Magnetic Resonance Spectroscopy metabolites as biomarkers of Alzheimer’s Disease

Abstract Background Magnetic resonance spectroscopy (MRS) is a non‐invasive method of evaluating metabolite levels in the cerebral cortex. Measurable metabolites can provide markers of neuronal damage, glial activation and, neurotransmission, pathological features of Alzheimer’s disease. Here we sought to establish the effectiveness of several metabolites as biomarkers for Alzheimer’s disease. Method 198 participants with a single‐voxel 1 H MRS scan were enrolled (n = 170 participants living with Alzheimer’s disease, n = 28 healthy controls). All participants underwent 3‐tesla magnetic resonance imaging and cognitive assessment with the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS‐cog). An experienced radiographer placed an 8cm 3 voxel within the posterior cingulate cortex for single‐voxel 1 H MRS acquisition. Scans were then processed to evaluate levels of N‐acetylaspartate, myo‐inositol, choline, and glutamate. Creatine peak was additionally evaluated as a reference. N‐acetylaspartate/creatine, myo‐inositol /creatine, choline/creatine ratios and glutamate were compared between Alzheimer’s participants and controls to calculate the effect size. Correlations were then performed between metabolite ratios and ADAS‐cog scores. Result N‐acetylaspartate/creatine effectively distinguished between Alzheimer’s patients and healthy controls (Cohens D = 0.83) with a lowered ratio in Alzheimer’s participants. Elevated glutamate signal and myo‐inositol/creatine ratios were also displayed in Alzheimer’s patients (Cohens D = 0.62 and 0.69, respectively). Choline/creatine ratio displayed no significant difference between groups (Cohens D = 0.26). Lower N‐acetylaspartate /creatine and glutamate correlated with higher ADAS‐cog scores (r = ‐0.29, p < 0.001, CIs: ‐0.42 to ‐0.14 and r = ‐0.30, p < 0.001, CIs: ‐0.44 to ‐0.16, respectively). Myo‐inositol and choline failed to correlate with cognitive impairment. Conclusion N‐acetylaspartate, a signature of neuronal damage, is an effective biomarker of Alzheimer’s disease and associated cognitive decline. Enhanced glial activity, measured with myo‐inositol, was shown in Alzheimer’s disease, suggesting that glial‐reactivity markers deserve consideration in the diagnosis of Alzheimer’s disease. Glutamate demonstrated the strongest association with cognitive impairment, despite showing a smaller effect size than N‐acetylaspartate and myo‐inositol in distinguishing between Alzheimer’s patients and controls. Together we establish MRS is a useful, non‐invasive biomarker of several pathological processes involved in the development of Alzheimer’s. Evaluation of N‐acetylaspartate, glutamate, and myo‐inositol may aid in the diagnosis of neurodegenerative disease, detecting markers undetectable by conventional MRI methodology.