scholarly journals From brain volumes to subgroup classification in genetic mutation carriers for frontotemporal dementia: A cluster analysis in the GENFI study

2021 ◽  
Vol 17 (S5) ◽  
Author(s):  
Martina Bocchetta ◽  
Emily G. Todd ◽  
Jennifer M. Nicholas ◽  
Carolin Heller ◽  
Imogen J. Swift ◽  
...  
Keyword(s):  
Cluster Analysis ◽  
Frontotemporal Dementia ◽  
Genetic Mutation ◽  
Brain Volumes ◽  
Mutation Carriers ◽  
Subgroup Classification

scholarly journals Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia

2021 ◽  
pp. jnnp-2020-323541
Author(s):  
Jessica L Panman ◽  
Vikram Venkatraghavan ◽  
Emma L van der Ende ◽  
Rebecca M E Steketee ◽  
Lize C Jiskoot ◽  
...  
Keyword(s):  
White Matter ◽  
Frontotemporal Dementia ◽  
Disease Severity ◽  
Grey Matter ◽  
Clinical Stage ◽  
Data Driven ◽  
Grey Matter Volume ◽  
Matter Volume ◽  
Mutation Carriers ◽  
Individual Disease

ObjectiveProgranulin-related frontotemporal dementia (FTD-GRN) is a fast progressive disease. Modelling the cascade of multimodal biomarker changes aids in understanding the aetiology of this disease and enables monitoring of individual mutation carriers. In this cross-sectional study, we estimated the temporal cascade of biomarker changes for FTD-GRN, in a data-driven way.MethodsWe included 56 presymptomatic and 35 symptomatic GRN mutation carriers, and 35 healthy non-carriers. Selected biomarkers were neurofilament light chain (NfL), grey matter volume, white matter microstructure and cognitive domains. We used discriminative event-based modelling to infer the cascade of biomarker changes in FTD-GRN and estimated individual disease severity through cross-validation. We derived the biomarker cascades in non-fluent variant primary progressive aphasia (nfvPPA) and behavioural variant FTD (bvFTD) to understand the differences between these phenotypes.ResultsLanguage functioning and NfL were the earliest abnormal biomarkers in FTD-GRN. White matter tracts were affected before grey matter volume, and the left hemisphere degenerated before the right. Based on individual disease severities, presymptomatic carriers could be delineated from symptomatic carriers with a sensitivity of 100% and specificity of 96.1%. The estimated disease severity strongly correlated with functional severity in nfvPPA, but not in bvFTD. In addition, the biomarker cascade in bvFTD showed more uncertainty than nfvPPA.ConclusionDegeneration of axons and language deficits are indicated to be the earliest biomarkers in FTD-GRN, with bvFTD being more heterogeneous in disease progression than nfvPPA. Our data-driven model could help identify presymptomatic GRN mutation carriers at risk of conversion to the clinical stage.

scholarly journals The Revised Self-Monitoring Scale detects early impairment of social cognition in genetic frontotemporal dementia within the GENFI cohort

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Hannah D. Franklin ◽  
Lucy L. Russell ◽  
Georgia Peakman ◽  
Caroline V. Greaves ◽  
Martina Bocchetta ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Medial Temporal Lobe ◽  
Social Cognitive ◽  
Early Stage ◽  
Self Monitoring ◽  
Self Presentation ◽  
Genetic Groups ◽  
Mutation Carriers ◽  
Large Patient ◽  
Weighted Magnetic Resonance Imaging

Abstract Background Although social cognitive dysfunction is a major feature of frontotemporal dementia (FTD), it has been poorly studied in familial forms. A key goal of studies is to detect early cognitive impairment using validated measures in large patient cohorts. Methods We used the Revised Self-Monitoring Scale (RSMS) as a measure of socioemotional sensitivity in 730 participants from the genetic FTD initiative (GENFI) observational study: 269 mutation-negative healthy controls, 193 C9orf72 expansion carriers, 193 GRN mutation carriers and 75 MAPT mutation carriers. All participants underwent the standardised GENFI clinical assessment including the ‘CDR® plus NACC FTLD’ scale and RSMS. The RSMS total score and its two subscores, socioemotional expressiveness (EX score) and modification of self-presentation (SP score) were measured. Volumetric T1-weighted magnetic resonance imaging was available from 377 mutation carriers for voxel-based morphometry (VBM) analysis. Results The RSMS was decreased in symptomatic mutation carriers in all genetic groups but at a prodromal stage only in the C9orf72 (for the total score and both subscores) and GRN (for the modification of self-presentation subscore) groups. RSMS score correlated with disease severity in all groups. The VBM analysis implicated an overlapping network of regions including the orbitofrontal cortex, insula, temporal pole, medial temporal lobe and striatum. Conclusions The RSMS indexes socioemotional impairment at an early stage of genetic FTD and may be a suitable outcome measure in forthcoming trials.

