Multimodal fMRI Resting-State Functional Connectivity in Granulin Mutations: The Case of Fronto-Parietal Dementia

Abstract

BackgroundMonogenic dementias represent a great opportunity to trace disease progression from preclinical to symptomatic stages. Frontotemporal Dementia related to Granulin (GRN) mutations presents a specific framework of brain damage, involving fronto-temporal regions and long inter-hemispheric white matter bundles. Multimodal resting-state functional MRI (rs-fMRI) is a promising tool to carefully describe disease signature from the earliest disease phase.ObjectiveTo define local connectivity alterations in GRN related pathology moving from the presymptomatic (asymptomatic GRN mutation carriers) to the clinical phase of the disease (GRN- related Frontotemporal Dementia).MethodsThirty-one GRN Thr272fs mutation carriers (14 patients with Frontotemporal Dementia and 17 asymptomatic carriers) and 38 healthy controls were recruited. Local connectivity measures (Regional Homogeneity (ReHo), Fractional Amplitude of Low Frequency Fluctuation (fALFF) and Degree Centrality (DC)) were computed, considering age and gender as nuisance variables as well as the influence of voxel-level gray matter atrophy.ResultsAsymptomatic GRN carriers had selective reduced ReHo in the left parietal region and increased ReHo in frontal regions compared to healthy controls. Considering Frontotemporal Dementia patients, all measures (ReHo, fALFF and DC) were reduced in inferior parietal, frontal lobes and posterior cingulate cortex. Considering GRN mutation carriers, an inverse correlation with age in the posterior cingulate cortex, inferior parietal lobule and orbitofrontal cortex was found.Conclusions GRN pathology is characterized by functional brain network alterations even decades before the clinical onset; they involve the parietal region primarily and then spread to the anterior regions of the brain, supporting the concept of molecular nexopathies.

Looking for Neuroimaging Markers in Frontotemporal Lobar Degeneration Clinical Trials: A Multi-Voxel Pattern Analysis Study in Granulin Disease

“…This was in line with our previous findings in GRN-related disease [9,16,20], demonstrating an impaired resting state functional connectivity in posterior regions as well as an increased (potentially compensatory) connectivity in prefrontal regions [50], in accordance with the concept of molecular nexopathies proposed by Warren et al [51]. In this sense, in line with GENFI study [17], GRN disease is characterized by a progressive fronto-parietal impairment moving from preclinical to clinical stages, representing the pathological spreading of the disease following long-distance white matter bundles [51].…”

“…Conversely, aGRN+ group was better classified by local connectivity measures (especially fALFF) with a discrimination pattern characterized by a widespread connectivity decrease in parietal and posterior associative areas, with a well-structured increased connectivity in prefrontal regions. Especially for aGRN+ and in line with literature data [16,20,36], the concept that red-yellow areas could be considered as increased connectivity was more plausible. Finally, fALFF index was the only measure with high (>80%) discriminative power in both comparisons (FTD-GRN+ versus oHC and aGRN+ versus yHC).…”

“…As previously described [16,20], all preprocessing steps were carried out using Advanced Data Processing Assistant for resting-state fMRI (DPARSFA) (http://rfmri.org/DPARSF) [27] which is based on Resting-State fMRI Data Analysis Toolkit (REST, http://www.restfmri.net) [28] and Statistical Parametric Mapping (SPM8) (http://www. fil.ion.ucl.ac.uk/spm).…”

“…MVPA [12,13] represents a promising approach to study the information that is represented in different patterns of neural activity, through the application of an automated classifier (i.e., support vector machine, SVM) [14] to capture the complex relationships among spatial pattern of brain activity in the studied populations [15]. From this perspective, monogenic FTD represents a privileged point of view to test the potential role of disease-modifying therapies, as cases with known neuropathology and following the continuum from presymptomatic to symtomatic stages [16,17]. As recently demonstrated by GENFI initiative [17], GRN carriers are characterized by insular and parietal structural alteration up to 15 years before the clinical onset, supporting the pivotal role of specific preclinical biomarker to trace neurodegenerative diseases like FTD and AD [18].…”

Age-related functional brain changes in young children

“…The functional metrics in the present study have been widely implemented to detect linear correlations with age (Biswal et al, 2009;Lopez-Larson et al, 2011;Premi et al, 2014;Zuo et al, 2012), behavioral measurements (Kwak et al, 2012;Ren et al, 2015;Schaefer et al, 2014;Tian et al, 2012;Wu et al, 2015;W. Xia et al, 2013), and clinical parameters Cai et al, 2015;Holiga et al, 2015;W.-C. Lin et al, 2015;Qiu et al, 2011;W.…”