This study provides evidence that increasing thickness of CIMT is weakly associated with lower verbal learning abilities but not global cognition among healthy cognitively intact middle-toolder aged individuals without clinically evident CVD but with elevated Hcy. The observed association remained robust after adjustment for CVD risk factors suggesting that CIMT may be an independent correlate of verbal learning. The association between CIMT and poor verbal learning may pertain particularly to men. Arterial calcium measures of subclinical atherosclerosis were not associated with lower cognitive function in any area assessed. Results from this study also suggest that individuals with the greatest burden of subclinical atherosclerosis may have lower global cognitive abilities compared to those with less burden. Taken together, our findings suggest that in healthy, non-demented adults, early subclinical atherosclerosis (i.e., increasing thickness of CIMT) is associated with lower verbal learning, whereas later stage subclinical atherosclerosis (calcifications of the arteries) is not. We did not find evidence that subclinical atherosclerosis was associated with executive function, logical, visual or semantic memory.
The associations observed in this population were small. Lower verbal learning performance per 0.1 mm CIMT corresponds to approximately 7% of an SD in the factor score, which is still well within the range of what is considered clinically “normal”(Norman et al., 2000
). The difference in verbal learning performance (nearly 30% of a SD lower) was more pronounced comparing individuals with CIMT in the highest quartile to the lowest. Stratified analyses suggest that the association between subclinical atherosclerosis and cognition may differ by gender, with an association between increasing CIMT and lower verbal learning apparent for men but not for women. This observation could be explained by the possibility that a threshold in the level of CIMT exists which must be reached for cognition associations to be observed, and that this threshold was reached in men but not women in the study population. This possibility is supported by the fact that mean CIMT was greater for male than female subjects.
While list-learning and recall, and story-learning and recall are both measures of verbal memory and a reasonable assumption would be that these two tests would be represented by a common factor, these tests loaded on different factors. However, no neuropsychological task measures only a single cognitive process, and cognitive skills involved in list-learning are not identical to skills in story-learning, which places a greater emphasis on thematic (conceptual) organization. Thus, the loading of these tests on two separate factors is not surprising.
Given the number of statistical tests performed, we cannot rule out the possibility that the association detected between increasing CIMT and lower verbal learning was due to chance. However, by employing a principal components analysis to derive uncorrelated cognitive factors, we minimized multiple statistically significant findings due to correlated outcomes. Furthermore, we adjusted the α level in our hypotheses testing of main effects to be more conservative. Finally, as our objectives were to address questions about different stages of subclinical atherosclerosis and different areas of cognition, multiple analyses were necessary.
Atherosclerosis could be acting through one or more possible mechanisms to exert an effect on cognitive function. Endothelial dysfunction represents the earliest stage of atherosclerosis(Libby, 2001
). Endothelial cells make up one component of the blood-brain barrier (BBB), which functions to maintain a constant intracerebral milieu critical for proper brain function(Hof et al., 1999
). By disrupting the function of endothelial cells, atherosclerosis could theoretically increase permeability of the BBB(McCarron et al., 2006
, Skoog et al., 1998
). Breaches to this barrier could allow neurotoxins and other substances from which the brain is normally protected into the cerebral environment. Over time, the cumulative effect of these substances within the brain could result in detectable losses of cognitive abilities.
The diminished delivery of oxygen resulting from reductions in blood flow is another possible mechanism by which atherosclerosis may affect cognition. One study (Ruitenberg et al., 2005
) showed that greater cerebral blood flow velocity was related to a lower prevalence of cognitive decline, suggesting that cerebral hypoperfusion may precede and contribute to the onset of cognitive dysfunction and dementia. It is possible that deficits in certain cognitive domains, such as verbal learning, may be explained by their association with areas of the brain that are more vulnerable to the effects of cerebral hypoxemia resulting from vascular disease. Areas of the brain irrigated by long penetrating arteries such as the hippocampus are less able to tolerate the effects of hypoperfusion(Roman, 2004
). An fMRI study of CVLT performance (the test with high factor loadings on the verbal learning factor) showed that an area of the brain most active during tasks associated with this test was the hippocampus(Johnson et al., 2001
). Thus, in populations that are cognitively normal, small decreases in oxygen supply to the brain associated with subclinical atherosclerosis may explain some of the differences in cognitive performance in middle age, and the cumulative effect of small decrements over time may contribute to observable declines in cognitive function.
