Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson's disease dementia and cognitive impairment in Parkinson's disease

Background - Previous Cochrane reviews have considered the use of cholinesterase inhibitors in both Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). The clinical features of DLB and PDD have much in common and are distinguished primarily on the basis of whether or not parkinsonism precedes dementia by more than a year. Patients with both conditions have particularly severe deficits in cortical levels of the neurotransmitter acetylcholine. Therefore, blocking its breakdown using cholinesterase inhibitors may lead to clinical improvement. Objectives - To assess the efficacy, safety and tolerability of cholinesterase inhibitors in dementia with Lewy bodies (DLB), Parkinson’s disease with dementia (PDD), and cognitive impairment in Parkinson’s disease falling short of dementia (CIND-PD) (considered as separate phenomena and also grouped together as Lewy body disease). Search methods - The trials were identified from a search of ALOIS, the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group (on 30 August 2011) using the search terms Lewy, Parkinson, PDD, DLB, LBD. This register consists of records from major healthcare databases (MEDLINE, EMBASE, PsycINFO, CINAHL) and many ongoing trial databases and is updated regularly. Reference lists of relevant studies were searched for additional trials. Selection criteria - Randomised, double-blind, placebo-controlled trials assessing the efficacy of treatment with cholinesterase inhibitors in DLB, PDD and cognitive impairment in Parkinson’s disease (CIND-PD). Data collection and analysis - Data were extracted from published reports by one review author (MR). The data for each 'condition' (that is DLB, PDD or CIND-PD) were considered separately and, where possible, also pooled together. Statistical analysis was conducted using Review Manager version 5.0. Main results - Six trials met the inclusion criteria for this review, in which a total of 1236 participants were randomised. Four of the trials were of a parallel group design and two cross-over trials were included. Four of the trials included participants with a diagnosis of Parkinson's disease with dementia (Aarsland 2002a; Dubois 2007; Emre 2004; Ravina 2005), of which Dubois 2007 remains unpublished. Leroi 2004 included patients with cognitive impairment and Parkinson's disease (both with and without dementia). Patients with dementia with Lewy bodies (DLB) were included in only one of the trials (McKeith 2000). For global assessment, three trials comparing cholinesterase inhibitor treatment to placebo in PDD (Aarsland 2002a; Emre 2004; Ravina 2005) reported a difference in the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) score of -0.38, favouring the cholinesterase inhibitors (95% CI -0.56 to -0.24, P < 0.0001). For cognitive function, a pooled estimate of the effect of cholinesterase inhibitors on cognitive function measures was consistent with the presence of a therapeutic benefit (standardised mean difference (SMD) -0.34, 95% CI -0.46 to -0.23, P < 0.00001). There was evidence of a positive effect of cholinesterase inhibitors on the Mini-Mental State Examination (MMSE) in patients with PDD (WMD 1.09, 95% CI 0.45 to 1.73, P = 0.0008) and in the single PDD and CIND-PD trial (WMD 1.05, 95% CI 0.42 to 1.68, P = 0.01) but not in the single DLB trial. For behavioural disturbance, analysis of the pooled continuous data relating to behavioural disturbance rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.36 to -0.04, P = 0.01). For activities of daily living, combined data for the ADCS and the Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.38 to -0.02, P = 0.03). For safety and tolerability, those taking a cholinesterase inhibitor were more likely to experience an adverse event (318/452 versus 668/842; odds ratio (OR) 1.64, 95% CI 1.26 to 2.15, P = 0.0003) and to drop out (128/465 versus 45/279; OR 1.94, 95% CI 1.33 to 2.84, P = 0.0006). Adverse events were more common amongst those taking rivastigmine (357/421 versus 173/240; OR 2.28, 95% CI 1.53 to 3.38, P < 0.0001) but not those taking donepezil (311/421 versus 145/212; OR 1.24, 95% CI 0.86 to 1.80, P = 0.25). Parkinsonian symptoms in particular tremor (64/739 versus 12/352; OR 2.71, 95% CI 1.44 to 5.09, P = 0.002), but not falls (P = 0.39), were reported more commonly in the treatment group but this did not have a significant impact on the UPDRS (total and motor) scores (P = 0.71). Fewer deaths occurred in the treatment group than in the placebo group (4/465 versus 9/279; OR 0.28, 95% CI 0.09 to 0.84, P = 0.03). Authors' conclusions - The currently available evidence supports the use of cholinesterase inhibitors in patients with PDD, with a positive impact on global assessment, cognitive function, behavioural disturbance and activities of daily living rating scales. The effect in DLB remains unclear. There is no current disaggregated evidence to support their use in CIND-PD.

