivity (method: https://doi.org/10.1002/alz.078748) (Table 1). We created three scenarios by changing at which step in the triaging process BBM were used. Other steps in the triaging process included seeing the medical doctor who determined clinical eligibility and an MRI (Table 1). A traditional screening approach including determination of amyloid positivity by CSF/amyloid‐PET after the MRI was taken as reference scenario A. Scenarios B, C and D all placed BBM determination at different triaging steps (Figure 1). In addition, we tested a scenario E with a high–intermediate–low likelihood categorisation using pre‐defined 90%‐sensitivity and 90%‐specificity levels.ResultsIn scenario A, 268 out of 1199 (22%) patients would undergo CSF/amyloid‐PET to select 183 individuals for DMT (Figure 1). When only patients with an abnormal BBM panel were selected to undergo CSF/amyloid‐PET, the number of CSF/amyloid‐PET was reduced with 47% to 141, at the cost of missing 59 (22%) eligible patients. Not performing CSF/amyloid‐PET after BBM measurement in scenario B‐D, resulted in 17 patients receiving treatment without being amyloid positive (12% of all patients receiving DMT) and missing 59 (22% of total eligible) eligible patients. Further consequences for the number of MRIs and medical consultations needed are summarized in Table 2. Only offering CSF/amyloid‐PET to patients with an intermediate chance of being amyloid positive in scenario E would result in 90 CSF/amyloid‐PET evaluations (49%) at the cost of missing 51 (19%) eligible patients and offering DMT to 11 (4%) amyloid negative patients.ConclusionsUsing BBM to preselect patients for DMT may reduce triaging costs, but it comes at the risk of under‐ or over‐treating patients. These unwanted effects can only be reduced by using blood‐based biomarkers with excellent diagnostic value.
Sex and amyloid burden modify tau spatial progression following entorhinal tau onset
Authors: Cody Karly , Heston Margo B. , Teague Jordan P , Alberson Sara Frost , Wintlend Madilynn , Bahr Melissa , Langhough Rebecca E. , Johnson Sterling C. , Betthauser Tobey J. 
Published: January 2025

AbstractBackgroundCharacterizing factors that impact longitudinal tau progression is important for understanding tau heterogeneity observed in clinical trials and research. This work examined factors associated with longitudinal tau PET (18F‐MK‐6240) accumulation relative to onset of entorhinal tau (EC) to better understand neurofibrillary tangle (NFT) spatial accumulation in Alzheimer’s disease.MethodParticipants (N=595; Table 1) from the Wisconsin Registry for Alzheimer’s Prevention and WADRC underwent serial amyloid and tau PET imaging. Amyloid burden was quantified from global cortical 11C‐PiB DVR(0‐70). Tau burden was quantified in regions of interest (ROIs) corresponding to Braak NFT1‐6 using 18F‐MK‐6240 SUVR(70‐90). Sampled iterative local approximation (SILA) was used to model EC tau trajectories and estimate EC tau‐time and onset age and, separately, to estimate amyloid level at tau scan. Regional tau accumulation was modeled with mixed effects models separately for Braak NFT2‐6 as a function of EC tau‐time (i.e. years of EC T+) starting with cubic polynomials. Models also included EC tau‐time*estimated CL at baseline tau (due to known associations between amyloid and tau) and additionally examined EC tau‐time interactions with age at baseline tau, self‐reported sex, and APOEe4.ResultIn this largely unimpaired cohort, there were no significant differences observed in APOEe4 carriage, baseline clinical status or amyloid level, or estimated age of A+ or EC T+ onset across males and females (Table 1). Regional T+ followed the expected spatiotemporal pattern (NFT2‐6) as time from EC T+ onset increased (Figure 1A). Across NFT3‐6, ROIs outside the medial temporal lobe (MTL), female sex and higher baseline amyloid were each associated with significantly faster tau accumulation rates relative to EC tau‐time (Figure 1A‐B). Post‐hoc comparisons indicated that rates of tau accumulation relative to EC tau‐time increased sequentially with increasing levels of amyloid, and that in NFT3‐6, the average rate of tau accumulation was significantly faster for females compared to males (Table 2).ConclusionThese findings provide evidence that tau accumulation and spread outside the MTL is accelerated by higher levels of amyloid and female sex. These data suggest that while people follow a similar spatial progression, the rate of progression varies, which may inform tau‐related dementia prediction.
ED care and Amyloid‐Related Imaging Abnormalities ‐ Impact and Future research
Authors: Aggarwal Neelum T. , Carpenter Christopher R 
Published: January 2025

AbstractWith the approval of disease modifying treatments for Alzheimer’s Disease, the practice of dementia care and treatment has changed. Amyloid related imaging changes, are the most common adverse effects of these types of drugs. There is limited guidance across multiple specialties on how to recognize and manage these changes in a dementia patient population. The use of these types of drugs for treatment, impacts multiple stakeholders regarding how they manage and treat dementia patients. ns. Thus the use of these types of drugs, involve multiple stakeholders with different perspectives on how they perceive their role in care and overall treatment plans. In order to optimize collaborative care in the ED setting, recognizing how ARIA may present in a patient who seeks care in the ED, and what types of treatment options are available are needed.
Clinical evaluation of a plasma Neurofilament Light chain electrochemiluminescence immunoassay in Alzheimer’s disease
Authors: Fatima Hadia A , Padmanabhan Nikhil , Cohen Rachel , Romero Daniel , Demos Catherine , Wohlstadter Jacob N , Sigal George , Arnold Steven E. , Kivisäkk Pia 
Published: January 2025

