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 metabolic 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

Publications

10 25 50
 
Description Our findings showed that sleep restriction in an animal model of Parkinson's disease altered several behavioural (reversal of locomotor activity impairment; cognitive impairment; delay of rest-activity rhythm) and metabolic parameters (branched-chain amino acids, tryptophan pathway, phenylalanine, and lipoproteins, pointing to mitochondrial impairment). If combined, our results reveal a plethora of parameters that represents reliable early-phase biomarkers of Parkinson's disease which can easily be measured and could be translated to human studies.
Exploitation Route Our findings in an animal model of Parkinson's disease revealed a panel of metabolite biomarkers that may signal early phase Parkinson's disease. These metabolites now need to be measured in human studies.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
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 Sleep and Circadian Biomarkers
Geographic Reach Europe 
Policy Influence Type Membership of a guideline committee
 
Description Talk at UNIFESP Brazil
Geographic Reach South America 
Policy Influence Type Influenced training of practitioners or researchers
Impact Deeper, improved understanding of the links between circadian timing, restricted sleep and metabolic dysfunction.
 
Description Anticipation of meal time in humans
Amount £810,047 (GBP)
Funding ID BB/S01814X/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2019 
End 09/2022
 
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 Public
Country United Kingdom
Start 03/2015 
End 10/2016
 
Description Molecular mapping of SARS-CoV2 and the host response with multiomics mass spectrometry to stratify disease outcomes
Amount £1,851,624 (GBP)
Funding ID BB/V011456/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2020 
End 04/2022
 
Description Seasonal rhythms
Amount $2,025,000 (USD)
Funding ID NIH 
Organisation Columbia University 
Sector Academic/University
Country United States
Start 09/2016 
End 08/2021
 
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 Melatonin nanocapsules 
Organisation Cochin Institute
Country France 
Sector Academic/University 
PI Contribution Data analysis and joint papers
Collaborator Contribution Data analysis and joint papers
Impact Joint papers have been published
Start Year 2020
 
Description Melatonin nanocapsules 
Organisation Universidade de São Paulo
Country Brazil 
Sector Academic/University 
PI Contribution Data analysis and joint papers
Collaborator Contribution Data analysis and joint papers
Impact Joint papers have been published
Start Year 2020
 
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 Peripheral neuropathy metabolomics 
Organisation University of Milano-Bicocca
Country Italy 
Sector Academic/University 
PI Contribution We will perform targeted LC/MS metabolomics on samples collected by our partners
Collaborator Contribution Our partners will perform experiments (effect of chemotherapy on peripheral neuropathy in an animal model) and collect samples for our analysis
Impact Experiments are ongoing.
Start Year 2018
 
Description Sleep in animal model of Parkinson's 
Organisation Biomedical Research Institute of Lleida
Country Spain 
Sector Public 
PI Contribution Data analysis, postgraduate student exchange, joint publications
Collaborator Contribution Data analysis, postgraduate student exchange, joint publications
Impact Joint publications
Start Year 2019
 
Description Sleep in animal model of Parkinson's 
Organisation Federal University of Rio Grande do Norte
Country Brazil 
Sector Academic/University 
PI Contribution Data analysis, postgraduate student exchange, joint publications
Collaborator Contribution Data analysis, postgraduate student exchange, joint publications
Impact Joint publications
Start Year 2019
 
Description Sleep in rotenone model of Parkinson's disease 
Organisation Federal University of Paraná
Country Brazil 
Sector Academic/University 
PI Contribution Offered initial support to establish a network of researchers
Collaborator Contribution Lima at UFPR has created a Network of researchers to facilitate funding opportunities and collaborative research
Impact Joint publications
Start Year 2017
 
Description Sleep in rotenone model of Parkinson's disease 
Organisation Federal University of Rio Grande do Norte
Country Brazil 
Sector Academic/University 
PI Contribution Offered initial support to establish a network of researchers
Collaborator Contribution Lima at UFPR has created a Network of researchers to facilitate funding opportunities and collaborative research
Impact Joint publications
Start Year 2017
 
Description Sleep in rotenone model of Parkinson's disease 
Organisation University of Lleida
Country Spain 
Sector Academic/University 
PI Contribution Offered initial support to establish a network of researchers
Collaborator Contribution Lima at UFPR has created a Network of researchers to facilitate funding opportunities and collaborative research
Impact Joint publications
Start Year 2017
 
