Charlotte L. Allan

Magnetic Resonance Imaging in Late-Life Depression Multimodal Examination of Network Disruption

CONTEXT Disruption of frontal-subcortical and limbic networks is hypothesized to have a key role in late-life depression (LLD) and can be examined using magnetic resonance imaging (MRI) techniques. Gray matter can be examined using T1-weighted MRI, white matter using T2-weighted MRI and diffusion tensor imaging, and functional connectivity in resting-state networks using functional MRI. Although independent MRI studies have supported gray and white matter abnormalities in frontosubcortical and limbic networks and increased functional connectivity in the default-mode network in depression, no study has concurrently examined gray matter, white matter, and functional connectivity. OBJECTIVE To examine whether results of different MRI techniques are complementary, multimodal MRI was used to compare gray matter, white matter, and resting-state networks between LLD and control groups. DESIGN Cross-sectional, case-control, multimodal MRI analysis. SETTING University research department. PARTICIPANTS Thirty-six recovered participants with LLD (mean age, 71.8 years) and 25 control participants (mean age, 71.8 years). MAIN OUTCOME MEASURES Gray matter was examined across the whole brain using voxel-based morphometry. Subcortical gray matter structures were also automatically segmented, and volumetric and shape analyses were performed. For white matter analysis, fractional anisotropy, axial diffusivity, and radial diffusivity values were examined using tract-based spatial statistics. For resting-state network analysis, correlation coefficients were compared using independent components analysis followed by dual regression. RESULTS White matter integrity was widely reduced in LLD, without significant group differences in gray matter volumes or functional connectivity. CONCLUSIONS The present work strongly supports the hypothesis that white matter abnormalities in frontal-subcortical and limbic networks play a key role in LLD even in the absence of changes in resting functional connectivity and gray matter. Factors that could contribute to the lack of significant differences in gray matter and functional connectivity measures, including current symptom severity, medication status, and age of participants with LLD, are discussed.

Exploring the pattern and neural correlates of neuropsychological impairment in late-life depression

BACKGROUND Neuropsychological impairment is a key feature of late-life depression, with deficits observed across multiple domains. However, it is unclear whether deficits in multiple domains represent relatively independent processes with specific neural correlates or whether they can be explained by cognitive deficits in executive function or processing speed. METHOD We examined group differences across five domains (episodic memory; executive function; language skills; processing speed; visuospatial skills) in a sample of 36 depressed participants and 25 control participants, all aged ≥ 60 years. The influence of executive function and processing speed deficits on other neuropsychological domains was also investigated. Magnetic resonance imaging correlates of executive function, processing speed and episodic memory were explored in the late-life depression group. RESULTS Relative to controls, the late-life depression group performed significantly worse in the domains of executive function, processing speed, episodic memory and language skills. Impairments in executive function or processing speed were sufficient to explain differences in episodic memory and language skills. Executive function was correlated with anisotropy of the anterior thalamic radiation and uncinate fasciculus; processing speed was correlated with anisotropy of genu of the corpus callosum. Episodic memory was correlated with anisotropy of the anterior thalamic radiation, the genu and body of the corpus callosum and the fornix. CONCLUSIONS Executive function and processing speed appear to represent important cognitive deficits in late-life depression, which contribute to deficits in other domains, and are related to reductions in anisotropy in frontal tracts.

Transcranial magnetic stimulation in the management of mood disorders.

Background: Many trials of transcranial magnetic stimulation (TMS) have used small samples and, therefore, lack power. Here we present an up-to-date meta-analysis of TMS in the treatment of depression. Methods: We searched Medline and Embase from 1996 until 2008 for randomized sham-controlled trials, with patients and investigators blinded to treatment, and outcome measured using a version of the Hamilton Depression Rating Scale (or similar). We identified 1,789 studies. Thirty-one were suitable for inclusion, with a cumulative sample of 815 active and 716 sham TMS courses. Results: We found a moderately sized effect in favour of TMS [Random Effects Model Hedges’ g = 0.64, 95% confidence interval (95% CI) = 0.50–0.79]. The corresponding Pooled Peto Odds Ratio for treatment response (≤50% reduction in depression scores) was 4.1 (95% CI = 2.9–5.9). There was significant variability between study effect sizes. Meta-regressions with relevant study variables did not reveal any predictors of treatment efficacy. Nine studies included follow-up data with an average follow-up time of 4.3 weeks; there was no mean change in depression severity between the end of treatment and follow-up (Hedges’ g = –0.02, 95% CI = –0.22 to +0.18) and no heterogeneity in outcome. Discussion: TMS appears to be an effective treatment; however, at 4 weeks’ follow-up after TMS, there had been no further change in depression severity. Problems with finding a suitably blind and ineffective placebo condition may have confounded the published effect sizes. If the TMS effect is specific, only further large double-blind randomized controlled designs with systematic exploration of treatment and patient parameters will help to define optimum treatment indications and regimen.

