Homocysteine in Neurology: A Possible Contributing Factor to Small Vessel Disease

Abstract

Homocysteine (Hcy) is a sulfur-containing amino acid generated during methionine metabolism, accumulation of which may be caused by genetic defects or the deficit of vitamin B12 and folate. A serum level greater than 15 micro-mols/L is defined as hyperhomocysteinemia (HHcy). Hcy has many roles, the most important being the active participation in the transmethylation reactions, fundamental for the brain. Many studies focused on the role of homocysteine accumulation in vascular or degenerative neurological diseases, but the results are still undefined. More is known in cardiovascular disease. HHcy is a determinant for the development and progression of inflammation, atherosclerotic plaque formation, endothelium, arteriolar damage, smooth muscle cell proliferation, and altered-oxidative stress response. Conversely, few studies focused on the relationship between HHcy and small vessel disease (SVD), despite the evidence that mice with HHcy showed a significant end-feet disruption of astrocytes with a diffuse SVD. A severe reduction of vascular aquaporin-4-water channels, lower levels of high-functioning potassium channels, and higher metalloproteinases are also observed. HHcy modulates the N-homocysteinylation process, promoting a pro-coagulative state and damage of the cellular protein integrity. This altered process could be directly involved in the altered endothelium activation, typical of SVD and protein quality, inhibiting the ubiquitin-proteasome system control. HHcy also promotes a constant enhancement of microglia activation, inducing the sustained pro-inflammatory status observed in SVD. This review article addresses the possible role of HHcy in small-vessel disease and understands its pathogenic impact.

Sitagliptin Attenuates the Cognitive Deficits in L-Methionine-Induced Vascular Dementia in Rats

“…The amino acid Hcy is a significant by-product of methionine metabolism [ 6 ]. Hcy accumulation could disrupt endothelial function, cause oxidative damage, and increase neuroinflammatory and neurodegenerative processes [ 7 ]. As a result, oxidative stress, inflammation, and neuronal apoptosis have all been linked to the pathophysiology of VaD [ 8 ].…”

Emerging role of white matter lesions in cerebrovascular disease

“…In this context, a lower level of serum vitamin B12 has been proven to be associated with severe periventricular WMLs in lacunar stroke patients (Pieters et al, 2009). This is poignant as vitamin B12 is also implicated in mediating serum homocysteine (HCys) levels, where elevated HCys levels (hyperhomocysteinaemia) is known to be associated with endothelial dysfunction (Hassan et al, 2004), and with increased risk of cerebral small vessel disease (or WMLs) (Moretti et al, 2021) and/or stroke (Weikert et al, 2007). Further studies to delineate the causal role of vitamin B12 deficiency in the development or worsening of WML are required.…”

Small Vessel Disease: Ancient Description, Novel Biomarkers

“…Homocysteine could be a potential marker of neuroinflammation inside SVD, promoting the increase in TNF-alpha and IL1-beta, upregulating the transcriptional fibroblast growth factor-2, IL-6, and IL-8, [ 177 , 178 ], and enhancing the VEGF/ERK1/2 signaling pathway [ 179 , 180 ], which can be seen frequently in the atherosclerosis process. Homocysteine is directly linked to the B-inflammatory pathway through a direct upregulation of pyruvate kinase muscle isoenzyme 2 (PKM-2), B-mediated, which mainly promotes the inflammatory basis of atherosclerosis cascade [ 181 , 182 ].…”