Early life risk factors for cerebrovascular disease and depressive symptoms in later life

Cerebrovascular disease (CVD) can result in cerebral small vessel disease (cSVD) and structural brain changes such as decreased cortical volume, brain atrophy and cerebral infarcts which are major causes of stroke and dementia. CVD is also associated with increased depression and depressive symptoms in later life. Midlife vascular disease and adult socioeconomic status (SES) are well established risk factors but less is known about the effect of factors from earlier in life on CVD and depressive symptoms in later life. A series of systematic reviews of current literature examining early life factors and stroke, cSVD and depression following stroke are presented at the beginning of this thesis. These reviews found that childhood IQ, education and childhood SES were associated with stroke and cSVD in later life. The reviews also found that education level was associated with depression following stroke. However few of the studies adjusted for vascular risk factors and adult SES. Therefore this thesis aimed to investigate associations between birth and childhood factors and cerebrovascular disease and depressive symptoms, after adjustment for vascular risk factors and adult SES, in four community dwelling cohorts: the Stratifying Resilience & Depression Longitudinally (STRADL) cohort (n=280, 45% male, mean age= 62.1 (SD=4.1) years), the Dutch Famine Birth cohort (n= 151, 44% male, mean age 67.6 (SD=0.9) years), the Lothian Birth Cohort 1936 (LBC 1936, n= 865, 50% male, mean age 72.7 (SD=0.7) years), and the Simpson cohort (n=130, 31% male, mean age 78.5, (SD=1.5) years). This Thesis first examined associations between (i) cSVD burden (ii) total and regional brain volumes and (iii) self-reported symptoms of depression and anxiety measured using the Hospital Anxiety and Depression Scale. All analyses were adjusted for age, sex, hypertension, smoking behaviour, adult SES and cognition. Neither cSVD nor brain volumes were associated with symptoms of anxiety. Higher white matter hyperintensity volumes, having one or more cerebral infarct and increased cerebral atrophy were associated with increased depressive symptoms independent of vascular risk factors and adult SES. Secondly, this thesis examined associations between birth and childhood factors and cSVD burden and total and regional brain volumes. Each cohort was analysed individually and then all available data meta-analysed. All analyses were adjusted for age, sex, hypertension, smoking behaviour, adult SES and other early life factors. Meta-analysis found that increasing birth weight was associated with decreased risk of lacunes across all cohorts. Placental weight, which was only available for the Simpson cohort, was associated with decreased risk total cSVD, WMH severity and volume and cerebral infarcts. In the LBC 1936 and Simpson cohort increasing childhood and premorbid IQ and more years of education were associated with fewer cortical infarcts. The association between premorbid and childhood IQ and infarcts was independent of education level. Across three cohorts low education level was associated with more microbleeds. These findings suggest that factors other than traditional vascular risk factors may contribute to cSVD and structural brain changes in later life. Thirdly, this thesis examined associations between birth and childhood factors and self-reported symptoms of depression and anxiety measured using the Hospital Anxiety and Depression Scale (HADS) and the Quick Inventory of Depressive Symptoms (QIDS-16). All analyses were adjusted for age, sex, hypertension, smoking behaviour, adult SES and cognition In the Dutch Famine Birth Cohort people born before the famine had lower scores of depression and anxiety on the HADS compared to those exposed to famine in early gestation and those conceived after the famine. In the LBC 1936 increasing ponderal index was associated with lower depressive symptoms, increasing childhood and premorbid IQ were associated with lower symptoms of anxiety and depression. Lower educational attainment and some indicators of childhood SES were associated with higher symptoms of depression and anxiety. Overall results suggest that early life factors, particularly childhood IQ, may contribute to structural brain changes and symptoms of depression and anxiety in later life, independent of vascular risk factors and other early life factors. Efforts to understand factors which may contribute to late life health, from the earliest stages of life, are important and may be used to inform changes in social policy. The effect sizes and potential impact of these findings suggest that larger sample sizes with more vascular disease and more depression are needed to robustly test these associations

Cognitive ability, education and socioeconomic status in childhood and risk of post-stroke depression in later life:A systematic review and meta-analysis

