Frontotemporal dementia spectrum: first genetic screen in a Greek cohort.
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ABSTRACT:
SUBMITTER: Ramos EM
PROVIDER: S-EPMC6553875 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
Publications
Frontotemporal dementia spectrum: first genetic screen in a Greek cohort.
Ramos Eliana Marisa EM Koros Christos C Dokuru Deepika Reddy DR Van Berlo Victoria V Kroupis Christos C Wojta Kevin K Wang Qing Q Andronas Nikolaos N Matsi Stavroula S Beratis Ion N IN Huang Alden Y AY Lee Suzee E SE Bonakis Anastasios A Florou-Hatziyiannidou Chryseis C Fragkiadaki Stella S Kontaxopoulou Dionysia D Agiomyrgiannakis Dimitrios D Kamtsadeli Vasiliki V Tsinia Niki N Papastefanopoulou Vasiliki V Stamelou Maria M Miller Bruce L BL Stefanis Leonidas L Papatriantafyllou John D JD Papageorgiou Sokratis G SG Coppola Giovanni G
Neurobiology of aging 20181103
Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative syndromes associated with several causative and susceptibility genes. Herein, we aimed to determine the incidence of the most common causative dementia genes in a cohort of 118 unrelated Greek FTD spectrum patients. We also screened for novel possible disease-associated variants in additional 21 genes associated with FTD or amyotrophic lateral sclerosis. Pathogenic or likely pathogenic variants were identified in 16 case ...[more]
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Project description:BackgroundThere are relatively few data on the genetic spectrum of Chinese frontotemporal dementia (FTD) population.ObjectiveWith the dementia cohort of Peking Union Medical College Hospital, we aim to illustrate the genetic spectrum of FTD patients, as well as the phenotypic heterogeneity of FTD-gene variant carriers.Methods204 unrelated, clinically diagnosed FTD patients of Chinese ancestry were enrolled. All the participants received demographic survey, history inquiry, physical examination, cognitive assessment, blood biochemical test, brain CT/MRI, and gene sequencing.Results56.4% (115/204) participants were clinically diagnosed with behavioral variant of FTD, 20.6% (42/204) with nonfluent/agrammatic variant primary progressive aphasia (PPA), 20.1% (41/204) with semantic variant PPA, and 2.9% (6/204) with mixed variant PPA. 11.8% (24/204) subjects harbored the potential causative variants in FTD-related genes, including the MAPT (n = 7), TBK1 (n = 7), GRN (n = 2), TBK1+GRN (n = 1), VCP (n = 1), TARDBP (n = 1), UBQLN2 (n = 1), SQSTM1 (n = 1), DCTN1 (n = 1), HNRNPA1 (n = 1), and C9orf72 GGGGCC repeats (n = 1). The TBK1 T31fs, T457fs, K622fs, c.359-1G>A, the VCP P188T, and the GRN P50fs, P439fs were novel pathogenic/likely pathogenic variants. The TBK1 carriers showed a later disease onset and a higher incidence of parietal atrophy relative to the MAPTcarriers.ConclusionThere is genetic and clinical heterogeneity among Chinese FTD population. The TBK1 has a high mutation frequency in Chinese FTD patients.
