Biomarkers.

Background: Aging is associated with heightened systemic inflammation, decline in selective aspects of cognition, and an increase in white matter lesions (WMLs). Both WMLs and systemic inflammation have been related to cognition. However, it is not clear how they interdependently relate to cognitive aging.

Biomarkers.

Background: The choroid plexus (ChP) plays a vital role in CSF production and waste clearance. While existing imaging studies have established connections between ChP volume changes and age-related neurodegenerative diseases, a comprehensive investigation into the microstructural and vascular changes associated with aging remains insufficient. This study aims to explore ChP changes in normal aging using diffusion and perfusion MRI in the HCP-Aging dataset to enhance our understanding of age-related microstructural and vascular changes in the ChP.

Biomarkers.

Background: Alzheimer's Disease (AD) is associated with sleep disturbances. Moreover, individuals with sleep disturbances have been reported to have a higher risk for developing AD. The measurement of sleep behavior therefore opens the opportunity for a potential digital biomarker of AD.

Biomarkers.

Background: Use of neuroimaging [e.g. magnetic resonance imaging (MRI), positron emission tomography (PET), or computed tomography (CT) scan], cerebrospinal fluid (CSF), and blood biomarker tests can contribute to a more accurate and earlier diagnosis of Alzheimer's disease (AD).

Biomarkers.

Background: Growth/differentiation factor-15 (GDF15) has been associated with dementia risk, yet its predictive value across cohorts and sub-population, as well as its relationship with endophenotypes relevant to dementia, remains unknown.

Methods: Using the Atherosclerosis Risk in Communities (ARIC) study as the discovery cohort, we examined the relationship between plasma GDF15 levels (SomaScan) and risk for incident all-cause dementia (ACD) in late-life (N=4,287, 7-year follow-up, M=75±5) and in midlife (N=11,595, 20-year follow-up, M=57±6). Utilizing the UK Biobank (UKB; replication cohort), we related plasma GDF15 (Olink) to incident ACD (N=35,673, 14-year follow-up, M=61±5), vascular dementia (VaD) and Alzheimer's disease dementia (AD).

Biomarkers.

Background: With the approval of several anti-amyloid antibodies and a robust pipeline of new amyloid-based therapies, attention turns towards questions related to real-world clinical practice. Here we explore the impact of several biological pathways on the amyloid biomarker response of AD patients using a Quantitative Systems Pharmacology (QSP) approach with the ultimate objective to find measurable biomarkers for responder identification.

Method: Using a well-validated QSP biophysically realistic model of amyloid aggregation, we performed sensitivity analysis to identify key drivers of amyloid biomarkers both in a longitudinal observational context and after treatment with specific amyloid antibodies.

Biomarkers.

Background: Blood-based biomarkers will be essential for providing clinicians an accessible and cost-effective Alzheimer's disease (AD) screening tool. Elevated levels of two phosphorylated tau biomarkers (pTau181 & pTau217) correlated with amyloid and tau-PET consistent with AD diagnosis. We evaluated the analytical and clinical performance of each biomarkers using two different high-sensitivity methodologies (CLEIA and Simoa®) in a single laboratory to compare the performance of pTau181 and 217 in a clinical (CLIA-certified) laboratory.

Biomarkers.

Background: This research introduces a novel method for quantifying aggregated tau in body fluids, specifically cerebrospinal fluid (CSF), aiming to enhance the diagnosis and monitoring of neurodegenerative diseases, with a focus on Alzheimer's disease (AD).

Method: By combining tau protein amplification with a highly sensitive single-molecule array (Simoa) immunoassay using an anti-tau antibody CT19.1 in a homogenous manner, the approach enables precise measurements of tau aggregates in CSF.

Biomarkers.

Background: Obstructive sleep apnea (OSA) is a complex and heterogeneous condition associated with chronic physiological and neuropsychological disturbances (1-4). One notable neuropsychological effect observed in OSA patients is memory impairment (2,5). Additionally, some reports suggest that OSA may be associated with Alzheimer's Disease (AD) (4).

Biomarkers.