Frontotemporal dementia and psychosis: Literature review

2016 ◽  
Vol 33 (S1) ◽  
pp. S367-S367
Author(s):  
D. Brandão ◽  
J. Massano
Keyword(s):  
Literature Review ◽  
Frontotemporal Dementia ◽  
Positive Family History ◽  
Genetic Mutation ◽  
Conclusive Evidence ◽  
Psychotic Symptoms ◽  
Initial Symptom ◽  
Clinical Criteria ◽  
Competing Interest ◽  
The Right

IntroductionFrontotemporal dementia (FTD) is a progressive neurodegenerative disease especially sporadic. About 30–40% have positive family history, with an identifiable genetic mutation in a percentage of cases increasing. Although the FTD psychosis has been recognized for many years, it is not included in the clinical criteria.ObjectivesTo assess the prevalence and characteristics of psychotic symptoms in FTD, compare the presence of psychosis in FTD C9+ versus C9− and analyze the occurrence of wrong diagnoses in FTD with psychosis.MethodsLiterature review, using computerized databases (Pubmed®). Articles were selected based on the content of their abstract and their relevance.ResultsIt is frequently the presence of psychotic symptoms in FTD associated with C9+ versus C9−. These may arise as initial symptom often leading to a psychiatric diagnosis years before obtaining diagnosis of FTD. There is no conclusive evidence about the anatomical correlation of psychotic features in the FTD, although there is the possible association with the right brain degeneration.ConclusionsThe existence of psychotic symptoms do not argues against the diagnosis of FTD verifying a high frequency of psychosis in FTD – C9+. As can be the first symptom in FTD is critical to differentiate psychiatric disorders. Further studies are needed in order to obtain a better characterization of psychotic symptoms in FTD – C9+.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Corrigendum to ‘Single-subject classification of presymptomatic frontotemporal dementia mutation carriers user multimodal MRI’ NeuroImage: Clinical 20 (2018) 188–196

2019 ◽  
Vol 22 ◽  
pp. 101717
Author(s):  
Rogier A. Feis ◽  
Mark J.R.J. Bouts ◽  
Jessica L. Panman ◽  
Lize C. Jiskoot ◽  
Elise G.P. Dopper ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Subject Classification ◽  
Single Subject ◽  
Mutation Carriers ◽  
Multimodal Mri

scholarly journals Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: a GENFI study

Brain ◽  
2019 ◽  
Vol 142 (4) ◽  
pp. 1108-1120 ◽  
Author(s):  
Henri J M M Mutsaerts ◽  
Saira S Mirza ◽  
Jan Petr ◽  
David L Thomas ◽  
David M Cash ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Frontotemporal Dementia ◽  
Symptom Onset ◽  
Arterial Spin Labelling ◽  
Anterior Cingulate ◽  
Middle Temporal Gyrus ◽  
Inverse Association ◽  
Mutation Carriers ◽  
Spin Labelling

Abstract Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.

scholarly journals P.002 Exosomal miR-204-5 and miR-632 in CSF are candidate biomarkers for frontotemporal dementia: a GENFI study

2018 ◽  
Vol 45 (s2) ◽  
pp. S16-S16
Author(s):  
R Schneider ◽  
P McKeever ◽  
T Kim ◽  
C Graff ◽  
J van Swieten ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Mutation Carrier ◽  
Mirna Expression ◽  
Pathogenic Mutation ◽  
Healthy Controls ◽  
Degree Relative ◽  
Sporadic Alzheimer’S Disease ◽  
Diagnostic Biomarkers ◽  
Mutation Carriers ◽  
Receiver Operator Characteristics

Background: To determine whether exosomal microRNAs (miRNAs) in CSF of patients with FTD can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic FTD Initiative (GENFI) cohort and in sporadic FTD. Methods: GENFI participants were either carriers of a pathogenic mutation or at risk of carrying a mutation because a first-degree relative was a symptomatic mutation carrier. Exosomes were isolated from CSF of 23 -pre-symptomatic and 15 symptomatic mutation carriers, and 11 healthy non-mutation carriers. Expression of miRNAs was measured using qPCR arrays. MiRNAs differentially expressed in symptomatic compared to pre-symptomatic mutation carriers were evaluated in 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer’s disease (AD), and 10 healthy controls (HCs). Results: In the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared to pre-symptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 [90% CI: 0.79-0.98] and 0.81 [90% CI: 0.68-0.93], and when combined an area of 0.93 [90% CI: 0.87-0.99]. In sporadic FTD, only miR-632 was significantly decreased compared to sporadic AD and HCs. Decrease of miR-632 revealed an area of 0.89 [90% CI: 0.80-0.98]. Conclusions: Exosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD.

