BACKGROUND AND PURPOSE: Increased blood-brain barrier (BBB) permeability occurs in cerebral small vessel disease (SVD). It is not known if BBB changes predate progression of SVD. METHODS: We followed up patients with non-disabling lacunar or cortical stroke and BBB permeability MR imaging following their original stroke. About three years later, we assessed functional outcome (Oxford Handicap Score, OHS, poor outcome defined as 3-6), recurrent neurological events and white matter hyperintensity (WMH) progression on MRI. RESULTS: Amongst 70 patients, mean age 68 (SD±11) years, median time to clinical follow up was 39 months (IQR 30-45), median OHS was 2 (IQR 1-3); poor functional outcome was associated with higher baseline WMH score (p<0.001) and increased basal ganglia BBB permeability (p=0.046). Amongst 48 patients with follow-up MRI, WMH progression at follow-up was associated with baseline WMH (ANCOVA p<0.0001) and age (ANCOVA p=0.032). CONCLUSIONS: Further long term studies to evaluate the role of BBB dysfunction in progression of SVD are required in studies that are large enough to account for key prognostic influences such as baseline WMH and age

Armitage, Paul A.

Carpenter, Trevor C.

Chappell, Francesca M.

Dennis, Martin S.

Doubal, Fergus

Shuler, Kirsten

Valdes Hernandez, Maria

Wang, Xin

Wardlaw, Joanna M.

PubMed


            Background and Purpose—
            Increased blood–brain barrier (BBB) permeability occurs in cerebral small vessel disease. It is not known if BBB changes predate progression of small vessel disease.
          
          
            Methods—
            We followed-up patients with nondisabling lacunar or cortical stroke and BBB permeability magnetic resonance imaging after their original stroke. Approximately 3 years later, we assessed functional outcome (Oxford Handicap Score, poor outcome defined as 3–6), recurrent neurological events, and white matter hyperintensity (WMH) progression on magnetic resonance imaging.
          
          
            Results—
            
              Among 70 patients with mean age of 68 (SD±11) years, median time to clinical follow-up was 39 months (interquartile range, 30–45) and median Oxford Handicap Score was 2 (interquartile range, 1–3); poor functional outcome was associated with higher baseline WMH score (
              P
              &lt;0.001) and increased basal ganglia BBB permeability (
              P
              =0.046). Among 48 patients with follow-up magnetic resonance imaging, WMH progression at follow-up was associated with baseline WMH (ANCOVA
              P
              &lt;0.0001) and age (ANCOVA
              P
              =0.032).
            
          
          
            Conclusions—
            Further long-term studies to evaluate the role of BBB dysfunction in progression of small vessel disease are required in studies that are large enough to account for key prognostic influences such as baseline WMH and age.
          </jats:sec

Joanna M. Wardlaw

Fergus N. Doubal

Maria Valdes-Hernandez

Xin Wang

Francesca M. Chappell

Kirsten Shuler

Paul A. Armitage

Trevor C. Carpenter

Martin S. Dennis

Crossref

Stroke

Blood–Brain Barrier Permeability and Long-Term Clinical and Imaging Outcomes in Cerebral Small Vessel Disease

Background and Purpose-Increased blood-brain barrier (BBB) permeability occurs in cerebral small vessel disease. It is not known if BBB changes predate progression of small vessel disease. Methods-We followed-up patients with nondisabling lacunar or cortical stroke and BBB permeability magnetic resonance imaging after their original stroke. Approximately 3 years later, we assessed functional outcome (Oxford Handicap Score, poor outcome defined as 3-6), recurrent neurological events, and white matter hyperintensity (WMH) progression on magnetic resonance imaging. Results-Among 70 patients with mean age of 68 (SD +/- 11) years, median time to clinical follow-up was 39 months (interquartile range, 30-45) and median Oxford Handicap Score was 2 (interquartile range, 1-3); poor functional outcome was associated with higher baseline WMH score (P &lt; 0.001) and increased basal ganglia BBB permeability (P=0.046). Among 48 patients with follow-up magnetic resonance imaging, WMH progression at follow-up was associated with baseline WMH (ANCOVA P &lt; 0.0001) and age (ANCOVA P=0.032). Conclusions-Further long-term studies to evaluate the role of BBB dysfunction in progression of small vessel disease are required in studies that are large enough to account for key prognostic influences such as baseline WMH and age.</p

Edinburgh Research Explorer

     Edinburgh Research Explorer                                      Blood-Brain Barrier Permeability and Long-Term Clinical andImaging Outcomes in Cerebral Small Vessel DiseaseCitation for published version:Wardlaw, JM, Doubal, F, Valdes Hernandez, M, Wang, X, Chappell, FM, Shuler, K, Armitage, PA,Carpenter, TC & Dennis, MS 2013, 'Blood-Brain Barrier Permeability and Long-Term Clinical and ImagingOutcomes in Cerebral Small Vessel Disease', Stroke, vol. 44, no. 2, pp. 525-527.https://doi.org/10.1161/STROKEAHA.112.669994Digital Object Identifier (DOI):10.1161/STROKEAHA.112.669994Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Peer reviewed versionPublished In:StrokePublisher Rights Statement:Published in final edited form as:Stroke. 2013 February; 44(2): 10.1161/STROKEAHA.112.669994.General rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 28. Nov. 2025Blood-brain barrier permeability and long term clinical andimaging outcomes in cerebral small vessel diseaseJoanna M Wardlaw, MD1,2,3,4, Fergus N Doubal, PhD1,2,4, Maria Valdes-Hernandez, PhD1,3,4,Xin Wang, MSc1,3,4, Francesca M Chappell, PhD1,3, Kirsten Shuler, BSc1,3, Paul AArmitage, PhD1,3, Trevor C Carpenter, PhD1,3, and Martin S Dennis, MD21Brain Research Imaging Centre, University of Edinburgh, Edinburgh, UK2Stroke Medicine, Division of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK3Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration,Edinburgh, UK4Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh,UKAbstractBackground and Purpose—Increased blood-brain barrier (BBB) permeability occurs incerebral small vessel disease (SVD). It is not known if BBB changes predate progression of SVD.Methods—We followed up patients with non-disabling lacunar or cortical stroke and BBBpermeability MR imaging following their original stroke. About three years later, we assessedfunctional outcome (Oxford Handicap Score, OHS, poor outcome defined as 3-6), recurrentneurological events and white matter hyperintensity (WMH) progression on MRI.Results—Amongst 70 patients, mean age 68 (SD±11) years, median time to clinical follow upwas 39 months (IQR 30-45), median OHS was 2 (IQR 1-3); poor functional outcome wasassociated with higher baseline WMH score (p<0.001) and increased basal ganglia BBBpermeability (p=0.046). Amongst 48 patients with follow-up MRI, WMH progression at follow-upwas associated with baseline WMH (ANCOVA p<0.0001) and age (ANCOVA p=0.032).Conclusions—Further long term studies to evaluate the role of BBB dysfunction in progressionof SVD are required in studies that are large enough to account for key prognostic influences suchas baseline WMH and age.KeywordsBlood-brain barrier; leukoaraiosis; stroke; lacunar strokeIntroductionThe BBB becomes increasingly permeable with normal advancing age,1 particularly inpatients with vascular dementia1 and small vessel disease (SVD, Figure 1).2-4 Cross-Corresponding author: Joanna M Wardlaw, Western General Hospital, Edinburgh, EH4 2XU, UK, tel +44 131 537 2943, fax +44131 332 5150, Joanna.wardlaw@ed.ac.uk.This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providingthis early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before itis published in its final citable form. Please note that during the production process errors may be discovered which could affect thecontent, and all legal disclaimers that apply to the journal pertain.Europe PMC Funders GroupAuthor ManuscriptStroke. Author manuscript; available in PMC 2013 November 29.Published in final edited form as:Stroke. 2013 February ; 44(2): . doi:10.1161/STROKEAHA.112.669994. Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscriptssectional studies do not determine whether increased BBB permeability predates progressionof SVD and therefore might be causative. We followed up patients previously recruited inour cross-sectional study of BBB permeability changes in lacunar stroke2 to see if increasedBBB permeability might predate progression of SVD.MethodsWe originally recruited 97 previously independent patients with non-disabling ischaemicstroke,2 half lacunar, half cortical (controls). We assessed stroke severity (NIHSS score),performed diagnostic MR imaging (with DWI, T1, T2, FLAIR, T2*) to confirm strokesubtype and quantify white matter hyperintensities (WMH). We assessed BBB permeabilityin basal ganglia, cortex, white matter and lateral ventricular cerebrospinal fluid (CSF) 1-3months after the index stroke with sequential MR T1 imaging before and after intravenousgadolinium (described previously2, 5). The study was approved by the Lothian ResearchEthics Committee (2002/W/RA/03); all participants gave written informed consent.About three years later, we followed-up all patients to determine functional status (OxfordHandicap Score, OHS,6 similar to the modified Rankin Score: poor functionaloutcome=OHS 3-6, dead=OHS 6), recurrent strokes and assess SVD progression onstructural MR imaging. We cross-checked the patients’ histories with hospital records.Follow-up MR imaging was performed on the same 1.5T MR scanner (GE Signa LX,Milwaukee, WI, USA, 22 mTm−1 maximum strength gradients) using the same diagnosticsequences (T1, T2, FLAIR, T2*, DWI) described previously.2 We analysed imagingfeatures blind, noting new infarcts or haemorrhages, WMH (Fazekas score7) and change inWMH (Prins score8). The intra-class correlation coefficient for WMH rating by theneuroradiologist was 0.964. We registered follow-up to baseline scans and measuredintracranial, whole brain, and WMH volumes using a validated multispectral image analysistool.9 We masked infarcts to avoid confounding WMH volume,10 normalised brain andWMH volumes to intracranial volume (ICV) and determined WMH volume change.We performed univariate and multivariate analysis (binary logistic regression) to identifyvariables associated with functional status and WMH change at follow-up adjusted forduration of follow-up. We performed uni- and multi-variate linear regression to examineassociations between BBB permeability at baseline, WMH progression and functionaloutcome. We analysed factors associated with WMH volume change by ANCOVA. Allanalyses were performed in Minitab version 15, State College, Pennsylvania, US or SAS 9.1(www.sas.com).ResultsWe obtained clinical follow-up on 70/97 (78%) and MR imaging on 48 (49% of 97) of theoriginal study patients. The 70 patients with clinical follow-up did not differ from the 27without clinical follow-up in baseline age (mean at original presentation 68+/−11 vs 63+/−12, p=NS), median NIHSS (both 2 IQR 1-3), hypertension (both 66%) or lacunar stroke(50% vs 43%). The median baseline Fazekas deep and periventricular WMH scores wereeach 1; periventricular and deep Fazekas scores were >2 in 20 and nine patients respectively.At clinical follow-up at median 39 months (IQR 30-48), 25% had poor outcome (12 OHS3-5, six dead). Twenty-five had clinical and/or imaging evidence of recurrent neurologicalevents (36%): two, clinically-diagnosed recurrent stroke; 23, new focal weakness; four, newinfarct on follow-up imaging. In univariate analyses, poor functional outcome wasassociated with increasing age, higher baseline WMH score and basal ganglia BBBpermeability, but not baseline NIHSS, hypertension, diabetes or stroke subtype (Table 1).Wardlaw et al. Page 2Stroke. Author manuscript; available in PMC 2013 November 29. Europe PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsOn multivariate logistic regression (adjusted for baseline age, WMH score, BBBpermeability) predictors of poor outcome were baseline total WMH score (OR 4.8, 2.0-11.4,p<0.001) and basal ganglia BBB permeability (OR 2.2, 1.0-4.6, p=0.046).Forty-eight patients had follow-up MR imaging, median 39 (IQR 30-45) months after indexstroke; baseline age (67+/−10), median NIHSS (2, IQR 2-3), proportion hypertensive (65%),lacunar index stroke (48%) and WMH score were the same as for all 70 with clinical follow-up. 6/48 (13%) were OHS=3-5.WMH score had increased in 33/48 and remained unchanged in 15/48 (according to Prinsand Fazekas scores, Figure 1b). On univariate analyses, baseline WMH score, but not age ortime since stroke, strongly predicted progression of WMH (OR 8.7, 2.1-35.3, p<0.001).Median WMH volume at baseline was 8.5 ml (IQR 5.9-15.2), at follow-up was 12.2 ml(IQR 8.6-19.7), median increase 3.2 ml (IQR 1.2-7.5, p<0.0001). The strongest predictors ofincreasing WMH volume at follow-up were baseline WMH volume (ANCOVA p<0.0001)and age (ANCOVA p=0.032). WMH volume at follow-up increased by: 1.80 times(1.56-2.08) per unit (mm3) of WMH volume and 1.01 times (1.00-1.02) per additional yearof age at baseline.DiscussionPoor functional outcome three years after lacunar or mild cortical ischaemic stroke wasassociated with having more WMH, being older and having increased BBB permeability inthe basal ganglia. Worsening of WMH was dominated by having more WMH at baselineand older age. A third had clinical/imaging evidence of recurrent neurological events,although only two were formally diagnosed as recurrent stroke, consistent with recentrecognition of WMH-associated subtle neurological symptoms.11 Long term poor functionaloutcome and WMH progression were not associated with vascular risk factors, baselineNIHSS or stroke subtype, possibly because the study was small, NIHSS very mild, or due tosecondary prevention, although this does not control risk factors perfectly.WMH increased in most patients at follow-up. Similar change in WMH scores (27-74%increase)12 or volume (1.1-2.4 ml) have been noted previously but the magnitude of effect ofWMH or age on WMH progression, and the association with BBB permeability, are novel.1These data on WMH progression, particularly the 95% confidence intervals (increase overthree years of 1.56-2.08 times per additional mm3 of baseline WMH volume and 1.00-1.02times per additional year of age at baseline), provide useful data for sample size calculationsfor studies wishing to use WMH change as a surrogate outcome measure.The study strengths include testing clinical and imaging predictors of SVD progression, useof qualitative and quantitative WMH measures, careful blinding, validated imagingmethods.5,9,10 Weaknesses include small sample size, limited power for multivariate testing,22% loss to clinical follow-up (possibly reflecting the three-year time lapse).Future studies assessing BBB permeability in SVD should: assess recurrent stroke, covertneurological symptoms, accumulating SVD features, vascular risk factors; track BBBpermeability to new lesion formation;4 be powered to adjust for multiple overlappingcovariates, particularly WMH load.AcknowledgmentsFunding: The Chief Scientist Office of the Scottish Executive (CZB/4/281), the Wellcome Trust (075611), theRow Fogo Charitable Trust, and the RCUK Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE)Edinburgh, supported the study. The imaging was conducted in the Brain Research Imaging Centre, University ofWardlaw et al. Page 3Stroke. Author manuscript; available in PMC 2013 November 29. Europe PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsEdinburgh (www.bric.ed.ac.uk) a centre in the Scottish Imaging Network, A Platform for Scientific Excellence(SINAPSE) Collaboration.Disclosures: The work was supported by research grants to the host institution but the authors have no conflict ofinterests. The authors had full access to the data and take responsibility for its integrity.References1. Farrall AJ, Wardlaw JM. Blood brain barrier: ageing and microvascular disease - systemic reviewand meta-analysis. Neurobiol Aging. 2007; 30:337–352. [PubMed: 17869382]2. Wardlaw JM, Doubal F, Armitage P, Chappell F, Carpenter T, Maniega SM, et al. Lacunar stroke isassociated with diffuse blood-brain barrier dysfunction. Ann Neurol. 2009; 65:194–202. [PubMed:19260033]3. Topakian R, Barrick TR, Howe FA, Markus HS. Blood-brain barrier permeability is increased innormal-appearing white matter in patients with lacunar stroke and leucoaraiosis. JNNP. 2010;81:192–197. [PubMed: 19710048]4. Taheri S, Gasparovic C, Huisa BN, Adair JC, Edmonds E, Prestopnik J, et al. Blood-brain barrierpermeability abnormalities in vascular cognitive impairment. Stroke. 2011; 42:2158–2163.[PubMed: 21719768]5. Armitage PA, Farrall AJ, Carpenter TK, Doubal FN, Wardlaw JM. Use of dynamic contrast-enhanced MRI to measure subtle blood-brain barrier abnormalities. Magn Reson Imaging. 2011;29:305–314. [PubMed: 21030178]6. Bamford J, Sandercock P, Warlow C, Slattery J. Interobserver agreement for the assessment ofhandicap in stroke patients. Stroke. 1989; 20:828. [PubMed: 2728057]7. Fazekas F. Magnetic resonance signal abnormalities in asymptomatic individuals: their incidenceand functional correlates. Eur Neurol. 1989; 29:164–168. [PubMed: 2731564]8. Prins ND, van Straaten ECW, van Dijk EJ, Simoni M, van Schijndel RA, Vrooman HA, et al.Measuring progression of cerebral white matter lesions on MRI. Visual rating and volumetrics.Neurology. 2004; 62:1533–1539. [PubMed: 15136677]9. Valdes Hernandez MC, Ferguson KJ, Chappell FM, Wardlaw JM. New multispectral MRI datafusion technique for white matter lesion segmentation: method and comparison with thresholding inFLAIR images. Eur Radiol. 2010; 20:1684–1691. [PubMed: 20157814]10. Wang X, Valdes-Hernandez MC, Doubal FN, Wardlaw JM. The effects of infarcts on theassessment of brain atrophy in longitudinal studies. Cerebrovasc Dis. 2011; 31:148.11. Windham BG, Griswold ME, Shibata D, Penman A, Catellier DJ, Mosley TH Jr. Covertneurological symptoms associated with silent infarcts from midlife to older age: theAtherosclerosis Risk in Communities study. Stroke. 2012; 43:1218–1223. [PubMed: 22382163]12. Cavalieri M, Schmidt R. New developments in diagnosis of vascular cognitive impairment. JNeurol Sci. 2010; 299:11–14. [PubMed: 20850800]Wardlaw et al. Page 4Stroke. Author manuscript; available in PMC 2013 November 29. Europe PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsFigure 1.72-year-old patient with right hemisphere lacunar stroke. (a) two days after stroke MR DWIshows the acute right centrum semiovale lacunar infarct, T2* shows a few microbleeds,FLAIR shows numerous WMHs. BBB imaging six weeks later: FLAIR 30 minutes after ivGadolinium (Gd) shows Gadolinium in cortical sulci and perivascular spaces (arrows). (b)FLAIR and T2* images two years later show increased WMHs and microbleeds (baselineFLAIR and T2* shown for comparison).Wardlaw et al. Page 5Stroke. Author manuscript; available in PMC 2013 November 29. Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsWardlaw et al. Page 6Table 1Predictors of poor outcome (OHS 3-6) three years after lacunar or mild cortical strokeUnivariate MultivariateVariable OR/unitincrease95% CI P value OR (95% CI)/unit increaseP valueAge (per year) 1.09 1.03-1.17 0.007Male 1.50 0.4-6.2 0.5Hypertension y/n 1.00 0.3-3.1 1.0Diabetes y/n 1.50 0.3-6.7 0.6Cortical v lacunarstroke1.67 0.55-5.05 0.364Baseline NIHSS 1.10 0.7-1.9 0.6Cortical greypermeability1.30 0.6-2.7 0.5 1.37 (0.61–3.10)* 0.4Basal gangliapermeability2.10 1.1-4.3 0.027 2.15 (1.01-4.57)* 0.046White matterpermeability0.9 0.2-5.5 0.9 1.5 (0.19–11.8)* 0.7CSF permeability 0.8 0.6-1.0 0.06 0.8 (0.6–1.1) * 0.2Fazekas DWMH score(0-3)3.91 1.82-8.39 <0.001 3.3 (1.4-7.5)# 0.005Fazekas PVWMHscore (0-3)4.09 1.90-8.78 <0.001 3.5 (1.4-8.6)# 0.006Fazekas WMHcombined score (0-6)4.50 2.0-10.0 <0.001 4.8 (2.0-11.4)* +4.1 (1.6-10.3)# +<0.001*=corrected for baseline WMH;#=corrected for age;+per unit increase in WMHStroke. Author manuscript; available in PMC 2013 November 29.

