Quantifying blood‐brain barrier leakage in small vessel disease: Review and consensus recommendations

Thrippleton, Michael J.; Backes, Walter H.; Sourbron, Steven; Ingrisch, Michael; Osch, Matthias J.P. van; Dichgans, Martin; Fazekas, Franz; Ropele, Stefan; Frayne, Richard; Oostenbrugge, Robert J. van; Smith, Eric E.; Wardlaw, Joanna M.

doi:10.1016/j.jalz.2019.01.013

Cited by 145 publications

(195 citation statements)

References 88 publications

(182 reference statements)

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“…Exactly what DTI free water is measuring in tissue is unknown, however one hypothesis is that excess extracellular fluid results from blood-brain barrier leakage with leaking serum proteins damaging myelin and axons. Leakage of the blood-brain barrier is proposed to play a central role in the pathogenesis of cSVD with increased contrast-enhancement within T2/FLAIR white matter hyperintensities compared to normal appearing white matter using dynamic contrast enhanced MRI (DCE-MRI) techniques [60,61]. In a population of recent lacunar stroke patients, blood-brain barrier leakage within white matter was also associated with impaired cognition at 1 year.…”

Section: Fig 5 Ics Increases With Vascular Risk Factorsmentioning

confidence: 99%

An IL-18-centered inflammatory network as a biomarker for cerebral white matter injury

et al. 2020

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Chronic systemic sterile inflammation is implicated in the pathogenesis of cerebrovascular disease and white matter injury. Non-invasive blood markers for risk stratification and dissection of inflammatory molecular substrates in vivo are lacking. We sought to identify whether an interconnected network of inflammatory biomarkers centered on IL-18 and all previously associated with white matter lesions could detect overt and antecedent white matter changes in two populations at risk for cerebral small vessel disease. In a cohort of 167 older adults (mean age: 76, SD 7.1, 83 females) that completed a cognitive battery, physical examination, and blood draw in parallel with MR imaging including DTI, we measured cerebral white matter hyperintensities (WMH) and free water (FW). Concurrently, serum levels of a biologic network of inflammation molecules including MPO, GDF-15, RAGE, ST2, IL-18, and MCP-1 were measured. The ability of a log-transformed population mean-adjusted inflammatory composite score (ICS) to associate with MR variables was demonstrated in an age and total intracranial volume adjusted model. In this cohort, ICS was significantly associated with WMH (β = 0.222, p = 0.013), FW (β = 0.3, p = 0.01), and with the number of vascular risk factor diagnoses (r = 0.36, p<0.001). In a second cohort of 131 subjects presenting for the evaluation of acute neurologic deficits concerning for stroke, we used serum levels of 11 inflammatory biomarkers in an unbiased principal component analysis which identified a single factor significantly associated with WMH. This single factor was strongly correlated with the six component ICS identified in the first cohort and was associated with WMH in a generalized linear regression model adjusted for age and gender (p = 0.027) but not acute stroke. A network of inflammatory molecules driven by IL-18

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Section: Fig 5 Ics Increases With Vascular Risk Factorsmentioning

confidence: 99%

An IL-18-centered inflammatory network as a biomarker for cerebral white matter injury

et al. 2020

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“…Certain features are less commonly reported; however, PVS were only recently identified clinically and appear on histology in pericyte-deficient mice [19]. Therefore, optimised parameters enhancing visibility of disease-related features should be used and standardised where possible (https:// harness-neuroimaging.org/) [4]. Translational SVD research must account for practical differences.…”

Section: Structural Mri In Rodents and Humansmentioning

confidence: 99%

“…MRI, contrast-enhanced CT (CE-CT), PET and biofluid biomarker approaches can measure BBB permeability [4]. MRI methods include dynamic or static contrast-enhanced MRI [4,11] and non-contrast-based methods (e.g. ASL [108,109] and T1-w black-blood imaging [110]).…”