AbstractBackgroundNeurofilament light chain (NfL) is a key biomarker for axonal injury providing diagnostic and prognostic value in many neurodegenerative diseases. The sensitivity of electrochemiluminescence (ECL) immunoassays has previously not been adequate to quantify plasma NfL levels in Alzheimer’s disease (AD). Here we performed clinical evaluation of a recently developed ultra‐sensitive plasma NfL ECL S‐PLEX® immunoassay in individuals with AD and other neurodegenerative diseases.MethodWe measured NfL in banked plasma samples from 541 participants in the Massachusetts ADRC’s longitudinal cohort. Of these, 262 had a diagnosis of AD, 121 non‐AD neurodegenerative diseases (Ndgen), 46 other neurological diseases (OND), and 112 were controls (CON). The clinical diagnoses (AD/no AD) were verified by AD biomarkers (neuropathology, amyloid PET, CSF amyloid‐β 42/40 ratio, and/or plasma pTau181). Longitudinal analysis identified 223 participants with mild cognitive impairment (CDR 0.5) at baseline and 4 years of follow up. Of these, 131 remained stable with unchanged CDR, and 92 declined with worsening cognitive impairment (CDR³1.0). NfL was measured in all participants using an ECL immunoassays from Meso Scale Discovery (MSD) and in 72 participants using a SIMOA assay from Quanterix.ResultNfL levels measured using the two assays were highly correlated. Cross‐sectional analysis using the MSD assay showed the expected differences between the diagnostic groups with highest NfL levels in the Ndgen group, followed by AD, and the two control groups. NfL levels correlated with disease severity measured by cognitive testing (MoCA, global CDR, CDR SOB, and FAQ) at the time of blood collection. NfL levels at baseline were furthermore higher in participants who declined during follow‐up compared to stable participants both when studying the whole cohort and when limiting the analysis to participants with a final diagnosis of AD.ConclusionThe ultrasensitive ECL plasma NfL assay demonstrated utility for detection of AD and correlated with disease severity. Moreover, baseline plasma levels of NfL reflect cognitive decline over the next 4 years, providing prognostic information that may have utility in both clinical practice and clinical trial populations.
Hearing Loss and Default‐Mode Network Connectivity in Older Adults with Subjective Cognitive Decline and Mild Cognitive Impairment
Authors: Grant Nicole , Phillips Natalie 
Published: January 2025

AbstractBackgroundHearing loss (HL) is a risk factor for dementia that is prevalent in older adults. Altered brain connectivity is present in individuals with HL, individuals with subjective cognitive decline (SCD), and individuals with mild cognitive impairment (MCI). In individuals with HL, altered brain connectivity has been associated with impaired scores on cognitive tests. In individuals with MCI, altered brain connectivity has been associated with degree of cognitive impairment and progression to dementia. Therefore, altered brain connectivity is a potential mechanism by which HL is associated with increased dementia risk.MethodsData are from the Comprehensive Assessment of Neurodegeneration in Dementia study (Data Release 6, May 2023). Participants include cognitively unimpaired (CU, n=78, age=69.5), %female=77%), SCD (n=85, age=70.0, %female=74%), and MCI (n=159, age=72.2), %female=40%) individuals. Independent component analysis was used to identify the default‐mode network (DMN), a resting‐state network that is altered in individuals at risk for dementia. Hearing data include a pure‐tone hearing screening protocol and speech‐in‐noise perception. Based on the pure‐tone hearing screening, participants were classified as having normal hearing (NH) or HL. In each diagnostic group (CU, SCD, MCI), analyses of covariance compared DMN connectivity between the NH and HL participants and linear regressions evaluated the relationship between speech‐in‐noise perception and DMN connectivity.ResultsPreliminary results are available for 94 older adults with MCI (NH = 60, pure‐tone HL=34). Compared to individuals with MCI and NH, those with MCI and HL had decreased connectivity between the DMN and the caudate and thalamus. There was no relationship between DMN connectivity and speech‐in‐noise perception. The CU and SCI groups are expected to have a greater capacity for compensatory changes in functional connectivity. Therefore, it is expected that in the CU and SCI groups, pure‐tone HL and speech‐in‐noise perception will be associated with increased DMN connectivity.ConclusionCurrent results suggest that the increased dementia risk associated with HL may be due to decreased DMN connectivity and that pure‐tone HL and speech‐in‐noise perception are differentially related to DMN connectivity. Future research will determine whether the relationship between hearing and DMN connectivity differs between older adults with varying risk of cognitive impairment.
AT(N), neuronal and glial pathologies underlying neuropsychiatric symptoms and cognition in young‐onset dementia
Authors: Chiu Wei‐Hsuan , Goh Anita M Y , Malpas Charles B , Eratne Dhamidhu , Kelso Wendy , Walterfang Mark , Velakoulis Dennis , Loi Samantha M 
Published: January 2025

