Psychological Medicine (2015), 45, 1931–1944. © Cambridge University Press 2015 doi:10.1017/S0033291714003055

OR I G I N A L A R T I C L E

Depression, depressive symptoms, and rate of hippocampal atrophy in a longitudinal cohort of older men and women M. Elbejjani1, R. Fuhrer1*, M. Abrahamowicz1, B. Mazoyer2,3,4, F. Crivello2,3,4, C. Tzourio4,5 and C. Dufouil4,5 1

Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, 1020 Pine Avenue West, Montreal, Quebec, Canada CNRS, GIN UMR5296, Bordeaux, France 3 CEA, GIN UMR5296, Bordeaux, France 4 University of Bordeaux, Bordeaux, France 5 INSERM, Centre INSERM U897 and CIC-1401, Bordeaux School of Public Health, Bordeaux, France 2

Background. Several studies have reported smaller hippocampal volume (HcV) in depression patients; however, the temporality of the association remains unknown. One proposed hypothesis is that depression may cause HcV loss. This study evaluates whether previous depression and recent depressive symptoms are associated with HcV and HcV loss. Method. We used a prospective cohort of older adults (n = 1328; age = 65–80 years) with two cerebral magnetic resonance imaging examinations at baseline and 4-year follow-up. Using multivariable linear regression models, we estimated, in stratified analyses by gender, the association between indicators of history of depression and its severity (age at onset, recurrence, hospitalization for depression), proximal depressive symptoms [Center for Epidemiologic Studies-Depression (CES-D) scale], baseline antidepressant use, and the outcomes: baseline HcV and annual percentage change in HcV. Results. At baseline, women with more depressive symptoms had smaller HcV [−0.05 cm3, 95% confidence interval (CI) −0.1 to −0.01 cm3 per 10-unit increase in CES-D scores]. History of depression was associated with a 0.2% faster annual HcV loss in women (95% CI 0.01–0.36%). More baseline depressive symptoms and worsening of these symptoms were also associated with accelerated HcV loss in women. No associations were observed in men. Treatment for depression was associated with slower HcV loss in women and men. Conclusions. While only concomitant depressive symptoms were associated with HcV, both previous depression and more proximal depressive symptoms were associated with faster HcV loss in women. Received 4 November 2013; Revised 23 November 2014; Accepted 26 November 2014 Key words: Aging, atrophy, cohort studies, depression, hippocampus, imaging.

Introduction Magnetic resonance imaging (MRI) studies have identified structural brain alterations associated with depression. Several reviews and meta-analyses summarizing these studies have reported a reduced hippocampal volume (HcV) in depressed patients (Campbell et al. 2004; Videbech & Ravnkilde, 2004; Koolschijn et al. 2009; Lorenzetti et al. 2009; Kempton et al. 2011). However, the direction of this association remains unresolved. Some studies have found that HcV is smaller in first-episode depression patients, suggesting that a reduced HcV is already present at the first manifestation

* Address for correspondence: R. Fuhrer, Ph.D., Department of Epidemiology, Biostatistics, and Occupational Health, McGill University Faculty of Medicine, 1020 Pine Avenue West, Montreal, Quebec H3A 1A2, Canada. (Email: [email protected])

of the illness and could therefore be a susceptibility factor for depression (Frodl et al. 2002; Kronmüller et al. 2009; Dedovic et al. 2010). Other studies in clinical settings favor the converse, i.e. that smaller HcV can be the consequence of depression as they have found links between recurrence and duration of depression and HcV reductions (Bell-McGinty et al. 2002; MacQueen et al. 2003; Sheline et al. 2003). One proposed explanation for the relationship between depression and smaller HcV is the neurotoxicity hypothesis, which implies that biological alterations that accompany depression tax the hippocampus, its morphology, and its functionality (Sapolsky et al. 1986; McEwen & Gianaros, 2010). It is derived from observations that depression is accompanied by deregulations of key neural pathways such as the glucocorticoids and glutamate networks, which eventually cause neuronal damages and losses (Sapolsky et al. 1986; Bremner, 1999; Sapolsky, 2000; McEwen & Gianaros, 2010).

