Theme 1: Improving neurobehavioural outcomes in sleep apnea
Problem: Obstructive sleep apnea (OSA) is a debilitating breathing disorder that affects at least one million Australians. It is associated with major adverse health outcomes including cardiovascular disease, and patients with untreated OSA are seven to eight times more likely to have vehicle crashes. Our work has shown that 41% of truck drivers in Australia have OSA . Problems with alertness, attention and cognition are highly prevalent and there is emerging evidence that many OSA patients will progress to dementia . Patients with OSA also demonstrate highly variable outcomes despite currently available therapies. Some patients have great improvements with treatment but this is not universal and at the moment not predictable.
- Build upon “phenotyping” techniques (i.e. categorising OSA sufferers into subtypes of the disease) to develop personalised medicine approaches to improve individual patient outcomes.
- Use novel neuroimaging and neurophysiology techniques to identify vulnerable patients at high risk of negative outcomes from OSA (e.g. motor vehicle crashes, dementia and depression).
- Optimise treatment adherence via targeted behavioural interventions and conduct randomised controlled trials (RCTs) of novel combination therapies.
- Integrate simplified neurocognitive testing into office-based clinical practice to detect neurobiological damage and characterise best predictors of brain dysfunction.
- Determine potential associations between respiratory neurobiology phenotyping and brain damage/sleepiness.
- Build upon current research into brain electrical activity (qEEG) markers predicting likelihood of falling asleep while driving in OSA.
- Investigate alternative strategies for improving neurocognition in OSA either in combination with CPAP or in treatment non-responders. Therapies to be investigated include wakefulness promoters, neuroprotective agents such as melatonin or creatine and light.
- Test a stepped intervention approach for prospective CPAP users who report poor self-efficacy at baseline and compare telehealth-enhanced expert rural CPAP care with usual care.
- Examine usage and barriers to treatment uptake (ethnicity, neurodegenerative disorders).
- Sharwood, L.N., et al., Assessing sleepiness and sleep disorders in Australian long-distance commercial vehicle drivers: self-report versus an “at home” monitoring device. Sleep, 2012. 35(4): p. 469-75.
- Yaffe, K., et al., Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. JAMA, 2011. 306(6): p. 613-9.
Theme 2: The unhealthy shift worker
Problem: Sixteen per cent of the Australian workforce (approximately 1.8 million people) are shift workers , who commonly experience excessive sleepiness and neurocognitive impairment. This increases the risk of injury, error and motor vehicle crash. One of the major challenges facing industries (especially 24-hour industries like mining, transport, manufacturing, health) is to identify workers who are most vulnerable to the effects of sleep loss and circadian misalignment, and thus the adverse health and safety effects of shift work.
Shift work, and our modern lifestyle in general, lead to a disconnect between our internal circadian clock and when we choose to eat, sleep, socialise, and exercise. These temporal alterations correlate with increasing metabolic disorders and obesity and shift workers have a 40% higher rate of cardiovascular disease . Circadian rhythms are strongly regulated by light input and melatonin. Despite this, light intervention strategies and timed melatonin administration are poorly used by shift workers and their employers.
- Measure and predict adverse neurocognitive and cardio-metabolic outcomes in shift workers, first in the laboratory then in the field, extending a model developed by our team to predict alertness to other physiological markers.
- Examine the interactive effects of sleep disorders and shift work on neurocognitive and cardio-metabolic outcomes. We will study individuals with and without sleep apnea, to understand how sleep apnea influences the health and safety risks associated with shift work.
- Data collected will inform shift work policy, including work schedule limits and medical screening, and form the basis for effectiveness trials of sleep apnea screening and management in shift workers.
- Undertake randomised, controlled trials evaluating light, melatonin and dietary manipulations to reduce neurocognitive and cardio-metabolic dysfunction in shift workers. We will then combine these intervention approaches to develop an evidence-based shift work health management system that will be trialled in individuals found to be most vulnerable to adverse health outcomes.
- Australian Bureau of Statistics, 6342.0 – Working Time Arrangements, Australia, November 2009. 2009: Canberra.
- Barger, L.K., et al., Neurobehavioral, health, and safety consequences associated with shift work in safety-sensitive professions. Curr Neurol Neurosci Rep, 2009. 9(2): p. 155-64.
- Rajaratnam, S.M., et al., Health in a 24-h society. Lancet, 2001. 358(9286): p. 999-1005.
