Contrasting Sodium and Potassium Perturbations in the Hippocampus Indicate Potential Na+/K+-ATPase Dysfunction in Vascular Dementia.

Sasha A Philbert,Garth J S Cooper,Melissa Scholefield,Jingshu Xu,Stephanie J Church,Richard D Unwin

doi:10.3389/fnagi.2022.822787

Abstract

Vascular dementia (VaD) is thought to be the second most common cause of age-related dementia amongst the elderly. However, at present, there are no available disease-modifying therapies for VaD, probably due to insufficient understanding about the molecular basis of the disease. While the notion of metal dyshomeostasis in various age-related dementias has gained considerable attention in recent years, there remains little comparable investigation in VaD. To address this evident gap, we employed inductively coupled-plasma mass spectrometry to measure the concentrations of nine essential metals in both dry- and wet-weight hippocampal post-mortem tissue from cases with VaD (n = 10) and age-/sex-matched controls (n = 10). We also applied principal component analysis to compare the metallomic pattern of VaD in the hippocampus with our previous hippocampal metal datasets for Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and type-2 diabetes, which had been measured using the same methodology. We found substantive novel evidence for elevated hippocampal Na levels and Na/K ratios in both wet- and dry-weight analyses, whereas decreased K levels were present only in wet tissue. Multivariate analysis revealed no distinguishable hippocampal differences in metal-evoked patterns between these dementia-causing diseases in this study. Contrasting levels of Na and K in hippocampal VaD tissue may suggest dysfunction of the Na+/K+-exchanging ATPase (EC 7.2.2.13), possibly stemming from deficient metabolic energy (ATP) generation. These findings therefore highlight the potential diagnostic importance of cerebral sodium measurement in VaD patients.

Highlights

Within the spectrum of age-related dementias, vascular dementia (VaD) is widely recognized as the second leading cause of dementia after Alzheimer’s disease (AD), and accounts for about 20% of all cases (Rizzi et al, 2014)
VaD is characterized as a heterogeneous class of brain disorders caused by cerebrovascular pathology which results in the impairment of several cognitive domains, as well
Small-vessel abnormalities comprising arteriosclerosis/lipohyalinosis, commonly referred to as type-1 cerebral small-vessel disease (Pantoni, 2010), initially develop in the basal ganglia and deep white matter before expanding into the vessels of the thalamus, leptomeninges, cerebellum, and brain stem (Thal et al, 2003, 2012). This pattern of pathology is highly characteristic of VaD, post-mortem evidence suggests that AD cases exhibit a high frequency of cerebrovascular pathology (Jellinger and Attems, 2003; Deramecourt et al, 2012), highlighting the pathological similarity between the two diseases

Summary

Introduction

Within the spectrum of age-related dementias, vascular dementia (VaD) is widely recognized as the second leading cause of dementia after Alzheimer’s disease (AD), and accounts for about 20% of all cases (Rizzi et al, 2014). Small-vessel abnormalities comprising arteriosclerosis/lipohyalinosis, commonly referred to as type-1 cerebral small-vessel disease (Pantoni, 2010), initially develop in the basal ganglia and deep white matter before expanding into the vessels of the thalamus, leptomeninges, cerebellum, and brain stem (Thal et al, 2003, 2012). This pattern of pathology is highly characteristic of VaD, post-mortem evidence suggests that AD cases exhibit a high frequency of cerebrovascular pathology (Jellinger and Attems, 2003; Deramecourt et al, 2012), highlighting the pathological similarity between the two diseases. While the precise location and volume of cerebrovascular insults are known to contribute to the development of cognitive impairment in VaD, the key molecular mechanisms underlying the disease are yet to be identified

Methods

Results

Conclusion