Cumulative Cardiovascular Risk Measured in Young Adulthood Associates With Midlife White Matter Hyperintensity Burden: The Bogalusa Heart Study

Authors:
Franklin M. Epps¹˒², Christian P. Corsten¹˒²˒³, Ileana De Anda-Duran⁴, Lydia A. Bazzano⁴˒⁵, Owen T. Carmichael¹

Affiliations:
¹Pennington Biomedical Research Center, Baton Rouge, LA, USA
²LSU College of Science, Baton Rouge, LA, USA
³LSU Health Sciences Center, New Orleans, LA, USA
⁴Tulane University, New Orleans, LA, USA
⁵Internal Medicine, UTSW, Dallas, TX, USA

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Introduction

Cardiovascular risk in young adulthood may leave a lasting imprint on midlife brain health.

• Cardiovascular risk factors are established predictors of dementia and cerebral small vessel disease, with strongest evidence from midlife (age 40+) [1,2]
• Blood pressure is the single strongest modifiable risk factor for white matter hyperintensities (WMH), accounting for ~10.5% of total variance [7]
• Most studies measure risk at a single time point — cumulative burden from young adulthood is understudied [8]
• This study tests whether cumulative cardiovascular risk from young adulthood predicts midlife WMH burden, comparing three risk algorithms (FGCRS, ASCVD, SCORE)

Bogalusa Heart Study Sample

A 50-year community cohort links life-course cardiovascular health to midlife brain imaging.

• Community-based cohort followed from childhood into midlife since 1972 [15,16]
• Analytic sample: participants with ≥2 cardiovascular exams (1985–2010) + brain MRI (2017–2025)
• N = 190; 66.3% female; 80.5% White American, 19.5% Black American
• Mean age 24.0 ± 3.3y at first exam; 57.0 ± 4.9y at MRI
• Three risk algorithms compared: FGCRS (total CVD, sex-specific), ASCVD (hard atherosclerotic events, race/sex-specific), SCORE (fatal CVD only, sex-specific)

Participant Flow

Figure 3. Of 254 participants with midlife brain MRI, 190 had at least two valid cardiovascular assessments and were included in the analytic sample.

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Quantifying Cumulative CV Risk

All three algorithms were recalibrated to Louisiana and integrated across young adulthood.

• FGCRS, ASCVD, SCORE calculated at up to 6 exams per participant (ages ~24–41)
• Recalibrated to Louisiana-specific mortality (CDC 2000–2005) via the Ratio Method: S₀ = exp(−Rate × 10)
• Cumulative risk = area under the risk-by-age curve (AUC rate), standardized to Z-scores

Figure 1. Conceptual illustration of cumulative risk burden via area under the curve.

Statistical Analysis

OLS regression tested whether cumulative risk predicts WMH, with outlier sensitivity checks.

• WMH volume rank-based inverse normal (Blom) transformed to address skew
• OLS regression adjusted for age at MRI; sex and race excluded from covariates — already incorporated in risk score inputs, avoiding collinearity
• Outlier sensitivity analysis excluded extreme Z-scored AUC rates (Z > 4 for SCORE/FGCRS, Z > 8 for ASCVD)
• All analyses run in Python (pandas, scipy, statsmodels)

Sample Characteristics

The analytic sample (N = 190) was predominantly female and White American, in midlife.

• Total WMH volume highly skewed: median 0.19 mL (IQR 0.05–0.51), mean 0.52 ± 1.18 mL
• Systolic blood pressure increased from 110 ± 9 mmHg at first exam (mean age 23) to 116 ± 13 mmHg at last exam (mean age 43)
• HDL cholesterol declined from 52 ± 23 mg/dL to 47 ± 13 mg/dL over the same period
• Smoking prevalence decreased from 26.0% to 20.5%; diabetes prevalence increased from 0% to 8.2%

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Results

Greater cumulative cardiovascular risk predicts greater midlife white matter injury.

• SCORE: β = 0.212, 95% CI [0.061, 0.364], p = 0.006 (N = 190) — a 0.086 mL (48%) increase in WMH at the median
• FGCRS: borderline significant, β = 0.151, p = 0.050 — a 0.054 mL (31%) increase at the median
• ASCVD: not significant, β = 0.132, p = 0.065
• Outlier sensitivity: FGCRS strengthened after excluding 4 extreme values (β = 0.243, p = 0.027); SCORE attenuated after excluding 2 extreme values (β = 0.157, p = 0.099)

Figure 2. Standardized β coefficients (95% CI) by risk algorithm.

Conclusion

Cardiovascular risk from young adulthood is an early marker of brain injury in midlife.

• Cumulative cardiovascular risk from the mid-twenties through the early forties is associated with WMH burden ~15 years later
• Provides a cerebrovascular rationale for the 2019 ACC/AHA recommendation to assess lifetime CV risk beginning at age 20 [11]
• Supports cardiovascular risk management beginning in young adulthood to help preserve long-term brain health

References, Contact Info, and Funding

1. Livingston G, et al. Lancet. 2020;396:413-446.
2. Iadecola C, et al. Hypertension. 2016;68:e67-e94.
3. Habes M, et al. J Am Heart Assoc. 2024;13:e030676.
4. Prickett C, et al. Obes Res Clin Pract. 2015;9:93-113.
5. Arnett DK, et al. Circulation. 2019;140:e596-e646.
6. Berenson GS, et al. N Engl J Med. 1998;338:1650-1656.

Funded by the Pennington Biomedical Research Foundation and NIH grants R01AG077497, R01AG077000, RF1AG075769, RF1AG041200, and R01AG062309.

Franklin M. Epps | Mitchell.Epps@pbrc.edu