Newton001 SLEEP DEPRIVATION IN PARKINSON'S DISEASE: BRAZIL AND UNITED KINGDOM RESEARCH NETWORK

Lead Research Organisation: University of Surrey
Department Name: Biochemistry & Physiology

Abstract

The project aims to address the important topic of sleep disturbances in Parkinson's disease (PD) which is a growing health issue in Brazil, since life expectancy is significantly increasing across the decades (1970: 58.9 years; 1980: 62.8 years; 1990: 66.6 years; 2011: 74.3 years - World Health Rankings) and PD affects 1-3% of people over 65 years. Prevalence of neurodegenerative diseases is increasing in developing countries, in Brazil this is estimated to be 5.3%. In addition, economic development is associated with increased urbanization and shift work, which negatively impacts on sleep quality, generating several health problems (e.g. obesity, higher incidence of cancer, cardiovascular and metabolic disturbances) and increasing demand on the public health system. This project thus aims to address a strategic health problem in Brazil and will create a scientific Brazil-UK network to study the basic mechanisms underlying PD with novel, state-of-the-art analytical tools and approaches.

The overall aim of the project is to investigate the behavioural, neurochemical and metabolic changes following sleep restriction in an animal model of PD. We hypothesise that sleep deprivation will produce cognitive deficits, neurochemical and metabolic disruption. The behavioural and neurochemical experiments will be undertaken in the Neurophysiology Laboratory (Profs Lima and Louzada, Federal University of Paraná), a centre of excellence for the study of Parkinson's disease in Brazil. Samples will be analysed by targeted liquid chromatography/mass spectrometry (LC/MS) metabolomics (Prof Skene (University of Surrey). Additional added value will be provided by employing a second metabolomics platform, untargeted 1H NMR metabolomics to characterise brain, plasma and urine metabolite changes in the rat model (Dr Swann, University of Reading). The application of two complementary analytical approaches ensures wide metabolome coverage and using multiple sample types allows the metablic perturbations induced by sleep deprivation in PD to be studied at different levels.

The planned combination of behavioural, neurochemical and metabolomic approaches will enable a multi-faceted observation of circulating and central neuronal parameters that could identify possible molecular biomarkers of early neurodegeneration in PD with potential diagnostic value. There will also be a mutual exchange of researchers and postgraduate students between the UK and Brazil to share new ideas, techniques and approaches allowing mutual (global) growth. The results of the proposed experiments will advance understanding of the mechanisms of PD and its inter-relationship with sleep/wake processing. Creation of a Brazil-United Kingdom research network will also provide a foundation for future studies and collaboration.

Technical Summary

Parkinson's disease (PD) is the second most common neurodegenerative disease, afflicting about 1% of people over 65 years and 4-5% of people over 85 years. The major clinical features include asymmetric onset of bradykinesia, rigidity, rest tremor and disturbances in balance. PD patients also experience prodromal, non-motor features, such as sleep disorders (insomnia, restless legs and periodic limb movements, rapid eye movement (REM) sleep behaviour disorder, excessive daytime sleepiness) and neuropsychiatric symptoms (depression, anxiety, apathy). Sleep disturbances and metabolic alterations may thus precede the cardinal motor features of PD by many years, and have been considered as early biomarkers of the premotor phase of PD. Accordingly, the overall aim of the present project is to investigate the behavioural, neurochemical and metabolic changes following chronic partial sleep deprivation in an animal model of PD. We hypothesise that sleep deprivation will produce cognitive deficits, neurochemical and metabolic disruption.

Control and PD rats will be sleep deprived by "gentle stimulation" made by tapping or gentle shaking of the cage whenever drowsiness or attempts to engage in a sleeping posture are observed (from 7:00 to 13:00 h daily, totally 6 h of sleep deprivation per day during 21 days). The animals will be kept undisturbed from 13:00-07:00 h, totally 18 h/day sleep recovery. Hence, this protocol is consistent with a chronic sleep restriction procedure that is similar to the sleep restriction experienced in our society today. Behavioural testing will be conducted in the open-field and object recognition tests for analysis of motor and cognitive parameters. Blood, urine and brain samples will be collected and analysed by capillary electrophoresis with laser-induced detection (LIF) (neurochemical analysis) and targeted liquid chromatography/mass spectrometry (LC/MS) and NMR metabolomics analysis.

Planned Impact

N/A
 
Description Genone scale analysis guidelines
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact The published guidelines is a multi-author paper and will act as a blue print for large scale omics analysis of time-series data.
 
Description FAPESP - CONFAP - UK Academies
Amount R$ 35,000 (BRL)
Funding ID 2016/50417-3 
Organisation São Paulo Research Foundation (FAPESP) 
Sector Public
Country Brazil
Start 05/2017 
End 04/2018
 
Description MRC Newton001
Amount £49,000 (GBP)
Funding ID MR/N006321/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 03/2015 
End 10/2016
 
Title Metabolomics in an animal model of Parkinson's disease 
Description Combination of NMR and targeted LC-MS metabolomics approaches to provide broad coverage of the metabolome 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2019 
Provided To Others? Yes  
Impact Using both NMR and targeted metabolomics approaches to investigate the effect of chronic sleep restriction in an animal mode of Parkinson's Disease (PD) has identified a broader range of metabolites involved. We propose that these metabolites may serve as reliable early-phase PD biomarkers which can easily be measured and could be translated to human studies. 
URL https://www.ncbi.nlm.nih.gov/pubmed/30760786
 
Title Metabolomics in PD 
Description Database of metabolomics data from two analytical platforms (NMR and LC/MS) looking at the effect of chronic sleep restriction on an animal model of Parkinson's disease (PD) 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? No  
Impact The research database will only be made available once these data are published. Once this has occurred the subsequent impact can be assessed. 
 
