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 Valdez Hernandez; Susana Muñoz Maniega; Matthew A. Harris; Aleks  Stolicyn; Archie Campbell; Douglas Steele; Douglas Steele; Gordon Waiter; Anca-Larisa Sandu-Giuraniuc; Jennifer M J Waymont; Alison Murray; Simon R. Cox; Susanne de Rooij; Tessa J. Roseboom; Joanna M. Wardlaw

doi:10.1093/brain/awab331

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 Valdez Hernandez, Susana Muñoz Maniega, Matthew A. Harris, Aleks Stolicyn, Archie Campbell, Douglas Steele, Douglas Steele, Gordon Waiter, Anca-Larisa Sandu-Giuraniuc, Jennifer M J Waymont, Alison Murray, Simon R. Cox, Susanne de Rooij, Tessa J. Roseboom, Joanna M. Wardlaw^* (Corresponding Author)

^*Corresponding author for this work

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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

Original language	English
Pages (from-to)	3769–3778
Number of pages	10
Journal	Brain
Volume	144
Issue number	12
DOIs	https://doi.org/10.1093/brain/awab331
Publication status	Published - 28 Sept 2021

Bibliographical note

Funding:
Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006] and is currently supported by the Wellcome Trust [216767/Z/19/Z]. The MRI data collection was funded by the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z).” The LBC1936 is supported by Age UK [MR/M01311/1] (http://www.disconnectedmind.ed.ac.uk) and the Medical Research Council [G1001245/96099]. LBC1936 MRI brain imaging was supported by Medical Research Council (MRC) grants [G0701120], [G1001245], [MR/M013111/1] and [MR/R024065/1] and Row Fogo Charitable Trust (Grant No. BROD.FID3668413). Simpson’s Cohort was supported by the UK MRC and Chest Heart Stroke Scotland. JMJW received funding from TauRx Pharmaceuticals Ltd. EB received funding from the Sackler Foundation. JMW received funding from the UK Dementia Research Institute (DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK) and SVDs@Target, the Fondation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease, ref no. 16 CVD 05

Keywords

cerebral small vessel disease
education
childhood
MRI
epidemiology

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Backhouse, E. V., Shenkin, S. D., McIntosh, A. M., Bastin, M. E., Whalley, H. C., Valdez Hernandez, M., Muñoz Maniega, S., Harris, M. A., Stolicyn, A., Campbell, A., Steele, D., Steele, D., Waiter, G., Sandu-Giuraniuc, A.-L., Waymont, J. M. J., Murray, A., Cox, S. R., de Rooij, S., Roseboom, T. J., & Wardlaw, J. M. (2021). Early life predictors of late life cerebral small vessel disease in four prospective cohort studies. Brain, 144(12), 3769–3778. https://doi.org/10.1093/brain/awab331

Backhouse, EV, Shenkin, SD, McIntosh, AM, Bastin, ME, Whalley, HC, Valdez Hernandez, M, Muñoz Maniega, S, Harris, MA, Stolicyn, A, Campbell, A, Steele, D, Steele, D, Waiter, G , Sandu-Giuraniuc, A-L, Waymont, JMJ, Murray, A, Cox, SR, de Rooij, S, Roseboom, TJ & Wardlaw, JM 2021, 'Early life predictors of late life cerebral small vessel disease in four prospective cohort studies', Brain, vol. 144, no. 12, pp. 3769–3778. https://doi.org/10.1093/brain/awab331

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title = "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{\textquoteright}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",

keywords = "cerebral small vessel disease, education, childhood, MRI, epidemiology",

author = "Backhouse, {Ellen V.} and Shenkin, {Susan D} and McIntosh, {Andrew M.} and Bastin, {Mark E} and Whalley, {Heather C.} and {Valdez Hernandez}, Maria and {Mu{\~n}oz Maniega}, Susana and Harris, {Matthew A.} and Aleks Stolicyn and Archie Campbell and Douglas Steele and Douglas Steele and Gordon Waiter and Anca-Larisa Sandu-Giuraniuc and Waymont, {Jennifer M J} and Alison Murray and Cox, {Simon R.} and {de Rooij}, Susanne and Roseboom, {Tessa J.} and Wardlaw, {Joanna M.}",

note = "Funding: Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006] and is currently supported by the Wellcome Trust [216767/Z/19/Z]. The MRI data collection was funded by the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z).” The LBC1936 is supported by Age UK [MR/M01311/1] (http://www.disconnectedmind.ed.ac.uk) and the Medical Research Council [G1001245/96099]. LBC1936 MRI brain imaging was supported by Medical Research Council (MRC) grants [G0701120], [G1001245], [MR/M013111/1] and [MR/R024065/1] and Row Fogo Charitable Trust (Grant No. BROD.FID3668413). Simpson{\textquoteright}s Cohort was supported by the UK MRC and Chest Heart Stroke Scotland. JMJW received funding from TauRx Pharmaceuticals Ltd. EB received funding from the Sackler Foundation. JMW received funding from the UK Dementia Research Institute (DRI Ltd, funded by the UK Medical Research Council, Alzheimer{\textquoteright}s Society and Alzheimer{\textquoteright}s Research UK) and SVDs@Target, the Fondation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease, ref no. 16 CVD 05",

year = "2021",

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doi = "10.1093/brain/awab331",

language = "English",

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T1 - Early life predictors of late life cerebral small vessel disease in four prospective cohort studies

AU - Backhouse, Ellen V.

AU - Shenkin, Susan D

AU - McIntosh, Andrew M.

AU - Bastin, Mark E

AU - Whalley, Heather C.

AU - Valdez Hernandez, Maria

AU - Muñoz Maniega, Susana

AU - Harris, Matthew A.

AU - Stolicyn, Aleks

AU - Campbell, Archie

AU - Steele, Douglas

AU - Waiter, Gordon

AU - Sandu-Giuraniuc, Anca-Larisa

AU - Waymont, Jennifer M J

AU - Murray, Alison

AU - Cox, Simon R.

AU - de Rooij, Susanne

AU - Roseboom, Tessa J.

AU - Wardlaw, Joanna M.

N1 - Funding: Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006] and is currently supported by the Wellcome Trust [216767/Z/19/Z]. The MRI data collection was funded by the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z).” The LBC1936 is supported by Age UK [MR/M01311/1] (http://www.disconnectedmind.ed.ac.uk) and the Medical Research Council [G1001245/96099]. LBC1936 MRI brain imaging was supported by Medical Research Council (MRC) grants [G0701120], [G1001245], [MR/M013111/1] and [MR/R024065/1] and Row Fogo Charitable Trust (Grant No. BROD.FID3668413). Simpson’s Cohort was supported by the UK MRC and Chest Heart Stroke Scotland. JMJW received funding from TauRx Pharmaceuticals Ltd. EB received funding from the Sackler Foundation. JMW received funding from the UK Dementia Research Institute (DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK) and SVDs@Target, the Fondation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease, ref no. 16 CVD 05

PY - 2021/9/28

Y1 - 2021/9/28

N2 - 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

AB - 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

KW - cerebral small vessel disease

KW - education

KW - childhood

KW - MRI

KW - epidemiology

U2 - 10.1093/brain/awab331

DO - 10.1093/brain/awab331

M3 - Article

SN - 0006-8950

VL - 144

SP - 3769

EP - 3778

JO - Brain

JF - Brain

IS - 12

ER -

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

Abstract

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