The FSRP was associated with reduced white-matter integrity in participants with depression. Our results suggest that white-matter tracts, including, corpus callosum, corticospinal tract and cingulum, warrant further investigation in order to investigate the mechanisms underlying vascular depression. These white-matter tracts with significant correlations were examined in more detail to compare FSRP and FA between depressed and control groups. Greater variability in FA values was evident in controls (), a particularly interesting finding given that both groups were matched for vascular risk, as measured by FSRP. This leads to the hypothesis that the greater white-matter integrity in controls provides resilience against the effects of vascular risk, and the subsequent development of depression. Though there was one area of regional significance in controls (body of corpus callosum), this was less significant than in the depressed group.
High vascular burden of disease is more likely with advancing age, thus “vascular depression” is especially relevant to those with late-onset depression. Vascular disease may precipitate both relapse in those who have had depression in the past, and first-onset of the disease in later life. The knowledge that vascular illness and elevated risk factors might have a specific effect on brain structure is important in understanding depression, and raises further questions about the links between depression and cognitive impairment. Both conditions not only share common risk factors, but also structural changes (such as hippocampal atrophy (McKinnon et al., 2009
) and reduced brain volume (Dotson et al., 2009
)). Also, neuropsychological deficits in executive function and processing speed are well documented in depression (Herrmann et al., 2007
). Impaired white-matter integrity within pre-frontal regions would be a plausible explanation linking structural and functional changes in both conditions (Buckner, 2004
; Park and Reuter-Lorenz, 2009
; Shimony et al., 2009
A key strength of this study was the MRI acquisition process which entailed two repeats of sixty-direction DTI. This exceeds the suggested minimum of thirty directions estimated as needed for robust estimation of FA (Jones, 2004
) and is higher than many published studies (Sexton, et al., 2009
). There are, however, limitations to this study particularly in the recruitment of the sample which was not systematically ascertained. Furthermore, most of the depressed participants had early-onset disease (n=23), before the age of 60, rather than late-onset disease (n=13). Although age at onset was not the focus of this study, the literature suggests that the impact of vascular risk on mood is greater for those developing depression over the age of 60, and it will be of interest to explore the effect of age at onset in more detail within a larger sample.
Participants were not excluded on the basis of medication. Whilst this means that our results are more representative of those who are routinely seen in specialist mental health care settings, it is also possible that medication may lead to structural brain changes that could influence our results. Given the age of our sample, where many have co-morbid health problems, and the nature of the sample (recruitment of those with major depressive disorder), excluding people on the basis of medication would have not only made recruitment much more difficult, but would also have introduced new bias to the study.
Framingham scores and spread were similar in both groups, yet there was no correlation with FA in the control group. There are several possible explanations for this, relating to both cases and controls. It may be that those people becoming “cases” have pre-existing impairments in white-matter integrity which provide a biological vulnerability to depression, not uniquely related to vascular disease. Another explanation is that depression itself might induce changes within white-matter structure. Whilst this cross-sectional study does not provide information about the causality of vascular brain changes, this could be addressed through future longitudinal studies. On the other hand, controls may have specific protective factors which offer them resilience against white-matter change, and developing depression. These are most likely to be biological, for example, functional differences with increased recruitment of other parts of the brain, particularly in frontal regions (Buckner, 2004
; Park and Reuter-Lorenz, 2009
). Medication may also be a protective factor (greater use of statins could be one possibility). Finally, it may mean that the level of cardiovascular risk as measured by FSRP does not correlate accurately with structural brain changes, and that alternative measures of vascular risk need to be investigated. Although this study was not designed to address these questions, they provide interesting scope for future research.
In summary, this exploratory study combines the FSRP, a well validated, multi-factorial, cardiovascular risk algorithm, with white-matter changes quantified with DTI. Our results suggest that even in the absence of major vascular disease, elevated FSRPs in those with depression are associated with significant changes in white-matter connectivity, to a degree not observed within the control group. This is apparent in widespread regions of the brain, most significantly within the corpus callosum and corticospinal tract. Greater understanding of the mechanisms by which vascular risk may contribute to pathophysiology in depression is important, in order to prevent and treat this common illness. These results support the vascular depression hypothesis, and should lead to further research within larger, systematically (and preferably prospectively) acquired cohorts.