Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort

Background and ObjectivesDisease-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).MethodsC9orf72, 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\u27s 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.ResultsA 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.DiscussionWe 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

Linking changes in species composition and biomass in a globally distributed grassland experiment

Global change drivers, such as anthropogenic nutrient inputs, are increasing globally. Nutrient deposition simultaneously alters plant biodiversity, species composition and ecosystem processes like aboveground biomass production. These changes are underpinned by species extinction, colonisation and shifting relative abundance. Here, we use the Price equation to quantify and link the contributions of species that are lost, gained or that persist to change in aboveground biomass in 59 experimental grassland sites. Under ambient (control) conditions, compositional and biomass turnover was high, and losses (i.e. local extinctions) were balanced by gains (i.e. colonisation). Under fertilisation, the decline in species richness resulted from increased species loss and decreases in species gained. Biomass increase under fertilisation resulted mostly from species that persist and to a lesser extent from species gained. Drivers of ecological change can interact relatively independently with diversity, composition and ecosystem processes and functions such as aboveground biomass due to the individual contributions of species lost, gained or persisting.Fil: Ladouceur, Emma. Martin Luther University Halle-Wittenberg; Alemania. Universitat Leipzig; Alemania. German Centre for Integrative Biodiversity Research (iDiv) Leipzig-Halle-Jena; AlemaniaFil: Blowes, Shane A.. Martin Luther University Halle-Wittenberg; Alemania. German Centre for Integrative Biodiversity Research (iDiv) Leipzig-Halle-Jena; AlemaniaFil: Chase, Jonathan M.. German Centre for Integrative Biodiversity Research (iDiv) Leipzig-Halle-Jena; Alemania. Martin Luther University Halle-Wittenberg; AlemaniaFil: Clark, Adam T.. Martin Luther University Halle-Wittenberg; Alemania. German Centre for Integrative Biodiversity Research (iDiv) Leipzig-Halle-Jena; Alemania. University of Graz; AustriaFil: Garbowski, Magda. German Centre for Integrative Biodiversity Research (iDiv) Leipzig-Halle-Jena; Alemania. Universitat Leipzig; AlemaniaFil: Alberti, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Arnillas, Carlos Alberto. University of Toronto; CanadáFil: Bakker, Jonathan. University of Washington; Estados UnidosFil: Barrio, Isabel C.. Agricultural University of Iceland; IslandiaFil: Bharath, Siddharth. Atria University; IndiaFil: Borer, Elizabeth. University of Minnesota; Estados UnidosFil: Brudvig, Lars A.. Michigan State University; Estados UnidosFil: Cadotte, Marc W.. University of Toronto; CanadáFil: Chen, Qingqing. Peking University; ChinaFil: Collins, Scott L.. University of New Mexico; Estados UnidosFil: Dickman, Christopher R.. The University Of Sydney; AustraliaFil: Donohue, Ian. Trinity College Dublin; IrlandaFil: Du, Guozhen. Lanzhou University; ChinaFil: Ebeling, Anne. Universitat Jena; AlemaniaFil: Eisenhauer, Nico. Martin Luther University Halle—Wittenberg; Alemania. German Centre For Integrative Biodiversity Research (idiv) Halle-jena-leipzig; AlemaniaFil: Fay, Philip A.. USDA-ARS Grassland Soil and Water Research Lab; Estados UnidosFil: Hagenah, Nicole. University Of Pretoria; SudáfricaFil: Hautier, Yann. University of Utrecht; Países BajosFil: Jentsch, Anke. University of Bayreuth; AlemaniaFil: Jónsdóttir, Ingibjörg S.. University of Iceland; IslandiaFil: Komatsu, Kimberly J.. Smithsonian Environmental Research Center; Estados UnidosFil: MacDougall, Andrew. University of Guelph; CanadáFil: Martina, Jason P.. Texas State University; Estados UnidosFil: Moore, Joslin L.. Arthur Rylah Institute For Environmental Research; Australia. Monash University; AustraliaFil: Morgan, John W.. La Trobe University; AustraliaFil: Peri, Pablo Luis. Instituto Nacional de Tecnología Agropecuaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Prodromal language impairment in genetic frontotemporal dementia within the GENFI cohort

