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Early life predictors of late life cerebral small vessel disease in four prospective cohort studies.

ABSTRACT: Development of cerebral small vessel disease, a major cause of stroke and dementia, may be influenced by early life factors. It is unclear whether these relationships are independent of each other, of adult socio-economic status or of vascular risk factor exposures. We examined associations between factors from birth (ponderal index, birth weight), childhood (IQ, education, socio-economic status), adult small vessel disease, and brain volumes, using data from four prospective cohort studies: STratifying Resilience And Depression Longitudinally (STRADL) (n = 1080; mean age = 59 years); the Dutch Famine Birth Cohort (n = 118; mean age = 68 years); the Lothian Birth Cohort 1936 (LBC1936; n = 617; mean age = 73 years), and the Simpson's cohort (n = 110; mean age = 78 years). We analysed each small vessel disease feature individually and summed to give a total small vessel disease score (range 1-4) in each cohort separately, then in meta-analysis, adjusted for vascular risk factors and adult socio-economic status. Higher birth weight was associated with fewer lacunes [odds ratio (OR) per 100 g = 0.93, 95% confidence interval (CI) = 0.88 to 0.99], fewer infarcts (OR = 0.94, 95% CI = 0.89 to 0.99), and fewer perivascular spaces (OR = 0.95, 95% CI = 0.91 to 0.99). Higher childhood IQ was associated with lower white matter hyperintensity burden (OR per IQ point = 0.99, 95% CI 0.98 to 0.998), fewer infarcts (OR = 0.98, 95% CI = 0.97 to 0.998), fewer lacunes (OR = 0.98, 95% CI = 0.97 to 0.999), and lower total small vessel disease burden (OR = 0.98, 95% CI = 0.96 to 0.999). Low education was associated with more microbleeds (OR = 1.90, 95% CI = 1.33 to 2.72) and lower total brain volume (mean difference = -178.86 cm3, 95% CI = -325.07 to -32.66). Low childhood socio-economic status was associated with fewer lacunes (OR = 0.62, 95% CI = 0.40 to 0.95). Early life factors are associated with worse small vessel disease in later life, independent of each other, vascular risk factors and adult socio-economic status. Risk for small vessel disease may originate in early life and provide a mechanistic link between early life factors and risk of stroke and dementia. Policies investing in early child development may improve lifelong brain health and contribute to the prevention of dementia and stroke in older age.

SUBMITTER: Backhouse EV

PROVIDER: S-EPMC8719837 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionCerebral small vessel disease (SVD) is one of the leading causes of stroke; each neuroimaging marker of SVD is correlated with vascular risk factors and associated with poor prognosis after stroke. However, longitudinal studies investigating the association between comprehensive SVD burden scoring system, "total SVD score" - which encompasses the established neuroimaging markers of lacunae, cerebral microbleeds (CMBs), white matter hyperintensities (WMH) including periventricular hyperintensities, and perivascular spaces in basal ganglia- and clinical outcomes are limited. The aim of this study is to determine the association between SVD burden and long-term prognosis in patients with ischemic stroke.Methods and designThis prospective, single-center, observational study enrolled patients with acute ischemic stroke, including cerebral infarction and transient ischemic attack. Magnetic resonance imaging scans were performed, and then total SVD score (range, 0-4) was calculated. We recorded baseline characteristics and evaluated the relationships of long-term outcomes to SVD neuroimaging markers and total SVD score. Stroke recurrence was thought as primary outcome. Hazard ratios (HRs) of events during follow-up were calculated using Cox proportional hazards modeling with adjustments for age, sex, hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, and smoking. Cumulative event rates were estimated using the Kaplan-Meier method.ResultsConsecutive 564 acute ischemic stroke patients were enrolled according to inclusion and exclusion criteria. A total of 467 participants with first-ever ischemic stroke were analyzed (median age 75.0 [interquartile range, 64.0-83.0] years, 59.3% male). Total SVD score was 0 point in 47 individuals (12.0%), 1 point in 83 (21.2%), 2 points in 103 (26.3%), 3 points in 85 (21.7%), and 4 points in 73 (18.7%). Twenty-eight recurrent stroke events were identified during follow-up. Total SVD score ≥ 2, presence of CMBs, and moderate-to-severe WMH were associated with increased risk of recurrent stroke events (HR 9.31, 95% confidence interval [CI] 2.33-64.23; HR 2.81, 95% CI 1.08-7.30; HR 2.90, 95% CI 1.22-6.88, respectively).ConclusionThe accumulation of SVD biomarkers as determined by total SVD score offered a reliable predictor of stroke recurrence. This study established a firm understanding of SVD prognosis in clinical settings.

