Background/Aims: This study investigated the relation of midlife blood pressure, total cholesterol, body mass index (BMI), their changes over time, apolipoprotein E, and white matter lesions (WML). Methods: Participants of the Cardiovascular Risk Factors, Aging and Incidence of Dementia study were derived from random, population-based samples previously surveyed in 1972, 1977, 1982 or 1987. In 1998, 1,449 (73%) individuals aged 65–79 years were re-examined (average follow-up 21 years). A subpopulation (n = 112) was scanned with a 1.5-tesla MRI scanner in 1998, and WML were assessed from fluid-attenuated inversion recovery images using a semi-quantitative visual rating scale. Results: Risk of late-life WML was related to midlife overweight (relative risk = 2.53; 95% CI = 1.70–2.89), obesity (2.94; 2.44–3.03), and hypertension (2.73; 1.81–3.08), even after adjustments for several confounding factors. Elevated BMI (>25) (2.26; 1.42–2.62) and hypertension (3.14; 1.83–3.40) from midlife to late life also increased the risk of WML. In addition, an association with WML was seen for decreasing blood pressure (hypertension at midlife but not at late life) (3.25; 2.46–3.41), even after controlling for antihypertensive treatment. Lipid-lowering drugs had a protective effect against WML (0.13; 0.02–0.59). Conclusions: These results indicate that early and sustained vascular risk factor control is associated with a lower likelihood of having more severe WML in late life.

Keywords:
White matter lesions, Overweight, Obesity, Blood pressure, Cholesterol, Apolipoprotein E
1.
Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A: Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal, population based study. BMJ 2001;322:1447–1451.
2.
Launer LJ, Ross GW, Petrovitch H, Masaki K, Foley D, White LR, Havlik RJ: Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol Aging 2000;21:49–55.
3.
Notkola IL, Sulkava R, Pekkanen J, Erkinjuntti T, Ehnholm C, Kivinen P, Tuomilehto J, Nissinen A: Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer’s disease. Neuroepidemiology 1998;17:14–20.
4.
Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kareholt I, Winblad B, Helkala EL, Tuomilehto J, Soininen H, Nissinen A: Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol 2005;62:1556–1560.
5.
Whitmer RA, Gunderson EP, Barrett-Connor E, Quesenberry CP Jr, Yaffe K: Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. BMJ 2005;330:1360.
6.
Scheltens P, Barkhof F, Valk J, Algra PR, van der Hoop RG, Nauta J, Wolters EC: White matter lesions on magnetic resonance imaging in clinically diagnosed Alzheimer’s disease. Evidence for heterogeneity. Brain 1992;115:735–748.
7.
van der Flier WM, Barkhof F, Scheltens P: Shifting paradigms in dementia: toward stratification of diagnosis and treatment using MRI. Ann NY Acad Sci 2007;1097:215–224.
8.
De Groot JC, De Leeuw FE, Oudkerk M, Van Gijn J, Hofman A, Jolles J, Breteler MM: Periventricular cerebral white matter lesions predict rate of cognitive decline. Ann Neurol 2002;52:335–341.
9.
van Straaten EC, Harvey D, Scheltens P, Barkhof F, Petersen RC, Thal LJ, Jack CR Jr, DeCarli C, Alzheimer’s Disease Cooperative Study Group: Periventricular white matter hyperintensities increase the likelihood of progression from amnestic mild cognitive impairment to dementia. J Neurol 2008;255:1302–1308.
10.
Gunning-Dixon FM, Raz N: The cognitive correlates of white matter abnormalities in normal aging: a quantitative review. Neuropsychology 2000;14:224–232.
11.
Inzitari D, Simoni M, Pracucci G, Poggesi A, Basile AM, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Hennerici M, Langhorne P, O’Brien J, Barkhof F, Visser MC, Wahlund LO, Waldemar G, Wallin A, Pantoni L, LADIS Study Group: Risk of rapid global functional decline in elderly patients with severe cerebral age-related white matter changes: the LADIS study. Arch Intern Med 2007;167:81–88.
12.
Schmidt R, Fazekas F, Kapeller P, Schmidt H, Hartung HP: MRI white matter hyperintensities: three-year follow-up of the Austrian Stroke Prevention Study. Neurology 1999;53:132–139.
13.