| S-EPMC9535560 | biostudies-literature
Project description:Abstract Biomarkers that can predict disease progression in individuals with genetic frontotemporal dementia are urgently needed. We aimed to identify whether baseline MRI-based grey and white matter abnormalities are associated with different clinical progression profiles in presymptomatic mutation carriers in the GENetic Frontotemporal dementia Initiative. Three hundred eighty-seven mutation carriers were included (160 GRN, 160 C9orf72, 67 MAPT), together with 240 non-carrier cognitively normal controls. Cortical and subcortical grey matter volumes were generated using automated parcellation methods on volumetric 3T T1-weighted MRI scans, while white matter characteristics were estimated using diffusion tensor imaging. Mutation carriers were divided into two disease stages based on their global CDR®+NACC-FTLD score: presymptomatic (0 or 0.5) and fully symptomatic (1 or greater). The w-scores in each grey matter volumes and white matter diffusion measures were computed to quantify the degree of abnormality compared to controls for each presymptomatic carrier, adjusting for their age, sex, total intracranial volume, and scanner type. Presymptomatic carriers were classified as ‘normal’ or ‘abnormal’ based on whether their grey matter volume and white matter diffusion measure w-scores were above or below the cut point corresponding to the 10th percentile of the controls. We then compared the change in disease severity between baseline and one year later in both the ‘normal’ and ‘abnormal’ groups within each genetic subtype, as measured by the CDR®+NACC-FTLD sum-of-boxes score and revised Cambridge Behavioural Inventory total score. Overall, presymptomatic carriers with normal regional w-scores at baseline did not progress clinically as much as those with abnormal regional w-scores. Having abnormal grey or white matter measures at baseline was associated with a statistically significant increase in the CDR®+NACC-FTLD of up to 4 points in C9orf72 expansion carriers, and 5 points in the GRN group as well as a statistically significant increase in the revised Cambridge Behavioural Inventory of up to 11 points in MAPT, 10 points in GRN, and 8 points in C9orf72 mutation carriers. Baseline regional brain abnormalities on MRI in presymptomatic mutation carriers are associated with different profiles of clinical progression over time. These results may be helpful to inform stratification of participants in future trials. Bocchetta et al. quantified brain anomalies on MRI in a large cohort of C9orf72, MAPT, and GRN mutation carriers. They defined the imaging markers associated with the largest clinical and behavioral changes over one year in presymptomatic carriers, providing important data to inform participants’ stratification in trials. Graphical Abstract Graphical abstract
| S-EPMC10036293 | biostudies-literature
Project description:A key symptom of frontotemporal dementia (FTD) is difficulty interacting socially with others. Social cognition problems in FTD include impaired emotion processing and theory of mind difficulties, and whilst these have been studied extensively in sporadic FTD, few studies have investigated them in familial FTD. Facial Emotion Recognition (FER) and Faux Pas (FP) recognition tests were used to study social cognition within the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort of C9orf72, GRN, and MAPT mutation carriers. 627 participants undertook at least one of the tasks, and were separated into mutation-negative healthy controls, presymptomatic mutation carriers (split into early and late groups) and symptomatic mutation carriers. Groups were compared using a linear regression model with bootstrapping, adjusting for age, sex, education, and for the FP recognition test, language. Neural correlates of social cognition deficits were explored using a voxel-based morphometry (VBM) study. All three of the symptomatic genetic groups were impaired on both tasks with no significant difference between them. However, prior to onset, only the late presymptomatic C9orf72 mutation carriers on the FER test were impaired compared to the control group, with a subanalysis showing differences particularly in fear and sadness. The VBM analysis revealed that impaired social cognition was mainly associated with a left hemisphere predominant network of regions involving particularly the striatum, orbitofrontal cortex and insula, and to a lesser extent the inferomedial temporal lobe and other areas of the frontal lobe. In conclusion, theory of mind and emotion processing abilities are impaired in familial FTD, with early changes occurring prior to symptom onset in C9orf72 presymptomatic mutation carriers. Future work should investigate how performance changes over time, in order to gain a clearer insight into social cognitive impairment over the course of the disease.