Moderate alcohol consumption as risk factor for adverse brain outcomes and cognitive decline: longitudinal cohort study

Objectives To investigate whether moderate alcohol consumption has a favourable or adverse association or no association with brain structure and function. Design Observational cohort study with weekly alcohol intake and cognitive performance measured repeatedly over 30 years (1985-2015). Multimodal magnetic resonance imaging (MRI) was performed at study endpoint (2012-15). Setting Community dwelling adults enrolled in the Whitehall II cohort based in the UK (the Whitehall II imaging substudy). Participants 550 men and women with mean age 43.0 (SD 5.4) at study baseline, none were “alcohol dependent” according to the CAGE screening questionnaire, and all safe to undergo MRI of the brain at follow-up. Twenty three were excluded because of incomplete or poor quality imaging data or gross structural abnormality (such as a brain cyst) or incomplete alcohol use, sociodemographic, health, or cognitive data. Main outcome measures Structural brain measures included hippocampal atrophy, grey matter density, and white matter microstructure. Functional measures included cognitive decline over the study and cross sectional cognitive performance at the time of scanning. Results Higher alcohol consumption over the 30 year follow-up was associated with increased odds of hippocampal atrophy in a dose dependent fashion. While those consuming over 30 units a week were at the highest risk compared with abstainers (odds ratio 5.8, 95% confidence interval 1.8 to 18.6; P≤0.001), even those drinking moderately (14-21 units/week) had three times the odds of right sided hippocampal atrophy (3.4, 1.4 to 8.1; P=0.007). There was no protective effect of light drinking (1-<7 units/week) over abstinence. Higher alcohol use was also associated with differences in corpus callosum microstructure and faster decline in lexical fluency. No association was found with cross sectional cognitive performance or longitudinal changes in semantic fluency or word recall. Conclusions Alcohol consumption, even at moderate levels, is associated with adverse brain outcomes including hippocampal atrophy. These results support the recent reduction in alcohol guidance in the UK and question the current limits recommended in the US.

Use of self-administered instruments to assess psychiatric disorders in older people: Validity of the General Health Questionnaire, the Center for Epidemiologic Studies Depression Scale and the self-completion version of the revised Clinical Interview Schedule

Background Diagnosis of depressive disorder using interviewer-administered instruments is expensive and frequently impractical in large epidemiological surveys. The aim of this study was to assess the validity of three self-completion measures of depressive disorder and other psychiatric disorders in older people against an interviewer-administered instrument. Method A random sample stratified by sex, age and social position was selected from the Whitehall II study participants. This sample was supplemented by inclusion of depressed Whitehall II participants. Depressive disorder and other mental disorders were assessed by the interviewer-administered structured revised Clinical Interview Schedule (CIS-R) in 277 participants aged 58–80 years. Participants also completed a computerized self-completion version of the CIS-R in addition to the General Health Questionnaire (GHQ) and the Center for Epidemiologic Studies Depression Scale (CES-D). Results The mean total score was similar for the interviewer-administered (4.43) and self-completion (4.35) versions of the CIS-R [95% confidence interval (CI) for difference −0.31 to 0.16]. Differences were not related to sex, age, social position or presence of chronic physical illness. Sensitivity/specificity of self-completion CIS-R was 74%/98% for any mental disorder and 75%/98% for depressive episode. The corresponding figures were 86%/87% and 78%/83% for GHQ and 77%/89% and 89%/86% for CES-D. Conclusions The self-completion computerized version of the CIS-R is feasible and has good validity as a measure of any mental disorder and depression in people aged ⩾ 60 years. GHQ and CES-D also have good criterion validity as measures of any mental disorder and depressive disorder respectively.

Magnetic resonance imaging in late-life depression: vascular and glucocorticoid cascade hypotheses.

BACKGROUND Late-life depression is a common and heterogeneous illness, associated with structural abnormalities in both grey and white matter. AIMS To examine the relationship between age at onset and magnetic resonance imaging (MRI) measures of grey and white matter to establish whether they support particular hypotheses regarding the anatomy and aetiology of network disruption in late-life depression. METHOD We studied 36 participants with late-life depression. Grey matter was examined using T(1)-weighted MRI and analysed using voxel-based morphometry. The hippocampus was automatically segmented and volume and shape analysis performed. White matter was examined using diffusion tensor imaging and analysed using tract-based spatial statistics. RESULTS Later age at onset was significantly associated with reduced fractional anisotropy of widespread tracts, in particular the anterior thalamic radiation and superior longitudinal fasciculus. Earlier age at onset was associated with reduced hippocampal volume normalised to whole brain size bilaterally. However, no significant correlations were detected using hippocampal shape analysis or voxel-based morphometry. CONCLUSIONS Overall, the results were compatible with the vascular hypothesis, and provided some support for the glucocorticoid cascade hypothesis.

