The longitudinal evaluation of familial frontotemporal dementia subjects protocol: Framework and methodology.
Ontology highlight
ABSTRACT: Introduction
It is important to establish the natural history of familial frontotemporal lobar degeneration (f-FTLD) and provide clinical and biomarker data for planning these studies, particularly in the asymptomatic phase.Methods
The Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects protocol was designed to enroll and follow at least 300 subjects for more than at least three annual visits who are members of kindreds with a mutation in one of the three most common f-FTLD genes-microtubule-associated protein tau, progranulin, or chromosome 9 open reading frame 72.Results
We present the theoretical considerations of f-FTLD and the aims/objectives of this protocol. We also describe the design and methodology for evaluating and rating subjects, in which detailed clinical and neuropsychological assessments are performed, biofluid samples are collected, and magnetic resonance imaging scans are performed using a standard protocol.Discussion
These data and samples, which are available to interested investigators worldwide, will facilitate planning for upcoming disease-modifying therapeutic trials in f-FTLD.
SUBMITTER: Boeve B
PROVIDER: S-EPMC6949411 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
Publications
The longitudinal evaluation of familial frontotemporal dementia subjects protocol: Framework and methodology.
Boeve Bradley B Bove Jessica J Brannelly Patrick P Brushaber Danielle D Coppola Giovanni G Dever Rielly R Dheel Christina C Dickerson Bradford B Dickinson Susan S Faber Kelley K Fields Julie J Fong Jamie J Foroud Tatiana T Forsberg Leah L Gavrilova Ralitza R Gearhart Debra D Ghoshal Nupur N Goldman Jennifer J Graff-Radford Jonathan J Graff-Radford Neill N Grossman Murray M Haley Dana D Heuer Hilary H Hsiung Ging-Yuek Robin GR Huey Edward E Irwin David D Jones David D Jones Lynne L Kantarci Kejal K Karydas Anna A Knopman David D Kornak John J Kraft Ruth R Kramer Joel J Kremers Walter W Kukull Walter W Lapid Maria M Lucente Diane D Mackenzie Ian I Manoochehri Masood M McGinnis Scott S Miller Bruce B Pearlman Rodney R Petrucelli Len L Potter Madeline M Rademakers Rosa R Ramos Eliana Marisa EM Rankin Kate K Rascovsky Katya K Sengdy Pheth P Shaw Les L Syrjanen Jeremy J Tatton Nadine N Taylor Joanne J Toga Arthur A Trojanowski John J Weintraub Sandra S Wong Bonnie B Wszolek Zbigniew Z Boxer Adam A Rosen Howard H
Alzheimer's & dementia : the journal of the Alzheimer's Association 20200106 1
<h4>Introduction</h4>It is important to establish the natural history of familial frontotemporal lobar degeneration (f-FTLD) and provide clinical and biomarker data for planning these studies, particularly in the asymptomatic phase.<h4>Methods</h4>The Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects protocol was designed to enroll and follow at least 300 subjects for more than at least three annual visits who are members of kindreds with a mutation in one of the three most co ...[more]
Similar Datasets
Project description:Developing and validating sensitive biomarkers for the presymptomatic stage of familial frontotemporal dementia is an important step in early diagnosis and for the design of future therapeutic trials. In the longitudinal Frontotemporal Dementia Risk Cohort, presymptomatic mutation carriers and non-carriers from families with familial frontotemporal dementia due to microtubule-associated protein tau (MAPT) and progranulin (GRN) mutations underwent a clinical assessment and multimodal MRI at baseline, 2-, and 4-year follow-up. Of the cohort of 73 participants, eight mutation carriers (three GRN, five MAPT) developed clinical features of frontotemporal dementia ('converters'). Longitudinal whole-brain measures of white matter integrity (fractional anisotropy) and grey matter volume in these converters (n = 8) were compared with healthy mutation carriers ('non-converters'; n = 35) and non-carriers (n = 30) from the same families. We also assessed the prognostic performance of decline within white matter and grey matter regions of interest by means of receiver operating characteristic analyses followed by stepwise logistic regression. Longitudinal whole-brain analyses demonstrated lower fractional anisotropy values in extensive white matter regions (genu corpus callosum, forceps minor, uncinate fasciculus, and superior longitudinal fasciculus) and smaller grey matter volumes (prefrontal, temporal, cingulate, and insular cortex) over time in converters, present from 2 years before symptom onset. White matter integrity loss of the right uncinate fasciculus and genu corpus callosum provided significant classifiers between converters, non-converters, and non-carriers. Converters' within-individual disease trajectories showed a relatively gradual onset of clinical features in MAPT, whereas GRN mutations had more rapid changes around symptom onset. MAPT converters showed more decline in the uncinate fasciculus than GRN converters, and more decline in the genu corpus callosum in GRN than MAPT converters. Our study confirms the presence of spreading predominant frontotemporal pathology towards symptom onset and highlights the value of multimodal MRI as a prognostic biomarker in familial frontotemporal dementia.
