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Background: As disease modifying therapies for familial frontotemporal lobar degenerations (f-FTLD) move into both the symptomatic and asymptomatic patient populations, it will be necessary to develop robust biomarkers that are sensitive to disease progression in both of these populations. In this study we investigated the longitudinal change in brain MRI and neuropsychological measures in asymptomatic and symptomatic carriers of microtubule associated protein tau (MAPT) mutations.
Methods: All available neuroimaging and neuropsychological data on MAPT mutation carriers (symptomatic = +m CDR≥0.5 and asymptomatic = +m CDR=0) evaluated at Mayo Clinic were analyzed; non-mutation carrier family members (-m CDR=0) were used as controls (Table 1). Longitudinal structural brain MRI scans for each subject were processed using the Symmetric Diffeomorphic Image Normalization method for normalization of serial scans to obtain Tensor Based Morphometry (TBM-SyN) maps. We also compared baseline and longitudinal data on the Controlled Oral Word Association Test (COWAT), Trailmaking Test B (TMT B), Boston Naming Test (BNT) and Category Fluency (Cat Fl). We used linear mixed models with random slopes and intercepts to analyze longitudinal clinical and imaging data with years from baseline as the time scale.
Results: The +m CDR≥0.5 subjects had non-zero rates of decline in annual % change in all regions analyzed with TBM-SyN. These rates were significantly different from both +m CDR=0 and -m CDR=0 family members (Figure 1a). The +m CDR=0 subjects had a non-zero rate of decline in the temporal ROI (p = 0.009) and trends in the composite frontotemporal region (p = 0.08) and the ventricular volume (p = 0.08). There was no significant difference when comparing the rates between +m CDR=0 and -m CDR=0. A similar pattern was also observed for all neuropsychological measures without any evidence for non-zero rates of change in +m CDR=0 (Figure 1b).
Conclusions: Regional brain MRI volumes and neuropsychological measures longitudinally decline in +m CDR≥0.5 subjects and may be useful as biomarkers in this phase of the disease. TBM-SyN analysis of +m CDR=0 subjects identified a non-zero rate of temporal lobe change in this relatively young group, which may indicate that brain MRI is a suitable biomarker in the asymptomatic phase of the disease.
Table 1Demographics table of asymptomatic and symptomatic familial FTLD subjects with mutations of MAPT.