• Lize C Jiskoot, Jessica L Panman, Lieke H Meeter, DopperElise G PEGPDepartment of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.Department of Neurology, VU Medical Center, Amsterdam, The Netherlands., Laura Donker Kaat, Sanne Franzen, Emma L van der Ende, Rick van Minkelen, RomboutsSerge A R BSARBDepartment of Radiology, Leiden University Medical Center, Leiden, The Netherlands.Institute of Psychology, Leiden University, Leiden, The Netherlands.Leiden Institute for Brain and Cognition, Leiden University, Leiden, The Netherla, Janne M Papma, and John C van Swieten.
• Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.
• Brain. 2019 Jan 1; 142 (1): 193-208.

AbstractDeveloping 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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