Associations between self-reported sleep quality and white matter in community-dwelling older adults: A prospective cohort study.

Both sleep disturbances and decline in white matter microstructure are commonly observed in ageing populations, as well as in age-related psychiatric and neurological illnesses. A relationship between sleep and white matter microstructure may underlie such relationships, but few imaging studies have directly examined this hypothesis. In a study of 448 community-dwelling members of the Whitehall II Imaging Sub-Study aged between 60 and 82 years (90 female, mean age 69.2 ± 5.1 years), we used the magnetic resonance imaging technique diffusion tensor imaging to examine the relationship between self-reported sleep quality and white matter microstructure. Poor sleep quality at the time of the diffusion tensor imaging scan was associated with reduced global fractional anisotropy and increased global axial diffusivity and radial diffusivity values, with small effect sizes. Voxel-wise analysis showed that widespread frontal-subcortical tracts, encompassing regions previously reported as altered in insomnia, were affected. Radial diffusivity findings remained significant after additional correction for demographics, general cognition, health, and lifestyle measures. No significant differences in general cognitive function, executive function, memory, or processing speed were detected between good and poor sleep quality groups. The number of times participants reported poor sleep quality over five time-points spanning a 16-year period was not associated with white matter measures. In conclusion, these data demonstrate that current sleep quality is linked to white matter microstructure. Small effect sizes may limit the extent to which poor sleep is a promising modifiable factor that may maintain, or even improve, white matter microstructure in ageing. Hum Brain Mapp 38:5465-5473, 2017. © 2017 Wiley Periodicals, Inc.

Promoting early dementia diagnosis: a video designed by patients, for patients.

Early diagnosis of dementia allows people to access effective treatment and make advance decisions while they still have capacity. We aimed to encourage people to attend memory clinic, in order to boost rates of diagnosis. We created a patient information video about Oxford Health NHS Foundation Trust Memory Clinics, to inform and empower those awaiting assessment and to promote early diagnosis. Fourteen people (patients, carers, and staff) were approached prior to developing the video to ascertain their views on the themes the video should cover. The video consisted of unscripted interviews with patients, carers, and staff. We surveyed participants and new patients attending memory clinic to get feedback on the video and to assess patients' level of understanding and confidence about a memory assessment before and after watching the video. The video content was refined based on this feedback and a final version was produced. Patient feedback demonstrated that confidence and understanding increased after watching the video. Although this study is limited by its small sample size and lack of access to those with undiagnosed dementia, feedback suggested that the video empowered and reassured those awaiting assessment and could be used as a tool to reduce barriers to early diagnosis. Patients and carers involved in making the video found it a therapeutic activity in itself.

Diagnosing and managing mild cognitive impairment.

There has been a rapid rise in the number of people diagnosed with dementia in England from 232,000 in 2008 to 850,000 in 2014. Currently, it is estimated that the prevalence of mild cognitive impairment in adults aged 65 and over is 10-20%. It is likely that this figure will increase in line with trends in dementia diagnosis. In some cases, mild cognitive impairment may be a prodrome for dementia, and my be caused by any of the dementia pathology subtypes. The relationship between depression in the elderly and mild cognitive impairment is difficult to tease out as they are frequently comorbid conditions and both have been found to be independent risk factors for subsequent dementia: about 10% convert to dementia each year, compared with 1-2% of the general elderly population. It is important to obtain a history of cognitive changes over time, as well as information about the onset and nature of cognitive symptoms, confirmed by a reliable informant, if available. To confirm the diagnosis objective evidence of cognitive impairment is required. However, there are no specific neuropsychological tests for patients with mild cognitive impairment. On neuropsychological tests, individuals with mild cognitive impairment typically score 1-15 SD below the mean for their age and education, although these ranges are guidelines and not cut-off scores. GPs should consider referring people who signs of mild cognitive impairment for assessment by specialist memory assessment services to aid early identification of dementia, because more than 50% of people with mild cognitive impairment later develop dementia.

