MINocyclinE to Reduce inflammation and blood brain barrier leakage in small Vessel diseAse (MINERVA) trial study protocol
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ABSTRACT: Background:
Cerebral small vessel disease (SVD) is a common cause of stroke and cognitive
SUBMITTER: Brown R
PROVIDER: S-EPMC9445404 | biostudies-literature | 2022 May
REPOSITORIES: biostudies-literature
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Project description:ObjectiveIn patients with acute ischemic stroke, we aimed to investigate the relation between preexisting small vessel disease (SVD) and the amount of blood-brain barrier (BBB) leakage in ischemic and nonischemic area before IV thrombolysis.MethodsWe retrospectively accessed anonymous patient-level data from the Stroke Imaging Repository and the Virtual International Stroke Trials Archive resources and included patients treated with IV thrombolysis with pretreatment MRI. We rated SVD features using validated qualitative magnetic resonance (MR) scales. Leakage of BBB was assessed with postprocessing of perfusion-weighted images. We evaluated associations between SVD features (individually and summed in a global SVD score) and BBB leakage using linear regression analysis, adjusting for major clinical confounders.ResultsA total of 212 patients, mean age (±SD) 69.5 years (±16.1), 102 (48%) male, had available MR before IV thrombolysis. Evidence of BBB leakage was present in 175 (80%) and 205 (94%) patients in the ischemic and nonischemic area, respectively. Lacunar infarcts (β = 0.17, p = 0.042) were associated with BBB leakage in the ischemic area, and brain atrophy was associated with BBB leakage in both ischemic (β = 0.20, p = 0.026) and nonischemic (β = 0.27, p = 0.001) areas. Increasing SVD grade was independently associated with BBB leakage in both ischemic (β = 0.26, p = 0.007) and nonischemic (β = 0.27, p = 0.003) area.ConclusionsGlobal SVD burden is associated with increased BBB leakage in both acutely ischemic and nonischemic area. Our results support that SVD score has construct validity, and confirm a relation between SVD and BBB disruption also in patients with acute stroke.
| S-EPMC5696647 | biostudies-literature
Project description:BackgroundBlood-brain barrier (BBB) damage is considered an important part of Alzheimer's disease (AD) progression, and cerebral small-vessel disease (CSVD) is commonly associated with AD. However, the relationship between BBB damage, small cerebrovascular lesions, especially cerebral microbleeds (CMBs), and amyloid and tau biomarkers remains controversial. Therefore, our study aimed to further investigate their association in our cohort of patients with AD.MethodsA total of 139 individuals were divided into probable AD (18F-florbetapir PET positive, n = 101) and control group (cognitively normal, n = 38). The levels of cerebrospinal fluid (CSF) and plasma t-tau, p-tau181, Aβ40, Aβ42, and albumin were measured using corresponding commercial assay kits, and the CSF/plasma albumin ratio (Qalb), an indicator of BBB dysfunction, was calculated. CSVD burden and the number of CMBs were defined using magnetic resonance imaging.ResultsPatients with AD had higher Qalb (p = 0.0024), higher numbers of CMBs (p = 0.03), and greater CSVD burden (p < 0.0001). In the AD group, CMBs and CSVD correlated with a higher Qalb (p = 0.03), and the numbers of CMBs negatively correlated with CSF Aβ42 (p = 0.02).ConclusionBlood-brain barrier damage was accompanied by a more severe burden of CSVD, including CMB, in patients with AD.
