XVII. European Stroke Conference
Nice, France

Oral Session:

Small vessel disease 
Date: Thursday 15 May 2008  
Time: 10:30 - 10:40 -  Room: Hermes
Chair: J. M. Orgogozo, France and L. Pantoni, Italy

01
Increased blood-brain permeability in normal-appearing white matter in subjects with small vessel disease. A MRI study.
R. Topakian    T.R.Barrick    R.A.Charlton    F. Schiavone    F.A.Howe    H.S.Markus                            
 

Clinical Neuroscience, St. George´s University of London

UNITED KINGDOM

Background: The pathogenesis of cerebral small vessel disease (SVD) is incompletely understood but endothelial dysfunction has been implicated, particularly in SVD with leukoaraiosis. It has been hypothesised that this results in increased blood-brain barrier (BBB) permeability with leakage of blood constituents into the vessel wall and white matter. BBB permeability can be estimated using contrast enhanced magnetic resonance imaging (MRI). We tested the hypothesis that MRI can detect increased BBB permeability in patients with stroke due to SVD compared to age-matched controls. Methods: 24 patients with symptomatic SVD and 18 controls underwent T1 volumetric MRI before and after injection of 40ml gadodiamide. Scanning was continued for 32 minutes post injection to determine the time course of contrast enhancement. Pre-contrast T1 images were subtracted from post-contrast images at each time point. Mean signal intensity change was plotted against time to calculate area under curve values. Fluid-attenuated inversion recovery images were used to score leukoaraiosis on the Fazekas scale and to produce a mask containing all white matter lesions (WML). Using the WML mask and high resolution T1 images, the brain was automatically segmented to determine permeability in different compartments: cerebrospinal fluid (CSF), grey matter (GM), normal-appearing white matter (NAWM), and WML. Results: In both patients and controls, permeability within WML was increased compared to NAWM. Degree of leukoaraiosis was significantly correlated with permeability in CSF (p=0.001), GM (p<0.0005), and NAWM (p=0.007), but not with permeability in WML (p=0.81). Multivariate regression analyses identified leukoaraiosis grade as an independent predictor of BBB permeability in NAWM after adjustment for subject status, age, weight, gender, hypertension, diabetes, smoking, and brain atrophy. Discussion: This study provides evidence of increased BBB permeability in NAWM in SVD. Longitudinal studies are needed to determine whether BBB permeability in NAWM predicts future development of WML.

Small vessel disease 
Date: Thursday 15 May 2008  
Time: 10:40 - 10:50 -  Room: Hermes
Chair: J. M. Orgogozo, France and L. Pantoni, Italy

02
On the etiology of incident brain lacunes: longitudinal observations from the LADIS study.
A.A.Gouw    W.M. van der Flier    L. Pantoni    D. Inzitari    T.  Erkinjuntti    L.O. Wahlund    G.  Waldemar    R. Schmidt    F. Fazekas    P. Scheltens
F. Barkhof

department of neurology and Alzheimer Center, Vrije Universiteit Medical Center.

THE NETHERLANDS

Background: Lacunes are regarded as subcortical ischaemic infarcts, resulting from the occlusion of small perforating arteries. However, the pathogenetic mechanisms have not been fully elucidated. We studied the relation between incident lacunes and white matter hyperintensities (WMH) in a group of initially independently living elderly over a three year period. Methods: Baseline and repeat MRI (3-year follow-up) were collected within the multi-center, multinational LADIS study (n=358). Incident lacunes were characterized with respect to brain region (subcortical white matter (WM), basal ganglia, infratentorial region), their appearance within pre-existent WMH at baseline (yes/no) and (change in) WMH size surrounding the incident lacune. Results: In total, 106 new lacunes were observed in 62 patients (range 1 – 8). There were 58 (55%) incident lacunes in the subcortical WM, 35 (33%) in the basal ganglia and 13 (12%) in the infratentorial region. Lacunes in the subcortical WM often occurred (47%) within pre-existing hyperintensities, in contrast to basal ganglia (17%) and infratentorial (23%) lacunes (p= 0.01). When lacunes developed outside pre-existing WMH, those located in the subcortical WM were mostly accompanied by newly emerging WMH (71%), while most of the new basal ganglia (86%) and infratentorial incident lacunes (90%) only had a hyperintense rim or no rim at all (p< 0.001). Conclusion: Incident lacunes in the subcortical WM seem to be more closely related to WMH than those in the basal ganglia and infratentorial region. We suggest that new lacunes in the subcortical WM develop slowly from ongoing or increasing hypoxia in pre-existing WMH, ultimately leading to cavitation. On the contrary, new basal ganglia or infratentorial lacunes most often appear in previously unaffected tissue, probably as the result of ischemia due to an acute occlusion.

Small vessel disease 
Date: Thursday 15 May 2008  
Time: 10:50 - 11:00 -  Room: Hermes
Chair: J. M. Orgogozo, France and L. Pantoni, Italy

03
Genelarized microvascular changes in patients with cerebral small vessel disease: evidence from sublingual Side-stream Dark Field (SDF)-imaging.
M. Khalilzada    K. Dogan    C. Ince    J. Stam                                          
 

Departments of Neurology and Physiology; Academic Medical Center, University of Amsterdam

THE NETHERLANDS

Background: Cerebral small vessel disease (SVD) is a subtype of stroke with pathologic changes in the cerebral arterioles. It is not known if these changes are limited to the brain, or part of a generalized vascular disorder. Methods: We studied the sublingual microcirculation in 10 healthy controls, 10 patients with large artery strokes (LVD), and 8 patients with SVD (lacunar infarcts, no cardio-embolism or large artery atherosclerosis) by Side-stream Dark Field (SDF)-imaging, using a hand-held SDF microscope connected to a monitor and video recorder. Artifact-free video fragments were analyzed with previously validated methods, by an observer blinded to the origin of the video's. Imaging software measured the length of functional capillaries per surface unit of imaged tissue (functional capillary density, FCD, mm/mm2). Blood flow was assessed qualitatively using a visual scoring system, and expressed as the percentage of blood vessels with abnormal flow (abnormal flow index, AFI). We also recorded the presence of extravascular erythrocyte material (EEM) as possible evidence of past microbleeds or obliterated vessels. Differences were analyzed with the Kruskal-Wallis test. Results: FCD differed between the three groups (SVD; LVD; controls: mean 14.8; 17.0; 16.1 mm/mm2; P 0.01). AFI was significantly higher for SVD patients compared with LVD patients and controls (median 10.2 %; 5.4 %; 4.4 %, respectively; P 0.04). EEM was more frequent in patients with SVD (median 23 %; 0 %; 0 %; P 0.004). Discussion: We found evidence of pathologic changes in the sublingual microcirculation in patients with SVD, in excess to LVD patients and healthy controls. This is consistent with the hypothesis that cerebral small vessel disease is part of a generalized disorder of the microcirculation.

Small vessel disease 
Date: Thursday 15 May 2008  
Time: 11:00 - 11:10 -  Room: Hermes
Chair: J. M. Orgogozo, France and L. Pantoni, Italy

04
Age-related white matter changes progression over time and disability transition. The LADIS (Leukoaraiosis And DISability) Study.
A. Poggesi    A. Gouw    G. Pracucci    T. Erkinjuntti    F. Fazekas    J. Ferro    M. Hennerici    P. Scheltens    D. Inzitari    L. Pantoni
on behalf of the LADIS group

Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy

ITALY

Objective: Our aim was to establish the role of ARWMC progression on the transition from functional autonomy to disability in a cohort of initially non-disabled elderly subjects. Methods: The LADIS (Leukoaraiosis And DISability) Study is a longitudinal observational study that involves 11 European centers. Six-hundred-thirty-nine subjects with no or only mild disability according to the Instrumental Activities of Daily Living (IADL) Scale, and with ARWMC of different severity degrees were assessed and followed up for 3 years. The main outcome was transition from 0 or 1 to 2 or more IADL activities limited. ARWMC severity was scored on baseline MRI by the Fazekas scale (mild, moderate, severe group); ARWMC progression after 3 years was assessed with the Rotterdam Progression scale (absence/presence of progression in 9 brain regions). Results: Out of the 639 subjects enrolled (mean age 74.1+/-5.0, M/F:288/351), 391 had both MRI scan and IADL status reassessed at the 3-year follow-up (mean age 73.6+/-5.0, M/F:183/208). Disability transition occurred in 26% of these subjects. In a logistic regression analysis, adjusting for other possible determinants of disability, ARWMC progression turned out to predict disability transition (OR 1.37, 95%CI 1.15-1.63 for each point progression). When baseline ARWMC severity was entered in the model, both ARWMC progression and baseline severity retained an independent impact on disability transition (Rotterdam Progression scale: OR 1.27, 95%CI 1.05-1.54; Fazekas scale severe vs. mild: OR 3.83, 95%CI 1.69-8.66). Discussion: In our cohort of initially non-disabled subjects, both ARWMC progression and baseline severity were independent predictors of functional decline.

Small vessel disease 
Date: Thursday 15 May 2008  
Time: 11:10 - 11:20 -  Room: Hermes
Chair: J. M. Orgogozo, France and L. Pantoni, Italy

05
Progressive motor compromise is closely related to disability and death in age-related white matter changes – 3-year results of the LADIS study
H. Bäzner    C. Blahak    L. Pantoni    D. Inzitari    M.G.Hennerici                                   
on behalf of the LADIS study group

Universitätsklinikum Mannheim, University of Heidelberg

GERMANY

Background: In the LADIS (Leukoaraiosis And DISability) study eleven European centres collaborated to evaluate age-related white matter changes (ARWMC) as an independent predictor of the transition to disability in the elderly. We aimed at prospectively determining the association between clinical measures of gait and balance with the attainment of the primary study endpoint (transition to >/=2 IADL activities limited or death) at 3-year follow-up in the LADIS population. Methods: 639 non-disabled individuals were followed-up for 3 years. According to central MRI ratings, patients were stratified into three groups of mild, moderate, and severe ARWMC. The short physical performance battery (SPPB) was performed to assess standing balance, walking speed, and repeated chair stands with total scores ranging from 0-12. A decline in motor performance was defined as a score difference of >/=1 point in SPPB at 3-year follow-up. Results: At 3-year follow-up data of 457 individuals with complete SPPB scores demonstrated a progressive worsening of SPPB scores in all three ARWMC severity groups (baseline data in brackets): 9.8+/-2.4 (10.3+/-2.0, p<0.001) in the mild, 9.4+/-2.4 (10.0+/-2.0, p<0.001) in the moderate, and significantly worse with a score of 7.6+/-3.4 (9.2+/-2.5, p<0.001) in the severe group. 128 individuals (20%) showed a decline >/=1 score point in SPPB which was correlated with a high risk of transition to disability or death within the 3-year follow-up (OR: 3.2, 95% CI: 1.9-5.3; p<0.001 in multivariate logistic regression). Discussion: This large prospective study demonstrates the significant impact of worsening motor performance over a 3-year follow-up period on the transition to disability or death in elderly individuals with ARWMC.

Small vessel disease 
Date: Thursday 15 May 2008  
Time: 11:20 - 11:30 -  Room: Hermes
Chair: J. M. Orgogozo, France and L. Pantoni, Italy

06
Balance disturbances and falls predict transition to disability in patients with age-related white matter changes – longitudinal results from the LADIS study
C. Blahak    H. Baezner    L. Pantoni    D.  Inzitari    M.G.Hennerici                                   
on behalf of the LADIS Study Group

Universitaetsklinikum Mannheim, University of Heidelberg

GERMANY

Background: Previous results of the LADIS (Leukoariosis And DISability) study demonstrated a significant association of age-related white matter changes (ARWMC) with falls and balance disturbances. However, the impact of postural control deficits on the transition to disability in patients with ARWMC have not been examined in a prospective study so far. Methods: 639 initially non-disabled individuals (mean age 74.1±5.0) were followed-up for 3 years with various clinical and functional tests, including scales to assess disability and scores for motor testing. Centralized rating of MRI was performed to quantify the severity of ARWMC. Results: Transition to disability or death within the three years of follow-up was predicted by severe ARWMC (OR 2.72; 95% CI 1.84-4.02; p<0.001 in multivariate logistic regression), history of falls (OR 1.72; CI 1.19-2.51; p=0.004) and balance disturbances (OR 2.85; CI 2.01-4.04; p<0.001) at baseline. The rate of disability after three year follow-up was 77.5% in patients with severe ARWMC, history of falls and balance disturbances at baseline, in contrast to just 12% in patients with mild ARWMC and normal postural control (p<0.001 in Fisher's exact test). Continuous physical activity significantly reduces the risk of transition to disability or death (OR 0.69; CI 0.49-0.96; p=0.029), primarily in patients with existing postural control deficits at baseline. Discussion: These data reveal the significant impact of falls and balance disturbances on transition to disability or death in patients with ARWMC within three years. However, continuous physical activity already has a beneficial effect to prevent rapid transition to disability in patients with postural control deficits at baseline.

Small vessel disease 
Date: Thursday 15 May 2008  
Time: 11:30 - 11:40 -  Room: Hermes
Chair: J. M. Orgogozo, France and L. Pantoni, Italy

07
Cerebral White Matter Hyperintensities, Gait and the Risk of Incident Falls – a Population-based Study
V. Srikanth    R. Beare    C.L.Blizzard    T.G.Phan    J. Chen    J.M.Stapleton    M. Callisaya    K.L.Martin    D.C.Reutens       
 

Monash University, Melbourne

AUSTRALIA

Background: Although cerebral white matter hyperintensities are postulated to cause falls in older people, this has not been demonstrated prospectively. Methods: We obtained the volume of white matter hyperintensities (WMHV) on magnetic resonance imaging (MRI), computerized gait measurements and physiological measures of falls risk in a randomly selected population-based sample (n = 294, mean age 72.3 years). Incident falls were recorded prospectively over a 12 month period. Using regression modelling, we estimated the risk of incident falls associated with WMHV and examined the relative contributions of WMHV, gait and other physiological factors to falls risk. Results: Increasing baseline WMHV was associated with any incident fall (p = 0.008) and multiple falls (p = 0.01) after adjusting for age, sex, total brain volume and other physiological predictors of falls. Greater WMHV was associated with poorer gait and greater gait variability (both p < 0.001). The effect of WMHV on the risk of falls was magnified in people with poorer quadriceps muscle strength (p = 0.03) and greater gait variability (p = 0.001). Conclusions: These data provide the first evidence supporting a role for cerebral white matter hyperintensities in the causation of falls in the general older population. They should be considered as therapeutic targets for interventional trials in falls prevention.

Small vessel disease 
Date: Thursday 15 May 2008  
Time: 11:40 - 11:50 -  Room: Hermes
Chair: J. M. Orgogozo, France and L. Pantoni, Italy

08
Enlarged Perivascular Spaces are Associated with Ischaemic Stroke, Increasing Age, White Matter Lesions and Hypertension but not with Subtypes of Stroke.
F.N.Doubal    M.S.Dennis    J.M.Wardlaw                                                 
 

University of Edinburgh

UNITED KINGDOM

Introduction: Enlarged perivascular spaces (EPVS) in the basal ganglia (BG) and centrum semiovale (CS) are frequent on brain magnetic resonance imaging (MRI) and often regarded as normal. Their pathophysiology and clinical significance are uncertain. We hypothesised that if EPVS were related to small vessel disease they would be associated with other features of small vessel disease. Methods: We prospectively recruited patients presenting to our stroke service with ischaemic stroke. All patients had 1.5T brain MRI. Stroke was subtyped as cortical or lacunar by an experienced stroke physician on clinical and radiological criteria. 100 healthy age matched controls were recruited from the community. Blind to clinical data, a neuroradiologist rated EPVS 0-4 (0=none, 4=>40) in the basal ganglia (BG) and centrum semiovale (CS) on T2-weighted MRI, and white matter lesions (WML) on FLAIR with the Fazekas score. We compared EPVS between stroke subtypes and normal controls and assessed associations with hypertension, age and WML. Results: We recruited 208 patients; 106 lacunar and 102 cortical (mean ages 67 and 71 yrs respect.). Similar proportions had a history of hypertension (lacunar 58%, cortical 67%) and diabetes (lacunar 20%, cortical 13%). There were similar distributions of EPVS scores (0:1:2:3:4) in the BG for lacunar (2:56:25:12:11) and cortical (5:60:11:16:10) strokes –and in the CS for lacunar (2:35:35:27:7) and cortical (3:41:32:19:7) strokes. EPVS for both stroke subtypes were higher than age-matched normal controls (Chi squared test for trend p<0.01), associated with increasing age (ANOVA p<0.001), WML load (Spearman’s rho 0.55, p=0.01) and hypertension (BG EPVS only, Chi square test for trend p=0.03). Conclusions: EPVS are not normal but are associated with stroke, increasing age, WML and hypertension although not with stroke subtype. The exact pathophysiology of EPVS remains unclear but EPVS should be considered when assessing WML and related risk factors.

Small vessel disease 
Date: Thursday 15 May 2008  
Time: 11:50 - 12:00 -  Room: Hermes
Chair: J. M. Orgogozo, France and L. Pantoni, Italy

09
VALUE OF RETINAL MICROANGIOPATHY AS LEUKOARAIOSIS, LACUNAR INFARCT AND COGNITIVE IMPAIRMENT MARKER.
M. Rodríguez-Yáñez    I. Rodríguez    R. Leira    I. Lema    M. Blanco    M. Castellanos    D. Santos    S. Arias    X. Rodríguez-Osorio    J. Castillo
 

Hospital Clínico Universitario, Santiago de Compostela

SPAIN

Background: Retinal vascularization shares embryological and physiological characteristics with brain microcirculation. We study the diagnostic value of retinal microangiopathy disturbances as possible marker of leukoaraiosis, lacunar infarcts and cognitive impairment. Methods: We included 150 patients (70.9 (9.1) years, 56% male) with first ischemic stroke between 3 and 6 months from stroke onset and 50 controls (68.3 (8.2) years, 60% male). Fifty subjects (43 patients and 7 controls) had diabetes type 2, diagnosed >1 year before. Microangiopathy was defined as the presence of two or more signs of microvascular disturbances. Leukoaraiosis was classified according to its intensity. Cognitive impairment was evaluated by Minimental State Examination (MMSE). Results: Retinal microangiopathy was associated with higher relative risk of combined neurological disease (leukoaraiosis and/or lacunar infarct and/or cognitive impairment) of 3.0 (CI 95% 1.1 to 8.1) in all subjects, and of 3.8 (CI 95% 1.1 to 12.6) in non-diabetic subjects. The degree of retinal microangiopathy was significantly associated with leukoaraiosis intensity and MMSE score. Retinal microangiopathy was associated with the presence of lacunar infarcts (OR 7.1, CI 95% 1.6 to 30.6), but not with leukoaraiosis (OR 1.5, CI 95% 0.4 to 6.2), nor cognitive impairment (OR 3.0, CI 95% 0.7 to 13.2) after adjustment by significant variables in univariated analysis. In non-diabetic subjects, this association was maintained for lacunar infarcts (OR 4.4, CI 95% 1.1 to 27.1) and leukoaraiosis (OD 3.7, CI 95% 1.1 to 24.2), but not for cognitive impairment (OR 2.5, CI 95% 0.4 to 17.3). Conclusions: The identification of retinal microangiopathy in a fundoscopic examination is a useful screening tool to stratify patients with risk of suffers leukoaraiosis and/or silent lacunar infarcts, especially in non-diabetic subjects with high vascular risk.

Small vessel disease 
Date: Thursday 15 May 2008  
Time: 12:10 - 12:20 -  Room: Hermes
Chair: J. M. Orgogozo, France and L. Pantoni, Italy

10
A hospital-based study of Impact Factors and Prognosis of Chinese Patients with Lacunar Infarct
B. Wu    M. Liu                                                        
 

West China Hospital, Sichuan University

CHINA

Objectives: The aim of this study was to investigate the case fatality and functional outcome following a first-ever lacunar infarct, accounting for all stroke, ischemic stroke subtypes (lacunar infarct vs non-lacunar infarct) and relevant prognostic variables. Methods: All patients with a first-ever stroke within 1-month after stroke onset were registered from 4 Chinese hospital-based prospective registries centers between March 2002 and March 2007. We collected stroke risk factors and characteristics and used a cross-sectional follow-up. We analyzed 30-day, 90-day, 180-day, and 1-year case fatality, death and dependency, and stroke recurrence by means of logistic regression analysis. We constructed Kaplan-Meier survival curves, and compared the respective subgroups by means of log-rank tests for significant difference. Results: A total of 3905 patients with first-ever cerebral infarct were included, of which 1650 (42.3%) were lacunar infarct, 2255 non-lacunar infarct. Age and hypertension were the independent risk factors for lacunar infarct. Case fatality was at all four time points lower in lacunar infarct (5.3, 6.4, 7.8, and 17.4%, respectively), higher in non-lacunar infarct (9.5, 14.3, 16.5, and 20.1%, respectively). Age, diabetes, smoking and the NIHSS score at admission were the independent predictors of 1-year case fatality. Death and dependency was also lower in lacunar infarct patients than that in non-lacunar infarct patients. Recurrent stroke was important death cause. Conclusions: 1. This is the first large-scale prospective study for lacunar infarct in China. The ratio of lacunar infarct in China was much higher than that of in western country. 2. Age and hypertension were independent risk factor for lacunar infarct. 3. The prognosis after lacunar infarct is not benign. 4. Age, diabetes, smoking and the NIHSS score at admission were the independent predictors of 1-year case fatality. 5. Stroke recurrence is common in the patents with lacunar infarct. Secondary prevention of lacunar infarct is very important.

Small vessel disease 
Date: Thursday 15 May 2008  
Time: 12:20 - 12:30 -  Room: Hermes
Chair: J. M. Orgogozo, France and L. Pantoni, Italy

11
IMPAIRED VITALITY OF ENDOTHELIAL PROGENITOR CELLS IN PATIENTS WITH CEREBRAL SMALL VESSEL DISEASE: THE IMPORTANCE OF VITAMIN B12 AND HAPTOGLOBIN PHENOTYPE
R.P.W.Rouhl    R.J.van Oostenbrugge    J.G.M.C.Damoiseaux    L.L.Debrus-Palmans    J. Delanghe    J.W.Cohen Tervaert    J. Lodder                     
 

University Hospital Maastricht

THE NETHERLANDS

BACKGROUND – Earlier, we reported that endothelial progenitor cells (EPC), which are important for the maintenance of endothelial integrity, were less vital in lacunar infarct patients, whereas patient serum attenuated EPC outgrowth. In the present study, we investigate two candidate factors for this effect. 1) Vitamin B12 (Vit B12): deficiency relates to higher TNF-α levels, which in turn induce endothelial dysfunction and lower EPC vitality; and 2) haptoglobin phenotypes (Hpt): the Hpt 1-1 may relate to more severe small vessel disease, an effect that might be mediated by lower EPC vitality. METHODS – In 32 prospectively included first-ever lacunar stroke patients, EPC vitality was assessed using cultures (median counts of EPC clusters per well with interquartile range: c/w; IQR). Vit B12 levels and Hpt were determined using previously described methods. For Vit B12, we took the mean concentration in a large group of lacunar stroke patients as a cut-off point. RESULTS – 13 Patients with Vit B12 < 200 pmol/l had lower EPC vitality (28.5 c/w; IQR 38.3) than 19 patients > 200 pmol/l (79.8 c/w; IQR 65.1; p=.03). Furthermore, 8 patients with Hpt 1-1 had lower EPC vitality (37.9; IQR 45.4) than 21 patients with other Hpt (96.3; IQR 94.6; p=.02). CONCLUSION –Vit B12 deficiency as well the Hpt 1-1 phenotype relate to lower EPC vitality in lacunar stroke. Though mechanisms have yet to be determined, these findings could open new strategies for the treatment of patients with lacunar stroke and its consequences.

Small vessel disease 
Date: Thursday 15 May 2008  
Time: 12:30 - 12:40 -  Room: Hermes
Chair: J. M. Orgogozo, France and L. Pantoni, Italy

12
Plasma vitamin B12 status and cerebral white matter lesions
L.M.de Lau    A.D.Smith    H. Refsum    C. Johnston    M.M.Breteler                                   
 

Erasmus Medical Center, Rotterdam

THE NETHERLANDS

Background Elevated homocysteine levels have been associated with higher prevalence of cerebral white matter lesions and infarcts, and worse cognitive performance. This raises the question whether factors involved in homocysteine metabolism, such as vitamin B12, are also related to these outcomes. We aimed to examine the association of several markers of vitamin B12 status with cerebral white matter lesions, infarcts, and cognition. Methods We evaluated the association of plasma concentrations of vitamin B12, methylmalonic acid, holotranscobalamin, and transcobalamin saturation with cerebral white matter lesions, infarcts and cognitive performance among 1,019 non-demented elderly participants of the population-based Rotterdam Scan Study. Analyses were adjusted for several potential confounders, including homocysteine and folate concentration. Results Poorer vitamin B12 status was significantly associated with greater severity of white matter lesions, in particular periventricular white matter lesions, in a concentration-related manner. Adjustment for common vascular risk factors (including blood pressure, smoking and intima media thickness) did not alter the associations. Adjustment for homocysteine and folate modestly weakened the associations. No association was observed for any of the studied markers of vitamin B12 status with presence of brain infarcts and cognitive performance. Discussion Our results indicate that vitamin B12 status in the normal range is associated with severity of white matter lesions, especially periventricular lesions. Given the absence of an association with cerebral infarcts, we hypothesize that this association is explained by direct effects on methylation reactions and myelin integrity in the brain.