Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort

Coinvestigators are listed at https://links.lww.com/WNL/B988.Copyright © 2022 The Author(s). Background and Objectives: Disease-modifying therapeutic trials for genetic frontotemporal dementia (FTD) are underway, but sensitive cognitive outcome measures are lacking. The aim of this study was to identify such cognitive tests in early stage FTD by investigating cognitive decline in a large cohort of genetic FTD pathogenic variant carriers and by investigating whether gene-specific differences are moderated by disease stage (asymptomatic, prodromal, and symptomatic). Methods: C9orf72, GRN, and MAPT pathogenic variant carriers as well as controls underwent a yearly neuropsychological assessment covering 8 cognitive domains as part of the Genetic FTD Initiative, a prospective multicenter cohort study. Pathogenic variant carriers were stratified according to disease stage using the global Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center (NACC) FTLD score (0, 0.5, or ≥1). Linear mixed-effects models were used to investigate differences between genetic groups and disease stages as well as the 3-way interaction between time, genetic group, and disease stage. Results: A total of 207 C9orf72, 206 GRN, and 86 MAPT pathogenic variant carriers and 255 controls were included. C9orf72 pathogenic variant carriers performed lower on attention, executive function, and verbal fluency from CDR plus NACC FTLD 0 onwards, with relatively minimal decline over time regardless of the CDR plus NACC FTLD score (i.e., disease progression). The cognitive profile in MAPT pathogenic variant carriers was characterized by lower memory performance at CDR plus NACC FTLD 0.5, with decline over time in language from the CDR plus NACC FTLD 0.5 stage onwards, and executive dysfunction rapidly developing at CDR plus NACC FTLD ≥1. GRN pathogenic variant carriers declined on verbal fluency and visuoconstruction in the CDR plus NACC FTLD 0.5 stage, with progressive decline in other cognitive domains starting at CDR plus NACC FTLD ≥1. Discussion: We confirmed cognitive decline in the asymptomatic and prodromal stage of genetic FTD. Specifically, tests for attention, executive function, language, and memory showed clear differences between genetic groups and controls at baseline, but the speed of change over time differed depending on genetic group and disease stage. This confirms the value of neuropsychological assessment in tracking clinical onset and progression and could inform clinical trials in selecting sensitive end points for measuring treatment effects as well as characterizing the best time window for starting treatment.European Reference Network for Rare Neurological Diseases 739510; Miriam Marks Brain Research UK Senior Fellowship; UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MR/M008525/1; NIHR Rare Disease Translational Research Collaboration BRC149/NS/MH; UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MR/M023664/1; JPND GENFIPROX grant 2019-02248; Bluefield Project; Dioraphte Foundation 09-02-00; Association for Frontotemporal Dementias Research Grant 2009; Netherlands Organization for Scientific Research (NWO) HCMI 056-13-018; ZonMw Memorabel (Deltaplan Dementie) 733 050 103 and 733 050 813; JPND PreFrontAls consortium 733051042; Alzheimer Nederland WE.15-2019.02; Tau Consortium; Instituto de Salud Carlos IIIPI20/00448; United States Department of Health & Human Services National Institutes of Health (NIH) - USA; Swedish Research Council European Commission; JPND grant GENFI-PROX 201902248; JPND grant PrefrontALS 2015-02926; Swedish Research Council European Commission 2018-02754; Schorling Foundation; Swedish FTD Initiative; Swedish Alzheimer Foundation; Swedish Brain Foundation; Region StockholmALF project; Karolinska Institutet; Swedish Dementia Foundation; National Institute for Health Research (NIHR); UK Research & Innovation (UKRI) Medical Research Council UK (MRC) BRC-1215-20014 and SUAG/051 G101400; Canadian Institutes of Health Research (CIHR); Physician's Services Incorporated Foundation

Using social and behavioural science to support COVID-19 pandemic response

The COVID-19 pandemic represents a massive global health crisis. Because the crisis requires large-scale behaviour change and places significant psychological burdens on individuals, insights from the social and behavioural sciences can be used to help align human behavior with the recommendations of epidemiologists and public health experts. Here we discuss evidence from a selection of research topics relevant to pandemics, including work on navigating threats, social and cultural influences on behaviour, science communication, moral decision-making, leadership, and stress and coping. In each section, we note the nature and quality of prior research, including uncertainty and unsettled issues. We identify several insights for effective response to the COVID-19 pandemic, and also highlight important gaps researchers should move quickly to fill in the coming weeks and months

Identification of context-dependent expression quantitative trait loci in whole blood

Genetic risk factors often localize to noncoding regions of the genome with unknown effects on disease etiology. Expression quantitative trait loci (eQTLs) help to explain the regulatory mechanisms underlying these genetic associations. Knowledge of the context that determines the nature and strength of eQTLs may help identify cell types relevant to pathophysiology and the regulatory networks underlying disease. Here we generated peripheral blood RNA-seq data from 2,116 unrelated individuals and systematically identified context-dependent eQTLs using a hypothesis-free strategy that does not require previous knowledge of the identity of the modifiers. Of the 23,060 significant cis-regulated genes (false discovery rate (FDR) ≤ 0.05), 2,743 (12%) showed context-dependent eQTL effects. The majority of these effects were influenced by cell type composition. A set of 145 cis-eQTLs depended on type I interferon signaling. Others were modulated by specific transcription factors binding to the eQTL SNPs