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.

Polygenic Hazard Score for Predicting Age-associated Risk of Alzheimer's Disease in European Populations: Development and Validation.

Objectives: Polygenic hazard score (PHS) models can be used to predict the age-associated risk for complex diseases, including Alzheimer's disease (AD). In this study, we present an improved PHS model for AD that incorporates a large number of genetic variants and demonstrates enhanced predictive accuracy for age of onset in European populations compared to alternative models.

Methods: We used the genotyped European Alzheimer & Dementia Biobank (EADB) sample (n=42,120) to develop and evaluate the performance of the PHS model.

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.

Machine learning in Alzheimer's disease genetics.

Traditional statistical approaches have advanced our understanding of the genetics of complex diseases, yet are limited to linear additive models. Here we applied machine learning (ML) to genome-wide data from 41,686 individuals in the largest European consortium on Alzheimer's disease (AD) to investigate the effectiveness of various ML algorithms in replicating known findings, discovering novel loci, and predicting individuals at risk. We utilised Gradient Boosting Machines (GBMs), biological pathway-informed Neural Networks (NNs), and Model-based Multifactor Dimensionality Reduction (MB-MDR) models.

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.

Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations.

A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries.

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.

stratified genome-wide association studies provide novel insights into the genetic etiology of Alzheimers's disease.

Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E gene () ε2/ε3/ε4 polymorphism remains the longstanding benchmark for genetic disease risk with a consistently large effect across studies. Despite this massive signal, the exact mechanisms for how ε4 increases and for how ε2 decreases dementia risk is not well-understood. Importantly, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in s4 carriers, hampering the treatment of those with the highest unmet need.

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.

Caregiver burden in mild cognitive impairment due to Alzheimer's disease-a longitudinal study.

Background: Caregivers of people with mild forms of cognitive decline, namely mild cognitive impairment (MCI), are subjected to caregiver burden. In recent years, a major breakthrough was the possibility of diagnosing Alzheimer's disease (AD) reliably in patients that present with MCI, as required for the use of the recently approved anti-amyloid therapies. We aimed to examine the caregiver burden in caregivers of patients with MCI due to AD, describe how caregiver burden evolves with time, and determine caregiver baseline factors that might predict the progression of burden.

Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes.

We used an untargeted mass spectrometric approach, tandem mass tag proteomics, for the identification of proteomic signatures in genetic frontotemporal dementia (FTD). A total of 238 cerebrospinal fluid (CSF) samples from the Genetic FTD Initiative were analyzed, including samples from 107 presymptomatic (44 , 38 , and 25 ) and 55 symptomatic (27 , 17 , and 11 ) mutation carriers as well as 76 mutation-negative controls ("noncarriers"). We found shared and distinct proteomic alterations in each genetic form of FTD.

RADAR-AD: assessment of multiple remote monitoring technologies for early detection of Alzheimer's disease.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting millions worldwide, leading to cognitive and functional decline. Early detection and intervention are crucial for enhancing the quality of life of patients and their families. Remote Monitoring Technologies (RMTs) offer a promising solution for early detection by tracking changes in behavioral and cognitive functions, such as memory, language, and problem-solving skills.

Depressive Symptoms and Amyloid Pathology.

Importance: Depressive symptoms are associated with cognitive decline in older individuals. Uncertainty about underlying mechanisms hampers diagnostic and therapeutic efforts. This large-scale study aimed to elucidate the association between depressive symptoms and amyloid pathology.

Assessment of Dementia in Minority Ethnic Groups in Europe: A 14-Year Follow-Up Survey.

Objectives: There is no European consensus on good clinical practice for timely diagnosis and culturally appropriate care of people with dementia from minority ethnic groups. Despite significant advances in culture-sensitive dementia diagnostics, little is known about how this has been implemented in clinical practice. The aims of this follow-up survey were to explore current practices for assessing dementia in patients from minority ethnic groups in Europe and to determine whether barriers in access to specialized dementia services have changed during the last 14 years.

Frequency, sociodemographic, and neuropsychological features of patients with subjective cognitive decline diagnosed using different neuropsychological criteria.

Background: Subjective Cognitive Decline (SCD) is recognized as a risk stage for future cognitive impairment and dementia. The criteria for SCD include normal performance on neuropsychological testing; however, there is a lack of consensus regarding standard score cut-offs for neuropsychological tests to define cognitive impairment and to differentiate between SCD and Mild Cognitive Impairment (MCI). This study aimed to assess the frequency of SCD diagnosis using various neuropsychological definitions of cognitive normality and to characterize the sociodemographic and neuropsychological features of SCD patients diagnosed under these criteria.

Association of Changes in Cerebral and Hypothalamic Structure With Sleep Dysfunction in Patients With Genetic Frontotemporal Dementia.

Background And Objectives: Sleep dysfunction is common in patients with neurodegenerative disorders; however, its neural underpinnings remain poorly characterized in genetic frontotemporal dementia (FTD). Hypothalamic nuclei important for sleep regulation may be related to this dysfunction. Thus, we examined changes in hypothalamic structure across the lifespan in patients with genetic FTD and whether these changes related to sleep dysfunction.

Association of Initial Side of Brain Atrophy With Clinical Features and Disease Progression in Patients With Frontotemporal Dementia.

Background And Objectives: Pathogenic variants in the gene cause frontotemporal dementia (FTD-) with marked brain asymmetry. This study aims to assess whether the disease progression of FTD- depends on the initial side of the atrophy. We also investigated the potential use of brain asymmetry as a biomarker of the disease.

Frontoparietal network integrity supports cognitive function in pre-symptomatic frontotemporal dementia: Multimodal analysis of brain function, structure, and perfusion.

Introduction: Genetic mutation carriers of frontotemporal dementia can remain cognitively well despite neurodegeneration. A better understanding of brain structural, perfusion, and functional patterns in the pre-symptomatic stage could inform accurate staging and potential mechanisms.

Methods: We included 207 pre-symptomatic genetic mutation carriers and 188 relatives without mutations.

Frequency and Longitudinal Course of Behavioral and Neuropsychiatric Symptoms in Participants With Genetic Frontotemporal Dementia.

Background And Objectives: Behavioral and neuropsychiatric symptoms are frequent in patients with genetic frontotemporal dementia (FTD). We aimed to describe behavioral and neuropsychiatric phenotypes in genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy.

Methods: We analyzed data of pathogenic variant carriers in the chromosome 9 open reading frame 72 (), progranulin (), or microtubule-associated protein tau () gene from the Genetic Frontotemporal dementia Initiative cohort study that enrolls both symptomatic pathogenic variant carriers and first-degree relatives of known carriers.