Design considerations for C9orf72 disease prevention trials.

The idea that it might be possible to prevent some forms of amyotrophic lateral sclerosis and frontotemporal dementia has finally come of age. The hexanucleotide repeat expansion in the C9orf72 gene accounts for ∼10% of all amyotrophic lateral sclerosis and 10-15% of all frontotemporal dementia diagnoses, with the two clinical syndromes co-manifesting in a significant number of patients. As a result, clinically unaffected carriers of pathogenic C9orf72 repeat expansions are currently the largest identifiable population at significantly elevated risk for both amyotrophic lateral sclerosis and frontotemporal dementia, and in whom it might be possible to prevent the emergence of clinically manifest disease.

Brain transcriptomics highlight abundant gene expression and splicing alterations in non-neuronal cells in aFTLD-U.

Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is a rare cause of frontotemporal lobar degeneration (FTLD), characterized postmortem by neuronal inclusions of the FET family of proteins (FTLD-FET). The recent discovery of TAF15 amyloid filaments in aFTLD-U brains represents a significant step toward improved diagnostic and therapeutic strategies. However, our understanding of the etiology of this FTLD subtype remains limited, which severely hampers translational research efforts.

Neurodegenerative plasma biomarkers for prediction of hippocampal atrophy in older adults with suspected Alzheimer's disease in Kinshasa, Democratic Republic of Congo.

BackgroundHippocampal atrophy is a key feature of Alzheimer's disease (AD), but neuroimaging is often inaccessible in low-resource settings. Blood-based biomarkers such as amyloid-β (Aβ), phosphorylated tau-181 (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) may offer a practical alternative, though their utility in African populations remains understudied.ObjectiveThis study investigated the ability of plasma biomarkers of AD and AD-related dementias-Aβ, p-tau181, NfL, and GFAP-to predict hippocampal atrophy in older adults in Kinshasa, Democratic Republic of Congo.

The Global Neurodegeneration Proteomics Consortium: biomarker and drug target discovery for common neurodegenerative diseases and aging.

More than 57 million people globally suffer from neurodegenerative diseases, a figure expected to double every 20 years. Despite this growing burden, there are currently no cures, and treatment options remain limited due to disease heterogeneity, prolonged preclinical and prodromal phases, poor understanding of disease mechanisms, and diagnostic challenges. Identifying novel biomarkers is crucial for improving early detection, prognosis, staging and subtyping of these conditions.

Opposing role of phagocytic receptors MERTK and AXL in Progranulin deficient FTD.

Genetic mutations in the progranulin gene, GRN, cause frontotemporal dementia and a lysosomal storage disorder. Using single-nuclei RNA sequencing of the post-mortem brain tissue from adult heterozygous pathogenic granulin variant (GRN+/-) carriers we find dysregulation of microglia, phagocytosis and the phagocytic receptors MERTK and AXL. Exogenous progranulin regulates MERTK and AXL RNA expression in human microglia induced from iPSCs irrespective of GRN mutation status, without directly binding to MERTK or AXL proteins.

Brain Networks Route Neurodegeneration Patterns in Patients with Progressive Supranuclear Palsy.

Background: Progressive supranuclear palsy (PSP) is a neurodegenerative disease driven by 4-repeat τ pathology, which is thought to propagate across interconnected neurons.

Objectives: We hypothesized that interconnected brain regions exhibit correlated atrophy, and that atrophy propagates network-like from fast-declining epicenters to connected regions in PSP.

Methods: We combined resting-state functional magnetic resonance imaging (fMRI) connectomics with two independent 12-month longitudinal structural magnetic resonance imaging (MRI) datasets of PSP-Richardson syndrome (PSP-RS) patients (n/n = 114/90).

Association of [F]Flortaucipir-PET and plasma p-tau217 with tau neuropathology in AD and other neurodegenerative disorders.

