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Depressive symptoms, brain volumes and subclinical cerebrovascular disease in postmenopausal women: The Women's Health Initiative MRI Study

https://doi.org/10.1016/j.jad.2011.01.020Get rights and content

Abstract

Objective

Late-life depressive symptoms (DS) increase the risk of incident mild cognitive impairment and probable dementia in the elderly. Our objectives were to examine the relationship between elevated DS and regional brain volumes including frontal lobe subregions, hippocampus and amygdala, and to determine whether elevated DS were associated with increased subclinical cerebrovascular disease in postmenopausal women.

Methods

DS were assessed an average of 8 years prior to structural brain MRI in 1372 women. The 8-item Burnam regression algorithm was used to define DS with a cut-point of 0.009. Adjusting for potential confounders, mean differences in total brain, frontal lobe subregions, hippocampus and amygdala volumes and total ischemic lesion volumes in the basal ganglia and the cerebral white and gray matter outside the basal ganglia were compared between women with and without DS.

Results

Depressed women had lower baseline global cognition and were more likely to have prior hormone therapy history. After full adjustment, DS at baseline were associated with smaller superior and middle frontal gyral volumes. Hippocampal and amygdala volumes, and ischemic lesion volumes were similar in depressed and non-depressed women.

Limitations

Depression was not assessed based on semi-structured interview, and MRI scans were obtained cross-sectionally rather than longitudinally. Longitudinal MRI assessments will be necessary to define the temporal relationships between DS and frontal lobe volumes.

Conclusions

Elevated DS were associated with lower volumes in certain frontal lobe subregions but not in the medial temporal lobe structures. Our findings support the role of frontal lobe structures in late-life DS among women.

Introduction

The societal impact of clinically significant depressive symptoms among the geriatric population is enormous. Syndromal and subthreshold depression is associated with poorer outcomes of co-morbid medical disorders and accelerated cognitive and functional decline (Alexopoulos, 2005, Wilson et al., 2002, Steffens et al., 2006, Dotson et al., 2008, Lyness et al., 2009). Further, late-life depressive symptoms (DS) are also associated with subsequent cognitive impairment, including increased incidence of mild cognitive impairment (MCI) and probable dementia (Devanand et al., 1996, Chen et al., 1999, Wilson et al., 2002, Ownby et al., 2006, Barnes et al., 2006). However, the neurobiological mechanisms of these relationships are not well understood despite evidence that as many as 43% of individuals with late-life depression and mild cognitive deficits at baseline will ultimately be diagnosed with dementia (Alexopoulos et al., 1993). Neurodegeneration and cerebrovascular disease are two plausible mechanisms that may explain the relationship between DS, cognitive decline, and incident cognitive impairment (Alexopoulos, 2005, Steffens et al., 2006).

Cross-sectional and longitudinal studies have shown volumetric declines in the frontal and temporal lobes in individuals with geriatric depression (Sheline et al., 1996, Sheline et al., 1999, Kumar et al., 1998, Steffens et al., 2000, Steffens et al., 2002, Bell-McGinty et al., 2002, Ballmaier et al., 2004, O'Brien et al., 2004, Taylor et al., 2007, Andreescu et al., 2008, Smith et al., 2009, Dotson et al., 2009a). Specifically, volume reductions in the frontal lobe subregions including the orbitofrontal cortex (Ballmaier et al., 2004, Taylor et al., 2007, Andreescu et al., 2008), anterior cingulate cortex (Ballmaier et al., 2004), superior, middle and inferior frontal gyri (Ballmaier et al., 2004, Andreescu et al., 2008, Smith et al., 2009), are reported in late-life subsyndromal and syndromal depression, regardless of the age of onset. In addition, volumetric reductions in the temporal lobe structures such as hippocampus and amygdala (Sheline et al., 1996, Sheline et al., 1999, Steffens et al., 2000, Bell-McGinty et al., 2002, O'Brien et al., 2004, Andreescu et al., 2008) are reported mainly in geriatric major depression and not found in subclinical depressive syndromes. Late-onset depression (mostly defined as the first episode of depression after the age of 60), which may be a marker of incipient dementia, also is associated with smaller volumes in these frontal and temporal lobe subregions (Kumar et al., 1998, Steffens et al., 2000, Andreescu et al., 2008). In addition, the depressed elderly with smaller hippocampal volumes are at increased risk of subsequent cognitive decline and incident dementia (Steffens et al., 2002, O'Brien et al., 2004). In the neuroimaging substudy of the Baltimore Longitudinal Study of Aging (BLSA), subthreshold DS were associated with orbitofrontal cortex and cingulate gyrus volume declines with advancing age, during a 9 year follow-up period (Dotson et al., 2009a). In addition, the presence and the level of severity of white matter hyperintensities and subclinical strokes also have been associated with DS and late-life depression (Krishnan et al., 1997, Alexopoulos et al., 1997, Nebes et al., 2002, O'Brien et al., 2006). Some studies indicate that these white matter abnormalities are also associated with poorer cognitive outcomes and development of dementia (Kramer-Ginsberg et al., 1999, Steffens et al., 2007).