| S-EPMC6308313 | biostudies-literature
Project description:ObjectiveNovel biomarkers for monitoring progression in neurodegenerative conditions are needed. Measurement of microstructural changes in white matter (WM) using diffusion tensor imaging (DTI) may be a useful outcome measure. Here we report trajectories of WM change using serial DTI in a cohort with behavioral variant frontotemporal dementia (bvFTD).MethodsTwenty-three patients with bvFTD (12 having genetic mutations), and 18 age-matched control participants were assessed using DTI and neuropsychological batteries at baseline and ~1.3 years later. Baseline and follow-up DTI scans were registered using a groupwise approach. Annualized rates of change for DTI metrics, neuropsychological measures, and whole brain volume were calculated. DTI metric performances were compared, and sample sizes for potential clinical trials were calculated.ResultsIn the bvFTD group as a whole, rates of change in fractional anisotropy (FA) and mean diffusivity (MD) within the right paracallosal cingulum were greatest (FA: -6.8%/yr, p < 0.001; MD: 2.9%/yr, p = 0.01). MAPT carriers had the greatest change within left uncinate fasciculus (FA: -7.9%/yr, p < 0.001; MD: 10.9%/yr, p < 0.001); sporadic bvFTD and C9ORF72 carriers had the greatest change within right paracallosal cingulum (sporadic bvFTD, FA: -6.7%/yr, p < 0.001; MD: 3.8%/yr, p = 0.001; C9ORF72, FA: -6.8%/yr, p = 0.004). Sample size estimates using FA change were substantially lower than neuropsychological or whole brain measures of change.InterpretationSerial DTI scans may be useful for measuring disease progression in bvFTD, with particular trajectories of WM damage emerging. Sample size calculations suggest that longitudinal DTI may be a useful biomarker in future clinical trials.
| S-EPMC4305215 | biostudies-literature
Project description:We performed 4-year follow-up neuropsychological assessment to investigate cognitive decline and the prognostic abilities from presymptomatic to symptomatic familial frontotemporal dementia (FTD).Presymptomatic MAPT (n?=?15) and GRN mutation carriers (n?=?31), and healthy controls (n?=?39) underwent neuropsychological assessment every 2 years. Eight mutation carriers (5 MAPT, 3 GRN) became symptomatic. We investigated cognitive decline with multilevel regression modeling; the prognostic performance was assessed with ROC analyses and stepwise logistic regression.MAPT converters declined on language, attention, executive function, social cognition, and memory, and GRN converters declined on attention and executive function (p?<?0.05). Cognitive decline in ScreeLing phonology (p?=?0.046) and letter fluency (p?=?0.046) were predictive for conversion to non-fluent variant PPA, and decline on categorical fluency (p?=?0.025) for an underlying MAPT mutation.Using longitudinal neuropsychological assessment, we detected a mutation-specific pattern of cognitive decline, potentially suggesting prognostic value of neuropsychological trajectories in conversion to symptomatic FTD.
| S-EPMC5990575 | biostudies-other
Project description:ObjectiveWe aimed to investigate whether cognitive deficits and structural and functional connectivity changes can be detected before symptom onset in a large cohort of carriers of microtubule-associated protein tau and progranulin mutations.MethodsIn this case-control study, 75 healthy individuals (aged 20-70 years) with 50% risk for frontotemporal dementia (FTD) underwent DNA screening, neuropsychological assessment, and structural and functional MRI. We used voxel-based morphometry and tract-based spatial statistics for voxelwise analyses of gray matter volume and diffusion tensor imaging measures. Using resting-state fMRI scans, we assessed whole-brain functional connectivity to frontoinsula, anterior midcingulate cortex (aMCC), and posterior cingulate cortex.ResultsAlthough carriers (n = 37) and noncarriers (n = 38) had similar neuropsychological performance, worse performance on Stroop III, Ekman faces, and Happé cartoons correlated with higher age in carriers, but not controls. Reduced fractional anisotropy and increased radial diffusivity throughout frontotemporal white matter tracts were found in carriers and correlated with higher age. Reductions in functional aMCC connectivity were found in carriers compared with controls, and connectivity between frontoinsula and aMCC seeds and several brain regions significantly decreased with higher age in carriers but not controls. We found no significant differences or age correlations in posterior cingulate cortex connectivity. No differences in regional gray matter volume were found.ConclusionsThis study convincingly demonstrates that alterations in structural and functional connectivity develop before the first symptoms of FTD arise. These findings suggest that diffusion tensor imaging and resting-state fMRI may have the potential to become sensitive biomarkers for early FTD in future clinical trials.
