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Falls are a major cause of morbidity and mortality in dementia, but there have been no prospective studies of risk factors for falling specific to this patient population, and no successful falls intervention/prevention trials. This prospective study aimed to identify modifiable risk factors for falling in older people with mild to moderate dementia. 179 participants aged over 65 years were recruited from outpatient clinics in the UK (38 Alzheimer's disease (AD), 32 Vascular dementia (VAD), 30 Dementia with Lewy bodies (DLB), 40 Parkinson's disease with dementia (PDD), 39 healthy controls). A multifactorial assessment of baseline risk factors was performed and fall diaries were completed prospectively for 12 months. Dementia participants experienced nearly 8 times more incident falls (9118/1000 person-years) than controls (1023/1000 person-years; incidence density ratio: 7.58, 3.11-18.5). In dementia, significant univariate predictors of sustaining at least one fall included diagnosis of Lewy body disorder (proportional hazard ratio (HR) adjusted for age and sex: 3.33, 2.11-5.26), and history of falls in the preceding 12 months (HR: 2.52, 1.52-4.17). In multivariate analyses, significant potentially modifiable predictors were symptomatic orthostatic hypotension (HR: 2.13, 1.19-3.80), autonomic symptom score (HR per point 0-36: 1.055, 1.012-1.099), and Cornell depression score (HR per point 0-40: 1.053, 1.01-1.099). Higher levels of physical activity were protective (HR per point 0-9: 0.827, 0.716-0.956). The management of symptomatic orthostatic hypotension, autonomic symptoms and depression, and the encouragement of physical activity may provide the core elements for the most fruitful strategy to reduce falls in people with dementia. Randomised controlled trials to assess such a strategy are a priority.

Dementia with Lewy bodies is the second most common form of neurodegenerative dementia, yet scarce evidence is available about its prognosis and natural history, which are crucial to inform clinical practice and research. Patients with dementia with Lewy bodies might have a less favourable prognosis, with accelerated cognitive decline, shorter lifespan, and increased admission to residential care than patients with Alzheimer's disease. Health-care costs and, importantly, caregiver burden, are also reported to be higher in dementia with Lewy bodies than in Alzheimer's disease. It is probable that causative factors for this less favourable prognosis are the increased prevalence and early emergence of neuropsychiatric symptoms in patients with dementia with Lewy bodies, and the challenge of accurate diagnosis. Evidence concerning quality of life and hospital admission rates is limited, despite their clinical and economic relevance.

Dementia is one of the most common and important aspects of Parkinson's disease and has consequences for patients and caregivers, and has health-related costs. Mild cognitive impairment is also common and frequently progresses to dementia. The underlying mechanisms of dementia associated with Parkinson's disease are only partly known and no mechanism-based treatments are available. Both dysmetabolism of α-synuclein and amyloid-protein and cholinergic deficits contribute to cognitive impairment in Parkinson's disease, and preliminary findings show that imaging and neurophysiological and peripheral biomarkers could be useful in diagnosis and prognosis. Rivastigmine is the only licensed treatment for dementia in Parkinson's disease, but emerging evidence suggests that memantine might also be useful. Whether these or other treatments can delay the progression from mild cognitive impairment to dementia in Parkinson's disease is a key research question.

Down's syndrome is the most common genetic cause of learning difficulties, and individuals with this condition represent the largest group of people with dementia under the age of 50 years. Genetic drivers result in a high frequency of Alzheimer's pathology in these individuals, evident from neuroimaging, biomarker, and neuropathological findings, and a high incidence of cognitive decline and dementia. However, cognitive assessment is challenging, and diagnostic methods have not been fully validated for use in these patients; hence, early diagnosis remains difficult. Evidence regarding the benefits of cholinesterase inhibitors and other therapeutic options to treat or delay progressive cognitive decline or dementia is very scarce. Despite close similarities with late-onset Alzheimer's disease, individuals with Down's syndrome respond differently to treatment, and a targeted approach to drug development is thus necessary. Genetic and preclinical studies offer opportunities for treatment development, and potential therapies have been identified using these approaches.

