Increased total homocysteine level is associated with clinical status and severity of white matter changes in symptomatic patients with subcortical small vessel disease

doi:10.1016/j.clineuro.2011.07.004

Clinical Neurology and Neurosurgery

Volume 113, Issue 9, November 2011, Pages 711-715

https://doi.org/10.1016/j.clineuro.2011.07.004 Get rights and content

Abstract

Objective

Elevated plasma total homocysteine (tHcy) is an independent risk factor for ischemic stroke and has been linked to cerebral small vessel disease (SVD), in particular. Controversy persists as to whether increased tHcy is associated with functional status and cognitive decline in these patients.

Methods

Plasma tHcy, MTHFR polymorphism, vascular risk factors, functional and cognitive status and severity of lesions on MRI, assessed with the Age-Related White Matter Changes (ARWMC) visual grading scale, were analyzed in 95 patients with SVD and 41 healthy control subjects.

Results

Plasma tHcy levels were higher in patients with SVD (14.4 ± 5.0 μmol/L) compared to healthy SVD-free controls (8.9 ± 3.9 μmol/L). In SVD patients, tHcy levels strongly correlated with cognitive status (age-adjusted risk 5.8, 95% CI 1.3–25.3, p = 0.015), functional status (age-adjusted risk 3.2, 95% CI 1.2–8.8, p = 0.022) and severity of MRI lesions (age-adjusted risk 1.2, 95% CI 1.1–1.4; p = 0.004). Only total ARWMC score was independently associated with increased tHcy levels (OR 1.2, 95%CI 1.1–1.4, p = 0.004). Independent predictors of WMC occurrence were tHcy levels (OR 1.2, 95%CI 1.1–1.3, p = 0.003) and mRS score (OR 2.2, 95%CI 1.2–4.1, p = 0.017).

Conclusions

In patients with cerebral SVD there is a positive association of increased plasma tHcy levels with clinical status and severity of WMC.

Introduction

Elevated plasma total homocysteine (tHcy) is an independent risk factor (RF) for atherosclerosis in general and increases the risk of ischemic stroke at least 2.5-fold [1], [2], [3], [4]. Epidemiological studies indicate that even moderately elevated plasma tHcy levels (>10.0 μmol/L) increase stroke risk [5]. Hyperhomocysteinemia can be secondary to genetic variations of enzymes critical in Hcy metabolism (most often methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism), systemic disorders (such as renal failure), nutritional status (vitamin B12 and folate deficits) or medications. Elevated tHcy levels promote atherothrombosis through several mechanisms, including increased oxidative stress, impairment of endothelium-dependent vasorelaxation, smooth muscle cell proliferation and activation of coagulation pathways [3], [6], [7].

Hyperhomocysteinemia has been linked to cerebral small vessel disease (SVD) in particular, including lacunar infarcts and confluent white matter changes (WMC) [3], [7], [8], [9], [10]. Both silent lacunes and leukoaraiosis are frequently detected on brain magnetic resonance imaging (MRI) in patients with vascular RFs, and are associated with an increased risk of stroke and dementia [11]. Positive correlation between tHcy and severity of SVD has been reported [3], [9], [11], [12], [13], although there are negative studies as well [14]. Similarly, a relationship between increasing tHcy levels and decreasing cognitive status has been documented in different SVD patient populations, but with some contradictory studies [2], [9], [15]. In this exploratory study we aimed to analyze clinical and MRI correlates of plasma tHcy levels and MTHFR status in Serbian patients with SVD.

Section snippets

Subjects

Prospective enrolment of 95 consecutive patients with MRI findings consistent with SVD, evaluated for vascular RFs and managed for secondary stroke prevention, was performed at the Institute of Neurology in Belgrade between June 1st 2006 and June 1st 2007. Patients presenting with transient ischemic attack (TIA) (23 or 24.2% of patients) or subcortical stroke (72 or 75.8% of patients) at least 1 month and within 6 months of ictus, were included in the study. TIA was defined as a brief episode

Results

Of 95 patients with SVD, 27 (28.4%) had single lacunar infarction, 10 (10.5%) multiple lacunar infarctions and 58 (61.1%) confluent WMC. Demographic, clinical and neuroimaging characteristics of healthy controls and SVD patients are shown in Table 1. There were no differences between control subjects and SVD patients in regard to sex, age or years of education. None of the controls and 45.3% of SVD patients had cognitive decline (VCI or dementia) (p < 0.0001). Patients with SVD were more

Discussion

Mean plasma tHcy levels were significantly increased in patients with SVD compared to SVD-free control subjects. Most SVD patients had moderately increased tHcy levels, higher than the recommended 10.0 μmol/L [5]. Increased plasma tHcy concentrations significantly correlated with WMC score on MRI, functional status expressed using mRS score and decline in cognitive status, after adjusting for patients’ age and disease duration. However, extent of WMC was the only parameter independently

Conflicts of interest/disclosures

None.