Objective: To identify whether language impairment exists presymptomatically in genetic frontotemporal de-mentia (FTD), and if so, the key differences between the main genetic mutation groups. Methods: 682 participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 290 asymptomatic and 82 prodromal mutation carriers (with C9orf72, GRN, and MAPT mutations) as well as 310 mutation-negative controls. Language was assessed using items from the Progressive Aphasia Severity Scale, as well as the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency task. Participants also underwent a 3 T volumetric T1-weighted MRI from which regional brain volumes within the language network were derived and compared between the groups. Results: 3% of asymptomatic (4% C9orf72, 4% GRN, 2% MAPT) and 48% of prodromal (46% C9orf72, 42% GRN, 64% MAPT) mutation carriers had impairment in at least one language symptom compared with 13% of controls. In prodromal mutation carriers significantly impaired word retrieval was seen in all three genetic groups whilst significantly impaired grammar/syntax and decreased fluency was seen only in C9orf72 and GRN mutation carriers, and impaired articulation only in the C9orf72 group. Prodromal MAPT mutation carriers had significant impairment on the category fluency task and the BNT whilst prodromal C9orf72 mutation carriers were impaired on the category fluency task only. Atrophy in the dominant perisylvian language regions differed between groups, with earlier, more widespread volume loss in C9orf72, and later focal atrophy in the temporal lobe in MAPT mutation carriers. Conclusions: Language deficits exist in the prodromal but not asymptomatic stages of genetic FTD across all three genetic groups. Improved understanding of the language phenotype prior to phenoconversion to fully symp-tomatic FTD will help develop outcome measures for future presymptomatic trials

Multidimensional responses of grassland stability to eutrophication

Eutrophication usually impacts grassland biodiversity, community composition, and biomass production, but its impact on the stability of these community aspects is unclear. One challenge is that stability has many facets that can be tightly correlated (low dimensionality) or highly disparate (high dimensionality). Using standardized experiments in 55 grassland sites from a globally distributed experiment (NutNet), we quantify the effects of nutrient addition on five facets of stability (temporal invariability, resistance during dry and wet growing seasons, recovery after dry and wet growing seasons), measured on three community aspects (aboveground biomass, community composition, and species richness). Nutrient addition reduces the temporal invariability and resistance of species richness and community composition during dry and wet growing seasons, but does not affect those of biomass. Different stability measures are largely uncorrelated under both ambient and eutrophic conditions, indicating consistently high dimensionality. Harnessing the dimensionality of ecological stability provides insights for predicting grassland responses to global environmental change

Genetic forms of primary progressive aphasia within the GENetic Frontotemporal dementia Initiative (GENFI) cohort: comparison with sporadic primary progressive aphasia

Samra et al. report that progranulin mutations are the commonest genetic cause of primary progressive aphasia. Two subtypes are seen: a nonfluent variant (similar in phenotype to its sporadic counterpart) and a 'not otherwise specified' variant (with unique linguistic features). Revised criteria for primary progressive aphasia should consider genetic phenotypes. Primary progressive aphasia is most commonly a sporadic disorder, but in some cases, it can be genetic. This study aimed to understand the clinical, cognitive and imaging phenotype of the genetic forms of primary progressive aphasia in comparison to the canonical nonfluent, semantic and logopenic subtypes seen in sporadic disease. Participants with genetic primary progressive aphasia were recruited from the international multicentre GENetic Frontotemporal dementia Initiative study and compared with healthy controls as well as a cohort of people with sporadic primary progressive aphasia. Symptoms were assessed using the GENetic Frontotemporal dementia Initiative language, behavioural, neuropsychiatric and motor scales. Participants also underwent a cognitive assessment and 3 T volumetric T1-weighted MRI. One C9orf72 (2%), 1 MAPT (6%) and 17 GRN (44%) symptomatic mutation carriers had a diagnosis of primary progressive aphasia. In the GRN cohort, 47% had a diagnosis of nonfluent variant primary progressive aphasia, and 53% had a primary progressive aphasia syndrome that did not fit diagnostic criteria for any of the three subtypes, called primary progressive aphasia-not otherwise specified here. The phenotype of the genetic nonfluent variant primary progressive aphasia group largely overlapped with that of sporadic nonfluent variant primary progressive aphasia, although the presence of an associated atypical parkinsonian syndrome was characteristic of sporadic and not genetic disease. The primary progressive aphasia -not otherwise specified group however was distinct from the sporadic subtypes with impaired grammar/syntax in the presence of relatively intact articulation, alongside other linguistic deficits. The pattern of atrophy seen on MRI in the genetic nonfluent variant primary progressive aphasia group overlapped with that of the sporadic nonfluent variant primary progressive aphasia cohort, although with more posterior cortical involvement, whilst the primary progressive aphasia-not otherwise specified group was strikingly asymmetrical with involvement particularly of the insula and dorsolateral prefrontal cortex but also atrophy of the orbitofrontal cortex and the medial temporal lobes. Whilst there are overlapping symptoms between genetic and sporadic primary progressive aphasia syndromes, there are also distinct features. Future iterations of the primary progressive aphasia consensus criteria should encompass such information with further research needed to understand the earliest features of these disorders, particularly during the prodromal period of genetic disease

