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Self-reported sleep relates to hippocampal atrophy across the adult lifespan: results from the Lifebrain consortium.
OBJECTIVES: Poor sleep is associated with multiple age-related neurodegenerative and neuropsychiatric conditions. The hippocampus plays a special role in sleep and sleep-dependent cognition, and accelerated hippocampal atrophy is typically seen with higher age. Hence, it is critical to establish how the relationship between sleep and hippocampal volume loss unfolds across the adult lifespan. METHODS: Self-reported sleep measures and MRI-derived hippocampal volumes were obtained from 3105 cognitively normal participants (18-90 years) from major European brain studies in the Lifebrain consortium. Hippocampal volume change was estimated from 5116 MRIs from 1299 participants for whom longitudinal MRIs were available, followed up to 11 years with a mean interval of 3.3 years. Cross-sectional analyses were repeated in a sample of 21,390 participants from the UK Biobank. RESULTS: No cross-sectional sleep-hippocampal volume relationships were found. However, worse sleep quality, efficiency, problems, and daytime tiredness were related to greater hippocampal volume loss over time, with high scorers showing 0.22% greater annual loss than low scorers. The relationship between sleep and hippocampal atrophy did not vary across age. Simulations showed that the observed longitudinal effects were too small to be detected as age-interactions in the cross-sectional analyses. CONCLUSIONS: Worse self-reported sleep is associated with higher rates of hippocampal volume decline across the adult lifespan. This suggests that sleep is relevant to understand individual differences in hippocampal atrophy, but limited effect sizes call for cautious interpretation.
Leisure Activities and Their Relationship With MRI Measures of Brain Structure, Functional Connectivity, and Cognition in the UK Biobank Cohort.
Introduction: This study aimed to evaluate whether engagement in leisure activities is linked to measures of brain structure, functional connectivity, and cognition in early old age. Methods: We examined data collected from 7,152 participants of the United Kingdom Biobank (UK Biobank) study. Weekly participation in six leisure activities was assessed twice and a cognitive battery and 3T MRI brain scan were administered at the second visit. Based on responses collected at two time points, individuals were split into one of four trajectory groups: (1) stable low engagement, (2) stable weekly engagement, (3) low to weekly engagement, and (4) weekly to low engagement. Results: Consistent weekly attendance at a sports club or gym was associated with connectivity of the sensorimotor functional network with the lateral visual (β = 0.12, 95%CI = [0.07, 0.18], FDR q = 2.48 × 10-3) and cerebellar (β = 0.12, 95%CI = [0.07, 0.18], FDR q = 1.23 × 10-4) networks. Visiting friends and family across the two timepoints was also associated with larger volumes of the occipital lobe (β = 0.15, 95%CI = [0.08, 0.21], FDR q = 0.03). Additionally, stable and weekly computer use was associated with global cognition (β = 0.62, 95%CI = [0.35, 0.89], FDR q = 1.16 × 10-4). No other associations were significant (FDR q > 0.05). Discussion: This study demonstrates that not all leisure activities contribute to cognitive health equally, nor is there one unifying neural signature across diverse leisure activities.
Development and validation of a dementia risk score in the UK Biobank and Whitehall II cohorts.
BACKGROUND: Current dementia risk scores have had limited success in consistently identifying at-risk individuals across different ages and geographical locations. OBJECTIVE: We aimed to develop and validate a novel dementia risk score for a midlife UK population, using two cohorts: the UK Biobank, and UK Whitehall II study. METHODS: We divided the UK Biobank cohort into a training (n=176 611, 80%) and test sample (n=44 151, 20%) and used the Whitehall II cohort (n=2934) for external validation. We used the Cox LASSO regression to select the strongest predictors of incident dementia from 28 candidate predictors and then developed the risk score using competing risk regression. FINDINGS: Our risk score, termed the UK Biobank Dementia Risk Score (UKBDRS), consisted of age, education, parental history of dementia, material deprivation, a history of diabetes, stroke, depression, hypertension, high cholesterol, household occupancy, and sex. The score had a strong discrimination accuracy in the UK Biobank test sample (area under the curve (AUC) 0.8, 95% CI 0.78 to 0.82) and in the Whitehall cohort (AUC 0.77, 95% CI 0.72 to 0.81). The UKBDRS also significantly outperformed three other widely used dementia risk scores originally developed in cohorts in Australia (the Australian National University Alzheimer's Disease Risk Index), Finland (the Cardiovascular Risk Factors, Ageing, and Dementia score), and the UK (Dementia Risk Score). CLINICAL IMPLICATIONS: Our risk score represents an easy-to-use tool to identify individuals at risk for dementia in the UK. Further research is required to determine the validity of this score in other populations.