Background: The mitochondrial cascade hypothesis suggests that mitochondrial dysfunction plays an important role in the pathogenesis of Alzheimer's disease dementia. Recent data have shown that mitochondrial DNA copy number (mtDNAcn) in human blood is associated with dementia risk and cognitive function, but which specific cognitive measures or domains are associated with mitochondrial dysfunction and whether this relationship is affected by health deterioration such as physical frailty or mitochondrial somatic mutations is not clear.

Methods: We measured mtDNAcn and heteroplasmies using fastMitoCalc and MitoCaller, respectively, from UK Biobank Whole Genome Sequencing (WGS) data at study entry (2006-2010).

Biomarkers.

Background: In recent efforts to improve early identification, staging, and prediction of risk of persons at risk for vascular contributions to cognitive impairment and dementia (VCID) in relation with small vessel disease (SVD), the MarkVCID consortium has worked to identify and validate fluid- and imaging-based biomarkers for SVD associated with VCID. Free water (FW) measured derived from diffusion tensor imaging and one of the selected neuroimaging biomarker "kits", has been demonstrated to have excellent instrumental validity and to be a sensitive biomarker of cognitive performances. We sought to further examine FW clinical relevance by investigating whether FW predicts cognitive worsening over time.

Biomarkers.

Background: Amyloid related imaging abnormalities (ARIA), a group of neuropathological features seen in anti-amyloid immunotherapy patients, arises partly from CAA (Aβ buildup in blood vessels). Squirrel monkeys (SQMs), developing prominent age-related CAA exceeding brain Aβ, offer a unique NHP model for ARIA study. Evaluating edema-related neurobiological defects (ARIA-E) involves preferential use of T-weighted (T-w) and flow-attenuated inversion recovery (FLAIR) MRI while T*-weighted (T*-w) MRI is better suited for investigating iron-related pathology like microbleeds, hemorrhaging, and iron-homing in plaques.

Biomarkers.

Background: The MarkVCID consortium was established to address the paucity of biomarkers for vascular contributions to cognitive impairment and dementia (VCID), a leading cause of dementia. Plasma neurofilament light (NfL), a neuroaxonal injury marker elevated in several neurological and neurodegenerative diseases, was selected as one of the first biomarkers to be examined. We performed comprehensive instrumental and clinical validation of the Quanterix Simoa NfL assay using the first MarkVCID cohort.

Biomarkers.

Background: Phase four of the Alzheimer's Disease Neuroimaging Initiative (ADNI4) began in 2023. This time-period corresponded to MRI vendors introducing product sequences with compressed sensing (CS), cross-vendor adoption of arterial spin-labelling (ASL) and multi-band slice excitation, and hardware improvements (head-coils, increased gradient amplitudes). These advances enabled the acquisition of new imaging measures and reduced scan times.

Biomarkers.

Background: Phenotyping Alzheimer's Disease (AD) can be crucial to providing personalized treatment. Several studies have analyzed the use of digital biomarkers to characterize a subject's behavior, usually obtained from a single modality, such as speech. However, combining several modalities in a single study has not been deeply studied.

Biomarkers.

Background: Diffusion tensor imaging along perivascular spaces index (DTI-ALPS), which measures diffusivity increases in the perivascular spaces along the medullary veins, is being increasingly utilized as a surrogate marker of glymphatic clearance (Taoka et. al. Jpn J Radio 2017).

Biomarkers.

Background: To aid development of prevention strategies, we investigated whether a composite measure of late-midlife lifestyle health was associated with (1) change in brain tau burden, vascular burden and neurodegeneration and (2) cognitive trajectories when accounting for these brain changes.

Method: We included 324 individuals from the Wisconsin Registry for Alzheimer's Prevention. Late-midlife lifestyle was assessed using the Lifestyle for Brain Health (LIBRA) score, encompassing 12 risk-and protective factors for cognitive decline and dementia.

Biomarkers.

