AUTHOR=Philbert Sasha A. , Xu Jingshu , Scholefield Melissa , Patassini Stefano , Church Stephanie J. , Unwin Richard D. , Roncaroli Federico , Cooper Garth J. S. 

TITLE=Extensive multiregional urea elevations in a case-control study of vascular dementia point toward a novel shared mechanism of disease amongst the age-related dementias

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 16 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2023.1215637

DOI=10.3389/fnmol.2023.1215637

ISSN=1662-5099

ABSTRACT=Vascular dementia (VaD) is one of the most common causes of dementia among the elderly. Despite this, the molecular basis of VaD remains poorly characterised when compared to other age-related dementias. Pervasive cerebral elevations of urea have recently been reported in several dementias; however, a similar analysis was not yet available for VaD. Here, we utilised ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to measure urea levels from seven brain regions in post-mortem tissue from cases of VaD (n = 10) and controls (n = 8/9). Brainurea measurements from our previous investigations of several dementias were also used to generate comparisons with VaD. Elevated urea levels ranging from 2.2-to 2.4-fold-change in VaD cases were identified in six out of the seven regions analysed, which are similar in magnitude to those observed in uraemic encephalopathy. Fold-elevation of urea was highest in the basal ganglia and hippocampus (2.4-fold-change), consistent with the observation that these regions are severely affected in VaD. Taken together, these data not only describe a multiregional elevation of brain-urea levels in VaD but also implies the existence of a common urea-mediated disease mechanism that is now known to be present in at least four of the main age-related dementias.