Acknowledgements

This work has been supported by the Ministry of Science and Environmental Protection of Serbia (Scientific Projects No. 175022 and 175087). The authors would like to thank Dr. Christen Barras, Department of Radiology, Royal Melbourne Hospital, Melbourne, Australia for his valuable help with the manuscript.

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Age-associated cerebral small vessel disease (CSVD) represents a clinically heterogenous condition, arising from diverse microvascular mechanisms. These lead to chronic cerebrovascular dysfunction and carry a substantial risk of subsequent stroke and vascular cognitive impairment in aging populations. Owing to advances in neuroimaging, in vivo visualization of cerebral vasculature abnormities and detection of CSVD, including lacunes, microinfarcts, microbleeds and white matter lesions, is now possible, but remains a resource-, skills- and time-intensive approach. As a result, there has been a recent proliferation of blood-based biomarker studies for CSVD aimed at developing accessible screening tools for early detection and risk stratification. However, a good understanding of the pathophysiological processes underpinning CSVD is needed to identify and assess clinically useful biomarkers. Here, we provide an overview of processes associated with CSVD pathogenesis, including endothelial injury and dysfunction, neuroinflammation, oxidative stress, perivascular neuronal damage as well as cardiovascular dysfunction. Then, we review clinical studies of the key biomolecules involved in the aforementioned processes. Lastly, we outline future trends and directions for CSVD biomarker discovery and clinical validation.
Inflammation and cerebral small vessel disease: A systematic review
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Inflammation is increasingly implicated as a risk factor for dementia, stroke, and small vessel disease (SVD). However, the underlying mechanisms and causative pathways remain unclear. We systematically reviewed the existing literature on the associations between markers of inflammation and SVD (i.e., white matter hyperintensities (WMH), lacunes, enlarged perivascular spaces (EPVS), cerebral microbleeds (CMB)) in cohorts of older people with good health, cerebrovascular disease, or cognitive impairment. Based on distinctions made in the literature, markers of inflammation were classified as systemic inflammation (e.g. C-reactive protein, interleukin-6, fibrinogen) or vascular inflammation/endothelial dysfunction (e.g. homocysteine, von Willebrand factor, Lp-PLA2). Evidence from 82 articles revealed relatively robust associations between SVD and markers of vascular inflammation, especially amongst stroke patients, suggesting that alterations to the endothelium and blood-brain barrier may be a driving force behind SVD. Conversely, cross-sectional findings on systemic inflammation were mixed, although longitudinal investigations demonstrated that elevated levels of systemic inflammatory markers at baseline predicted subsequent SVD severity and progression. Importantly, regional analysis revealed that systemic and vascular inflammation were differentially related to two distinct forms of SVD. Specifically, markers of vascular inflammation tended to be associated with SVD in areas typical of hypertensive arteriopathy (e.g., basal ganglia), while systemic inflammation appeared to be involved in CAA-related vascular damage (e.g., centrum semiovale). Nonetheless, there is insufficient data to establish whether inflammation is causal of, or secondary to, SVD. Findings have important implications on interventions, suggesting the potential utility of treatments targeting the brain endothelium and blood brain barrier to combat SVD and associated neurodegenerative diseases.
Single-nucleotide polymorphisms of the adherent junction component cadherin gene are associated with leukoaraiosis
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Citation Excerpt :
LA is a complex disorder with both genetic and environmental risk factors, including homocysteine, diabetes and hypertension, which play vital roles in its development and progression (Lindgren et al., 1994; Pantoni and Garcia, 1997; Hill and Bisognano, 2005; Sacco and Carolei, 2007). Homocysteine (Hcy) inhibits angiogenesis both in vitro and in vivo (Roybal et al., 2004) and several studies have shown a significant association between cerebral white matter lesions and Hcy (Vermeer et al., 2002; Dufouil et al., 2003; Wright et al., 2005; Wong et al., 2006; Pavlovic et al., 2011). This study also found that individuals with heterozygous and homozygous alleles composed of these SNPs had a higher risk for LA compared to wild-type carriers, suggesting that CDH1 polymorphisms may be associated with Hcy levels in blood.
Leukoaraiosis (LA) is one of the manifestations of cerebral small vessel disease. Blood-brain barrier (BBB) disruption plays a key role in LA. Cadherin is a component of adherent junctions (AJ), which play a crucial role in cell-cell adhesion, cell-cell recognition and homeostasis in BBB development. We hypothesized that alterations in cadherin genes might be a potential cause of BBB abnormalities that result in LA.
A total of 339 LA individuals (LA-PVWM, 183; LA-DWM 156) were enrolled, who underwent brain magnetic resonance imaging with obtainable vascular risk factors. Genotyping of cadherin single-nucleotide polymorphisms (SNPs) (rs5030625, rs1801026, and rs16260) was performed by real-time polymerase chain reaction with LightSNiP reagents (coupled primer and probe) and FastStart DNAMaster HybProbe (Roche Diagnostic, GmBH, Mannheim, Germany) on a LightCycler 2.0 instrument.
Two SNPs, rs1801026 and rs16260, were significantly different between the control and LA groups. The combinatorial effects of the three SNPs were also significant. The haplotypes G-T-C and GA-T-A increased the development of LA-PVWM (OR = 1.76 and OR = 40.7, respectively). The haplotypes G-T-A and GA-T-A increased the development of LA-DWM (OR = 2.56 and OR = 10.48, respectively), but G-C-C decreased the development of LA-DWM (OR = 17.57).
This study provides evidence for genetic polymorphisms of the AJ component cadherin gene and the association of its haplotypes with LA.
Association between Homocysteine and Cerebral Small Vessel Disease: A Meta-Analysis