Description Bile acids 
Organisation Imperial College London
Department Imperial College Trust
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Our expertise in chronobiology and sleep, access to biological samples, data and facilities
Collaborator Contribution Access to their facilities and expertise in metabolomics and bile acid measurment
Impact Research collaboration and research grant
Start Year 2015
 
Description Gut microbiota 
Organisation Imperial College London
Department Department of Surgery and Cancer
Country United Kingdom 
Sector Academic/University 
PI Contribution Metabolomics LC/MS dataset; expert knowledge of circadian rhythms
Collaborator Contribution Expertise in gut microbiota analysis; training of research staff
Impact Collaboration is multi-disciplinary (physiology/pharmacology; analytical chemistry).
Start Year 2018
 
Description Model of Hyperammonemia 
Organisation University of Helsinki
Country Finland 
Sector Academic/University 
PI Contribution Development of targeted LC/MS method to measure metabolites in rat brain tissue
Collaborator Contribution Designed and performed sleep deprivation experiments in a rat model of hyperammonemia; collected brain tissue samples
Impact Research publication and conference presentations
Start Year 2016
 
Description Model of Hyperammonemia 
Organisation University of Padova
Country Italy 
Sector Academic/University 
PI Contribution Development of targeted LC/MS method to measure metabolites in rat brain tissue
Collaborator Contribution Designed and performed sleep deprivation experiments in a rat model of hyperammonemia; collected brain tissue samples
Impact Research publication and conference presentations
Start Year 2016
 
Description NMR and LC/MS metabolomics in Parkinsons disease 
Organisation Federal University of Paraná
Country Brazil 
Sector Academic/University 
PI Contribution Our expertise in chronobiology and sleep, protocol design, LC/MS metabolomics and data sharing
Collaborator Contribution Imperial's expertise in NMR metabolomics; Federal University of Parana's expertise in animal model of Parkinson's disease; National Institute for Public Health and Environment (RIVM) expertise in statistical and data analysis
Impact Metabolomics data generation; Conference presentations; Grants and scholarship proposals; Collaboration is multi-disciplinary
Start Year 2015
 
Description NMR and LC/MS metabolomics in Parkinsons disease 
Organisation Imperial College London
Department Department of Surgery and Cancer
Country United Kingdom 
Sector Academic/University 
PI Contribution Our expertise in chronobiology and sleep, protocol design, LC/MS metabolomics and data sharing
Collaborator Contribution Imperial's expertise in NMR metabolomics; Federal University of Parana's expertise in animal model of Parkinson's disease; National Institute for Public Health and Environment (RIVM) expertise in statistical and data analysis
Impact Metabolomics data generation; Conference presentations; Grants and scholarship proposals; Collaboration is multi-disciplinary
Start Year 2015
 
Description NMR and LC/MS metabolomics in Parkinsons disease 
Organisation National Institute for Public Health and Environment (RIVM)
Country Netherlands 
Sector Academic/University 
PI Contribution Our expertise in chronobiology and sleep, protocol design, LC/MS metabolomics and data sharing
Collaborator Contribution Imperial's expertise in NMR metabolomics; Federal University of Parana's expertise in animal model of Parkinson's disease; National Institute for Public Health and Environment (RIVM) expertise in statistical and data analysis
Impact Metabolomics data generation; Conference presentations; Grants and scholarship proposals; Collaboration is multi-disciplinary
Start Year 2015
 
Description International Biomarkers Workshop 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Representatives from international Sleep and Circadian Rhythm Societies attended a day workshop (Boston, US) to discuss standardisation of methods to uncover sleep and circadian biomarkers. A white paper has been proposed.
Year(s) Of Engagement Activity 2017
 
Description Milano-Bicocca Workshop 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Gave a talk at Neurobiology Workshop (University of Milan-Bicocca) emphasising the value of Metabolomics as a tool for neuroscience research. Developed a research collaboration with Prof Guido Cavaletti. We are actively seeking research funding.
Year(s) Of Engagement Activity 2017
 
Description Mood, Mind and Microbes annual meeting Amsterdam 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact An invited talk at the Mood, Mind and Microbes annual meeting in Amsterdam. The focus of my talk was the role of the microbiota in the gut-brain axis including in disease states such as Parkinson's. The audience was made up of academic researchers, post-graduate students, industry representatives from food and pharmaceutical companies as well as writers/journalists. A promotional video was created from the conference and I gave an interview that is now publicly available about the gut-brain axis.
Year(s) Of Engagement Activity 2019
URL https://www.mindmoodmicrobes.org