Background And Objectives: Evaluating tau biomarkers in patients with available autopsy data is critical for validating their sensitivity and specificity to detect Alzheimer's disease neuropathologic changes (ADNC). We examined the association between tau-PET (using [F]Flortaucipir), plasma ptau-217, and measures of AD neuropathology in a group of clinically-impaired participants from a tertiary dementia center, including patients with AD and FTLD.

Methods: We analyzed Flortaucipir-PET (80-100 minutes post-injection acquisition, normalized to inferior cerebellar cortex) from 73 patients with a clinical diagnosis of various neurodegenerative diseases who underwent autopsy at the Neurodegenerative Disease Brain Bank (median [IQR] age: 67 [59, 73] years, 60% male, median [IQR] PET-to-autopsy duration: 3.

Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration.

The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. Here we leveraged aptamer-based proteomics (>4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations (C9orf72, GRN and MAPT) compared with 39 non-carrier controls. Network analysis identified 31 protein co-expression modules.

Developing digital health technologies for frontotemporal degeneration.

Frontotemporal degeneration (FTD) is a rare neurodegenerative disease in which patients can present with cognitive, behavioral, motor, and speech impairment. Currently, there are no approved therapies available to slow or halt disease progression. Detection and monitoring of patient symptoms is challenging for this heterogeneous disease and has negatively impacted progress in FTD clinical trials.

Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 patients and 3,153 controls compiled from 26 institutions/brain banks in North America, Europe and Australia, and meta-analysis with the Dementia-seq cohort. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor.

Sex differences in the clinical manifestation of autosomal dominant frontotemporal dementia.

Introduction: Sex differences are apparent in neurodegenerative diseases but have not been comprehensively characterized in frontotemporal dementia (FTD).

Methods: Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to 6 years.

Sex differences in clinical phenotypes of behavioral variant frontotemporal dementia.

Introduction: Higher male prevalence in sporadic behavioral variant frontotemporal dementia (bvFTD) has been reported. We hypothesized differences in phenotypes between genetic and sporadic bvFTD females resulting in underdiagnosis of sporadic bvFTD females.

Methods: We included genetic and sporadic bvFTD patients from two multicenter cohorts.

Development and validation of a harmonized memory score for multicenter Alzheimer's disease and related dementia research.

Introduction: List-learning tasks are important for characterizing memory in ADRD research, but the Uniform Data Set neuropsychological battery (UDS-NB) lacks a list-learning paradigm; thus, sites administer a range of tests. We developed a harmonized memory composite that incorporates UDS memory tests and multiple list-learning tasks.

Methods: Item-banking confirmatory factor analysis was applied to develop a memory composite in a diagnostically heterogenous sample (n=5943) who completed the UDS-NB and one of five list-learning tasks.

Comprehensive cross-sectional and longitudinal comparisons of plasma glial fibrillary acidic protein and neurofilament light across FTD spectrum disorders.

Background: Therapeutic development for frontotemporal dementia (FTD) is hindered by the lack of biomarkers that inform susceptibility/risk, prognosis, and the underlying causative pathology. Blood glial fibrillary acidic protein (GFAP) has garnered attention as a FTD biomarker. However, investigations of GFAP in FTD have been hampered by symptomatic and histopathologic heterogeneity and small cohort sizes contributing to inconsistent findings.

Distinct spatiotemporal atrophy patterns in corticobasal syndrome are associated with different underlying pathologies.

Although the corticobasal syndrome was originally most closely linked with the pathology of corticobasal degeneration, the 2013 Armstrong clinical diagnostic criteria, without the addition of aetiology-specific biomarkers, have limited positive predictive value for identifying corticobasal degeneration pathology in life. Autopsy studies demonstrate considerable pathological heterogeneity in corticobasal syndrome, with corticobasal degeneration pathology accounting for only ∼50% of clinically diagnosed individuals. Individualized disease stage and progression modelling of brain changes in corticobasal syndrome may have utility in predicting this underlying pathological heterogeneity, and in turn improve the design of clinical trials for emerging disease-modifying therapies.

Copy Number Variation and Haplotype Analysis of 17q21.31 Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells.

Background: The 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP).

Objective: To investigate the association between CNVs and structural forms on 17q.

