SABRE (Southall and Brent Revisited) Association of mid-life vascular risk factors associated with late-life hippocampal volume: A prospective multi-ethnic population-based study Dr. Gayan perera, Epidemiologist King’s college London (institute of Psychiatry), UK

Background Smaller hippocampal volume is an important correlate of cognitive decline and dementia in later life. Vascular factors are important determinants of risk for cognitive decline and dementia Potentially multiple causal pathways … “which may differ between risk factors” … “and between ethnic groups”

Aims and objectives To investigate relationships between mid-life vascular risk factors and late-life hippocampal volume; To compare these between different vascular risk factors To compare these between different ethnic groups

Southall and Brent Revisited (SABRE) study Baseline recruitment 1988-91 (n-4502) Age 40-69 Primary Care lists and workforces Response 68-81%, male preponderance Interviews and examinations Vascular risk profiles ascertained European (n=2196) South Asian (n=1531) African-Caribbean (n=775) Follow-up 2008-11 Interviews and clinical examinations MRI head 3410 survivors 2101 followed Mean (SD) interval 19.7 (1.2) years 1110 with MRI data

Baseline & follow-up measurements Demographic factors Self-reported smoking status Body size (BMI, waist:hip ratio, height) Fasting blood assays – glucose, insulin, lipid profile Diabetes – WHO criteria / physician diagnosis / medication Resting, seated blood pressure (random zero, mean of 2 readings) Follow-up Automated segmentation of the hippocampus, using FIRST in FSL 4.1 Brain volumes computed as the volume of the brain after skull stripping of the T1- weighted image using BET

Sample characteristics at baseline Frequency or mean (SD) Sociodemography Mean (SD) age at baseline 49.9 (6.2) Mean (SD) age at follow-up 69.6 (6.1) Female sex 31.5% Ethnic group European 48.8% South Asian 34.0% African-Caribbean 17.2% Less than 10 years duration of education 15.8% Characteristic Frequency or mean (SD) CVD risk factors Current smoker 17.8% Mean (SD) BMI (kg/m2) 25.9 (3.6) Mean (SD) systolic blood pressure (mmHg) 121.1 (15.5) Presence of diabetes 7.9% Mean (SD) fasting insulin (umol/ml) 9.4 (6.7) Mean (SD) fasting glucose (mmol/l) 5.7 (1.5) Mean (SD) fasting HDL cholesterol 1.4 (0.4) Imaging variables at follow-up Presence of infarct 20.2% Presence of white matter hyperintensities 34.2% Mean (SD) hippocampal volume (cm3) 7.4 (1.0) Mean (SD) brain volume (cm3) 1424 (297)

Associations with hippocampal volume (adj Associations with hippocampal volume (adj. age, sex, ethnicity, follow-up duration) Variable B-coef. P value Socio-demography   Age (per 10 year increase) -0.5 <0.001 Female sex -0.35 Years of education (per 10 year increase) 0.2 0.049 Lower social class (per group increment) -0.32 0.027 Imaging variables at follow-up Presence of white matter hyperintensities -0.12 0.043 Presence of infarcts 0.065 Total brain volume (in CC3, SD increase) 0.05 0.04 Variable B-coef. P value CVD risk factors at baseline   BMI (SD increase) -0.01 0.471 Waist/hip ratio (SD increase) -0.09 0.815 SBP (SD increase) -0.02 0.043 DBP (SD increase) 0.974 Diabetes -0.3 0.002 Fasting insulin (SD increase) -0.08 0.009 Fasting glucose (SD increase) -0.1 <0.001 Fasting HDL-cholesterol (SD increase) 0.02 0.464 Fasting triglycerides (SD increase) -0.04 0.213 Fasting total cholesterol (SD increase) 0.731 When diabetes patients were removed from the model, fasting glucose and insulin was significantly associated with lower hippocampal volume.

Associations with hippocampal volume: Stratification by ethnic group Diabetes Fasting insulin (SD increase) Fasting glucose (SD increase)   B coef. (95% CI) P European -0.08 (-0.56, 0.40) 0.747 -0.11 (-0.23, 0.01) 0.073 -0.04 (-0.14, 0.07) 0.500 Overall model R2 19.5% 20.0% South Asian -0.26 (-0.56, 0.02) 0.066 -0.04 (-0.13, 0.06) 0.446 -0.13 (-0.23, -0.04) 0.006 17.9% 18.8% 18.0% African-Caribbean -0.08 (-0.43, 0.27) 0.647 -0.03 (-0.19, 0.12) 0.656 -0.07 (-0.18, 0.04) 0.391 34.2% 34.7% 34.4%

Contribution of vascular risk factors to final model (in the context of other factors)

Key findings Diabetes/glucose/insulin were the main ‘vascular’ predictors of hippocampal volume Glucose and insulin remain predictors in the absence of diabetes Potential ethnic group variation in risk associations (diabetes and glucose strongest in South Asian group; insulin strongest in European)

Potential mechanisms The hippocampus contains a high number of insulin receptors and glucose transporters (Lobnig, 2006) and may be relatively sensitive to changes in glucose metabolism (McEwen, 2002) A cortisol increase activated by the inability of insulin to increase glucose intake potentially aggravating hippocampal dysfunction (Dhikav, 2011) Glucose-related increases in inflammatory responses and blood coagulation activation, leading to clinical and subclinical strokes and subsequent volume loss (Cherbuin, 2012) Direct ‘toxic’ effects of glucose on neuronal structures disturbances of intracellular second messenger pathways imbalance in the generation and scavenging of reactive oxygen species advanced glycation of functional and structural proteins negative effects on neuronal membrane integrity increased extracellular water content (Kale, 2006), supported by higher hippocampal mean diffusivity (Kerti, 2013)

Conclusions Vascular risk factors are important predictors of hippocampal volume Need to consider full profiles rather than individual risks Need to consider heterogeneity in causal pathways Need to consider heterogeneity in populations

Acknowledgement Robert Stewart1;; Dean Shibata3; Therese Tillin2; Clare Taylor1 ; Nish Chaturvedi2 1King’s College London (Institute of Psychiatry), London, United Kingdom. 2Institute of Cardiovascular Science at University College London 3Department of Radiology, University of Washington, USA Funding: The SABRE study was funded jointly by the Wellcome Trust and the British Heart Foundation, and the SABRE Cognitive Function study was funded by the Wellcome Trust. The baseline Southall study was funded by the UK Medical Research Council, the British Diabetic Association (now Diabetes UK), the Wellcome Trust and the British Heart Foundation. For further information on SABRE study: http://www.sabrestudy.org/