Dufouil C, de Kersaint-Gilly A, Besancon V, Levy C, Auffray E, Brunnereau L, Alperovitch A, Tzourio C: Longitudinal study of blood pressure and white matter hyperintensities: the EVA MRI Cohort. Neurology 2001;56:921–926.
14.
Firbank MJ, Wiseman RM, Burton EJ, Saxby BK, O’Brien JT, Ford GA: Brain atrophy and white matter hyperintensity change in older adults and relationship to blood pressure: brain atrophy, WMH change and blood pressure. J Neurol 2007;254:713–721.
15.
Swan GE, DeCarli C, Miller BL, Reed T, Wolf PA, Jack LM, Carmelli D: Association of midlife blood pressure to late-life cognitive decline and brain morphology. Neurology 1998;51:986–993.
16.
Carmelli D, Swan GE, Reed T, Wolf PA, Miller BL, DeCarli C: Midlife cardiovascular risk factors and brain morphology in identical older male twins. Neurology 1999;52:1119–1124.
17.
de Leeuw FE, de Groot JC, Oudkerk M, Witteman JC, Hofman A, van Gijn J, Breteler MM: A follow-up study of blood pressure and cerebral white matter lesions. Ann Neurol 1999;46:827–833.
18.
Gustafson DR, Steen B, Skoog I: Body mass index and white matter lesions in elderly women. An 18-year longitudinal study. Int Psychogeriatr 2004;16:327–336.
19.
de Leeuw FE, Richard F, de Groot JC, van Duijn CM, Hofman A, Van Gijn J, Breteler MM: Interaction between hypertension, apoE, and cerebral white matter lesions. Stroke 2004;35:1057–1060.
20.
Godin O, Tzourio C, Maillard P, Alperovitch A, Mazoyer B, Dufouil C: Apolipoprotein E genotype is related to progression of white matter lesion load. Stroke 2009;40:3186–3190.
21.
Kuller LH, Shemanski L, Manolio T, Haan M, Fried L, Bryan N, Burke GL, Tracy R, Bhadelia R: Relationship between ApoE, MRI findings, and cognitive function in the Cardiovascular Health Study. Stroke 1998;29:388–398.
22.
Hirono N, Yasuda M, Tanimukai S, Kitagaki H, Mori E: Effect of the apolipoprotein E epsilon4 allele on white matter hyperintensities in dementia. Stroke 2000;31:1263–1268.
23.
Vartiainen E, Puska P, Jousilahti P, Korhonen HJ, Tuomilehto J, Nissinen A: Twenty-year trends in coronary risk factors in north Karelia and in other areas of Finland. Int J Epidemiol 1994;23:495–504.
24.
Kivipelto M, Helkala EL, Hanninen T, Laakso MP, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A: Midlife vascular risk factors and late-life mild cognitive impairment: a population-based study. Neurology 2001;56:1683–1689.
25.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders ed 4. Washington, American Psychiatric Association, 1994.
26.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM: Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34:939–944.
27.
Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E: Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999;56:303–308.
28.
Kuulasmaa K, Tunstall-Pedoe H, Dobson A, Fortmann S, Sans S, Tolonen H, Evans A, Ferrario M, Tuomilehto J: Estimation of contribution of changes in classic risk factors to trends in coronary-event rates across the WHO MONICA Project populations. Lancet 2000;355:675–687.
29.
Tsukamoto K, Watanabe T, Matsushima T, Kinoshita M, Kato H, Hashimoto Y, Kurokawa K, Teramoto T: Determination by PCR-RFLP of apo E genotype in a Japanese population. J Lab Clin Med 1993;121:598–602.
30.
Wahlund LO, Barkhof F, Fazekas F, Bronge L, Augustin M, Sjogren M, Wallin A, Ader H, Leys D, Pantoni L, Pasquier F, Erkinjuntti T, Scheltens P, European Task Force on Age-Related White Matter Changes: A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke 2001;32:1318–1322.
31.
de Leeuw FE, de Groot JC, Achten E, Oudkerk M, Ramos LM, Heijboer R, Hofman A, Jolles J, van Gijn J, Breteler MM: Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study. The Rotterdam Scan Study. J Neurol Neurosurg Psychiatry 2001;70:9–14.
32.
Zhang J, Yu KF: What’s the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA 1998;280:1690–1691.
