Homocysteine and Its Relationship to Stroke Subtypes in a UK Black Population

Crossley, Carollyn; Kalra, Lalit; Rudd, Anthony; Wolfe, Charles D.A.; Collinson, Paul; Markus, Hugh S.

doi:10.1161/strokeaha.107.513416

Cited by 75 publications

(58 citation statements)

References 37 publications

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“…40 Several laboratories have uncovered a specific association between HHcy and the lacunar subtype of stroke. [41][42][43] Disruption of the BBB in rodents 44,45 and humans 46 is among the most striking homeostatic disturbances caused by Hcy (vascular complications of HHcy 5,6 ). There is a growing recognition that lacunar strokes may result from reduced BBB integrity.…”

Section: Discussionmentioning

confidence: 99%

Hyperhomocysteinemia increases permeability of the blood-brain barrier by NMDA receptor-dependent regulation of adherens and tight junctions

Beard

Reynolds

Bearden

2011

Blood

135

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IntroductionMicrovessels are responsible for facilitating the exchange of nutrients between blood and tissue while maintaining a barrier against the undesired movement of other molecules. This barrier is most finely tuned and structurally competent at the interface between the blood and the brain, the blood-brain barrier (BBB). The BBB is formed by intercellular junctions that limit paracellular diffusion combined with a low-flux transcellular system that selectively transports molecules either into or out of the brain parenchyma. Increasing evidence implicates chronic BBB permeability in the onset of neurologic and neurovascular diseases (eg, Alzheimer disease, dementia, small-vessel disease, stroke). 1 Although the BBB prevents the flux of harmful substances into the brain, it can also exclude the delivery of therapeutic drugs. Understanding the molecular regulation of the BBB is therefore important for the understanding of disease etiology and treatment.Paracellular diffusion of molecules at the BBB is minimized by endothelial cell-cell (EC-EC) junctions. Chief among these are the adherens junctions and tight junctions, of which vascularendothelial cadherin (VE-cadherin; VEC) and claudin-5 are wellknown members, respectively. Although VEC is endothelial specific, the claudin family of proteins is found in many epithelial tissues. However, claudin-5 is specific to tight junctions of ECs and is required to block paracellular diffusion of small molecules (Ͻ ϳ 800 Da) in the microvasculature of the brain. 2 In particular, claudin-5 is now recognized as the predominant claudin isoform in tight junctions of the BBB. Although claudins 1, 10, 11, and 12 (at least) are also expressed in brain endothelium, claudin-5 mRNA is nearly 600-fold higher than the other claudins expressed in microvascular ECs freshly isolated from the brain. 3 On electron microscopy, plasma membranes of adjacent cells associate close enough to merge without apparent intercellular space at tight junctions. 4 Homocysteine (Hcy) is an intermediate aminothiol derived from methionine catabolism, and its elevation in plasma, known as hyperhomocysteinemia (HHcy), is a chronic condition associated with cerebral small-vessel disease, stroke, and dementia (Alzheimer and vascular). 5,6 The list of Hcy-mediated vasculopathies is still growing but includes endothelial dysfunction, vessel wall malformations, loss of extracellular matrix collagen, and loosening of the BBB in rodents and humans. 5,6 Mounting evidence suggests that an increase in BBB permeability is an important factor in initiating cerebral small-vessel disease and lacunar stroke. 7,8 Hence, identifying the mechanisms by which HHcy opens the BBB is of great clinical interest. We reported that treating human umbilical vein ECs with Hcy increases EC monolayer permeability and decreases expression of claudin-5. 9 However, the mechanism by which Hcy triggers these events has not been elucidated, and the intracellular mechanisms for decreased expression of claudin-5 in HHcy are unknown.Recently, a ...

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Section: Discussionmentioning

confidence: 99%

Hyperhomocysteinemia increases permeability of the blood-brain barrier by NMDA receptor-dependent regulation of adherens and tight junctions

Beard

Reynolds

Bearden

2011

Blood

135

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“…We recorded method of stroke diagnosis, criteria/system used for stroke subtyping, details of imaging, definition of lacunar stroke and the grade of clinician involved in the stroke diagnosis. We contacted one author [9] to clarify time of blood draw. Some studies drew blood at multiple time points.…”

