Is Breakdown of the Blood-Brain Barrier Responsible for Lacunar Stroke, Leukoaraiosis, and Dementia?

Wardlaw, Joanna M.; Sandercock, Peter; Dennis, Martin; Starr, John M.

doi:10.1161/01.str.0000058480.77236.b3

Cited by 560 publications

(474 citation statements)

References 66 publications

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“…Blood-brain barrier breakdown may lead to ischemia, leukoaraiosis, and lacunar infarcts. 45 Mild chronic hypertension may damage cerebrovascular endothelium in small vessels leading to thickening of the arterial wall and narrowing of the lumen, resulting in ischemia (leukoaraiosis if ischemia occurs in white matter) or infarction. Alternatively, the damage to the arterial wall may progress, causing disintegration and a leak of blood.…”

Section: Blood-brain Barrier Dysfunctionmentioning

confidence: 99%

“…Alternatively, the damage to the arterial wall may progress, causing disintegration and a leak of blood. 45 Blood-brain barrier leakage may be visualized as an increase in vessel permeability using dynamic contrast enhanced MRI 46 or as small areas of low signal on T2*-weighted magnetic resonance images that may be deposits of hemosiderin, a breakdown product of hemoglobin, usually indicating a brain microbleed. 47 Blood-brain barrier dysfunction is certainly described as a consequence of seizures, but given that BBB opening is also recognized to promote seizures in humans, and the association of BBB dysfunction with CVD, this is likely to represent an area worthy of further investigation in the clinical context.…”

Section: Blood-brain Barrier Dysfunctionmentioning

confidence: 99%

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Late-Onset Epilepsy and Occult Cerebrovascular Disease

Gibson

Hanby

Al–Bachari

et al. 2014

J Cereb Blood Flow Metab

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The interface between cerebrovascular disease (CVD) and epilepsy is complex and multifaceted. Late-onset epilepsy (LOE) is increasingly common and is often attributed to CVD, and is indeed associated with an increased risk of stroke. This relationship is easily recognizable where there is a history of stroke, particularly involving the cerebral cortex. However, the relationship with otherwise occult, subcortical CVD is currently less well established yet causality is often invoked. In this review, we consider the diagnosis of LOE in clinical practice-including its behaviour as a potential mimic of acute ischemic stroke and transient ischemic attack; evidence for an association between occult CVD and LOE; and potential mechanisms of epileptogenesis in occult CVD, including potential interrelationships between disordered cerebral metabolism and perfusion, disrupted neurovascular unit integrity, blood-brain barrier dysfunction, and inflammation. We also discuss recently recognized issues concerning antiepileptic drug treatment and vascular risk and consider a variety of less common CVD entities associated with seizures.

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Section: Blood-brain Barrier Dysfunctionmentioning

confidence: 99%

Section: Blood-brain Barrier Dysfunctionmentioning

confidence: 99%

Late-Onset Epilepsy and Occult Cerebrovascular Disease

Gibson

Hanby

Al–Bachari

et al. 2014

J Cereb Blood Flow Metab

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“…As noted above, the incidence of stroke in hemodialysis patients is at least 15 percent. Systemic microvascular disease due to diabetes, hypertension, and elevated inflammatory factors involving both the renal and cerebral vasculature are a potential uniting mechanism in the natural history of cognitive impairment in CKD and hemodialysis patients (62,63,65). It may be helpful to use the paradigm of end-organ disease to describe a model of vascular cognitive impairment in CKD and dialysis patients.…”

Section: The Pathophysiology Of Cognitive Impairment In Hemodialysis mentioning

confidence: 99%

“…In the kidney as end-organ, microvascular disease is manifested by nephrosclerosis, secondary leaky glomeruli and proteinuria. With the brain as end-organ, disruption of the blood/brain barrier due to microvascular disease may play an analogous role, with damaged vascular endothelial tight junctions causing leakage of protein, potentially contributing to white matter disease and pre-amyloid oligomers (62,71,72).…”

Section: The Pathophysiology Of Cognitive Impairment In Hemodialysis mentioning

confidence: 99%

Cognitive Impairment in the Aging Dialysis and Chronic Kidney Disease Populations: An Occult Burden