Depression is a common symptom in patients with Parkinson disease (PD), and is found at higher rates in these individuals than in healthy populations or patients with other neurodegenerative disorders. Aarsland et al . discuss both the course of depression and the mechanisms that may contribute to the enhanced susceptibility to depression in patients with PD. Management strategies to control depression in these individuals are also highlighted. Depression occurs in around 35% of patients with Parkinson disease (PD) and is often persistent. Symptoms of depression can be evident in individuals at the time of diagnosis and might develop in the premotor stage of the disease. The underlying mechanisms of depression in PD are not known in detail, but changes in brain structure, signaling by neurotransmitters, and levels of inflammatory and neurotrophic factors are all suggested to contribute to its development. Psychosocial factors and pain could also have roles in depression. Changes in dopaminergic, noradrenergic and serotonergic systems in patients with PD might help to explain the incidence of depression in these individuals. Antidepressants that have dual serotonergic and noradrenergic effects are the drugs of choice for treating depression in PD. However, antiparkinsonian drugs might have beneficial effects not only on the motor symptoms of disease, but also on a patient's mood. Deep brain stimulation can worsen depression in some patients, but a preliminary study has suggested that transcranial magnetic stimulation could improve symptoms of depression. This Review describes the frequency and course of depression in patients with PD. The mechanisms that underlie depression in this disease are also discussed, and the management strategies for these patients are highlighted. Key Points Depression occurs in around 35% of patients with Parkinson disease (PD) Mild depression is often persistent in patients with PD, and is a risk factor for moderate to severe depression The etiology of depression in PD is not clear, but changes in neurotransmitter (monoaminergic) signaling and limbic Lewy body pathology might contribute The roles of other pathologies (such as cerebrovascular disease) and neurotrophic changes in depression are not known Pramipexole and nortriptyline are the only agents that have shown antidepressant effects in placebo-controlled clinical trials in patients with PD

Parkinson's disease psychosis, which includes hallucinations and delusions, is frequent and debilitating in people with Parkinson's disease. We aimed to assess safety and efficacy of pimavanserin, a selective serotonin 5-HT2A inverse agonist, in this population. In our 6 week, randomised, double-blind, placebo-controlled study, we enrolled adults (aged ≥40 years) with Parkinson's disease psychosis. Antipsychotic treatments were not permitted during the study, but controlled antiparkinsonian medication or deep brain stimulation was allowed. Eligible participants entered a 2 week non-pharmacological lead-in phase to limit the placebo response, after which they were randomly allocated (1:1) to receive pimavanserin 40 mg per day or matched placebo. The primary outcome was antipsychotic benefit as assessed by central, independent raters with the Parkinson's disease-adapted scale for assessment of positive symptoms (SAPS-PD) in all patients who received at least one dose of study drug and had a SAPS assessment at baseline and at least one follow-up. We assessed safety and tolerability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01174004. Between Aug 11, 2010, and Aug 29, 2012, we randomly allocated 199 patients to treatment groups. For 90 recipients of placebo and 95 recipients of pimavanserin included in the primary analysis, pimavanserin was associated with a −5·79 decrease in SAPS-PD scores compared with −2·73 for placebo (difference −3·06, 95% CI −4·91 to −1·20; p=0·001; Cohen's d 0·50). Ten patients in the pimavanserin group discontinued because of an adverse event (four due to psychotic disorder or hallucination within 10 days of start of the study drug) compared with two in the placebo group. Overall, pimavanserin was well tolerated with no significant safety concerns or worsening of motor function. Pimavanserin may benefit patients with Parkinson's disease psychosis for whom few other treatment options exist. The trial design used in this study to manage placebo response could have applicability to other studies in neuropsychiatric disease. ACADIA Pharmaceuticals.

Drug repositioning and repurposing can enhance traditional drug development efforts and could accelerate the identification of new treatments for individuals with Alzheimer disease (AD) dementia and mild cognitive impairment. Transcriptional profiling offers a new and highly efficient approach to the identification of novel candidates for repositioning and repurposing. In the future, novel AD transcriptional signatures from cells isolated at early stages of disease, or from human neurons or microglia that carry mutations that increase the risk of AD, might be used as probes to identify additional candidate drugs. Phase II trials assessing repurposed agents must consider the best target population for a specific candidate therapy as well as the mechanism of action of the treatment. In this Review, we highlight promising compounds to prioritize for clinical trials in individuals with AD, and discuss the value of Delphi consensus methodology and evidence-based reviews to inform this prioritization process. We also describe emerging work, focusing on the potential value of transcript signatures as a cost-effective approach to the identification of novel candidates for repositioning.Drug repositioning and repurposing can enhance traditional drug development efforts and could accelerate the identification of new treatments. In this Review, Ballard and colleagues highlight priority compounds for repurposing for the treatment of Alzheimer disease.

