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The effect of midlife cardiovascular risk factors on white matter hyperintensity volume and cognition two decades later in normal ageing women

Abstract

Cerebral White Matter Hyperintensity (WMH) lesions have been identified as markers of cerebrovascular diseases and they are associated with increased risk of cognitive impairment. In this study, we investigated the relationship between midlife cardiovascular risk factors and late life WMH volumes two decades later, and examined their association with cognitive performance. 135 participants from the Women’s Healthy Ageing Project had completed midlife cardiovascular risk measurement in 1992 and late life brain MRI scan and cognitive assessment in 2012. In these community-dwelling normal aging women, we found that higher midlife Framingham Cardiovascular Risk Profile (FCRP) score was associated with greater WMH volume two decades later, and was predominantly driven by the impact of HDL cholesterol level, controlling for age, education and APOE ε4 status. Structural equation modelling demonstrated that the relationship between midlife FCRP score and late life executive function was mediated by WMH volume. These findings suggest intervention strategies that target major cardiovascular risk factors at midlife might be effective in reducing the development of WMH lesions and thus late life cognitive decline.

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References

  1. Abraham, H. M. A., Wolfson, L., Moscufo, N., Guttmann, C. R., Kaplan, R. F., & White, W. B. (2015). Cardiovascular risk factors and small vessel disease of the brain: Blood pressure, white matter lesions, and functional decline in older persons. Journal of Cerebral Blood Flow & Metabolism, 36(1), 132–142.

  2. Allan, C. L., Zsoldos, E., Filippini, N., Sexton, C. E., Topiwala, A., Valkanova, V., Singh-Manoux, A., Tabák, A. G., Shipley, M. J., Mackay, C., & Mackay, C. (2014). Lifetime hypertension as a predictor of brain structure in older adults: cohort study with a 28-year follow up. The British Journal of Psychiatry, 206(4), 308–−315.

  3. Arntzen, K., Schirmer, H., Wilsgaard, T., & Mathiesen, E. (2011). Impact of cardiovascular risk factors on cognitive function: The Tromsø study. European Journal of Neurology, 18(5), 737–743.

  4. Au, R., Massaro, J. M., Wolf, P. A., Young, M. E., Beiser, A., Seshadri, S., D’Agostino, R. B., & DeCarli, C. (2006). Association of white matter hyperintensity volume with decreased cognitive functioning: The Framingham heart study. Archives of Neurology, 63(2), 246–250.

  5. Avants, B. B., Tustison, N. J., Song, G., Cook, P. A., Klein, A., & Gee, J. C. (2011). A reproducible evaluation of ANTs similarity metric performance in brain image registration. Neuroimage, 54(3), 2033–2044.

  6. Bangen, K. J., Beiser, A., Delano-Wood, L., Nation, D. A., Lamar, M., Libon, D. J., Bondi, M. W., Seshadri, S., Wolf, P. A., & Au, R. (2013). APOE genotype modifies the relationship between midlife vascular risk factors and later cognitive decline. Journal of Stroke and Cerebrovascular Diseases, 22(8), 1361–1369.

  7. Barter, P. J., Nicholls, S., Rye, K. A., Anantharamaiah, G., Navab, M., & Fogelman, A. M. (2004). Antiinflammatory properties of HDL. Circulation Research, 95(8), 764–772.

  8. Bitton, A., & Gaziano, T. (2010). The Framingham heart Study's impact on global risk assessment. Progress in Cardiovascular Diseases, 53(1), 68–78.

  9. Brindle, P., Beswick, A., Fahey, T., & Ebrahim, S. (2006). Accuracy and impact of risk assessment in the primary prevention of cardiovascular disease: A systematic review. Heart, 92(12), 1752–1759.

  10. Carass, A., Roy, S., Jog, A., Cuzzocreo, J. L., Magrath, E., Gherman, A., & Sudre, C. H. (2017). Longitudinal multiple sclerosis lesion segmentation: Resource and challenge. Neuroimage, 148(12), 77–102.

