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Longitudinal multimodal imaging and clinical endpoints for frontotemporal dementia clinical trials.

ABSTRACT: Frontotemporal dementia refers to a group of progressive neurodegenerative syndromes usually caused by the accumulation of pathological tau or TDP-43 proteins. The effects of these proteins in the brain are complex, and each can present with several different clinical syndromes. Clinical efficacy trials of drugs targeting these proteins must use endpoints that are meaningful to all participants despite the variability in symptoms across patients. There are many candidate clinical measures, including neuropsychological scores and functional measures. Brain imaging is another potentially attractive outcome that can be precisely quantified and provides evidence of disease modification. Most imaging studies in frontotemporal dementia have been cross-sectional, and few have compared longitudinal changes in cortical volume with changes in other measures such as perfusion and white matter integrity. The current study characterized longitudinal changes in 161 patients with three frontotemporal dementia syndromes: behavioural variant frontotemporal dementia (n = 77) and the semantic (n = 45) and non-fluent (n = 39) variants of primary progressive aphasia. Visits included comprehensive neuropsychological and functional assessment, structural MRI (3 T), diffusion tensor imaging, and arterial spin labelled perfusion imaging. The goal was to identify measures that are appropriate as clinical trial outcomes for each group, as well as those that might be appropriate for trials that would include more than one of these groups. Linear mixed effects models were used to estimate changes in each measure, and to examine the correlation between imaging and clinical changes. Sample sizes were estimated based on the observed effects for theoretical clinical trials using bootstrapping techniques to provide 95% confidence intervals for these estimates. Declines in functional and neuropsychological measures, as well as frontal and temporal cortical volumes and white matter microstructure were detected in all groups. Imaging changes were statistically significantly correlated with, and explained a substantial portion of variance in, the change in most clinical measures. Perfusion and diffusion tensor imaging accounted for variation in clinical decline beyond volume alone. Sample size estimates for atrophy and diffusion imaging were comparable to clinical measures. Corpus callosal fractional anisotropy led to the lowest sample size estimates for all three syndromes. These findings provide further guidance on selection of trial endpoints for studies in frontotemporal dementia and support the use of neuroimaging, particularly structural and diffusion weighted imaging, as biomarkers. Diffusion and perfusion imaging appear to offer additional utility for explaining clinical change beyond the variance explained by volume alone, arguing for considering multimodal imaging in treatment trials.

SUBMITTER: Staffaroni AM

PROVIDER: S-EPMC6351779 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Longitudinal multimodal imaging and clinical endpoints for frontotemporal dementia clinical trials.

Staffaroni Adam M AM Ljubenkov Peter A PA Kornak John J Cobigo Yann Y Datta Samir S Marx Gabe G Walters Samantha M SM Chiang Kevin K Olney Nick N Elahi Fanny M FM Knopman David S DS Dickerson Bradford C BC Boeve Bradley F BF Gorno-Tempini Maria Luisa ML Spina Salvatore S Grinberg Lea T LT Seeley William W WW Miller Bruce L BL Kramer Joel H JH Boxer Adam L AL Rosen Howard J HJ

Brain : a journal of neurology 20190201 2

Frontotemporal dementia refers to a group of progressive neurodegenerative syndromes usually caused by the accumulation of pathological tau or TDP-43 proteins. The effects of these proteins in the brain are complex, and each can present with several different clinical syndromes. Clinical efficacy trials of drugs targeting these proteins must use endpoints that are meaningful to all participants despite the variability in symptoms across patients. There are many candidate clinical measures, inclu ...[more]

PMID: 30698757

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Project description:BackgroundAlzheimer's disease (AD) and frontotemporal dementia (FTD) are the two main types of dementia. We investigated the electroencephalogram (EEG) difference and clinical correlation in early-onset Alzheimer's disease (EOAD), and FTD using multimodal EEG analyses. EOAD had more severe EEG abnormalities than late-onset AD (LOAD). Group comparisons between EOAD and LOAD were also performed.MethodsThirty patients diagnosed with EOAD, nine patients with LOAD, and 14 patients with FTD (≤65 y) were recruited (2008.1-2020.2), along with 24 healthy controls (≤65 y, n = 18; >65 y, n = 6). Clinical data were reviewed. Visual EEG, EEG microstate, and spectral analyses were performed.ResultsCompared to controls, markedly increased mean microstate duration, reduced mean occurrence, and reduced global field power (GFP) peaks per second were observed in EOAD and FTD. We found increased durations of class B in EOAD and class A in FTD. EOAD had reduced occurrences in classes A, B, and C, while only class C occurrence was reduced in FTD. The visual EEG results did not differ between AD and FTD. Microstate B showed correlations with activities of daily living score (r = 0.780, p = 0.008) and cerebrospinal fluid (CSF) Aβ42 (r = -0.833, p = 0.010) in EOAD. Microstate D occurrence was correlated with the CSF Aβ42 level in FTD (r = 0.786, p = 0.021). Spectral analysis revealed a general slowing EEG, which may contribute to microstate dynamic loss. Power in delta was significantly higher in EOAD than in FTD all over the head. In addition, EOAD had a marked increased duration and decreased occurrence than late-onset AD (LOAD), with no group differences in visual EEG results.ConclusionThe current study found that EOAD and FTD had different EEG changes, and microstate had an association with clinical severity and CSF biomarkers. EEG microstate is more sensitive than visual EEG and may be useful for the differentiation between AD and FTD. The observations support that EEG can be a potential biomarker for the diagnosis and assessment of early-onset dementias.

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Longitudinal multimodal imaging and clinical endpoints for frontotemporal dementia clinical trials.

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Longitudinal multimodal imaging and clinical endpoints for frontotemporal dementia clinical trials.

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