Background: Recent advances in diagnostics have made it possible to identify early signs of the pathophysiological changes underlying Alzheimer's Disease (AD) via blood tests. However, the use of blood-based biomarkers (BBBMs) for the early detection of AD may be limited in primary care settings despite its potential for wide access and early detection of AD (PMID: 37295421) Therefore, there is a need to understand the barriers and facilitators of BBBM testing for AD in primary care.

Method: We employed a combination of qualitative research, advisory board, and quantitative survey to engage with clinical/scientific advisors and community-based physicians in primary care.

Biomarkers.

Background: Recent advances in automatic face recognition have increased the risk that de-identified research imaging data could be re-identified from face imagery in brain scans.

Method: An ADNI committee of independent imaging experts evaluated 11 published techniques for face-deidentification ("de-facing") and selected four algorithms (FSL-UK Biobank, HCP/XNAT, mri_reface, and BIC) for formal testing using 183 longitudinal scans of 61 racially and ethnically diverse ADNI participants, evaluated by their facial feature removal on 3D rendered surfaces (confirming sufficient privacy protection) and by comparing measurements from ADNI routine image analyses on unmodified vs. de-faced images (confirming negligible side effects on analyses).

Biomarkers.

Background: The association between [F]Flortaucipir (FTP) and [F]MK6240, two commonly used tau-PET tracers in Alzheimer's disease (AD), varies due to distinct binding properties and off-target signal regions. Our study aims to elucidate the biological factors influencing this association and evaluate the applicability of a common equation across different on-target regions.

Method: 113 individuals from the HEAD dataset (11 young, 58 cognitively unimpaired elderly, and 44 cognitively impaired) underwent [F]MK6240, [F]FTP and Aβ-PET scans.

Biomarkers.

Background: Tau-PET tracers allow for in vivo Braak staging of individuals in the Alzheimer's disease (AD) continuum. The impact of tracers' characteristics for Braak staging using tau-PET remains unclear. Therefore, we performed a head-to-head comparison of Braak staging using first- and second-generation tau-PET tracers.

Biomarkers.

Background: Many proposed clinical decision support systems (CDSS) require multiple disparate data elements as input, which makes implementation difficult, and furthermore have a black-box nature leading to low interpretability. Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) is an established modality for the diagnosis of dementia, and a CDSS that uses only an FDG-PET image to produce a reliable and understandable result would ease both of these challenges to clinical application.

Method: A deep variational autoencoder (VAE) was used to extract a latent representation of each image through prior training from FDG-PET brain images (n=2000).

Biomarkers.

Background: The brain's ability to perform a cognitive task is a dynamic process and requires small blood vessels to dilate or constrict in real time to adjust blood flow in a region-specific manner. Cerebrovascular Reactivity (CVR) measures the ability of vessels to react to vasoactive challenges. In this work, we investigated the role of CVR as a possible biomarker in small vessel disease related vascular contributions to cognitive impairment and dementia (VCID), as part of the NINDS-funded MarkVCID study.

Biomarkers.

Background: The location of proposed brain MRI markers of small vessel disease (SVD) might reflect their pathogenesis and may translate into differential associations with cognition. We derived regional MRI markers of SVD and studied: (i) associations with cognitive performance, (ii) patterns most likely to reflect underlying SVD, (iii) mediating effects on the relationships of age and cardiovascular disease (CVD) risk with cognition.

Method: In 891 participants from The Multi-Ethnic Study of Atherosclerosis, we segmented enlarged perivascular spaces (ePVS), white matter hyperintensities (WMH) and microbleeds (MBs) using deep learning-based algorithms, and calculated white matter (WM) microstructural integrity measures of fractional anisotropy (FA), trace (TR) and free water (FW) using automated DTI-processing pipelines.

Biomarkers.

Background: APOE genotype is the most important genetic risk factor for Alzheimer's disease (AD), but whether it affects the proteins associated with AD risk is unclear. Circulating proteins may reveal biology underlying pathologic processes.

Methods: We evaluated log2 standardized levels of 4979 proteins quantified using modified aptamer technology [SomaScan] in plasma from 2725 participants in the Cardiovascular Health Study who were free of dementia and stroke.