Neuropsychiatric symptoms in genetic frontotemporal dementia: developing a new module for Clinical Rating Scales

BackgroundCurrent clinical rating scales in frontotemporal dementia (FTD) often do not incorporate neuropsychiatric features and may therefore inadequately measure disease stage. Methods832 participants from the Genetic FTD Initiative (GENFI) were recruited: 522 mutation carriers and 310 mutation-negative controls. The standardised GENFI clinical questionnaire assessed the frequency and severity of 14 neuropsychiatric symptoms: visual, auditory, and tactile hallucinations, delusions, depression, anxiety, irritability/lability, agitation/aggression, euphoria/elation, aberrant motor behaviour, hypersexuality, hyperreligiosity, impaired sleep, and altered sense of humour. A principal component analysis (PCA) was performed to identify key groupings of neuropsychiatric and behavioural items in order to create a new neuropsychiatric module that could be used as an addition to the Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center Behaviour and Language Domains (NACC FTLD) rating scale. ResultsOverall, 46.4% of mutation carriers had neuropsychiatric symptoms (51.6% C9orf72, 40.8% GRN, 46.6% MAPT) compared with 24.5% of controls. Anxiety and depression were the most common in all genetic groups but fluctuated longitudinally and loaded separately in the PCA. Hallucinations and delusions loaded together, with the remaining neuropsychiatric symptoms loading with the core behavioural features of FTD. These results suggest using a single 'psychosis' neuropsychiatric module consisting of hallucinations and delusions. Adding this to the CDR plus NACC FTLD, called the CDR plus NACC FTLD-N, leads to a number of participants being scored more severely, including those who were previously considered asymptomatic now being scored as prodromal. ConclusionsNeuropsychiatric symptoms occur in mutation carriers at all disease stages across all three genetic groups. However, only psychosis features provided additional staging benefit to the CDR plus NACC FTLD. Inclusion of these features brings us closer to optimising the rating scale for use in trials

Prodromal language impairment in genetic frontotemporal dementia within the GENFI cohort

Objective: To identify whether language impairment exists presymptomatically in genetic frontotemporal dementia (FTD), and if so, the key differences between the main genetic mutation groups. Methods: 682 participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 290 asymptomatic and 82 prodromal mutation carriers (with C9orf72, GRN, and MAPT mutations) as well as 310 mutation-negative controls. Language was assessed using items from the Progressive Aphasia Severity Scale, as well as the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency task. Participants also underwent a 3 T volumetric T1-weighted MRI from which regional brain volumes within the language network were derived and compared between the groups. Results: 3% of asymptomatic (4% C9orf72, 4% GRN, 2% MAPT) and 48% of prodromal (46% C9orf72, 42% GRN, 64% MAPT) mutation carriers had impairment in at least one language symptom compared with 13% of controls. In prodromal mutation carriers significantly impaired word retrieval was seen in all three genetic groups whilst significantly impaired grammar/syntax and decreased fluency was seen only in C9orf72 and GRN mutation carriers, and impaired articulation only in the C9orf72 group. Prodromal MAPT mutation carriers had significant impairment on the category fluency task and the BNT whilst prodromal C9orf72 mutation carriers were impaired on the category fluency task only. Atrophy in the dominant perisylvian language regions differed between groups, with earlier, more widespread volume loss in C9orf72, and later focal atrophy in the temporal lobe in MAPT mutation carriers. Conclusions: Language deficits exist in the prodromal but not asymptomatic stages of genetic FTD across all three genetic groups. Improved understanding of the language phenotype prior to phenoconversion to fully symptomatic FTD will help develop outcome measures for future presymptomatic trials

Motor symptoms in genetic frontotemporal dementia: developing a new module for clinical rating scales

