Joanna Wardlaw

• University of Edinburgh

Introduction Small vessel disease (SVD) lesions may cause symptoms apart from stroke. We aimed to determine whether white matter hyperintensity (WMH) progression and incident infarcts associate with gait, mood, and cognitive symptoms. Method We recruited patients with non-disabling stroke (modified Rankin Scale <3), performed diagnostic MRI, and q...

Environmental exposures including toxins and nutrition may hamper the developing brain in utero, limiting the brain’s reserve capacity and increasing the risk for Alzheimer’s disease (AD). The purpose of this systematic review is to summarize all currently available evidence for the association between prenatal exposures and AD-related volumetric b...

Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed (N = 774), i...

Objectives To test whether Mediterranean-type Diet (MeDi) at age 70 years is associated with longitudinal trajectories of total brain MRI volume over a six-year period from age 73 to 79. Design Cohort study which uses a correlational design. Setting Participants residing in the Lothian region of Scotland and living independently in the community....

Characterising associations between the epigenome, proteome and phenome may provide insight into molecular regulation of biological pathways governing health. However, epigenetic signatures for many neurologically-associated plasma protein markers remain uncharacterised. Here, we report an epigenome and phenome-wide association study of the circula...

Cerebral small vessel disease (SVD) is a leading cause of vascular cognitive impairment, however the precise nature of SVD-related cognitive deficits, and their associations with structural brain changes, remain unclear. We combined computational volumes and visually-rated MRI markers of SVD to quantify total SVD burden, using data from the Lothian...

Introduction Cerebral small vessel disease (cSVD) causes stroke, with an increasing burden in the ageing population. cSVD develops due to a combination of environmental and genetic factors. A minority of individuals undergo genetic testing for a mutation in the NOTCH3 gene, which causes CADASIL. However, several other Mendelian cSVD genes have been...

Slowed processing speed is considered a hallmark feature of cognitive decline in cerebral small vessel disease (SVD); however, it is unclear whether SVD’s association with slowed processing might be due to its association with overall declining general cognitive ability. We quantified the total MRI-visible SVD burden of 540 members of the Lothian B...

Different brain regions can be grouped together, based on cross-sectional correlations among their cortical characteristics; this patterning has been used to make inferences about ageing processes. However, cross-sectional brain data conflate information on ageing with patterns that are present throughout life. We characterised brain cortical agein...

BACKGROUND: Post-stroke cognitive impairment (PSCI) occurs in approximately half of people in the first year after stroke. Infarct location is a potential determinant of PSCI, but a comprehensive map of strategic infarct locations predictive of PSCI is unavailable. We aimed to identify infarct locations most strongly predictive of PSCI after acute...

Introduction Small vessel disease (SVD) commonly causes stroke and dementia. Early clinical predictors of disease progression are lacking. We aimed to determine whether informant reports of chronic cognitive/functional decline, prerequisites for dementia diagnosis, are associated with (a)baseline SVD burden, measured by Fazekas scores and (b)SVD ch...

Objective A study was undertaken to assess whether cerebral small vessel disease (SVD) computed tomographic (CT) biomarkers are associated with long‐term outcome after intracerebral hemorrhage. Methods We performed a prospective, community‐based cohort study of adults diagnosed with spontaneous intracerebral hemorrhage between June 1, 2010 and May...

Background: Investigation of differential effects of early intensive versus guideline-recommended blood pressure (BP) lowering between lacunar and non-lacunar acute ischemic stroke (AIS) in the BP arm of Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). Methods: In 1632 participants classified as having definite or probab...

Objective: To test the hypothesis that imaging signs of 'brain frailty' and acute ischaemia predict clinical outcomes and symptomatic intracranial haemorrhage (sICH) after thrombolysis for acute ischaemic stroke (AIS) in the alteplase dose arm of ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED). Methods: Blinded assessors...

Background Stroke commonly affects cognition and, by definition, much vascular dementia follows stroke. However, there are fundamental limitations in our understanding of vascular cognitive impairment, restricting understanding of prevalence, trajectories, mechanisms, prevention, treatment and patient-service needs. Aims Rates, Risks and Routes to...

Background: Small vessel disease causes a quarter of ischaemic strokes (lacunar subtype), up to 45% of dementia either as vascular or mixed types, cognitive impairment and physical frailty. However, there is no specific treatment to prevent progression of small vessel disease. Aim: We designed the LACunar Intervention Trial-2 (LACI-2) to test fe...

