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Meta-analysis of generalized additive models in neuroimaging studies.
Analyzing data from multiple neuroimaging studies has great potential in terms of increasing statistical power, enabling detection of effects of smaller magnitude than would be possible when analyzing each study separately and also allowing to systematically investigate between-study differences. Restrictions due to privacy or proprietary data as well as more practical concerns can make it hard to share neuroimaging datasets, such that analyzing all data in a common location might be impractical or impossible. Meta-analytic methods provide a way to overcome this issue, by combining aggregated quantities like model parameters or risk ratios. Most meta-analytic tools focus on parametric statistical models, and methods for meta-analyzing semi-parametric models like generalized additive models have not been well developed. Parametric models are often not appropriate in neuroimaging, where for instance age-brain relationships may take forms that are difficult to accurately describe using such models. In this paper we introduce meta-GAM, a method for meta-analysis of generalized additive models which does not require individual participant data, and hence is suitable for increasing statistical power while upholding privacy and other regulatory concerns. We extend previous works by enabling the analysis of multiple model terms as well as multivariate smooth functions. In addition, we show how meta-analytic p-values can be computed for smooth terms. The proposed methods are shown to perform well in simulation experiments, and are demonstrated in a real data analysis on hippocampal volume and self-reported sleep quality data from the Lifebrain consortium. We argue that application of meta-GAM is especially beneficial in lifespan neuroscience and imaging genetics. The methods are implemented in an accompanying R package metagam, which is also demonstrated.
ICA-based artefact removal and accelerated fMRI acquisition for improved resting state network imaging.
The identification of resting state networks (RSNs) and the quantification of their functional connectivity in resting-state fMRI (rfMRI) are seriously hindered by the presence of artefacts, many of which overlap spatially or spectrally with RSNs. Moreover, recent developments in fMRI acquisition yield data with higher spatial and temporal resolutions, but may increase artefacts both spatially and/or temporally. Hence the correct identification and removal of non-neural fluctuations is crucial, especially in accelerated acquisitions. In this paper we investigate the effectiveness of three data-driven cleaning procedures, compare standard against higher (spatial and temporal) resolution accelerated fMRI acquisitions, and investigate the combined effect of different acquisitions and different cleanup approaches. We applied single-subject independent component analysis (ICA), followed by automatic component classification with FMRIB's ICA-based X-noiseifier (FIX) to identify artefactual components. We then compared two first-level (within-subject) cleaning approaches for removing those artefacts and motion-related fluctuations from the data. The effectiveness of the cleaning procedures was assessed using time series (amplitude and spectra), network matrix and spatial map analyses. For time series and network analyses we also tested the effect of a second-level cleaning (informed by group-level analysis). Comparing these approaches, the preferable balance between noise removal and signal loss was achieved by regressing out of the data the full space of motion-related fluctuations and only the unique variance of the artefactual ICA components. Using similar analyses, we also investigated the effects of different cleaning approaches on data from different acquisition sequences. With the optimal cleaning procedures, functional connectivity results from accelerated data were statistically comparable or significantly better than the standard (unaccelerated) acquisition, and, crucially, with higher spatial and temporal resolution. Moreover, we were able to perform higher dimensionality ICA decompositions with the accelerated data, which is very valuable for detailed network analyses.
Neuroimaging in dementia.
Over the last few years, advances in neuroimaging have generated biomarkers, which increase diagnostic certainty, provide valuable information about prognosis, and suggest a particular pathology underlying the clinical dementia syndrome. We aim to review the evidence for use of already established imaging modalities, along with selected techniques that have a great potential to guide clinical decisions in the future. We discuss structural, functional and molecular imaging, focusing on the most common dementias: Alzheimer's disease, fronto-temporal dementia, dementia with Lewy bodies and vascular dementia. Finally, we stress the importance of conducting research using representative cohorts and in a naturalistic set up, in order to build a strong evidence base for translating imaging methods for a National Health Service. If we assess a broad range of patients referred to memory clinic with a variety of imaging modalities, we will make a step towards accumulating robust evidence and ultimately closing the gap between the dramatic advances in neurosciences and meaningful clinical applications for the maximum benefit of our patients.