However, observations of reduced regional brain volumes (Pantel et al., 1997, Ashtari et al., 1999) and greater vascular lesion burden (Barnes et al., 2006) among individuals with late-life DS are not universal. Furthermore, there are no studies to our knowledge that have examined how late-life DS are related to future cerebrovascular lesion and regional brain volumes in postmenopausal women.

The Women's Health Initiative Memory Study (WHIMS), an ancillary study to the Women's Health Initiative Hormone Therapy (WHI-HT) trials, provides a unique opportunity to address the temporal relationship between elevated DS and both regional brain volumes and ischemic lesion burden (Resnick et al., 2009, Coker et al., 2009). In WHIMS, the presence of DS at baseline was independently associated with an increased incidence of mild cognitive impairment (MCI) and probable dementia in postmenopausal women 65 years of age and older (Goveas et al., 2011).

The objective of the present study was to examine whether late-life higher DS were associated with increased cerebrovascular disease and smaller regional brain volumes among the WHIMS subjects who also participated in the WHIMS-MRI study. We hypothesized that postmenopausal women with elevated DS at WHIMS baseline will have smaller frontal and temporal lobe regional volumes and larger ischemic lesion volumes on brain MRI an average of eight years later, after controlling for potential confounding variables including sociodemographic characteristics, global cognitive function, cardiovascular disease and hormone therapy.

Section snippets

WHIMS study design and sample

WHIMS, an ancillary study to the WHI randomized clinical trials of hormone therapy, was designed to examine the effect of postmenopausal hormone therapy on risk for dementia and change in global cognitive function in generally healthy women who were 65 to 79 years of age and free of dementia at study baseline. From the thirty-nine of the 40 WHI clinical centers that participated in the WHIMS, 7479 community-dwelling postmenopausal women were enrolled. The study design, eligibility criteria,

Results

Of the total sample of 1403 participants that met study criteria for central MRI reading, the Burnam score could not be calculated for 31 women due to missing data. Therefore, 1372 participants were included in this analysis. At baseline, 18% (N = 253) of women met the Burnam score cut-point of 0.009 for elevated DS. At baseline, depressed compared with non-depressed women had lower global cognitive function and were more likely to have a history of prior hormone therapy (Table 1).

Discussion

This is the first study that has examined the relationship between elevated DS and regional brain volumes and subclinical cerebrovascular disease in a large cohort of postmenopausal women. Elevated DS were associated with lower superior, middle and inferior frontal gyral volumes after adjusting for several potential confounding variables. Highest depressive symptom severity was associated with the smallest volumes in these frontal lobe subregions. However, contrary to our hypotheses, we found

Role of funding source

The Women's Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100–2, 32105–6, 32108–9, 32111–13, 32115, 32118–32119, 32122, 42107–26, 42129–32, and 44221. The active study drug and placebo were supplied by Wyeth-Ayerst Research Laboratories, Philadelphia, Pennsylvania.

The Women's Health Initiative Memory Study was funded in part by Wyeth

Conflict of interest

No conflict declared.

