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

K. Kantarci, B. F. Boeve, Z. K. Wszolek, R. Rademakers, J. L. Whitwell, M. C. Baker, M. L. Senjem, A. R. Samikoglu, D. S. Knopman, R. C. Petersen, C. R. Jack

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)771-778
Number of pages8
JournalNeurology
Volume75
Issue number9
DOIs
StatePublished - Aug 31 2010

ASJC Scopus subject areas

  • Clinical Neurology

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