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: Speech abnormalities are increasingly recognized as a manifestation of cognitive deficits in Alzheimer's disease (AD) and its preclinical and prodromal stages. Here, we investigated whether MRI measures of brain atrophy, specifically in the basal forebrain and cortical language areas, can predict cognitive decline and speech difficulties in older adults within the AD spectrum.

Method: The ongoing Prospect-AD study aims to develop an algorithm to automatically identify speech biomarkers in individuals with early signs of AD.

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: Type 2 diabetes (T2D) is a prevalent health condition associated with cognitive impairment and dementia. T2D induces adverse effects not only on the pancreas but also on the liver, kidneys, muscles, fat cells, and, notably, the brain. Both T2D and Alzheimer's disease (AD) exhibit associations with neurodegeneration, yet the extent of their shared patterns of brain atrophy remains poorly understood, potentially indicating common pathways.

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: In Alzheimer's disease (AD), a major gap remains in the understanding of how the interplay between peripheral and central immune systems drives neuroinflammation and disease progression. More recently, the concept of brain lymph drainage has sparked interest as it may shed light on how the dynamics of T cell interactions contribute to AD. Our preliminary study aims to characterize alterations in the peripheral blood lymphocyte population among individuals with AD-dementia and mild cognitive impairment (MCI), as compared with cognitively unimpaired (CU) individuals.

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: This study investigated microstructural features of the locus coeruleus to entorhinal cortex pathway (LC-EC) in relation to amyloid (A), tau (T), neurodegeneration (N) markers and cognitive impairment in memory clinic patients.

Method: 124 participants were recruited from the Geneva Memory Clinic (n=30 cognitively unimpaired - CU; n=80 MCI and n=14 dementia - CI) and underwent clinical assessment, 3T MRI scan including diffusion weighted imaging, amyloid PET, and tau PET. Diffusivity indices (fractional anisotropy - FA, mean, axial and radial diffusivities - MD, AxD, RD) were assessed in the LC-EC pathway using a probabilistic atlas.

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: Alzheimer's disease (AD) impacts over 50 million individuals and imposes a substantial burden on patients, caregivers, and society at large. Recent research suggests that AD is a continuum comprising preclinical, prodromal, and dementia stages, with underlying pathology manifesting well before symptoms appear. Early and accurate diagnosis is therefore crucial for optimal clinical outcomes; yet current diagnostic methods, such as neuroimaging and cerebrospinal fluid lumbar puncture, are expensive and invasive.

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: The Centiloid method (CL) was introduced as a tracer-independent measure for cortical amyloid load and is now commonly used in Alzheimer's disease (AD) clinical trials. To facilitate its implementation into clinical settings, the AMYPAD consortium set out to integrate existing literature and recent work from the consortium to provide clinical context-of-use recommendations of the Centiloid scale, which has been submitted to the European Medicine Agency for endorsement as a Biomarker Qualification Opinion.

Method: Screening of the literature was performed on the 7/11/23 on PubMed to identify articles mentioning "Centiloid".

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: A key neuropathological feature in the early stages of Alzheimer's disease (AD) involves hippocampal dysfunction arising from the accumulation of amyloid-β (Aβ). Previously, our laboratory identified a shift in the synaptic plasticity long term potentiation (LTP)/long term depression (LTD) induction threshold, leading to memory deficits in a non-transgenic murine model of early AD generated by intracerebroventricular (icv.) injections Aβ oligomers (oAβ), one of the most predominant pathogenetic factors in initial stages of the disease.

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: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a common neuropathologic finding at advanced age that associates with hippocampal sclerosis (HS) and is often comorbid with AD pathology. Neuroimaging measurements of LATE-NC-associated limbic degeneration have been proposed as indirect biomarkers, but molecular-specific biomarkers for LATE-NC are still lacking. Here we used combined ante-mortem blood and MRI data to study TDP-43 levels in plasma-derived small extracellular vesicles (sEV-TDP-43) and hippocampal volume (HV) in relation to LATE-NC and HS at autopsy.

Biomarkers.

Background: Prostatic malignancy with paraneoplastic subacute encephalitis -A rare syndrome METHOD: We present a case of 76 year old male without any previous comorbidity and addiction who manifested a rapid neuropsychiatric decline with a frontotemporal syndrome over a period of 6 months. He was anemic and cerebrospinal fluid study showed 10 cells with lymphocytic predominance. The extensive workup of csf for infection, malignancy revealed nothing.

Biomarkers.

Background: To investigate the neuroanatomical characteristics at the whole-brain level associated with progression from amyloid-positive preclinical to prodromal Alzheimer's disease (AD) in relation to amyloid deposition and regional atrophy.

Method: We included 45 participants with amyloid-positive preclinical AD and 135 participants with prodromal AD matched 1:3 by age, sex, and education, from participants in the Korean Longitudinal Study on Cognitive Aging and Dementia and visitors to the dementia clinic of Seoul National University Bundang Hospital. All participants underwent F-florbetaben positron emission tomography and 3D structural T1-weighted magnetic resonance imaging.

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.