Depression is linked to dementia in older adults.

Depression and dementia are both common conditions in older people, and they frequently occur together. Late life depression affects about 3.0-4.5% of adults aged 65 and older. Depression occurs in up to 20% of patients with Alzheimer's disease and up to 45% of patients with vascular dementia. Rather than a risk factor, depression with onset in later life is more likely to be either prodromal to dementia or a condition that unmasks pre-existing cognitive impairment by compromising cognitive reserve. Depression can be a psychological response to receiving a diagnosis of dementia. The distinction between depression and early dementia may be particularly difficult. Detailed histories obtained from patients and their relatives as well as longitudinal follow-up are important. Cognitive testing can be very helpful. It is preferable to use a neuropsychological test that is sensitive to subtle cognitive changes and assesses all cognitive domains, such as the Montreal Cognitive Assessment. Older people with depression are at raised risk of dementia and this risk is increased if they have had symptoms for a long time, if their symptoms are severe, where there are multiple (vascular) comorbidities, and where there are structural brain changes including hippocampal atrophy and white matter abnormalities.

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.

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.

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.

Early diagnosis beneficial in Alzheimer's disease.

GPs should consider a diagnosis of dementia when a patient presents with functional impairment in addition to at least two changes in cognitive function e.g. short-term memory, language, reasoning, spatial orientation, or personality change. The patient, friends, family or professional carers should have noticed these changes for at least six months. Patients should be referred to a memory clinic to make a formal diagnosis of probable or possible Alzheimer's disease and to exclude other types of dementia. Key to assessment is a careful history of cognitive and functional changes, medical conditions and past psychiatric history. An objective cognitive assessment is important, and in primary care screening tools such as the General Practitioner Assessment of Cognition provide a useful adjunct to justify referral to specialist services. Patients should have a physical examination and a dementia screen to exclude treatable causes of cognitive impairment. Acetylcholinesterase inhibitors and memantine both slow the progression of cognitive decline and extend independence in activities of daily living. NICE recommends donepezil, rivastigmine or galantamine for mild to moderate Alzheimer's disease, and memantine for severe disease. Primary care is optimally placed to screen for cognitive impairments, to provide essential longitudinal information that will make a diagnosis of dementia safer. Primary care also has a crucial role in primary and, particularly secondary, prevention programmes to tackle excessive weight, lack of activity, smoking, and other lifestyle risk factors for dementia, including Alzheimer's disease, as well as the treatment of medical conditions which increase dementia risk.

Diagnosis and management of autism in adults.

Autism affects 1.1% of the adult population. The spectrum of symptoms is wide; some individuals have above average intelligence and are fully independent, while others have limited independence because of a learning disability. Developmental delay is a core feature, and autism is usually diagnosed in childhood. High-functioning individuals with autism, Asperger's syndrome, may remain undiagnosed until adulthood. Autism is a life-long condition characterised by problems in two core dimensions: difficulties with social communication and strongly repetitive behaviour, resistance to change or restricted interests.The history should identify early developmental and behavioural problems in different settings e.g. at home, in education or employment. Sensory and GI problems are very common, and should be asked about. The Autism-Spectrum Quotient (AQ-10) is a 10-item questionnaire for people with suspected autism. The advantage of using this in primary care is that it provides a time-efficient, structured way of ascertaining key symptoms and clearly signals those who should be referred for further assessment. Patients should be referred if autism is suspected clinically and a diagnosis of autism should be confirmed by a specialist multidisciplinary team. If a diagnosis of autism is made, clinicians should do a risk assessment and formulate risk and crisis management plans. These should include details of the roles and responsibilities of both the specialist team and primary care team in managing crisis situations. For adults with autism a group-based or an individual learning programme to improve social interaction is recommended. Adults with autism have high rates of unemployment, and employment programmes have been successfully used to support people

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.

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.

Primary care management of patients who self-harm.

