COMMENTARIES

Atherosclerosis and Cognitive Function

Andreana P. Haley, Ph.D., Department of Psychology, University of Texas at Austin, 1 University Station, A8000, Austin, TX, USA

Andreana P. Haley

Atherosclerosis has long been recognized in clinical lore as an important factor in the development of dementia later in life. Patients of older generations were often told that their cognitive difficulties were due to “hardening of the arteries.” Consistent with clinical wisdom, large epidemiological studies have shown a significant relationship between surrogate markers of peripheral atherosclerosis and risk for dementia [1]. In non-demented populations, however, the relationship between peripheral atherosclerosis and brain function has been much harder to elucidate despite accumulating evidence that patients with cardiovascular disease exhibit subtle cognitive difficulties long before the onset of dementia [2-9]. Because cognitive changes in this population are most likely mediated by compromises in the structural and functional integrity of cerebral blood vessels as well as the large arteries supplying blood to the brain, continued examination of the relationship between markers of vessel health and cognition is of utmost importance.

          Carotid artery intima-media thickness (IMT) assessed by B-mode ultrasound, is a reliable, non-invasive marker of pathological arterial wall changes [10]. At levels higher than 0.9 mm, IMT is associated with atherosclerotic vascular disease and end-organ damage [11]. Studies examining the relationship between IMT and cognitive function, however, have found inconsistent results. One community-based study reported a significant association between increased IMT and lower visual attention and psychomotor speed for both men and women [12], while another found a similar relationship only in men with carotid plaques [13]. IMT was found to be a good predictor of cognitive decline over time in stroke patients [14], but not in community dwelling elderly [15]. These differences may be due to the fact that IMT values in community samples are generally well below the accepted clinical cut off indicating vascular damage from atherosclerosis [13-15].

          In a recently published study [16], our research group examined the relationship between increased IMT and neuropsychological test performance in a sample of stable outpatients with documented cardiovascular disease. We chose this patient population because they tend to exhibit pathological arterial wall changes at levels much higher than the general population. We theorized that a certain level of pathology has to be reached before increased IMT consistently relates to poor cognitive test performance. Specifically, we hypothesized that people with IMT levels greater than 0.9 mm (the accepted clinical cut off) would exhibit poorer cognitive functioning in the attention-exec cognitive domain. We postulated that this relationship would be strongest for attention-executive-psychomotor speed since the frontal subcortical networks in the brain that are responsible for executive function and attention appear to be particularly vulnerable to ischemic damage resulting from blood flow abnormalities [17].

          Consistent with our prediction, our results showed that increased carotid artery IMT was associated with lower attention-executive-psychomotor test performance in our sample of non-demented patients with a variety of cardiovascular diagnoses. The effect was independent of age, sex, education, cardiovascular risk, current systolic blood pressure, and history of coronary artery disease (CAD). In support of the threshold hypothesis, we demonstrated that the slope of the linear relationship between IMT and attention-executive-psychomotor performance was significantly steeper in the high IMT sub-group of our study sample (i.e. IMT ≥ 0.9 mm) as compared to the slope of the same relationship in the low IMT sub-group (IMT < 0.9 mm). This observation indicates a stronger relationship between higher IMT and poorer neuropsychological test performance in the high IMT group.

          Due to the cross-sectional design of our study, we can only speculate about the nature of the observed relationship between increased IMT and diminished attention-executive-psychomotor functioning. One possibility is that carotid artery intimal-medial thickening leads to chronic cerebral hypoperfusion and ischemic damage even in the absence of frank infarctions. This idea is supported by previous reports of impaired attention-executive-psychomotor performance in patients with documented subcortical white matter disease, presumably of vascular origin [18-20]. Though the exact mechanism through which subcortical white matter lesions relate to cognition is unknown, a diaschisis model might be applicable. This model suggests that vascular damage to subcortical white matter disrupts higher order cognitive functions by causing a disconnection between brain regions responsible for storing, rehearsing, and organizing information. Furthermore, mild, diffuse brain damage related to chronic hypoperfusion may affect the brain’s ability to process information quickly and efficiently even in the absence of discrete white matter lesions. A reduction in cognitive processing speed is likely most detrimental to cognitive functions such as complex attention and planning ability. This hypothesis is supported by our observation of a relationship between IMT and performance on attention-executive-psychomotor tests in patients with intact global cognition, language, and memory.