Section: Methodsmentioning

confidence: 99%

Blood Markers of Coagulation, Fibrinolysis, Endothelial Dysfunction and Inflammation in Lacunar Stroke versus Non-Lacunar Stroke and Non-Stroke: Systematic Review and Meta-Analysis

et al. 2013

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Background: The cause of cerebral small vessel disease is not fully understood, yet it is important, accounting for about 25% of all strokes. It also increases the risk of having another stroke and contributes to about 40% of dementias. Various processes have been implicated, including microatheroma, endothelial dysfunction and inflammation. A previous review investigated endothelial dysfunction in lacunar stroke versus mostly non-stroke controls while another looked at markers of inflammation and endothelial damage in ischaemic stroke in general. We have focused on blood markers between clinically evident lacunar stroke and other subtypes of ischaemic stroke, thereby controlling for stroke in general. Summary: We systematically assessed the literature for studies comparing blood markers of coagulation, fibrinolysis, endothelial dysfunction and inflammation in lacunar stroke versus non-stroke controls or other ischaemic stroke subtypes. We assessed the quality of included papers and meta-analysed results. We split the analysis on time of blood draw in relation to the stroke. We identified 1,468 full papers of which 42 were eligible for inclusion, including 4,816 ischaemic strokes, of which 2,196 were lacunar and 2,500 non-stroke controls. Most studies subtyped stroke using TOAST. The definition of lacunar stroke varied between studies. Markers of coagulation/fibrinolysis (tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI), fibrinogen, D-dimer) were higher in lacunar stroke versus non-stroke although fibrinogen was no different to non-stroke in the acute phase. tPA and PAI were no different between lacunar and non-lacunar stroke. Fibrinogen and D-dimer were significantly lower in lacunar stroke compared to other ischaemic strokes, both acutely and chronically. Markers of endothelial dysfunction (homocysteine, von Willebrand Factor (vWF), E-selectin, P-selectin, intercellular adhesion molecule-1 (ICAM), vascular cellular adhesion molecule-1 (VCAM)) were higher or had insufficient or conflicting data (P-selectin, VCAM) in lacunar stroke versus non-stroke. Compared to other ischaemic stroke subtypes, homocysteine did not differ in lacunar stroke while vWF was significantly lower in lacunar stroke acutely [atherothrombotic standardized mean difference, SMD, -0.34 (-0.61, -0.08); cardioembolic SMD -0.38 (-0.62, -0.14)], with insufficient data chronically. Markers of inflammation (C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6)) were higher in lacunar stroke versus non-stroke, although there were no studies measuring TNF-α chronically and the sole study measuring IL-6 chronically showed no difference between lacunar stroke and non-stroke. Compared to other ischaemic stroke subtypes, there was no difference (CRP) or insufficient or conflicting data (TNF-α) to lacunar stroke. IL-6 was significantly lower [atherothrombotic SMD -0.37 (-0.63, -0.10); cardioembolic SMD -0.52 (-0.82, -0.22)] in lacunar stroke acutely, with insufficient data chronically. Key Messages: ...

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“…A recent study confirmed the association between HHcy and stroke in a black population, and a strong association was detected with lacunar infarction with leukoaraiosis compared with those without such an infection. 19 The risk of stroke increased by 6-7% in the Rotterdam Scan Study for each 1µmol/l increase in plasma Hcy concentration. 20 Moreover, a graded positive association was also shown between concentrations of Hcy and the risk of stroke in the British Regional Heart Study.…”

Section: Homocysteine In Cerebrovascular Diseasesmentioning

confidence: 97%

Evaluation of the Current Evidence on Hyperhomocysteinemia in Neurological Diseases

Obeid¹,

Faßbender²,

Herrmann³

2008

US Neurology

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Homocysteine (Hcy) is the demethylated product of methionine. This toxic amino acid can be removed by remethylation to methionine via methionine synthase, which utilizes 5-methyl tetrahydrofolate as a methyl donor and methyl cobalamin as a co-factor. An alternative remethylation pathway for Hcy depends on betaine-Hcy-methyltransferase, which utilizes betaine as a methyl donor. Another method of Hcy catabolism is via two vitamin-B 6 -dependent enzymes, cystathionine beta synthase and cystathioninase, to cysteine. subjects 70-79 years of age were followed for a mean of seven years. The

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Homocysteine and Its Relationship to Stroke Subtypes in a UK Black Population

Cited by 75 publications

References 37 publications

Hyperhomocysteinemia increases permeability of the blood-brain barrier by NMDA receptor-dependent regulation of adherens and tight junctions

Hyperhomocysteinemia increases permeability of the blood-brain barrier by NMDA receptor-dependent regulation of adherens and tight junctions

Blood Markers of Coagulation, Fibrinolysis, Endothelial Dysfunction and Inflammation in Lacunar Stroke versus Non-Lacunar Stroke and Non-Stroke: Systematic Review and Meta-Analysis

Evaluation of the Current Evidence on Hyperhomocysteinemia in Neurological Diseases

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