Dataset Information

Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH-EXAMINER as a potential clinical trial endpoint.

ABSTRACT:

Introduction

Identifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression.

Methods

Ninety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes.

Results

NIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss.

Discussion

The NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint.

SUBMITTER: Staffaroni AM

PROVIDER: S-EPMC6842665 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH-EXAMINER as a potential clinical trial endpoint.

Staffaroni Adam M AM Bajorek Lynn L Casaletto Kaitlin B KB Cobigo Yann Y Goh Sheng-Yang M SM Wolf Amy A Heuer Hilary W HW Elahi Fanny M FM Ljubenkov Peter A PA Dever Reilly R Kornak John J Appleby Brian B Bove Jessica J Bordelon Yvette Y Brannelly Patrick P Brushaber Danielle D Caso Christina C Coppola Giovanni G Dheel Christina C Dickerson Bradford C BC Dickinson Susan S Dominguez Sophia S Domoto-Reilly Kimiko K Faber Kelly K Ferrall Jessica J Fields Julie A JA Fishman Ann A Fong Jamie J Foroud Tatiana T Forsberg Leah K LK Gavrilova Ralitza R Gearhart Debra D Ghazanfari Behnaz B Ghoshal Nupur N Goldman Jill J Graff-Radford Jonathan J Graff-Radford Neill N Grant Ian I Grossman Murray M Haley Dana D Hsiung Ging-Yuek GY Huey Edward D ED Irwin David J DJ Jones David T DT Jones Lynne L Kantarci Kejal K Karydas Anna A Kaufer Daniel I DI Kerwin Diana R DR Knopman David S DS Kraft Ruth R Kremers Walter K WK Kukull Walter A WA Litvan Irene I Lucente Diane D Lungu Codrin C Mackenzie Ian R IR Maldonado Miranda M Manoochehri Masood M McGinnis Scott M SM McKinley Emily E Mendez Mario F MF Miller Bruce L BL Multani Namita N Onyike Chiadi C Padmanabhan Jaya J Pantelyat Alex A Pearlman Rodney R Petrucelli Len L Potter Madeline M Rademakers Rosa R Ramos Eliana Marisa EM Rankin Katherine P KP Rascovsky Katya K Roberson Erik D ED Rogalski Emily E Sengdy Pheth P Shaw Leslie M LM Syrjanen Jeremy J Tartaglia M Carmela MC Tatton Nadine N Taylor Joanne J Toga Arthur A Trojanowski John Q JQ Weintraub Sandra S Wang Ping P Wong Bonnie B Wszolek Zbigniew Z Boxer Adam L AL Boeve Brad F BF Kramer Joel H JH Rosen Howard J HJ

Alzheimer's & dementia : the journal of the Alzheimer's Association 20200101 1

<h4>Introduction</h4>Identifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression.<h4>Methods</h4>Ninety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia ...[more]

PMID: 31914230

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.

Project description:BackgroundThe emotion recognition task (ERT) was developed to overcome shortcomings of static emotion recognition paradigms, by identifying more subtle deficits in emotion recognition across different intensity levels. In this study, we used the ERT to investigate emotion recognition deficits across the frontotemporal (FTD) and Alzheimer's Dementia (AD) spectrum.MethodsWith the ERT, we assessed the recognition of facial emotional expressions (anger-disgust-fear-happiness-sadness-surprise) across four intensities (40-60-80-100%) in patients with behavioural variant FTD (bvFTD; n = 32), and AD (n = 32), presymptomatic FTD mutation carriers (n = 47) and controls (n = 49). We examined group differences using multilevel linear regression with age, sex and education level as covariates, and performed post hoc analyses on presymptomatic (MAPT, GRN and C9orf72) mutation carriers. Classification abilities were investigated by means of logistic regression.ResultsLowest ERT total scores were found in patients with bvFTD and AD, whereas equal highest performance was found in presymptomatic mutation carriers and controls. For all emotions, significantly lower subscores were found in patients with bvFTD than in presymptomatic mutation carriers and in controls (highest p value = 0.025). Patients with bvFTD performed lower than patients with AD on anger (p = 0.005) and a trend towards significance was found for a lower performance on happiness (p = 0.065). Task performance increased with higher emotional intensity, and classification was better at the lowest than at the highest intensity. C9orf72 mutation carriers performed worse on recognizing anger at the lowest intensity than GRN mutation carriers (p = 0.047) and controls (p = 0.038). The ERT differentiated between patients with bvFTD and controls, and between patients with AD and controls (both p < 0.001).DiscussionOur results demonstrate emotion recognition deficits in both bvFTD and AD, and suggest the presence of subtle emotion recognition changes in presymptomatic C9orf72-FTD. This highlights the importance of incorporating emotion recognition paradigms into standard neuropsychological assessment for early differential diagnosis, and as clinical endpoints in upcoming therapeutic trials.

Project description:ObjectiveTo identify potential biomarkers of preclinical and clinical progression in chromosome 9 open reading frame 72 gene (C9orf72)-associated disease by assessing the expression levels of plasma microRNAs (miRNAs) in C9orf72 patients and presymptomatic carriers.MethodsThe PREV-DEMALS study is a prospective study including 22 C9orf72 patients, 45 presymptomatic C9orf72 mutation carriers and 43 controls. We assessed the expression levels of 2576 miRNAs, among which 589 were above noise level, in plasma samples of all participants using RNA sequencing. The expression levels of the differentially expressed miRNAs between patients, presymptomatic carriers and controls were further used to build logistic regression classifiers.ResultsFour miRNAs were differentially expressed between patients and controls: miR-34a-5p and miR-345-5p were overexpressed, while miR-200c-3p and miR-10a-3p were underexpressed in patients. MiR-34a-5p was also overexpressed in presymptomatic carriers compared with healthy controls, suggesting that miR-34a-5p expression is deregulated in cases with C9orf72 mutation. Moreover, miR-345-5p was also overexpressed in patients compared with presymptomatic carriers, which supports the correlation of miR-345-5p expression with the progression of C9orf72-associated disease. Together, miR-200c-3p and miR-10a-3p underexpression might be associated with full-blown disease. Four presymptomatic subjects in transitional/prodromal stage, close to the disease conversion, exhibited a stronger similarity with the expression levels of patients.ConclusionsWe identified a signature of four miRNAs differentially expressed in plasma between clinical conditions that have potential to represent progression biomarkers for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. This study suggests that dysregulation of miRNAs is dynamically altered throughout neurodegenerative diseases progression, and can be detectable even long before clinical onset.Trial registration numberNCT02590276.

Dataset Information

Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH-EXAMINER as a potential clinical trial endpoint.

Introduction

Methods

Results

Discussion

Publications

Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH-EXAMINER as a potential clinical trial endpoint.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets