ReviewWhite matter lesions and depression: A systematic review and meta-analysis
Introduction
White matter hyperintensities (WMH) on T2 and fluid-attenuated inverse recovery (FLAIR) MRI sequences are often reported in patients with late-onset depression (Greenwald et al., 1996, Tupler et al., 2002, Taylor et al., 2005). However, it is unclear to what extent, if any, WMH represent lesions that play a role in the development of depression. Currently, the predominant view is that WMH are representative of underlying small vessel disease (Van Swieten et al., 1991, Moody et al., 1997) that, via hypoperfusion injury to cortical fiber tracts, predisposes for depression (Culang-Reinlieb et al., 2010). However, the findings are inconsistent.
Four reviews (Culang-Reinlieb et al., 2010, Casanova et al., 2011, Gorelick et al., 2011, Hommet et al., 2012) and 2 meta-analyses (Herrmann et al., 2008, Arnone et al., 2012) have been conducted recently that have included at least some data concerning WMH and depression. Of the two recent meta-analyses, one conducted a meta-regression analysis of studies examining the morphometric correlates of depression and reported that WMH volumes were larger in depressed patients (Arnone et al., 2012). These findings were generated from pooling the results of 4 studies (Kumar et al., 2000, Hannestad et al., 2006, Taylor et al., 2007, Dalby et al., 2010) that included WMH data, yielding a total of 448 patients (mean age 68, standard deviation 7). Only one of the included studies (51 patients) reported adjusted odds ratios (Kumar et al., 2000).
The second meta-analysis (Herrmann et al., 2008), which was conducted in 2008, specifically investigated (in a secondary analysis) the association of WMH across late versus early onset depression. Depending on the onset group (late onset, early onset, late life), analyses were conducted using between 133 and 514 patients per analysis. The authors (Herrmann et al., 2008) found that patients with late onset depression were more likely to have WMH than those with early onset and postulated that cerebrovascular etiologies might explain this discrepancy. They cautiously noted however that no certain cut-point could be introduced to dichotomize age of onset and that reporting bias may have enhanced observed differences between the groups.
Several factors might be of importance when considering the possible relationship between WMH and depression. First, it seems plausible that WMH occurring in certain anatomic locations (e.g. frontal and paralimbic areas) exhibit stronger associations with depression than others (Thomas and O'Brien, 2009). To date, the majority of research has differentiated between WMH occurring in periventricular (PVWMH) and deep (DWMH) cortical locations. Neuropathology evidence suggests however that the etiology of PVWMH and DWMH may differ (Thomas, 2003). Moreover, PVWMH and DWMH may differentially associate with depression.
Secondly, when assessing the relationship between WMH and depression, it is important to take risk factors predisposing for WMH into account. Age and hypertension are among the most frequently cited risk factors for WMH (De Leeuw et al., 2001, Dufouil et al., 2001), but evidence suggests that additional risk factors like diabetes mellitus and the metabolic syndrome are likely to also play a role in WMH development (Bokura et al., 2008).
Finally, risk factors predisposing for depression are worth consideration. Physical disability, cognitive impairment, cardiovascular disease, and previous history of depression have all been shown to associate with depression (Hackett and Anderson, 2005).
To our knowledge, no meta-analyses to date have leveraged risk factor-adjusted data and performed a comprehensive meta-analysis of WMH (differentiating between PVWMH and DWMH) and depression.
The purpose of this meta-analysis was to determine whether an association between WMH and depression exists if data from studies that have reported adjusted findings are pooled. Additionally, along these lines, we sought to determine if PVWMH and DWMH differentially associate with depression.
Section snippets
Searching data sources
This review was conducted in accordance with MOOSE guidelines (Stroup et al., 2000). We identified original epidemiological studies assessing the relationship between WMHs and depression using computerized literature searches of the PubMed (based on MEDLINE) and Scopus (based on EMBASE) databases. Two readers (CL and LW) searched the PubMed and Scopus databases using the medical subject heading (MeSH) terms: “White matter lesions” OR “white matter disease” OR “Cerebrovascular Disease” OR
Results
Nineteen reports matched initial inclusion criteria. Of those, 10 prospective cohort studies and 1 case–control study reported data from cross-sectional analyses (Table 2). Six prospective cohort studies performed longitudinal (Table 3) analyses. One prospective cohort study (Versluis et al., 2006) performed both cross-sectional and longitudinal assessments. Three case–control analyses were identified that assessed the relationship between WMH and depression (binary outcome variable). One
Discussion
In general, this review and meta-analysis revealed that although most studies have reported a positive relationship to exist between WMH and depression, the effect is likely quite small (odds ratio of approximately 1.19). However, it must be noted that the majority of the current literature has rated WMH (either volumetrically or visually) according to a somewhat simplified, albeit a more manageable, approach—namely, identifying WMH as DWMH, PVWMH, and/or OWMH. Pooling studies that used this
Role of funding source
The research leading to these results has received funding from the Federal Ministry of Education and Research via the grant Center for Stroke Research Berlin (01 E0 0801). LW additionally received funding from the China Scholarship Council. Funding sources had no further role in study design, data collection/analysis/interpretation, writing of the manuscript, or decision to submit for publication.
Contributors
ME and PS designed the study, provided mentoring, and oversaw data collection, analyses, and manuscript preparation. CL and LW performed computerized literature searches and wrote the first draft of the manuscript. CL performed statistical analyses. All authors contributed to and have approved the final manuscript.
Conflict of interest
The authors report no financial or other relationship relevant to the subject of this article.
Acknowledgments
None.
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