<div><p>Background</p><p>Depression after stroke is common and is associated with poorer recovery. Risk factors such as gender, age and stroke severity are established, but it is unclear whether factors from earlier in life might also contribute.</p><p>Methods</p><p>We searched MEDLINE, PsycINFO, EMBASE and meta-analysed all available evidence on childhood (premorbid) IQ, socioeconomic status (SES), education and stroke in adulthood. We included all studies reporting data on >50 patients, calculating overall odds ratios (OR), mean difference, correlation, 95% confidence intervals (CI) and 95% predictive intervals (PI) using random effects methods. We quality assessed all studies, performed sensitivity analyses, assessed heterogeneity and publication bias.</p><p>Results</p><p>We identified 33 studies including 2,664 participants with post-stroke depression and 5,460 without (314 participants not classified). Low education (< = 8 years) was associated with post-stroke depression in studies which defined depression as score of mild and above on a depression rating scale (OR 1.47 95% CI 1.10–1.97, p<0.01) but not in studies where depression was defined as severe depressive symptoms or a clinical diagnosis of major depression (OR 1.04 95% CI 0.90–1.31, p = 0.60). Low education was not associated with an increased risk for post-stroke depression in studies that adjusted for age and sex (OR 0.86 95% CI 0.50–1.48 p = 0.58). Those with post-stroke depression had fewer years of education than those without post-stroke depression (MD 0.68 95% CI 0.05–1.31 p = 0.04). Few studies adjusted for vascular risk factors or stroke severity. Heterogeneity between studies was moderate and was partly explained by severity of depression. In the one study identified premorbid IQ did not differ between those with post-stroke depression (mean IQ 10.1.8 SD 9.8) vs those without (mean IQ 104 SD 10.1). There were no studies that examined childhood socioeconomic status and risk of post-stroke depression.</p><p>Conclusions</p><p>Having less education is associated with an increased risk of post-stroke depressive symptoms but with large confidence intervals and heterogeneity. Future studies should explore the relationship between early and late life risk factors to improve risk identification and to target prevention and treatment strategies.</p></div

Cognitive impairment in sporadic cerebral small vessel disease:A systematic review and meta-analysis

This paper is a proposal for an update on the characterization of cognitive impairments associated with sporadic cerebral small vessel disease (SVD). We pose a series of questions about the nature of SVD-related cognitive impairments and provide answers based on a comprehensive review and meta-analysis of published data from 69 studies. Although SVD is thought primarily to affect executive function and processing speed, we hypothesize that SVD affects all major domains of cognitive ability. We also identify low levels of education as a potentially modifiable risk factor for SVD-related cognitive impairment. Therefore, we propose the use of comprehensive cognitive assessments and the measurement of educational level both in clinics and research settings, and suggest several recommendations for future research

Sex Differences in Cerebral Small Vessel Disease: A Systematic Review and Meta-Analysis

Background: Cerebral small vessel disease (SVD) is a common cause of stroke, mild cognitive impairment, dementia and physical impairments. Differences in SVD incidence or severity between males and females are unknown. We assessed sex differences in SVD by assessing the male-to-female ratio (M:F) of recruited participants and incidence of SVD, risk factor presence, distribution, and severity of SVD features. Methods: We assessed four recent systematic reviews on SVD and performed a supplementary search of MEDLINE to identify studies reporting M:F ratio in covert, stroke, or cognitive SVD presentations (registered protocol: CRD42020193995). We meta-analyzed differences in sex ratios across time, countries, SVD severity and presentations, age and risk factors for SVD. Results: Amongst 123 relevant studies (n = 36,910 participants) including 53 community-based, 67 hospital-based and three mixed studies published between 1989 and 2020, more males were recruited in hospital-based than in community-based studies [M:F = 1.16 (0.70) vs. M:F = 0.79 (0.35), respectively; p &lt; 0.001]. More males had moderate to severe SVD [M:F = 1.08 (0.81) vs. M:F = 0.82 (0.47) in healthy to mild SVD; p &lt; 0.001], and stroke presentations where M:F was 1.67 (0.53). M:F did not differ for recent (2015–2020) vs. pre-2015 publications, by geographical region, or age. There were insufficient sex-stratified data to explore M:F and risk factors for SVD. Conclusions: Our results highlight differences in male-to-female ratios in SVD severity and amongst those presenting with stroke that have important clinical and translational implications. Future SVD research should report participant demographics, risk factors and outcomes separately for males and females. Systematic Review Registration: [PROSPERO], identifier [CRD42020193995]