Background Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but wh...

Introduction: We assessed whether modest systemic cooling started within 6 hours of symptom onset improves functional outcome at three months in awake patients with acute ischaemic stroke. Patients and methods: In this European randomised open-label clinical trial with blinded outcome assessment, adult patients with acute ischaemic stroke were r...

Aims Several factors are known to increase risk for cerebrovascular disease and dementia, but there is limited evidence on associations between multiple vascular risk factors (VRFs) and detailed aspects of brain macrostructure and microstructure in large community-dwelling populations across middle and older age. Methods and results Associations...

Higher polygenic risk score for schizophrenia (szPGRS) has been associated with lower cognitive function and might be a predictor of decline in brain structure in apparently healthy populations. Age-related declines in structural brain connectivity-measured using white matter diffusion MRI -are evident from cross-sectional data. Yet, it remains unc...

Background: Carotid atherosclerosis is a significant risk factor for stroke and has been associated with cognitive decline and dementia. Methods: We assessed 554 community-dwelling subjects from the Lothian Birth Cohort of 1936 (LBC1936) who underwent brain MRI and carotid Doppler ultrasound studies at age 73 years. The relationship between carotid...

We aimed to explore the morphological evolution of recent small subcortical infarcts (RSSIs) over 15 months. Moreover, we hypothesized that quantitative lesion apparent diffusion coefficient (ADC) values and serum neurofilament light (NfL) levels predict subsequent lacunar cavitation. We prospectively studied 78 RSSI patients, who underwent pre-def...

Can we use simple tests (CT and APOE genotype - The Edinburgh CT and genetic criteria for CAA-associated lobar ICH) in patients with lobar intracerebral haemorrhage to predict recurrent haemorrhage risk

Objective To investigate brain structural connectivity in relation to cognitive abilities and systemic damage in systemic lupus erythematosus (SLE). Methods Structural and diffusion MRI data were acquired from 47 patients with SLE. Brains were segmented into 85 cortical and subcortical regions and combined with whole brain tractography to generate...

We aimed to assess whether and how changes in brain volume and increases in white matter hyperintensity (WMH) volume over three years predict gait speed and its change independently of demographics, vascular risk factors and physical status. We analyzed 443 individuals from the Lothian Birth Cohort 1936, at mean age 73 and 76 years. Gait speed at a...

Voxel-by-voxel data. The data fields are described in the second row of the table. (CSV)

Background Cerebral small vessel disease (cSVD) is a major cause of stroke and dementia. Midlife vascular disease and adult socioeconomic status (SES) are established risk factors. Less is known about the effect of factors earlier in life. A recent meta-analysis found that lower levels of childhood IQ, childhood SES and education increased the risk...

Background: Iodine deficiency is one of the three key micronutrient deficiencies highlighted as major public health issues by the World Health Organisation. Iodine deficiency is known to cause brain structural alterations likely to affect cognition. However, it is not known whether or how different (lifelong) levels of exposure to dietary iodine i...

Neighbourhood tractography aims to automatically segment equivalent brain white matter tracts from diffusion magnetic resonance imaging (dMRI) data in different subjects by using a “reference tract” as a prior for the shape and length of each tract of interest. In the current work we present a means of improving the technique by using references tr...

Age-associated disease and disability are placing a growing burden on society. However, ageing does not affect people uniformly. Hence, markers of the underlying biological ageing process are needed to help identify people at increased risk of age-associated physical and cognitive impairments and ultimately, death. Here, we present such a biomarker...

Gait and balance impairment is highly prevalent in older people. We aimed to assess whether and how single markers of small vessel disease (SVD) or a combination thereof explain gait and balance function in the elderly. We analysed 678 community-dwelling healthy subjects from the Lothian Birth Cohort 1936 at the age of 71–74 years who had undergone...

Background: Stroke is associated with the development of cognitive impairment and dementia. We assessed the effect of intensive blood pressure (BP) and/or lipid lowering on cognitive outcomes in patients with recent stroke in a pilot trial. Methods: In a multicentre, partial-factorial trial, patients with recent stroke, absence of dementia, and sys...

Dementia is a global problem and major target for health care providers. Although up to 45% of cases are primarily or partly due to cerebrovascular disease, little is known of these mechanisms or treatments because most dementia research still focuses on pure Alzheimer's disease. An improved understanding of the vascular contributions to neurodegen...

