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.

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.

Predicting outcome in mild cognitive impairment: 4-year follow-up study.

BACKGROUND: Cognitive impairment precedes the diagnosis of Alzheimer's disease. It is unclear which psychometric measures predict dementia, and what cut-off points should be used. Replicable cognitive measures to provide information about differential diagnosis and prognosis would be clinically useful. AIMS: In a prospective cohort study we investigated which measures distinguish between individuals with amnestic mild cognitive impairment (aMCI) that converts to dementia and those whose impairment does not, and which combination of measures best predicts the fate of people with aMCI. METHOD: Forty-four participants with aMCI underwent extensive neuropsychological assessment at baseline and annually thereafter for an average of 4 years. Differences in baseline cognitive performance of participants who were converters and non-converters to clinically diagnosed dementia were analysed. Classification accuracy was estimated by sensitivity, specificity, positive and negative predictive values and using logistic regression. RESULTS: Forty-one percent of participants had progressed to dementia by the end of study, with a mean annual conversion rate of 11%. Most (63%) showed persisting or progressive cognitive impairment, irrespective of diagnosis. The Addenbrooke's Cognitive Examination together with the discrimination index of the Hopkins Verbal Learning Test - Revised (but none of the demographic indices) differentiated the participants who were converters from the non-converters at baseline with 74% accuracy. CONCLUSIONS: Targeted neuropsychological assessment, beyond simple cognitive screening, could be used in clinical practice to provide individuals with aMCI with prognostic information and aid selective early initiation of monitoring and treatment among those who progress towards a clinically diagnosable dementia.

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.

5-(123)I-A-85380 binding to the α4ß2-nicotinic receptor in mild cognitive impairment.

Treatments currently licensed for Alzheimer's dementia target cholinergic brain systems. In vivo nicotinic receptor binding may provide an early marker of illness and treatment suitability. In this pilot, we examined nine patients with amnestic mild cognitive impairment (MCI) and 10 age and education matched healthy volunteers with high resolution SPECT and the nicotinic receptor ligand 5-(123)I-A-85380. Uptake data were analysed using voxel-based techniques for group comparisons and regression analyses with cognitive impairment as covariates. MCI patients had discrete reductions in uptake in medial temporal cortex. Correlations with cognitive impairment were found in left temporo-parietal areas (Addenbrooke's Cognitive Examination) and bilateral temporo-limbic areas (Rey Auditory Verbal Learning Test), and right parahippocampal gyrus (Rey Complex Figure Test) within the patient group. In vivo nicotinic receptor binding appears to be sensitive to brain changes in MCI. Larger scale explorations of patients undergoing treatment will be necessary to evaluate its use in predicting or monitoring treatment response.

Lexical and semantic fluency discrepancy scores in aMCI and early Alzheimer's disease.

Episodic memory is compromised in amnestic mild cognitive impairment (aMCI), but lesser deficits in other cognitive domains are also commonly observed and may be helpful in identifying this group. The relative difference in performance on lexical and semantic fluency tasks may be a sensitive and specific measure in aMCI and early Alzheimer's disease (AD). We compared four groups of participants, 35 early AD, 47 aMCI, 24 healthy controls, and 18 depressive out-patient controls, on semantic and lexical fluency as well as other neuropsychological tests. Early AD and aMCI patients showed a distinct pattern of semantic impairment in the two fluency measures compared with the healthy and depressive controls. The findings implicate early failure of the semantic memory system in aMCI and AD and suggest that consideration of the discrepancy in performance on semantic and lexical fluency measures may help in the early identification of AD.

Clinical referral patterns and cognitive profile in mild cognitive impairment.

BACKGROUND: There is current interest in exploring the different subtypes of mild cognitive impairment (MCI), in terms of both their epidemiology and their cognitive profile. AIMS: To examine the frequency of MCI subtypes presenting to a memory clinic and to document detailed neuropsychological profiles of patients with the amnestic subtype. METHOD: Consecutive tertiary referrals (n=187) were psychiatrically evaluated; 45 patients met criteria for amnestic mild cognitive impairment (aMCI). A subgroup of 33 patients with aMCI as well as 21 healthy controls took part in a thorough neuropsychological examination. RESULTS: Of the patients who were examined in greater neuropsychological detail, ten had pure aMCI (none with visual memory impairment only). Fifteen met criteria for non-amnestic MCI. Fifteen had normal neuropsychological profiles. Using more than one test increased sensitivity to detect episodic memory impairment. CONCLUSIONS: Amnestic MCI is an important diagnosis in secondary and tertiary memory clinics. There is scope to improve the efficacy and sensitivity of the clinical assessment of this impairment.

The cognitive neuropsychology of depression in the elderly.

BACKGROUND: The cognitive impairment of older depressed patients with late- as opposed to early-onset illness may show important differences, in that patients with early onset may suffer predominantly from impaired episodic memory, and those with late onset mainly from reductions of executive function and processing speed. METHOD: We searched Medline and EMBASE as well as individual papers' reference lists for relevant publications, recording comparisons in neuropsychological test results between early-onset depression (EOD), late-onset depression (LOD) and healthy volunteers. Effect sizes are presented for cognitive domains, such as executive function, processing speed, episodic memory, semantic memory and mental state examination. RESULTS: Patients with LOD showed greater reductions in processing speed and executive function than patients with EOD and controls. Both patient groups showed reduced function in all domains, except mental state, compared with controls. CONCLUSION: Pronounced executive deficits are typical of the late-onset patients described in published studies, while episodic memory impairment is not specific to early-onset illness. Possible reasons and confounders are discussed.

Factors modifying the efficacy of transcranial magnetic stimulation in the treatment of depression: a review.

OBJECTIVE: So far no convincing answer has emerged to the question of whether transcranial magnetic stimulation (TMS) can make a clinically useful contribution to the treatment of depression. Here we examine whether multiple sensitivity analyses can highlight parameters that predict a favorable treatment response. DATA SOURCES: Medline, Embase, and the Cochrane database for controlled trials were searched for relevant randomized controlled trials using the expression (transcranial magnetic stimulation or TMS) and depression. STUDY SELECTION: Thirty-three studies were identified and included in the random-effects meta-analysis, and between 17 and 31 studies were included in the secondary analyses comparing outcome of studies with different parameters. DATA EXTRACTION: Study data were extracted with a standardized data sheet. A meta-analysis based on Cohen d effect size measure was done for all studies and various subsets. Regression analysis of effect sizes with study parameters was done in 24 studies. DATA SYNTHESIS: Active TMS treatment was more effective than sham, but variability was too great to take any single study design as paradigmatic. No significant predictors of study effect size were found. Mean effect sizes were reduced, although still significant, in studies with stimulation intensity below 90% of motor threshold and new medication starting within 7 days before to 7 days after start of TMS. CONCLUSIONS: The absence of significant outcome predictors in the presence of significant variability of outcome measures can be interpreted in 2 ways: either study sizes and numbers and designs are insufficient to afford the power necessary to detect such predictors or TMS has a nonspecific effect on depression that is not influenced by study parameters. Large-scale comparative trials are necessary to decide between these interpretations.