Description Delivered a Metabolomics workshop to the Federal University of Ceara, Brazil 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact A workshop on metabolomics was delivered to researchers and clinicians based at the Federal University of Ceara in Northeastern Brazil. This two day workshop covered analytical chemistry, multivariate statistics, and biological interpretation of results. All statistical tools used were open access and the research groups had access to necessary analytical chemistry platforms so this added value to their research.
Year(s) Of Engagement Activity 2020
 
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 Lecture delivered at University College Cork, Ireland 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Delivered a talk at the University College Cork in Ireland 2020. The lecture was largely attended by principal investigators, post-doctoral researchers and PhD students. The lecture focused on our current understanding of gut microbial metabolism and how metabolites arising from this activity can impact on host health and disease. Discussions afterwards led to the emergence of several new collaborations between my research group and investigators based in Cork. This spanned potential projects relating to the gut-brain axis, exercise, muscle metabolism, classical microbiology.
Year(s) Of Engagement Activity 2020
 
Description Member of the Organising and Programme Committee for Mind, Mood and Microbes - the international conference on the microbiota-gut-brain axis 
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 Part of the organising (1/4) and programme (1/14) committee for 'Mind, Mood and Microbes' - the international conference on the microbiota-gut-brain axis. Responsible for deciding the scientific direction of the conference and selecting and inviting speakers.
Year(s) Of Engagement Activity 2020,2021
URL https://www.mindmoodmicrobes.org
 
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
 
Description Panel member for a Q&A event for Mind, Mood & Microbes - the International conference on the microbiota-gut-brain axis 
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 One of 8 experts on the microbiota-gut-brain axis that sat on the Q&A panel discussing emerging mechanisms and translational challenges and innovations in this area. Over 1000 individuals registered for this event from 48 countries.
Year(s) Of Engagement Activity 2021
URL https://www.mindmoodmicrobes.org/mmm-expert-qa
 
Description Pint of Science - Human Brain? Microbial Mind? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact This was a national outreach activity (Pint of Science) intended to educate the general public about novel areas of research occurring in the UK. It was designed to be an informal 15 minute talk delivered in a pub with minimal scientific jargon. Several questions were asked after the talk about how to improve the health of the intestinal microbiota through the diet.
Year(s) Of Engagement Activity 2019
URL https://pintofscience.co.uk/
 
Description Scientific Advisory Board for the RENEW project on the Gut-Bone Axis led by Prof Hanne Bertram (Aarhus University) 
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 A member of the Scientific Advisory Board for the RENEW project on the role of calcium absorption on the Gut-Bone axis funded by Innovation Fund Denmark. Providing expertise on the application of metabolomics and the gut microbiota.
Year(s) Of Engagement Activity 2020,2021
URL https://pure.au.dk/portal/en/projects/renew--valorisering-af-sidestroemme-fra-mejeriindustrien-til-f...
 
Description Talk at University of Manchester Centre For Biological Timing 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Around 80 UK researchers attended my online Zoom talk at the University of Manchester Centre For Biological Timing.
Year(s) Of Engagement Activity 2020
 
Description Talk delivered at the Medica Labmed Forum 2020 virtual conference on the biochemical language of the microbiota-gut-brain axis 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A talk titled 'The biochemical language of the microbiota-gut-brain axis' was delivered at the virtual event of the MEDICA LABMED FORUM 2020 as part of the 'Progress in microbiome and infection diagnostics' session. This was largely targeted towards a clinical audience
Year(s) Of Engagement Activity 2020
URL https://www.medica-tradefair.com/en/Forums_Conferences/Forums/MEDICA_LABMED_FORUM/MEDICA_LABMED_FORU...
 
Description Talk on the Gut-Brain-axis at the European Behavioural Pharmacology Society / Canadian Biomarker Integration Network in Depression (CAN-BIND) - Behaviour to Biomarkers virtual workshop 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A talk was delivered at the European Behavioural Pharmacology Society (EBPS) / Canadian Biomarker Integration Network in Depression (CAN-BIND) - Behaviour to Biomarkers virtual workshop. This was a 20 minute talk on the application of metabolomics to study the metabolic components of the gut-brain axis.
Year(s) Of Engagement Activity 2021
URL https://www.canbind.ca/canbindwebsitetest/ebps/