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Background:\ud \ud A structural magnetic resonance imaging measure of combined neurovascular and neurodegenerative burden may be useful as these features often coexist in older people, stroke and dementia.\ud Aim:\ud \ud We aimed to develop a new automated approach for quantifying visible brain injury from small vessel disease and brain atrophy in a single measure, the brain health index.\ud Materials and methods:\ud \ud We computed brain health index in N = 288 participants using voxel-based Gaussian mixture model cluster analysis of T1, T2, T2*, and FLAIR magnetic resonance imaging. We tested brain health index against a validated total small vessel disease visual score and white matter hyperintensity volumes in two patient groups (minor stroke, N = 157; lupus, N = 51) and against measures of brain atrophy in healthy participants (N = 80) using multiple regression. We evaluated associations with Addenbrooke’s Cognitive Exam Revised in patients and with reaction time in healthy participants.\ud Results:\ud \ud The brain health index (standard beta = 0.20–0.59, P 0.05) and small vessel disease score (standard beta = 0.02–0.27, P > 0.05) alone in both patient groups. Further, the brain health index (standard beta = 0.57–0.59, P 0.05) in healthy participants.\ud Conclusions:\ud \ud The brain health index is a new image analysis approach that may usefully capture combined visible brain damage in large-scale studies of ageing, neurovascular and neurodegenerative disease.

Cerebral small vessel disease (SVD) is a distinct microvascular disorder that can lead to lacunar stroke, an important stroke subtype that accounts for a quarter of all ischaemic strokes. SVD is associated with imaging biomarkers such as white matter hyperintensities (WMH). The cause of SVD is largely unknown, although inflammation and blood-brain barrier failure via endothelial dysfunction have been implicated. Elevated plasma biomarkers of inflammation are associated with coronary heart disease and large vessel stroke but the role of inflammation in SVD is less well understood. Our hypothesis is that inflammation plays a role in SVD and we sought to examine this by reviewing the literature for evidence of this, and by conducting a brain imaging study of patients with a known inflammatory disease and reviewing the images for evidence of inflammation and SVD, and comparing findings with controls groups. Section A: This thesis begins with a systematic review and meta-analysis of 13 plasma biomarkers of four physiological processes (coagulation, fibrinolysis, endothelial dysfunction and inflammation) in lacunar stroke versus non-lacunar stroke (to control for having any stroke) and non-stroke (to compare to the general population). We sought to know if there were differences in these biomarkers between lacunar stroke and other stroke subtypes and non-stroke controls as a way of generating hypotheses for the disease mechanisms that might lead to lacunar stroke. Findings revealed differences in several biomarkers between lacunar stroke and healthy controls but only fibrinogen, D-dimer, von Willebrand factor and interleukin-6 were different (all significantly lower in lacunar stroke) between lacunar stroke and other stroke subtypes. There was heterogeneity between studies, including variations in the definition of lacunar stroke and most studies measured the biomarkers in the acute phase post stroke, which is potentially confounding. To further examine plasma biomarkers of inflammation and endothelial dysfunction in SVD, we used data from a prior study of mild stroke conducted at the Brain Research Imaging Centre, University of Edinburgh, UK. Lacunar stroke patients were compared to cortical stroke patients. The lacunar group had lower levels of tissue plasminogen activator independent of age, sex and vascular risk factors but we found no difference in the other plasma biomarkers. Section B: Non-resolving systemic inflammation is a feature of inflammatory autoimmune rheumatic diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). These patients are at increased risk of stroke but much knowledge relates to stroke in general; less is known about associations with stroke subtypes including SVD, or when in life stroke risk is greatest. Consequently, we sought to better understand the influence of inflammatory rheumatic diseases on stroke and SVD. The review and meta-analysis of cerebrovascular disease in rheumatic diseases showed an excess risk of stroke in RA, SLE, ankylosing spondylitis, gout and psoriasis over the general population. Meta-analyses of stroke subtypes (ischaemic and haemorrhagic) in RA and SLE showed an excess risk of stroke over the general population. Stroke risk across rheumatic diseases was highest in those aged

In structural Magnetic Resonance Imaging (MRI) of patients with a recent small subcortical infarct (RSSI), small vessel disease (SVD) imaging markers coexist. However, their spatial distribution and prevalence with respect to the hemisphere of the RSSI is not yet known.From brain MRI in 187 patients with an acute lacunar ischaemic stroke clinical syndrome and a relevant DWI-positive lesion, we semi-automatically extracted the RSSI, microbleeds, lacunes, old cortical infarcts and white matter hyperintensities (WMH) using optimised 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 that had the RSSI in each hemisphere separately. We used the Wilcoxon and χ2 tests to compare the volumes and frequencies of occurrence, respectively, of the SVD markers between hemispheres throughout the sample.52% 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=0.10) 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 % volume of the right RSSIs versus left (p=0.16). Neither was there a significant inter-hemispheric 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.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.

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.