Self-harm is best defined as 'any act of self-poisoning or self-injury carried out by an individual irrespective of motivation'. With a 10.5% lifetime risk, self-reported self-harm is common in the community. Self-harm can occur at any age but is most common in young people. Prior self-harm is the key risk factor both for repeated self-harm and also for subsequent suicide. The presence of depressive symptoms predicts repeated self-harm, as does any history of psychiatric illness. Assessment of self-harm (actual or planned) should include: details of preplanning; final acts; the event itself; what happened afterwards; as well as broader psychosocial risk factors. Patients should be asked to reflect on the episode to consider whether they regret it, or whether they are likely to repeat it. Patients should be screened for depression, anxiety, psychosis and history of self-harm. Physical illness and substance misuse increase risk. Referral to secondary care community mental health teams should be considered for patients who present in primary care with a history of self-harm and a risk of repetition. Patients with continuing thoughts or serious intent of self-harm, where supportive or protective factors cannot be identified, may need urgent referral to secondary care. Prediction of further episodes of self-harm is difficult. Some clinicians may find the use of standardised rating scales, such as the SAD PERSONS scale, a useful way to identify patients who warrant referral and further assessment. The GP should provide long-term continuity of care, and maintain a holistic awareness of a patient's life events enabling discussion of the patient's emotional problems at an early stage with the aim of intervening before a crisis.

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.

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

OBJECTIVE: ApoE4 is a risk factor for the development of Alzheimer's 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. METHODS: We searched Medline, Embase and PsychINFO from 1990 until April 2009, for case control or cohort studies which investigated the effect of ApoE4 on progression of dementia. We identified 427 studies; 17 were suitable for inclusion. In total, there were 1733 participants with dementia at baseline, of whom 975 were heterozygous or homozygous for ApoE4. RESULTS: There was no significant difference in cognitive decline (random-model effect size = 0.02; 95% C.-I.: -0.09 to 0.14; p = 0.67) or mortality (random-model pooled odds ratio = 0.74; 95% C.-I.: 0.36 to 1.53; p = 0.41) based on the presence of ApoE4. There was no significant heterogeneity between studies using cognitive decline as an outcome. In meta-regressions of cognitive decline, duration of symptoms, age, gender and frequency of participants with ApoE4 in the samples did not contribute to outcome. CONCLUSION: Different ApoE alleles do not modify the speed of clinical progression of dementia in a way that would be detectable in a sample of 1700 patients.

The use of ECT and MST in treating depression.

Electroconvulsive therapy (ECT) has been used clinically since 1938. Its most common use is in the treatment of depression: first line treatment where rapid recovery is a priority, but more frequently as an effective treatment for patients who do not respond to pharmacological and psychological approaches. Whilst it is widely hailed as an effective treatment, concerns about its effect on cognition remain. The development of magnetic seizure therapy (MST) over the past decade has attempted to devise a therapy with comparable efficacy to ECT, but without the associated cognitive side effects. The rationale for this is that MST uses magnetic fields to induce seizures in the cortex, without electrical stimulation of brain structures involved with memory. MST has been used successfully in the treatment of depression, yet there is a dearth of literature in comparison with ECT. We present a systematic review of the literature on ECT (from 2009-2011) and MST (from 2001-2011).

Association of trajectories of depressive symptoms with vascular risk, cognitive function and adverse brain outcomes: The Whitehall II MRI sub-study.

