Dataset Information

Longitudinal structural gray matter and white matter MRI changes in presymptomatic progranulin mutation carriers.

ABSTRACT: Mutations in the progranulin (GRN) gene are a major source of inherited frontotemporal degeneration (FTD) spectrum disorders associated with TDP-43 proteinopathy. We use structural MRI to identify regions of baseline differences and longitudinal changes in gray matter (GM) and white matter (WM) in presymptomatic GRN mutation carriers (pGRN+) compared to young controls (yCTL).Cognitively intact first-degree relatives of symptomatic GRN+ FTD patients with identified GRN mutations (pGRN+; N?=?11, mean age?=?41.4) and matched yCTL (N?=?11, mean age?=?53.6) were identified. They completed a MRI session with T1-weighted imaging to assess GM density (GMD) and diffusion-weighted imaging (DWI) to assess fractional anisotropy (FA). Participants completed a follow-up session with T1 and DWI imaging (pGRN+ mean interval 2.20?years; yCTL mean interval 3.27?years). Annualized changes of GMD and FA were also compared.Relative to yCTL, pGRN+ individuals displayed reduced GMD at baseline in bilateral orbitofrontal, insular, and anterior temporal cortices. pGRN+ also showed greater annualized GMD changes than yCTL at follow-up in right orbitofrontal and left occipital cortices. We also observed reduced FA at baseline in bilateral superior longitudinal fasciculus, left corticospinal tract, and frontal corpus callosum in pGRN+ relative to yCTL, and pGRN+ displayed greater annualized longitudinal FA change in right superior longitudinal fasciculus and frontal corpus callosum.Longitudinal MRI provides evidence of progressive GM and WM changes in pGRN+ participants relative to yCTL. Structural MRI illustrates the natural history of presymptomatic GRN carriers, and may provide an endpoint during disease-modifying treatment trials for pGRN+ individuals at risk for FTD.

SUBMITTER: Olm CA

PROVIDER: S-EPMC6029561 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Longitudinal structural gray matter and white matter MRI changes in presymptomatic progranulin mutation carriers.

Olm Christopher A CA McMillan Corey T CT Irwin David J DJ Van Deerlin Vivianna M VM Cook Philip A PA Gee James C JC Grossman Murray M

NeuroImage. Clinical 20180515

<h4>Introduction</h4>Mutations in the progranulin (<i>GRN</i>) gene are a major source of inherited frontotemporal degeneration (FTD) spectrum disorders associated with TDP-43 proteinopathy. We use structural MRI to identify regions of baseline differences and longitudinal changes in gray matter (GM) and white matter (WM) in presymptomatic <i>GRN</i> mutation carriers (pGRN+) compared to young controls (yCTL).<h4>Methods</h4>Cognitively intact first-degree relatives of symptomatic GRN+ FTD patie ...[more]

PMID: 29984158

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Project description:Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD. The aim of the current study was to investigate the longitudinal change in WMH and the associations of WMH burden with grey matter (GM) loss, markers of neurodegeneration and cognitive function in GRN mutation carriers. 336 participants in the Genetic FTD Initiative (GENFI) study were included in the analysis: 101 presymptomatic and 32 symptomatic GRN mutation carriers, as well as 203 mutation-negative controls. 39 presymptomatic and 12 symptomatic carriers, and 73 controls also had longitudinal data available. Participants underwent MR imaging acquisition including isotropic 1?mm T1-weighted and T2-weighted sequences. WMH were automatically segmented and locally subdivided to enable a more detailed representation of the pathology distribution. Log-transformed WMH volumes were investigated in terms of their global and regional associations with imaging measures (grey matter volumes), biomarker concentrations (plasma neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP), genetic status (TMEM106B risk genotype) and cognition (tests of executive function). Analyses revealed that WMH load was higher in both symptomatic and presymptomatic groups compared with controls and this load increased over time. In particular, lesions were seen periventricularly in frontal and occipital lobes, progressing to medial layers over time. However, there was variability in the WMH load across GRN mutation carriers - in the symptomatic group 25.0% had none/mild load, 37.5% had medium and 37.5% had a severe load - a difference not fully explained by disease duration. GM atrophy was strongly associated with WMH load both globally and in separate lobes, and increased WMH burden in the frontal, periventricular and medial regions was associated with worse executive function. Furthermore, plasma NfL and to a lesser extent GFAP concentrations were seen to be associated with increased lesion burden. Lastly, the presence of the homozygous TMEM106B rs1990622 TT risk genotypic status was associated with an increased accrual of WMH per year. In summary, WMH occur in GRN mutation carriers and accumulate over time, but are variable in their severity. They are associated with increased GM atrophy and executive dysfunction. Furthermore, their presence is associated with markers of WM damage (NfL) and astrocytosis (GFAP), whilst their accrual is modified by TMEM106B genetic status. WMH load may represent a target marker for trials of disease modifying therapies in individual patients but the variability across the GRN population would prevent use of such markers as a global outcome measure across all participants in a trial.

Project description:BACKGROUND:Frontotemporal dementia (FTD) and Alzheimer's disease (AD) are associated with divergent differences in grey matter volume, white matter diffusion, and functional connectivity. However, it is unknown at what disease stage these differences emerge. Here, we investigate whether divergent differences in grey matter volume, white matter diffusion, and functional connectivity are already apparent between cognitively healthy carriers of pathogenic FTD mutations, and cognitively healthy carriers at increased AD risk. METHODS:We acquired multimodal magnetic resonance imaging (MRI) brain scans in cognitively healthy subjects with (n=39) and without (n=36) microtubule-associated protein Tau (MAPT) or progranulin (GRN) mutations, and with (n=37) and without (n=38) apolipoprotein E ε4 (APOE4) allele. We evaluated grey matter volume using voxel-based morphometry, white matter diffusion using tract-based spatial statistics (TBSS), and region-to-network functional connectivity using dual regression in the default mode network and salience network. We tested for differences between the respective carriers and controls, as well as for divergence of those differences. For the divergence contrast, we additionally performed region-of-interest TBSS analyses in known areas of white matter diffusion differences between FTD and AD (i.e., uncinate fasciculus, forceps minor, and anterior thalamic radiation). RESULTS:MAPT/GRN carriers did not differ from controls in any modality. APOE4 carriers had lower fractional anisotropy than controls in the callosal splenium and right inferior fronto-occipital fasciculus, but did not show grey matter volume or functional connectivity differences. We found no divergent differences between both carrier-control contrasts in any modality, even in region-of-interest analyses. CONCLUSIONS:Concluding, we could not find differences suggestive of divergent pathways of underlying FTD and AD pathology in asymptomatic risk mutation carriers. Future studies should focus on asymptomatic mutation carriers that are closer to symptom onset to capture the first specific signs that may differentiate between FTD and AD.

Dataset Information

Longitudinal structural gray matter and white matter MRI changes in presymptomatic progranulin mutation carriers.

Publications

Longitudinal structural gray matter and white matter MRI changes in presymptomatic progranulin mutation carriers.

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