| S-EPMC9978776 | biostudies-literature
Project description:Blood-brain barrier (BBB) is known to be impaired in cerebral small vessel disease (SVD), and is measurable by dynamic-contrast enhancement (DCE)-MRI. In a cohort of 69 patients (42 sporadic, 27 monogenic SVD), who underwent 3T MRI, including DCE and cerebrovascular reactivity (CVR) sequences, we assessed the relationship of BBB-leakage hotspots to SVD lesions (lacunes, white matter hyperintensities (WMH), and microbleeds). We defined as hotspots the regions with permeability surface area product highest decile on DCE-derived maps within the white matter. We assessed factors associated with the presence and number of hotspots corresponding to SVD lesions in multivariable regression models adjusted for age, WMH volume, number of lacunes, and SVD type. We identified hotspots at lacune edges in 29/46 (63%) patients with lacunes, within WMH in 26/60 (43%) and at the WMH edges in 34/60 (57%) patients with WMH, and microbleed edges in 4/11 (36%) patients with microbleeds. In adjusted analysis, lower WMH-CVR was associated with presence and number of hotspots at lacune edges, and higher WMH volume with hotspots within WMH and at WMH edges, independently of the SVD type. In conclusion, SVD lesions frequently collocate with high BBB-leakage in patients with sporadic and monogenic forms of SVD.
| S-EPMC10414006 | biostudies-literature
Project description:IntroductionThe INflammation and Small Vessel Disease (INSVD) study aims to investigate whether peripheral inflammation, immune (dys)regulation and blood-brain barrier (BBB) permeability relate to disease progression in cerebral small vessel disease (SVD). This research aims to pinpoint specific components of the immune response in SVD relating to disease progression. This could identify biomarkers of SVD progression, as well as potential therapeutic targets to inform the development and repurposing of drugs to reduce or prevent SVD, cognitive decline and vascular dementia.Methods and analysisINSVD is a prospective observational multicentre cohort study in individuals with symptomatic SVD. This longitudinal study combines comprehensive immunophenotyping of the peripheral blood immune compartment with advanced neuroimaging markers of SVD and BBB permeability. The main SVD marker of interest is white matter microstructure as determined by diffusion tensor imaging, a valuable marker of disease progression owing to its sensitivity to early alterations to white matter integrity. The research is being conducted in two sites-in the UK (Cambridge) and the Netherlands (Nijmegen)-with each site recruiting 100 participants (total n=200). Participants undergo clinical and cognitive assessments, blood draws, and brain MRI at baseline and 2-year follow-up.Ethics and disseminationThis study received ethical approval from the local ethics boards (UK: East of England-Cambridge Central Research Ethics Committee (REC) ref: 22/EE/00141, Integrated Research Application System (IRAS) ID: 312 747. Netherlands: Medical Research Ethics Committee (MREC) Oost-Nederland, ref: 2022-13623, NL-number: NL80258.091.22). Written informed consent was obtained from all subjects before the study. Any participant-derived benefits resulting from this research, such as new insights into disease mechanisms or possible novel therapies, will be disseminated to study participants, patient groups and members of the public.Trial registration numberNCT05746221.
| S-EPMC10900331 | biostudies-literature
Project description:Blood-brain barrier (BBB) dysfunction is one of the pathophysiological mechanisms in cerebral small vessel disease (SVD). Previously, it was shown that BBB leakage volume is larger in patients with SVD compared with controls. In this study, we investigated the link between BBB leakage and cognitive decline over 2 years in patients with cSVD. At baseline, 51 patients with clinically overt cSVD (lacunar stroke or mild vascular cognitive impairment) received a dynamic contrast-enhanced MRI scan to quantify BBB permeability in the normal-appearing white matter (NAWM), white matter hyperintensities (WMH), cortical grey matter (CGM), and deep grey matter (DGM). Cognitive function in the domain executive function, information processing speed, and memory was measured in all patients at baseline and after 2 years. The association between baseline BBB leakage and cognitive decline over 2 years was determined with multivariable linear regression analysis, corrected for age, sex, educational level, baseline WMH volume, and baseline brain volume. Regression analyses showed that higher baseline leakage volume and rate in the NAWM and CGM were significantly associated with increased overall cognitive decline. Furthermore, higher baseline leakage volume in the NAWM and CGM, and higher baseline leakage rate in the CGM were significantly associated with increased decline in executive function. This longitudinal study showed that higher BBB leakage at baseline is associated with stronger cognitive decline, specifically in executive function, over 2 years of follow-up in patients with cSVD. These results emphasize the key role of BBB disruption in the pathophysiology and clinical progression of cSVD.