White matter hyperintensities (WMH) seen on FLAIR images are established as a key indicator of Vascular Dementia (VD) and other pathologies. We propose a novel modality transformation technique to generate a subject-specific pathology-free synthetic FLAIR image from a T\(_1\) -weighted image. WMH are then accurately segmented by comparing this synt...

Dementia is a global problem and major target for health care providers. Although up to 45% of cases are primarily or partly due to cerebrovascular disease, little is known of these mechanisms or treatments because most dementia research still focuses on pure Alzheimer's disease. An improved understanding of the vascular contributions to neurodegen...

Background and purpose: Several studies have reported associations between brain iron deposits (IDs), white matter hyperintensities (WMHs) and cognitive ability in older individuals. Whether the association between brain IDs and cognitive abilities in older people is mediated by or independent of total brain tissue damage represented by WMHs visib...

White matter hyperintensities accumulate with age and occur in patients with stroke, but their pathogenesis is poorly understood. We measured multiple magnetic resonance imaging biomarkers of tissue integrity in normal-appearing white matter and white matter hyperintensities in patients with mild stroke, to improve understanding of white matter hyp...

Objectives: We investigated the correlation between polygenic risk of ischemic stroke (and its subtypes) and cognitive ability in 3 relatively healthy Scottish cohorts: the Lothian Birth Cohort 1936 (LBC1936), the Lothian Birth Cohort 1921 (LBC1921), and Generation Scotland: Scottish Family Health Study (GS). Methods: Polygenic risk scores for i...

Incidental findings of imaging research studies can turn healthy individuals into anxious patients, while putting an extra burden on primary care. J M Wardlaw and colleagues argue that doctors should ensure that the personal, ethical, healthcare, and cost implications of these common findings are managed proportionately, sensitively, and economical...

Rationale Cerebral small vessel disease (SVD) is common in ageing and patients with dementia and stroke. Its manifestations on magnetic resonance imaging (MRI) include white matter hyperintensities, lacunes, microbleeds, perivascular spaces, small subcortical infarcts, and brain atrophy. Many studies focus only on one of these manifestations. A pro...

Purpose: present and assess clinical protocols and associated automated workflow for pre-surgical functional magnetic resonance imaging in brain tumor patients. Methods: Protocols were validated using a single-subject reliability approach based on 10 healthy control subjects. Results from the automated workflow were evaluated in 9 patients with br...

There is evidence that subtle breakdown of the blood-brain barrier (BBB) is a pathophysiological component of several diseases, including cerebral small vessel disease and some dementias. Dynamic contrast-enhanced MRI (DCE-MRI) combined with tracer kinetic modelling is widely used for assessing permeability and perfusion in brain tumours and body t...

Structural brain magnetic resonance imaging (MRI) traits share part of their genetic variance with cognitive traits. Here, we use genetic association results from large meta-analytic studies of genome-wide association (GWA) for brain infarcts (BI), white matter hyperintensities, intracranial, hippocampal, and total brain volumes to estimate polygen...

Background and purpose: We sought to establish whether the presence (versus absence) of a lesion on magnetic resonance imaging (MRI) with diffusion weighting (DWI-MRI) at presentation with acute stroke is associated with worse clinical outcomes at 1 year. Methods: We recruited consecutive patients with a nondisabling ischemic stroke and performe...

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 bilater...

Several studies have reported associations between brain iron deposits and cognitive status, and cardiovascular and neurodegenerative diseases in older individuals, but the mechanisms underlying these associations remain unclear. We explored the associations between regional brain iron deposits and different factors of cognitive ability (fluid inte...

Non-pathological, age-related cognitive decline varies markedly between individuals andplaces significant financial and emotional strain on people, their families and society as a whole.Understanding the differential age-related decline in brain function is critical not only for the development oftherapeutics to prolong cognitive health into old ag...

Later-life changes in brain tissue volumes—decreases in the volume of healthy grey and white matter and increases in the volume of white matter hyperintensities (WMH)—are strong candidates to explain some of the variation in ageing-related cognitive decline. We assessed fluid intelligence, memory, processing speed, and brain volumes (from structura...

People with larger brains tend to score higher on tests of general intelligence (g). It is unclear, however, how much variance in intelligence other brain measurements would account for if included together with brain volume in a multivariable model. We examined a large sample of individuals in their seventies (n = 672) who were administered a comp...

