title: Early Alzheimer's disease neuropathology detected by proton MR spectroscopy.
abstract: Proton magnetic resonance spectroscopy ((1)H-MRS) is sensitive to early neurodegenerative processes associated with Alzheimer's disease (AD). Although (1)H-MRS metabolite ratios of N-acetyl aspartate (NAA)/creatine (Cr), NAA/myoinositol (mI), and mI/Cr measured in the posterior cingulate gyrus reveal evidence of disease progression in AD, pathologic underpinnings of the (1)H-MRS metabolite changes in AD are unknown. Pathologically diagnosed human cases ranging from no likelihood to high likelihood AD (n = 41, 16 females and 25 males) who underwent antemortem (1)H-MRS of the posterior cingulate gyrus at 3 tesla were included in this study. Immunohistochemical evaluation was performed on the posterior cingulate gyrus using antibodies to synaptic vesicles, hyperphosphorylated tau (pTau), neurofibrillary tangle conformational-epitope (cNFT), amyloid-β, astrocytes, and microglia. The slides were digitally analyzed using Aperio software, which allows neuropathologic quantification in the posterior cingulate gray matter. MRS and pathology associations were adjusted for time from scan to death. Significant associations across AD and control subjects were found between reduced synaptic immunoreactivity and both NAA/Cr and NAA/mI in the posterior cingulate gyrus. Higher pTau burden was associated with lower NAA/Cr and NAA/mI. Higher amyloid-β burden was associated with elevated mI/Cr and lower NAA/mI ratios, but not with NAA/Cr. (1)H-MRS metabolite levels reveal early neurodegenerative changes associated with AD pathology. Our findings support the hypothesis that a decrease in NAA/Cr is associated with loss of synapses and early pTau pathology, but not with amyloid-β or later accumulation of cNFT pathology in the posterior cingulate gyrus. In addition, elevation of mI/Cr is associated with the occurrence of amyloid-β plaques in AD.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, and.
authors.forename: Melissa E
authors.identifier: http://orcid.org/0000-0001-7379-2545
authors.initials: ME
authors.lastname: Murray
authors.affiliation: Department of Biomedical Statistics.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Przybelski
authors.affiliation: Department of Biomedical Statistics.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Lesnick
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, and.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Liesinger
authors.affiliation: Department of Radiology.
authors.forename: Anthony
authors.initials: A
authors.lastname: Spychalla
authors.affiliation: Department of Radiology.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Radiology.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Gunter
authors.affiliation: Department of Pathology, and.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: David S
authors.identifier: http://orcid.org/0000-0002-6544-066X
authors.initials: DS
authors.lastname: Knopman
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Department of Radiology.
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, and.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Radiology, kantarci.kejal@mayo.edu.
authors.forename: Kejal
authors.initials: K
authors.lastname: Kantarci
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D001253:Astrocytes / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D042241:Early Diagnosis; D005260:Female; D059907:Functional Neuroimaging; D066128:Gray Matter / Q000378:metabolism / Q000473:pathology; D006179:Gyrus Cinguli / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007294:Inositol / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000473:pathology; D066244:Proton Magnetic Resonance Spectroscopy; D013572:Synaptic Vesicles / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D016875:tau Proteins; D001224:Aspartic Acid; D007294:Inositol; C000179:N-acetylaspartate
keywords: Alzheimer's disease; digital microscopy; magnetic resonance spectroscopy; neuropathology; posterior cingulate; tau