Textural Characterisation on Regions of Interest: A Useful Tool for the Study of Small Vessel Disease

Proponemos un marco para investigar las propiedades de los tejidos aparentemente normales en las imágenes de resonancia magnética de la estructura cerebral de pacientes con enfermedad de vasos pequeños (SVD). Implica la extracción de entidades texturales en regiones de interés (ROI) obtenidas a partir de una plantilla anatómicamente relevante, combinada con un análisis estadístico que considere la distribución relativa de marcadores SVD (por ejemplo, microsangrados, espacios perivasculares e hiperintensidades de materia blanca) con respecto a las características texturales de las regiones de interés, en los territorios arteriales derivados de otra plantilla. Aplicamos este enfoque a los datos de 42 pacientes de un estudio de accidente cerebrovascular leve para investigar si los tejidos normales en diferentes regiones cerebrales son homogéneos independientemente de la presencia de marcadores y variedades de SVD específicos en las manifestaciones de la patología (accidente cerebrovascular en diferentes territorios arteriales). Nuestros resultados sugieren que este no es el caso: que los tejidos normales son heterogéneos y que las variaciones locales (representadas por la entropía) están asociadas con marcadores SVD, de acuerdo con los informes clínicos

Assessment of blood-brain barrier disruption using dynamic contrast-enhanced MRI. A systematic review

AbstractThere is increasing recognition of the importance of blood–brain barrier (BBB) disruption in aging, dementia, stroke and multiple sclerosis in addition to more commonly-studied pathologies such as tumors. Dynamic contrast-enhanced MRI (DCE-MRI) is a method for studying BBB disruption in vivo. We review pathologies studied, scanning protocols and data analysis procedures to determine the range of available methods and their suitability to different pathologies. We systematically review the existing literature up to February 2014, seeking studies that assessed BBB integrity using T1-weighted DCE-MRI techniques in animals and humans in normal or abnormal brain tissues. The literature search provided 70 studies that were eligible for inclusion, involving 417 animals and 1564 human subjects in total. The pathologies most studied are intracranial neoplasms and acute ischemic strokes. There are large variations in the type of DCE-MRI sequence, the imaging protocols and the contrast agents used. Moreover, studies use a variety of different methods for data analysis, mainly based on model-free measurements and on the Patlak and Tofts models. Consequently, estimated KTrans values varied widely. In conclusion, DCE-MRI is shown to provide valuable information in a large variety of applications, ranging from common applications, such as grading of primary brain tumors, to more recent applications, such as assessment of subtle BBB dysfunction in Alzheimer's disease. Further research is required in order to establish consensus-based recommendations for data acquisition and analysis and, hence, improve inter-study comparability and promote wider use of DCE-MRI

Analysis of dynamic texture and spatial spectral descriptors of dynamic contrast-enhanced brain magnetic resonance images for studying small vessel disease

Cerebral small vessel disease (SVD) comprises various pathological processes affecting small brain vessels and damaging white and grey matter. In this paper, we propose a framework comprising region of interest sampling, dynamic spectral and texture description, functional principal component analysis, and statistical analysis to study exogenous contrast agent distribution over time in various brain regions in patients with recent mild stroke and SVD features.We compared our results against current semi-quantitative surrogates of dysfunction such as signal enhancement area and slope. Biological sex, stroke lesion type and overall burden of white matter hyperintensities (WMH) were significant predictors of intensity, spectral, and texture features extracted from the ventricular region (p-value < 0.05), explaining between a fifth and a fourth of the data variance (0.20 ≤Adj.R2 ≤ 0.25). We observed that spectral feature reflected more the dysfunction compared to other descriptors since the overall WMH burden explained consistently the power spectra variability in blood vessels, cerebrospinal fluid, deep grey matter and white matter. Our preliminary results show the potential of the framework for the analysis of dynamic contrast-enhanced brain magnetic resonance imaging acquisitions in SVD since significant variation in our metrics was related to the burden of SVD features. Therefore, our proposal may increase sensitivity to detect subtle features of small vessel dysfunction. A public version of the code will be released on our research website

Blood pressure and sodium: association with MRI markers in cerebral small vessel disease

Dietary salt intake and hypertension are associated with increased risk of cardiovascular disease including stroke. We aimed to explore the influence of these factors, together with plasma sodium concentration, in cerebral small vessel disease (SVD). In all, 264 patients with nondisabling cortical or lacunar stroke were recruited. Patients were questioned about their salt intake and plasma sodium concentration was measured; brain tissue volume and white-matter hyperintensity (WMH) load were measured using structural magnetic resonance imaging (MRI) while diffusion tensor MRI and dynamic contrast-enhanced MRI were acquired to assess underlying tissue integrity. An index of added salt intake (P = 0.021), pulse pressure (P = 0.036), and diagnosis of hypertension (P = 0.0093) were positively associated with increased WMH, while plasma sodium concentration was associated with brain volume (P = 0.019) but not with WMH volume. These results are consistent with previous findings that raised blood pressure is associated with WMH burden and raise the possibility of an independent role for dietary salt in the development of cerebral SVD