Two markers of cerebral small vessel disease are white matter hyperintensities and cerebral microbleeds, which commonly occur in people with Alzheimer's disease. To test for independent associations between two Alzheimer's disease-susceptibility gene loci - APOE ε and the TOMM40 '523' poly-T repeat - and white matter hyperintensities/cerebral micro...

Background: Spontaneous intracerebral haemorrhage is a devastating form of stroke and its incidence increases with age. Obtaining brain tissue following intracerebral haemorrhage helps to understand its cause. Given declining autopsy rates worldwide, the feasibility of establishing an autopsy-based collection and its generalisability are uncertain...

Examining the dynamics of stroke ischemia is limited by the standard use of 2D-volume or voxel-based analysis techniques. Recently developed spatiotemporal models such as the 4D metamorphosis model showed promise for capturing ischemia dynamics. We used a 4D metamorphosis model to evaluate acute ischemic stroke lesion morphology from the acute diff...

Elevated glucocorticoid (GC) levels putatively damage specific brain regions, which in turn may accelerate cognitive ageing. However, many studies are cross-sectional or have relatively short follow-up periods, making it difficult to relate GCs directly to changes in cognitive ability with increasing age. Moreover, studies combining endocrine, MRI...

Cognitive decline, especially the slowing of information processing speed, is associated with normal ageing. This decline may be due to brain cortico-cortical disconnection caused by age-related white matter deterioration. We present results from a large, narrow age range cohort of generally healthy, community-dwelling subjects in their seventies w...

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...

Intracranial internal carotid artery calcification is associated with cerebrovascular risk factors and stroke, but few quantification methods are available. We tested the reliability of visual scoring, semiautomated Agatston score, and calcium volume measurement in patients with recent stroke. We used scans from a prospective hospital stroke regist...

Permutation testing has been widely implemented in voxel-based morphometry (VBM) tools. However, this type of non-parametric inference has yet to be thoroughly compared with traditional parametric inference in VBM studies of brain structure. Here we compare both types of inference and investigate what influence the number of permutations in permuta...

The HydroCoil Endovascular Aneurysm Occlusion and Packing Study was a randomized controlled trial that compared HydroCoils to bare platinum coils. Using data from this trial, we performed a subgroup analysis of angiographic and clinical outcomes of patients with "difficult-to-treat" aneurysms, defined as irregularly shaped and/or having a dome-to-n...

Vascular cognitive impairment (VCI) is the diagnostic term used to describe a heterogeneous group of sporadic and hereditary diseases of the large and small blood vessels. Subcortical small vessel disease (SVD) leads to lacunar infarcts and progressive damage to the white matter. Patients with progressive damage to the white matter, referred to as...

We propose a framework for investigating the properties of apparently normal tissues on brain structural magnetic resonance images of patients with small vessel disease (SVD). It involves the extraction of textural features in regions of interest (ROIs) obtained from an anatomically-relevant template, combined with a statistical analysis that consi...

Cerebrovascular disease may present in later life with stroke or cognitive impairment and dementia, or may be silent, with changes seen incidentally on imaging or pathology. Midlife vascular risk factors such as hypertension, smoking and diabetes are well recognised. However, factors from much earlier in life may contribute to later vascular risk....

Patients with TIA have high risk of recurrent stroke and require rapid assessment and treatment. The ABCD2 clinical risk prediction score is recommended for patient triage by stroke risk, but its ability to stratify by known risk factors and effect on clinic workload are unknown. We performed a systematic review and meta-analysis of all studies pub...

Background Acute 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 prese...

Cerebral small vessel disease (SVD) may cause cognitive dysfunction. We tested the association between the combined presence of magnetic resonance imaging (MRI) features of SVD and cognitive ability in older age. Cognitive testing and brain MRI were performed in 680 older participants. MRI presence of lacunes, white matter hyperintensities, microbl...

Randomized trial evidence on the risk/benefit ratio of thrombolysis for mild stroke is limited. We sought to determine the efficacy of intravenous recombinant tissue-type plasminogen activator (IV r-tPA) in a subset of patients with mild deficit in the third International Stroke Trial (IST-3). IST-3 compared IV r-tPA with control within 6 hours of...

Understanding aging-related cognitive decline is of growing importance in aging societies, but relatively little is known about its neural substrates. Measures of white matter microstructure are known to correlate cross-sectionally with cognitive ability measures, but only a few small studies have tested for longitudinal relations among these varia...