| S-EPMC8492799 | biostudies-literature
Project description:Blood-brain barrier (BBB) leakage increases with age and is involved in the pathophysiology of cerebral small vessel disease (cSVD). We examined the relationship between BBB leakage and white matter hyperintensity (WMH) volume and cognition, in cSVD patients and healthy controls. Seventy-seven patients with clinically overt cSVD and thirty-nine age matched healthy controls underwent dynamic contract-enhanced and structural brain MRI and neuropsychological assessment. We quantified BBB leakage volume and rate in normal appearing white matter (NAWM), WMH and cortical grey matter (CGM). Larger leakage volume and lower leakage rate in WMH were associated with larger WMH volume in cSVD but not in controls. Higher leakage rate in NAWM was associated with lower scores on executive function and information processing speed in healthy controls, whereas no relation with cognition was found in cSVD patients. Our findings support the involvement of BBB leakage in cSVD and aging. They also suggest that the mechanism of cognitive dysfunction in cSVD is more complex and multifactorial in cSVD compared with normal aging.
| S-EPMC6486901 | biostudies-literature
Project description:Abstract Cerebral amyloid angiopathy is a small vessel disease associated with cortical microbleeds and lobar intracerebral haemorrhage due to amyloid-β deposition in the walls of leptomeningeal and cortical arterioles. The mechanisms of cerebral amyloid angiopathy–related haemorrhage remain largely unknown. Recent work has demonstrated that ruptured blood vessels have limited (or no) amyloid-β at the site of bleeding and evidence of local vascular remodelling. We hypothesized that blood–brain barrier leakage and perivascular inflammation may be involved in this remodelling process. This study examined cortical arterioles at various stages of cerebral amyloid angiopathy–related vascular pathology (without evidence of microhaemorrhage) in autopsy tissue from seven cases with definite cerebral amyloid angiopathy. We included temporo-occipital sections with microbleeds guided by ex vivo MRI from two cases with severe cerebral amyloid angiopathy and systematically sampled occipital sections from five consecutive cases with varying cerebral amyloid angiopathy severity. Haematoxylin and eosin stains and immunohistochemistry against amyloid-β, fibrin(ogen), smooth muscle actin, reactive astrocytes (glial fibrillary acidic protein) and activated microglia (cluster of differentiation 68) were performed. Arterioles were graded using a previously proposed scale of individual vessel cerebral amyloid angiopathy severity, and a blinded assessment for blood–brain barrier leakage, smooth muscle actin and perivascular inflammation was performed. Blood–brain barrier leakage and smooth muscle actin loss were observed in significantly more vessels with mild amyloid-β deposition (Grade 1 vessels; P = 0.044 and P = 0.012, respectively) as compared to vessels with no amyloid-β (Grade 0), and blood–brain barrier leakage was observed in 100% of vessels with evidence of vessel remodelling (Grades 3 and 4). Perivascular inflammation in the form of reactive astrocytes and activated microglia was observed predominantly surrounding arterioles at later stages of vessel pathology (Grades 2–4) and consistently around vessels with the same morphological features as ruptured vessel segments (Grade 4). These findings suggest a role for blood–brain barrier leakage and perivascular inflammation leading to arteriolar remodelling and haemorrhage in cerebral amyloid angiopathy, with early blood–brain barrier leakage as a potential trigger for subsequent perivascular inflammation. Kozberg et al. examined blood–brain barrier leakage and perivascular inflammation at the individual vessel level in cerebral amyloid angiopathy. They report blood–brain barrier leakage at early stages of vascular pathology, a potential trigger for perivascular inflammation and vascular remodelling leading to haemorrhage. Graphical Abstract Graphical abstract
| S-EPMC9576155 | biostudies-literature
Project description:Subtle blood-brain barrier (BBB) permeability increases have been shown in small vessel disease (SVD) using various analysis methods. Following recent consensus recommendations, we used Patlak tracer kinetic analysis, considered optimal in low permeability states, to quantify permeability-surface area product (PS), a BBB leakage estimate, and blood plasma volume (vP) in 201 patients with SVD who underwent dynamic contrast-enhanced MRI scans. We ran multivariable regression models with a quantitative or qualitative metric of white matter hyperintensity (WMH) severity, demographic and vascular risk factors. PS increased with WMH severity in grey (B = 0.15, Confidence Interval (CI): [0.001,0.299], p = 0.049) and normal-appearing white matter (B = 0.015, CI: [-0.008,0.308], p = 0.062). Patients with more severe WMH had lower vP in WMH (B = -0.088, CI: [-0.138,-0.039], p < 0.001), but higher vP in normal-appearing white matter (B = 0.031, CI: [-0.004,0.065], p = 0.082). PS and vP were lower at older ages in WMH, grey and white matter. We conclude higher PS in normal-appearing tissue with more severe WMH suggests impaired BBB integrity beyond visible lesions indicating that the microvasculature is compromised in normal-appearing white matter and WMH. BBB dysfunction is an important mechanism in SVD, but associations with clinical variables are complex and underlying damage affecting vascular surface area may alter interpretation of tracer kinetic results.
