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: Glymphatic system dysfunction as characterized by increased MRI-visible Perivascular Spaces (PVS) is speculated to play a role in the acceleration of amyloid accumulation in Alzheimer's Disease (AD). However, while PVS is also prevalent amongst Vascular Dementia (VD), the pathological distinctions between regional PVS in AD- and VD-driven cohorts remain largely unknown. Through a mixed dementia cohort, we examined these pathology-driven localization patterns via automated PVS segmentations from T2-weighted MRI.

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: 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: 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: 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 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: The heart-brain connection has been proposed to correlate cardiac disorders with brain health. However, the associations between subclinical alterations in cardiac structure or function and Alzheimer's disease (AD) pathologies haven't been fully elucidated. This study aimed to delineate the interrelationships between the subclinical alterations in the left heart, cerebrospinal fluid (CSF) AD biomarkers, and cognition.

Biomarkers.

Background: Despite an aging population, it remains challenging to reliably differentiate between loss of cognitive function associated with normal aging and cognitive decline associated with pathologic processes. With growing interest in using retinal and optic nerve biomarkers to diagnose neurodegenerative diseases, characterization of the velocity of normal retinal age-related changes will further our understanding. We evaluated longitudinal microvascular changes in cognitively normal older adults using optical coherence tomography (OCT) and OCT angiography (OCTA).

Biomarkers.

Background: Previous studies have shown that carriage of the VEGF 1154A (rs1570360) and the VEGF 2578C (rs699947) alleles may confer a protective effect on the development of Alzheimer's disease (AD). However, it is unknown if these associations are APOE-dependent and whether they can be observed in asymptomatic individuals with varying levels of amyloid pathology. The aim of this study is to determine whether interactions between the APOE ε4 allele, VEGF 1154A, and VEGF 2578C are associated with amyloid load in cognitively unimpaired (CU) older adults.

Biomarkers.

Background: The nuclear clearance and cytoplasmic aggregation of splicing repressor TAR DNA/RNA-binding protein-43 (TDP-43) occur in approximately 50% of Alzheimer's disease (AD) cases and about 45% of frontotemporal dementia (FTD). However, it is not clear how early such mechanism occurs in AD and FTD as there is no method of detecting TDP-43 dysregulation in living individuals. Since the loss of nuclear TDP-43 leads to cryptic exon inclusion, we propose that cryptic exon-encoded peptides may be detected in patient biofluids as biomarkers of TDP-43 loss of function.

Biomarkers.

Background: Plasma tau phosphorylated at threonine 231 (p-tau231) is a promising novel biomarker of emerging Alzheimer's disease (AD) pathology. We aimed to characterize cross-sectional and longitudinal plasma p-tau231 measurements and estimated ages of biomarker onset in an exceptionally large number of presenilin (PSEN1) E280A (Glu280Ala) mutation carriers and age-matched non-carriers from the Colombian autosomal dominant Alzheimer's disease kindred.

Method: We included a cohort of 722 PSEN1 E280A mutation carriers (mean age 36.

Biomarkers.

Background: There is a strong link between tau and progression of Alzheimer's disease (AD), necessitating an understanding of tau spreading mechanisms. Prior research, predominantly in typical AD, suggested that tau propagates from epicenters (regions with earliest tau) to functionally connected regions. However, given the constrained spatial heterogeneity of tau in typical AD, validating this connectivity-based tau spreading model in AD variants with distinct tau deposition patterns is crucial.

Biomarkers.

Background: Intrathecally (IT) delivered antisense oligonucleotides (ASOs) are promising therapies that can reduce tau pathology in Alzheimer's Disease (AD). However, current plasma and CSF sampling methods to estimate brain tissue exposure of ASOs are inherently limited, hampering ASO clinical developmental plans. We developed the PET tracer [F]BIO-687, which binds ASO conjugates (ASO-Tz) in vivo, allowing us to image ASO distribution in a living brain using "pretargeted" imaging.

Biomarkers.

Background: Parkinson's disease (PD) is a debilitating condition that affects millions of people worldwide, yet there are currently no reliable biomarkers for its diagnosis. Alpha-synuclein aggregation is a well-known hallmark of PD pathology, but the behavior and kinetics of these aggregates are poorly understood. To address this gap in knowledge, this study utilized several approaches to evaluate the potential of alpha-synuclein aggregates as potential biomarker for PD.