Association of cerebral small vessel disease burden with brain structure and cognitive and vascular risk trajectories in mid-to-late life.
We characterize the associations of total cerebral small vessel disease (SVD) burden with brain structure, trajectories of vascular risk factors, and cognitive functions in mid-to-late life. Participants were 623 community-dwelling adults from the Whitehall II Imaging Sub-study with multi-modal MRI (mean age 69.96, SD = 5.18, 79% men). We used linear mixed-effects models to investigate associations of SVD burden with up to 25-year retrospective trajectories of vascular risk and cognitive performance. General linear modelling was used to investigate concurrent associations with grey matter (GM) density and white matter (WM) microstructure, and whether these associations were modified by cognitive status (Montreal Cognitive Asessment [MoCA] scores of < 26 vs. ≥ 26). Severe SVD burden in older age was associated with higher mean arterial pressure throughout midlife (β = 3.36, 95% CI [0.42-6.30]), and faster cognitive decline in letter fluency (β = -0.07, 95% CI [-0.13--0.01]), and verbal reasoning (β = -0.05, 95% CI [-0.11--0.001]). Moreover, SVD burden was related to lower GM volumes in 9.7% of total GM, and widespread WM microstructural decline (FWE-corrected p
Multi-centre diagnostic classification of individual structural neuroimaging scans from patients with major depressive disorder.
Quantitative abnormalities of brain structure in patients with major depressive disorder have been reported at a group level for decades. However, these structural differences appear subtle in comparison with conventional radiologically defined abnormalities, with considerable inter-subject variability. Consequently, it has not been possible to readily identify scans from patients with major depressive disorder at an individual level. Recently, machine learning techniques such as relevance vector machines and support vector machines have been applied to predictive classification of individual scans with variable success. Here we describe a novel hybrid method, which combines machine learning with feature selection and characterization, with the latter aimed at maximizing the accuracy of machine learning prediction. The method was tested using a multi-centre dataset of T(1)-weighted 'structural' scans. A total of 62 patients with major depressive disorder and matched controls were recruited from referred secondary care clinical populations in Aberdeen and Edinburgh, UK. The generalization ability and predictive accuracy of the classifiers was tested using data left out of the training process. High prediction accuracy was achieved (~90%). While feature selection was important for maximizing high predictive accuracy with machine learning, feature characterization contributed only a modest improvement to relevance vector machine-based prediction (~5%). Notably, while the only information provided for training the classifiers was T(1)-weighted scans plus a categorical label (major depressive disorder versus controls), both relevance vector machine and support vector machine 'weighting factors' (used for making predictions) correlated strongly with subjective ratings of illness severity. These results indicate that machine learning techniques have the potential to inform clinical practice and research, as they can make accurate predictions about brain scan data from individual subjects. Furthermore, machine learning weighting factors may reflect an objective biomarker of major depressive disorder illness severity, based on abnormalities of brain structure.
Diagnosing and managing vascular dementia.
Vascular dementia (VaD) is common. Pure vascular disease may account for 5-20% of all cases of dementia, while mixed dementia, Alzheimer's disease (AD) with VaD, occurs at least as frequently. There is no specific treatment or cure for VaD, but its proximity to other conditions may make it amenable to interventions at various stages. The causes of VaD are multifactorial and involve neuronal networks needed for memory and cognition, executive function and behaviour. Hypertensive angiopathy is the major known causative factor for VaD. Recent research suggests that VaD and AD occupy ends of the same spectrum and share common risk factors. As VaD is closely related to cardiovascular disease, modifying cardiovascular risk factors may assist in its prevention. Hypertension in midlife increases the risk of all-cause dementia. Regular screening of high-risk individuals could help to detect dementia early on enabling appropriate preventive intervention. Medication for hypertension, diabetes, and hypercholesterolaemia is recommended. Behavioural treatments include enhancing and encouraging cognitive and physical activity, social engagement, smoking cessation and healthy diet, including alcohol reduction. Comorbid depression is common in older people with dementia and treating this can improve cognition. Typically, patients are in their late sixties or early seventies, and may present after a cerebrovascular event. The onset is usually more acute than that of AD. Typical signs and symptoms are gait disturbance, unsteadiness and falls, urinary symptoms not explained by urological disease, pseudobulbar palsy and personality and mood changes. Insight is preserved until late in the disease and seizures or other manifestations of cerebral ischaemic accidents are not infrequent. VaD is characterised by stepwise deterioration with periods of partial recovery that can last months between periods of deterioration and cognitive decline.