Background: The cause of lacunar ischemic stroke, a clinical feature of cerebral small vessel disease (SVD), is largely unknown. Inflammation and endothelial dysfunction have been implicated. Plasma biomarkers could provide mechanistic insights but current data are conflicting. White matter hyperintensities (WMHs) are an important imaging biomarker of SVD. It is unknown if plasma biomarkers add predictive capacity beyond age and vascular risk factors in explaining WMH. Methods: We prospectively recruited patients presenting with non-disabling ischemic stroke, classifying them clinically and with the help of MRI as lacunar or cortical. We measured biomarkers of inflammation, endothelial dysfunction and hemostasis for >1 month after stroke and compared biomarker levels between stroke subtypes. We quantitatively calculated WMH. We used multiple linear regression analysis to model WMH as a function of age, sex, hypertension and smoking (the baseline model). We fitted exploratory models using plasma biomarkers as predictor variables to assess model improvement over baseline. Results: We recruited 125 patients. The lacunar group (n = 65) had lower tissue plasminogen activator (t-PA) levels in unadjusted (7.39 vs. 8.59 ng/ml, p = 0.029) and adjusted (p = 0.035) analyses compared with the cortical group (n = 60). There were no significant differences in the other plasma biomarkers. The results for t-PA were consistent with an updated meta-analysis, although the effect remains non-significant (standardized mean difference -0.08 (95% CI -0.25 to 0.09)). The baseline regression model explained 29% of the variance in quantitative WMH (R2 0.289). Inflammatory biomarkers showed minor improvement over baseline (R2 0.291), but the other plasma biomarkers did not improve the baseline model. Conclusion: Plasma t-PA levels appear to differ between lacunar and cortical stroke subtypes, late after stroke, independent of age, sex and vascular risk factors and may reflect endothelial dysfunction. Except for a minor additional predictive effect of inflammatory markers, plasma biomarkers do not relate to WMH severity in this small stroke population.

Background: The cause of lacunar ischemic stroke, a clinical feature of cerebral small vessel disease (SVD), is largely unknown. Inflammation and endothelial dysfunction have been implicated. Plasma biomarkers could provide mechanistic insights but current data are conflicting. White matter hyperintensities (WMHs) are an important imaging biomarker of SVD. It is unknown if plasma biomarkers add predictive capacity beyond age and vascular risk factors in explaining WMH. Methods: We prospectively recruited patients presenting with non-disabling ischemic stroke, classifying them clinically and with the help of MRI as lacunar or cortical. We measured biomarkers of inflammation, endothelial dysfunction and hemostasis for >1 month after stroke and compared biomarker levels between stroke subtypes. We quantitatively calculated WMH. We used multiple linear regression analysis to model WMH as a function of age, sex, hypertension and smoking (the baseline model). We fitted exploratory models using plasma biomarkers as predictor variables to assess model improvement over baseline. Results: We recruited 125 patients. The lacunar group (n = 65) had lower tissue plasminogen activator (t-PA) levels in unadjusted (7.39 vs. 8.59 ng/ml, p = 0.029) and adjusted (p = 0.035) analyses compared with the cortical group (n = 60). There were no significant differences in the other plasma biomarkers. The results for t-PA were consistent with an updated meta-analysis, although the effect remains non-significant (standardized mean difference -0.08 (95% CI -0.25 to 0.09)). The baseline regression model explained 29% of the variance in quantitative WMH (R2 0.289). Inflammatory biomarkers showed minor improvement over baseline (R2 0.291), but the other plasma biomarkers did not improve the baseline model. Conclusion: Plasma t-PA levels appear to differ between lacunar and cortical stroke subtypes, late after stroke, independent of age, sex and vascular risk factors and may reflect endothelial dysfunction. Except for a minor additional predictive effect of inflammatory markers, plasma biomarkers do not relate to WMH severity in this small stroke population.

BackgroundAcute lacunar ischaemic stroke, white matter hyperintensities, and lacunes are all features of cerebral small vessel disease. It is unclear why some small vessel disease lesions present with acute stroke symptoms, whereas others typically do not.AimTo test if lesion location could be one reason why some small vessel disease lesions present with acute stroke, whereas others accumulate covertly.MethodsWe identified prospectively patients who presented with acute lacunar stroke symptoms with a recent small subcortical infarct confirmed on magnetic resonance diffusion imaging. We compared the distribution of the acute infarcts with that of white matter hyperintensity and lacunes using computational image mapping methods.ResultsIn 188 patients, mean age 67 ± standard deviation 12 years, the lesions that presented with acute lacunar ischaemic stroke were located in or near the main motor and sensory tracts in (descending order): posterior limb of the internal capsule (probability density 0·2/mm3), centrum semiovale (probability density = 0·15/mm3), medial lentiform nucleus/lateral thalamus (probability density = 0·09/mm3), and pons (probability density = 0·02/mm3). Most lacunes were in the lentiform nucleus (probability density = 0·01–0·04/mm3) or external capsule (probability density = 0·05/mm3). Most white matter hyperintensities were in centrum semiovale (except for the area affected by the acute symptomatic infarcts), external capsules, basal ganglia, and brainstem, with little overlap with the acute symptomatic infarcts (analysis of variance, P ConclusionsLesions that present with acute lacunar ischaemic stroke symptoms may be more likely noticed by the patient through affecting the main motor and sensory tracts, whereas white matter hyperintensity and asymptomatic lacunes mainly affect other areas. Brain location could at least partly explain the symptomatic vs. covert development of small vessel disease.

Research involving brain imaging is important for understanding common brain diseases. Study endpoints can include features and measures derived from imaging modalities, providing a benchmark against which other phenotypical data can be assessed. In trials, imaging data provides objective evidence of beneficial and adverse outcomes. Multi-centre studies increase generalizability and statistical power. However, there is a lack of practical guidelines for the set-up and conduct of large neuroimaging studies. We address this deficit by describing aspects of study design and other essential practical considerations that will help researchers avoid common pitfalls and data loss. The recommendations are grouped as: 1. Get help from experts in the field and plan the study, 2. Define the imaging endpoints, develop an imaging manual and have a system in place to manage the workflow, 3. Perform a dummy run test scan and test the analysis methods, 4. Acquire the scans, 5. Data anonymisation and transfer, 6. Quality control, 7. Data sharing. Implementing these steps will lead to valuable and usable data and help avoid imaging data wastage. Additionally, we highlight the importance of data sharing to maximize the benefits of the research to society by making the data available to other researchers.