MRS in presymptomatic MAPT mutation carriers: a potential biomarker for tau-mediated pathology.
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.
Kantarci
K
K
Departmentsof Radiology, Mayo Clinic, Rochester, MN 55905, USA. kantarci.kejal@mayo
Boeve
B F
BF
Wszolek
Z K
ZK
Rademakers
R
R
Whitwell
J L
JL
Baker
M C
MC
Senjem
M L
ML
Samikoglu
A R
AR
Knopman
D S
DS
Petersen
R C
RC
Jack
C R
CR
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*
D015415:Biomarkers; C054369:MAPT protein, human; D016875:tau Proteins
Magn Reson Med. 2001 Dec;46(6):1072-8
11746571
Radiology. 2008 Jul;248(1):210-20
18566174
Magn Reson Imaging. 2000 Nov;18(9):1159-65
11118771
Brain. 2008 Mar;131(Pt 3):665-80
18263627
J Biol Chem. 2005 Mar 18;280(11):10444-54
15640150
Parkinsonism Relat Disord. 2007 May;13(4):230-9
17196872
Am J Psychiatry. 1999 Dec;156(12):1879-86
10588400
Brain Res Brain Res Rev. 1995 Sep;21(2):195-218
8866675
Nature. 1998 Jun 18;393(6686):702-5
9641683
Biochim Biophys Acta. 1989 Aug 8;1004(2):169-79
2546591
Neuron. 2007 Feb 1;53(3):337-51
17270732
AJNR Am J Neuroradiol. 1999 Oct;20(9):1619-27
10543631
Arch Neurol. 2008 Apr;65(4):460-4
18413467
Magn Reson Med. 1995 Jun;33(6):858-61
7651126
Neurobiol Dis. 2006 May;22(2):401-3
16503405
Hum Mutat. 2004 Oct;24(4):277-95
15365985
Alzheimers Dement. 2008 Mar;4(2):89-93
18631953
Neurology. 2009 Mar 3;72(9):813-20
19255408
Neuroimage. 2002 Jan;15(1):273-89
11771995
Neuropathol Appl Neurobiol. 1996 Feb;22(1):17-22
8866778
Radiology. 1997 Jun;203(3):829-36
9169712
Neuropathology. 2007 Feb;27(1):73-80
17319286
Trends Mol Med. 2002 Dec;8(12):555-62
12470988
Eur J Neurol. 2009 Mar;16(3):297-309
19364361
Ann Neurol. 1997 Jun;41(6):706-15
9189031
Neuroradiology. 2006 Jun;48(6):428-33
16598479
Magn Reson Med. 1994 Apr;31(4):365-73
8208111
NMR Biomed. 2008 Mar;21(3):233-41
17562554
Ann Neurol. 1992 Sep;32(3):312-20
1416801
Neurology. 2004 Oct 26;63(8):1393-8
15505154
Neurology. 2006 Mar 14;66(5):718-22
16534109
Neurology. 2000 Jul 25;55(2):210-7
10908893
J Biol Chem. 2006 Apr 28;281(17):11856-63
16495230
Br J Radiol. 2007 Dec;80 Spec No 2:S146-52
18445744
J Neuropathol Exp Neurol. 1998 Jun;57(6):588-601
9630238
AJNR Am J Neuroradiol. 2003 May;24(5):843-9
12748083
Neurology. 2009 May 19;72(20):1735-40
19451528
Neuroimage. 2005 Jul 1;26(3):839-51
15955494