Occupational stress, bullying and resilience in old age.
Our working years increasingly extend into the late 60s and may soon include the 70s for some people. Thus the question whether work stress has a cumulative effect in older age, and whether older employees are more vulnerable to certain sources of work stress, such as bullying in the work place, is becoming increasingly relevant. We review some of the mechanisms, which translate cumulative stress at work into ill health, particularly in older age, and summarise what is known about the effect of age-specific stress, taking age-related bullying as an example.
Apolipoprotein E genotype, gender and age modulate connectivity of the hippocampus in healthy adults.
Important risk factors for Alzheimer's disease (AD) are ageing and the Apolipoprotein E (APOE) ε4 allele, with female APOE ε4 carriers having the greatest risk. In this study we investigated effects of AD risk factors on connectivity of the hippocampus, a structure that shows early AD related pathology. Resting-state functional magnetic resonance imaging and diffusion tensor imaging data from 86 cognitively healthy subjects aged 30 to 78years were analysed. Female APOE ε4 carriers showed overall significantly reduced functional connectivity between the hippocampus and precuneus/posterior cingulate cortex (PCC) and a significant age-related decrease in connectivity of these regions. In females and APOE ε4 carriers we found significantly reduced white matter integrity of the tract connecting the hippocampus and PCC with a significant positive correlation of white matter integrity and resting-state connectivity. Increased vulnerability of the connection between the hippocampus and PCC might be one reason for increased AD risk in female APOE ε4 carriers. Interventions targeting hippocampal connectivity might be especially effective in this at risk population.
Study protocol: The Whitehall II imaging sub-study.
BACKGROUND: The Whitehall II (WHII) study of British civil servants provides a unique source of longitudinal data to investigate key factors hypothesized to affect brain health and cognitive ageing. This paper introduces the multi-modal magnetic resonance imaging (MRI) protocol and cognitive assessment designed to investigate brain health in a random sample of 800 members of the WHII study. METHODS/DESIGN: A total of 6035 civil servants participated in the WHII Phase 11 clinical examination in 2012-2013. A random sample of these participants was included in a sub-study comprising an MRI brain scan, a detailed clinical and cognitive assessment, and collection of blood and buccal mucosal samples for the characterisation of immune function and associated measures. Data collection for this sub-study started in 2012 and will be completed by 2016. The participants, for whom social and health records have been collected since 1985, were between 60-85 years of age at the time the MRI study started. Here, we describe the pre-specified clinical and cognitive assessment protocols, the state-of-the-art MRI sequences and latest pipelines for analyses of this sub-study. DISCUSSION: The integration of cutting-edge MRI techniques, clinical and cognitive tests in combination with retrospective data on social, behavioural and biological variables during the preceding 25 years from a well-established longitudinal epidemiological study (WHII cohort) will provide a unique opportunity to examine brain structure and function in relation to age-related diseases and the modifiable and non-modifiable factors affecting resilience against and vulnerability to adverse brain changes.
Report of the CSM Expert Working Group on the Safety of Selective Serotonin Reuptake Inhibitor Antidepressants
Executive summary: Context Selective Serotonin Reuptake Inhibitors (SSRIs) and related antidepressants have been used in the treatment of depressive illness and anxiety disorders since the late 1980s. The safety of SSRIs has been under close review by the Medicines and Healthcare products Regulatory Agency (MHRA) since the products were first marketed. Background In May 2003, in response to continuing public concerns about the safety of SSRIs, an Expert Working Group of the Committee on Safety of Medicines (CSM) was convened to investigate ongoing safety concerns with these medicines, in particular around suicidal behaviour and withdrawal reactions/dependence. The Expert Working Group has studied all the available data including that from published and unpublished clinical trials, spontaneous reporting data from health professionals and patients, evidence from key stakeholders and data from the General Practice Research Database (GPRD). This included a study commissioned by the MHRA. Output of the Working Group The work of the Group resulted in CSM advice on the use of SSRIs in the paediatric population, advice to the European review of paroxetine, conclusions on the key issues relating to adult use which are general to all the medicines included in the review, and regulatory action in relation to particular medicines. This is the final report of the Group.
