Cerebrovascular Reactivity at Rest and Its Association With Cognitive Function in People With Genetic Frontotemporal Dementia.

Background And Objectives: Cerebrovascular reactivity (CVR) is an indicator of cerebrovascular health, and its signature in familial frontotemporal dementia (FTD) remains unknown. The primary aim was to investigate CVR in genetic FTD using an fMRI index of vascular contractility termed resting-state fluctuation amplitudes (RSFAs) and to assess whether RSFA differences are moderated by age. A secondary aim was to study the relationship between RSFA and cognition.

Noradrenergic therapies in neurodegenerative disease: from symptomatic to disease modifying therapy?

A feature shared by many different neurodegenerative diseases is early pathology and degeneration of the pontine locus coeruleus. The human locus coeruleus contains about 50 000 neurons and is the primary source of the neurotransmitter noradrenaline. We propose the hypothesis that noradrenergic drugs can have broad, transdiagnostic benefit in slowing or preventing the progression of neurodegenerative diseases.

Pharmacological and pupillary evidence for the noradrenergic contribution to reinforcement learning in Parkinson's disease.

Noradrenaline plays an integral role in learning by optimising behavioural strategies and facilitating choice execution. Testing the noradrenergic framework of learning in the context of human diseases offers a test bed for current normative neuroscience theories and may also indicate therapeutic potential. Parkinson's disease is often considered as a model of dopamine deficits, including dopamine's role in reinforcement learning.

Connectivity as a universal predictor of tau progression in atypical Alzheimer's disease.

The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution across disease variants. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicenters. However, given the limited spatial heterogeneity of tau in typical AD, atypical (non-amnestic-predominant) AD variants with distinct tau patterns provide a key opportunity to investigate the universality of connectivity as a scaffold for tau progression.

Noradrenaline for progressive supranuclear palsy syndromes (NORAPS): a randomised, double-blind, placebo-controlled, crossover Phase IIb clinical trial evaluating the efficacy and safety of oral atomoxetine for treating cognitive and behavioural changes in people with progressive supranuclear palsy syndromes in the UK.

Introduction: Progressive supranuclear palsy (PSP) is a devastating neurodegenerative disease characterised by cognitive, behavioural and motor problems. Motor symptoms are highly disabling, while cognitive and behavioural changes have a major impact on carer burden, quality of life and prognosis. Apathy and impulsivity are very common, often coexistent in PSP, and negatively predict survival.

Executive Function Deficits in Genetic Frontotemporal Dementia: Results From the GENFI Study.

Background And Objectives: Executive dysfunction is a core feature of frontotemporal dementia (FTD). While there has been extensive research into such impairments in sporadic FTD, there has been little research in the familial forms.

Methods: Seven hundred fifty-two individuals were recruited in total: 214 ; 205 and 86 mutation carriers, stratified into asymptomatic, prodromal, and fully symptomatic; and 247 mutation-negative controls.

Structural and functional connectivity in tau mutation carriers: from presymptomatic to symptomatic frontotemporal dementia.

Introduction: Microtubule-associated protein tau (MAPT) mutations cause frontotemporal dementia (FTD), characterised by behavioural, language, and motor impairments due to brain connectivity disruptions. We investigated structural and functional connectivity in 86 mutation carriers and 272 controls to map connectivity changes at different disease stages.

Methods: The CDR Dementia Staging Instrument plus National Alzheimer's Coordinating Center (NACC) Behaviour and Language domains (CDR plus NACC FTLD) stratified carriers into three groups: asymptomatic, prodromal, and symptomatic.

Tau PET positivity in individuals with and without cognitive impairment varies with age, amyloid-β status, APOE genotype and sex.

Tau positron emission tomography (PET) imaging allows in vivo detection of tau proteinopathy in Alzheimer's disease, which is associated with neurodegeneration and cognitive decline. Understanding how demographic, clinical and genetic factors relate to tau PET positivity will facilitate its use for clinical practice and research. Here we conducted an analysis of 42 cohorts worldwide (N = 12,048), including 7,394 cognitively unimpaired (CU) participants, 2,177 participants with mild cognitive impairment (MCI) and 2,477 participants with dementia.