1932 M. Elbejjani et al. The association between HcV and depression is of particular interest in older populations given the extensive literature linking depression to cognitive functioning and dementia (Chen et al. 1999; Schweitzer et al. 2002; Fuhrer et al. 2003; Thomas et al. 2009) and implicating hippocampal atrophy in cognitive impairment and dementia (Jack et al. 2000; Lister & Barnes, 2009; Kaup et al. 2011). In order to explore the directionality of the depression–HcV relationship and to assess the neurotoxicity hypothesis, longitudinal studies are needed and few have been undertaken so far. Moreover, among the published studies in older adults, there is a lack of standardization in the definition of depression [ranging from life-time depression diagnosis (Geerlings et al. 2013), to recent depressive symptoms (Dotson et al. 2009), to categorizing depression based on depressive symptoms (Geerlings et al. 2008; den Heijer et al. 2011; Goveas et al. 2011)]. Furthermore, only two studies used longitudinal measures of HcV (Dotson et al. 2009; den Heijer et al. 2011) and both focused on depressive symptoms concurrent to the HcV changes. In this study, we investigate further the relationship between depression and HcV in older populations, by studying within a population-based cohort of older adults the association of history of depression and more proximal depressive symptoms with both HcV and change in HcV over 4 years. We assessed the association between history of depression and both baseline HcV and change in HcV, with the objective of evaluating whether distal depressive episodes are linked to HcV and/or HcV loss at older age. We also examined the relationship between HcV and concurrent depressive symptoms in an attempt to replicate the correlation between smaller HcV and depression found in clinical samples. Finally, we looked at more proximal measurements of depressive symptoms and their association with changes in HcV. Given the well-documented higher prevalence of depressive symptoms and depression in women (Holden, 2005; Marcus et al. 2005) and reports suggesting that age-related hippocampal atrophy (Zhang et al. 2010; Holland et al. 2013) is faster in women compared with men, we assessed gender differences in the relationship between depression-related measures and HcV outcomes.

Method Study population and data The Three City (3C) Study is a population-based prospective study of older adults. Between 1999 and 2001, individuals selected from the electoral rolls of three French cities (Bordeaux, Dijon and Montpellier) were invited to participate if they were non-institutionalized

and aged 565 years. In total, 9294 subjects agreed to participate (2104 in Bordeaux, 4931 in Dijon, and 2259 in Montpellier) and have been followed every 2 years since inception. The study protocol has been described previously (3C Study Group, 2003) and was approved by the Ethics Committee of the University Hospital of Kremlin-Bicêtre. Each participant signed an informed consent. We report results from the Dijon cohort, where brain MRI examinations were performed. At baseline, an MRI was proposed to all subjects aged 65–80 years and enrolled between 1999 and 2000 (n = 2763); 2285 subjects agreed to participate (83%). Due to financial restrictions, 1924 MRIs were performed. Of those, 1806 had valid HcV measurements. We further excluded eight subjects with prevalent dementia and 23 participants who were >80 years at baseline, resulting in a sample of 1775 subjects with one valid HcV measurement. At the 4-year follow-up, 1328 subjects had a second valid MRI scan and follow-up HcV measurements; these subjects with two MRIs constitute our final sample. Of the 447 subjects without a second MRI, 49 were deceased before the second MRI, 111 had poor-quality scans, and 287 refused or were not offered a second MRI. These 447 subjects were older and had smaller HcV, higher depressive symptoms, poorer cognitive functioning and a higher percentage of antidepressant use at baseline. Measures Depression-related measures At baseline, subjects reported whether they had a history of treated depression, age at onset of first treated depression and age at last episode, and whether they had been hospitalized at least once for depression. We considered that subjects had recurrent depression when ages at first and last episodes were different. A severity index of depression history was created by combining the indicators for previous treated depression and hospitalization for depression, generating a three-level index: no previous depression; previous depression without hospitalization; and previous depression with hospitalization. At baseline and each biennial study wave, depressive symptoms were measured using the Center for Epidemiologic Studies-Depression (CES-D) scale (Radloff, 1977). The CES-D includes 20 self-report items about feelings and symptoms experienced during the preceding week; its suitability for measuring depressive symptoms in older adults has been established, including in the French population (Fuhrer & Rouillon, 1989). Of interest to this analysis are CES-D scores collected throughout the 4 years over which

Depression, depressive symptoms, and rate of hippocampal atrophy 1933 hippocampal changes were measured (baseline, first, and second follow-up visits). Information on antidepressant use at baseline was collected as part of the questionnaire on all medications (prescribed and over-the-counter) used regularly in the previous month. To reduce under-reporting and recall bias, participants showed medical prescriptions and drug packages whenever possible. Information on depression-related measures was collected through standardized face-to-face interviews administered by trained psychologists at each subject’s home. Hippocampal outcomes Baseline and follow-up MRIs were performed using the same scanner (1.5 Tesla Magnetom; Siemens, USA) and analysed using identical procedures, as described previously (Maillard et al. 2008; Crivello et al. 2010). Tissue segmentation and brain tissue probability maps were obtained using Statistical Probability Mapping software (http://www.fil.ion.ucl.ac.uk/spm/) and a voxel-based morphometry protocol that was modified to account for characteristics of aged brains (Good et al. 2001; Lemaitre et al. 2005) (for details, see online Supplementary Appendix). Gray matter (GM), white matter (WM), and cerebrospinal fluid volumes were computed as the integral of the voxel intensities of the modulated tissue partition images; total intracranial volume (TIV) was generated as their sum. Volumes of GM in specific regions of interest were automatically computed by integrating within these regions the voxel intensities of the modulated GM partition images (Tzourio-Mazoyer et al. 2002; Crivello et al. 2010). In this project, we investigated HcV (total = sum of left and right hemispheres). We explored baseline HcV and change in HcV, which was expressed as the annualized percentage change and computed as the change between HcV at baseline scan (T0) and follow-up scan (T2), relative to baseline HcV, divided by the individual delay in years between scans:   HcVT0 − HcVT2 × 100 HcVT0 (T2 − T0) Positive values indicate HcV loss (henceforth referred to as atrophy); higher (positive) values correspond to faster atrophy. Covariates Several covariates were taken into account because of their potential associations with HcV or their possible role as confounders in the depression–HcV relationship.

