Early Life Risk Factors for Stroke and Cognitive Impairment

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 socioeconomic status or of vascular risk factor exposures. We examined associations between factors from birth (ponderal index, birth weight), childhood (IQ, education, socioeconomic 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 socioeconomic status. Higher birth weight was associated with fewer lacunes (OR per 100 g, 0.93 95%CI = 0.88–0.99), fewer infarcts (OR = 0.94 95%CI = 0.89–0.99), and fewer perivascular spaces (OR = 0.95 95%CI = 0.91–0.99). Higher childhood IQ was associated with lower white matter hyperintensity burden (OR per IQ point = 0.99 95%CI 0.98–0.998), fewer infarcts (OR = 0.98, 95%CI = 0.97–0.998), fewer lacunes (OR = 0.98, 95%CI = 0.97–0.999), and lower total small vessel disease burden (OR = 0.98, 95%CI = 0.96–0.999). Low education was associated with more microbleeds (OR = 1.90 95%CI = 1.33–2.72) and lower total brain volume (MD=-178.86 cm3, 95%CI=-325.07- -32.66). Low childhood socioeconomic status was associated with fewer lacunes (OR = 0.62, 95%CI = 0.40–0.95). Early life factors are associated with worse small vessel disease in later life, independent of each other, vascular risk factors and adult socioeconomic 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 contribute to improve lifelong brain health to prevent dementia and stroke in older age.

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“…Adapted from Figure 1 in Backhouse et al . 8 AF = atrial fibrillation; BP = blood pressure; Chol = cholesterol.…”

Section: Methodsmentioning

confidence: 99%

“… 6 , 7 However, a large proportion of the variance in the presence and severity of SVD is unexplained by vascular risk factors 7 and factors from earlier in life may also be important. 8 …”

Section: Introductionmentioning

confidence: 99%

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

Backhouse

Shenkin

McIntosh

et al. 2021

Brain

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“…In addition, the ENIGMA-Epigenetics group is prioritizing the analysis of DNA methylation sites based on their effects on gene expression or association with stress- and anxiety-related phenotypes. There is some evidence of early life changes in stress response genes through methylation ( Backhouse et al, 2015 ), just as early life events influence later life disease expression — notably stroke, white matter hyperintensities, and cognitive impairment. Of great interest are epigenetic changes throughout the life span, and with aging, which may predict mortality from all causes, as well as physical and cognitive performance.…”

Section: Enigma's Disease Studiesmentioning

confidence: 99%

ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide

et al. 2017

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In this review, we discuss recent work by the ENIGMA Consortium (http://enigma.ini.usc.edu) – a global alliance of over 500 scientists spread across 200 institutions in 35 countries collectively analyzing brain imaging, clinical, and genetic data. Initially formed to detect genetic influences on brain measures, ENIGMA has grown to over 30 working groups studying 12 major brain diseases by pooling and comparing brain data. In some of the largest neuroimaging studies to date – of schizophrenia and major depression – ENIGMA has found replicable disease effects on the brain that are consistent worldwide, as well as factors that modulate disease effects. In partnership with other consortia including ADNI, CHARGE, IMAGEN and others1, ENIGMA's genomic screens – now numbering over 30,000 MRI scans – have revealed at least 8 genetic loci that affect brain volumes. Downstream of gene findings, ENIGMA has revealed how these individual variants – and genetic variants in general – may affect both the brain and risk for a range of diseases. The ENIGMA consortium is discovering factors that consistently affect brain structure and function that will serve as future predictors linking individual brain scans and genomic data. It is generating vast pools of normative data on brain measures – from tens of thousands of people – that may help detect deviations from normal development or aging in specific groups of subjects. We discuss challenges and opportunities in applying these predictors to individual subjects and new cohorts, as well as lessons we have learned in ENIGMA's efforts so far.

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“…Moreover, the interval between stroke presentation and baseline MRI assessment is an important factor (eTable 2, links.lww.com/WNL/B796 ) because SVD lesions are dynamic. 1 In the assessment of poststroke cognition, it is important to adjust for factors that are associated with premorbid cognitive ability, 22 later-life cerebrovascular disease, 41 , 42 and cognitive decline. 42 One previous study adjusted for ICV and education, 12 and another adjusted for premorbid IQ.…”

Section: Discussionmentioning

confidence: 99%

Impact of Small Vessel Disease Progression on Long-term Cognitive and Functional Changes After Stroke

et al. 2022

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Background and ObjectivesThe severity of white matter hyperintensities (WMH) at presentation with stroke associates with post-stroke dementia and dependency. However, WMH can decrease or increase after stroke, prediction of cognitive decline is imprecise, and there are few data assessing longitudinal interrelationships between changing WMH, cognition, and function after stroke, despite the clinical importance.MethodsWe recruited patients within three months of a minor ischaemic stroke, defined as NIHSS score <8 and not expected to result in a modified Rankin Score (mRS) >2. Participants repeated MRI at one year, and cognitive and mRS assessments at one and three years. We ran longitudinal mixed-effects models assessing change in Addenbrooke’s Cognitive Examination-Revised (ACE-R) and modified Rankin Scores (mRS). For mRS, we assessed longitudinal WMH volumes (cube root; percentage intracranial volume [ICV]), adjusting for age, NIHSS, ACE-R, stroke subtype, and time to assessment. For ACE-R, we additionally adjusted for ICV, mRS, premorbid IQ, and vascular risk factors. We then used a multivariate model to jointly assess changing cognition/mRS, adjusted for prognostic variables, using all available data.ResultsWe recruited 264 patients; mean age was 66.9 (SD 11.8); 41.7% were female; median mRS 1 (IQR 1-2). One year after stroke, normalised WMH volumes associated more strongly with one-year ACE-R (β= -0.259, 95% confidence interval [CI] -0.407 to -0.111 more WMH per 1-point ACE-R decrease, p=0.001) compared to subacute WMH volumes and ACE-R (β=0.105, 95%CI -0.265 to 0.054, p=0.195). Three-year mRS associated with three-year ACE-R (β=-0.272, 95%CI -0.429 to -0.115, p=0.001). Combined change in baseline-one-year jointly assessed ACE-R/mRS associated with fluctuating WMH volumes (F=9.3, p=0.03).DiscussionAfter stroke, fluctuating WMH mean that one-year, but not baseline, WMH volumes associate strongly with contemporaneous cognitive scores. Co-varying longitudinal decline in cognition and independence post-stroke, central to dementia diagnosis, is associated with increasing WMH volumes.

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Early Life Risk Factors for Stroke and Cognitive Impairment

Cited by 5 publications

References 66 publications

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

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

ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide

Impact of Small Vessel Disease Progression on Long-term Cognitive and Functional Changes After Stroke

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