Acknowledgments

We acknowledge the valuable contributions of the WHIMS clinical coordinating center, WHIMS clinical centers, WHIMS external advisory board, WHI program office, WHI clinical coordinating centers, and WHI clinical centers. This manuscript has been reviewed and approved for publication by the WHI publications and presentation committee.

WHIMS-MRI Clinical Centers: Albert Einstein College of Medicine, Bronx, NY: Sylvia Wassertheil-Smoller, Mimi Goodwin, Richard DeNise, Michael Lipton, James

References (62)

  • M.L. Stefanick et al.

    The Women's Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants

    Ann. Epidemiol.

    (2003)
  • D.C. Steffens et al.

    Hippocampal volume in geriatric depression

    Biol. Psychiatry

    (2000)
  • D.C. Steffens et al.

    Hippocampal volume and incident dementia in geriatric depression

    Am. J. Geriatr. Psychiatry

    (2002)
  • D.C. Steffens et al.

    Longitudinal magnetic resonance imaging vascular changes, apolipoprotein E genotype, and development of dementia in the neurocognitive outcomes of depression in the elderly study

    Am. J. Geriatr. Psychiatry

    (2007)
  • V.L. Villemagne et al.

    Abeta deposits in older non-demented individuals with cognitive decline are indicative of preclinical Alzheimer's disease

    Neuropsychologia

    (2008)
  • G.S. Alexopoulos et al.

    The course of geriatric depression with “reversible dementia”: a controlled study

    Am. J. Psychiatry

    (1993)
  • G.S. Alexopoulos et al.

    ‘Vascular depression’ hypothesis

    Arch. Gen. Psychiatry

    (1997)
  • C. Andreescu et al.

    Gray matter changes in late life depression—a structural MRI analysis

    Neuropsychopharmacology

    (2008)
  • M. Ashtari et al.

    Hippocampal/amygdala volumes in geriatric depression

    Psychol. Med.

    (1999)
  • M. Ballmaier et al.

    Anterior cingulate, gyrus rectus, and orbitofrontal abnormalities in elderly depressed patients: an MRI-based parcellation of the prefrontal cortex

    Am. J. Psychiatry

    (2004)
  • D.E. Barnes et al.

    Depressive symptoms, vascular disease, and mild cognitive impairment: findings from the Cardiovascular Health Study

    Arch. Gen. Psychiatry

    (2006)
  • S. Bell-McGinty et al.

    Brain morphometric abnormalities in geriatric depression: long-term neurobiological effects of illness duration

    Am. J. Psychiatry

    (2002)
  • R.N. Bryan et al.

    A method for using MR to evaluate the effects of cardiovascular disease on the brain: the Cardiovascular Health Study

    AJNR Am. J. Neuroradiol.

    (1994)
  • M.A. Burnam et al.

    Development of a brief screening instrument for detecting depressive disorders

    Med. Care

    (1988)
  • M.A. Butters et al.

    Imaging Alzheimer pathology in late-life depression with PET and Pittsburgh Compound-B

    Alzheimer Dis. Assoc. Disord.

    (2008)
  • P. Chen et al.

    The temporal relationship between depressive symptoms and dementia: a community-based prospective study

    Arch. Gen. Psychiatry

    (1999)
  • L.H. Coker et al.

    Postmenopausal hormone therapy and subclinical cerebrovascular disease: the WHIMS-MRI Study

    Neurology

    (2009)
  • D.P. Devanand et al.

    Depressed mood and the incidence of Alzheimer's disease in the elderly living in the community

    Arch. Gen. Psychiatry

    (1996)
  • V.M. Dotson et al.

    Depressive symptoms and brain volumes in older adults: a longitudinal magnetic resonance imaging study

    J. Psychiatry Neurosci.

    (2009)
  • V.M. Dotson et al.

    Longitudinal study of chronic depressive symptoms and regional cerebral blood flow in older men and women

    Int. J. Geriatr. Psychiatry

    (2009)
  • I. Driscoll et al.

    Longitudinal pattern of regional brain volume change differentiates normal aging from MCI

    Neurology

    (2009)
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