In addition to peripheral vascular disease, aging is also the most common risk factor for cerebrovascular disease, including stroke and dementia. Dementias afflict 1 in 10 adults over the age of 65, and half over the age of 85. Alzheimer disease (AD) and vascular dementia (VD) are the 2 most common causes of dementia among the elderly population. In the United States and Europe, AD accounts for the majority of cases, with VD the second most common cause.19,20 This relationship is reversed in Asia and many developing countries, where VD is the most common cause of dementia.21 However, recent advances have highlighted the frequent overlap of these 2 syndromes.
Vascular pathology, which has traditionally been thought as a diagnostic demarcation in the differential diagnosis between AD and VD, may, in fact, be part of the spectrum of changes underlying a common pathogenesis. The connection of vascular disease with AD rests on 3 lines of evidence. First, on the basis of epidemiologic studies, a remarkable number of risk factors are apparently shared between AD and VD.22,23 These risk factors include increasing age, ApoE4 genotype, hypertension, arteriosclerosis, diabetes mellitus, smoking, and atrial fibrillation.22 Second, clinical manifestations of pathologically diagnosed AD appear to be significantly modulated by cerebral infarction. In the first year after a cerebral infarct, the incidence of dementia is 9 times greater than expected24 and after the first year there is a 50% increase in the likelihood of developing AD.25 Moreover, stroke shortens the duration of preclinical AD.25 Finally, neuropathologic findings in these disorders are overlapping.26 There are neurofibrillary plaques and tangles in VD and vascular pathology in AD. In addition to the commonly seen vascular lesions such as cerebral amyloid angiopathy, microvascular degeneration, and periventricular white matter lesions, there are numerous structural and functional cerebromicrovascular abnormalities in AD.19,27 These vascular abnormalities in AD include: impairment of BBB, decreased microvascular density, vascular distortions, functional alteration and derangement of cerebral endothelial function, and arteriolar changes such as lipohyalinosis.19
A mostly animal and epidemiologic literature suggests that flavonoids may play a role in reducing the risk of dementia.28 Galli et al29 reported that fruit polyphenols decreased the susceptibility of rat brains to the damages of oxidative stress seen with aging. In a cohort of over 1300 French elderly, the intake of flavonoids was found to be inversely related to the risk of incident dementia.3 One intriguing possibility is that the benefits of flavonoids involve improving vascular function and increasing CBF. Several studies have recently implicated a decline in CBF in the development of dementias. From the community-based Rotterdam Study, cognitive function and CBF were measured in 1730 participants over the age of 55 over a 6-year period. Their data suggest that cerebral hypoperfusion precedes and possibly contributes to the onset of clinical dementia.30 Using single-photon emission computed tomography, other groups have also found that that CBF in certain brain regions, including prefrontal and inferior parietal cortices, was significantly lower in those who progressed rapidly to AD.31,32
1. Vita JA. Polyphenols and cardiovascular disease: effects on endothelial and platelet function. Am J Clin Nutr. 2005;81:292S–297S.
2. Engelhart MJ, Geerlings MI, Ruitenberg A, et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA. 2002;287:3223–3229.
3. Commenges D, Scotet V, Renaud S, et al. Intake of flavonoids and risk of dementia. Eur J Epidemiol. 2000;16:357–363.
4. Hollenberg NK, Martinez G, McCullough M, et al. Aging, acculturation, salt intake, and hypertension in the Kuna of Panama. Hypertension. 1997;29:171–176.
5. Karim M, McCormick K, Kappagoda CT. Effects of cocoa
extracts on endothelium-dependent relaxation. J Nutr. 2000;130:2105S–2108S.
6. Diebolt M, Bucher B, Andriantsitohaina R. Wine polyphenols decrease blood pressure, improve NO vasodilatation, and induce gene expression. Hypertension. 2001;38:159–165.
7. Leikert JF, Rathel TR, Wohlfart P, et al. Red wine polyphenols enhance endothelial nitric oxide synthase expression and subsequent nitric oxide release from endothelial cells. Circulation. 2002;106:1614–1617.
8. Fitzpatrick DF, Hirschfield SL, Ricci T, et al. Endothelium-dependent vasorelaxation caused by various plant extracts. J Cardiovasc Pharmacol. 1995;26:90–95.
