Brief reportVascular risk and low serum B12 predict white matter lesions in patients with major depression
Introduction
Hyperintense signals observed on magnetic resonance imaging (MRI) are more prevalent and/or more severe within the deep white matter, periventricular or subcortical regions in some subgroups of patients with major depression (Greenwald et al., 1996, Hickie et al., 1995, Krishnan et al., 1997). Such lesions have been associated with older age, later age of depression onset, psychomotor change, vascular risk factors and an absence of a family history of affective disorder (Alexopoulos et al., 1997, Greenwald et al., 2001, Hickie et al., 1995, Hickie et al., 1997, Steffens and Krishnan, 1998). Importantly, lesions are predictive of treatment resistance and progression to institutional care (Hickie et al., 1995, Hickie et al., 1997, Hickie et al., 2003, O'Brien et al., 1998).
Previously, we have reported associations between depression of later onset, and mutation of the methelenetetrahydrofolate reductase (MTHFR) allele (Hickie et al., 2001). MTHFR activity is integral to homocysteine metabolism. Elevated homocysteine is recognised as a risk factor to vascular (Gallagher et al., 1996, Markus et al., 1997, Wilcken, 1998) disease, and now, potentially, dementia (Hermann and Knapp, 2002). Recent population-based studies have linked homocysteine and/or MTHFR to silent brain infarcts, white matter disease (Kohara et al., 2003, Vermeer et al., 2002), depressive symptoms (Bjelland et al., 2003), and, in clinical cohorts, cognitive slowing (Naismith et al., 2002, Naismith et al., 2003). Hyperhomocysteinemia can be corrected by dietary supplementation of vitamin B12 and/or folic acid. While many studies have shown associations between B12 (Bell et al., 1990, Tiemeier et al., 2002) or folate (Fava et al., 1997, Reynolds, 2002) levels and depressive disorders, the pathophysiological mechanism(s) for such effects remain unclear. As we move to preventative strategies (Bird and Parslow, 2002, Hickie and Scott, 1998), elucidation of the relationships between such vascular risk, dietary factors and structural brain changes is increasingly important.
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Subjects
As detailed elsewhere (Hickie et al., 2001, Naismith et al., 2002, Naismith et al., 2003), 21 healthy volunteers (age range 40–74 years, mean=54.7, SD=9.1) and 47 patients with major depression (age range 30–82 years, mean=52.8, SD=12.6) were recruited.
Magnetic resonance imaging
Participants underwent MRI scanning (124×1.5 mm coronal slices; TR=24 ms, TE=5 ms, FOV=26 cm, matrix 256×256) using a 1.5 Tesla GE Signa machine. White matter lesion (WML) ratings were performed by an experienced rater with demonstrated
Results
As shown in Table 1, there was no difference in age, sex or cognition between patients with depression and control subjects. There was also no difference in the extent of DWM, PV or SC lesions, or in cumulative lesion load. However, patients with depression had more vascular risk factors, lower folate levels and an increased rate of the ApoE2 allele.
Discussion
The prevalence and severity of WMLs in this new cohort was lower than that in our previous cohort (Hickie et al., 1995). This is consistent with other recent studies in younger patients or those with less severe depressive disorders (e.g. Sassi et al., 2003). Importantly, this was a relatively small sample of patients with depression and compared with other studies may have had fewer patients at high risk of having lesions (i.e. those with later ages of onset, vascular risk factor or
Acknowledgments
The NHMRC Program Grant No. 953208 supported this project financially.
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2012, NeuroImageCitation Excerpt :Although these lesions may be found in healthy subjects, their presence and severity has been associated with cognitive disorders, gait and balance disorders and depression (de Groot et al., 2000) (Guttmann et al., 2000; Whitman et al., 2001). Associations with measurements of atherosclerosis, i.e. intima–media thickness of the carotid arteries (Manolio et al., 1999), retinopathy (Wong et al., 2002) and changed endothelial marker profiles (Hickie et al., 2005; Ovbiagele and Saver, 2006) have further strengthened this concept. The most important risk factors for WMH are increasing age (Breteler et al., 1994; Liao et al., 1997; Schmidt et al., 2000) and hypertension (Basile et al., 2006; De Leeuw, 2004; Jeerakathil et al., 2004; Longstreth et al., 1996).
White matter abnormalities in major depression: Evidence from post-mortem, neuroimaging and genetic studies
2011, Journal of Affective DisordersCitation Excerpt :In terms of correlations with other clinical factors, hypofolatemia was associated with more accentuated subcortical white matter hyperintensities (Iosifescu et al., 2005) which is in turn correlated with poorer anti-depressant treatment response in patients with MDD (Papakostas et al., 2005). Vitamin B12 levels and hypertension were associated with the presence of deep white matter hyperintensities underscoring the need to examine the role of metabolic and vascular factors in the context of white matter changes (Hickie et al., 2005; Papakostas et al., 2005). In terms of diffusion tensor imaging (DTI), studies reported lower fractional anisotropy (FA) values within the cortical and subcortical brain regions (Kieseppä et al., 2010; Li et al., 2007; Ma et al., 2007; Zou et al., 2008).
No clear potentiation of antidepressant medication effects by folic acid + vitamin B<inf>12</inf> in a large community sample
2011, Journal of Affective DisordersCitation Excerpt :While other research has shown that a dose of 400 mcg/day FA is associated with 90% of the maximal decrease in Hcy (van Oort et al., 2003), it is possible that the FA and B12 dose used here was too low to have any effect on Hcy levels. There are reasons to believe that persons with depression are more likely to have genetic factors critical to the regulation of Hcy metabolism (Hickie et al., 2001a,b, 2005), but whether these factors are the cause of the apparent lack of effect on Hcy in this study requires further investigation. Consequently, it is likely that a higher dose of FA is required to change Hcy levels in this subgroup of the population.