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 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 100g, 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=-178.86cm3, 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.

Correspondence to: Prof Joanna M. Wardlaw
Centre for Clinical Brain Sciences, University of Edinburgh, The Chancellors Building, 49 Little France Crescent, Edinburgh, EH16 4SB Email: [email protected] Tel: 0131 537 2943
Running title: Early life risk factors for SVD

Keywords: cerebral small vessel disease, education, childhood, MRI, epidemiology

Abbreviations: ACDS= Aberdeen Child Development Survey; ACONF= Aberdeen Children of the 1950s cohort; DOHAD= Developmental Origins of Adult Heath and Disease; GS:SFHS= Generation Scotland: Scottish Family Health Study; ICV= intracranial volume; LBC1936= the Lothian Birth Cohort 1936; LGA= Lesion Growth Algorithm; PVS= perivascular spaces; SES= socioeconomic status; STRADL= STratifying Resilience and Depression Longitudinally; SVD= cerebral small vessel disease; WMH= white matter hyperintensities.