  11. Collins, P. (2008). HDL-C in post-menopausal women: An important therapeutic target. International Journal of Cardiology, 124(3), 275–282.

  12. D’Agostino, R. B., Vasan, R. S., Pencina, M. J., Wolf, P. A., Cobain, M., Massaro, J. M., & Kannel, W. B. (2008). General cardiovascular risk profile for use in primary care the Framingham heart study. Circulation, 117(6), 743–753.

  13. De Leeuw, F. E., De Groot, J. C., Oudkerk, M., Witteman, J., Hofman, A., Van Gijn, J., & Breteler, M. (1999). A follow-up study of blood pressure and cerebral white matter lesions. Annals of Neurology, 46(6), 827–833.

  14. De Leeuw, F.-E., Richard, F., de Groot, J. C., van Duijn, C. M., Hofman, A., van Gijn, J., & Breteler, M. M. (2004). Interaction between hypertension, apoE, and cerebral white matter lesions. Stroke, 35(5), 1057–1060.

  15. Debette, S., Seshadri, S., Beiser, A., Au, R., Himali, J., Palumbo, C., Wolf, P., & DeCarli, C. (2011). Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline. Neurology, 77(5), 461–468.

  16. Delis, D. C., Kramer, J. H., Kaplan, E., & Ober, B. A. (1987). CVLT, California Verbal Learning Test: Adult Version: Manual: Psychological corporation.

  17. Dennerstein, L., Dudley, E. C., Hopper, J. L., Guthrie, J. R., & Burger, H. G. (2000). A prospective population-based study of menopausal symptoms. Obstetrics & Gynecology, 96(3), 351–358.

  18. Dickie, D. A., Ritchie, S. J., Cox, S. R., Sakka, E., Royle, N. A., Aribisala, B. S., Hernández, M. C. V., Maniega, S. M., Pattie, A., & Corley, J. (2016). Vascular risk factors and progression of white matter hyperintensities in the Lothian birth cohort 1936. Neurobiology of Aging, 42, 116–123.

  19. Van Exel, E., de Craen, A. J., Gussekloo, J., Houx, P., Bootsma-van der Wiel, A., Macfarlane, P. W., Blauw, G. J., & Westendorp, R. G. (2002). Association between high-density lipoprotein and cognitive impairment in the oldest old. Annals of Neurology, 51(6), 716–721.

  20. Fernando, M. S., Simpson, J. E., Matthews, F., Brayne, C., Lewis, C. E., Barber, R., Kalaria, R. N., Forster, G., Esteves, F., & Wharton, S. B. (2006). White matter lesions in an unselected cohort of the elderly molecular pathology suggests origin from chronic hypoperfusion injury. Stroke, 37(6), 1391–1398.

  21. Fischl, B. (2012). FreeSurfer. Neuroimage, 62(2), 774–781.

  22. Gattringer, T., Enzinger, C., Ropele, S., Gorani, F., Petrovic, K. E., Schmidt, R., & Fazekas, F. (2012). Vascular risk factors, white matter hyperintensities and hippocampal volume in normal elderly individuals. Dementia and Geriatric Cognitive Disorders, 33(1), 29–34.

  23. Godin, O., Tzourio, C., Maillard, P., Alpérovitch, A., Mazoyer, B., & Dufouil, C. (2009). Apolipoprotein E genotype is related to progression of white matter lesion load. Stroke, 40(10), 3186–3190.

  24. Golden, C. J., & Freshwater, S. M. (1978). Stroop color and word test.

  25. Gouw, A. A., Seewann, A., Van Der Flier, W. M., Barkhof, F., Rozemuller, A. M., Scheltens, P., & Geurts, J. J. (2010). Heterogeneity of small vessel disease: A systematic review of MRI and histopathology correlations. Journal of Neurology, Neurosurgery & Psychiatry, 82(2), 126–135.