| S-EPMC7754789 | biostudies-literature
Project description:Importance:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons. Although novel ALS genetic variants have been identified, the shared genetic risk between ALS and other neurodegenerative disorders remains poorly understood. Objectives:To examine whether there are common genetic variants that determine the risk for ALS and other neurodegenerative diseases and to identify their functional pathways. Design, Setting, and Participants:In this study conducted from December 1, 2016, to August 1, 2017, the genetic overlap between ALS, sporadic frontotemporal dementia (FTD), FTD with TDP-43 inclusions, Parkinson disease (PD), Alzheimer disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) were systematically investigated in 124 876 cases and controls. No participants were excluded from this study. Diagnoses were established using consensus criteria. Main Outcomes and Measures:The primary outcomes were a list of novel loci and their functional pathways in ALS, FTD, PSP, and ALS mouse models. Results:Among 124 876 cases and controls, genome-wide conjunction analyses of ALS, FTD, PD, AD, CBD, and PSP revealed significant genetic overlap between ALS and FTD at known ALS loci: rs13302855 and rs3849942 (nearest gene, C9orf72; P = .03 for rs13302855 and P = .005 for rs3849942) and rs4239633 (nearest gene, UNC13A; P = .03). Significant genetic overlap was also found between ALS and PSP at rs7224296, which tags the MAPT H1 haplotype (nearest gene, NSF; P = .045). Shared risk genes were enriched for pathways involving neuronal function and development. At a conditional FDR P < .05, 22 novel ALS polymorphisms were found, including rs538622 (nearest gene, ERGIC1; P = .03 for ALS and FTD), which modifies BNIP1 expression in human brains (35 of 137 females; mean age, 59 years; P = .001). BNIP1 expression was significantly reduced in spinal cord motor neurons from patients with ALS (4 controls: mean age, 60.5 years, mean [SE] value, 3984 [760.8] arbitrary units [AU]; 7 patients with ALS: mean age, 56 years, mean [SE] value, 1999 [274.1] AU; P = .02), in an ALS mouse model (mean [SE] value, 13.75 [0.09] AU for 2 SOD1 WT mice and 11.45 [0.03] AU for 2 SOD1 G93A mice; P = .002) and in brains of patients with PSP (80 controls: 39 females; mean age, 82 years, mean [SE] value, 6.8 [0.2] AU; 84 patients with PSP: 33 females, mean age 74 years, mean [SE] value, 6.8 [0.1] AU; β = -0.19; P = .009) or FTD (11 controls: 4 females; mean age, 67 years; mean [SE] value, 6.74 [0.05] AU; 17 patients with FTD: 10 females; mean age, 69 years; mean [SE] value, 6.53 [0.04] AU; P = .005). Conclusions and Relevance:This study found novel genetic overlap between ALS and diseases of the FTD spectrum, that the MAPT H1 haplotype confers risk for ALS, and identified the mitophagy-associated, proapoptotic protein BNIP1 as an ALS risk gene. Together, these findings suggest that sporadic ALS may represent a selectively pleiotropic, polygenic disorder.
| S-EPMC6043387 | biostudies-literature
Project description:Background and objectivesTo assess cortical, subcortical, and cerebellar gray matter (GM) atrophy using MRI in patients with disorders of the frontotemporal lobar degeneration (FTLD) spectrum with known genetic mutations.MethodsSixty-six patients carrying FTLD-related mutations were enrolled, including 44 with pure motor neuron disease (MND) and 22 with frontotemporal dementia (FTD). Sixty-one patients with sporadic FTLD (sFTLD) matched for age, sex, and disease severity with genetic FTLD (gFTLD) were also included, as well as 52 healthy controls. A whole-brain voxel-based morphometry (VBM) analysis was performed. GM volumes of subcortical and cerebellar structures were obtained.ResultsCompared with controls, GM atrophy on VBM was greater and more diffuse in genetic FTD, followed by sporadic FTD and genetic MND cases, whereas patients with sporadic MND (sMND) showed focal motor cortical atrophy. Patients carrying C9orf72 and GRN mutations showed the most widespread cortical volume loss, in contrast with GM sparing in SOD1 and TARDBP. Globally, patients with gFTLD showed greater atrophy of parietal cortices and thalami compared with sFTLD. In volumetric analysis, patients with gFTLD showed volume loss compared with sFTLD in the caudate nuclei and thalami, in particular comparing C9-MND with sMND cases. In the cerebellum, patients with gFTLD showed greater atrophy of the right lobule VIIb than sFTLD. Thalamic volumes of patients with gFTLD with a C9orf72 mutation showed an inverse correlation with Frontal Behavioral Inventory scores.DiscussionMeasures of deep GM and cerebellar structural involvement may be useful markers of gFTLD, particularly C9orf72-related disorders, regardless of the clinical presentation within the FTLD spectrum.