Tracer kinetic assessment of blood–brain barrier leakage and blood volume in cerebral small vessel disease: Associations with disease burden and vascular risk factors

Funding Information: The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: Wellcome Trust [grant number WT088134/Z/09/A ; SDJM, FC]; Row Fogo Charitable Trust (MCVH, FC, AKH, PAA); Scottish Funding Council Scottish Imaging Network A Platform for Scientific Excellence collaboration (JMW); NHS Lothian R + D Department (MJT); the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK MRC, Alzheimer’s Research UK and the Alzheimer’s Society (MS, FC, ES, JMW); the Fondation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease [reference number 16 CVD 05] (MS); and European Union Horizon 2020 [project number 666881, SVDs@Target] (MS, FC). We acknowledge the participants, their relatives, and carers for their participation in this study, and the staff of NHS Lothian Stroke Services and Brain Research Imaging Centre Edinburgh for their assistance in recruiting and assessing the patients.Peer reviewedPublisher PD

Integrity of normal-appearing white matter: influence of age, visible lesion burden and hypertension in patients with small vessel disease

White matter hyperintensities accumulate with age and occur in patients with stroke, but their pathogenesis is poorly understood. We measured multiple magnetic resonance imaging biomarkers of tissue integrity in normal-appearing white matter and white matter hyperintensities in patients with mild stroke, to improve understanding of white matter hyperintensities origins. We classified white matter into white matter hyperintensities and normal-appearing white matter and measured fractional anisotropy, mean diffusivity, water content (T1-relaxation time) and blood–brain barrier leakage (signal enhancement slope from dynamic contrast-enhanced magnetic resonance imaging). We studied the effects of age, white matter hyperintensities burden (Fazekas score) and vascular risk factors on each biomarker, in normal-appearing white matter and white matter hyperintensities, and performed receiver-operator characteristic curve analysis. Amongst 204 patients (34.3–90.9 years), all biomarkers differed between normal-appearing white matter and white matter hyperintensities (P < 0.001). In normal-appearing white matter and white matter hyperintensities, mean diffusivity and T1 increased with age (P < 0.001), all biomarkers varied with white matter hyperintensities burden (P < 0.001; P = 0.02 signal enhancement slope), but only signal enhancement slope increased with hypertension (P = 0.028). Fractional anisotropy showed complex age-white matter hyperintensities-tissue interactions; enhancement slope showed white matter hyperintensities-tissue interactions. Mean diffusivity distinguished white matter hyperintensities from normal-appearing white matter best at all ages. Blood–brain barrier leakage increases with hypertension and white matter hyperintensities burden at all ages in normal-appearing white matter and white matter hyperintensities, whereas water mobility and content increase as tissue damage accrues, suggesting that blood–brain barrier leakage mediates small vessel disease-related brain damage

Blood-brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study

Introduction: Small vessel disease (SVD) is a common contributor to dementia. Subtle blood-brain barrier (BBB) leakage may be important in SVD-induced brain damage. Methods: We assessed imaging, clinical variables, and cognition in patients with mild (i.e., nondisabling) ischemic lacunar or cortical stroke. We analyzed BBB leakage, interstitial fluid, and white matter integrity using multimodal tissue-specific spatial analysis around white matter hyperintensities (WMH). We assessed predictors of 1 year cognition, recurrent stroke, and dependency. Results: In 201 patients, median age 67 (range 34–97), BBB leakage, and interstitial fluid were higher in WMH than normal-appearing white matter; leakage in normal-appearing white matter increased with proximity to WMH (P , .0001), with WMH severity (P 5 .033), age (P 5 .03), and hypertension (P , .0001). BBB leakage in WMH predicted declining cognition at 1 year. Discussion: BBB leakage increases in normal-appearing white matter with WMH and predicts worsening cognition. Interventions to reduce BBB leakage may prevent SVD-associated dementia

