TY - JOUR T1 - Early Alzheimer's Disease Neuropathology Detected by Proton MR Spectroscopy JF - The Journal of Neuroscience JO - J. Neurosci. SP - 16247 LP - 16255 DO - 10.1523/JNEUROSCI.2027-14.2014 VL - 34 IS - 49 AU - Melissa E. Murray AU - Scott A. Przybelski AU - Timothy G. Lesnick AU - Amanda M. Liesinger AU - Anthony Spychalla AU - Bing Zhang AU - Jeffrey L. Gunter AU - Joseph E. Parisi AU - Bradley F. Boeve AU - David S. Knopman AU - Ronald C. Petersen AU - Clifford R. Jack, Jr AU - Dennis W. Dickson AU - Kejal Kantarci Y1 - 2014/12/03 UR - http://www.jneurosci.org/content/34/49/16247.abstract N2 - Proton magnetic resonance spectroscopy (1H-MRS) is sensitive to early neurodegenerative processes associated with Alzheimer's disease (AD). Although 1H-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 1H-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 1H-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. 1H-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. ER -