Using structural and diffusion magnetic resonance imaging to differentiate the dementias.
Dementia is one of the major causes of personal, societal and financial dependence in older people and in today's ageing society there is a pressing need for early and accurate markers of cognitive decline. There are several subtypes of dementia but the four most common are Alzheimer's disease, Lewy body dementia, vascular dementia and frontotemporal dementia. These disorders can only be diagnosed at autopsy, and ante-mortem assessments of "probable dementia (e.g. of Alzheimer type)" are traditionally driven by clinical symptoms of cognitive or behavioural deficits. However, owing to the overlapping nature of symptoms and age of onset, a significant proportion of dementia cases remain incorrectly diagnosed. Misdiagnosis can have an extensive impact, both at the level of the individual, who may not be offered the appropriate treatment, and on a wider scale, by influencing the entry of patients into relevant clinical trials. Magnetic resonance imaging (MRI) may help to improve diagnosis by providing non-invasive and detailed disease-specific markers of cognitive decline. MRI-derived measurements of grey and white matter structural integrity are potential surrogate markers of disease progression, and may also provide valuable diagnostic information. This review summarises the latest evidence on the use of structural and diffusion MRI in differentiating between the four major dementia subtypes.
Depression in older people is underdiagnosed.
Depression is more common in old age than dementia yet is underdiagnosed and undertreated. It is important to recognise that patients may not always present in a typical way, features that may indicate depression include anxiety, a preoccupation with somatic symptoms, and a change in function. The presence of understandable triggers and causes should not deter GPs from offering treatment, as long as symptoms are pervasive and continuously persist beyond two weeks. Age-related disabilities and changes to physical health are major risk factors for depression in older people. Vascular diseases, including stroke, MI and diabetes increase the risk of depression, both through direct effects on the brain and the psychological effects. Likewise, dementia is a risk factor for depression. Psychological factors such as loneliness and loss of a valued role, as well as social factors related to retirement, bereavement and reduced independence may also increase the risk. Patients with a previous history of depression and anxiety disorders are at increased risk of depression in later life. Assessment and diagnosis are largely based on a careful history. This should focus on eliciting current features of depression, which have been present for at least two weeks, and are associated with a significant change in function. It is important to exclude organic disorders including anaemia, B12 and folate deficiency, and hypothyroidism that may mimic symptoms of depressive disorder. Referral to specialist mental health services is indicated in the following cases: diagnostic difficulty, poor response to treatment, psychotic symptoms, significant psychiatric comorbidity or a risk of self-neglect or suicide.
Predictors of cognitive impairment in an early stage Parkinson's disease cohort.
The impact of Parkinson's disease (PD) dementia is substantial and has major functional and socioeconomic consequences. Early prediction of future cognitive impairment would help target future interventions. The Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), and fluency tests were administered to 486 patients with PD within 3.5 years of diagnosis, and the results were compared with those from 141 controls correcting for age, sex, and educational years. Eighteen-month longitudinal assessments were performed in 155 patients with PD. The proportion of patients classified with normal cognition, mild cognitive impairment (MCI), and dementia varied considerably, depending on the MoCA and MMSE thresholds used. With the MoCA total score at screening threshold, 47.7%, 40.5%, and 11.7% of patients with PD were classified with normal cognition, MCI, and dementia, respectively; by comparison, 78.7% and 21.3% of controls had normal cognition and MCI, respectively. Cognitive impairment was predicted by lower education, increased age, male sex, and quantitative motor and non-motor (smell, depression, and anxiety) measures. Longitudinal data from 155 patients with PD over 18 months showed significant reductions in MoCA scores, but not in MMSE scores, with 21.3% of patients moving from normal cognition to MCI and 4.5% moving from MCI to dementia, although 13.5% moved from MCI to normal; however, none of the patients with dementia changed their classification. The MoCA may be more sensitive than the MMSE in detecting early baseline and longitudinal cognitive impairment in PD, because it identified 25.8% of those who experienced significant cognitive decline over 18 months. Cognitive decline was associated with worse motor and non-motor features, suggesting that this reflects a faster progressive phenotype.