Section: Blood-brain Barrier Impairmentmentioning

confidence: 99%

“…Magnetic resonance imaging (MRI) is used extensively in clinics and research to identify SVD-associated lesions and imaging biomarkers. Key SVD-related features, image acquisition and quantification methods are summarised in recent position papers [3,4].…”

Section: Introductionmentioning

confidence: 99%

“…Resting CBF can be measured by dynamic susceptibility contrast (DSC), arterial spin labelling (ASL) and phase contrast MRI (PC-MRI). Dynamic contrast-enhanced (DCE) MRI using intravenous injection of gadolinium (Gd) contrast [9] shows increased BBB permeability in SVD [4,[10][11][12]. Magnetic resonance spectroscopy (MRS) detects neuro-metabolite changes, including evidence of axonal loss/disruption [13,14].…”

Section: Introductionmentioning

confidence: 99%

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A Review of Translational Magnetic Resonance Imaging in Human and Rodent Experimental Models of Small Vessel Disease

Stringer

Lee

Huuskonen

et al. 2020

Transl. Stroke Res.

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Cerebral small vessel disease (SVD) is a major health burden, yet the pathophysiology remains poorly understood with no effective treatment. Since much of SVD develops silently and insidiously, non-invasive neuroimaging such as MRI is fundamental to detecting and understanding SVD in humans. Several relevant SVD rodent models are established for which MRI can monitor in vivo changes over time prior to histological examination. Here, we critically review the MRI methods pertaining to salient rodent models and evaluate synergies with human SVD MRI methods. We found few relevant publications, but argue there is considerable scope for greater use of MRI in rodent models, and opportunities for harmonisation of the rodent-human methods to increase the translational potential of models to understand SVD in humans. We summarise current MR techniques used in SVD research, provide recommendations and examples and highlight practicalities for use of MRI SVD imaging protocols in pre-selected, relevant rodent models.

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Framework for Clinical Trials in Cerebral Small Vessel Disease (FINESSE)

et al. 2022

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ImportanceCerebral small vessel disease (SVD) causes a quarter of strokes and is the most common pathology underlying vascular cognitive impairment and dementia. An important step to developing new treatments is better trial methodology. Disease mechanisms in SVD differ from other stroke etiologies; therefore, treatments need to be evaluated in cohorts in which SVD has been well characterized. Furthermore, SVD itself can be caused by a number of different pathologies, the most common of which are arteriosclerosis and cerebral amyloid angiopathy. To date, there have been few sufficiently powered high-quality randomized clinical trials in SVD, and inconsistent trial methodology has made interpretation of some findings difficult.ObservationsTo address these issues and develop guidelines for optimizing design of clinical trials in SVD, the Framework for Clinical Trials in Cerebral Small Vessel Disease (FINESSE) was created under the auspices of the International Society of Vascular Behavioral and Cognitive Disorders. Experts in relevant aspects of SVD trial methodology were convened, and a structured Delphi consensus process was used to develop recommendations. Areas in which recommendations were developed included optimal choice of study populations, choice of clinical end points, use of brain imaging as a surrogate outcome measure, use of circulating biomarkers for participant selection and as surrogate markers, novel trial designs, and prioritization of therapeutic agents using genetic data via Mendelian randomization.Conclusions and RelevanceThe FINESSE provides recommendations for trial design in SVD for which there are currently few effective treatments. However, new insights into understanding disease pathogenesis, particularly from recent genetic studies, provide novel pathways that could be therapeutically targeted. In addition, whether other currently available cardiovascular interventions are specifically effective in SVD, as opposed to other subtypes of stroke, remains uncertain. FINESSE provides a framework for design of trials examining such therapeutic approaches.

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Quantifying blood‐brain barrier leakage in small vessel disease: Review and consensus recommendations

Cited by 145 publications

References 88 publications

An IL-18-centered inflammatory network as a biomarker for cerebral white matter injury

An IL-18-centered inflammatory network as a biomarker for cerebral white matter injury

A Review of Translational Magnetic Resonance Imaging in Human and Rodent Experimental Models of Small Vessel Disease

Framework for Clinical Trials in Cerebral Small Vessel Disease (FINESSE)

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