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Relationship between progression of brain white matter changes and late-life depression: 3-year results from the LADIS study

  • Michael J. Firbank (a1), Andrew Teodorczuk (a1), Wiesje M. Van Der Flier (a2), Alida A. Gouw (a2), Anders Wallin (a3), Timo Erkinjuntti (a4), Domenico Inzitari (a5), Lars-Olof Wahlund (a6), Leonardo Pantoni (a5), Anna Poggesi (a5), Giovanni Pracucci (a5), Peter Langhorne (a1) and John T. O'Brien (a1)...

Abstract

Background

Brain white matter changes (WMC) and depressive symptoms are linked, but the directionality of this association remains unclear.

Aims

To investigate the relationship between baseline and incident depression and progression of white matter changes.

Method

In a longitudinal multicentre pan-European study (Leukoaraiosis and Disability in the elderly, LADIS), participants aged over 64 underwent baseline magnetic resonance imaging (MRI) and clinical assessments. Repeat scans were obtained at 3 years. Depressive outcomes were assessed in terms of depressive episodes and the Geriatric Depression Scale (GDS). Progression of WMC was measured using the modified Rotterdam Progression scale.

Results

Progression of WMC was significantly associated with incident depression during year 3 of the study (P = 0.002) and remained significant after controlling for transition to disability, baseline WMC and baseline history of depression. There was no significant association between progression of WMC and GDS score, and no significant relationship between progression of WMC and history of depression at baseline.

Conclusions

Our results support the vascular depression hypothesis and implicate WMC as causal in the pathogenesis of late-life depression.

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Copyright

Corresponding author

Michael Firbank, PhD, Institute for Ageing and Health, Newcastle University Wolfson Research Centre, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK. Email: michael.firbank@ncl.ac.uk

Footnotes

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Declaration of interest

A.W. is a member of advisory boards for Lundbeck and ADAD-IJ, and has received honoraria from Pfizer, Lundbeck, Novartis and Philips. D.I. served on a scientific advisory board for Servier, and has received speaker honoraria from Bayer Schering Pharma, Novartis, Pfizer and Sanofi-Aventis. L.P. has received travel funds from Bayer Italy. J.T.O'B. has been a consultant for GE Healthcare, Servier and Bayer Healthcare and has received honoraria for talks from Pfizer, GE Healthcare, Eisai, Shire, Lundbeck, Lilly and Novartis.

Footnotes

References

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Relationship between progression of brain white matter changes and late-life depression: 3-year results from the LADIS study

  • Michael J. Firbank (a1), Andrew Teodorczuk (a1), Wiesje M. Van Der Flier (a2), Alida A. Gouw (a2), Anders Wallin (a3), Timo Erkinjuntti (a4), Domenico Inzitari (a5), Lars-Olof Wahlund (a6), Leonardo Pantoni (a5), Anna Poggesi (a5), Giovanni Pracucci (a5), Peter Langhorne (a1) and John T. O'Brien (a1)...
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Assessing the Role of Cerebrovascular Disease in the Incidence of Geriatric Depression

The association between vascular disease and late life depression is an example of how a common 'medical' disorder could have clinically significant neuropsychiatric sequelae. With cerebrovascular disease a prominent cause of mortality and disability in the aged population, this is a major public health issue. In their longitudinal study of white matter change (WMC) and depression incidence, Firbank et al 1 note that the cross-sectional nature of existing work prohibits conclusions about the direction of causality, with their prospective investigation a welcomecontribution to this exciting field. A temporal sequence of white matter disease before depression supports the use of neuroimaging in screening 'at risk' individuals and implicates cardiovascular risk factors in the pathogenesis of geriatric mood disorder. However, other recent studies have suggested that this sequence could be bidirectional 2. As I have argued elsewhere 3, the relationship between physical disease and mood disorder in the elderly is likely to be aetiologically complex and characterised by reciprocity.

Firbank et al present results from the LADIS study and conclude that in their patients, progression of white matter disease was associated withdepression incidence. However, I believe the analytical methods used by the authors affect the significance of this finding and warrant discussion.

A cohort study of harm typically compares individuals exposed to a risk factor (WMC) with those unexposed. The two groups are followed to monitor the incidence of the adverse effect (depression incidence), which allows for the calculation of a relative risk (the hazard ratio). However,in this study the authors used the equivalent of a t-test for non parametric data to compare the level of WMC between groups of patients according to their depression status. When the results are presented in this manner, depression status effectively becomes the exposure. Therefore, whilst it is possible for the authors to conclude that exposureto depression at baseline did not lead to WMC, their claim that WMC predicts depression incidence seems less certain. The presence of overlapping 95% confidence intervals between cohorts also introduces doubtabout whether the true value of WMC between populations is significantly different, although a wide confidence interval in those patients with depression onset in year 3 of the study is likely related to the small number of patients in this group.

Firbank et al then make a careful attempt to identify and control forpotential confounders in their regression analysis. Here, however, the 95%confidence interval for the relationship between white matter change and depression includes 1 (unity). With such marginal significance, the fate of those patients who were lost to follow up (over 30%) seems increasinglyrelevant. Moreover, I wonder why the authors chose to use the Folstein Mini-Mental State Examination as a correlate of cognitive impairment, whenexecutive dysfunction is often most problematic in these patients 4.

Future studies might dichotomise patients into 'high WMC' and 'low WMC' exposure cohorts to more accurately quantify risk and demonstrate a biological gradient for the effects of vascular disease on mood disorder.

References:

1 Firbank MJ, Teodorczuk A, van der Flier WM, Gouw AA, Wallin A, Erkinjuntti T, et al. Relationship between progression of brain white matter changes and late-life depression: 3-year results from the LADIS study. Br J Psychiatry 2012; 201: 40-5.

2 Dotson VM, Zonderman AB, Kraut MA, Resnick SM. Temporal relationships between depressive symptoms and white matter hyperintensities in older men and women. Int J Geriatr Psychiatry 2012.

3 Mosley PE, Lyness JM. Physical co-morbidity with mood disorders. In: Oxford handbook of clinical geropsychology: International perspectives(Pachana NA, Laidlaw K, editors). Oxford University Press (under contract), due 2013.

4 Alexopoulos GS, Kiosses DN, Heo M, Murphy CF, Shanmugham B, Gunning-Dixon F. Executive dysfunction and the course of geriatric depression. Biol Psychiatry 2005; 58: 204-10.

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Conflict of interest: None declared

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