Asymmetric Dimethylarginine: A Possible Link between Vascular Disease and Dementia

Abstract

There is good epidemiological evidence that vascular disease predisposes to cognitive decline and dementia. The impact of vascular disease on dementia is likely to increase further because of the poor diagnosis and management of vascular risk factors, the increase in life expectancy, and the improved survival following major cardiovascular events, e.g. acute stroke. It is estimated that the adequate management of vascular risk factors, with pharmacological and/or nonpharmacological interventions, might result in a 50% reduction in the forecasted dementia prevalence. The exact mechanisms by which vascular risk factors and vascular disease adversely affect brain function remain unclear, but it is hypothesized that endothelial dysfunction plays an important role. Reduced synthesis and availability of endothelial nitric oxide (NO) may contribute to the development of dementia by at least two mechanisms: (1) favoring the onset and progression of atherosclerosis, vasoconstriction, and impaired cerebral blood flow regulation; and (2) reduced neuroprotection.Several studies have shown that asymmetric dimethylarginine (ADMA), an endogenous methylated form of the amino acid L-arginine, inhibits NO synthesis and favors oxidative stress and vascular damage. Unlike NO, ADMA concentrations are relatively stable and can be accurately measured in plasma. There is good evidence that higher plasma ADMA concentrations favor atherosclerosis and independently predict adverse cardiovascular and cerebrovascular outcomes in several patient groups. ADMA might represent a unifying pathophysiological pathway linking the presence of vascular risk factors with the onset and progression of cognitive decline and dementia. This review discusses the biological role of ADMA, its potential contribution to the onset and progression of dementia through vascular disease and atherosclerosis, the available evidence linking ADMA with cognitive impairment and dementia, and the strategies to characterize the predictive role of ADMA in cognitive impairment in epidemiological studies. Therapeutic implications and suggestions for future research directions are also discussed.

Ameliorative Effect of a Selective Endothelin ETAReceptor Antagonist in Rat Model of L-Methionine-induced Vascular Dementia

“…Hyperhomocysteinemia has been shown to induce endothelial dysfunction by decreasing the bioavailability of NO and by increasing vascular oxidative stress [17,38]. Moreover, endothelial dysfunction (vascular defects) has been reported to induce varying degree of memory impairment in animals and humans [39]. Furthermore, hyperhomocysteinemia is noted to produce a change in the structure and function of cerebral blood vessels as a consequence of cerebral vascular endothelial dysfunction [40].…”

Dimethylarginines ADMA and SDMA: The Real Water-Soluble Small Toxins?

“…73 Hence, the effects of ADMA on central and peripheral nerve function in CKD warrants further investigation because some investigators consider ADMA to be a contributor to the onset and progression of dementia through vascular disease and atherosclerosis and therefore might be of importance for cognitive impairment and dementia. 74 This considerable body of experimental and clinical studies suggests that ADMA is not only a marker but also a potent mediator of endothelial dysfunction and atherosclerosis, as well as of other clinical problems associated with CKD-like impaired cognitive function and depression.…”

New Insights into Possible Role of NOS-NO-ADMA Pathway Dysfunction in the Development of Cognitive Decline and Dementia: Exploring the Vascular Features of Alzheimer’s Disease

“…In line with these remarks, Asif et al [34] recently proposed ADMA as a possible link between vascular disease and dementia. Authors suggested that ADMA might represent a unifying pathophysiological pathway linking the presence of vascular risk factors with the onset and progression of cognitive decline and dementia.…”

“…Possible role of disturbed production and bioavailability of NO in the development and progression of dementia has been suggested by Colton et al [33] based on the findings from the study in a mouse model of Alzheimer's disease. Reduced synthesis and availability of endothelial NO may contribute to the development of dementia by at least two mechanisms: favoring the onset and progression of atherosclerosis, vasoconstriction, and impaired cerebral blood flow regulation; and by reduced neuroprotection [34] . Oxidative stress and inhibitors of NO synthase are regarded as most potent initiators of disturbed production and bioavailability of NO [35] .…”

“…Important endogenous inhibitor of all three isoforms of NOS is asymmetrical dimethylarginine (ADMA) [36] . Most prominent feature of ADMA actions besides inhibition of NO synthesis is promotion of oxidative stress and vascular damage [34] . Moreover, ADMA is regarded as reliable non-invasive marker of endothelial dysfunction.…”