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

Ellen V. Backhouse, Susan D . Shenkin, Andrew M. McIntosh, Mark E. Bastin, Heather C. Whalley, Maria Valdes Hernandez, Susana Muñoz Maniega, Mat Harris, Aleks Stolicyn, Archie Campbell, Douglas Steele, Gordon D. Waiter, Anca-Larisa Sandu, Jennifer M. J. Waymont, Alison D. Murray, Simon R. Cox, Susanne R. de Rooij, Tessa J. Roseboom, Joanna M. Wardlaw (Lead / Corresponding author)

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Development of cerebral small vessel disease (SVD), 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 (SES) or of vascular risk factor exposures.

We examined associations between factors from birth (ponderal index, birth weight), childhood (IQ, education, SES), adult SVD, 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 SVD feature individually and summed to give a total SVD score (range 1-4) in each cohort separately, then in meta-analysis, adjusted for vascular risk factors and adult SES. 

Higher birth weight was associated with fewer lacunes (OR per 100g, 0.93 95%CI=0.88-0.99, p=0.01), fewer infarcts (OR=0.94 95%CI=0.89-0.99, p=0.01), and fewer perivascular spaces (OR=0.95 95%CI=0.91-0.99, p=0.02). Ponderal index was not associated with SVD. Higher childhood IQ was associated with lower white matter hyperintensity burden (OR per IQ point=0.99 95%CI 0.98-0.998, p=0.03), fewer infarcts (OR=0.98, 95%CI=0.97-0.998, p=0.03), fewer lacunes (OR=0.98, 95%CI=0.97-0.999, p=0.04), and lower total SVD burden (OR=0.98, 95%CI=0.96-0.999, p=0.04). Low education was associated with more micro-bleeds (OR=1.90 95%CI=1.33-2.72, p<0.001) and lower total brain volume (MD=-178.86cm3, 95%CI=-325.07- -32.66, p=0.02). Low childhood SES was associated with with fewer lacunes (OR=0.62, 95%CI=0.40-0.95, p=0.03).

Early life factors are associated with worse SVD in later life, independent of each other, vascular risk factors and adult SES. Risk for SVD 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.
Original languageEnglish
Pages (from-to)3769-3778
Number of pages10
Issue number12
Early online date28 Sept 2021
Publication statusPublished - Dec 2021


  • cerebral small vessel disease
  • education
  • childhood
  • MRI
  • epidemiology


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