Author + information
- aLC Campbell Cognitive Neurology Unit, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
- bDepartment of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada
- cCardiac Rehabilitation Program, University Health Network Toronto Rehabilitation Institute, Toronto, Ontario, Canada
- dDepartment of Medicine (Neurology), Sunnybrook Health Sciences Centre & University of Toronto, Toronto, Ontario, Canada
- ↵∗Reprint requests and correspondence:
Dr. Sandra E. Black, Cognitive Neurology, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Room A4 21, Toronto, Ontario M4N 3M5, Canada.
In this cognitive study cohort from the Cardiovascular Health Study (CHS) in this issue of the Journal, Kuller et al. (1) examine coronary artery calcification (CAC), a measure of subclinical cardiovascular disease, as a predictor of incident dementia and coronary events among individuals without a baseline history of clinical cardiovascular events who were predominantly 80+ years of age. The study extends previous findings by examining dementia incidence prospectively over a longer follow-up duration. The results suggest that for people who live into their 8th decade without a cardiovascular event, dementia is a more likely incident impediment to healthy longevity than a heart attack or stroke; dementia affected 64% of participants before their deaths. However, the findings do not imply a lesser role for atherosclerosis—in fact, quite the opposite—CAC was a risk factor for incident dementia as well as incident coronary events.
The prospective association between CAC and dementia is consistent with cross-sectional analyses from the AGES (Age, Gene/Environment Susceptibility)-Reykjavik Study, wherein CAC was associated with poorer cognitive performance and dementia (2). In that study, brain magnetic resonance imaging markers, including cerebral infarcts and microbleeds, volumes of grey and white matter and white matter hyperintensities, collectively accounted for the association. Therefore, CAC may be related to dementia due to strokes, brain atrophy, and abnormalities of the small cerebral blood vessels leading to small chronic hemorrhages and lesions to the white matter (3). Microinfarcts correlated with cognitive impairment in autopsy studies (4) also likely contribute.
In general, CAC occurs when atherosclerotic lesions are present, and it reflects plaque burden. It is an active process regulated similarly to bone formation, which occurs both in the vascular intima and media (5). Clinical correlates of intimal calcification include aging, hyperlipidemia, diabetes, hypertension, osteoporosis, male gender, smoking, and inflammation. Calcific vasculopathy of the tunica media tends to be associated with aging, diabetes, and chronic kidney disease, contributing to arterial stiffness. Risk factors for CAC are also risk factors for dementia (Table 1). Accordingly, the findings of the CHS Cognitive Study may in part reflect the cumulative burden of these risk factors, although relationships with CAC were not shown. In the coronary arteries, CAC weakens vasomotor responses and elasticity, worsens ejection fraction, hypertrophy and ischemia, and affects plaque stability.
In the present study, black men and women had lower levels of CAC, consistent with previous findings from the Multi-Ethnic Study of Atherosclerosis (6). In white men, CAC was a risk factor for mortality; however, when found in women, CAC was a more portentous risk factor for dementia. CAC did not predict dementia in men (probably due to a small comparison group with low CAC scores), or mortality in women (significant only at trend level p = 0.110), but these findings likely reflect the sample size and the distribution of CAC more than a true lack of effect.
Kuller et al. (1) emphasize the importance of determining whether preventing atherosclerosis will also prevent Alzheimer disease (AD). The question is germane because AD is the most common dementia diagnosis, and the clinical risk factors for AD are also risk factors for atherosclerosis. However, how exactly AD and vascular disease may be cocontributors or causally related remains unclear (Figure 1). White matter hyperintensities, presumed to indicate cerebral small vessel disease (3,7), are correlated with brain atrophy and cognition in AD (8), and with progression of amyloid burden (9). The findings agree with suggestions that perivascular drainage pathways may help clear amyloid-β (10). Amyloid-β deposition occurs both interstitially in the brain, and in the cerebral vasculature, where it contributes to angiopathy often seen as microbleeds in lobar brain regions, particularly posteriorly (11). In particular, the amyloid-β1-40 fragment damages cerebrovascular endothelial cells, impairing vasodilation and blood flow regulation during active brain processes (12). Glucose utilization during brain activation plus impaired blood flow may result in metabolic deficits, oxidative stress, and brain cell loss. Insulin resistance associated with type 2 diabetes, also a risk factor for CAC and dementia, may exacerbate this process. Aortic calcification and stiffness may transfer pulsatility further downstream to the smaller vessels perforating the substantia innominata, including the nucleus basalis of Meynert from which cholinergic brain circuits originate. These circuits degenerate in AD, and vascular insults may additively impair their function (13).