Object: We sought to measure brain metabolite levels in healthy older people. Materials and methods: Spectroscopic imaging at the level of the basal ganglia was applied in 40 participants aged 73–74 years. Levels of the metabolites N-acetyl aspartate (NAA), choline, and creatine were determined in "institutional units" (IU) corrected for T1 and T2...

Introduction: Neurodegenerative disease diagnoses may be supported by the comparison of an individual patient's brain magnetic resonance image (MRI) with a voxel-based atlas of normal brain MRI. Most current brain MRI atlases are of young to middle-aged adults and parametric, e.g., mean ± standard deviation (SD); these atlases require data to be G...

Objective: There is some evidence that people who score higher on tests of intelligence in childhood have lower carotid intima-media thickness and higher ankle brachial index in middle age. These findings need replicating in other, older populations. We investigated the prospective relationship between intelligence in childhood and atherosclerosis...

Dietary salt intake and hypertension are associated with increased risk of cardiovascular disease including stroke. We aimed to explore the influence of these factors, together with plasma sodium concentration, in cerebral small vessel disease (SVD). In all, 264 patients with nondisabling cortical or lacunar stroke were recruited. Patients were que...

New imaging criteria for recent small subcortical infarcts have recently been proposed, replacing the earlier term 'lacunar infarction', but their applicability and impact on lesion selection is yet unknown. To collect information on the morphologic characteristics and variability of recent small subcortical infarcts on magnetic resonance imaging i...

Alper and colleagues question the validity of the Cochrane review of thrombolytic treatment in stroke and our conclusion that treatment improves outcome if given up to 4.5 hours after stroke.1 They find the review confusing, but fail to acknowledge that the review includes 25 years’ worth of data from trials of several different thrombolytic drugs,...

Background: To assess the differences across continental regions in terms of stroke imaging obtained for making acute revascularization therapy decisions, and to identify obstacles to participating in randomized trials involving multimodal imaging. Methods: STroke Imaging Repository (STIR) and Virtual International Stroke Trials Archive (VISTA)-...

Background Randomised trials have shown that alteplase improves the odds of a good outcome when delivered within 4·5 h of acute ischaemic stroke. However, alteplase also increases the risk of intracerebral haemorrhage; we aimed to determine the proportional and absolute effects of alteplase on the risks of intracerebral haemorrhage, mortality, and...

High blood pressure is common in acute ischemic stroke and associated with a poor outcome. Transdermal glyceryl trinitrate (GTN), a nitric oxide donor, is a candidate treatment for acute stroke, especially if given within 6 hours. Patients randomized into the large Efficacy of Nitric Oxide in Stroke(ENOS) trial were included in this subgroup analysi...

Perivascular spaces (PVS) are an important component of cerebral small vessel disease (SVD), several inflammatory disorders, hypertension and blood-brain barrier breakdown, but are difficult to quantify. A recent international collaboration of SVD experts has highlighted the need for a robust, easy-to-use PVS rating scale for the effective investig...

The HydroCoil Endovascular Aneurysm Occlusion and Packing Study (HELPS) was a randomized, controlled trial comparing HydroCoils with bare-platinum coils. The purpose of this study was to perform a subgroup analysis of angiographic and clinical outcomes of medium-sized aneurysms in the HELPS trial. Patients with medium-sized aneurysms (5-9.9 mm) wer...

Patients with sickle cell anemia (SCA) are at a high risk to develop cerebral damage. Most common are silent cerebral infarctions (SCIs), visible as white matter hyperintensities (WMHs) on MRI in a patient without neurological deficits. The etiology of SCIs remains largely unclear. In addition, patients are at an increased risk for overt stroke, wh...

The degree to which genetic factors influence brain connectivity is beginning to be understood. Large-scale efforts are underway to map the profile of genetic effects in various brain regions. The NIH-funded Human Connectome Project (HCP) is providing data valuable for analyzing the degree of genetic influence underlying brain connectivity revealed...

Small vessel disease encompasses lacunar stroke, white matter hyperintensities, lacunes and microbleeds. It causes a quarter of all ischemic strokes, is the commonest cause of vascular dementia, and the cause is incompletely understood. Vascular prophylaxis, as appropriate for large artery disease and cardioembolism, includes antithrombotics, and b...

Erratum in Lancet. 2015 Feb 14;385(9968):606. Abstract BACKGROUND: High blood pressure is associated with poor outcome after stroke. Whether blood pressure should be lowered early after stroke, and whether to continue or temporarily withdraw existing antihypertensive drugs, is not known. We assessed outcomes after stroke in patients given drugs to...