2018, Journal of Stroke and Cerebrovascular Diseases
Citation Excerpt :
Two-sided P values less than .05 were considered as a statistical significance. The initial search identified 424 possible studies after screening abstracts, and 26 studies were considered eligible after a detailed review, but 8 were excluded because of overlapping, resulting in 18 studies,14-31 involving 5088 participants (1987 patients with CSVD and 3101 controls), for inclusion in this meta-analysis (Fig 1). Of the included studies, 6 reported SBI type,14-19 8 reported WML type,20-26 2 reported LI type,27,28 1 reported CMB type,21 and 3 have no specific CSVD subtypes.29-31
This study aimed to evaluate whether elevated homocysteine levels is associated with risk of different subtypes of cerebral small vessel disease (CSVD) by using meta-analysis.
Electronic databases were systematically searched up to April 2018 for collecting the studies reporting homocysteine levels in CSVD or CSVD subtypes. After an inclusion and exclusion criteria, the data was extracted. All data was analyzed using Stata software v.12.0 (Stata Corp LP, College Station, TX). The standardized mean difference (SMD) and 95% confidence interval (CI) were used to compare continuous variables.
Eighteen studies met eligibility criteria with 5088 participants (1987 patients with CSVD and 3101 controls) included in the meta-analysis. Meta-analysis revealed that, compared with the controls group, the CSVD group had significantly higher homocysteine levels, with the SMD of .50 and 95% CI (.36-.64). Subgroup analyses suggested white matter lesion had significantly higher levels of homocysteine compared with controls (SMD = .56, 95% CI .39-.73), followed by silent brain infarction (SMD = .33, 95% CI .24-.42) and lacunar infarction (SMD = .17, 95% CI −.06 to .40).
This meta-analysis found that CSVD or CSVD subtypes have a significantly higher homocysteine levels than in controls. Further prospective population-based studies are needed to longitudinally evaluate the association between homocysteine levels and progression of different CSVD subtypes.
Homocysteine and cognition: A systematic review of 111 studies
2016, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
Conversely, another study showed a significant inverse relationship between the plasma Hcy levels and MMSE scores (Tay et al., 2006). One study using a case-control design found that the Hcy levels were strongly correlated with cognitive decline in patients with small vessel disease (Pavlovic et al., 2011). The controversies persisted in two cohort studies of populations with cerebrovascular diseases.
Elevated plasma homocysteine (Hcy) levels have been associated with cognitive dysfunction in a wide range of conditions. The aim of this review is to establish which cognitive domains and populations are the most affected.
We systematically review the literature and consider all articles that showed any relationship between plasma Hcy levels and scores achieved on cognitive performance tests in both, the general population and patients suffering from central nervous system disorders and other diseases. When effect sizes were available and combinable, several meta-analyses were performed.
We found 111 pertinent articles. There were 24 cohort studies, 18 randomized trials, 21 case-control studies, and 48 cross-sectional studies. This review reveals a positive trend between cognitive decline and increased plasma Hcy concentrations in general population and in patients with cognitive impairments. Results from the meta-analyses also confirm this trend. Treatment with vitamin supplementation fails to show a reduction in cognitive decline.
Further investigations are warranted to clarify this relationship. Earlier detection of the elevated Hcy levels may be an effective intervention to prevent cognitive impairment and dementia.
Association of rs2075575 and rs9951307 polymorphisms of aqp-4 gene with leukoaraiosis
2014, Journal of Stroke and Cerebrovascular Diseases
Citation Excerpt :
Hcy inhibits angiogenesis in vitro and in vivo.21 Several studies have found an association between cerebral white matter lesions and Hcy.22-28 We also found that Hcy was significantly associated with the different genotypes of AQP-4 rs9951307 (P = .031), whereas AQP-4 rs2075575 CT + TT genotypes were marginally significantly associated with Hcy (OR = 2.02, 95% CI = .96-4.22, P = .07), suggesting that AQP-4 polymorphisms may be weakly associated with Hcy levels in the Korean population.
Leukoaraiosis (LA) is associated with structural and functional vascular changes that correlate with motor and gait disturbances, depressive symptoms, urinary disturbances, and dementia. The blood–brain barrier (BBB) plays a key role in development of lacunar stroke, leukoaraiosis, and other feature of cerebral small-vessel disease, and there are numerous studies examining changes in the BBB with normal aging and in dementia and LA. Aquaporin-4 (AQP-4), the primary water channel protein in the central nervous system, is involved in BBB development, function, and integrity, and its dysfunction induces several neurologic diseases. The aim of our study was to evaluate whether genetic variations in AQP-4 gene are associated with the development of LA.
DNA was amplified and the single-nucleotide polymorphisms in AQP-4 gene were investigated by melting curve analysis using real-time polymerase chain reaction.
The frequency of both T allele and CT/TT genotypes of rs2075575 was significantly higher in LA group than in control group (C versus T, P = .0145; CC versus CT/TT, P = .038). However, no significant difference was observed between LA group and control group in rs9951307. Interestingly, the rs9951307 AG + GG genotype may confer a synergistic effect in odds ratio (OR) values when combined with the rs2075575 CT + TT genotypes (OR = 1.65 → 2.51). The C-A haplotype was significantly different between LA group and the control group (P = .005). By stratified analysis, rs2075575 and rs9951307 polymorphisms were statistically significant in the subjects with hypertension and hemoglobin A1c (P < .05), whereas the rs2075575 polymorphism was associated with high serum cholesterol (P < .05) and the rs9951307 polymorphism was associated with low serum homocysteine (P < .05).
Our results indicate that AQP-4 genetic variations and haplotypes might contribute to the risk factors for LA.