Pulse Pressure Impairs Cognition via White Matter Disruption.

Background: In older adults, elevated pulse pressure predicts cognitive decline, independent of overall blood pressure. It is proposed to compromise cerebrovascular integrity, potentially leading to brain damage, though the underlying mechanisms remain unclear. We hypothesized that pulse pressure affects cognition by disrupting white matter microstructure, and that it does so independently of other cardiovascular risk factors.

Accuracy of blood-based neurofilament light to different genetic frontotemporal dementia from primary psychiatric disorders.

BackgroundGenetic frontotemporal dementia (FTD) along with Alzheimer's disease (AD), is one of the most prevalent early-onset dementias. The differential diagnosis of FTD from primary psychiatric disorder (PPD) has been challenging due to significant symptom overlap, particular as FTD often presents with prolonged psychiatric prodromes.ObjectiveThis study aims to evaluate whether blood-based neurofilament light chain (NfL) can differentiate genetic FTD from PPD, and to determine a global clinical cutoff to differentiate genetic FTD carriers from PPD with high specificity and sensitivity.

Self- versus caregiver-reported apathy across neurological disorders.

Apathy is a prevalent and persistent neuropsychiatric syndrome across many neurological disorders, significantly impacting both patients and caregivers. We systematically quantified discrepancies between self- and caregiver-reported apathy in 335 patients with a variety of diagnoses, such as frontotemporal dementia (behavioural variant and semantic dementia subtypes), Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies, Alzheimer's disease dementia, mild cognitive impairment, small vessel cerebrovascular disease, subjective cognitive decline and autoimmune encephalitis. Using the Apathy Motivation Index (AMI) and its analogous caregiver version (AMI-CG), we found that caregiver-reported apathy consistently exceeded self-reported levels across all conditions.

Diagnostic and prognostic value of α-synuclein seed amplification assay kinetic measures in Parkinson's disease: a longitudinal cohort study.

Background: α-synuclein seed amplification assay (SAA) positivity has been proposed as a diagnostic biomarker for Parkinson's disease. However, studies of the prognostic value of this biomarker have been limited to small, single-centre studies over short follow-up periods. We aimed to assess the diagnostic and prognostic value of quantitative CSF α-synuclein SAA kinetic measures in Parkinson's disease.

Frequency and Clinical Outcomes Associated With Tau Positron Emission Tomography Positivity.

Importance: Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD).

Objective: To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes.

Design, Setting, And Participants: Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024.

Insights into pathophysiology, biomarkers, and therapeutics in tauopathies: Proceedings of the Tau2024 Global Conference.

Recent years have seen major advances in tau-associated brain disorders through interdisciplinary research spanning molecular biology, neuroimaging, clinical trials, and therapeutic development. The Tau2024 Global Conference, hosted by the Alzheimer's Association, CurePSP, and Rainwater Charitable Foundation, showcased these efforts by bringing together researchers and experts worldwide to discuss the latest advancements in tau research. The conference aimed to attract talent and funding to study tauopathies, particularly among early-career researchers, and to foster interdisciplinary alignment and collaboration around challenges in tau research.

Anatomical progression of genetic frontotemporal lobar degeneration across the lifespan.

The recent development of brain charts for the human lifespan offers an ideal modeling framework for pathologies such as genetic frontotemporal lobar degeneration (FTLD) which likely involve both neurodevelopmental and neurodegenerative processes over a lifetime. We have therefore combined this new methodological approach with MRI data from asymptomatic and symptomatic subjects, carrying C9orf72, MAPT or GRN mutations from the GENFI and ALLFTD cohorts. We analyzed 37,532 MRIs from control subjects covering the entire lifespan and a total of 1,341 MRIs from subjects with a pathogenic FTLD mutation, aged from 18 to 86 years old.

Neurophysiological Progression in Alzheimer's Disease: Insights From Dynamic Causal Modelling of Longitudinal Magnetoencephalography.