Project description:IntroductionThe INflammation and Small Vessel Disease (INSVD) study aims to investigate whether peripheral inflammation, immune (dys)regulation and blood-brain barrier (BBB) permeability relate to disease progression in cerebral small vessel disease (SVD). This research aims to pinpoint specific components of the immune response in SVD relating to disease progression. This could identify biomarkers of SVD progression, as well as potential therapeutic targets to inform the development and repurposing of drugs to reduce or prevent SVD, cognitive decline and vascular dementia.Methods and analysisINSVD is a prospective observational multicentre cohort study in individuals with symptomatic SVD. This longitudinal study combines comprehensive immunophenotyping of the peripheral blood immune compartment with advanced neuroimaging markers of SVD and BBB permeability. The main SVD marker of interest is white matter microstructure as determined by diffusion tensor imaging, a valuable marker of disease progression owing to its sensitivity to early alterations to white matter integrity. The research is being conducted in two sites-in the UK (Cambridge) and the Netherlands (Nijmegen)-with each site recruiting 100 participants (total n=200). Participants undergo clinical and cognitive assessments, blood draws, and brain MRI at baseline and 2-year follow-up.Ethics and disseminationThis study received ethical approval from the local ethics boards (UK: East of England-Cambridge Central Research Ethics Committee (REC) ref: 22/EE/00141, Integrated Research Application System (IRAS) ID: 312 747. Netherlands: Medical Research Ethics Committee (MREC) Oost-Nederland, ref: 2022-13623, NL-number: NL80258.091.22). Written informed consent was obtained from all subjects before the study. Any participant-derived benefits resulting from this research, such as new insights into disease mechanisms or possible novel therapies, will be disseminated to study participants, patient groups and members of the public.Trial registration numberNCT05746221.

Project description:BackgroundImpaired cerebral blood flow (CBF) autoregulation during cardiopulmonary bypass (CPB) is associated with stroke and other adverse outcomes. Large and small arterial stenosis is prevalent in patients undergoing cardiac surgery. We hypothesize that large and/or small vessel cerebral arterial disease is associated with impaired cerebral autoregulation during CPB.MethodsA retrospective cohort analysis of data from 346 patients undergoing cardiac surgery with CPB enrolled in an ongoing prospectively randomized clinical trial of autoregulation monitoring were evaluated. The study protocol included preoperative transcranial Doppler (TCD) evaluation of major cerebral artery flow velocity by a trained vascular technician and brain magnetic resonance imaging (MRI) between postoperative days 3 and 5. Brain MRI images were evaluated for chronic white matter hyperintensities (WMHI) by a vascular neurologist blinded to autoregulation data. "Large vessel" cerebral vascular disease was defined by the presence of characteristic TCD changes associated with stenosis of the major cerebral arteries. "Small vessel" cerebral vascular disease was defined based on accepted scoring methods of WMHI. All patients had continuous TCD-based autoregulation monitoring during surgery.ResultsImpaired autoregulation occurred in 32.4% (112/346) of patients. Preoperative TCD demonstrated moderate-severe large vessel stenosis in 67 (25.2%) of 266 patients with complete data. In adjusted analysis, female sex (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.25-0.86; P = .014) and higher average temperature during CPB (OR, 1.23; 95% CI, 1.02-1.475; P = .029), but not moderate-severe large cerebral arterial stenosis (P = .406), were associated with impaired autoregulation during CPB. Of the 119 patients with available brain MRI data, 42 (35.3%) demonstrated WMHI. The presence of small vessel cerebral vascular disease was associated with impaired CBF autoregulation (OR, 3.25; 95% CI, 1.21-8.71; P = .019) after adjustment for age, history of peripheral vascular disease, preoperative hemoglobin level, and preoperative treatment with calcium channel blocking drugs.ConclusionsThese data confirm that impaired CBF autoregulation is prevalent during CPB predisposing affected patients to brain hypoperfusion or hyperperfusion with low or high blood pressure, respectively. Small vessel, but not large vessel, cerebral vascular disease, male sex, and higher average body temperature during CPB appear to be associated with impaired autoregulation.

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Early life predictors of late life cerebral small vessel disease in four prospective cohort studies.

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