scholarly journals Ventricular volume expansion in presymptomatic genetic frontotemporal dementia

Neurology ◽  
2019 ◽  
Vol 93 (18) ◽  
pp. e1699-e1706 ◽  
Author(s):  
Tamara P. Tavares ◽  
Derek G.V. Mitchell ◽  
Kristy Coleman ◽  
Christen Shoesmith ◽  
Robert Bartha ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Volume Expansion ◽  
Time Course ◽  
Automatic Segmentation ◽  
Disease Onset ◽  
Onset Time ◽  
Ventricular Volume ◽  
Mutation Carriers ◽  
Mri Scans

ObjectiveTo characterize the time course of ventricular volume expansion in genetic frontotemporal dementia (FTD) and identify the onset time and rates of ventricular expansion in presymptomatic FTD mutation carriers.MethodsParticipants included patients with a mutation in MAPT, PGRN, or C9orf72, or first-degree relatives of mutation carriers from the GENFI study with MRI scans at study baseline and at 1 year follow-up. Ventricular volumes were obtained from MRI scans using FreeSurfer, with manual editing of segmentation and comparison to fully automated segmentation to establish reliability. Linear mixed models were used to identify differences in ventricular volume and in expansion rates as a function of time to expected disease onset between presymptomatic carriers and noncarriers.ResultsA total of 123 participants met the inclusion criteria and were included in the analysis (18 symptomatic carriers, 46 presymptomatic mutation carriers, and 56 noncarriers). Ventricular volume differences were observed 4 years prior to symptom disease onset for presymptomatic carriers compared to noncarriers. Annualized rates of ventricular volume expansion were greater in presymptomatic carriers relative to noncarriers. Importantly, time-intensive manually edited and fully automated ventricular volume resulted in similar findings.ConclusionsVentricular volume differences are detectable in presymptomatic genetic FTD. Concordance of results from time-intensive manual editing and fully automatic segmentation approaches support its value as a measure of disease onset and progression in future studies in both presymptomatic and symptomatic genetic FTD.

scholarly journals Clinical Phenotype and Mutation Spectrum of Alzheimer’s Disease with Causative Genetic Mutation in a Chinese Cohort

2021 ◽  
Vol 18 ◽  
Author(s):  
Chenhui Mao ◽  
Jie Li ◽  
Liling Dong ◽  
Xinying Huang ◽  
Dan Lei ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Onset ◽  
Clinical Phenotype ◽  
Genetic Mutation ◽  
Mutation Spectrum ◽  
Systemic Review ◽  
Genetic Mutations ◽  
Csf Biomarkers ◽  
Mutation Carriers

Background: Alzheimer’s disease with a causative genetic mutation (AD-CGM) is an un- common form, characterized by a heterogeneous clinical phenotype and variations in the genotype of racial groups affected. Objective: We aimed to systemically describe the phenotype variance and mutation spectrum in the large sample size of the Peking Union Medical College Hospital (PUMCH) cohort, Beijing, China. Method: Next-generation sequencing (NGS) was carried out in 1108 patients diagnosed with dementia. A total of 40 Han Chinese patients with three AD gene mutations were enrolled. A systemic review of all the patients was performed, including clinical history, neurocognitive assessment, brain magnetic resonance imaging, and cerebrospinal fluid (CSF) biomarkers. Results: We studied the following gene mutation variants: 12 AβPP, 13 PSEN1, and 9 PSEN2, and 23 among them were novel. Most of them were early-onset, but PSEN1 mutation carriers had the youngest onset age. The commonest symptoms were similar to those of AD, including an amnestic syndrome, followed by psychiatric symptoms and movement disorder. On MRI, parietal and posterior temporal atrophy was prominent in PSEN1 and PSEN2 mutation carriers, while AβPP mutation carriers had more vascular changes. The CSF biomarkers profile was indistinguishable from sporadic AD. Conclusion: We identified a small group of AD-CGM subjects representing 3.6% among more than 1000 demented patients in the PUMCH cohort. These subjects usually presented with early-onset de- mentia and exhibited significant clinical and genetic heterogeneity. Identification required complete screening of genetic mutations using NGS. Although family history was usually present, we found non-familial cases of all three genetic mutations.

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