Visual hallucinations in the Parkinsonian syndromes

Differential clinical diagnosis of the parkinsonian syndromes,viz., Parkinson's disease (PD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and corticobasal degeneration (CBD) can be difficult. Visual hallucinations, however, are a chronic complication of some parkinsonian disorders and their presence may be a useful aid to diagnosis. The visual hallucinations in parkinsonism are often recurrent, well-formed, and detailed and occur in a significant proportion of cases of DLB and PD but are less common in PSP, MSA, and CBD. Hallucinations in PD often occur later in the disease and are complex, with flickering lights, and illusionary misconceptions often preceding the most common manifestation, viz., stereotypical colourful images. Hallucinations in DLB, however, are often present earlier in the disease and are similar to those in the 'misidentification syndromes', 'visual agnosias', and in 'delerium' but differ from those produced by hallucinogenic drugs such as LSD. Most typically in DLB, the hallucinations involve people or animals invading the patient's home but may also include inanimate objects and the appearance of writing on walls or ceilings. Visual hallucinations may involve a number of brain mechanisms including a change in the balance of neurotransmitter activity between the cholinergic and monoaminergic systems and may be a specific consequence of Lewy body (LB) pathology in brain stem nuclei. Ocular and retinal pathology may also contribute to hallucinations by reducing occipital stimulation. Hence, in patients with unclassifiable or with indeterminate parkinsonian symptoms, the presence of visual hallucinations should be regarded as a 'red flag' symptom indicating underlying Lewy body pathology and therefore, supporting a diagnosis of PD or DLB rather than PSP, MSA, or CBD. The presence of early visual hallucinations would support a diagnosis of DLB rather than PD. © 2013 Nova Science Publishers, Inc. All rights reserved.

Bromocriptine:old drug, new formulation and new indication

Bromocriptine is an ergot alkaloid dopamine D receptor agonist that has been used extensively in the past to treat hyperprolactinaemia, galactorrhoea and Parkinsonism. It is known that hypothalamic hypodopaminergic states and disturbed circadian rhythm are associated with the development of insulin resistance, obesity and diabetes in animals and humans. When administered in the early morning at the start of the light phase, a new quick release (QR) formulation of bromocriptine appears to act centrally to reset circadian rhythms of hypothalamic dopamine and serotonin and improve insulin resistance and other metabolic abnormalities. Phase II and III clinical studies show that QR-bromocriptine lowers glycated haemoglobin by 0.6-1.2% (7-13 mmol/mol) either as monotherapy or in combination with other antidiabetes medications. Apart from nausea, the drug is well tolerated. The doses used to treat diabetes (up to 4.8 mg daily) are much lower than those used to treat Parkinson's disease and have not been associated with retroperitoneal fibrosis or heart valve abnormalities. QR-bromocriptine (Cycloset™) has recently been approved in the USA for the treatment of type 2 diabetes mellitus (T2DM). Thus, a QR formulation of bromocriptine timed for peak delivery in the early morning may provide a novel neurally mediated approach to the control of hyperglycaemia in T2DM. © 2010 Blackwell Publishing Ltd.

