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.

Digital Outcomes of Upper Limb Ataxia Capture Meaningful Longitudinal Change and Treatment Response.

Background: Digital-motor outcomes promise better responsiveness than clinician-reported outcomes in ataxia trials. However, their patient meaningfulness and sensitivity to change remain to be demonstrated, particularly in the upper limb domain.

Objectives: Validation of quantitative motor (Q-Motor) assessment for upper limb ataxia against patient-reported outcomes and regarding sensitivity to both longitudinal and treatment-induced change, the latter in n-of-1 treatment settings.

GAA-FGF14 Expansions and CACNA1A Variants: Phenotypic Overlap and Diagnostic Implications.

Background: An intronic (GAA)•(TTC) repeat expansion in FGF14 was recently identified as the cause of spinocerebellar ataxia 27B (SCA27B), a disorder presenting with both chronic cerebellar ataxia and episodic symptoms. The phenotype of SCA27B overlaps with that of CACNA1A spectrum disorders.

Objective: The objective of this work was to investigate the prevalence of GAA-FGF14 repeat expansions in patients with ataxia so far considered to be related to underlying CACNA1A variants.

Spastic Ataxia Composite (SPAXCOM): A Scale to Evaluate the Progression of Subjects with Spasticity and Ataxia.

Background: Current clinical scales that track disease progression are more tailored to spasticity or ataxia, with limited sensitivity to change.

Objectives: The aim was to develop a sensitive and valid scale specifically geared towards optimized sensitivity to change and adapted to patients presenting with both spasticity and ataxia.

Methods: Longitudinal data from 127 spastic paraplegia type 7 (SPG7) and 112 autosomal recessive spastic ataxia Charlevoix-Saguenay (ARSACS) patients were collected within the multicenter PROSPAX study.

A Pharmacometrics-Informed Trial Simulation Framework for Optimizing Study Designs for Disease-Modifying Treatments in Rare Neurological Disorders.

The development of new treatments for rare neurological diseases (RNDs) may be very challenging due to limited natural history data, lack of relevant biomarkers and clinical endpoints, small and heterogeneous patient populations, and other complexities. A systematic approach is needed for comparing various design and analysis strategies to identify "optimal" approaches for a clinical trial in a chosen RND with the given resource constraints. For this purpose, we propose a pharmacometrics-informed clinical scenario evaluation framework (CSE-PMx), which includes some important research hallmarks relevant to RND clinical trials: a disease progression model for simulating individual longitudinal outcomes, the choice of a suitable randomization method for trial design, and an option to perform subsequent statistical analysis with randomization tests.

Comparing randomized trial designs to estimate treatment effect in rare diseases with longitudinal models: a simulation study showcased by Autosomal Recessive Cerebellar Ataxias using the SARA score.

Parallel designs with an end-of-treatment analysis are commonly used for randomised trials, but they remain challenging to conduct in rare diseases due to small sample size and heterogeneity. A more powerful alternative could be to use model-based approaches. We investigated the performance of longitudinal modelling to evaluate disease-modifying treatments in rare diseases using simulations.

Tailored antisense oligonucleotides for ultrarare CNS diseases: An experience-based best practice framework for individual patient evaluation.

Individualized mutation-specific RNA therapies offer promise, in particular, for individuals with ultrarare neurological diseases that affect only few families or even single patients worldwide. Outside traditional drug development pathways, however, clinicians and scientists face the challenge of systematically evaluating whether individual patients with severe ultrarare diseases might be eligible for and potentially benefit from such approaches. This complex evaluation involves biological, clinical, psychological, and ethical aspects.

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.

Disease stage-specific atrophy markers in Alzheimer's disease.

Introduction: Structural magnetic resonance imaging (MRI) often lacks diagnostic, prognostic, and monitoring value in Alzheimer's disease (AD), particularly in early disease stages. To improve its utility, we aimed to identify optimal atrophy markers for different intended uses.

Methods: We included 363 older adults; cognitively unimpaired individuals who were negative or positive for amyloid beta (Aβ) and Aβ-positive patients with subjective cognitive decline, mild cognitive impairment, or dementia of the Alzheimer type.

Integrated Modeling of Digital-Motor and Clinician-Reported Outcomes Using Item Response Theory: Towards Powerful Trials for Rare Neurological Diseases.

Robust and highly sensitive outcomes are crucial for small trials in rare diseases. Combining different outcome types might improve sensitivity to identify disease severity and progression, yet innovative methodologies are scarce. Here we develop an Item Response Theory framework that allows integrated modeling of both continuous and categorical outcomes (ccIRT).