| S-EPMC3598452 | biostudies-literature
Project description:A familial behavioral variant frontotemporal dementia associated with astrocyte-predominant tauopathy is described in 2 sisters born from consanguineous parents. The neuropathologic examination revealed massive accumulation of abnormally hyperphosphorylated, conformational, truncated tau at aspartic acid 421, ubiquitinated and nitrated tau at Tyr29 in cortical astrocyte (including their perivascular foot processes), and Bergmann glia. Smaller amounts of abnormal tau were observed in neurons and rarely in oligodendrocytes. There was decreased expression of glial glutamate transporter in the majority of tau-positive astrocytes. Gel electrophoresis of sarkosyl-insoluble fractions showed 2 bands of 64 and 60 kDa and a doublet of 67 to 70 kDa (which are different from those seen in Alzheimer disease and in typical 4R and 3R tauopathies) together with several bands of lower molecular weight indicative of truncated tau. Analysis of the expression of MAPT isoforms further revealed altered splicing and representation of tau isoforms involving exons 2, 3, and 10. Genetic testing revealed no known mutations in PSEN1, PSEN2, APP, MAPT, GRN, FUS, and TARDBP and no pathologic expansion in C9ORF72. However, a novel rare heterozygous sequence variant(p.Q140H) of uncertain significance was identified in FUS in both siblings.
| S-EPMC4366320 | biostudies-literature
Project description:Frontotemporal dementia is a degenerative brain condition characterized by focal atrophy affecting the frontal and temporal lobes predominantly. Changes in white matter with disease progression and their relationship to grey matter atrophy remain unknown in FTD. This study aimed to establish longitudinal white matter changes and compare these changes to regional grey matter atrophy in the main FTD subtypes. Diffusion and T?-weighted images were collected from behavioral-variant FTD (bvFTD: 12), progressive non-fluent aphasia (PNFA: 10), semantic dementia (SD: 11), and 15 controls at baseline and 12 months apart. Changes in white matter integrity were established by fractional anisotropy, mean, axial and radial diffusivity measurements using tract-based spatial statistics. Patterns of cortical grey matter atrophy were measured using voxel-based morphometry. At baseline, bvFTD showed severe cross-sectional changes in orbitofrontal and anterior temporal tracts, which progressed to involve posterior temporal and occipital white matter over the 12-month. In PNFA, cross-sectional changes occurred bilaterally in frontotemporal white matter (left > right), with longitudinal changes more prominent on the right. Initial white matter changes in SD were circumscribed to the left temporal lobe, with longitudinal changes extending to bilateral frontotemporal tracts. In contrast, progression of grey matter change over time was less pronounced in all FTD subtypes. Mean diffusivity was most sensitive in detecting baseline changes while fractional anisotropy and radial diffusivity revealed greatest changes over time, possibly reflecting different underlying pathological processes with disease progression. Our results indicate that investigations of white matter changes reveal important differences across FTD syndromes with disease progression.