Topological relationships between perivascular spaces and progression of white matter hyperintensities:A pilot study in a sample of the Lothian Birth Cohort 1936

Enlarged perivascular spaces (PVS) and white matter hyperintensities (WMH) are features of cerebral small vessel disease which can be seen in brain magnetic resonance imaging (MRI). Given the associations and proposed mechanistic link between PVS and WMH, they are hypothesized to also have topological proximity. However, this and the influence of their spatial proximity on WMH progression are unknown. We analyzed longitudinal MRI data from 29 out of 32 participants (mean age at baseline = 71.9 years) in a longitudinal study of cognitive aging, from three waves of data collection at 3-year intervals, alongside semi-automatic segmentation masks for PVS and WMH, to assess relationships. The majority of deep WMH clusters were found adjacent to or enclosing PVS (waves−1: 77%; 2: 76%; 3: 69%), especially in frontal, parietal, and temporal regions. Of the WMH clusters in the deep white matter that increased between waves, most increased around PVS (waves−1–2: 73%; 2–3: 72%). Formal statistical comparisons of severity of each of these two SVD markers yielded no associations between deep WMH progression and PVS proximity. These findings may suggest some deep WMH clusters may form and grow around PVS, possibly reflecting the consequences of impaired interstitial fluid drainage via PVS. The utility of these relationships as predictors of WMH progression remains unclear

Identification of plasma proteins relating to brain neurodegeneration and vascular pathology in cognitively normal individuals

This project was funded by DPUK through MRC (grant no. MR/L023784/2) and the UK Medical Research Council Award to the University of Oxford (grant no. MC_PC_17215). L.S is funded by the Virtual Brain Cloud from European comission (grant no. H2020-SC1-DTH-2018-1). C.R.B is funded by National Institutes of Health (NIH) research grant R01AG054628. S.R.C is funded by National Institutes of Health (NIH) research grant (R01AG054628), Medical Research Council (MR/R024065/1), Age UK and Economic and Social Research Council. R.E.M. was supported by Alzheimer's Research UK major project grant ARUKPG2017B-10. C.H was supported by an MRC Human Genetics Unit programme grant “Quantitative traits in health and disease” (U.MC_UU_00007/10). H.C.W received funding from Wellcome Trust. J.W is funded by TauRx pharmaceuticals Ltd and received Educational grant from Biogen paid to Alzheimer Scotland/Brain Health Scotland. G.W received GRAMPIAN UNIVERSITY HOSPITALS NHS TRUST, Scottish Government—Chief Scientist Office, ROLAND SUTTON ACADEMIC TRUST, Medical Research Scotland, Sutton Academic Trust and ROLAND SUTTON ACADEMIC TRUST. J.M.W received Wellcome Trust Strategic Award, MRC UK Dementia Research Institute and MRC project grants, Fondation Leducq, Stroke Association, British Heart Foundation, Alzheimer Society, and the European Union H2020 PHC-03-15 SVDs@Target grant (666881). D.S received MRC (MR/S010351/1), MRC (MR/W002388/1) and MRC (MR/W002566/1). A.M is supported by the Wellcome Trust (104036/Z/14/Z, 216767/Z/19/Z, 220857/Z/20/Z) and UKRI MRC (MC_PC_17209, MR/S035818/1). This work is part of a project that has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847776. In addition, A.M has received grant support from The Sackler Trust, outside of the work presented. N.B received grant to institution from GSK as part of GSK/Oxford FxG initiative. A.N.H received John Black Charitable Fund-Rosetrees, H2020 funding from European Comission-Project Virtual Brain Cloud, AI for the Discovery of new therapies in Parkinson's (A2926), Rising Start Initiative—stage 2, Brain-Gut Microbiome (Call: PAR-18-296; Award ID: 1U19AG063744-01), Gut-liver-brain biochemical axis in Alzheimer's disease (5RF1AG057452-01), Virtual Brain Cloud (Call: H2020-SC1-DTH- 2018-1; Grant agreement ID: 826421). Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006) and is currently supported by the Wellcome Trust (216767/Z/19/Z). Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” [STRADL] Reference 104036/Z/14/Z). We are grateful to all the families who took part; the general practitioners and the Scottish School of Primary Care for their help in recruiting them; and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, health-care assistants, and nurses.Peer reviewedPublisher PD