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.
Diagnosing and managing psychosis in primary care.
Psychosis is broadly defined as the presence of delusions and hallucinations. It can be organic or functional. The former is secondary to an underlying medical condition, such as delirium or dementia, the latter to a psychiatric disorder, such as schizophrenia or bipolar disorder. The identification and treatment of psychosis is vital as it is associated with a 10% lifetime risk of suicide and significant social exclusion. Psychosis can be recognised by taking a thorough history, examining the patient's mental state and obtaining a collateral history. The history usually enables a distinction to be made between bipolar disorder, schizophrenia and other causes. Early symptoms often include low mood, declining educational or occupational functioning, poor motivation, changes in sleep, perceptual changes, suspiciousness and mistrust. The patient's appearance, e.g. unkempt or inappropriately attired, may reflect their predominant mental state. There may be signs of agitation, hostility or distractibility. Speech may be disorganised and difficult to follow or there may be evidence of decreased speech. Mood may be depressed or elated or change rapidly. Patients may describe abnormal thoughts and enquiry into thoughts of suicide should be routine. Disturbances of thought such as insertion or withdrawal may be present along with perceptual abnormalities i.e. illusions, hallucinations. Insight varies during the course of a psychotic illness but should be explored as it has implications for management. All patients presenting with first episode psychosis for which no organic cause can be found should be referred to the local early intervention service. In patients with a known diagnosis consider referral if there is: poor response or nonadherence to treatment; intolerable side effects; comorbid substance misuse; risk to self or others.
Specialty choice in UK junior doctors: is psychiatry the least popular specialty for UK and international medical graduates?
BACKGROUND: In the UK and many other countries, many specialties have had longstanding problems with recruitment and have increasingly relied on international medical graduates to fill junior and senior posts. We aimed to determine what specialties were the most popular and desirable among candidates for training posts, and whether this differed by country of undergraduate training. METHODS: We conducted a database analysis of applications to Modernising Medical Careers for all training posts in England in 2008. Total number of applications (as an index of popularity) and applications per vacancy (as an index of desirability) were analysed for ten different specialties. We tested whether mean consultant incomes correlated with specialty choice. RESULTS: In, 2008, there were 80,949 applications for specialty training in England, of which 31,434 were UK graduates (39%). Among UK medical graduates, psychiatry was the sixth most popular specialty (999 applicants) out of 10 specialty groups, while it was fourth for international graduates (5,953 applicants). Among UK graduates, surgery (9.4 applicants per vacancy) and radiology (8.0) had the highest number of applicants per vacancy and paediatrics (1.2) and psychiatry (1.1) the lowest. Among international medical graduates, psychiatry had the fourth highest number of applicants per place (6.3). Specialty popularity for UK graduates was correlated with predicted income (p = 0.006). CONCLUSION: Based on the number of applicants per place, there was some consistency in the most popular specialties for both UK and international medical graduates, but there were differences in the popularity of psychiatry. With anticipated decreases in the number of new international medical graduates training in the UK, university departments and professional associations may need to review strategies to attract more UK medical graduates into certain specialties, particularly psychiatry and paediatrics.
Transcranial magnetic stimulation
Depression has an annual prevalence of 1-6% in the community; 50-60% of depressed individuals might not respond to conventional pharmacotherapy. Transcranial magnetic stimulation (TMS) non-invasively stimulates superficial cortex in patients, for investigative and therapeutic purposes. It is usually applied over the prefrontal cortex at frequencies of 1-20 Hz at motor threshold intensity. We present a meta-analysis of 24 studies evaluating the antidepressant effect of TMS for major depressive or bipolar disorder in treatment groups ≥10 patients. Out of 617 patients receiving active rTMS, 218 (35.3%) were classified as 'responders', whereas only 71 (13.1%) of 543 patients undergoing sham rTMS met the criteria for clinical response. The Peto odds ratio meta-analysis indicated that this difference is statistically significant, with an odds ratio of 3.88 (95%-CI: 2.94-5.13). Heterogeneity between studies did not exceed that expected by chance and there was no significant publication bias. Based on these data, five patients (95% CI = 4-6) need to be treated in order to obtain a clinical response attributable to rTMS, a respectable effect size among psychiatric (add-on) treatments. Unfortunately, there is no compelling evidence regarding the most effective combination of rTMS parameters. The literature indicates that future trials should employ a greater number of rTMS sessions, adequate concealment allocation and an individualized approach to locating the DLPFC using neuroimaging. Also, more knowledge is needed regarding the characteristics of patients who benefit from this treatment and the size and persistence of clinical effects. © 2009 Elsevier Ltd. All rights reserved.