33.
Gazdzinski S, Kornak J, Weiner MW, Meyerhoff DJ: Body mass index and magnetic resonance markers of brain integrity in adults. Ann Neurol 2008;63:652–657.
34.
van Dijk EJ, Breteler MM, Schmidt R, Berger K, Nilsson LG, Oudkerk M, Pajak A, Sans S, de Ridder M, Dufouil C, Fuhrer R, Giampaoli S, Launer LJ, Hofman A, CASCADE Consortium: The association between blood pressure, hypertension, and cerebral white matter lesions: cardiovascular determinants of dementia study. Hypertension 2004;44:625–630.
35.
Qiu C, Winblad B, Fratiglioni L: Low diastolic pressure and risk of dementia in very old people: a longitudinal study. Dement Geriatr Cogn Disord 2009;28:213–219.
36.
den Heijer T, Launer LJ, Prins ND, van Dijk EJ, Vermeer SE, Hofman A, Koudstaal PJ, Breteler MM: Association between blood pressure, white matter lesions, and atrophy of the medial temporal lobe. Neurology 2005;64:263–267.
37.
Amarenco P, Labreuche J: Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol 2009;8:453–463.
38.
Mok VC, Lam WW, Fan YH, Wong A, Ng PW, Tsoi TH, Yeung V, Wong KS: Effects of statins on the progression of cerebral white matter lesion: post hoc analysis of the ROCAS (Regression of Cerebral Artery Stenosis) study. J Neurol 2009;256:750–757.
39.
ten Dam VH, van den Heuvel DM, van Buchem MA, Westendorp RG, Bollen EL, Ford I, de Craen AJ, Blauw GJ, PROSPER Study Group: Effect of pravastatin on cerebral infarcts and white matter lesions. Neurology 2005;64:1807–1809.
40.
De Michele M, Panico S, Iannuzzi A, Celentano E, Ciardullo AV, Galasso R, Sacchetti L, Zarrilli F, Bond MG, Rubba P: Association of obesity and central fat distribution with carotid artery wall thickening in middle-aged women. Stroke 2002;33:2923–2928.
41.
Kivipelto M, Solomon A, Ngandu T: Vascular factors in Alzheimer’s disease: from diagnostic dichotomy to integrative etiology; in Wahlund LO, Erkinjunti T, Gauthier S (eds): Vascular Cognitive Impairment in Clinical Practice. Cambridge, Cambridge University Press, 2009.
42.
Trayhurn P, Wood IS: Signalling role of adipose tissue: adipokines and inflammation in obesity. Biochem Soc Trans 2005;33:1078–1081.
43.
van Dijk EJ, Prins ND, Vermeer SE, Vrooman HA, Hofman A, Koudstaal PJ, Breteler MM: C-reactive protein and cerebral small-vessel disease: the Rotterdam Scan Study. Circulation 2005;112:900–905.
44.
Macey PM, Henderson LA, Macey KE, Alger JR, Frysinger RC, Woo MA, Harper RK, Yan-Go FL, Harper RM: Brain morphology associated with obstructive sleep apnea. Am J Respir Crit Care Med 2002;166:1382–1387.
45.
Morrell MJ, McRobbie DW, Quest RA, Cummin AR, Ghiassi R, Corfield DR: Changes in brain morphology associated with obstructive sleep apnea. Sleep Med 2003;4:451–454.
46.
Gale SD, Hopkins RO: Effects of hypoxia on the brain: neuroimaging and neuropsychological findings following carbon monoxide poisoning and obstructive sleep apnea. J Int Neuropsychol Soc 2004;10:60–71.
47.
Zimmerman ME, Aloia MS: A review of neuroimaging in obstructive sleep apnea. J Clin Sleep Med 2006;2:461–471.
48.
Macey PM, Kumar R, Woo MA, Valladares EM, Yan-Go FL, Harper RM: Brain structural changes in obstructive sleep apnea. Sleep 2008;31:967–977.
49.
Wen W, Sachdev PS, Li JJ, Chen X, Anstey KJ: White matter hyperintensities in the forties: their prevalence and topography in an epidemiological sample aged 44–48. Hum Brain Mapp 2009;30:1155–1167.
© 2011 S. Karger AG, Basel
2011
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.