title: 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.
  
  
  CONCLUSIONS
  (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.affiliation: Departmentsof Radiology, Mayo Clinic, Rochester, MN 55905, USA. kantarci.kejal@mayo
authors.forename: K
authors.initials: K
authors.lastname: Kantarci
authors.forename: B F
authors.initials: BF
authors.lastname: Boeve
authors.forename: Z K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: R
authors.initials: R
authors.lastname: Rademakers
authors.forename: J L
authors.initials: JL
authors.lastname: Whitwell
authors.forename: M C
authors.initials: MC
authors.lastname: Baker
authors.forename: M L
authors.initials: ML
authors.lastname: Senjem
authors.forename: A R
authors.initials: AR
authors.lastname: Samikoglu
authors.forename: D S
authors.initials: DS
authors.lastname: Knopman
authors.forename: R C
authors.initials: RC
authors.lastname: Petersen
authors.forename: C R
authors.initials: CR
authors.lastname: Jack
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D003704:Dementia / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation; D024801:Tauopathies / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D015415:Biomarkers; C054369:MAPT protein, human; D016875:tau Proteins
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