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Multimodal MRI of grey matter, white matter, and functional connectivity in cognitively healthy mutation carriers at risk for frontotemporal dementia and Alzheimer's disease.

ABSTRACT: 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.

SUBMITTER: Feis RA

PROVIDER: S-EPMC6933911 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

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Multimodal MRI of grey matter, white matter, and functional connectivity in cognitively healthy mutation carriers at risk for frontotemporal dementia and Alzheimer's disease.

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