MRS in presymptomatic MAPT mutation carriers: A potential biomarker for tau-mediated pathology

Objective: To determine the proton magnetic resonance spectroscopy (H MRS) changes in carriers of microtubule-associated protein (MAPT) mutations in a case-control study. Methods: Patients with MAPT mutations (N279K, V337M, R406W, IVS9-10G>T, P301L) from 5 different families (n = 24) underwent MRI and single voxel H MRS from the posterior cingulate gyrus inferior precuneus at 3 T. Ten of the patients were symptomatic with median Clinical Dementia Rating sum of boxes score (CDR-SOB) of 6.5 and 14 patients were presymptomatic with CDR-SOB of 0. Age-and sex-matched controls (n = 24) were recruited. Results: Symptomatic MAPT mutation carriers were characterized by decreased N-acetylaspartate/creatine (NAA/Cr) ratio, an index of neuronal integrity, increased myoinositol (mI)/Cr ratio, a possible marker for glial activity, decreased NAA/mI, and hippocampal atrophy (p < 0.001). Whereas presymptomatic MAPT mutation carriers had elevated mI/Cr and decreased NAA/mI (p < 0.001), NAA/Cr levels and hippocampal volumes were not different from controls. Decrease in NAA/Cr (R² = 0. 22; p = 0.021) and hippocampal volumes (R = 0.46; p < 0.001) were associated with proximity to the expected or actual age at symptom onset in MAPT mutation carriers. Conclusion: ¹H MRS metabolite abnormalities characterized by an elevated mI/Cr and decreased NAA/mI are present several years before the onset of symptoms in MAPT mutation carriers. The data suggest an ordered sequencing of the ¹H MRS and MRI biomarkers. MI/Cr, a possible index of glial proliferation, precedes the decrease in neuronal integrity marker NAA/Cr and hippocampal atrophy. ¹H MRS may be a useful inclusion biomarker for preventive trials in presymptomatic carriers of MAPT mutations and possibly other proteinopathies.