Effect ofTMEM106BPolymorphism on Functional Network Connectivity in AsymptomaticGRNMutation Carriers

Abstract

rontotemporal dementia (FTD) is a neurodegenerative disorder in which behavioral abnormalities, language impairment, and executive function deficits represent the most typical clinical features. 1,2 One of the most common causes of inherited FTD is the loss-of-function mutations within the granulin (GRN) gene (OMIM 138945). 3,4 More than 60 different pathogenetic mutations have been identified so far (http://www.molgen.ua.ac.be/FTDmutations). GRN mutations lead to FTD with TDP-43 inclusions 5 and have a wide clinical phenotype. Age at disease onset is highly heterogeneous, 6 and presenting symptoms frequently resemble either behavioral variant FTD or the agrammatic variant of primary progressive aphasia. Neuroimaging studies have demonstrated that patients carrying GRN mutations have an asymmetric gray matter loss in the frontal, posterior temporal, and parietal cortices. 7,8 Notwithstanding, little is known about the preclinical stages of the disease, such as the early and specific brain regional damage of GRN disease and the factors antedating and modulating disease onset. Studies of those who will develop the disease at some point are essential to understanding the pattern and timing of brain damage and symptom onset. Recent works by our group, carried out in a genetically coalescent cohort of families with the GRN Thr272fs mutation, 9,10 have demonstrated early abnormalities of functional network connectivity even in presymptomatic stages of disease, 11 without gray matter loss 11 but with significant alterations in white matter bundles. In light of this, resting-state functional magnetic resonance imaging (fMRI) represents the most promising IMPORTANCE Granulin (GRN) mutations represent one of the most frequent genetic causes of inherited frontotemporal dementia. The study of asymptomatic carriers of GRN Thr272fs mutation (aGRN+) provides a unique opportunity to study the natural history of the disease and the role of modulating factors on disease onset. It has been demonstrated that the TMEM106B polymorphism is associated with GRN-related frontotemporal dementia and affects age at onset in GRN mutation carriers. OBJECTIVE To ascertain whether TMEM106B genetic status modulates GRN disease by evaluating resting-state functional connectivity in aGRN+ individuals according to TMEM106 genetic variation. DESIGN, SETTING, AND PARTICIPANTS Academic tertiary referral center for neurodegenerative disorders in 17 asymptomatic carriers of aGRN+ and 14 healthy controls. MAIN OUTCOMES AND MEASURES Changes in resting-state functional connectivity, focusing on the default mode network, ventral and dorsal salience networks, executive network, frontoparietal networks, and attentive network and the effect of TMEM106B genotypes in aGRN+ participants and healthy controls (statistical nonparametric mapping). RESULTS aGRN+ participants showed decreased brain connectivity within the left frontoparietal network and increased connectivity in the executive network compared with healthy controls. The TMEM106B at-risk polymorphism (T/T...

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

“…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).…”

“…molecular pathway [6,17,43]. GRN mutations lead to a homogeneous FTD-TDP pathology and give the opportunity to unravel FTD from asymptomatic to symptomatic stages [17,20,44]. The definition of surrogate endpoints will be mandatory to test the efficacy of future pharmacological treatments [17].…”

“…In the present work, we applied the multivariate approach of MVPA to different magnetic resonance imaging (MRI) metrics to study GRN-related disease (asymptomatic subjects carrying GRN Thr272fs mutation and FTD patients bearing the same mutation): voxelbased morphometry (VBM, for structural grey and white matter alterations) [19] and a series of functional network connectivity measures. First of all, we explored different brain functional networks by independent component analysis (ICA), considering the involvement of specific networks in FTD related to GRN [20]. More recently, a number of functional parameters has been used to study local properties of brain activity at rest, also in FTD related to GRN, like regional homogeneity (ReHo), to look at the coherence of focal resting state fluctuations [21], the fractional amplitude of low frequency fluctuation (fALFF, that describes the power of the signal in the low frequency range) [22], degree centrality (DC, that allows the study of the nodes that form the whole-brain network [23]), and the voxel homotopic connectivity (VMHC, as index of functional symmetry in resting-state brain activity) [24].…”

C9orf72 promoter hypermethylation is neuroprotective

“…For example, recent work demonstrated several associations between neuroanatomical structure and single nucleotide polymorphisms in sporadic forms of FTD and ALS. 36 Others have suggested that TMEM106B is a modifier of functional connectivity in FTD 37 and that cognitive reserve mechanisms such as education may provide regionally protective modifiers of neuroanatomic structure. 38 Other potential caveats to consider in the current study are related to our study population.…”