Improving the detection and treatment of schizophrenia.
Schizophrenia is a debilitating, often chronic, psychotic disorder with early onset and a lifetime prevalence of 7.2/1,000. The longer the period without treatment, the worse the outcome. In the UK, the mean duration of untreated psychosis is one to two years. The new NICE guidelines for schizophrenia recommend that all patients who are distressed and have a decline in social functioning accompanied by psychotic symptoms or behaviour suggesting psychosis should be comprehensively assessed by a specialist mental health service. Antipsychotic medication remains the cornerstone of treatment in schizophrenia for the acute and the stabilisation-maintenance phase. The NICE guidelines recommend the use of psychological, social, occupational and educational interventions early in treatment. Mortality rates in schizophrenia are high and the majority of premature deaths are accounted for by physical illnesses. These include cardiovascular disease, diabetes mellitus, COPD, certain cancers and infectious diseases e.g. HIV, hepatitis C, and tuberculosis. Primary care has a significant role to play in monitoring mental state and physical health. Monitoring mental state is crucial. When relapse is threatened because of poor response to treatment, non-adherence to medication, intolerable side effects from medication, comorbid substance misuse, or if risk to self or others is suspected, GPs should refer the patient to the mental health team. GPs should provide a comprehensive health check yearly or more often if there is an indication.
Reduced cerebrovascular reactivity in young adults carrying the APOE ε4 allele.
BACKGROUND: Functional magnetic resonance imaging (MRI) studies have shown that APOE ε2- and ε4-carriers have similar patterns of blood-oxygenation-level-dependent (BOLD) activation suggesting that we need to look beyond the BOLD signal to link APOE's effect on the brain to Alzheimer's disease (AD)-risk. METHODS: We evaluated APOE-related differences in BOLD activation in response to a memory task, cerebrovascular reactivity using a CO2-inhalation challenge (CO2-CVR), and the potential contribution of CO2-CVR to the BOLD signal. RESULTS: APOE ε4-carriers had the highest task-related hippocampal BOLD signal relative to non-carriers. The largest differences in CO2-CVR were between ε2- and ε4-carriers, with the latter having the lowest values. Genotype differences in CO2-CVR accounted for ∼70% of hippocampal BOLD differences between groups. CONCLUSION: Because CO2-CVR gauges vascular health, the differential effect of APOE in young adults may reflect a vascular contribution to the vulnerability of ε4-carriers to late-life pathology. Studies confirming our findings are warranted.
The Genetics of Dementia
The book begins with the medical facts/concerns: What is dementia? Who gets it? What are the current and future therapeutic and palliative options? What are the main challenges for medical and nursing care?
Geographic trends of scientific output and citation practices in psychiatry.
BACKGROUND: Measures of research productivity are increasingly used to determine how research should be evaluated and funding decisions made. In psychiatry, citation patterns within and between countries are not known, and whether these differ by choice of citation metric. METHOD: In this study, we examined publication characteristics and citation practices in articles published in 50 Web of Science indexed psychiatric and relevant clinical neurosciences journals, between January 2004 and December 2009 comprising 51,072 records that produced 375,962 citations. We compared citation patterns, including self-citations, between countries using standard x(2) tests. RESULTS: We found that most publications came from the USA, with Germany being second and UK third in productivity. USA articles received most citations and the highest citation rate with an average 11.5 citations per article. The UK received the second highest absolute number of citations, but came fourth by citation rate (9.7 citations/article), after the Netherlands (11.4 citations/article) and Canada (9.8 citations/article). Within the USA, Harvard University published most articles and these articles were the most cited, on average 20.0 citations per paper. In Europe, UK institutions published and were cited most often. The Institute of Psychiatry/Kings College London was the leading institution in terms of number of published records and overall citations, while Oxford University had the highest citation rate (18.5 citations/record). There were no differences between the self-citation practices of American and European researchers. Articles that examined some aspect of treatment in psychiatry were the most published. In terms of diagnosis, papers about schizophrenia-spectrum disorders were the most published and the most cited. CONCLUSIONS: We found large differences between and within countries in terms of their research productivity in psychiatry and clinical neuroscience. In addition, the ranking of countries and institutions differed widely by whether productivity was assessed by total research records published, overall citations these received, or citations per paper. The choice of measures of scientific output could be important in determining how research output translates into decisions about resource allocation.