| S-EPMC8548958 | biostudies-literature
Project description:Frontotemporal dementia (FTD) is the most common form of dementia before 60 years of age. Rare pathogenic mutations in CHMP2B, which encodes a component of the endosomal sorting complex required for transport (ESCRT-III), are associated with FTD linked to chromosome 3 (FTD3). Animal models of FTD3 have not yet been reported, and what signaling pathways are misregulated by mutant CHMP2B in vivo is unknown. Here we report the establishment of a Drosophila model of FTD3 and show the genetic interactions between mutant CHMP2B and other components of ESCRT. Through an unbiased genome-wide screen, we identified 29 modifier loci and found that serpin5 (Spn5), a largely uncharacterized serine protease inhibitor, suppresses the melanization phenotype induced by mutant CHMP2B in the fly eye. We also found that Spn5 is a negative regulator of the Toll pathway and functions extracellularly, likely by blocking the proteolytic activation of Spaetzle, the Toll receptor ligand. Moreover, Spn5 inhibited activation of the Toll pathway by mutant CHMP2B. Our findings identify Spn5 as a regulator of the Toll pathway and CHMP2B toxicity and show that the Toll pathway is a major signaling pathway misregulated by mutant CHMP2B in vivo. This fly model will be useful to further dissect genetic pathways that are potentially relevant to the pathogenesis and treatment of FTD.
| S-EPMC2715505 | biostudies-other
Project description:Frontotemporal dementia (FTD) is a highly heritable group of neurodegenerative disorders, with around 30% of patients having a strong family history. The majority of that heritability is accounted for by autosomal dominant mutations in the chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT) genes, with mutations more rarely seen in a number of other genes. This review will discuss the recent updates in the field of genetic FTD. Age at symptom onset in genetic FTD is variable with recently identified genetic modifiers including TMEM106B (in GRN carriers particularly) and a polymorphism at a locus containing two overlapping genes LOC101929163 and C6orf10 (in C9orf72 carriers). Behavioural variant FTD (bvFTD) is the most common diagnosis in each of the genetic groups, although in C9orf72 carriers amyotrophic lateral sclerosis either alone, or with bvFTD, is also common. An atypical neuropsychiatric presentation is also seen in C9orf72 carriers and family members of carriers are at greater risk of psychiatric disorders including schizophrenia and autistic spectrum disorders. Large natural history studies of presymptomatic genetic FTD are now underway both in Europe/Canada (GENFI-the Genetic FTD Initiative) and in the US (ARTFL/LEFFTDS study), collaborating together under the banner of the FTD Prevention Initiative (FPI). These studies are taking forward the validation of cognitive, imaging and fluid biomarkers that aim to robustly measure disease onset, staging and progression in genetic FTD. Grey matter changes on MRI and hypometabolism on FDG-PET are seen at least 10 years before symptom onset with white matter abnormalities seen earlier, but the pattern and exact timing of changes differ between different genetic groups. In contrast, tau PET has yet to show promise in genetic FTD. Three key fluid biomarkers have been identified so far that are likely to be helpful in clinical trials-CSF or blood neurofilament light chain levels (in all groups), CSF or blood progranulin levels (in GRN carriers) and CSF poly(GP) dipeptide repeat protein levels (in C9orf72 carriers). Increased knowledge about genetic FTD has led to more clinical presymptomatic genetic testing but this has not yet been mirrored in the development of either an accepted FTD-specific testing protocol or provision of appropriate psychological support mechanisms for those living through the at-risk phase. This will become even more relevant as disease-modifying therapy trials start in each of the genetic groups over the next few years.