| S-EPMC6869363 | biostudies-literature
Project description:ObjectiveTo compare the sensitivity of structural MRI and 18F-fludeoxyglucose PET (18FDG-PET) to detect longitudinal changes in frontotemporal dementia (FTD).MethodsThirty patients with behavioral variant FTD (bvFTD), 7 with nonfluent/agrammatic variant primary progressive aphasia (nfvPPA), 16 with semantic variant primary progressive aphasia (svPPA), and 43 cognitively normal controls underwent 2-4 MRI and 18FDG-PET scans (total scans/visit = 270) as part of the Frontotemporal Lobar Degeneration Neuroimaging Initiative study. Linear mixed-effects models were carried out voxel-wise and in regions of interest to identify areas showing decreased volume or metabolism over time in patients as compared to controls.ResultsAt baseline, patients with bvFTD showed bilateral temporal, dorsolateral, and medial prefrontal atrophy/hypometabolism that extended with time into adjacent structures and parietal lobe. In nfvPPA, baseline atrophy/hypometabolism in supplementary motor cortex extended with time into left greater than right precentral, dorsolateral, and dorsomedial prefrontal cortex. In svPPA, baseline atrophy/hypometabolism encompassed the anterior temporal and medial prefrontal cortex and longitudinal changes were found in temporal, orbitofrontal, and lateral parietal cortex. Across syndromes, there was substantial overlap in the brain regions showing volume and metabolism loss. Even though the pattern of metabolic decline was more extensive, metabolic changes were also more variable and sample size estimates were similar or higher for 18FDG-PET compared to MRI.ConclusionOur findings demonstrated the sensitivity of 18FDG-PET and structural MRI for tracking disease progression in FTD. Both modalities showed highly overlapping patterns of longitudinal change and comparable sample size estimates to detect longitudinal changes in future clinical trials.
| S-EPMC7455324 | biostudies-literature
Project description:IntroductionSome models of therapy for neurodegenerative diseases envision starting treatment before symptoms develop. Demonstrating that such treatments are effective requires accurate knowledge of when symptoms would have started without treatment. Familial frontotemporal lobar degeneration offers a unique opportunity to develop predictors of symptom onset.MethodsWe created dementia risk scores in 268 familial frontotemporal lobar degeneration family members by entering covariate-adjusted standardized estimates of brain atrophy into a logistic regression to classify asymptomatic versus demented participants. The score's predictive value was tested in a separate group who were followed up longitudinally (stable vs. converted to dementia) using Cox proportional regressions with dementia risk score as the predictor.ResultsCross-validated logistic regression achieved good separation of asymptomatic versus demented (accuracy = 90%, SE = 0.06). Atrophy scores predicted conversion from asymptomatic or mildly/questionably symptomatic to dementia (HR = 1.51, 95% CI: [1.16,1.98]).DiscussionIndividualized quantification of baseline brain atrophy is a promising predictor of progression in asymptomatic familial frontotemporal lobar degeneration mutation carriers.
| S-EPMC6938544 | biostudies-literature
Project description:Unlike familial Alzheimer's disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects.
| S-EPMC9951811 | biostudies-literature
Project description:Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurodegenerative disorders that share genetic causes and pathogenic mechanisms. The critical genetic players of ALS and FTD are the TARDBP, FUS and C9orf72 genes, whose protein products, TDP-43, FUS and the C9orf72-dipeptide repeat proteins, accumulate in form of cytoplasmic inclusions. The majority of the studies focus on the understanding of how cells control TDP-43 and FUS aggregation in the cytoplasm, overlooking how dysfunctions occurring at the nuclear level may influence the maintenance of protein solubility outside of the nucleus. However, protein quality control (PQC) systems that maintain protein homeostasis comprise a cytoplasmic and a nuclear arm that are interconnected and share key players. It is thus conceivable that impairment of the nuclear arm of the PQC may have a negative impact on the cytoplasmic arm of the PQC, contributing to the formation of the cytoplasmic pathological inclusions. Here we focused on two stress-inducible condensates that act as transient deposition sites for misfolding-prone proteins: Promyelocytic leukemia protein (PML) nuclear bodies (PML-NBs) and cytoplasmic stress granules (SGs). Upon stress, PML-NBs compartmentalize misfolded proteins, including defective ribosomal products (DRiPs), and recruit chaperones and proteasomes to promote their nuclear clearance. SGs transiently sequester aggregation-prone RNA-binding proteins linked to ALS-FTD and mRNAs to attenuate their translation. We report that PML assembly is impaired in the human brain and spinal cord of familial C9orf72 and FUS ALS-FTD cases. We also show that defective PML-NB assembly impairs the compartmentalization of DRiPs in the nucleus, leading to their accumulation inside cytoplasmic SGs, negatively influencing SG dynamics. Although it is currently unclear what causes the decrease of PML-NBs in ALS-FTD, our data highlight the existence of a cross-talk between the cytoplasmic and nuclear PQC systems, whose alteration can contribute to SG accumulation and cytoplasmic protein aggregation in ALS-FTD.
| S-EPMC10349866 | biostudies-literature