Identification of Pivotal Markers in Vascular Dementia Based on Proteomics Data

Wang, Chunyan; Zhao, Jingkun; Xu, Ran; Zhao, Jiwei; Duan, Shurong

doi:10.1159/000375296

Cited by 7 publications

(5 citation statements)

References 34 publications

(37 reference statements)

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“…Therefore, despite the absence of clinical evidence for hippocampal hypometabolism in VaD patients, increased Na levels in VaD post-mortem tissue may imply hippocampal energy dysfunction in late-stage VaD. This observation is consistent with proteomic findings from the middle-temporal gyrus in VaD post-mortem tissue, whereby downregulation of ATP synthase (electron transport chain complex V; EC 7.1.2.2) subunits (Datta et al, 2014;Wang et al, 2015) and upregulation of Na/K-ATPase alpha subunit 3 (ATP1A3) (Adav et al, 2014) were identified. Elevated Na levels may also highlight the potential application of clinical 23 Na magnetic resonance imaging as a diagnostic method in VaD, which has already been shown to be informative in patients with multiple sclerosis (Inglese et al, 2010;Eisele et al, 2016).…”

Section: Discussionsupporting

confidence: 80%

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

Philbert

Scholefield

et al. 2022

Front. Aging Neurosci.

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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.

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Section: Discussionsupporting

confidence: 80%

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

Philbert

Scholefield

et al. 2022

Front. Aging Neurosci.

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“…This gives reason to believe that defective energy utilization leading to diminished pools of ATP could lead to the observed intracellular Na elevations seen here that are likely due to reduced Na + /K + -ATPase activity. This is further supported by proteomic evidence showing downregulation of ATP synthase (electron transport chain complex V; EC 7.1.2.2) subunits ( Datta et al, 2014 ; Wang et al, 2015 ) and upregulation of Na/K-ATPase alpha subunit 3 ( Adav et al, 2014 ) in VaD middle-temporal gyrus post-mortem tissue. Reduced activity of Na/K-ATPase can also lead to neuronal cell death ( Xiao et al, 2002 ; Kurauchi et al, 2018 ) potentially via glutamate neurotoxicity and alterations in dopamine release ( Lees, 1991 ), which could further exacerbate cerebrovascular pathology in VaD.…”

Section: Discussionmentioning

confidence: 60%

Pan-cerebral sodium elevations in vascular dementia: Evidence for disturbed brain-sodium homeostasis

Philbert

Church

et al. 2022

Front. Aging Neurosci.

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Vascular dementia (VaD) is the second most common cause of cognitive impairment amongst the elderly. However, there are no known disease-modifying therapies for VaD, probably due to incomplete understanding of the molecular basis of the disease. Despite the complex etiology of neurodegenerative conditions, a growing body of research now suggests the potential involvement of metal dyshomeostasis in the pathogenesis of several of the age-related dementias. However, by comparison, there remains little research investigating brain metal levels in VaD. In order to shed light on the possible involvement of metal dyshomeostasis in VaD, we employed inductively coupled plasma-mass spectrometry to quantify the levels of essential metals in post-mortem VaD brain tissue (n = 10) and age-/sex-matched controls (n = 10) from seven brain regions. We found novel evidence for elevated wet-weight cerebral sodium levels in VaD brain tissue in six out of the seven regions analyzed. Decreased cerebral-potassium levels as well as increased Na/K ratios (consistent with high tissue sodium and low potassium levels) were also observed in several brain regions. These data suggest that reduced Na+/K+-exchanging ATPase (EC 7.2.2.13) activity could contribute to the contrasting changes in sodium and potassium measured here.

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“…Two metabolic pathways, pentose and glucuronate interconversions ( Zheng et al, 2019 ), and starch and sucrose metabolism ( Ling et al, 2021 ) may play roles in learning and cognitive impairment that are caused by abnormal nitric oxide production and monoaminergic neurotransmitters in AD, BPD, and/or dementia patients. Other metabolisms, including porphyrin and chlorophyll metabolism ( Wang et al, 2015 ), and ascorbate and aldarate metabolism ( Chen et al, 2011 ) were biologically or molecularly connected with psychiatric disorders (e.g., AD, BPD) and dementia. We noticed that some of enriched network pathways that were not reported previously suggest that there may be potential links between BPD and the risk of dementia or possibly a chance association.…”

Section: Discussionmentioning

confidence: 99%

Genetic Pathways and Functional Subnetworks for the Complex Nature of Bipolar Disorder in Genome-Wide Association Study

Kuo

Chen

Kao

et al. 2021

Front. Mol. Neurosci.

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Bipolar disorder is a complex psychiatric trait that is also recognized as a high substantial heritability from a worldwide distribution. The success in identifying susceptibility loci for bipolar disorder (BPD) has been limited due to its complex genetic architecture. Growing evidence from association studies including genome-wide association (GWA) studies points to the need of improved analytic strategies to pinpoint the missing heritability for BPD. More importantly, many studies indicate that BPD has a strong association with dementia. We conducted advanced pathway analytics strategies to investigate synergistic effects of multilocus within biologically functional pathways, and further demonstrated functional effects among proteins in subnetworks to examine mechanisms underlying the complex nature of bipolarity using a GWA dataset for BPD. We allowed bipolar susceptible loci to play a role that takes larger weights in pathway-based analytic approaches. Having significantly informative genes identified from enriched pathways, we further built function-specific subnetworks of protein interactions using MetaCore. The gene-wise scores (i.e., minimum p-value) were corrected for the gene-length, and the results were corrected for multiple tests using Benjamini and Hochberg’s method. We found 87 enriched pathways that are significant for BPD; of which 36 pathways were reported. Most of them are involved with several metabolic processes, neural systems, immune system, molecular transport, cellular communication, and signal transduction. Three significant and function-related subnetworks with multiple hotspots were reported to link with several Gene Ontology processes for BPD. Our comprehensive pathway-network frameworks demonstrated that the use of prior knowledge is promising to facilitate our understanding between complex psychiatric disorders (e.g., BPD) and dementia for the access to the connection and clinical implications, along with the development and progression of dementia.

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Identification of Pivotal Markers in Vascular Dementia Based on Proteomics Data

Cited by 7 publications

References 34 publications

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

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

Pan-cerebral sodium elevations in vascular dementia: Evidence for disturbed brain-sodium homeostasis

Genetic Pathways and Functional Subnetworks for the Complex Nature of Bipolar Disorder in Genome-Wide Association Study

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