| S-EPMC6647117 | biostudies-literature
Project description:IntroductionWe aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD).MethodsNeuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD generating a new CDR plus NACC FTLD-NM scale. This was assessed in 522 mutation carriers and 310 mutation-negative controls from the Genetic Frontotemporal dementia Initiative (GENFI).ResultsThe new scale led to higher global severity scores than the CDR plus NACC FTLD: 1.4% of participants were now considered prodromal rather than asymptomatic, while 1.3% were now considered symptomatic rather than asymptomatic or prodromal. No participants with a clinical diagnosis of an FTD spectrum disorder were classified as asymptomatic using the new scales.DiscussionAdding new domains to the CDR plus NACC FTLD leads to a scale that encompasses the wider phenotypic spectrum of FTD with further work needed to validate its use more widely.HighlightsThe new Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains neuropsychiatric and motor (CDR plus NACC FTLD-NM) rating scale was significantly positively correlated with the original CDR plus NACC FTLD and negatively correlated with the FTD Rating Scale (FRS).No participants with a clinical diagnosis in the frontotemporal dementia spectrum were classified as asymptomatic with the new CDR plus NACC FTLD-NM rating scale.Individuals had higher global severity scores with the addition of the neuropsychiatric and motor domains.A receiver operating characteristic analysis of symptomatic diagnosis showed nominally higher areas under the curve for the new scales.
| S-EPMC11016817 | biostudies-literature
Project description:We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS.
| S-EPMC5324646 | biostudies-literature
Project description:BackgroundFrontotemporal dementia (FTD) is a spectrum of diseases characterised by language, behavioural and motor symptoms. Among the different subcortical regions implicated in the FTD symptomatology, the hypothalamus regulates various bodily functions, including eating behaviours which are commonly present across the FTD spectrum. The pattern of specific hypothalamic involvement across the clinical, pathological, and genetic forms of FTD has yet to be fully investigated, and its possible associations with abnormal eating behaviours have yet to be fully explored.MethodsUsing an automated segmentation tool for volumetric T1-weighted MR images, we measured hypothalamic regional volumes in a cohort of 439 patients with FTD (197 behavioural variant FTD [bvFTD]; 7 FTD with associated motor neurone disease [FTD-MND]; 99 semantic variant primary progressive aphasia [svPPA]; 117 non-fluent variant PPA [nfvPPA]; 19 PPA not otherwise specified [PPA-NOS]) and 118 age-matched controls. We compared volumes across the clinical, genetic (29 MAPT, 32 C9orf72, 23 GRN), and pathological diagnoses (61 tauopathy, 40 TDP-43opathy, 4 FUSopathy). We correlated the volumes with presence of abnormal eating behaviours assessed with the revised version of the Cambridge Behavioural Inventory (CBI-R).ResultsOn average, FTD patients showed 14% smaller hypothalamic volumes than controls. The groups with the smallest hypothalamic regions were FTD-MND (20%), MAPT (25%) and FUS (33%), with differences mainly localised in the anterior and posterior regions. The inferior tuberal region was only significantly smaller in tauopathies (MAPT and Pick's disease) and in TDP-43 type C compared to controls and was the only regions that did not correlate with eating symptoms. PPA-NOS and nfvPPA were the groups with the least frequent eating behaviours and the least hypothalamic involvement.ConclusionsAbnormal hypothalamic volumes are present in all the FTD forms, but different hypothalamic regions might play a different role in the development of abnormal eating behavioural and metabolic symptoms. These findings might therefore help in the identification of different underlying pathological mechanisms, suggesting the potential use of hypothalamic imaging biomarkers and the research of potential therapeutic targets within the hypothalamic neuropeptides.
| S-EPMC9218583 | biostudies-literature