Visual signs and symptoms of multiple system atrophy

Multiple system atrophy (MSA) is a rare movement disorder and a member of the 'parkinsonian syndromes', which also include Parkinson's disease (PD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB) and corticobasal degeneration (CBD). Multiple system atrophy is a complex syndrome, in which patients exhibit a variety of signs and symptoms, including parkinsonism, ataxia and autonomic dysfunction. It can be difficult to separate MSA from the other parkinsonian syndromes but if ocular signs and symptoms are present, they may aid differential diagnosis. Typical ocular features of MSA include blepharospasm, excessive square-wave jerks, mild to moderate hypometria of saccades, impaired vestibular-ocular reflex (VOR), nystagmus and impaired event-related evoked potentials. Less typical features include slowing of saccadic eye movements, the presence of vertical gaze palsy, visual hallucinations and an impaired electroretinogram (ERG). Aspects of primary vision such as visual acuity, colour vision or visual fields are usually unaffected. Management of the disease to deal with problems of walking, movement, daily tasks and speech problems is important in MSA. Optometrists can work in collaboration with the patient and health-care providers to identify and manage the patient's visual deficits. A more specific role for the optometrist is to correct vision to prevent falls and to monitor the anterior eye to prevent dry eye and control blepharospasm.

Detecting and monitoring the symptoms of Parkinson's disease using smartphones:a pilot study

Background: Remote, non-invasive and objective tests that can be used to support expert diagnosis for Parkinson's disease (PD) are lacking. Methods: Participants underwent baseline in-clinic assessments, including the Unified Parkinson's Disease Rating Scale (UPDRS), and were provided smartphones with an Android operating system that contained a smartphone application that assessed voice, posture, gait, finger tapping, and response time. Participants then took the smart phones home to perform the five tasks four times a day for a month. Once a week participants had a remote (telemedicine) visit with a Parkinson disease specialist in which a modified (excluding assessments of rigidity and balance) UPDRS performed. Using statistical analyses of the five tasks recorded using the smartphone from 10 individuals with PD and 10 controls, we sought to: (1) discriminate whether the participant had PD and (2) predict the modified motor portion of the UPDRS. Results: Twenty participants performed an average of 2.7 tests per day (68.9% adherence) for the study duration (average of 34.4 days) in a home and community setting. The analyses of the five tasks differed between those with Parkinson disease and those without. In discriminating participants with PD from controls, the mean sensitivity was 96.2% (SD 2%) and mean specificity was 96.9% (SD 1.9%). The mean error in predicting the modified motor component of the UPDRS (range 11-34) was 1.26 UPDRS points (SD 0.16). Conclusion: Measuring PD symptoms via a smartphone is feasible and has potential value as a diagnostic support tool.

Quantitative pathological changes in the cerebellum of multiple system atrophy

Multiple system atrophy (MSA) is a rare neurodegenerative disorder associated with parkinsonism, ataxia, and autonomic dysfunction. Its pathology is primarily subcortical comprising vacuolation, neuronal loss, gliosis, and α-synuclein-immunoreactive glial cytoplasmic inclusions (GO). To quantify cerebellar pathology in MSA, the density and spatial pattern of the pathological changes were studied in α-synuclein-immunolabelled sections of the cerebellar hemisphere in 10 MSA and 10 control cases. In MSA, densities of Purkinje cells (PC) were decreased and vacuoles in the granule cell layer (GL) increased compared with controls. In six MSA cases, GCI were present in cerebellar white matter. In the molecular layer (ML) and GL of MSA, vacuoles were clustered, the clusters exhibiting a regular distribution parallel to the edge of the folia. Purkinje cells were randomly or regularly distributed with large gaps between surviving cells. Densities of glial cells and surviving neurons in the ML and surviving cells and vacuoles in the GL were negatively correlated consistent with gliosis and vacuolation in response to neuronal loss. Principal components analysis (PCA) suggested vacuole densities in the ML and vacuole density and cell losses in the GL were the main source of neuropathological variation among cases. The data suggest that: (1) cell losses and vacuolation of the GCL and loss of PC were the most significant pathological changes in the cases studied, (2) pathological changes were topographically distributed, and (3) cerebellar pathology could influence cerebral function in MSA via the cerebello-dentato-thalamic tract.