Progression of biological markers in spinocerebellar ataxia type 3: longitudinal analysis of prospective data from the ESMI cohort.

Background: Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly inherited adult-onset disease. We aimed to describe longitudinal changes in clinical and biological findings and to identify predictors for clinical progression.

Methods: We used data from participants enrolled in the ESMI cohort collected between Nov 09, 2016 and July 18, 2023.

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.

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.

An Unsupervised XAI Framework for Dementia Detection with Context Enrichment.

Introduction: Explainable Artificial Intelligence (XAI) methods enhance the diagnostic efficiency of clinical decision support systems by making the predictions of a convolutional neural network's (CNN) on brain imaging more transparent and trustworthy. However, their clinical adoption is limited due to limited validation of the explanation quality. Our study introduces a framework that evaluates XAI methods by integrating neuroanatomical morphological features with CNN-generated relevance maps for disease classification.

Mini social cognition and emotional assessment: Diagnostic performance and neural correlates in behavioural-variant frontotemporal dementia.

We aimed at validating the Mini Social Cognition and Emotional Assessment (Mini-SEA) in a German cohort of mildly impaired behavioural-variant frontotemporal dementia (bvFTD) patients and healthy controls. The Mini-SEA comprises the Facial Emotion Recognition Test (FERT) and the Faux Pas Test (FPT) measuring Theory of Mind (ToM) abilities in social norm-related real-life stories. We examined the diagnostic performance of the Mini-SEA alongside other neuropsychological assessments and investigated its structural neural correlates.

"The DESCRIBE-ALS-FTD study: a prospective multicenter observational study of the ALS-FTD spectrum".

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) exhibit significant clinical, genetic and neuropathological abnormalities, and are regarded as belonging to a common disease spectrum, referred to as the ALS-FTD spectrum disorders. Our understanding of the underlying mechanisms of these diseases has advanced significantly, including molecular neuropathology, genetics and molecular pathophysiology. The heterogeneity of these diseases poses significant challenges to translational research and drug development, particularly in sporadic cases.

Autosomal Recessive Cerebellar Ataxias: Translating Genes to Therapies.

Autosomal recessive cerebellar ataxias (ARCAs) represent over 200 clinically heterogeneous genetic conditions involving degeneration of the cerebellum and associated tracts with resultant impairment of balance and coordination. Advancements in genomic testing have enabled rapid identification of the majority of known recessive disorders, shifting research focus to the development of targeted mechanistic treatments addressing underlying physiological pathways. Molecular classification allows recognition of cellular, biochemical, and genetic targets for high-effect precision therapy development.

From roadmap to a sustainable end-to-end individualized therapy pathway.

The field of individualized, or N-of-1, therapy development is growing and increasingly gaining attention as a novel option for people with serious diseases, caused by unique genetic variants for whom approved therapies are not available. The N-of-1 taskforce of the International Rare Disease Research Consortium previously outlined a roadmap of aspects involved in N-of-1 therapy development and implementation. Here, this follow-up paper looks forward and reflects on how to address existing gaps to advance the current state of individualized interventions toward an integrated and sustainable treatment development model.

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.

Capture of Longitudinal Change in Real-Life Walking in Cerebellar Ataxia Increases Patient Relevance and Effect Size.

Background: With disease-modifying drugs for degenerative ataxias on the horizon, ecologically valid measures of gait performance that can detect patient-relevant changes in trial-like time frames are highly warranted.

Objectives: In this 2-year longitudinal study, we aimed to unravel ataxic gait measures sensitive to longitudinal changes in patients' real lives using wearable sensors.

Methods: We assessed longitudinal gait changes of 26 participants with degenerative cerebellar disease (Scale for the Assessment and Rating of Ataxia [SARA]: 9.

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 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.

The genetic landscape of sporadic adult-onset degenerative ataxia: a multi-modal genetic study of 377 consecutive patients from the longitudinal multi-centre SPORTAX cohort.

Background: While most sporadic adult-onset neurodegenerative diseases have only a minor monogenic component, given several recently identified late adult-onset ataxia genes, the genetic burden may be substantial in sporadic adult-onset ataxias. We report systematic mapping of the genetic landscape of sporadic adult-onset ataxia in a well-characterised, multi-centre cohort, combining several multi-modal genetic screening techniques, plus longitudinal natural history data.

Methods: Systematic clinico-genetic analysis of a prospective longitudinal multi-centre cohort of 377 consecutive patients with sporadic adult-onset ataxia (SPORTAX cohort), including clinically defined sporadic adult-onset ataxia of unknown aetiology (SAOA) (n = 229) and 'clinically probable multiple system atrophy of cerebellar type' (MSA-C) (n = 148).