Cognitive Decline and Brain Natriuretic Peptide: How Are They Related? “I am a brain, Watson. The rest of me is pure appendix.” —Arthur Conan Doyle, The Adventure of the Mazarin Stone


n this edition of Annals of Neurology, Wisjman and colleagues report the association of a metabolite of brain natriuretic peptide (BNP) and cognitive dysfunction among elderly predominantly white northern European patients in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).1 Half the individuals in this study had established cardiovascular disease, including angina, intermittent claudication, stroke, transient ischemic attack, myocardial infarction, and/or vascular surgery, and the others had 1 cardiovascular risk factors, defined as hypertension, smoking, or diabetes mellitus. The investigators showed that those who had the highest levels of N-terminal proBNP (NT-proBNP) had worse baseline cognitive function and also had steeper cognitive declines on later neuropsychological testing than those with lower NTproBNP levels. Other large studies cited by the investigators also have found an association of these peptides with brain functioning. Much of the literature about BNP and NTproBNP relates to cardiac conditions. BNP (also called B-type natriuretic peptide, as opposed to the related atrial natriuretic peptide) was first discovered in brain tissue. However, circulating BNP is mostly secreted by cardiac atrial myocytes in response to atrial stretch. NTproBNP is more stable at room temperature than BNP, and levels correlate with those of BNP. These peptides are excreted in the kidney. The atria contain the highest BNP concentrations in healthy individuals, but this is shifted to the ventricles in patients with heart failure.2 Levels of BNP and NT-proBNP have been shown to be elevated in patients with congestive heart failure, atrial fibrillation, and renal failure.2–4 NT-proBNP has been used to screen for those who are likely to develop atrial fibrillation and as such are candidates for prolonged cardiac rhythm monitoring. How can neurologists explain the association of putative cardiac peptides with cognitive functions of the brain? The heart and the brain are arguably the

most important organs in the human body. The heart’s pumping action keeps the brain and other body organs alive. The brain exerts control over cardiac function and so the heart and brain are interdependent and interrelated. The brain is particularly vulnerable to any decrease in its blood, oxygen, or fuel supply or a change in its chemical milieu. Patients with hypotension often present to their physicians or the emergency room with symptoms of brain dysfunction. In the most general sense, heart trouble 5 brain trouble. Unfortunately, the investigators did not include in this report anything about the presence of cerebrovascular-related brain lesions in the form of brain infarcts or white matter disease. They did analyze statistically and found no association of most cognitive scores with the presence of previous stroke and/or transient ischemic attack or myocardial infarction. Associations do not prove causality—that is, that the cardiac abnormalities implied by the high peptide levels caused the cognitive dysfunction. The association serves mostly to generate hypotheses about potential relationships that then can be studied further: 1. Because high NT-proBNP is a marker for atrial fibrillation, and atrial fibrillation is a very important cause of brain embolism, cognitive dysfunction could be explained by embolic brain infarcts in strategic locations for cognitive dysfunction. 2. Chronic disease of penetrating brain arteries is an important cause of cognitive dysfunction in the elderly. Vascular brain disease often coexists with and compounds Alzheimer disease, so that patients with both vascular disease and Alzheimer pathology have poorer intellectual function than those with only Alzheimer abnormalities.5 In the analysis of the PROSPER study data, higher NT-proBNP levels were associated with higher systolic blood pressure.1 Hypertension and the presence of renal dysfunction (not analyzed) correlate with the presence and severity of penetrating artery disease of the brain. The brain pathologies that indicate the presence and severity of

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penetrating artery disease in the brain—lacunae and white matter abnormalities—were not analyzed in this report. 3. High NT-proBNP levels can indicate congestive heart failure. Some reports of patients with severe heart disease, syncope, and congestive heart failure found a high frequency of cognitive abnormalities, although none defined the pathogenesis of the loss of intellectual function.6–8 Zuccala et al studied 57 consecutive patients, whose average age was 77 years, with chronic congestive heart failure. More than half had low scores on cognitive function tests; the presence of low scores was highly correlated with left ventricular ejection fractions of

Cognitive decline and brain natriuretic peptide: how are they related?

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