Autopsy series confirm that AD dementia in the oldest old often reflects comorbid cerebrovascular pathology. Whereas AD is the most common contributor to dementia, the combination of cerebrovascular disease with AD plaques and tangles is the most common finding at autopsy. Among people 90 years of age and older, AD pathology increased the risk of dementia only 3.48-fold, whereas in combination with any other pathology, the risk of dementia increased 13.38-fold (14). Recognizing synergism between AD and cerebrovascular pathologies will become increasingly important as more people survive to encounter dementia at later ages. The prevention and treatment of vascular disease and risk factors will become an increasingly important public health concern.
Kuller et al. (1) note a greater number of blocks walked and lower prevalence of hypertension among nondemented individuals, commenting that little evidence informs clinical recommendations. Trial data are needed because of the possibility of reverse causality and confounding by inter-related risk factors in epidemiological studies. Despite overwhelming observational evidence in favor of physical activity, optimal modalities, durations, and intensities of exercise training, insofar as they improve brain function, remain largely to be determined, as do many of the precise physiological mechanisms by which physical activity may counteract various risk factors for dementia. Aerobic exercise can regress coronary plaques; however, among 2,031 individuals free of clinical cardiovascular disease from the Dallas Heart Study, each hour of daily sedentary time was associated with 14% higher CAC, regardless of physical exercise (15). It remains to determine how midlife physical activity and sedentary behavior affect dementia outcomes, and what the most effective interventions might be.
Evidence for antihypertensive intervention to prevent dementia rests at the level of consensus (grade C1). The picture is complicated by the possibility that different medications with equivalent antihypertensive effects may differentially affect cognition. For instance, the angiotensin-converting enzyme inhibitors may promote the deposition of cerebral amyloid, whereas the angiotensin receptor blockers may promote amyloid clearance (16). Thus, these medications may have different effects on the accumulation of AD pathology, although both ameliorate the harmful effects of hypertension on the vasculature of the brain. To offer guidance to clinicians, differences in the rate of brain atrophy and cognitive decline are being monitored in an ongoing trial of patients with hypertension who have been randomized to telmisartan versus perindopril (NCT02085265).
The findings of Kuller et al. (1) reinforce the notion that as more individuals live to older ages, we can expect a dramatic increase in the incidence and prevalence of dementia. Atherosclerosis, even if clinically undeclared, will likely contribute to these cases, suggesting the importance of pharmacological and nonpharmacological management of vascular risk factors beginning in midlife. Accurate, well-understood predictive biomarkers and precisely targeted intervention studies are urgently needed to optimize cognitive and functional outcomes that support the healthy longevity of the body and mind.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Swardfager is supported by the Department of Psychiatry, Sunnybrook Health Sciences Centre; Hurvitz Brain Sciences Program, Sunnybrook Research Institute; and the Canadian Partnership for Stroke Recovery. Dr. Black is supported by the Brill Chair in Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto; Toronto Dementia Research Alliance, University of Toronto; and internally by the Department of Medicine, Sunnybrook Health Sciences Centre; Hurvitz Brain Sciences Program, Sunnybrook Research Institute; has received institutional grants from Pfizer, GE Healthcare, Eli Lilly, Transition Therapeutics, Novartis, Roche, Cognoptix, Biogen Idec; and has received personal honoraria from Boehringer Ingelheim, Novartis, and Merck.
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