English

Blood-Brain Barrier Permeability and Long-Term Clinical and Imaging Outcomes in Cerebral Small Vessel Disease

     Edinburgh Research Explorer                                      Blood-Brain Barrier Permeability and Long-Term Clinical andImaging Outcomes in Cerebral Small Vessel DiseaseCitation for published version:Wardlaw, JM, Doubal, FN, Valdes-Hernandez, M, Wang, X, Chappell, FM, Shuler, K, Armitage, PA,Carpenter, TC & Dennis, MS 2013, 'Blood-Brain Barrier Permeability and Long-Term Clinical and ImagingOutcomes in Cerebral Small Vessel Disease' Stroke, vol 44, no. 2, pp. 525-527. DOI:10.1161/STROKEAHA.112.669994Digital Object Identifier (DOI):10.1161/STROKEAHA.112.669994Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Peer reviewed versionPublished In:StrokePublisher Rights Statement:Published in final edited form as:Stroke. 2013 February; 44(2): 10.1161/STROKEAHA.112.669994.General rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 28. Apr. 2017Blood-brain barrier permeability and long term clinical andimaging outcomes in cerebral small vessel diseaseJoanna M Wardlaw, MD1,2,3,4, Fergus N Doubal, PhD1,2,4, Maria Valdes-Hernandez, PhD1,3,4,Xin Wang, MSc1,3,4, Francesca M Chappell, PhD1,3, Kirsten Shuler, BSc1,3, Paul AArmitage, PhD1,3, Trevor C Carpenter, PhD1,3, and Martin S Dennis, MD21Brain Research Imaging Centre, University of Edinburgh, Edinburgh, UK2Stroke Medicine, Division of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK3Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration,Edinburgh, UK4Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh,UKAbstractBackground and Purpose—Increased blood-brain barrier (BBB) permeability occurs incerebral small vessel disease (SVD). It is not known if BBB changes predate progression of SVD.Methods—We followed up patients with non-disabling lacunar or cortical stroke and BBBpermeability MR imaging following their original stroke. About three years later, we assessedfunctional outcome (Oxford Handicap Score, OHS, poor outcome defined as 3-6), recurrentneurological events and white matter hyperintensity (WMH) progression on MRI.Results—Amongst 70 patients, mean age 68 (SD±11) years, median time to clinical follow upwas 39 months (IQR 30-45), median OHS was 2 (IQR 1-3); poor functional outcome wasassociated with higher baseline WMH score (p<0.001) and increased basal ganglia BBBpermeability (p=0.046). Amongst 48 patients with follow-up MRI, WMH progression at follow-upwas associated with baseline WMH (ANCOVA p<0.0001) and age (ANCOVA p=0.032).Conclusions—Further long term studies to evaluate the role of BBB dysfunction in progressionof SVD are required in studies that are large enough to account for key prognostic influences suchas baseline WMH and age.KeywordsBlood-brain barrier; leukoaraiosis; stroke; lacunar strokeIntroductionThe BBB becomes increasingly permeable with normal advancing age,1 particularly inpatients with vascular dementia1 and small vessel disease (SVD, Figure 1).2-4 Cross-Corresponding author: Joanna M Wardlaw, Western General Hospital, Edinburgh, EH4 2XU, UK, tel +44 131 537 2943, fax +44131 332 5150, Joanna.wardlaw@ed.ac.uk.This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providingthis early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before itis published in its final citable form. Please note that during the production process errors may be discovered which could affect thecontent, and all legal disclaimers that apply to the journal pertain.Europe PMC Funders GroupAuthor ManuscriptStroke. Author manuscript; available in PMC 2013 November 29.Published in final edited form as:Stroke. 2013 February ; 44(2): . doi:10.1161/STROKEAHA.112.669994. Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscriptssectional studies do not determine whether increased BBB permeability predates progressionof SVD and therefore might be causative. We followed up patients previously recruited inour cross-sectional study of BBB permeability changes in lacunar stroke2 to see if increasedBBB permeability might predate progression of SVD.MethodsWe originally recruited 97 previously independent patients with non-disabling ischaemicstroke,2 half lacunar, half cortical (controls). We assessed stroke severity (NIHSS score),performed diagnostic MR imaging (with DWI, T1, T2, FLAIR, T2*) to confirm strokesubtype and quantify white matter hyperintensities (WMH). We assessed BBB permeabilityin basal ganglia, cortex, white matter and lateral ventricular cerebrospinal fluid (CSF) 1-3months after the index stroke with sequential MR T1 imaging before and after intravenousgadolinium (described previously2, 5). The study was approved by the Lothian ResearchEthics Committee (2002/W/RA/03); all participants gave written informed consent.About three years later, we followed-up all patients to determine functional status (OxfordHandicap Score, OHS,6 similar to the modified Rankin Score: poor functionaloutcome=OHS 3-6, dead=OHS 6), recurrent strokes and assess SVD progression onstructural MR imaging. We cross-checked the patients’ histories with hospital records.Follow-up MR imaging was performed on the same 1.5T MR scanner (GE Signa LX,Milwaukee, WI, USA, 22 mTm−1 maximum strength gradients) using the same diagnosticsequences (T1, T2, FLAIR, T2*, DWI) described previously.2 We analysed imagingfeatures blind, noting new infarcts or haemorrhages, WMH (Fazekas score7) and change inWMH (Prins score8). The intra-class correlation coefficient for WMH rating by theneuroradiologist was 0.964. We registered follow-up to baseline scans and measuredintracranial, whole brain, and WMH volumes using a validated multispectral image analysistool.9 We masked infarcts to avoid confounding WMH volume,10 normalised brain andWMH volumes to intracranial volume (ICV) and determined WMH volume change.We performed univariate and multivariate analysis (binary logistic regression) to identifyvariables associated with functional status and WMH change at follow-up adjusted forduration of follow-up. We performed uni- and multi-variate linear regression to examineassociations between BBB permeability at baseline, WMH progression and functionaloutcome. We analysed factors associated with WMH volume change by ANCOVA. Allanalyses were performed in Minitab version 15, State College, Pennsylvania, US or SAS 9.1(www.sas.com).ResultsWe obtained clinical follow-up on 70/97 (78%) and MR imaging on 48 (49% of 97) of theoriginal study patients. The 70 patients with clinical follow-up did not differ from the 27without clinical follow-up in baseline age (mean at original presentation 68+/−11 vs 63+/−12, p=NS), median NIHSS (both 2 IQR 1-3), hypertension (both 66%) or lacunar stroke(50% vs 43%). The median baseline Fazekas deep and periventricular WMH scores wereeach 1; periventricular and deep Fazekas scores were >2 in 20 and nine patients respectively.At clinical follow-up at median 39 months (IQR 30-48), 25% had poor outcome (12 OHS3-5, six dead). Twenty-five had clinical and/or imaging evidence of recurrent neurologicalevents (36%): two, clinically-diagnosed recurrent stroke; 23, new focal weakness; four, newinfarct on follow-up imaging. In univariate analyses, poor functional outcome wasassociated with increasing age, higher baseline WMH score and basal ganglia BBBpermeability, but not baseline NIHSS, hypertension, diabetes or stroke subtype (Table 1).Wardlaw et al. Page 2Stroke. Author manuscript; available in PMC 2013 November 29. Europe PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsOn multivariate logistic regression (adjusted for baseline age, WMH score, BBBpermeability) predictors of poor outcome were baseline total WMH score (OR 4.8, 2.0-11.4,p<0.001) and basal ganglia BBB permeability (OR 2.2, 1.0-4.6, p=0.046).Forty-eight patients had follow-up MR imaging, median 39 (IQR 30-45) months after indexstroke; baseline age (67+/−10), median NIHSS (2, IQR 2-3), proportion hypertensive (65%),lacunar index stroke (48%) and WMH score were the same as for all 70 with clinical follow-up. 6/48 (13%) were OHS=3-5.WMH score had increased in 33/48 and remained unchanged in 15/48 (according to Prinsand Fazekas scores, Figure 1b). On univariate analyses, baseline WMH score, but not age ortime since stroke, strongly predicted progression of WMH (OR 8.7, 2.1-35.3, p<0.001).Median WMH volume at baseline was 8.5 ml (IQR 5.9-15.2), at follow-up was 12.2 ml(IQR 8.6-19.7), median increase 3.2 ml (IQR 1.2-7.5, p<0.0001). The strongest predictors ofincreasing WMH volume at follow-up were baseline WMH volume (ANCOVA p<0.0001)and age (ANCOVA p=0.032). WMH volume at follow-up increased by: 1.80 times(1.56-2.08) per unit (mm3) of WMH volume and 1.01 times (1.00-1.02) per additional yearof age at baseline.DiscussionPoor functional outcome three years after lacunar or mild cortical ischaemic stroke wasassociated with having more WMH, being older and having increased BBB permeability inthe basal ganglia. Worsening of WMH was dominated by having more WMH at baselineand older age. A third had clinical/imaging evidence of recurrent neurological events,although only two were formally diagnosed as recurrent stroke, consistent with recentrecognition of WMH-associated subtle neurological symptoms.11 Long term poor functionaloutcome and WMH progression were not associated with vascular risk factors, baselineNIHSS or stroke subtype, possibly because the study was small, NIHSS very mild, or due tosecondary prevention, although this does not control risk factors perfectly.WMH increased in most patients at follow-up. Similar change in WMH scores (27-74%increase)12 or volume (1.1-2.4 ml) have been noted previously but the magnitude of effect ofWMH or age on WMH progression, and the association with BBB permeability, are novel.1These data on WMH progression, particularly the 95% confidence intervals (increase overthree years of 1.56-2.08 times per additional mm3 of baseline WMH volume and 1.00-1.02times per additional year of age at baseline), provide useful data for sample size calculationsfor studies wishing to use WMH change as a surrogate outcome measure.The study strengths include testing clinical and imaging predictors of SVD progression, useof qualitative and quantitative WMH measures, careful blinding, validated imagingmethods.5,9,10 Weaknesses include small sample size, limited power for multivariate testing,22% loss to clinical follow-up (possibly reflecting the three-year time lapse).Future studies assessing BBB permeability in SVD should: assess recurrent stroke, covertneurological symptoms, accumulating SVD features, vascular risk factors; track BBBpermeability to new lesion formation;4 be powered to adjust for multiple overlappingcovariates, particularly WMH load.AcknowledgmentsFunding: The Chief Scientist Office of the Scottish Executive (CZB/4/281), the Wellcome Trust (075611), theRow Fogo Charitable Trust, and the RCUK Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE)Edinburgh, supported the study. The imaging was conducted in the Brain Research Imaging Centre, University ofWardlaw et al. Page 3Stroke. Author manuscript; available in PMC 2013 November 29. Europe PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsEdinburgh (www.bric.ed.ac.uk) a centre in the Scottish Imaging Network, A Platform for Scientific Excellence(SINAPSE) Collaboration.Disclosures: The work was supported by research grants to the host institution but the authors have no conflict ofinterests. The authors had full access to the data and take responsibility for its integrity.References1. Farrall AJ, Wardlaw JM. Blood brain barrier: ageing and microvascular disease - systemic reviewand meta-analysis. Neurobiol Aging. 2007; 30:337–352. [PubMed: 17869382]2. Wardlaw JM, Doubal F, Armitage P, Chappell F, Carpenter T, Maniega SM, et al. Lacunar stroke isassociated with diffuse blood-brain barrier dysfunction. Ann Neurol. 