MRS in presymptomatic MAPT mutation carriers
A potential biomarker for tau-mediated pathology
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Abstract
Objective: To determine the proton magnetic resonance spectroscopy (1H 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 1H 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 (R2 = 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.
Footnotes
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Study funding: Supported by NIH K23 AG030935, P50 AG16574/P1, P50 AG16574/P2, R01 AG11378, R01 NS065782, the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation, and the NIH Construction Grant C06 RR018898.
Disclosure: Author disclosures are provided at the end of the article.
Received February 2, 2010. Accepted in final form May 12, 2010.
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