The molecular basis for vascular dementia

Abstract

Vascular dementia (VaD) is widely recognised as the second most common cause of dementia amongst the elderly, after Alzheimer's disease (AD). However, little is known about the molecular basis of the disease, particularly in relation to metals and metabolites, due to a lack of multi-omic research. This is best reflected by the scarcity of disease-modifying therapies and clinical biomarkers for VaD. Therefore, in order to broaden our understanding of the metallomic and metabolomic basis of VaD, here, a multi-omic approach was applied using various mass-spectrometry-based analytical platforms in human post-mortem VaD brain tissue and matched controls. In this thesis, we found evidence for elevated brain-sodium levels in VaD brain tissue in six out of the seven regions studied and decreased brain potassium levels as well as brain sodium/potassium ratios (consistent with high tissue sodium and low potassium levels). Using the same method, we then investigated metal levels in type 2 diabetes (T2D), which is a strong risk factor for VaD. Elevated copper levels were observed in the hippocampus of T2D brains across two technical replicates. Hippocampal-copper levels in T2D were also seen to be comparable to those in cases of untreated Wilson's disease, in which elevated cerebral copper causes neurodegeneration, and thus may imply a similar mechanism of copper toxicity in T2D. For metabolomic analyses, a targeted investigation of urea levels in VaD identified increased urea levels in six out of the seven regions studied. The urea fold-change seen in VaD was similar, albeit slightly lower, to the fold-change observed in our group's previous investigations of AD, Huntington's disease, and Parkinson's disease dementia. Subsequent untargeted metabolic analysis using the same tissue confirmed the presence of elevated urea levels in VaD and the absence of dysfunctional brain-glucose utilisation, as previously observed in our group's prior investigation of AD and Huntington's disease. Together, these data shed light on the alteration of two key metals (sodium and copper) in VaD and T2D brains, and imply the therapeutic and diagnostic implications of such perturbations. Corresponding targeted and untargeted metabolic analyses in VaD also confirmed the presence of widespread urea elevations and implies a possible common urea-mediated pathogenic mechanism amongst the age-related dementias. In addition, the absence of brain-glucose differences suggests that brain-glucose utilisation in VaD is fundamentally different to that of AD and Huntington's disease.

Date of Award	8 Nov 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Richard Unwin (Supervisor), Stuart Allan (Supervisor), Elizabeth Cartwright (Supervisor), Garth Cooper (Supervisor) & Federico Roncaroli (Supervisor)