Neurodegenerative diseases, including Alzheimer's disease, are characterised by selective neuronal vulnerability with regional, laminar, cellular and neurotransmitter specificity. The regional losses of neurons and their synapses are associated with neurophysiological changes and cognitive decline. Hypotheses related to these mechanisms can be tested and compared by dynamic causal modelling (DCM) of human neuroimaging data, including magnetoencephalography (MEG).

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.

Disease-modifying effects of TMEM106B in genetic frontotemporal dementia: a longitudinal GENFI study.

Common variants within TMEM106B are associated with risk for frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). The G allele of the top single nucleotide polymorphism, rs1990622, confers protection against FTLD-TDP, including genetic cases due to GRN mutations or C9orf72 hexanucleotide repeat expansions. However, the effects of interaction between TMEM106B-rs1990622 and frontotemporal dementia (FTD) mutations on disease endophenotypes in genetic FTD are unknown.

Intronic FGF14 GAA repeat expansions impact progression and survival in multiple system atrophy.

Partial phenotypic overlap has been suggested between multiple system atrophy and spinocerebellar ataxia 27B, the autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. In this study, we investigated the frequency of FGF14 GAA•TTC repeat expansion in clinically diagnosed and pathologically confirmed multiple system atrophy cases. We screened 657 multiple system atrophy cases (193 clinically diagnosed and 464 pathologically confirmed) and 1003 controls.

Cognitive and neuropsychiatric profiles distinguish atypical parkinsonian syndromes.

Atypical parkinsonian syndromes are distinguished from Parkinson's disease (PD) by additional neurological signs and characteristic underlying neuropathology. However, they can be diagnostically challenging, rapidly progressive and are often diagnosed late in disease course. Their different demographic features and prognoses are well studied, but the accompanying cognitive and psychiatric features may also facilitate diagnosis.

Novel blood-based proteomic signatures across multiple neurodegenerative diseases.

Introduction: Blood-based biomarkers have the potential to support early and accurate diagnoses of neurodegenerative diseases, which are sensitive to molecular pathology and are predictive of outcome. We evaluated a novel multiplex proteomic method in people with diverse neurodegenerative diseases.

Methods: Serum from people with Alzheimer's disease (N = 36), Lewy body dementia (N = 34), frontotemporal dementia (N = 36), and progressive supranuclear palsy (N = 36) and age-matched controls (N = 30) was analyzed with the nucleic acid linked immuno-sandwich assay (NULISA) central nervous system panel (≈ 120 analytes) and inflammation panel (250 analytes).

Analysis of C9orf72 repeat length in progressive supranuclear palsy, corticobasal syndrome, corticobasal degeneration, and atypical parkinsonism.

Background: Pathogenic hexanucleotide repeat expansions in C9orf72 are the commonest genetic cause of frontotemporal dementia and/or amyotrophic lateral sclerosis. There is growing interest in intermediate repeat expansions in C9orf72 and their relationship to a wide range of neurological presentations, including Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, corticobasal degeneration, and corticobasal syndromes.

Aims: To assess the prevalence of intermediate C9orf72 repeat expansions in a large cohort of prospectively-recruited patients clinically diagnosed with progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and atypical parkinsonism (APS), compared with healthy controls.

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.

Post-mortem validation of in vivo TSPO PET as a microglial biomarker.

Neuroinflammation is a feature of many neurodegenerative diseases and is quantified in vivo by PET imaging with radioligands for the translocator protein (TSPO, e.g. 11C-PK11195).

GABAergic modulation of beta power enhances motor adaptation in frontotemporal lobar degeneration.

Introduction: We examined how abnormal prefrontal neurophysiology and changes in gamma-aminobutyric acid-ergic (GABAergic) neurotransmission contribute to behavioral impairments in disorders associated with frontotemporal lobar degeneration (FTLD).

Methods: We recorded magnetoencephalography during an adaptive visuomotor task from 11 people with behavioral-variant frontotemporal dementia, 11 with progressive supranuclear palsy, and 20 age-matched controls. We used tiagabine, a gamma-aminobutyric acid (GABA) re-uptake inhibitor, as a pharmacological probe to assess the role of GABA during motor-related beta power changes.