Meta-analysis of magnetic resonance imaging studies of the corpus callosum in schizophrenia
Objectives: The corpus callosum plays a pivotal role in inter-hemispheric transfer and integration of information. Magnetic resonance studies have reported callosal abnormalities in schizophrenia but findings have been inconsistent. Uncertainty has persisted despite a meta-analytic evaluation of this structure several years ago. We set out to perform a further meta-analysis with the addition of the numerous reports published on the subject to test the hypothesis that the corpus callosum is abnormal in schizophrenia. Method: A systematic search was carried out to identify suitable magnetic resonance studies which reported callosal areas in schizophrenia compared to controls. Results from the retrieved studies were compared in a meta-analysis whilst the influence of biological and clinical variables on effect size was ascertained with meta-regression analysis. Results: Twenty-eight studies were identified. Corpus callosum area was reduced in schizophrenia in comparison to healthy volunteers. This effect was larger in first episode patients. similarly, heterogeneity detected among the studies was associated with course of illness indicating that chronic subjects with schizophrenia showed larger callosal areas. There was no evidence of publication bias. CONCLUsIONs: This study confirms the presence of reduced callosal areas in schizophrenia. The effect is of a larger magnitude at first presentation and less so in subjects with a chronic course generally medicated with antipsychotics.
Transcranial magnetic stimulation
Depression is a common disorder with an annual prevalence that varies from 1% to 6% in the community. It is associated with a high rate of recurrence; up to 50-60% of depressed individuals may not respond to conventional pharmacotherapy. This reinforces the need to find alternative treatments to improve the outcome of such patients. Transcranial magnetic stimulation (TMS) allows for the non-invasive stimulation of superficial cortex in patients, both for investigative and therapeutic purposes. It is usually applied over the prefrontal cortex at frequencies of 1-20 Hz and at an intensity around motor threshold. A meta-analysis is presented, including 31 studies evaluating the antidepressant effect of TMS. Repetitive (r)TMS was more effective in the treatment of depression than sham rTMS, with a medium-sized effect. Studies that have examined rTMS efficacy in the treatment of depression are highly heterogeneous in terms of both sample characteristics and treatment parameters. Moreover, most of them have employed a relatively small number of participants. Strict double-blinding cannot be guaranteed due to flawed sham conditions. All of these factors have the potential to lead to errors in the results of the individual studies and may have affected the result of the present meta-analysis. Unfortunately, there is no compelling evidence regarding the most effective combination of rTMS parameters. The literature suggests that future trials should employ a greater number of rTMS sessions, adequate concealment allocation and an individualized approach to locating the DLPFC using neuroimaging. Until the optimal treatment parameters are delineated, rTMS remains an experimental approach for the treatment of depression. More knowledge regarding the characteristics of patients who benefit from this treatment and the size and persistence of clinical effects is needed. © 2006 Elsevier Ltd. All rights reserved.
A meta-analysis of diffusion tensor imaging in mild cognitive impairment and Alzheimer's disease.
We reviewed case-control studies of diffusion tensor imaging (DTI) in patients with Alzheimer's dementia (AD) and mild cognitive impairment (MCI), in order to establish the relative severity and location of white matter microstructural changes. EMBASE and MEDLINE were searched using the keywords, (["diffusion tensor"] and ["Alzheimer*" or "mild cognitive impairment"]), as were reference lists of relevant papers. Forty-one diffusion tensor imaging studies contained data that were suitable for inclusion. Group means and standard deviations for fractional anisotropy and mean diffusivity, or p values from 2-sample tests, were extracted and pooled, using standard methods of meta-analysis and metaregression. Fractional anisotropy was decreased in AD in all regions except parietal white matter and internal capsule, while patients with MCI had lower values in all white matter regions except parietally and occipitally. Mean diffusivity was increased in AD in all regions, and in MCI in all but occipital and frontal regions.