A randomized trial of specialized versus standard neck physiotherapy in cervical dystonia

We thank: the patients who took part; Monsieur John-Pierre Bleton for training the physiotherapists; Gladys McPherson (Senior IT Manager), Adesoji Adeyemi (programmer) and Diana Collins (data entry) from the Centre for Healthcare Randomised Trials, University of Aberdeen who provided the randomisation and database service; and the funders including The Dystonia Society, the RS Macdonald Charitable Trust, The Sir Halley Stewart Trust, The Foyle Foundation and The Garfield Weston Foundation. The Dystonia Society and other funders had no role in the design, conduct, analysis or writing of the report or the decision to submit the manuscript.

Longitudinal diffusion tensor imaging in dementia with Lewy bodies and Alzheimer's disease

Copyright © 2016 Elsevier Ltd. All rights reserved. Acknowledgements The study was supported by the NIHR Biomedical Research Unit in Dementia and the Biomedical Research Centre awarded to Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, and the NIHR Biomedical Research Unit in Dementia and the Biomedical Research Centre awarded to Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. Elijah Mak was in receipt of a Gates Cambridge PhD studentship.

Medium-term prognosis of an incident cohort of parkinsonian patients compared to controls

Funding This work was supported by Parkinson's UK (grant numbers G0502, G0914), BMA Doris Hillier Award, the BUPA Foundation, NHS Grampian Endowments, RS MacDonald Trust.

Expression and purification of tau protein and its frontotemporal dementia variants using a cleavable histidine tag

Recombinant tau protein is widely used to study the biochemical, cellular and pathological aspects of tauopathies, including Alzheimer's disease and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTPD-17). Pure tau in high yield is a requirement for in vitro evaluation of the protein's physiological and toxic functions. However, the preparation of recombinant tau is complicated by the protein's propensity to aggregate and form truncation products, necessitating the use of multiple, time-consuming purification methods. In this study, we investigated parameters that influence the expression of wild type and FTPD-17 pathogenic tau, in an attempt to identify ways to maximise expression yield. Here, we report on the influence of the choice of host strain, induction temperature, duration of induction, and media supplementation with glucose on tau expression in Escherichia coli. We also describe a straightforward process to purify the expressed tau proteins using immobilised metal affinity chromatography, with favourable yields over previous reports. An advantage of the described method is that it enables high yield production of functional oligomeric and monomeric tau, both of which can be used to study the biochemical, physiological and toxic properties of the protein.

What to do when K-means clustering fails:a simple yet principled alternative algorithm

The K-means algorithm is one of the most popular clustering algorithms in current use as it is relatively fast yet simple to understand and deploy in practice. Nevertheless, its use entails certain restrictive assumptions about the data, the negative consequences of which are not always immediately apparent, as we demonstrate. While more flexible algorithms have been developed, their widespread use has been hindered by their computational and technical complexity. Motivated by these considerations, we present a flexible alternative to K-means that relaxes most of the assumptions, whilst remaining almost as fast and simple. This novel algorithm which we call MAP-DP (maximum a-posteriori Dirichlet process mixtures), is statistically rigorous as it is based on nonparametric Bayesian Dirichlet process mixture modeling. This approach allows us to overcome most of the limitations imposed by K-means. The number of clusters K is estimated from the data instead of being fixed a-priori as in K-means. In addition, while K-means is restricted to continuous data, the MAP-DP framework can be applied to many kinds of data, for example, binary, count or ordinal data. Also, it can efficiently separate outliers from the data. This additional flexibility does not incur a significant computational overhead compared to K-means with MAP-DP convergence typically achieved in the order of seconds for many practical problems. Finally, in contrast to K-means, since the algorithm is based on an underlying statistical model, the MAP-DP framework can deal with missing data and enables model testing such as cross validation in a principled way. We demonstrate the simplicity and effectiveness of this algorithm on the health informatics problem of clinical sub-typing in a cluster of diseases known as parkinsonism.