LONGITUDINAL MULTIMODAL NEUROIMAGING IN PRESYMPTOMATIC FRONTOTEMPORAL DEMENTIA: PREDICTING SYMPTOM ONSET IN THE DUTCH FTD RISK COHORT

Abstract

Converging evidence in familial frontotemporal dementia (FTD) supports the presence of a presymptomatic stage, with subtle cross-sectional changes in neuroimaging. These may serve as biomarkers for disease onset, but their usefulness can only be established in longitudinal follow-up studies. In the present study, we investigate 6 year follow-up changes in white matter (WM) integrity and grey matter (GM) volume in a large cohort of presymptomatic FTD due to MAPT and GRN mutations, and examine whether these measures can serve as prediction biomarkers for symptom onset. Since 2010, we track healthy 50% at-risk subjects within our prospective FTD Risk Cohort. Within this study window, 8 mutation carriers converted to clinical FTD (6 bvFTD; 5 MAPT, 1 GRN; 2 non-fluent PPA (nf-PPA); 2 GRN). We compared these converters with non-converters (n=35) and healthy controls from the same families (n=30) by means of 3T diffusion tensor and GM volumetric MRI at 4 and 2 years prior to symptom onset. We assessed the prognostic performance of WM and GM regions-of-interest (ROI) by means of ROC analyses in converters. Two years in advance, symptom onset could be accurately predicted by means of the WM integrity values (FA) of the bilateral uncinate fasciculus (UF), genu of corpus callosum, fornix, forceps minor and right inferior longitudinal fasciculus (AUC 0.74–0.78); and GM volumes of the bilateral frontal and temporal lobes, right anterior temporal lobe, parietal lobe, insula, and (anterior) cingulate (AUC 0.74–0.83). Additionally, the left UF had absolute classification accuracy for the clinical phenotypes bvFTD and nf-PPA (AUC 1.00; sensitivity/specificity 100%; optimal FA cut-off 0.47) (Figure 1). Four years before, WM integrity and GM volumes could not predict symptom onset. At none of the time points we could separate MAPT from GRN converters. We demonstrate that two years in advance, symptom onset can be accurately predicted by WM and GM neuroimaging measures within regions known to be affected in early stage to symptomatic FTD. Our findings point to the UF as the key pathological frontotemporal tract when moving from the presymptomatic into the symptomatic stage. These neuroimaging biomarkers can be of crucial importance for e.g. the design of disease-modifying trials and/or clinical purposes. Reduced white matter integrity (FA) of the left uncinate fasciculus 2 years before conversion into symptomatic FTD. Dotted lines represent the optimal cut-off values discriminating mutation carriers that will convert within two years from mutation carriers that not convert (black) and mutation carrier that will convert to bvFTD or non-fluent PPA (PNFA) (red).