  26. Grundy, S. M., Balady, G. J., Criqui, M. H., Fletcher, G., Greenland, P., Hiratzka, L. F., Houston-Miller, N., Kris-Etherton, P., Krumholz, H. M., & LaRosa, J. (1998). Primary prevention of coronary heart disease: Guidance from Framingham a statement for healthcare professionals from the AHA task force on risk reduction. Circulation, 97(18), 1876–1887.

  27. Guo, X., Pantoni, L., Simoni, M., Bengtsson, C., Björkelund, C., Lissner, L., & Skoog, I. (2009). Blood pressure components and changes in relation to white matter lesions. Hypertension, 54(1), 57–62.

  28. Havlik, R. J., Foley, D. J., Sayer, B., Masaki, K., White, L., & Launer, L. J. (2002). Variability in midlife systolic blood pressure is related to late-life brain white matter lesions the Honolulu-Asia aging study. Stroke, 33(1), 26–30.

  29. Hirono, N., Yasuda, M., Tanimukai, S., Kitagaki, H., & Mori, E. (2000). Effect of the apolipoprotein E ε4 allele on white matter hyperintensities in dementia. Stroke, 31(6), 1263–1268.

  30. Hixson, J. E., & Vernier, D. T. (1990). Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. Journal of Lipid Research, 31(3), 545–548.

  31. Hughes, C. P., Berg, L., Danziger, W. L., Coben, L. A., & Martin, R. (1982). A new clinical scale for the staging of dementia. The British Journal of Psychiatry, 140(6), 566–572.

  32. Jeerakathil, T., Wolf, P. A., Beiser, A., Massaro, J., Seshadri, S., D’Agostino, R. B., & DeCarli, C. (2004). Stroke risk profile predicts white matter hyperintensity volume the Framingham study. Stroke, 35(8), 1857–1861.

  33. Jenkinson, M., Beckmann, C. F., Behrens, T. E., Woolrich, M. W., & Smith, S. M. (2012). Fsl. Neuroimage, 62(2), 782–790.

  34. Kaffashian, S., Dugravot, A., Nabi, H., Batty, G. D., Brunner, E., Kivimäki, M., & Singh-Manoux, A. (2011). Predictive utility of the Framingham general cardiovascular disease risk profile for cognitive function: Evidence from the Whitehall II study. European Heart Journal, 32(18), 2326–2332.

  35. Kaffashian, S., Dugravot, A., Elbaz, A., Shipley, M. J., Sabia, S., Kivimäki, M., & Singh-Manoux, A. (2013). Predicting cognitive decline a dementia risk score vs the Framingham vascular risk scores. Neurology, 80(14), 1300–1306.

  36. King, K. S., Peshock, R. M., Rossetti, H. C., McColl, R. W., Ayers, C. R., Hulsey, K. M., & Das, S. R. (2014). Effect of normal aging versus hypertension, abnormal body mass index, and diabetes mellitus on white matter hyperintensity volume. Stroke, 45(1), 255–257.

  37. Kivipelto, M., Helkala, E. L., Hänninen, T., Laakso, M., Hallikainen, M., Alhainen, K., Soininen, H., Tuomilehto, J., & Nissinen, A. (2001). Midlife vascular risk factors and late-life mild cognitive impairment a population-based study. Neurology, 56(12), 1683–1689.

  38. Kloppenborg, R. P., Nederkoorn, P. J., Geerlings, M. I., & van den Berg, E. (2014). Presence and progression of white matter hyperintensities and cognition a meta-analysis. Neurology, 82(23), 2127–2138.

  39. Knopman, D., Boland, L., Mosley, T., Howard, G., Liao, D., Szklo, M., McGovern, P., Folsom, A., & Investigators, A. R. i. C. S. (2001). Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology, 56(1), 42–48.