          In conclusion, the heterogeneity of our population, and the fact that the relationship between IMT and cognition remained significant even after adjustment for traditional cardiovascular risk and history of CAD, suggest that IMT has value as an integrative measure of arterial health among patients with a variety of cardiovascular diagnoses. Increased IMT in isolation, however, is likely insufficient to contribute to significant vascular-related pathology in the brain. Therefore, the complex interactions between the various available indexes of cardiovascular health should continue to be explored in conjunction with their influences on brain structure and function.

References

  1.    van Oijen M, de Jong FJ, Witteman JC, et al. Atherosclerosis and risk for dementia. Ann Neurol 2007;61:403-10.
  2.    Cohen RA, Kaplan RF, Fischer M, Bogousslavsky J. Neuropsychological aspects of cerebrovascular disease. In: Current review of cerebrovascular diseases. Philadelphia: Current Medicine, 1995.
  3.    Cohen RA, Moser DJ, Clark MM, et al. Neurocognitive functioning and improvement in quality of life following participation in cardiac rehabilitation. Am J Cardiol 1999;83:1374-78.
  4.    Gunstad J, Macgregor KL, Paul RH, et al. Cardiac rehabilitation improves cognitive performance in older adults with cardiovascular disease. J Cardiopulm Rehabil 2005;25:173-76.
  5.    Gunstad J, Bausserman L, Paul RH, et al. C-reactive protein, but not homocysteine, is related to cognitive dysfunction in older adults with cardiovascular disease. J Clin Neurosci 2006;13:540-46.
  6.    Gunstad J, Poppas A, Smeal S, et al. Relation of brain natriuretic peptide levels to cognitive dysfunction in adults > 55 years of age with cardiovascular disease. Am J Cardiol 2006;98:538-40.
  7.    Jefferson AL, Poppas A, Paul RH, Cohen RA. Systemic hypoperfusion is associated with executive dysfunction in geriatric cardiac patients. Neurobiol Aging 2007;28:477-83.
  8.    Moser DJ, Cohen RA, Clark MM, et al. Neuropsychological functioning among cardiac rehabilitation patients. J Cardiopulm Rehabil 1999;19:91-97.
  9.    Paul RH, Gunstad J, Poppas A, et al. Neuroimaging and cardiac correlates of cognitive function among patients with cardiac disease. Cerebrovasc Dis 2005;20:129-33.
  10.    Bots ML, Dijk JM, Oren A, Grobbee DE. Carotid intima-media thickness, arterial stiffness and risk of cardiovascular disease: current evidence. J Hypertens 2002;20:2317-25.
  11.    Van Bortel LM. What does intima-media thickness tell us? J Hypertens 2005;23:37-39.
  12.    Cerhan JR, Folsom AR, Mortimer JA, et al. Correlates of cognitive function in middle-aged adults. Atherosclerosis Risk in Communities (ARIC) Study Investigators. Gerontology 1998;44:95-105.
  13.    Auperin A, Berr C, Bonithon-Kopp C, et al. Ultrasonographic assessment of carotid wall characteristics and cognitive functions in a community sample of 59- to 71-year-olds. The EVA Study Group. Stroke 1996;27:1290-95.
  14.    Talelli P, Ellul J, Terzis G, et al. Common carotid artery intima media thickness and post-stroke cognitive impairment. J Neurol Sci 2004;223:129-34.
  15.    Knopman D, Boland LL, Mosley T, et al. Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology 2001;56:42-48.
  16.    Haley AP, Forman DE, Poppas A, et al. Carotid artery intima-media thickness and cognition in cardiovascular disease. Int J Cardiol 2007;121:148-54.
  17.    Pantoni L, Garcia JH. Pathogenesis of leukoaraiosis: a review. Stroke 1997;28:652-59.
  18.    Cohen RA, Paul RH, Ott BR, et al. The relationship of subcortical MRI hyperintensities and brain volume to cognitive function in vascular dementia. J Int Neuropsychol Soc 2002;8:743-52.
  19.    Kramer JH, Reed BR, Mungas D, Weiner MW, Chui HC. Executive dysfunction in subcortical ischaemic vascular disease. J Neurol Neurosurg Psychiatry 2002;72:217-20.
  20.    Paul RH, Haque O, Gunstad J, et al. Subcortical hyperintensities impact cognitive function among a select subset of healthy elderly. Arch Clin Neuropsychol 2005;20:697-704.

 

 

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