Abstract
Background: Widespread elevations in brain urea have, in recent years, been reported in certain types of age-related dementia, notably Alzheimer’s disease (AD) and Huntington’s disease (HD). Urea increases in these diseases are substantive, and approximate in magnitude to levels present in uraemic encephalopathy. In AD and HD, elevated urea levels occur across the entire brain, and not only in regions heavily affected by neurodegeneration. However, measurements of brain urea have not hitherto been reported in Parkinson’s disease dementia (PDD), a condition defined by changes in thinking and behaviour in someone with a diagnosis of Parkinson's disease, which shares neuropathological and symptomatic overlap with both AD and HD. This study aims to address this gap in the current knowledge of PDD.Methods: Here we report measurements of tissue urea from nine neuropathologically-confirmed regions of the brain in PDD and post-mortem-delay-matched controls, in regions that included the cerebellum, motor cortex, sensory cortex, hippocampus, substantia nigra, middle temporal gyrus, medulla oblongata, cingulate gyrus, and pons, by applying ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Case-control differences were determined using multiple t-tests followed by correction with 10% false discovery rate.Results: We found urea concentrations to be substantively elevated in all nine regions, the average increase being 3-4-fold. Urea concentrations were remarkably consistent across regions in both cases and controls, with no clear distinction between regions heavily affected by neuronal loss in PDD compared to less severely affected areas. These urea elevations mirror those found in uraemic encephalopathy, where equivalent levels are generally considered to be pathogenic. These urea elevations also reflect those previously reported in AD and HD. Conclusions: Increased urea is a widespread metabolic perturbation in brain metabolism common to PDD, AD, and HD, at levels equal to those seen in uremic encephalopathy. This presents a novel pathogenic mechanism in PDD, which is shared with two other neurodegenerative diseases.
Age-related neuronal loss in the rat brain starts at the end of adolescence