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Increased total homocysteine level is associated with clinical status and severity of white matter changes in symptomatic patients with subcortical small vessel disease

Abstract

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Subjects

Results

Discussion

Conflicts of interest/disclosures

Acknowledgements

Thromb Res

J Neurol Sci

J Neurol Sci

Arch Med Res

J Stroke Cerebrovasc Dis

J Psychiatr Res

Am J Clin Nutr

Neurobiol Aging

J Neurol Sci

J Neurol Sci

Biomed Pharmacother

Neurobiol Aging

Arch Gerontol Geriatr Suppl

A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes

JAMA

Stroke

Endothelial dysfunction in lacunar stroke: a systematic review

Cerebrovasc Dis

Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction

Brain

Hyperhomocysteinemia is associated with volumetric white matter change in patients with small vessel disease

J Neurol

Association between cholesterols, homocysteine and silent brain infarcts

Intern Med J

Homocysteine, silent brain infarcts, and white matter lesions: the Rotterdam Scan Study

Ann Neurol

Elevated plasma homocysteine levels and risk of silent brain infarction in elderly people

Stroke

Plasma total homocysteine levels and cranial magnetic resonance imaging findings in elderly persons. The Cardiovascular Health Study

Arch Neurol

Homocysteine, white matter hyperintensities, and cognition in healthy elderly people

Ann Neurol