Magnetic Resonance Imaging Tissue Signatures Associated With White Matter Changes Due to Sporadic Cerebral Small Vessel Disease Indicate That White Matter Hyperintensities Can Regress

Background White matter hyperintensities (WMHs) might regress and progress contemporaneously, but we know little about underlying mechanisms. We examined WMH change and underlying quantitative magnetic resonance imaging tissue measures over 1 year in patients with minor ischemic stroke with sporadic cerebral small vessel disease. Methods and Results We defined areas of stable normal‐appearing white matter, stable WMHs, progressing and regressing WMHs based on baseline and 1‐year brain magnetic resonance imaging. In these areas we assessed tissue characteristics with quantitative T1, fractional anisotropy (FA), mean diffusivity (MD), and neurite orientation dispersion and density imaging (baseline only). We compared tissue signatures cross‐sectionally between areas, and longitudinally within each area. WMH change masks were available for N=197. Participants' mean age was 65.61 years (SD, 11.10), 59% had a lacunar infarct, and 68% were men. FA and MD were available for N=195, quantitative T1 for N=182, and neurite orientation dispersion and density imaging for N=174. Cross‐sectionally, all 4 tissue classes differed for FA, MD, T1, and Neurite Density Index. Longitudinally, in regressing WMHs, FA increased with little change in MD and T1 (difference estimate, 0.011 [95% CI, 0.006–0.017]; −0.002 [95% CI, −0.008 to 0.003] and −0.003 [95% CI, −0.009 to 0.004]); in progressing and stable WMHs, FA decreased (−0.022 [95% CI, −0.027 to −0.017] and −0.009 [95% CI, −0.011 to −0.006]), whereas MD and T1 increased (progressing WMHs, 0.057 [95% CI, 0.050–0.063], 0.058 [95% CI, 0.050 –0.066]; stable WMHs, 0.054 [95% CI, 0.045–0.063], 0.049 [95% CI, 0.039–0.058]); and in stable normal‐appearing white matter, MD increased (0.004 [95% CI, 0.003–0.005]), whereas FA and T1 slightly decreased and increased (−0.002 [95% CI, −0.004 to −0.000] and 0.005 [95% CI, 0.001–0.009]). Conclusions Quantitative magnetic resonance imaging shows that WMHs that regress have less abnormal microstructure at baseline than stable WMHs and follow trajectories indicating tissue improvement compared with stable and progressing WMHs

Rationale and design of a longitudinal study of cerebral small vessel diseases, clinical and imaging outcomes in patients presenting with mild ischaemic stroke: Mild Stroke Study 3

Background: Cerebral small vessel disease is a major cause of dementia and stroke, visible on brain magnetic resonance imaging. Recent data suggest that small vessel disease lesions may be dynamic, damage extends into normal-appearing brain and microvascular dysfunctions include abnormal blood–brain barrier leakage, vasoreactivity and pulsatility, but much remains unknown regarding underlying pathophysiology, symptoms, clinical features and risk factors of small vessel disease. Patients and Methods: The Mild Stroke Study 3 is a prospective observational cohort study to identify risk factors for and clinical implications of small vessel disease progression and regression among up to 300 adults with non-disabling stroke. We perform detailed serial clinical, cognitive, lifestyle, physiological, retinal and brain magnetic resonance imaging assessments over one year; we assess cerebrovascular reactivity, blood flow, pulsatility and blood–brain barrier leakage on magnetic resonance imaging at baseline; we follow up to four years by post and phone. The study is registered ISRCTN 12113543. Summary: Factors which influence direction and rate of change of small vessel disease lesions are poorly understood. We investigate the role of small vessel dysfunction using advanced serial neuroimaging in a deeply phenotyped cohort to increase understanding of the natural history of small vessel disease, identify those at highest risk of early disease progression or regression and uncover novel targets for small vessel disease prevention and therapy