  40. Knopman, D. S., Mosley, T. H., Catellier, D. J., & Coker, L. H. (2009). Fourteen-year longitudinal study of vascular risk factors, APOE genotype, and cognition: The ARIC MRI study. Alzheimer's & Dementia, 5(3), 207–214.

  41. Kortte, K. B., Horner, M. D., & Windham, W. K. (2002). The trail making test, part B: Cognitive flexibility or ability to maintain set? Applied Neuropsychology, 9(2), 106–109.

  42. Kurlowicz, L., & Wallace, M. (1999). The mini-mental state examination (MMSE). Journal of Gerontological Nursing, 25(5), 8–9.

  43. Laughlin, G. A., McEvoy, L. K., von Mühlen, D., Daniels, L. B., Kritz-Silverstein, D., Bergstrom, J., Cummins, K., Der-Martirosian, C., Jassal, S. K., & Barrett-Connor, E. (2011). Sex differences in the association of Framingham cardiac risk score with cognitive decline in community-dwelling elders without clinical heart disease. Psychosomatic Medicine, 73(8), 683–689.

  44. Mack, W. J., Freed, D. M., Williams, B. W., & Henderson, V. W. (1992). Boston naming test: Shortened versions for use in Alzheimer's disease. Journal of Gerontology, 47(3), 154–158.

  45. Marcus, J., Gardener, H., Rundek, T., Elkind, M. S., Sacco, R. L., DeCarli, C., & Wright, C. B. (2011). Baseline and longitudinal increases in diastolic blood pressure are associated with greater white matter hyperintensity volume the northern Manhattan study. Stroke, 42(9), 2639–2641.

  46. Meyers, J. E., & Meyers, K. R. (1995). Rey complex figure test under four different administration procedures. The Clinical Neuropsychologist, 9(1), 63–67.

  47. Modir, R., Gardener, H., & Wright, C. B. (2012). Blood pressure and white matter hyperintensity volume-a review of the relationship and implications for stroke prediction and prevention. European Neurological Review, 7(3), 174–177.

  48. Murray, A. D., Staff, R. T, Shenkin, S. D., Deary, I. J., Starr, J. M., & Whalley, L. J. (2005). Brain white matter hyperintensities: Relative importance of vascular risk factors in nondemented elderly people 1. Radiology, 237(1), 251–257.

  49. Nelson, H. E., & Willison, J. (1991). National Adult Reading Test (NART): Nfer-Nelson Windsor.

  50. Patterson, J. (2011). Controlled oral word association test Encyclopedia of clinical neuropsychology. In: Kreutzer J, DeLuca J, Caplan B, editors (pp. 703–770). New York: Springer.

  51. Prins, N. D., & Scheltens, P. (2015). White matter hyperintensities, cognitive impairment and dementia: An update. Nature Reviews Neurology, 11(3), 157–165.

  52. Raz, N., Rodrigue, K. M., Kennedy, K. M., & Acker, J. D. (2007). Vascular health and longitudinal changes in brain and cognition in middle-aged and older adults. Neuropsychology, 21(2), 149–157.

  53. Raz, N., Yang, Y., Dahle, C. L., & Land, S. (2012). Volume of white matter hyperintensities in healthy adults: Contribution of age, vascular risk factors, and inflammation-related genetic variants. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1822(3), 361–369.

  54. Rondina, J. M., Squarzoni, P., Souza-Duran, F. L., Tamashiro-Duran, J. H., Scazufca, M., Menezes, P. R., Vallada, H., & Filho, G. B. (2014). Framingham coronary heart disease risk score can be predicted from structural brain images in elderly subjects. Frontiers in Aging Neuroscience, 6, 300.

  55. Seshadri, S., Wolf, P., Beiser, A., Elias, M., Au, R., Kase, C., D’Agostino, R., & DeCarli, C. (2004). Stroke risk profile, brain volume, and cognitive function the Framingham offspring study. Neurology, 63(9), 1591–1599.

