Whole-brain phosphorus metabolism: regional distribution and associations with cognition

Studying brain metabolism can provide unique insight into the processes that underlie changes in brain structure and function, which occur in normal and pathological states. Phosphorus (31P) magnetic resonance spectroscopy (MRS) allows for non-invasive visualization of metabolic content for crucial high-energy phosphates and membrane phospholipids. These compounds provide the basis for the normal functioning of the brain on a cellular level, being key players in energy production and utilization, as well as membrane synthesis and breakdown. Changes in their content are associated with various pathological states, occur in healthy aging and correlate with cognitive changes. However, only a select number of studies have been able to assess the distribution of high-energy and membrane phosphates across the brain in healthy people, with the vast majority of research having focused on one brain area. To paint a comprehensive picture of how phosphorus metabolism impacts and is impacted in health and disease, whole-brain assessment is crucial. In this present study, we have utilized 31P-MRS to examine the regional disparity in phosphorus-containing metabolites in healthy young adults. Additionally, considering the known alterations of energy metabolism in various types of cognitive impairment, we evaluated the link between metabolite concentrations in different brain regions with cognitive measures.
Whole-brain 31P-MRS spectra (10x10x8 voxels) were collected from 74 healthy volunteers (32 male, 42 female) aged 18 to 40 years (mean age 26.2 years). 3D maps of phosphocreatine (PCr), adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (tNAD), phosphomonoesters (PME) and phosphodiesters (PDE) were quantified using an established convolutional neural network a (Songeon et al., 2022) (31P-SPAWNN)). All maps were registered to the standard MNI space using each participant’s structural scan. From this data, metabolites ATP, tNAD, PCr, PME and PDE were referenced to total phosphorus and assessed for voxel-wise whole brain distribution, as well as ratios ATP/PCr and PME/PDE. 8 tests from the MATRICS Consensus Cognitive Battery were administered to obtain a global cognitive score and 5 cognitive domain scores: executive function, processing speed, working memory, verbal and visual learning. We tested for possible correlations of metabolic content with age, sex and cognitive measures at the voxel level using cluster-based permutation testing in PALM, FSL. We used Friedman’s test with post hoc Wilcoxon’s tests for within-subject differences between regions.
Whole-brain maps of energy metabolism (ATP, tNAD, PCr, ATP/PCr) and membrane metabolism (PME, PDE, PME/PDE) were estimated. Regional analysis demonstrated significant heterogeneity in metabolite distribution across brain regions for all assessed metabolites (p<0.0001). Voxel-wise analysis showed a significant negative correlation of tNAD with age, as well as higher PME content in females (p value range <0.05). Negative correlations of phosphocreatine in parietal lobe voxels were found with global cognition and verbal learning (p value range <0.05). ATP/PCr and tNAD were found to correlate positively with verbal learning in parts of the parietal and frontal cortex (p value range <0.05).
To sum up, firstly, we have demonstrated that in young healthy adults, energy and membrane metabolism significantly vary across brain regions, which advances on findings from several previous 31P MRS studies and data from FDG-PET. Secondly, for the first time, we assess the link between cognitive measures and energy and membrane metabolism markers at voxel resolution. Our findings highlight the potential link between phosphate-containing energy metabolites and cognitive performance, particularly verbal learning. Overall, this study significantly advances our understanding of phosphate metabolite distribution across the brain in healthy individuals and its potential impact on cognitive function.