BACKGROUND: Trajectories of depressive symptoms over the lifespan vary between people, but it is unclear whether these differences exhibit distinct characteristics in brain structure and function. METHODS: In order to compare indices of white matter microstructure and cognitive characteristics of groups with different trajectories of depressive symptoms, we examined 774 participants of the Whitehall II Imaging Sub-study, who had completed the depressive subscale of the General Health Questionnaire up to nine times over 25 years. Twenty-seven years after the first examination, participants underwent magnetic resonance imaging to characterize white matter hyperintensities (WMH) and microstructure and completed neuropsychological tests to assess cognition. Twenty-nine years after the first examination, participants completed a further cognitive screening test. OUTCOMES: Using K-means cluster modelling, we identified five trajectory groups of depressive symptoms: consistently low scorers ("low"; n = 505, 62·5%), a subgroup with an early peak in depression scores ("early"; n = 123, 15·9%), intermediate scorers ("middle"; n = 89, 11·5%), a late symptom subgroup with an increase in symptoms towards the end of the follow-up period ("late"; n = 29, 3·7%), and consistently high scorers ("high"; n = 28, 3·6%). The late, but not the consistently high scorers, showed higher mean diffusivity, larger volumes of WMH and impaired executive function. In addition, the late subgroup had higher Framingham Stroke Risk scores throughout the follow-up period, indicating a higher load of vascular risk factors. INTERPRETATION: Our findings suggest that tracking depressive symptoms in the community over time may be a useful tool to identify phenotypes that show different etiologies and cognitive and brain outcomes.

Schizophrenia: from genes to phenes to disease.

This article provides an overview of the past year's literature on schizophrenia genetics. Quantitative genetics continues to be an important foundation in which family and twin studies have been used to evaluate potential endophenotypes. Research in molecular genetics has focused on detecting multiple genes of small effect, and developments relating to key positional and functional candidate genes are reviewed. Large-scale, multicenter studies are proving to be important in this quest. Research using neuroimaging and animal modeling studies continues to link genotype with phenotype. It is increasingly apparent that some candidate genes considered important in schizophrenia are likely to be relevant to the etiology of other psychotic disorders, including bipolar disorder. This notion may challenge traditional disease classifications, not only in research but potentially in clinical practice.

Challenges in end-of-life dementia care.

Dementia is a chronic, progressive disease that is now much more widely recognised and treated. Patients with dementia may require palliative care when they reach the end stage of their illness, or they may have mild-moderate cognitive symptoms comorbid with a life-limiting illness. The variety of presentations necessitates a highly individual approach to care planning, and patients should be encouraged to set their own goals and contribute to advanced care planning where possible. Assessment and management of distressing symptoms at the end of life can be greatly helped by a detailed knowledge of the individuals' prior wishes, interdisciplinary communication and recognition of changes in presentation that may result from new symptoms, for example, onset of pain, nutritional deficits and infection. To navigate complexity at the end of life, open communication that involves patients and families in decisions, and is responsive to their needs is vital and can vastly improve subjective experiences. Complex ethical dilemmas may pervade both the illness of dementia and provision of palliative care; we consider how ethical issues (eg, providing care under restraint) influence complex decisions relating to resuscitation, artificial nutrition and treatment refusal in order to optimise quality of life.

Reduced occipital GABA in Parkinson disease with visual hallucinations.

OBJECTIVE: To investigate the relationship between visual hallucinations in Parkinson disease (PD) and levels of γ-aminobutyric acid (GABA) in the primary visual cortex. METHODS: We utilized magnetic resonance spectroscopy to investigate occipital GABA levels in 36 participants with PD, 19 with and 17 without complex visual hallucinations, together with 20 healthy controls without hallucinations. In addition, we acquired T1-weighted MRI, whole-brain fMRI during a visual task, and diffusion tensor imaging. RESULTS: We found lower GABA+/creatine in PD with visual hallucinations (0.091 ± 0.010) vs those without (0.101 ± 0.010) and controls (0.099 ± 0.010) (F2,49 = 4.5; p = 0.016). Reduced gray matter in the hallucinations group was also observed in the anterior temporal lobe. Although there were widespread reductions in white matter integrity in the visual hallucinations group, this was no longer significant after controlling for cognitive function. CONCLUSIONS: The data suggest that reduced levels of GABA are associated with visual hallucinations in PD and implicate changes to the ventral visual stream in the genesis of visual hallucinations. Modulation of visual cortical excitability through, for example, pharmacologic intervention, may be a promising treatment avenue to explore.