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 (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

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Microtubule-Associated Proteins
Inositol
Biomarkers
Pathology
Creatine
Mutation
Neuroglia
Atrophy
Dementia
Parietal Lobe
Gyrus Cinguli
Age of Onset
Case-Control Studies
N-acetylaspartate
Proton Magnetic Resonance Spectroscopy

ASJC Scopus subject areas

  • Clinical Neurology
  • Medicine(all)

Cite this

@article{cb06cfd12d54402abc681a8929108400,
title = "MRS in presymptomatic MAPT mutation carriers: A potential biomarker for tau-mediated pathology",
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.",
author = "Kantarci, {Kejal M} and Boeve, {Bradley F} and Wszolek, {Zbigniew K} and Rademakers, {Rosa V} and Whitwell, {Jennifer Lynn} and Baker, {M. C.} and Senjem, {M. L.} and Samikoglu, {A. R.} and Knopman, {David S} and Petersen, {Ronald Carl} and Jack, {Clifford R Jr.}",
year = "2010",
month = "8",
day = "31",
doi = "10.1212/WNL.0b013e3181f073c7",
language = "English (US)",
volume = "75",
pages = "771--778",
journal = "Neurology",
issn = "0028-3878",
publisher = "Lippincott Williams and Wilkins",
number = "9",

}

TY - JOUR

T1 - MRS in presymptomatic MAPT mutation carriers

T2 - A potential biomarker for tau-mediated pathology

AU - Kantarci, Kejal M

AU - Boeve, Bradley F

AU - Wszolek, Zbigniew K

AU - Rademakers, Rosa V

AU - Whitwell, Jennifer Lynn

AU - Baker, M. C.

AU - Senjem, M. L.

AU - Samikoglu, A. R.

AU - Knopman, David S

AU - Petersen, Ronald Carl

AU - Jack, Clifford R Jr.

PY - 2010/8/31

Y1 - 2010/8/31

N2 - 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.

AB - 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.

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U2 - 10.1212/WNL.0b013e3181f073c7

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