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

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.

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.

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