Abstract
Parkinson's disease (PD) is one of the most common neurodegenerative diseases, most commonly characterised by motor dysfunction, but also with a high prevalence of cognitive decline in the decades following diagnosis-a condition known as Parkinson's disease dementia (PDD). Although several metabolic disruptions have been identified in PD, there has yet to be a multi-regional analysis of multiple metabolites conducted in PDD brains. This discovery study attempts to address this gap in knowledge. A semi-targeted liquid chromatography-mass spectrometry analysis of nine neuropathologically-confirmed PDD cases vs nine controls was performed, looking at nine different brain regions, including the cingulate gyrus, cerebellum, hippocampus, motor cortex, medulla, middle temporal gyrus, pons, substantia nigra and primary visual cortex. Case-control differences were determined by multiple t-tests followed by 10% FDR correction. Of 64 identified analytes, 49 were found to be altered in at least one region of the PDD brain. These included metabolites from several pathways, including glucose and purine metabolism and the TCA cycle, with widespread increases in fructose, inosine and ribose-5-phosphate, as well as decreases in proline, serine and deoxyguanosine. Higher numbers of alterations were observed in PDD brain regions that are affected during earlier α-synuclein Braak stages-with the exception of the cerebellum, which showed an unexpectedly high number of metabolic changes. PDD brains show multi-regional alterations in glucose and purine metabolic pathways that reflect the progression of α-synuclein Braak staging. Unexpectedly, the cerebellum also shows a high number of metabolic changes.