Theme 3: Translational neurobiological strategies for insomnia management
Problem: Insomnia is the most common sleep disorder resulting in absenteeism, increased health risks and health-care utilisation, progression to depression and neurocognitive impairment[1,2]. General practitioner data show that sedative hypnotics are prescribed in approximately 90% of consultations despite well-known problems of dependence, falls and impaired cognition[3,4]. Insomnia has multiple clinical phenotypes –– patients with hyperarousal but misperception of normal sleep length; others with hyperarousal and marked reduction in objectively measured sleep length (a group at risk of developing cardio-metabolic disorders); RLS a common familial sensori-motor disorder involving CNS dopamine neurones); delayed sleep phase disorder (DSPD) characterised by a delayed sleep and wake times, associated with delayed endogenous circadian rhythms. These phenotypes are associated with variable expression of anxiety and mood disorders. Insomnia research is hampered by lack of reliable and objective tests of insomnia severity, absence of information on how these phenotypes impact daytime function, and paucity of objective markers to guide treatment. There is also little data on the neurobiological consequences of restricted sleep hours and circadian misalignment in patients with different insomnia phenotypes. While the positive impact of behavioural approaches in insomnia are known, there is scant data on how best to deliver such therapies to avoid benzodiazepine use.
- Determine neurobiological correlates of insomnia phenotypes using neuroimaging, neurocognition, neurophysiology, circadian physiology and autonomic markers.
- Investigate the interactive effects of sleep loss and circadian misalignment on neurocognitive performance and mood in patients with insomnia.
- Evaluate effectiveness of novel treatments for insomnia in at-risk populations.
- Establish a standardised protocol for neurobiological insomnia phenotyping across CRE nodes, including neuroimaging, neurocognition, neurophysiology and circadian physiology and to determine insomnia subtypes.
- Examine the effects of sleep and circadian manipulations on neurocognitive performance and mood in insomnia patients
- Implement trials to determine whether well-defined phenotypic characterisation can inform and improve treatment responses to CBTi and/or melatonin in clinical cohorts across the CRE nodes.
- Shekleton, J.A., et al., Searching for the daytime impairments of primary insomnia. Sleep Med Rev, 2010. 14(1): p. 47-60.
- Sivertsen, B., et al., The long-term effect of insomnia on work disability: the HUNT-2 historical cohort study. Am J Epidemiol, 2006. 163(11): p. 1018-24.
- Charles, J., et al., Insomnia. Aust Fam Physician, 2009. 38(5): p. 283.
- Glass, J., et al., Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ, 2005. 331(7526): p. 1169.
Theme 4: Neurodegenerative and neuropsychiatric disorders in later life – sleep and circadian dysfunction
Problem: Australia’s ageing population will lead to a marked increase in the proportion of people affected by neurodegenerative conditions. For example, Alzheimer’s Disease (AD) currently affects over 300,000 Australians and is estimated to increase by 30% in less than 10 years, whilst Parkinson’s disease (PD), which currently affects 80,000 Australians, is predicted to rise by 80% over the next 20 years. Sleep-wake disturbances affect the majority of these patients with far reaching impact not only on their own quality of life but also on that of their families. Patients with mild cognitive impairment (MCI), who represent an at-risk population for developing dementia, as well as patients with PD, have higher rates of sleep apnea, sleep-wake and circadian disturbance.
These observations highlight the poorly understood neurobiological inter-relationships between neurodegenerative disease, depression and sleep at a pathophysiological level. Furthermore, it is not known whether targeted sleep-wake interventions can influence these mechanisms and/or ameliorate the progression of neurodegenerative disease. Interestingly, emerging evidence suggests that patients in later life who develop sleep-wake disturbances, such as sleep apnea and idiopathic REM sleep behaviour disorder (iRBD) are at higher risk of developing neurodegenerative conditions (e.g. patients with iRBD have a 50% transition to PD or dementia over 10 years).
Despite this growing awareness, definitive biomarkers have not been identified to facilitate early diagnosis and the impact that specific neuroprotective interventions might offer in prevention/delay of disease development is not known.
- Evaluate the efficacy of targeted sleep-wake interventions (e.g. CPAP, pharmacotherapy, bright light and behavioural programs) in at-risk patients and those with neurodegenerative disease.
- Examine the ability of sleep-wake interventions to ameliorate the longitudinal course of neurodegenerative disease and LLD.
- Determine clinically useful biomarkers for the robust prediction of disease development in at-risk populations to enable early intervention.
- Evaluate specific sleep-wake interventions within established, well-phenotyped samples of patients with neurodegenerative disorders. Using personalised medicine approaches, we will trial therapies such as CPAP and MAS to impact on disease progression, and examine chrono-pharmacological interventions (e.g. melatonin, melatonin agonists) and light therapy to realign circadian rhythms.
- Identify the specific aspects of sleep and circadian function that relate to memory impairment and determine how it relates to other neurobiological changes using brain imaging.
- Deloitte Access Economics, Dementia Across Australia: 2011-2050, 2011: Barton, ACT.
- Naismith, S.L., et al., Sleep-wake changes and cognition in neurodegenerative disease. Prog Brain Res, 2011. 190: p. 21-52.
- Postuma, R.B., et al., RBD as a biomarker for neurodegeneration: The past 10 years. Sleep Med, 2012.