2009; 65:194–202. [PubMed:19260033]3. Topakian R, Barrick TR, Howe FA, Markus HS. Blood-brain barrier permeability is increased innormal-appearing white matter in patients with lacunar stroke and leucoaraiosis. JNNP. 2010;81:192–197. [PubMed: 19710048]4. Taheri S, Gasparovic C, Huisa BN, Adair JC, Edmonds E, Prestopnik J, et al. Blood-brain barrierpermeability abnormalities in vascular cognitive impairment. Stroke. 2011; 42:2158–2163.[PubMed: 21719768]5. Armitage PA, Farrall AJ, Carpenter TK, Doubal FN, Wardlaw JM. Use of dynamic contrast-enhanced MRI to measure subtle blood-brain barrier abnormalities. Magn Reson Imaging. 2011;29:305–314. [PubMed: 21030178]6. Bamford J, Sandercock P, Warlow C, Slattery J. Interobserver agreement for the assessment ofhandicap in stroke patients. Stroke. 1989; 20:828. [PubMed: 2728057]7. Fazekas F. Magnetic resonance signal abnormalities in asymptomatic individuals: their incidenceand functional correlates. Eur Neurol. 1989; 29:164–168. [PubMed: 2731564]8. Prins ND, van Straaten ECW, van Dijk EJ, Simoni M, van Schijndel RA, Vrooman HA, et al.Measuring progression of cerebral white matter lesions on MRI. Visual rating and volumetrics.Neurology. 2004; 62:1533–1539. [PubMed: 15136677]9. Valdes Hernandez MC, Ferguson KJ, Chappell FM, Wardlaw JM. New multispectral MRI datafusion technique for white matter lesion segmentation: method and comparison with thresholding inFLAIR images. Eur Radiol. 2010; 20:1684–1691. [PubMed: 20157814]10. Wang X, Valdes-Hernandez MC, Doubal FN, Wardlaw JM. The effects of infarcts on theassessment of brain atrophy in longitudinal studies. Cerebrovasc Dis. 2011; 31:148.11. Windham BG, Griswold ME, Shibata D, Penman A, Catellier DJ, Mosley TH Jr. Covertneurological symptoms associated with silent infarcts from midlife to older age: theAtherosclerosis Risk in Communities study. Stroke. 2012; 43:1218–1223. [PubMed: 22382163]12. Cavalieri M, Schmidt R. New developments in diagnosis of vascular cognitive impairment. JNeurol Sci. 2010; 299:11–14. [PubMed: 20850800]Wardlaw et al. Page 4Stroke. Author manuscript; available in PMC 2013 November 29. Europe PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsFigure 1.72-year-old patient with right hemisphere lacunar stroke. (a) two days after stroke MR DWIshows the acute right centrum semiovale lacunar infarct, T2* shows a few microbleeds,FLAIR shows numerous WMHs. BBB imaging six weeks later: FLAIR 30 minutes after ivGadolinium (Gd) shows Gadolinium in cortical sulci and perivascular spaces (arrows). (b)FLAIR and T2* images two years later show increased WMHs and microbleeds (baselineFLAIR and T2* shown for comparison).Wardlaw et al. Page 5Stroke. Author manuscript; available in PMC 2013 November 29. Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsWardlaw et al. Page 6Table 1Predictors of poor outcome (OHS 3-6) three years after lacunar or mild cortical strokeUnivariate MultivariateVariable OR/unitincrease95% CI P value OR (95% CI)/unit increaseP valueAge (per year) 1.09 1.03-1.17 0.007Male 1.50 0.4-6.2 0.5Hypertension y/n 1.00 0.3-3.1 1.0Diabetes y/n 1.50 0.3-6.7 0.6Cortical v lacunarstroke1.67 0.55-5.05 0.364Baseline NIHSS 1.10 0.7-1.9 0.6Cortical greypermeability1.30 0.6-2.7 0.5 1.37 (0.61–3.10)* 0.4Basal gangliapermeability2.10 1.1-4.3 0.027 2.15 (1.01-4.57)* 0.046White matterpermeability0.9 0.2-5.5 0.9 1.5 (0.19–11.8)* 0.7CSF permeability 0.8 0.6-1.0 0.06 0.8 (0.6–1.1) * 0.2Fazekas DWMH score(0-3)3.91 1.82-8.39 <0.001 3.3 (1.4-7.5)# 0.005Fazekas PVWMHscore (0-3)4.09 1.90-8.78 <0.001 3.5 (1.4-8.6)# 0.006Fazekas WMHcombined score (0-6)4.50 2.0-10.0 <0.001 4.8 (2.0-11.4)* +4.1 (1.6-10.3)# +<0.001*=corrected for baseline WMH;#=corrected for age;+per unit increase in WMHStroke. Author manuscript; available in PMC 2013 November 29.

http://dx.doi.org/10.1161/STROKEAHA.112.669994

Blood-Brain Barrier Permeability and Long-Term Clinical and Imaging Outcomes in Cerebral Small Vessel Disease

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