Metabolite Profile of Alzheimer’s Disease in the Frontal Cortex as Analyzed by HRMAS 1H NMR

Abstract

Background: Investigation on neurochemical changes in the frontal cortex in individuals with Alzheimer’s disease (AD) and different Apolipoprotein E (APOE) genotypes, using ex vivo solid-state high-resolution NMR analysis, may lead to a better understanding of the neurochemistry associated with AD as well as new AD-specific metabolite biomarkers that might potentially improve the clinical diagnosis of AD.Methods: Intact tissue samples of the frontal cortex were obtained from 11 patients and 11 age-matched non-demented controls. Metabolite profiles in all samples were analyzed ex vivo, using solid-state high-resolution magic angle spinning (HRMAS) 600 MHz 1H nuclear magnetic resonance (NMR). A logistic regression analysis was used to rank metabolites based on their level of contribution in differentiating the AD patient tissues and the controls, and different AD-associated APOE genotypes (APOE ε4 vs. APOE ε3).Results: Tissue samples from the AD patients showed significantly lower NAA/Cr (p = 0.011), Ace/Cr (p = 0.027), GABA/Cr (p = 0.005), Asp/Cr (p < 0.0001), mI/Cr (p < 0.0001), and Tau/Cr (p = 0.021), and higher PCho/Cr (p < 0.0001), GPCho/Cr (p < 0.0001), and α&β-Glc/Cr (p < 0.0001) than the controls did. Specifically, a newly observed resonance at 3.71 ppm, referred to as α&β-Glc, was observed in 90.9% of the AD samples (10/11). Samples with APOE ε4 also exhibited higher PCho/Cr (p = 0.0002), GPCho/Cr (p = 0.0001), α&β-Glc/Cr (p < 0.0001), and lower Asp/Cr (p = 0.004) and GABA/Cr (p = 0.04) than the samples with APOE ε3 did. In the logistic regression analysis, PCho, GPCho, ASP, and α&β-Glc were found to be the most relevant metabolites for differentiating the AD patient tissues and the controls, and different APOE genotypes.Conclusion: HRMAS 1H NMR with high spectral resolution and sensitivity offers a powerful tool to gain quantitative information on AD associated neurochemical changes. There are important neurochemical differences in the frontal cortex between the AD patient tissues and the controls, and between those with different APOE genotypes. The resonance (α&β-Glc) found at 3.71 ppm in the AD patient tissues may be further investigated for its potential in the diagnosis and monitoring of AD.

Quantitation of in vivo brain glutathione conformers in cingulate cortex among age‐matched control, MCI, and AD patients using MEGA‐PRESS

“…In this work, we have shown significant depletion of Cho ( p < .001), Cr ( p < .001), and NAA ( p < .001) in both the ACC and PCC regions for MCI as compared to NC (Figure ). Our results for Cho level changes agree with the NMR study on FC tissue sample (Zhang et al, ) and the depletion in both NAA and Cr levels could be due to the damaged brain cells in diseased populations. These results further emphasize the association of metabolic changes in CC with the mild cognitive decline as an early sign of AD.…”

“…A systematic review on neurochemical changes in the aging brain also reported that NAA concentration was consistently reduced with age predominantly in the frontal lobe, whereas the mI concentration increased with age consistently in the PCC (Cleeland, Pipingas, Scholey, & White, ). Besides all the above‐mentioned MRS studies, the NMR analysis of a tissue sample from the FC of AD brain also showed a significant decrease in NAA and Cho levels (Zhang et al, ).…”

Metabolic Profiling of Female Tg2576 Mouse Brains Provides Novel Evidence Supporting Intranasal Low-Dose Pioglitazone for Long-Term Treatment at an Early Stage of Alzheimer’s Disease

“…Alanine, GABA, and choline levels were also found to be decreased in these mice, although the differences were not statistically significant. Clinically, the NAA peak is often the most prominent signal detectable with proton magnetic resonance spectroscopy in human brains, and this metabolite was frequently found to be significantly lowered in various brain regions of AD patients, including the cortex [ 74 , 75 ]. Since NAA is an amino acid exclusively produced in neuronal mitochondria, it is widely regarded as a surrogate marker of neuronal health in neurologic disorders [ 74 ].…”

A Method for Bridging Population-Specific Genotypes to Detect Gene Modules Associated with Alzheimer’s Disease

“…We applied the PrediXcan gene expression imputation tool (version 8 of Genome-Tissue Expression (GTEx) data) on each of the three AD genotypes studies independently. We imputed gene expression from 13 brain tissues available in GTEx that have been implicated in association with AD, including amygdala [ 14 ], anterior cingulate cortex ba24 [ 15 ], caudate basal ganglia [ 16 ], cerebellar hemisphere [ 17 ], cerebellum [ 18 ], cortex [ 19 , 20 ], frontal cortex ba9 [ 21 ], hippocampus [ 22 ], hypothalamus [ 23 , 24 ], putamen basal ganglia [ 16 ], spinal cord cervical c-1 [ 25 ]}, nucleus accumbens basal ganglia [ 16 , 26 ] and substantia nigra [ 27 ], obtaining imputed gene expression values per tissue ranging between 2040 and 6092 genes (3500 on average).…”