  56. Sheridan, L. K., Fitzgerald, H. E., Adams, K. M., Nigg, J. T., Martel, M. M., Puttler, L. I., Wong, M. M., & Zucker, R. A. (2006). Normative symbol digit modalities test performance in a community-based sample. Archives of Clinical Neuropsychology, 21(1), 23–28.

  57. Shulman, K. I., Shedletsky, R., & Silver, I. L. (1986). The challenge of time: Clock-drawing and cognitive function in the elderly. International Journal of Geriatric Psychiatry, 1(2), 135–140.

  58. Smith, S. M., Zhang, Y., Jenkinson, M., Chen, J., Matthews, P., Federico, A., & De Stefano, N. (2002). Accurate, robust, and automated longitudinal and cross-sectional brain change analysis. Neuroimage, 17(1), 479–489.

  59. Smith, S. M., Jenkinson, M., Woolrich, M. W., Beckmann, C. F., Behrens, T. E. J., Johansen-Berg, H., Bannister, P. R., De Luca, M., Drobnjak, I., Flitney, D. E. (2004). Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage, 23(S1), S208–SS19.

  60. Szoeke, C., Robertson, J. S., Rowe, C. C., Yates, P., Campbell, K., Masters, C. L., Ames, D., Dennerstein, L., & Desmond, P. (2013). The Women's healthy ageing project: Fertile ground for investigation of healthy participants 'at risk' for dementia. International Review of Psychiatry, 25(6), 726–737.

  61. Szoeke, C., Coulson, M., Campbell, S., & Dennerstein, L. (2016a). Cohort profile: Women’s healthy ageing project (WHAP)-a longitudinal prospective study of Australian women since 1990. Women's Midlife Health, 2(1), 5.

  62. Szoeke, C., Lehert, P., Henderson, V. W., Dennerstein, L., Desmond, P., & Campbell, S. (2016b). Predictive factors for verbal memory performance over decades of ageing: Data from the Women's healthy ageing project. The American Journal of Geriatric Psychiatry, 24(10), 857–867.

  63. Troyer, A. K. (2000). Normative data for clustering and switching on verbal fluency tasks. Journal of Clinical and Experimental Neuropsychology, 22(3), 370–378.

  64. van Dijk, E. J., Prins, N. D., Vrooman, H. A., Hofman, A., Koudstaal, P. J., & Breteler, M. M. (2008). Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences Rotterdam scan study. Stroke, 39(10), 2712–2719.

  65. Verhaaren, B. F., Vernooij, M. W., de Boer, R., Hofman, A., Niessen, W. J., van der Lugt, A., & Ikram, M. A. (2013). High blood pressure and cerebral white matter lesion progression in the general population. Hypertension, 61(6), 1354–1359.

  66. Vitali, C., Wellington, C. L., & Calabresi, L. (2014). HDL and cholesterol handling in the brain. Cardiovascular Research, 103(3), 405–413.

  67. Vuorinen, M., Solomon, A., Rovio, S., Nieminen, L., Kåreholt, I., Tuomilehto, J., Soininen, H., & Kivipelto, M. (2011). Changes in vascular risk factors from midlife to late life and white matter lesions: A 20-year follow-up study. Dementia and Geriatric Cognitive Disorders, 31(2), 119–125.

  68. Wang, R., Fratiglioni, L., Kalpouzos, G., Lövdén, M., Laukka, E. J., Bronge, L., Wahlund, L.-O., Bäckman, L., & Qiu, C. (2016). Mixed brain lesions mediate the association between cardiovascular risk burden and cognitive decline in old age: A population-based study. Alzheimer's & Dementia, 13, 247–256. https://doi.org/10.1016/j.jalz.2016.06.2363.

