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.

BrainAGE latent representation clustering is associated with longitudinal disease progression in early-onset Alzheimer's disease.

Introduction: Early-onset Alzheimer's disease (EOAD) population is a clinically, genetically and pathologically heterogeneous condition. Identifying biomarkers related to disease progression is crucial for advancing clinical trials and improving therapeutic strategies. This study aims to differentiate EOAD patients with varying rates of progression using Brain Age Gap Estimation (BrainAGE)-based clustering algorithm applied to structural magnetic resonance images (MRI).

Faster decline of very prodromal dementia with Lewy bodies when amyloid positive.

Introduction: The cognitive and neuroimaging evolution during dementia with Lewy bodies (DLB) from the prodromal phase (Pro-DLB; subjective cognitive impairment [SCI] to mild cognitive impairment [MCI]) according to amyloid beta (Aβ) status is poorly understood.

Methods: The decline of Lewy-Memento patients with SCI or MCI was compared according to Aβ status across four groups: Pro-DLB, prodromal Alzheimer's disease (Pro-AD), Pro-DLB+AD, and a group without prodromal DLB and AD (no symptoms [NS]). We observed the evolution of cognitive, functional, quality of life measures, brain volumetry, and metabolism on fluorodeoxyglucose positron emission tomography.

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.

Cognitive and neuroimaging outcome of very prodromal dementia with Lewy bodies.

The cognitive and neuroimaging evolution over the course of dementia with Lewy bodies (DLB) from prodromal stage - Pro-DLB (subjective (SCI) to mild cognitive impairment (MCI)) - is poorly understood. The aim of this study was to analyze from 5-year longitudinal data the trajectories of Pro-DLB patients. The "Lewy- MEMENTO" prospective clinical cohort recruited 773 patients for either SCI or MCI.

Experience with an online positive psychology intervention for caregivers of people with Alzheimer's disease: an interpretative phenomenological analysis.

Purpose: Considering the distress experienced by caregivers, numerous support systems have been devised. Recently, interventions focused on positive psychology have resulted in beneficial effects for caregivers. This study aimed to investigate the experience of caregivers of people with Alzheimer's disease with an online positive psychology intervention.

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.

Reduced venetoclax exposure to 7 days vs standard exposure with hypomethylating agents in newly diagnosed AML patients.

Hypomethylating agent (HMA) plus venetoclax (VEN) regimens are standard of care in patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy. While the VEN label recommends continuous 28-day cycles, shortened VEN durations may induce similar response rates and improve tolerability. It is unknown how a VEN exposure reduced to 7 days during cycles compares to standard HMA + VEN.

Clonal Evolution of PPM1D Mutations in the Spectrum of Myeloid Disorders.

Purpose: PPM1D, a central regulator of the DNA damage response, is commonly mutated in therapy-related clonal hematopoiesis, acute myeloid leukemia (AML), and myelodysplastic syndromes (MDS). PPM1D mutations have been shown to expand under the selective pressure of DNA-damaging chemotherapy. However, whether PPM1D mutations promote the development of hematologic malignancies remains unclear.

Comparing high and low amyloid producers in Alzheimer's disease: An in-depth analysis.

Background: The cerebrospinal fluid (CSF) Aβ ratio has proven to be a more reliable biomarker for amyloid pathology than CSF Aβ in Alzheimer's disease (AD), helping to correctly classify patients with positive tau biomarkers (T+) that would otherwise have remained outside of the AD continuum. It was shown that the Aβ ratio better captures a relative decrease of Aβ in patients with high CSF Aβ. However, whether patients with high-amyloid (HiA) AD, in whom A+ is defined by the Aβ ratio, exactly compare with their low-amyloid (LoA) counterparts, in whom A+ is defined by Aβ solely, deserves further analysis.

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.

Monocytes generated by interleukin-6-treated human hematopoietic stem and progenitor cells secrete calprotectin that inhibits erythropoiesis.

Elevated circulating levels of calprotectin (CAL), the S100A8/A9 heterodimer, are biomarkers of severe systemic inflammation. Here, we investigate the effects of CAL on early human hematopoiesis. CAL demonstrates limited impact on gene expression in stem and progenitor cells, in contrast with interleukin-6 (IL6), which promotes the expression of the and genes in hematopoietic progenitors and the generation of monocytes that release CAL.

Usefulness of Cerebrospinal Fluid Alzheimer's disease biomarkers in older patients: Evidence from a national multicenter prospective study.

Background: The use of cerebrospinal (CSF) biomarkers in the diagnosis of Alzheimer's disease (AD) has been gaining interest in clinical practice. Although their usefulness has been demonstrated, their potential value in older patients remains debated.

Objectives: To assess whether knowledge of the results of CSF AD biomarkers was associated with the same gain in diagnostic confidence in older adults > 80 than in younger patients.

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.

New approaches to standard of care in early-phase myeloproliferative neoplasms: can interferon-α alter the natural history of the disease?

The classical BCR::ABL-negative myeloproliferative neoplasms (MPN) include polycythemia vera, essential thrombocythemia, and primary myelofibrosis. They are acquired clonal disorders of hematopoietic stem cells leading to hyperplasia of one or several myeloid lineages. MPN are caused by three main recurrent mutations, JAK2V617F and mutations in the calreticulin (CALR) and thrombopoietin receptor (MPL) genes.

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.

Inflammatory plasma profile in genetic symptomatic and presymptomatic Frontotemporal Dementia - A GENFI study.

Background: Inflammation has been proposed as a crucial player in neurodegeneration, including Frontotemporal Dementia (FTD). A few studies on sporadic FTD lead to inconclusive results, whereas large studies on genetic FTD are lacking. The aim of this study is to determine cytokine and chemokine plasma circulating levels in a large cohort of genetic FTD, collected within the GENetic Frontotemporal dementia Initiative (GENFI).

Long Non-Coding RNA Profile in Genetic Symptomatic and Presymptomatic Frontotemporal Dementia: A GENFI Study.

Background: Long non-coding RNAs (lncRNAs) play crucial roles in gene regulation and are implicated in neurodegenerative diseases, including frontotemporal dementia (FTD). However, their expression patterns and potential as biomarkers in genetic FTD involving Chromosome 9 Open Reading Frame (C9ORF72), Microtubule Associated Protein Tau (MAPT), and Progranulin (GRN) genes are not well understood.

Objective: This study aimed to profile the expression levels of lncRNAs in peripheral blood mononuclear cells collected within the GENetic Frontotemporal dementia Initiative (GENFI).