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Background Impaired autoregulation may contribute to the pathogenesis of cerebral small vessel disease. Reliable protocols for measuring microvascular reactivity are required to test this hypothesis and for providing secondary endpoints in clinical trials. Aims To develop and assess a protocol for acquisition and processing of cerebrovascular reactivity by MRI, in subcortical tissue of patients with small vessel disease and minor stroke. Methods We recruited 15 healthy volunteers, testing paradigms using 1- and 3-min 6% CO 2 challenges with repeat scanning, and 15 patients with history of minor stroke. We developed a protocol to measure cerebrovascular reactivity and delay times, assessing tolerability and reproducibility in grey and white matter areas. Results The 3-min paradigm yielded more reproducible data than the 1-min paradigm (CV respectively: 7.9-15.4% and 11.7-70.2% for cerebrovascular reactivity in grey matter), and was less reproducible in white matter (16.1-24.4% and 27.5-141.0%). Tolerability was similar for the two paradigms, but mean cerebrovascular reactivity and cerebrovascular reactivity delay were significantly higher for the 3-min paradigm in most regions. Patient tolerability was high with no evidence of greater failure rate (1/15 patients vs. 2/15 volunteers withdrew at the first visit). Grey matter cerebrovascular reactivity was lower in patients than in volunteers (0.110-0.234 vs. 0.172-0.313%/mmHg; p < 0.05 in 6/8 regions), as was the white matter cerebrovascular reactivity delay (16.2-43.9 vs. 31.1-47.9 s; p < 0.05 in 4/8 regions). Conclusions An effective and well-tolerated protocol for measurement of cerebrovascular reactivity was developed for use in ongoing and future trials to investigate small vessel disease pathophysiology and to measure treatment effects.

Background: In structural Magnetic Resonance Imaging (MRI) of patients with a recent small subcortical infarct (RSSI) and small vessel disease (SVD) imaging markers coexist. However, their spatial distribution and prevalence with respect to the hemisphere of the RSSI remain unknown., Materials and Methods: From brain MRI in 187 patients with an acute lacunar ischemic stroke clinical syndrome and a relevant diffusion weighted imaging (DWI)-positive lesion, we semiautomatically extracted the RSSI, microbleeds, lacunes, old cortical infarcts, and white matter hyperintensities (WMH) using optimized thresholding in the relevant sequences, and rated the load of perivascular spaces. We registered all images to an age-relevant brain template and calculated the probability distribution of all SVD markers mentioned for patients who had the RSSI in each hemisphere separately. We used the Wilcoxon and chi-squared tests to compare the volumes and frequencies of occurrence, respectively, of the SVD markers between hemispheres throughout the sample., Results: Fifty-two percent patients ( n  = 97) had the RSSI in the left hemisphere, 42% ( n  = 78) in the right, 2.7% ( n  = 5) in both, and 3.7% ( n  = 7) in the cerebellum or brainstem. There was no significant difference in RSSI frequency between left and right hemispheres ( p  = .10) in the sample. The median volume of the RSSI (expressed as a percentage of the total intracranial volume) was 0.05% (IQR = 0.06). There was no difference in median percent volume of the right RSSIs versus left ( p  = .16). Neither was there a significant interhemispheric difference in the volume of any of the SVD markers regardless of the location of the RSSI and they were equally distributed in both hemispheres., Conclusion: Assessment of SVD imaging markers in the contralateral hemisphere could be used as a proxy for the SVD load in the whole brain to avoid contamination by the RSSI of the measurements, especially of WMH.

Brain imaging is essential for the diagnosis and characterization of cerebral small vessel disease. Several magnetic resonance imaging markers have therefore emerged, providing new information on the diagnosis, progression, and mechanisms of small vessel disease. Yet, the reproducibility of these small vessel disease markers has received little attention despite being widely used in cross-sectional and longitudinal studies. This review focuses on the main small vessel disease-related markers on magnetic resonance imaging including: white matter hyperintensities, lacunes, dilated perivascular spaces, microbleeds, and brain volume. The aim is to summarize, for each marker, what is currently known about: (1) its reproducibility in studies with a scan-rescan procedure either in single or multicenter settings; (2) the acquisition-related sources of variability; and, (3) the techniques used to minimize this variability. Based on the results, we discuss technical and other challenges that need to be overcome in order for these markers to be reliably used as outcome measures in future clinical trials. We also highlight the key points that need to be considered when designing multicenter magnetic resonance imaging studies of small vessel disease., (© The Author(s) 2016.)

Introduction: Subtle inhomogeneities in the scanner's magnetic fields (B0 and B1) alter the intensity levels of the structural magnetic resonance imaging (MRI) affecting the volumetric assessment of WMH changes. Here, we investigate the influence that (1) correcting the images for the B1 inhomogeneities (i.e. bias field correction (BFC)) and (2) selection of the WMH change assessment method can have on longitudinal analyses of WMH progression and discuss possible solutions., Methods: We used brain structural MRI from 46 mild stroke patients scanned at stroke onset and 3 years later. We tested three BFC approaches: FSL-FAST, N4 and exponentially entropy-driven homomorphic unsharp masking (E(2)D-HUM) and analysed their effect on the measured WMH change. Separately, we tested two methods to assess WMH changes: measuring WMH volumes independently at both time points semi-automatically (MCMxxxVI) and subtracting intensity-normalised FLAIR images at both time points following image gamma correction. We then combined the BFC with the computational method that performed best across the whole sample to assess WMH changes., Results: Analysis of the difference in the variance-to-mean intensity ratio in normal tissue between BFC and uncorrected images and visual inspection showed that all BFC methods altered the WMH appearance and distribution, but FSL-FAST in general performed more consistently across the sample and MRI modalities. The WMH volume change over 3 years obtained with MCMxxxVI with vs. without FSL-FAST BFC did not significantly differ (medians(IQR)(with BFC) = 3.2(6.3) vs. 2.9(7.4)ml (without BFC), p = 0.5), but both differed significantly from the WMH volume change obtained from subtracting post-processed FLAIR images (without BFC)(7.6(8.2)ml, p < 0.001). This latter method considerably inflated the WMH volume change as subtle WMH at baseline that became more intense at follow-up were counted as increase in the volumetric change., Conclusions: Measurement of WMH volume change remains challenging. Although the overall volumetric change was not significantly affected by the application of BFC, these methods distorted the image intensity distribution affecting subtle WMH. Subtracting the FLAIR images at both time points following gamma correction seems a promising technique but is adversely affected by subtle WMH. It is important to take into account not only the changes in volume but also in the signal intensity.