Exploring cognitive and neuroimaging profiles of dementia subtypes of individuals with dementia in the Democratic Republic of Congo.

Objective: The 2024 Alzheimer's Association (AA) research diagnostic criteria for Alzheimer's Disease (AD) considers fluid biomarkers, including promising blood-based biomarkers for detecting AD. This study aims to identify dementia subtypes and their cognitive and neuroimaging profiles in older adults with dementia in the Democratic Republic of Congo (DRC) using biomarkers and clinical data.

Methods: Forty-five individuals with dementia over 65 years old were evaluated using the Community Screening Instrument for Dementia and the informant-based Alzheimer's Questionnaire.

Detection of Alzheimer Neuropathology in Alzheimer and Non-Alzheimer Clinical Syndromes With Blood-Based Biomarkers.

Importance: Blood-based biomarkers for Alzheimer disease (AD) are clinically available, but their value is not well understood in syndromes typically associated with frontotemporal lobar degeneration syndromes (FTLD).

Objective: To investigate the clinical importance and detectability of AD in FTLD-related neurodegenerative syndromes using 3 plasma biomarkers, phosphorylated tau 217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP).

Design, Setting, And Participants: This clinicopathological study took place at the University of California San Francisco Alzheimer Disease Research Center from August 2008 to July 2022.

Clinical and neuropathological associations of plasma Aβ/Aβ, p-tau217 and neurofilament light in sporadic frontotemporal dementia spectrum disorders.

Introduction: Plasma amyloid beta/amyloid beta (Aβ/Aβ) and phosphorylated tau217 (p-tau217) identify individuals with primary Alzheimer's disease (AD). They may detect AD co-pathology in the setting of other primary neurodegenerative diseases, but this has not been systematically studied.

Methods: We compared the clinical, neuroimaging, and neuropathological associations of plasma Aβ/Aβ (mass spectrometry), p-tau217 (electrochemiluminescence), and neurofilament light ([NfL], single molecule array [Simoa]), as markers of AD co-pathology, in a sporadic frontotemporal dementia (FTD) cohort ( = 620).

Intranasal oxytocin for apathy in people with frontotemporal dementia (FOXY): a multicentre, randomised, double-blind, placebo-controlled, adaptive, crossover, phase 2a/2b superiority trial.

Background: No treatments exist for apathy in people with frontotemporal dementia. Previously, in a randomised double-blind, placebo-controlled, dose-finding study, intranasal oxytocin administration in people with frontotemporal dementia improved apathy ratings on the Neuropsychiatric Inventory over 1 week and, in a randomised, double-blind, placebo-controlled, crossover study, a single dose of 72 IU oxytocin increased blood-oxygen-level-dependent signal in limbic brain regions. We aimed to determine whether longer treatment with oxytocin improves apathy in people with frontotemporal dementia.

Brain aging rejuvenation factors in adults with genetic and sporadic neurodegenerative disease.

The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate 'pro-aging' or 'pro-youthful' effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear.

Montreal cognitive assessment as a cognitive outcome measure in progressive supranuclear palsy.

Background: The Montreal Cognitive assessment (MoCA) is a well-validated global cognitive screening instrument. Its validity in progressive supranuclear palsy (PSP) has not been assessed.

Objectives: To evaluate the MoCA as an outcome measure in PSP clinical trials.

Exploring Cognitive and Neuroimaging Profiles of Dementia Subtypes of Individuals with Dementia in the Democratic Republic of Congo.

Objective: The 2024 Alzheimer's Association (AA) research diagnostic criteria for Alzheimer's Disease (AD) considers fluid biomarkers, including promising blood-based biomarkers for detecting AD. This study aims to identify dementia subtypes and their cognitive and neuroimaging profiles in older adults with dementia in the Democratic Republic of Congo (DRC) using biomarkers and clinical data.

Methods: Forty-five individuals with dementia over 65 years old were evaluated using the Community Screening Instrument for Dementia and the informant-based Alzheimer's Questionnaire.