Subtle motor disturbances in PREDICT-PD participants.

OBJECTIVE: The PREDICT-PD study aims to identify increased risk of Parkinson''s disease (PD) using online assessments of previously identified risk and early features of PD and an evidence-based scoring algorithm. We sought to determine whether higher risk participants (defined as those above the 15th centile of risk estimates) were more likely to have mild parkinsonian signs compared with lower risk participants. METHODS: Video recordings of neurological examinations, including the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III, of 208 individuals who had previously completed an online risk assessment were scored blindly and independently by two movement-disorders experts. Higher risk and lower risk subjects were compared for MDS-UPDRS part III score (and derivations of this) to identify subclinical parkinsonism, and association of risk estimates with MDS-UPDRS III scores assessed. RESULTS: Higher risk subjects had significantly higher median UPDRS part III scores (3, IQR 1-5.5) than lower risk subjects (1, IQR 0-3.0; p<0.001), and there was a significantly greater proportion of individuals classified as having subclinical parkinsonism. 18% of the higher risk subjects and 6% of the lower risk subjects exceeded the most stringent published cut-off for subtle parkinsonism of three definitions examined (p=0.027). Linear regression analysis demonstrated a continuous relationship of log-transformed risk estimates with UPDRS part III scores (increase in MDS-UPDRS per doubling of odds 0.52, 95% CI 0.31 to 0.72; p<0.001), which remained after adjustment for multiple vascular risk factors and scores on the Montreal Cognitive Assessment (0.58, 95% CI 0.30 to 0.87; p<0.001). CONCLUSIONS: The PREDICT-PD algorithm identifies a population with an increased rate of motor disturbances.

PREDICT-PD: An online approach to prospectively identify risk indicators of Parkinson's disease.

BACKGROUND: A number of early features can precede the diagnosis of Parkinson's disease (PD). OBJECTIVE: To test an online, evidence-based algorithm to identify risk indicators of PD in the UK population. METHODS: Participants aged 60 to 80 years without PD completed an online survey and keyboard-tapping task annually over 3 years, and underwent smell tests and genotyping for glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 (LRRK2) mutations. Risk scores were calculated based on the results of a systematic review of risk factors and early features of PD, and individuals were grouped into higher (above 15th centile), medium, and lower risk groups (below 85th centile). Previously defined indicators of increased risk of PD ("intermediate markers"), including smell loss, rapid eye movement-sleep behavior disorder, and finger-tapping speed, and incident PD were used as outcomes. The correlation of risk scores with intermediate markers and movement of individuals between risk groups was assessed each year and prospectively. Exploratory Cox regression analyses with incident PD as the dependent variable were performed. RESULTS: A total of 1323 participants were recruited at baseline and >79% completed assessments each year. Annual risk scores were correlated with intermediate markers of PD each year and baseline scores were correlated with intermediate markers during follow-up (all P values < 0.001). Incident PD diagnoses during follow-up were significantly associated with baseline risk score (hazard ratio = 4.39, P = .045). GBA variants or G2019S LRRK2 mutations were found in 47 participants, and the predictive power for incident PD was improved by the addition of genetic variants to risk scores. CONCLUSIONS: The online PREDICT-PD algorithm is a unique and simple method to identify indicators of PD risk. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Acute temperature sensitivity in optic nerve axons explained by an electrogenic membrane potential.

Classical work in squid axon reports resting membrane potential is independent of temperature, but our findings suggest that this is not the case for axons in mammalian optic nerve. Refractory period duration changes over 10 times between 37 °C and room temperature, and afterpotential polarity is also acutely temperature sensitive, inconsistent with changes in temperature impacting nerve function only through altered rates of ion channel gating kinetics. Our evidence suggests that the membrane potential is enhanced by warming, an effect reduced by exposure to ouabain. The temperature dependence can be explained if axonal Na(+)/K(+) ATPase continuously expels Na(+) ions that enter axons largely electroneutrally, thereby adding a substantial electrogenic component to the membrane potential. Block of the Na(+) transporter NKCC1 with bumetanide increases refractoriness, like depolarization, indicating that this is a probable route by which Na(+) enters, raising the expectation that the rate of electroneutral Na(+) influx increases with temperature and suggesting a temperature-dependent transmembrane Na(+) cycle that contributes to membrane potential.

High-Dose Ionizing Radiation Impairs Healthy Dendrite Growth in C. elegans.

