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Editorial
John P. Blass, M.D., Ph.D., and Rajiv R. Ratan, M.D., Ph.D. An epidemiologic study by Vermeer et al. in this issue of the Journal indicates that "silent" strokes are a risk factor for dementia.1 Recurrent strokes during the three to four years of follow-up in this study appear to have been the mechanism of � or at least a marker for � cognitive decline. The presence of the apolipoprotein E 4 allele did not account for the relation between stroke and dementia, although that allele is known to be a risk factor for both Alzheimer's disease and vascular disease. These observations are intuitively attractive; stroke can impair brain function, including cognition. Previous stroke is a major risk factor for subsequent stroke. Whether a stroke is silent depends not only on its location and size and on whether it occurs while the patient is asleep or awake; it also depends on what the patient is asked to do by others and what the patient demands of himself or herself. Surprisingly large neuroanatomical defects can exist without the detection of functional abnormalities on standard neurologic examinations or without recognition of deficits by family and friends. One of our patients, who lost both prefrontal lobes as the result of an injury in an automobile accident, continued to be successful in business and appeared to continue to be a good father and husband. He had subtle abnormalities on detailed neuropsychological testing but not on standard neurologic examination. However, he himself felt that he had "lost something." Perhaps "unrecognized" stroke is a better term than "silent" stroke. As Vermeer et al.1 point out, the relation between stroke and dementia is complex. For the first 70 years after the description of Alzheimer's disease, mainstream opinion attributed senile dementia to cerebral arteriosclerosis. In the 1970s, an attempt was made to draw a sharp distinction between Alzheimer's disease and dementia due to strokes. The latter was renamed "multi-infarct dementia." Alzheimer's disease can certainly occur in people with no independent evidence of cerebrovascular or cardiovascular disease, although meticulous neuropathological studies have shown that vascular disease, particularly disease of the vessels supplying the white matter, very commonly accompanies the neuropathologic lesions of Alzheimer's disease.2 Although strokes frequently cause cognitive impairment, by themselves they tend not to lead to full-blown dementia, according to the current definitions of dementia.3,4 The memory impairment that must be present for a diagnosis of dementia tends to be associated with bilateral hippocampal damage.5 Such damage occurs characteristically in Alzheimer's disease or after global cerebral hypoxia�ischemia, such as that during prolonged cardiac arrest. The organization of the cerebral vasculature in humans, however, is such that bilateral hippocampal damage is a relatively rare consequence of strokes alone.5 Risk factors for cardiovascular disease and those for dementia tend to overlap, leading to suggestions that vascular disease itself can be one of the factors contributing to the development of neuropathologic Alzheimer's lesions and clinical Alzheimer's dementia.6 A recent addition to the list of risk factors common to Alzheimer's disease and vascular disease is elevated levels of homocysteine in the blood.7 The convergence of risk factors for Alzheimer's disease and stroke has led some to speculate that their underlying pathogenic mechanisms are similar � in other words, that both diseases begin with vascular insufficiency.8 Indeed, transgenic rodent models of Alzheimer's disease that harbor mutations in the amyloid precursor or presenilin protein found in humans have several vascular abnormalities. These abnormalities include defects in cerebral autoregulation and impairment in increases in cerebral blood flow in response to neuronal activity. These intriguing findings in animal models of Alzheimer's disease are consonant with reduced increases in cerebral blood flow in asymptomatic patients who are at risk for Alzheimer's disease. Together, the findings in animals and the observations in humans support the notion that vascular insufficiency may be not only a cause but also a consequence of pathogenic mechanisms operative in Alzheimer's disease. If so, then in some patients a silent stroke may be the first sign of Alzheimer's disease, rather than simply a risk factor for its expression. In clinical practice, the critical question is when and how to intervene so as to benefit the patient. Theoretical considerations about the relations between stroke and dementia are less important. Confident recommendations based on data will require appropriately powered, rigorous, prospective studies of the effects of proposed interventions on the development of dementia in people with silent strokes. Epidemiologic studies to test the robustness of the findings of Vermeer et al. in other populations are also necessary. The available data encourage the hope that treatments directed at abnormalities in the vasculature will reduce the burden of dementia in the future, but those data also illustrate that well-meaning attempts to prevent illness can do harm.9 For instance, although high blood pressure is a risk factor for dementia, treatment of hypertension with centrally acting sympatholytic agents has been reported to increase the risk of cognitive impairment.10 Some recommendations can already be made for patients in whom a clinically unrecognized stroke is discovered on imaging studies. These recommendations are based on a large body of well-documented evidence about vascular disease. Patients should optimize their cardiovascular health. They should avoid obesity and should not smoke. They should visit their doctors regularly and receive treatment if hypertension or an unhealthy blood lipid profile develops. One or two alcoholic beverages daily is probably healthy if there are no contraindications, such as liver disease or a history of alcohol abuse or other substance abuse. A baby aspirin taken daily in combination with extended-release dipyridamole (200 mg twice a day) has been shown to reduce the chances of recurrent stroke10 and is unlikely to be harmful unless there is a medical contraindication, such as gastric ulcer disease or a bleeding disorder. An important caveat in preventive treatment for dementia is not to exacerbate depression. Strokes, including minor white-matter damage, are a risk factor for depression as well as for dementia. People who are worried about their mentation are at least as likely to have depression or depression complicating a dementing illness as they are to have dementia alone. Among them are people with the masked depression of the high achiever, who obsess about their cognition. Elderly people, particularly older white men, may be at significant risk for suicide. One woman, when told she had incipient Alzheimer's disease, sought physician-assisted suicide. The observations reported by Vermeer et al.,1 if replicated, could lead to important changes in clinical practice that will reduce the human and economic burden of dementia, at least in people for whom magnetic resonance neuroimaging is readily available. However, the overriding principle remains, "First, do no harm."
From the Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, N.Y. References
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