1. 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

2. 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”

3. 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

4. Southall and Brent Revisited (SABRE) study
Baseline recruitment (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
Interviews and clinical examinations
MRI head
3410 survivors
2101 followed
Mean (SD) interval 19.7 (1.2) years
1110 with MRI data

5. 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

6. 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)

7. 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.

8. 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%

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

10. 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)

11. 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)

12. 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

13. 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.
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