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

Abstract

OBJECTIVE:

To determine the proton magnetic resonance spectroscopy ((1)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 (1)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 (R(2) = 0. 22; p = 0.021) and hippocampal volumes (R(2) = 0.46; p < 0.001) were associated with proximity to the expected or actual age at symptom onset in MAPT mutation carriers.

CONCLUSION:

(1)H 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 (1)H MRS and MRI biomarkers. MI/Cr, a possible index of glial proliferation, precedes the decrease in neuronal integrity marker NAA/Cr and hippocampal atrophy. (1)H MRS may be a useful inclusion biomarker for preventive trials in presymptomatic carriers of MAPT mutations and possibly other proteinopathies.

• Authors: 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 Jr
• Journal: Neurology (Neurology) Vol. 75 Issue 9 Pg. 771-8 (Aug 31 2010) ISSN: 1526-632X [Electronic] United States
• PMID: 20805522 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• MAPT protein, human
• tau Proteins

Topics

• Adult
• Aged
• Biomarkers (metabolism)
• Case-Control Studies
• Dementia (diagnosis, genetics, metabolism)
• Female
• Heterozygote
• Hippocampus (metabolism, pathology)
• Humans
• Magnetic Resonance Spectroscopy (methods)
• Male
• Middle Aged
• Mutation
• Tauopathies (diagnosis, genetics, metabolism)
• tau Proteins (genetics, metabolism, physiology)