In a recent paper, Sasha A. Philbert, Stephanie J. Church, Richard D. Unwin and Garth J.S. Cooper investigated levels of urea in post-mortem brains of people with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Based on the hypothesis that altered urea metabolism may represent a shared pathogenic mechanism across several dementias.
FTD and ALS are closely related neurodegenerative disorders that exist on a disease spectrum and share several genetic and pathological features. Previous studies had shown elevated brain urea levels in Alzheimer’s disease, Huntington’s disease, Parkinson’s disease dementia, dementia with Lewy bodies and vascular dementia, suggesting that disrupted urea metabolism may represent a common feature across multiple dementias.
Urea is a waste product generated during protein breakdown and is normally produced through the urea cycle before being excreted by the kidneys. Excessive accumulation of urea can be harmful to the brain and that elevated urea levels are known to occur in conditions such as uraemic encephalopathy, which can cause cognitive and neurological symptoms. Although the underlying cause of increased brain urea in FTD and ALS remains uncertain, the researchers suggest it may be linked to increased protein breakdown, disturbances in ammonia detoxification, alterations in the urea cycle or activation of cellular stress pathways.
To explore this possibility in FTD and ALS, urea concentrations in post-mortem brain tissue using ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) were measured. They analysed tissue from brain regions with high and low neuropathological burden, comparing samples from people with FTD and ALS with those from neurologically healthy controls. Specifically, the frontal cortex and primary visual cortex in FTD, and the primary motor cortex and dentate nucleus in ALS were examined.
The results showed significantly elevated urea levels in both brain regions examined in FTD. Urea concentrations were approximately 2.4 times higher in the frontal cortex and around two times higher in the primary visual cortex compared with controls. In ALS, significantly increased urea levels were found in the primary motor cortex, where concentrations were around 1.75 times higher than in controls. However, no statistically significant increase was observed in the dentate nucleus. These findings suggest that elevated brain urea may be more widespread throughout the brain in FTD, while in ALS it may be more closely associated with regions most affected by disease pathology.
In conclusion, the study provides the first direct evidence of elevated brain urea levels in FTD and ALS. Together with previous findings in other neurodegenerative diseases, the results support the hypothesis that altered urea metabolism may represent a common pathogenic mechanism across several dementias. The authors suggest that understanding how and why urea accumulates in the brain could open new avenues for therapeutic development, although further research will be needed to determine whether elevated urea contributes directly to disease processes or is a consequence of neurodegeneration.
Find the full article here: https://academic.oup.com/molecular-omics/article/22/4/aaiag019/8723802?login=false