OBJECTIVE: To investigate the optimal method of adding motor features to a clinical rating scale for frontotemporal dementia (FTD). METHODS: Eight hundred and thirty-two participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 522 mutation carriers (with C9orf72, GRN and MAPT mutations) and 310 mutation-negative controls. A standardised clinical questionnaire was used to assess eight motor symptoms (dysarthria, dysphagia, tremor, slowness, weakness, gait disorder, falls and functional difficulties using hands). Frequency and severity of each motor symptom was assessed, and a principal component analysis (PCA) was performed to identify how the different motor symptoms loaded together. Finally, addition of a motor component to the CDR® plus NACC FTLD was investigated (CDR® plus NACC FTLD-M). RESULTS: 24.3% of mutation carriers had motor symptoms (31.7% C9orf72, 18.8% GRN, 19.3% MAPT) compared to 6.8% of controls. Slowness and gait disorder were the commonest in all genetic groups while tremor and falls were the least frequent. Symptom severity scores were similar to equivalent physical motor examination scores. PCA revealed that all motor symptoms loaded together so a single additional motor component was added to the CDR® plus NACC FTLD to form the CDR® plus NACC FTLD-M. Individual global scores were more severe with the CDR® plus NACC FTLD-M, and no patients with a clinically diagnosed motor disorder (ALS/FTD-ALS or parkinsonism) were classified anymore as asymptomatic (unlike the CDR® plus NACC FTLD alone). CONCLUSIONS: Motor features are present in mutation carriers at all disease stages across all three genetic groups. Inclusion of motor symptoms in a rating scale that can be used in future clinical trials will not only ensure a more accurate severity measure is recorded but that a wider spectrum of FTD phenotypes can be included in the same trial

Prodromal language impairment in genetic frontotemporal dementia within the GENFI cohort

Objective: To identify whether language impairment exists presymptomatically in genetic frontotemporal dementia (FTD), and if so, the key differences between the main genetic mutation groups. Methods: 682 participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 290 asymptomatic and 82 prodromal mutation carriers (with C9orf72, GRN, and MAPT mutations) as well as 310 mutation-negative controls. Language was assessed using items from the Progressive Aphasia Severity Scale, as well as the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency task. Participants also underwent a 3 T volumetric T1-weighted MRI from which regional brain volumes within the language network were derived and compared between the groups. Results: 3% of asymptomatic (4% C9orf72, 4% GRN, 2% MAPT) and 48% of prodromal (46% C9orf72, 42% GRN, 64% MAPT) mutation carriers had impairment in at least one language symptom compared with 13% of controls. In prodromal mutation carriers significantly impaired word retrieval was seen in all three genetic groups whilst significantly impaired grammar/syntax and decreased fluency was seen only in C9orf72 and GRN mutation carriers, and impaired articulation only in the C9orf72 group. Prodromal MAPT mutation carriers had significant impairment on the category fluency task and the BNT whilst prodromal C9orf72 mutation carriers were impaired on the category fluency task only. Atrophy in the dominant perisylvian language regions differed between groups, with earlier, more widespread volume loss in C9orf72, and later focal atrophy in the temporal lobe in MAPT mutation carriers. Conclusions: Language deficits exist in the prodromal but not asymptomatic stages of genetic FTD across all three genetic groups. Improved understanding of the language phenotype prior to phenoconversion to fully symptomatic FTD will help develop outcome measures for future presymptomatic trials.</p

The TESS-Keck Survey. XV. Precise Properties of 108 TESS Planets and Their Host Stars

We present the stellar and planetary properties for 85 TESS Objects of Interest (TOIs) hosting 108 planet candidates which comprise the TESS-Keck Survey (TKS) sample. We combine photometry, high-resolution spectroscopy, and Gaia parallaxes to measure precise and accurate stellar properties. We then use these parameters as inputs to a lightcurve processing pipeline to recover planetary signals and homogeneously fit their transit properties. Among these transit fits, we detect significant transit-timing variations among at least three multi-planet systems (TOI-1136, TOI-1246, TOI-1339) and at least one single-planet system (TOI-1279). We also reduce the uncertainties on planet-to-star radius ratios $R_p/R_\star$ across our sample, from a median fractional uncertainty of 8.8$\%$ among the original TOI Catalog values to 3.0$\%$ among our updated results. With this improvement, we are able to recover the Radius Gap among small TKS planets and find that the topology of the Radius Gap among our sample is broadly consistent with that measured among Kepler planets. The stellar and planetary properties presented here will facilitate follow-up investigations of both individual TOIs and broader trends in planet properties, system dynamics, and the evolution of planetary systems.Comment: Accepted at The Astronomical Journal; 21 pages, 9 figure