Brief report
Vascular risk and low serum B12 predict white matter lesions in patients with major depression

https://doi.org/10.1016/j.jad.2004.11.003Get rights and content

Abstract

Background

While patients with depression have been shown to have a greater incidence of vascular risk factors and structural brain changes, any association with dietary co-factors is unclear.

Methods

Forty-seven patients with major depression (mean age=52.8 years, SD=12.6) and 21 healthy volunteers (mean age=54.7 years, SD=9.1) underwent high-resolution magnetic resonance imaging scanning. T2-weighted films were scored for deep white matter (DWM), periventricular (PV), and subcortical (SC) hyperintensities.

Results

There was no difference in lesion severity between patients and control subjects. After controlling for age, vitamin B12 levels were predictive of DWM lesions in patients. DWM and SC lesions were associated with histories of hypertension and diabetes.

Limitations

A relatively small sample of patients were recruited from specialist services and the findings may not represent those observed in larger or community-based cohorts.

Conclusions

In patients with major depression, vitamin B12 levels and histories of hypertension and/or diabetes are predictive of white matter lesions.

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.

Section snippets

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.

References (35)

  • I. Bjelland et al.

    Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study

    Arch. Gen. Psychiatry

    (2003)
  • C.E. Coffey et al.

    Subcortical hyperintensity on magnetic resonance imaging: a comparison of normal and depressed elderly subjects

    Am. J. Psychiatry

    (1990)
  • M. Fava et al.

    Folate, vitamin B12, and homocysteine in major depressive disorder

    Am. J. Psychiatry

    (1997)
  • P.M. Gallagher et al.

    Homocysteine and risk of premature coronary heart disease. Evidence for a common gene mutation

    Circulation

    (1996)
  • B.S. Greenwald et al.

    MRI signal hyperintensities in geriatric depression

    Am. J. Psychiatry

    (1996)
  • B.S. Greenwald et al.

    A controlled study of MRI signal hyperintensities in older depressed patients with and without hypertension

    J. Am. Geriatr. Soc.

    (2001)
  • M. Hamilton

    Development of a rating scale for primary depressive illness

    Br. J. Soc. Clin. Psychol.

    (1967)
  • Cited by (33)

    • The spatial distribution of age-related white matter changes as a function of vascular risk factors-Results from the LADIS study

      2012, NeuroImage
      Citation 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 Disorders
      Citation 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 Disorders
      Citation 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.

    View all citing articles on Scopus
    View full text