Purpose: Perivascular spaces (PVS) are associated with ageing, cerebral small vessel disease, inflammation and increased blood brain barrier permeability. Most studies to date use visual rating scales to assess PVS, but these are prone to observer variation., Methods: We developed a semi-automatic computational method that extracts PVS on bilateral ovoid basal ganglia (BG) regions on intensity-normalised T2-weighted magnetic resonance images. It uses Analyze™10.0 and was applied to 100 mild stroke patients' datasets. We used linear regression to test association between BGPVS count, volume and visual rating scores; and between BGPVS count & volume, white matter hyperintensity (WMH) rating scores (periventricular: PVH; deep: DWMH) & volume, atrophy rating scores and brain volume., Results: In the 100 patients WMH ranged from 0.4 to 119ml, and total brain tissue volume from 0.65 to 1.45l. BGPVS volume increased with BGPVS count (67.27, 95%CI [57.93 to 76.60], p<0.001). BGPVS count was positively associated with WMH visual rating (PVH: 2.20, 95%CI [1.22 to 3.18], p<0.001; DWMH: 1.92, 95%CI [0.99 to 2.85], p<0.001), WMH volume (0.065, 95%CI [0.034 to 0.096], p<0.001), and whole brain atrophy visual rating (1.01, 95%CI [0.49 to 1.53], p<0.001). BGPVS count increased as brain volume (as % of ICV) decreased (-0.33, 95%CI [-0.53 to -0.13], p=0.002)., Comparison With Existing Method: BGPVS count and volume increased with the overall increase of BGPVS visual scores (2.11, 95%CI [1.36 to 2.86] for count and 0.022, 95%CI [0.012 to 0.031] for volume, p<0.001). Distributions for PVS count and visual scores were also similar., Conclusions: This semi-automatic method is applicable to clinical protocols and offers quantitative surrogates for PVS load. It shows good agreement with a visual rating scale and confirmed that BGPVS are associated with WMH and atrophy measurements., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: If the diagnostic and prognostic significance of brain microbleeds (BMBs) are to be investigated and used for these purposes in clinical practice, observer variation in BMB assessment must be minimized., Methods: Two doctors used a pilot rating scale to describe the number and distribution of BMBs (round, low-signal lesions, <10 mm diameter on gradient echo MRI) among 264 adults with stroke or TIA. They were blinded to clinical data and their counterpart's ratings. Disagreements were adjudicated by a third observer, who informed the development of a new Brain Observer MicroBleed Scale (BOMBS), which was tested in a separate cohort of 156 adults with stroke., Results: In the pilot study, agreement about the presence of >/=1 BMB in any location was moderate (kappa=0.44; 95% CI, 0.32-0.56), but agreement was worse in lobar locations (kappa=0.44; 95% CI, 0.30-0.58) than in deep (kappa=0.62; 95% CI, 0.48-0.76) or posterior fossa locations (kappa=0.66; 95% CI, 0.47-0.84). Using BOMBS, agreement about the presence of >/=1 BMB improved in any location (kappa=0.68; 95% CI, 0.49-0.86) and in lobar locations (kappa=0.78; 95% CI, 0.60-0.97)., Conclusions: Interrater reliability concerning the presence of BMBs was moderate to good, and could be improved with the use of the BOMBS rating scale, which takes into account the main sources of interrater disagreement identified by our pilot scale.

Background and Purpose: Lacunar stroke is associated with endothelial dysfunction and histologically with intrinsic cerebral microvascular disease of unknown cause. Endothelial dysfunction could impair blood-brain barrier integrity. We assessed background blood-brain barrier leakage in patients with lacunar ischemic stroke compared with cortical stroke controls., Methods: We recruited patients with lacunar or mild cortical ischemic stroke and assessed generalized cerebral blood-brain barrier leak with MRI and intravenous gadolinium at least 1 month after stroke. We used detailed image processing to compare signal change before and for 30 minutes postcontrast throughout gray matter, white matter, and cerebrospinal fluid with summary analyses and general linear modeling., Results: Among 48 patients (29 lacunar, 19 cortical), postcontrast enhancement was significantly higher in cerebrospinal fluid (P=0.04, Mann-Whitney U), and nonsignificantly higher in white matter, in lacunar than in cortical strokes, with no difference in gray matter. General linear modeling confirmed significantly greater postcontrast enhancement in cerebrospinal fluid in lacunar patients than in cortical controls (t=3.37, P<0.0008)., Conclusions: These preliminary data suggest that the blood-brain barrier may be dysfunctional throughout subcortical white matter (white matter drains via interstitial spaces to cerebrospinal fluid) in patients with lacunar stroke. Further studies are required to confirm these findings and determine whether abnormal blood-brain barrier might predate development of lacunar disease. Blood-brain barrier dysfunction may be an important mechanism for brain damage in cerebral microvascular disease.