Purpose: The nervous system is vulnerable to radiation damage, and further optimization is required to increase the efficacy of radiation therapy while reducing harm to neurons. Given recent developments in heavy ion therapy, experimental models would be valuable to improve these therapies. We used the nematode Caenorhabditis elegans (C. elegans) to evaluate the effects of high-dose radiation on neuron development. Methods and Materials: In this study, we used confocal microscopy to assess dendritic growth of the PVD nociceptor after high-dose gamma-irradiation from a Cs-137 source. Results: Irradiation during an early larval stage (L2) delayed overall development but also independently impaired dendrite outgrowth in the PVD nociceptive neuron. Irradiation at L4 larval stage did not result in significant alterations in dendrite morphology. Conclusions: The nematode C. elegans can serve as a high-throughput model to study the effects of high-dose radiation on dendrite growth. We propose that C. elegans can be useful for studies of experimental radiation therapy modalities and dose rates for translational research.

Systems approach to health service design, delivery and improvement: a systematic review and meta-analysis.

OBJECTIVES: To systematically review the evidence base for a systems approach to healthcare design, delivery or improvement. DESIGN: Systematic review with meta-analyses. METHODS: Included were studies in any patients, in any healthcare setting where a systems approach was compared with usual care which reported quantitative results for any outcomes for both groups. We searched Medline, Embase, HMIC, Health Business Elite, Web of Science, Scopus, PsycINFO and CINAHL from inception to 28 May 2019 for relevant studies. These were screened, and data extracted independently and in duplicate. Study outcomes were stratified by study design and whether they reported patient and/or service outcomes. Meta-analysis was conducted with Revman software V.5.3 using ORs-heterogeneity was assessed using I2 statistics. RESULTS: Of 11 405 records 35 studies were included, of which 28 (80%) were before-and-after design only, five were both before-and-after and concurrent design, and two were randomised controlled trials (RCTs). There was heterogeneity of interventions and wide variation in reported outcome types. Almost all results showed health improvement where systems approaches were used. Study quality varied widely. Exploratory meta-analysis of these suggested favourable effects on both patient outcomes (n=14, OR=0.52 (95% CI 0.38 to 0.71) I2=91%), and service outcomes (n=18, OR=0.40 (95% CI 0.31 to 0.52) I2=97%). CONCLUSIONS: This study suggests that a systems approaches to healthcare design and delivery results in a statistically significant improvement to both patient and service outcomes. However, better quality studies, particularly RCTs are needed.PROSPERO registration numberCRD42017065920.

Does oxidative stress change ceruloplasmin from a protective to a vasculopathic factor?

Although ceruloplasmin (CP), a copper containing metalloenzyme, possesses antioxidant properties (e.g. ferroxidase activity), elevated circulating CP is associated with cardiovascular disease (CVD). This ambivalence is possibly due to the capacity of CP, via its coppers, to promote vasculopathic effects that include lipid oxidation, negation of nitric oxide bioactivity and endothelial cell apoptosis. In turn, these effects that are mediated by increased formation of reactive oxygen species (ROS), such as superoxide and hydrogen peroxide. There is also evidence that risk factors for CVD (in particular, diabetes mellitus and hyperhomocysteinaemia) may augment the vasculopathic impact of CP. In turn, it appears that ROS disrupt copper binding to CP, thereby impairing its normal protective function while liberating copper which in turn may promote oxidative pathology. The objective of this review, therefore, is to consider the epidemiology and pathophysiology of CP in relation to CVD, with particular emphasis on the relationship between CP and oxidative stress.

Elevated salivary protein in Parkinson's disease and salivary DJ-1 as a potential marker of disease severity.

INTRODUCTION: There is an urgent need to identify robust biomarkers for Parkinson's disease (PD). Previous studies have shown changes in composition and secretion of saliva in patients with PD, including an increase in salivary DJ-1 concentration. Autonomic dysfunction is a known feature of PD and could contribute to abnormal salivary gland function. METHODS: In this pilot cross-sectional study, characterisation of the saliva of 16 patients with PD and 22 age-matched controls was performed. Salivary DJ-1 concentration was measured with quantitative immunoblotting; total protein concentration with a BCA assay and spectrophotometry; amylase with an amylase activity assay; albumin with an ELISA and mucin concentration with periodic-acid Schiff staining of SDS-gels. RESULTS: Patient saliva showed an increase in both total protein concentration (8.4 vs 5.0 mg/ml, p = 0.0002) and DJ-1 concentration (0.84 vs 0.42 µg/ml, p = 0.001), but there was no difference in salivary DJ-1 after adjusting for total protein concentration. In patients, adjusted DJ-1 levels correlated with disease severity measured with the MDS-Unified Parkinson's Disease Rating Scale (p = 0.019). Patient saliva had elevated concentrations of amylase (127 vs 64 units/ml, p = 0.0005) and albumin (110 vs 47µg/ml, p = 0.0003) but not mucins. CONCLUSIONS: This study suggests that the saliva of patients with PD is different in composition to that of healthy age-matched controls, supporting the notion that saliva may be a good candidate for biomarker discovery in PD. The specific differences suggest that major salivary glands and gingival crevicular fluid may both be sources of additional DJ-1 and protein in patient saliva.