Interleukin-6 as a predictor of symptom resolution in psychological distress: a cohort study.
BACKGROUND: Elevated levels of interleukin-6 (IL-6) have been associated with the development of common mental disorders, such as depression, but its role in symptom resolution is unclear. METHOD: We examined the association between IL-6 and symptom resolution in a non-clinical sample of participants with psychological distress. RESULTS: Relative to high IL-6 levels, low levels at baseline were associated with symptom resolution at follow-up [age- and sex-adjusted risk ratio (RR) = 1.15, 95% confidence interval (CI) 1.06-1.25]. Further adjustment for covariates had little effect on the association. Symptomatic participants with repeated low IL-6 were more likely to be symptom-free at follow-up compared with those with repeated high IL-6 (RR = 1.21, 95% CI 1.03-1.41). Among the symptomatic participants with elevated IL-6 at baseline, IL-6 decreased along with symptom resolution. CONCLUSIONS: IL-6 is potentially related to the mechanisms underlying recovery from symptoms of mental ill health. Further studies are needed to examine these mechanisms and to confirm the findings in relation to clinical depression.
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.
Resilience and MRI correlates of cognitive impairment in community-dwelling elders.
BACKGROUND: The contribution of education and intelligence to resilience against age-related cognitive decline is not clear, particularly in the presence of 'normal for age' minor brain abnormalities. METHOD: Participants (n = 208, mean age 69.2 years, s.d. = 5.4) in the Whitehall II imaging substudy attended for neuropsychological testing and multisequence 3T brain magnetic resonance imaging. Images were independently rated by three trained clinicians for global and hippocampal atrophy, periventricular and deep white matter changes. RESULTS: Although none of the participants qualified for a clinical diagnosis of dementia, a screen for cognitive impairment (Montreal Cognitive Assessment (MoCA) <26) was abnormal in 22%. Hippocampal atrophy, in contrast to other brain measures, was associated with a reduced MoCA score even after controlling for age, gender, socioeconomic status, years of education and premorbid IQ. Premorbid IQ and socioeconomic status were associated with resilience in the presence of hippocampal atrophy. CONCLUSIONS: Independent contributions from a priori risk (age, hippocampal atrophy) and resilience (premorbid function, socioeconomic status) combine to predict measured cognitive impairment.
Establishing the cause of memory loss in older people.
Common causes of memory loss in older people are mild cognitive impairment, the various types of dementia, and psychiatric illness, mainly depression. Around 10% of patients with mild cognitive impairment progress to dementia each year. Alzheimer's disease accounts for 60-80% of cases. Other common types of dementia are vascular, fronto-temporal, Lewy body, Parkinson's, and mixed type dementia. There is evidence to suggest that dementia pathology is established before the onset of symptoms, and thus mild cognitive impairment can be considered as a predementia stage. NICE guidance suggests examination of: attention, concentration, short- and long-term memory, praxis, language and executive function. Particular attention should be paid to any signs of neglect, state of dress, agitation or poor attention. Dysphasia and difficulty in naming objects is often present. Mood symptoms (including suicidal ideation) may be primary or comorbid. Abnormal thoughts and perceptions should be probed for, as psychotic symptoms are common. Primary care options for cognitive testing include the General Practitioner Assessment of Cognition or the Abbreviated Mental Test Score. Physical examination should include observation of gait, inspection for tremor; examination for rigidity, bradykinesia, frontal release signs, upper motor neurone lesions, pulse and BP. Structural brain imaging can improve diagnostic accuracy, exclude other pathologies and act as a prognostic marker of dementia progression but the overlap in structural changes between the dementias makes imaging alone insufficient for diagnostic purposes. NICE guidelines recommend referral to a memory clinic for patients with mild cognitive impairment, those at high risk of dementia, such as patients with learning disabilities, Parkinson's disease, or patients who have had several strokes.