Based on prior research and bivariate relationships (described below) between each of the covariates and CES-D scores and/or hippocampal outcomes in our sample, we identified a primary set of covariates that was adjusted for in all analyses: age; gender; education (4primary school, intermediate/technical school, 5secondary school); baseline: hypertension (systolic blood pressure 5140 mmHg or diastolic blood pressure 590 mmHg or use of antihypertensive medication); smoking status (former, current, never-smoker); TIV; apolipoprotein E (APOE) genotype (Crivello et al. 2010); and WM lesion (WML) volumes (by adjusting for, respectively, baseline WML volume and annualized change in WML volume in analyses of baseline HcV and change in HcV). In sensitivity analyses, we additionally adjusted for baseline history of vascular events (at least one of: myocardial infarction, stroke, coronary surgery, angioplasty, and peripheral vascular diseases), body mass index (BMI), alcohol consumption (g/day), and cognitive functioning (Mini-Mental State Examination; MMSE; Folstein et al. 1975). Statistical analyses In preliminary analyses, we investigated the bivariate relationships between each of the covariates and baseline HcV, annualized percentage change in HcV, and baseline CES-D scores, using separate linear regression models adjusted for age and gender. These analyses helped identify the primary covariates (described above) that were included in all final multivariable models. The main analyses of associations between depressionrelated measures and hippocampal outcomes were divided into three parts that differed with respect to timing of the depression measurements and/or the HcV outcome and were based on multivariable linear regression models adjusted for primary covariates. We estimated separate models for each depression variable to avoid multi-collinearity between different measures of similar constructs. The first part of the analyses focused on HcV and investigated: (i) relationships between each indicator of previous depression (history of depression, age at first depression, recurrence of depression, previous hospitalization for depression, and the severity index) and baseline HcV; and (ii) cross-sectional associations between baseline HcV and concurrent CES-D scores and antidepressant use. The second part of the analyses assessed the association between indicators of previous depression and the annualized percentage change in HcV. The third part focused on the relationships between recent depressive symptoms and change in HcV. We

1934 M. Elbejjani et al. first estimated the associations between baseline CES-D scores, as well as baseline antidepressant use, and HcV changes over the following 4 years. Then, we estimated two models that focused on the associations of post-baseline changes in CES-D scores with change in HcV, while adjusting for baseline CES-D. The first model assessed the relationship between changes in depressive symptoms observed early during follow-up, between baseline (T0) and 2 years later (T1), and changes in HcV measured 2 years after T1 (i.e. HcV change measured over 4 years, from T0 to T2). The second model included, in addition to the early change (T0 to T1), the later change in CES-D score (T1 to T2) and aimed to assess the roles of shorter-term changes in CES-D, observed over different time intervals, and compare their relative importance in explaining the longer-term (T0 to T2) changes in HcV. Since cognitive functioning has been frequently associated with both HcV (Jack et al. 2000; Tisserand et al. 2004; Kaup et al. 2011) and depressive symptoms (Chen et al. 1999; Schweitzer et al. 2002), we assessed whether the relationships between changes in depressive symptoms and changes in HcV were independent of concurrent changes in cognitive functioning, by adjusting for changes in MMSE scores. In all analyses involving CES-D scores, we tested for potential non-linearity of the association between CES-D scores or their changes and HcV or change in HcV, using flexible fractional polynomial analyses, which permit identifying different patterns of nonlinear associations. Because we a priori expected these relationships to be monotonic, we restricted these analyses to first-order fractional polynomials (FP1) (Royston & Altman, 1994). In all analyses, we tested if the association between depression-related variables and hippocampal outcomes varied by gender, by including two-way interaction terms between the corresponding depression measure and gender. In most of the analyses of HcV atrophy, the interactions were statistically significant (p < 0.05 for the model-based F test) or close to statistical significance; therefore, we performed separate analyses for women and men. In sensitivity analyses, we repeated the analyses of change in HcV, described in parts two and three (see above), while redefining the outcome as the annualized absolute change in HcV (not dividing the change by baseline HcV). We restricted our analyses to complete observations for each model (missing data < 4%). Two-tailed p value

Depression, depressive symptoms, and rate of hippocampal atrophy in a longitudinal cohort of older men and women.

Several studies have reported smaller hippocampal volume (HcV) in depression patients; however, the temporality of the association remains unknown. On...
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