Vascular Risk Status as a Predictor of Later-Life Depressive Symptoms: A Cohort Study

Background Common etiology of vascular diseases and later-life depression may provide important synergies for prevention. We examined whether standard clinical risk profiles developed for vascular diseases also predict depressive symptoms in older adults. Methods Data were drawn from the Whitehall II study with baseline examination in 1991; follow-up screenings in 1997, 2003, and 2008; and additional disease ascertainment from hospital data and registry linkage on 5318 participants (mean age 54.8 years, 31% women) without depressive symptoms at baseline. Vascular risk was assessed with the Framingham Cardiovascular, Coronary Heart Disease, and Stroke Risk Scores. New depressive symptoms at each follow-up screening were identified by General Health Questionnaire caseness, a Center for Epidemiologic Studies Depression Scale score ≥16, and use of antidepressant medication. Results Diagnosed vascular disease (that is, coronary heart disease or stroke) was associated with an increased risk for depressive symptoms, age- and sex-adjusted odds ratios from 1.5 (95% confidence interval 1.0–2.2) to 2.0 (1.4–3.0), depending on the indicator of depressive symptoms. Among participants without manifest vascular disease, the Stroke Risk Score was associated with Center for Epidemiologic Studies Depression Scale depressive symptoms before age 65 (age- and sex-adjusted odds ratio per 10% absolute change in the score = 3.1 [1.5–6.5]), but none of the risk scores predicted new-onset depressive symptoms in those aged ≥65 (odds ratios from .8 to 1.2). Conclusions These data suggest that public health measures to improve vascular risk status will influence the incidence of later-life depressive symptoms via reduced rates of manifest vascular disease.

Lifetime hypertension as a predictor of brain structure in older adults: cohort study with a 28-year follow-up.

BACKGROUND Hypertension is associated with an increased risk of dementia and depression with uncertain longitudinal associations with brain structure. AIMS To examine lifetime blood pressure as a predictor of brain structure in old age. METHOD A total of 190 participants (mean age 69.3 years) from the Whitehall II study were screened for hypertension six times (1985-2013). In 2012-2013, participants had a 3T-magnetic resonance imaging (MRI) brain scan. Data from the MRI were analysed using automated and visual measures of global atrophy, hippocampal atrophy and white matter hyperintensities. RESULTS Longitudinally, higher mean arterial pressure predicted increased automated white matter hyperintensities (P<0.002). Cross-sectionally, hypertensive participants had increased automated white matter hyperintensities and visually rated deep white matter hyperintensities. There was no significant association with global or hippocampal atrophy. CONCLUSIONS Long-term exposure to high blood pressure predicts hyperintensities, particularly in deep white matter. The greatest changes are seen in those with severe forms of hypertension, suggesting a dose-response pattern.

The influence of ApoE4 on clinical progression of dementia: a meta-analysis

ApoE4 is a risk factor for the development of Alzheimers disease, and has a functional role suggesting its importance in the neuropathology of dementia. We present a meta‐analysis to investigate whether ApoE4 also affects the clinical progression of dementia in terms of cognitive decline or mortality.

Does the Framingham Stroke Risk Profile predict white-matter changes in late-life depression?

BACKGROUND Cardiovascular risk factors and diseases are important etiological factors in depression, particularly late-life depression. Brain changes associated with vascular disease and depression can be detected using magnetic resonance imaging. Using diffusion tensor imaging (DTI), we investigated whether the Framingham Stroke Risk Profile (FSRP), a well-validated risk prediction algorithm, is associated with changes in white-matter connectivity. We hypothesized that depressed participants would show reduced white-matter integrity with higher FSRP, and non-depressed controls (matched for mean vascular risk) would show minimal co-variance with white-matter changes. METHODS Thirty-six participants with major depression (age 71.8 ± 7.7 years, mean FSRP 10.3 ± 7.6) and 25 controls (age 71.8 ± 7.3 years, mean FSRP 10.1 ± 7.7) were clinically interviewed and examined, followed by 60-direction DTI on a 3.0 Tesla scanner. Image analysis was performed using FSL tools (www.fmrib.ox.ac.uk/fsl) to assess the correlation between FSRP and fractional anisotropy (FA). Voxelwise statistical analysis of the FA data was carried out using Tract Based Spatial Statistics. The significance threshold for correlations was set at p < 0.05 using threshold-free cluster-enhancement. Partial correlation analysis investigated significant correlations in each group. RESULTS Participants in the depressed group showed highly significant correlations between FSRP and FA within the body of corpus callosum (r = -0.520, p = 0.002), genu of corpus callosum (r = -0.468, p = 0.005), splenium of corpus callosum (r = -0.536, p = 0.001), and cortico-spinal tract (r = -0.473, p = 0.005). In controls, there was only one significant correlation in the body of corpus callosum (r = -0.473, p = 0.023). CONCLUSIONS FSRP is associated with impairment in white-matter integrity in participants with depression; these results suggest support for the vascular depression hypothesis.