White matter hyperintensity reduction and outcomes after minor stroke

Objective: To assess factors associated with white matter hyperintensity (WMH) change in a large cohort after observing obvious WMH shrinkage 1 year after minor stroke in several participants in a longitudinal study. Methods: We recruited participants with minor ischemic stroke and performed clinical assessments and brain MRI. At 1 year, we assessed recurrent cerebrovascular events and dependency and repeated the MRI. We assessed change in WMH volume from baseline to 1 year (normalized to percent intracranial volume [ICV]) and associations with baseline variables, clinical outcomes, and imaging parameters using multivariable analysis of covariance, model of changes, and multinomial logistic regression. Results: Among 190 participants (mean age 65.3 years, range 34.3–96.9 years, 112 [59%] male), WMH decreased in 71 participants by 1 year. At baseline, participants whose WMH decreased had similar WMH volumes but higher blood pressure (p = 0.0064) compared with participants whose WMH increased. At 1 year, participants with WMH decrease (expressed as percent ICV) had larger reductions in blood pressure (β = 0.0053, 95% confidence interval [CI] 0.00099–0.0097 fewer WMH per 1–mm Hg decrease, p = 0.017) and in mean diffusivity in normal-appearing white matter (β = 0.075, 95% CI 0.0025–0.15 fewer WMH per 1-unit mean diffusivity decrease, p = 0.043) than participants with WMH increase; those with WMH increase experienced more recurrent cerebrovascular events (32%, vs 16% with WMH decrease, β = 0.27, 95% CI 0.047–0.50 more WMH per event, p = 0.018). Conclusions: Some WMH may regress after minor stroke, with potentially better clinical and brain tissue outcomes. The role of risk factor control requires verification. Interstitial fluid alterations may account for some WMH reversibility, offering potential intervention targets

Isosorbide Mononitrate and Cilostazol Treatment in Patients With Symptomatic Cerebral Small Vessel Disease: The Lacunar Intervention Trial-2 (LACI-2) Randomized Clinical Trial

IMPORTANCE: Cerebral small vessel disease (cSVD) is a common cause of stroke (lacunar stroke), is the most common cause of vascular cognitive impairment, and impairs mobility and mood but has no specific treatment. OBJECTIVE: To test the feasibility, drug tolerability, safety, and effects of 1-year isosorbide mononitrate (ISMN) and cilostazol treatment on vascular, functional, and cognitive outcomes in patients with lacunar stroke. DESIGN, SETTING, AND PARTICIPANTS: The Lacunar Intervention Trial-2 (LACI-2) was an investigator-initiated, open-label, blinded end-point, randomized clinical trial with a 2 × 2 factorial design. The trial aimed to recruit 400 participants from 26 UK hospital stroke centers between February 5, 2018, and May 31, 2021, with 12-month follow-up. Included participants had clinical lacunar ischemic stroke, were independent, were aged older than 30 years, had compatible brain imaging findings, had capacity to consent, and had no contraindications to (or indications for) the study drugs. Data analysis was performed on August 12, 2022. INTERVENTIONS: All patients received guideline stroke prevention treatment and were randomized to ISMN (40-60 mg/d), cilostazol (200 mg/d), ISMN-cilostazol (40-60 and 200 mg/d, respectively), or no study drug. MAIN OUTCOMES: The primary outcome was recruitment feasibility, including retention at 12 months. Secondary outcomes were safety (death), efficacy (composite of vascular events, dependence, cognition, and death), drug adherence, tolerability, recurrent stroke, dependence, cognitive impairment, quality of life (QOL), and hemorrhage. RESULTS: Of the 400 participants planned for this trial, 363 (90.8%) were recruited. Their median age was 64 (IQR, 56.0-72.0) years; 251 (69.1%) were men. The median time between stroke and randomization was 79 (IQR, 27.0-244.0) days. A total of 358 patients (98.6%) were retained in the study at 12 months, with 257 of 272 (94.5%) taking 50% or more of the allocated drug. Compared with those participants not receiving that particular drug, neither ISMN (adjusted hazard ratio [aHR], 0.80 [95% CI, 0.59 to 1.09]; P = .16) nor cilostazol (aHR, 0.77 [95% CI, 0.57 to 1.05]; P = .10) alone reduced the composite outcome in 297 patients. Isosorbide mononitrate reduced recurrent stroke in 353 patients (adjusted odds ratio [aOR], 0.23 [95% CI, 0.07 to 0.74]; P = .01) and cognitive impairment in 308 patients (aOR, 0.55 [95% CI, 0.36 to 0.86]; P = .008). Cilostazol reduced dependence in 320 patients (aHR, 0.31 [95% CI, 0.14 to 0.72]; P = .006). Combination ISMN-cilostazol reduced the composite (aHR, 0.58 [95% CI, 0.36 to 0.92]; P = .02), dependence (aOR, 0.14 [95% CI, 0.03 to 0.59]; P = .008), and any cognitive impairment (aOR, 0.44 [95% CI, 0.23 to 0.85]; P = .02) and improved QOL (adjusted mean difference, 0.10 [95% CI, 0.03 to 0.17]; P = .005) in 153 patients. There were no safety concerns. CONCLUSIONS AND RELEVANCE: These results show that the LACI-2 trial was feasible and ISMN and cilostazol were well tolerated and safe. These agents may reduce recurrent stroke, dependence, and cognitive impairment after lacunar stroke, and they could prevent other adverse outcomes in cSVD. Therefore, both agents should be tested in large phase 3 trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03451591