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.

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.

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.

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.

Uncoupling protein 2 haplotype does not affect human brain structure and function in a sample of community-dwelling older adults.

Uncoupling protein 2 (UCP2) is a mitochondrial membrane protein that plays a role in uncoupling electron transport from adenosine triphosphate (ATP) formation. Polymorphisms of the UCP2 gene in humans affect protein expression and function and have been linked to survival into old age. Since UCP2 is expressed in several brain regions, we investigated in this study whether UCP2 polymorphisms might 1) affect occurrence of neurodegenerative or mental health disorders and 2) affect measures of brain structure and function. We used structural magnetic resonance imaging (MRI), diffusion-weighted MRI and resting-state functional MRI in the neuroimaging sub-study of the Whitehall II cohort. Data from 536 individuals aged 60 to 83 years were analyzed. No association of UCP2 polymorphisms with the occurrence of neurodegenerative disorders or grey and white matter structure or resting-state functional connectivity was observed. However, there was a significant effect on occurrence of mood disorders in men with the minor alleles of -866G>A (rs659366) and Ala55Val (rs660339)) being associated with increasing odds of lifetime occurrence of mood disorders in a dose dependent manner. This result was not accompanied by effects of UCP2 polymorphisms on brain structure and function, which might either indicate that the sample investigated here was too small and underpowered to find any significant effects, or that potential effects of UCP2 polymorphisms on the brain are too subtle to be picked up by any of the neuroimaging measures used.

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.

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

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

Diagnosing early cognitive decline-When, how and for whom?

Mild cognitive impairment (MCI) is a term used to describe cognitive impairment in one or more cognitive domains that is greater than any expected age-related changes, but not of the magnitude to warrant a diagnosis of dementia. This review considers how early cognitive decline is diagnosed, focusing on the use of neuropsychological tests and neuroimaging, as well as the differential diagnosis. Potential treatments, including secondary prevention, post-diagnostic support and self-help are discussed. Finally, medico-legal matters such as driving, lasting power of attorney and employment are outlined.

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.

Driving and dementia: a clinical update for mental health professionals.

Most people with mild dementia can continue to drive, but dementia is progressive and many patients and clinicians will be faced with questions about driving safety in the course of their illness. Determining when this happens is a complex decision, with risks of personal and public safety needing to be weighed against individual patient benefits of driving in terms of autonomy, independence and well-being. Decisions need to make reference to cognitive abilities, as well as other factors including physical comorbidity, vision, mobility, insight and history of driving errors and accidents. Deciding to stop driving, or being required to stop driving is often difficult for patients to accept and can be a particularly problematic consequence of a dementia diagnosis. Legal frameworks help in decision-making but may not provide sufficient detail to advise individual patients. We review the current guidelines and evidence relating to driving and dementia to help clinicians answer questions about driving safety and to consider the full range of assessment tools available.

Sub-threshold depressive symptoms and brain structure: A magnetic resonance imaging study within the Whitehall II cohort.

BACKGROUND: Late-life sub-threshold depressive symptoms (i.e. depressive symptoms that do not meet the criteria for a diagnosis of major depressive disorder) are associated with impaired physical health and function, and increased risk of major depressive disorder. Magnetic resonance imaging (MRI) studies examining late-life major depressive disorder find structural brain changes in grey and white matter. However, the extent to which late-life sub-threshold depression is associated with similar hallmarks is not well established. METHODS: Participants with no history of major depressive disorder were selected from the Whitehall Imaging Sub-Study (n=358, mean age 69±5 years, 17% female). Depressive symptoms were measured using the Centre for Epidemiological Studies Depression Scale (CES-D) at three previous Whitehall II Study phases (2003-04, 2007-09 and 2012-13) and at the time of the MRI scan (2012-14). The relationships between current and cumulative depressive symptoms and MRI brain measures were explored using Voxel-Based Morphometry (VBM) for grey matter and Tract Based Spatial Statistics (TBSS) for white matter. RESULTS: Current sub-threshold depressive symptoms were associated with significant reductions in fractional anisotropy and increases in axial and radial diffusivity. There were no significant relationships between current depressive symptoms and grey matter measures, or cumulative depressive symptoms and MRI measures. LIMITATIONS: The prevalence (10%) of sub-threshold depressive symptoms means that analyses may be underpowered to detect subtle differences in brain structure. CONCLUSIONS: Current sub-threshold depressive symptoms are associated with changes in white matter microstructure, indicating that even mild depressive symptoms are associated with similar MRI hallmarks to those in major depressive disorder.

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.

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

CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies.

BACKGROUND: Inflammatory markers are raised in cross-sectional studies of depressed patients and may represent an important mediating factor for behaviour, neural plasticity and brain structure. METHODS: We undertook a systematic review of longitudinal studies, investigating whether raised inflammatory markers indicate an increased risk of subsequent depressive symptoms. We searched three databases (1970-2012) for longitudinal studies with repeat data on CRP or IL-6 levels and subsequent depressive symptoms. We calculated effect sizes using a mixed-effects model, with separate meta-analyses for inflammatory markers and age groups. RESULTS: We identified eight papers for CRP (14,832 participants) and three for IL-6 (3695 participants). There was a significant association between increased CRP and depressive symptoms (weighted-mean effect size 'unadjusted r'=0.069, p<0.0005; 'adjusted r'=0.046, p<0.0005), with moderate heterogeneity between studies (Q=11.21, p=0.08, I(2)=46.5). For IL-6 the weighted-mean effect size was smaller ('unadjusted r'=0.045, p-value=0.007; 'adjusted r'=0.097, p-value=0.06). LIMITATIONS: The meta-analysis was based on a relatively small number of studies (particularly for IL-6) and only two inflammatory markers. There was moderate heterogeneity between studies and some evidence of publication bias. CONCLUSIONS: Raised inflammatory markers have a small but significant association with the subsequent development of depressive symptoms. This is a robust effect which remains significant after adjustment for age and a wide range of factors associated with risk for depression. Our results support the hypothesis that there is a causal pathway from inflammation to depression.

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.