  69. Ward, M. A., Bendlin, B. B., McLaren, D. G., Hess, T. M., Callagher, C. L., Kastman, E. K., Rowley, H. A., Asthana, S., Carlsson, C. M., & Sager, M. A. (2010). Low HDL cholesterol is associated with lower gray matter volume in cognitively healthy adults. Frontiers in Aging Neuroscience, 2, 29.

  70. Wechsler, D. (1955). Manual for the Wechsler adult intelligence scale.

  71. Welsh, K. A., Butters, N., Mohs, R. C., Beekly, D., Edland, S., Fillenbaum, G., & Heyman, A. (1994). The consortium to establish a registry for Alzheimer's disease (CERAD). Part V. a normative study of the neuropsychological battery. Neurology, 44(4), 609–609, 614.

  72. Whitmer, R., Sidney, S., Selby, J., Johnston, S. C., & Yaffe, K. (2005). Midlife cardiovascular risk factors and risk of dementia in late life. Neurology, 64(2), 277–281.

  73. Wilson, P. W., D’Agostino, R. B., Levy, D., Belanger, A. M., Silbershatz, H., & Kannel, W. B. (1998). Prediction of coronary heart disease using risk factor categories. Circulation, 97(18), 1837–1847.

  74. Wolf, P. A., D'Agostino, R. B., Belanger, A. J., & Kannel, W. B. (1991). Probability of stroke: A risk profile from the Framingham study. Stroke, 22(3), 312–318.

  75. Yoshita, M., Fletcher, E., & DeCarli, C. (2005). Current concepts of analysis of cerebral white matter hyperintensities on magnetic resonance imaging. Topics in magnetic resonance imaging: TMRI, 16(6), 399–407.

  76. Yushkevich, P. A., Piven, J., Hazlett, H. C., Smith, R. G., Ho, S., Gee, J. C., & Gerig, G. (2006). User-guided 3D active contour segmentation of anatomical structures: Significantly improved efficiency and reliability. Neuroimage, 31(3), 1116–1128.

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Acknowledgments

We would like to acknowledge the contribution of the participants and their supporters who have contributed their time and commitment for over 20 years to the University. A full list of all researchers contributing to the project and the membership of our Scientific Advisory Board is available at http://www.medrmhwh.unimelb.edu.au/Research/WHAP.html.

Funding

This study is funded by the National Health and Medical Research Council (NHMRC Grants 547500, 1032350 & 1062133), Ramaciotti Foundation, Australian Healthy Ageing Organisation, the Brain Foundation, the Alzheimer’s Association (NIA320312), Australian Menopausal Society, Bayer Healthcare, Shepherd Foundation, Scobie and Claire Mackinnon Foundation, Collier Trust Fund, J.O. & J.R. Wicking Trust, Mason Foundation and the Alzheimer’s Association of Australia. Inaugural funding was provided by VicHealth and the NHMRC. The Principal Investigator of WHAP (CSz) is supported by the National Health and Medical Research Council.

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Correspondence to Cassandra Szoeke.

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Conflict of interest

Dr. Szoeke has provided clinical consultancy and been on scientific advisory committees for the Australian Commonwealth Scientific and Industrial Research Organisation, Alzheimer’s Australia, University of Melbourne and other relationships which are subject to confidentiality clauses. She has been a named Chief Investigator on investigator driven collaborative research projects in partnership with Pfizer, Merck, Bayer and GE. She has been an investigator on clinical trials with Lundbeck within the last 2 years. Dr. Desmond has supported by the Royal Melbourne Hospital and the National Health and Medical Research Council of Australia. Other authors report no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Aljondi, R., Szoeke, C., Steward, C. et al. The effect of midlife cardiovascular risk factors on white matter hyperintensity volume and cognition two decades later in normal ageing women. Brain Imaging and Behavior 14, 51–61 (2020). https://doi.org/10.1007/s11682-018-9970-5

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Keywords

  • Midlife cardiovascular risk factors
  • Framingham cardiovascular risk profile score
  • White matter hyperintensity volume
  • Cognitive domains
  • Elderly women