Phosphorus metabolism in the brain of cognitively normal midlife individuals at risk for Alzheimer's disease

Abstract

Background

Neurometabolic abnormalities and amyloid-beta plaque deposition are important early pathophysiologic changes in Alzheimer's disease (AD). This study investigated the relationship between high-energy phosphorus-containing metabolites, glucose uptake, and amyloid plaque using phosphorus magnetic resonance spectroscopy (³¹P-MRS) and positron emission tomography (PET).

Methods

We measured ³¹P-MRS, fluorodeoxyglucose (FDG)-PET, and Pittsburgh Compound B (PiB)-PET in a cohort of 20 cognitively normal middle-aged adults at risk for AD. We assessed ³¹P-MRS reliability by scanning a separate cohort of 13 healthy volunteers twice each. We calculated the coefficient-of-variation (CV) of metabolite ratios phosphocreatine-to-adenosine triphosphate (PCr/α-ATP), inorganic phosphate (Pi)-to-α-ATP, and phosphomonoesters-to-phosphodiesters (PME/PDE), and pH in pre-defined brain regions. We performed linear regression analysis to determine the relationship between ³¹P measurements and tracer uptake, and Dunn's multiple comparison tests to investigate regional differences in phosphorus metabolism. Finally, we performed linear regression analysis on ³¹P-MRS measurements in both cohorts to investigate the relationship of phosphorus metabolism with age.

Results

Most regional ³¹P metabolite ratio and pH inter- and intra-day CVs were well below 10%. There was an inverse relationship between FDG-SUV levels and metabolite ratios PCr/α-ATP, Pi/α-ATP, and PME/PDE in several brain regions in the AD risk group. There were also several regional differences among ³¹P metabolites and pH in the AD risk group including elevated PCr/α-ATP, depressed PME/PDE, and elevated pH in the temporal cortices. Increased PCr/α-ATP throughout the brain was associated with aging.

Conclusions

Phosphorus spectroscopy in the brain can be performed with high repeatability. Phosphorus metabolism varies with region and age, and is related to glucose uptake in adults at risk for AD. Phosphorus spectroscopy may be a valuable approach to study early changes in brain energetics in high-risk populations.