Biomarkers.

Background: Subjective cognitive decline (SCD), in the absence of objective cognitive impairment, may be the first symptomatic manifestation of Alzheimer's disease (AD). Previous studies have suggested that its combination with amyloid-positivity (Aβ+) may represent stage 2 AD, and is associated with a higher risk of future cognitive decline. Here, we aim to (1) confirm this using the plasma Aβ42/40 ratio, and (2) test whether the addition of plasma phospho-tau181 (ptau, a marker of Aβ and tau pathology) could help refine the prediction of future cognitive decline in SCD patients.

Biomarkers.

Background: Post-COVID cognitive dysfunctions, impacting attention, memory, and learning, might be linked to inflammation-induced blood-brain barrier (BBB) impairment. This study explores post-COVID BBB permeability changes using a non-contrast water-exchange based MRI and their associations with blood Alzheimer's biomarkers.

Method: Sixty-seven participants were classified based on COVID (COV) and cognitive (COG) statuses into three groups: COV+/COG- (n=34), COV+/COG+ (n=23), and COV- (n=10) for comparisons (COV+: Laboratory-verified SARS-CoV-2 infection; COV-: No history of SARS-CoV-2 infection and negative SARS-CoV-2 nucleocapsid antibody test.

Biomarkers.

Background: With a global ageing population, there is an increasing demand for fast and reliable early diagnosis of individuals. Convolutional neural networks (CNNs) have an immense potential in assisting clinicians in diagnosing dementia. Regional atrophy patterns, which are visible in T1-weighted MRI scans, have been consistently identified by the CNNs with high accuracy.

Biomarkers.

Background: We currently lack in the dementia field accurate, noninvasive, quick, and affordable screening tools for brain dysfunctions associated with early subtle risk of mild cognitive impairment (MCI). Our Kentucky aging cohort demonstrates that asymptomatic older individuals with MCI-like frontal memory-related brainwave patterns convert to MCI within a short 5-year period, as opposed to individuals with NC-like patterns (1) that remain normal 10 years later (2). Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer's disease (3).

Biomarkers.

Background: This study introduces the Automated High-purity Exosome isolation-based AD diagnostics system (AHEADx). By analyzing and understanding the molecular cargo (proteins and miRNAs) carried by circulating exosomes, researchers found brain-derived exosome (BDE) levels of P-S396-tau, P-T181-tau, and Aβ1-42 are elevated up to 10 years prior to clinical symptoms. Currently, there is no available technology capable of simultaneously isolating and screening exosomal biomarkers for efficient and personalized precision medicine giving early AD diagnosis.

Biomarkers.

Background: This study examines an exceptional case of CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), a hereditary cerebrovascular disease caused by a mutation in the notch3 gene. In contrast to typical cases manifesting before the age of 50 with migraines, this report highlights an atypical presentation in a 70-year-old woman with no history of migraines nor cognitive impairment.

Method: The patient, with a history of type 2 diabetes, hypothyroidism, and dyslipidemia, was initially treated for cognitive impairment and behavioral changes under suspicion of autoimmune encephalitis.

Biomarkers.

Background: Type 2 diabetes (T2D) is a recognized risk factor for dementia. This study aimed to pinpoint blood DNA methylation biomarkers for cognitive decline in older adults with T2D by comparing those who developed dementia with those who remained cognitively normal during follow-up METHOD: Illumina Infinium MethylationEPIC microarray was used for the initial 24 couples and Infinium HumanMethylationEPIC microarray version 2.0 for the subsequent 8 couples.

Biomarkers.

Background: Changes in Amyloid-β (A) and hyperphosphorylated Tau (T) in the brain and cerebrospinal fluid (CSF) precedes AD symptoms, making the CSF proteome a potential avenue to understand disease pathophysiology and facilitate reliable diagnostics and therapies.

Method: We used the Somascan assay for measuring the protein levels of 7,029 analytes in CSF of 2,286 participants from four different cohorts. We employed a three-stage analytical approach (discovery, replication, and meta-analysis).