A third possibility is that CIMT may be a surrogate measure for intracranial atherosclerosis and its resultant localized pathology of infarction or ischemia due to blockage or deterioration of cerebral arterioles(Chui et al., 2000
). This is consistent with the fact that CIMT predicts stroke risk(Bots et al., 2007
), and would suggest that individuals with greater carotid atherosclerosis may also have more cerebral atherosclerosis, which individually leads to declines in cognition.
Other population-based studies that used CIMT as a measure of atherosclerosis reported associations between atherosclerosis and cognitive function. In the ARIC study (adults aged 45–64 years), CIMT was cross-sectionally correlated with psychomotor performance in men and women, and with verbal learning in women after adjustment for basic demographic factors(Cerhan et al., 1998
), but not longitudinally after 6 years(Knopman et al., 2001
). In contrast, we found evidence of an association between CIMT and decreased verbal learning in men but not in women.
In a study of 400 Dutch middle-aged and elderly men aged 40–80 years(Muller et al., 2007
), increased CIMT was significantly associated with lower memory (combined verbal and visual). Investigators in that study used the Rey verbal learning test to assess verbal memory, and the Doors test to assess visual memory. Our observed association between lower verbal learning and increasing CIMT among men is partly in line with these findings, although visual memory was not associated with CIMT in our sample.
A limitation of this cross-sectional study is the inability to address directionality of associations. We controlled for a number of factors including education and income that could be associated with both cognitive function and subclinical atherosclerosis in order to minimize their contribution to the observed associations. While we cannot rule out the possibility that a third factor not considered could be responsible for the detected associations, the fact that the association was specific to the verbal learning area of cognition makes this scenario less believable. Strengths of this study include the battery of neuropsychological tests that allowed an examination of a broad range of cognitive abilities, as well as highly reliable and well-validated measures of subclinical atherosclerosis. This study is limited by small numbers of elderly adults >80 years old and women aged 40–49 years given the selection criteria for postmenopausal women. Therefore, the findings of the study may not be generalizable to elderly adults and to premenopausal women. In addition, given that BVAIT selected healthy subjects with Hcy ≥8.5 µmol/L, results may not be generalizable to populations with lower Hcy. Previous research has shown that elevated Hcy is associated with atherosclerosis(Boushey et al., 1995
, Refsum et al., 1998
) as well as with deficits in cognitive performance, cognitive decline and dementia(Robbins et al., 2005a
). It is therefore possible that given study selection criteria, we may have been more likely to detect an association, if one existed, between subclinical atherosclerosis and lower cognitive function. It is important to note, however, that mean Hcy levels in the study population (10.3 µmol/L) are still within what is considered the normal range(Malinow et al., 1999
). Finally, selection criteria for our study excluding individuals with a history of CVD and diabetes may limit the generalizability of our findings. These selection criteria may have also limited our ability to detect an association between subclinical atherosclerosis and lower cognitive function if it is the combination of atherosclerosis across a spectrum of CVD risk factors that is important to detect an effect on cognition function.
In summary, our findings suggest that in a population of otherwise healthy middle-to-older aged hyperhomocysteinemic adults without clinically evident CVD, 1) CIMT but not CAC or AAC, is associated with lower verbal learning abilities but not other areas of cognitive function through mechanisms independent of standard CVD risk factors assessed in this study; 2) this association may pertain only to men perhaps because they met a threshold level of CIMT necessary for an association with cognition to be observed. An implication of this study is that interventions aimed at reducing the risk of atherosclerosis may have an added benefit of preventing future decrements in cognitive function. Additional studies are needed to further elucidate the relationship between subclinical atherosclerosis and cognitive function among healthy adults without clinically evident CVD.