Murray

2008

Advances in Chronic Kidney Disease

346

241

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The heavy burden of cognitive impairment in hemodialysis and chronic kidney disease patients has only recently become recognized. Up to 70 percent of hemodialysis patients ages 55 years and older have moderate to severe chronic cognitive impairment, yet it is largely undiagnosed. Recent studies describe the strong graded relation between estimated glomerular filtration rate (eGFR) and cognitive function in CKD patients. The process of conventional hemodialysis may induce recurrent episodes of acute cerebral ischemia, which in turn may contribute to acute decline in cognitive function during dialysis. Thus the worst time to communicate with dialysis patients may be during the hemodialysis session. Both symptomatic and occult, subclinical ischemic cerebrovascular disease appear to play a large role in a proposed model of accelerated vascular cognitive impairment in these populations. Severe cognitive impairment or dementia among hemodialysis patients is associated with an approximately two-fold increased risk of both mortality and dialysis withdrawal. Pre-dialysis cognitive screening and adding dementia to the list of comorbidities on Form 2728 would provide critical information regarding the benefit versus risks of receiving dialysis. It could also improve quality of care and outcomes by raising clinician's awareness of the potential effects of cognitive impairment on medication, fluid, and dietary compliance, and ability to make advance directive decisions among dialysis patients. While much remains to be learned regarding the pathophysiology of cognitive impairment in kidney disease, the public health implications of this substantial burden are immediate.

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“…For example, TJ disruptions and subsequent BBB perturbations are involved in the development of MS (Kirk et al, 2003;Neuwelt, 2004), while ischemic stroke and traumatic brain injury lead to BBB perturbations (Ilzecka, 1996;Morganti-Kossmann et al, 2001). There are many diseases, such as Alzheimer's disease, where the direct correlation is not yet known, but are currently being investigated (Wardlaw et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Biphasic cytoarchitecture and functional changes in the BBB induced by chronic inflammatory pain

et al. 2006

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The blood-brain barrier (BBB) is a dynamic system which maintains brain homeostasis and limits CNS penetration via interactions of transmembrane and intracellular proteins. Inflammatory pain (IP) is a condition underlying several diseases with known BBB perturbations, including stroke, Parkinson's, multiple sclerosis and Alzheimer's. Exploring the underlying pathology of chronic IP, we demonstrated alterations in BBB paracellular permeability with correlating changes in tight junction (TJ) proteins: occludin and claudin-5. The present study examines the IP-induced molecular changes leading to a loss in functional BBB integrity. IP was induced by injection of Complete Freund's Adjuvant (CFA) into the plantar surface of the right hindpaw of female Sprague-Dawley rats. Inflammation and hyperalgesia were confirmed, and BBB paracellular permeability was assessed by in situ brain perfusion of [ 14 C]sucrose (paracellular diffusion marker). The permeability of the BBB was significantly increased at 24 and 72 h post-CFA. Analysis of the TJ proteins, which control the paracellular pathway, demonstrated decreased claudin-5 expression at 24 h, and an increase at 48 and 72 h post-injection. Occludin expression was significantly decreased 72 h post-CFA. Expression of junction adhesion molecule-1 (JAM-1) increased 48 h and decreased by 72 h post-CFA. Confocal microscopy demonstrated continuous expression of both occludin and JAM-1, each co-localizing with ZO-1. The increased claudin-5 expression was not limited to the junction. These results provide evidence that chronic IP causes dramatic alterations in specific cytoarchitectural proteins and demonstrate alterations in molecular properties during CFA, resulting in significant changes in BBB paracellular permeability.

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Is Breakdown of the Blood-Brain Barrier Responsible for Lacunar Stroke, Leukoaraiosis, and Dementia?

Abstract: Proof that blood-brain barrier failure is key to these conditions could provide a target for new treatments to reduce the effects of vascular disease on the brain and prevent cognitive decline and dementia.

Cited by 560 publications

References 66 publications

Late-Onset Epilepsy and Occult Cerebrovascular Disease

Late-Onset Epilepsy and Occult Cerebrovascular Disease

Cognitive Impairment in the Aging Dialysis and Chronic Kidney Disease Populations: An Occult Burden

Biphasic cytoarchitecture and functional changes in the BBB induced by chronic inflammatory pain

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