Key Points Parkinson disease (PD) psychosis refers to a spectrum of illusions, hallucinations and delusions that occur throughout the disease course Evolving literature highlights the importance of recognizing and treating PD psychosis, and understanding its role as a clinical biomarker of disease stage, distribution and future progression Current evidence points to PD psychosis as a set of symptoms with distinct pathophysiological mechanisms, as opposed to a single pathophysiological symptom with a spectrum of severity The relationship between neuropathology in PD psychosis and in vivo measures of reduced metabolism, functional MRI alterations and cortical volume loss remains unclear Further studies are needed to explore the role of PD medication in unmasking psychosis symptoms, why psychosis symptoms predict worse cognitive outcome, comparisons of psychosis symptoms and mechanisms in different clinical conditions, and development of novel treatments The publication of a consensus definition of Parkinson disease (PD) psychosis in 2007 led to a rapid expansion of literature focusing on clinical aspects, mechanisms and treatment. The authors review this literature and discuss the evolving view of PD psychosis, from distinct classes of symptoms to a continuum progressing over the course of PD. In 2007, the clinical and research profile of illusions, hallucinations, delusions and related symptoms in Parkinson disease (PD) was raised with the publication of a consensus definition of PD psychosis. Symptoms that were previously deemed benign and clinically insignificant were incorporated into a continuum of severity, leading to the rapid expansion of literature focusing on clinical aspects, mechanisms and treatment. Here, we review this literature and the evolving view of PD psychosis. Key topics include the prospective risk of dementia in individuals with PD psychosis, and the causal and modifying effects of PD medication. We discuss recent developments, including recognition of an increase in the prevalence of psychosis with disease duration, addition of new visual symptoms to the psychosis continuum, and identification of frontal executive, visual perceptual and memory dysfunction at different disease stages. In addition, we highlight novel risk factors — for example, autonomic dysfunction — that have emerged from prospective studies, structural MRI evidence of frontal, parietal, occipital and hippocampal involvement, and approval of pimavanserin for the treatment of PD psychosis. The accumulating evidence raises novel questions and directions for future research to explore the clinical management and biomarker potential of PD psychosis.

[...]a substantial increase in long-term funding for multidisciplinary research programmes is absolutely essential to reduce the burden of individual suffering and the enormous societal cost of AD. In 2015, almost 47 million people worldwide were estimated to be affected by dementia, and the numbers are expected to reach 75 million by 2030, and 131 million by 2050, with the greatest increase expected in low-income and middle-income countries.2 In 2012 and 2015, the World Health Organization (WHO) presented reports in which it acknowledged this trend--sometimes described in terms of a fast-growing epidemic--and concluded that AD and other dementias should be regarded as a global public health priority.3,4 Similar policy declarations have been made by the European Union5 (EU) and by some individual countries. Care for people with dementia is provided by several sectors in society, with the social-care (long-term care and home services) and informal-care (provided by non-professional caregivers) sectors accounting for the greatest proportion of costs--even greater than the cost of direct medical care.6 In cost-of-illness studies, total societal cost estimates for dementia in Europe in 2010 were between $238·6 billion6 and [euro]105·6 billion.7 The economic costs of caring for a growing number of people with AD and other dementias are formidable, but the combined economic and societal burden of dementia is more daunting still, corresponding to the aggregate burden of people with dementia and their next of kin.

The aim of PROTECT-UK was to deliver an online ageing cohort for UK adults to facilitate large-scale high quality longitudinal data collection and delivery of remote and hybrid clinical trials as an innovative cost-effective low-risk research solution. PROTECT-UK recruits adults over 40 in the UK through a website and app. All activities are completed online including annual neuropsychological assessment with the computerized FLAME battery, neuropsychiatric symptoms, physical and mental health and lifestyle data. DNA is collected remotely. Clinical trials are delivered within the study platform via full consent-for-contact and cohort pre-screening which facilitates rapid recruitment. Participant engagement and retention is facilitated through access to evidence-based cognitive training, regular communications and the opportunity to inform the research agenda. PROTECT-UK has collated data from 54,000 participants to date and has 30,000 active participants. International instances of PROTECT are live in Norway (n = 5000) and Canada (n = 2500). Participant retention in the UK is up to 80% year-on-year. 17,000 DNA samples have been collected. PROTECT has recruited over 60,000 participants to online clinical trials, including large-scale trials of cognitive training that demonstrated significant benefits and nutritional supplement trails including vitamin D supplementation in people with early cognitive deficits (n = 654), dietary nitrate in people with the ApoE4 gene (n = 120) and a hybrid trial of a Mediterranean Diet supplement involving a sub-group recalled for venepuncture and physiological assessment (n = 150). Trials have achieved up to 95% retention and data completeness, with treatment compliance comparable to in-person trials. Genomic data has contributed to several published and ongoing studies including demonstrating increased schizophrenia and Alzheimer polygenic risk in people with mild behavioural impairment. Characterisation of the cohort shows there are >400 participants with GBA mutations and >800 E4 homozygotes with consent for contact. With proactive approaches, long term engagement can be achieved in digital platform studies. PROTECT has shown the feasibility of remotely running efficient and high quality clinical trials and collecting genomic and other biological materials to enhance research outputs.