AbstractBackgroundYoung‐onset dementia (YOD) refers to the occurrence of dementia symptoms in people under the age of 65. Neuropsychiatric symptoms (NPS) are increasingly considered as the preclinical manifestations of YOD, posing a challenge to differentiate from psychiatric conditions with overlapping symptoms. The aim of this study is to investigate the AT(N), neuronal and glial pathologies underlying NPS and cognition in YOD.MethodThis study used clinical data from the Neuropsychiatry Centre, the Royal Melbourne Hospital, Melbourne, Australia. Sixty‐nine people with YOD were identified and assessed for biomarkers, NPS and cognition (mean age [SD] = 57.6 [7.3], female N = 23 [33%]). Their cerebrospinal fluid and plasma levels of amyloid‐beta, total‐tau (t‐tau), phosphorylated‐tau (p‐tau), neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAP) were measured. Common NPS such as depressive and behavioural symptoms were also measured. Cognitive functions were measured by a comprehensive battery of neuropsychological assessments. General linear regressions were used to investigate the associations between biomarkers, NPS and cognition.ResultMemory recall was correlated with levels of amyloid‐beta (r = .52, 95% conference interval [CI] = [.32, .75]), t‐tau (r = ‐.4, 95% CI = [‐.65, ‐.16]) and p‐tau (r = ‐.34, 95% CI = [‐.58, ‐.11]). Executive function was correlated with levels of NfL (r = ‐.4, 95% CI = [‐.78, ‐.03]). Levels of NfL were further correlated with the severity of stress (r = ‐.41, 95% CI = [‐.73, ‐.11]). No evidence of associations between levels of GFAP and NPS or cognition was observed. Visuoconstruction was correlated with levels of amyloid‐beta (r = .45, 95% CI = [.24, .67]), in which this relationship was moderated by the severity of self‐care problems (F [6, 28] = 5.48, p < .05).ConclusionThe results suggest that the changes in memory recall are associated with an intricate interplay between AT(N) pathologies in people with YOD. Executive function in YOD may be related to neuronal alterations rather than glial alternations in the brain. Combining biomarker results, the real challenge of self‐care problems in people with YOD observed by their caregivers may serve as a surrogate estimate to predict outcomes in visuoconstruction.
Multivariate Neuroimaging Analyses Reveal an Important Role for Iron Metabolism in Populations at Risk for Alzheimer’s Disease
Authors: Badea Alexandra , Moon Hae Sol , Anderson Robert J , Mahzarnia Ali , Stout Jacques Andrew , Han Zay Yar , Johnson Kim G , O'Brien Richard J 
Published: January 2025

AbstractBackgroundAlzheimer's disease (AD) is multifactorial, thus multivariate analyses help untangle its effects. We employed multiple contrast MRI to reveal age‐related brain changes in populations at risk for AD, due to APOE4 carriage. We assessed volume and microstructure changes using diffusion weighted imaging, and quantitative magnetic susceptibility maps (QSM) reflective primarily of cerebral iron metabolism.MethodOur study included 48 non APOE4 carriers, and 42 APOE4 carriers, with age ranging from 20.2 to 83; males and females. Imaging was done at 3T using diffusion weighted imaging (DWI) with TE 60.6 ms, TR=14725 ms, 21 diffusion directions (b=1000 s/mm2), reconstructed at 1 mm isotropic resolution using MUSE. A T1‐weighted FSPGR sequence was used for morphometry and co‐registration, TE=3.2 ms, TR=2263.7 ms, α=8°, prep time 900 ms, recovery time 700 ms, 1 mm isotropic resolution. QSM were calculated using STISuite based on fGRE images using TEeff=24.3 ms, TR 100 ms, α=15°, 8 echoes, reconstructed at 1x1x1.5 mm. Images were mapped into a common space before univariate and multivariate voxel‐based analyses (VBA).ResultUnivariate VBA (Figure 1) showed accentuated age effects in APOE4 carriers in areas involved in visual information processing (pericalcarine and lingual cortex, precuneus); as well as in cognitive and motor control processes (superior frontal cortex). FA supported the findings in visual processing areas, and added regions in the left temporal lobe (entorhinal cortex, middle and inferior‐temporal cortices). FA also revealed a role for the anterior cingulate, insula, left cerebellum; pars triangularis and pars orbitalis, involved in language processing. QSM analyses supported the findings in visual, cingulate, and cerebellar cortices, and revealed a role for the hippocampus, amygdala, and basal ganglia (caudate, putamen, pallidum). Multivariate analyses (Figure 2) supported a role for the precuneus, cuneus, and lingual cortex, the inferior temporal and cingulate cortices, and the caudate. The canonical vectors (Figure 3) for the top significant clusters revealed an important role for QSM.ConclusionOur results suggest accelerated changes in multiple domains besides memory in aging APOE4 carriers. Multivariate analyses supported an important role for age associated changes in cerebral iron metabolism, and oxidative stress, suggesting increased vulnerability to toxic insults.