9. Andriambeloson E, Kleschyov AL, Muller B, et al. Nitric oxide production and endothelium-dependent vasorelaxation induced by wine polyphenols in rat aorta. Br J Pharmacol. 1997;120:1053–1058.
10. Cishek MB, Galloway MT, Karim M, et al. Effect of red wine on endothelium-dependent relaxation in rabbits. Clin Sci (London). 1997;93:507–511.
11. Fisher ND, Hughes M, Gerhard-Herman M, et al. Flavanol-rich cocoa
induces nitric-oxide-dependent vasodilation in healthy humans. J Hypertens. 2003;21:2281–2286.
12. Perticone F, Ceravolo R, Pujia A, et al. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation. 2001;104:191–196.
13. Engler MB, Engler MM, Chen CY, et al. Flavonoid-rich dark chocolate improves endothelial function and increases plasma epicatechin concentrations in healthy adults. J Am Coll Nutr. 2004;23:197–204.
14. Vlachopoulos C, Aznaouridis K, Alexopoulos N, et al. Effect of dark chocolate on arterial function in healthy individuals. Am J Hypertens. 2005;18:785–791.
15. Heiss C, Dejam A, Kleinbongard P, et al. Vascular effects of cocoa
rich in flavan-3-ols. JAMA. 2003;290:1030–1031.
16. Grassi D, Necozione S, Lippi C, et al. Cocoa
reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension. 2005;46:398–405.
17. Vapaatalo H, Mervaala E. Clinically important factors influencing endothelial function. Med Sci Monit. 2001;7:1075–1085.
18. Brunner H, Cockcroft JR, Deanfield J, et al. Endothelial function and dysfunction. Part II: association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension. J Hypertens. 2005;23:233–246.
19. Shi J, Perry G, Smith MA, et al. Vascular abnormalities: the insidious pathogenesis of Alzheimer's disease. Neurobiol Aging. 2000;21:357–361.
20. Fratiglioni L. Epidemiology. In: Winbald B, et al. ed. Health Economics of Dementia. New York: John Wiley & Sons.
21. Konno S, Meyer JS, Terayama Y, et al. Classification, diagnosis and treatment of vascular dementia. Drugs Aging. 1997;11:361–373.
22. Breteler MM. Vascular risk factors for Alzheimer's disease: an epidemiologic perspective. Neurobiol Aging. 2000;21:153–160.
23. Meyer JS, Rauch GM, Rauch RA, et al. Cardiovascular and other risk factors for Alzheimer's disease and vascular dementia. Ann NY Acad Sci. 2000;903:411–423.
24. Kokmen E, Whisnant JP, O’Fallon WM, et al. Dementia after ischemic stroke: a population-based study in Rochester, Minnesota (1960–1984). Neurology. 1996;46:154–159.
25. Kalaria RN. The role of cerebral ischemia in Alzheimer's disease. Neurobiol Aging. 2000;21:321–330.
26. Kalaria RN, Ballard C. Overlap between pathology of Alzheimer disease and vascular dementia. Alzheimer Dis Assoc Disord. 1999;13(Suppl 3):S115–S123.
27. Grammas P. A damaged microcirculation contributes to neuronal cell death in Alzheimer's disease. Neurobiol Aging. 2000;21:199–205.
28. Youdim KA, Spencer JP, Schroeter H, et al. Dietary flavonoids as potential neuroprotectants. Biol Chem. 2002;383:503–519.
29. Galli RL, Shukitt-Hale B, Youdim KA, et al. Fruit polyphenolics and brain aging: nutritional interventions targeting age-related neuronal and behavioral deficits. Ann NY Acad Sci. 2002;959:128–132.
30. Ruitenberg A, den Heijer T, Bakker SL, et al. Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study. Ann Neurol. 2005;57:789–794.
31. Nagahama Y, Nabatame H, Okina T, et al. Cerebral correlates of the progression rate of the cognitive decline in probable Alzheimer's disease. Eur Neurol. 2003;50:1–9.
32. Johnson KA, Jones K, Holman BL, et al. Preclinical prediction of Alzheimer's disease using SPECT. Neurology. 1998;50:1563–1571.