| S-EPMC8607271 | biostudies-literature
Project description:AbstractCerebral small vessel disease is a neurological disease that affects the brain microvasculature and which is commonly observed among the elderly. Although at first it was considered innocuous, small vessel disease is nowadays regarded as one of the major vascular causes of dementia. Radiological signs of small vessel disease include small subcortical infarcts, white matter magnetic resonance imaging hyperintensities, lacunes, enlarged perivascular spaces, cerebral microbleeds, and brain atrophy; however, great heterogeneity in clinical symptoms is observed in small vessel disease patients. The pathophysiology of these lesions has been linked to multiple processes, such as hypoperfusion, defective cerebrovascular reactivity, and blood-brain barrier dysfunction. Notably, studies on small vessel disease suggest that blood-brain barrier dysfunction is among the earliest mechanisms in small vessel disease and might contribute to the development of the hallmarks of small vessel disease. Therefore, the purpose of this review is to provide a new foundation in the study of small vessel disease pathology. First, we discuss the main structural domains and functions of the blood-brain barrier. Secondly, we review the most recent evidence on blood-brain barrier dysfunction linked to small vessel disease. Finally, we conclude with a discussion on future perspectives and propose potential treatment targets and interventions.
| S-EPMC11467932 | biostudies-literature
Project description:IntroductionWe explored how blood-brain barrier (BBB) leakage rate of gadolinium chelates (Ktrans) and BBB water exchange rate (kw) varied in cerebral small vessel disease (cSVD) subtypes.MethodsThirty sporadic cSVD, 40 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and 13 high-temperature requirement factor A serine peptidase 1 (HTRA) -related cSVD subjects were investigated parallel to 40 healthy individuals. Subjects underwent clinical, cognitive, and MRI assessment.ResultsIn CADASIL, no difference in Ktrans, but lower kw was observed in multiple brain regions. In sporadic cSVD, no difference in kw, but higher Ktrans was found in the whole brain and normal-appearing white matter. In HTRA1-related cSVD, both higher Ktrans in the whole brain and lower kw in multiple brain regions were observed. In each patient group, the altered BBB measures were correlated with lesion burden or clinical severity.DiscussionIn cSVD subtypes, distinct alterations of kw and Ktrans were observed. The combination of Ktrans and kw can depict the heterogeneous BBB dysfunction.HighlightsWe measured BBB leakage to gadolinium-based contrast agent (Ktrans) and water exchange rate (kw) across BBB in three subtypes of cSVD. CADASIL is characterized by lower kw, HTRA1-related cSVD exhibits both higher Ktrans and lower kw, while sporadic cSVD is distinguished by higher Ktrans. There are distinct alterations in kw and Ktrans among subtypes of cSVD, indicating the heterogeneous nature of BBB dysfunction.
| S-EPMC11247670 | biostudies-literature