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

Ellen V Backhouse,Aleks Stolicyn,Anca-Larisa Sandu,Archie Campbell,Mathew A Harris,Simon R Cox,Tessa J Roseboom,Jennifer M J Waymont,Alison D Murray,Joanna M Wardlaw,Douglas Steele,Susana Muñoz Maniega,Maria Valdez Hernandez,Heather C Whalley,Susan D Shenkin,Andrew M Mcintosh,Susanne R De Rooij,Mark E Bastin,Gordon D Waiter

doi:10.1093/brain/awab331

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.

Highlights

Cerebral small vessel disease (SVD) is common at older ages[1] and causes 20–25% of strokes and up to 45% of dementias, either as vascular or mixed with Alzheimer’s disease.[2]
We examined the relationships between birth and childhood factors and total and individual components of SVD and brain volumes, after adjustment for each other and common adult risk factors, in four well-phenotyped prospective cohort studies: STratifying Resilience And Depression Longitudinally (STRADL).[15] the Dutch Famine Birth Cohort,[16] the Lothian Birth Cohort 1936 (LBC1936),[17] and the Simpson’s cohort.[18]
Where data were available in comparable format, we have provided key characteristics of the wider Scottish and Dutch population in Supplementary Tables 3–6

Summary

Introduction

Cerebral small vessel disease (SVD) is common at older ages[1] and causes 20–25% of strokes and up to 45% of dementias, either as vascular or mixed with Alzheimer’s disease.[2]. Factors affecting foetal growth such as stress and poor nutrition[10,11] are often hard to measure but anthropometric measures such as birth weight and ponderal index (birth weight/birth length3) can be used as proxy measures.[12] Additional confounding or mediating factors in childhood may affect later disease risk.[13] A recent meta-analysis[14] found that lower levels of childhood IQ, poorer childhood SES, and less education increased the risk of SVD in later life by approximately 17– 39% It is not clear if these relationships are independent of each other, or if they persist after adjustment for vascular risk factors and adult SES. Few studies have examined the effect of these early life factors in combination and many rely on childhood measures assessed retrospectively in adulthood so may be subject to recall bias

Methods

Results

Discussion

Conclusion