Sleep and circadian dysfunction in ageing and neurodegeneration: a life course and biomarker study of the British 1946 birth cohort.
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
Sleep is an essential requirement of all animal life, including humans, who spend around a third of their life asleep. It is controlled by an internal biological clock, our circadian rhythm, which controls the timing of when we rest, sleep, and are active. We do not understand why humans need to sleep, however, it is becoming clear that sleep and circadian rhythms are linked to cognition (brain functions such as thinking and memory).
Sleep and circadian rhythms are disrupted in neurological diseases where the brain is gradually damaged over time, called neurodegenerative diseases. These diseases include Alzheimer's disease, the most common cause of dementia worldwide and a leading cause of death. Alzheimer's disease causes alterations in sleep and circadian rhythms. These changes can occur before other symptoms and may help us identify those who will develop these diseases. Early diagnosis is essential as it enables treatment before damage to the brain is too widespread. Evidence is also emerging that abnormal sleep and circadian rhythms may be part of the cause of Alzheimer's disease.
We do not know why abnormal sleep and circadian rhythms emerge, how they change over time, or how they relate to cognition in the long term. It is unclear if disturbed circadian rhythms are early signs of disease, or if they precede and cause neurodegenerative diseases.
To answer these questions we must analyse sleep and circadian rhythms in detail. Bed mats placed under the mattress, and worn devices, called actigraphy, allow us to closely monitor sleep and circadian rhythms in patients' own homes. The genes and sleep-promoting chemicals which control sleep and circadian rhythms can be detected in the blood and spinal fluid. Advanced brain imaging, blood and spinal fluid analysis allows us to detect signs of damage and neurodegenerative diseases in the brain.
The Medical Research Council National Survey for Health and Development (NSHD) offers a unique opportunity to examine the effects of abnormal sleep and circadian rhythms on cognition and neurodegenerative disease. It has followed 5362 people born in Britain on the same week in 1946, with regular questionnaires throughout their lives. The Insight 46 study has recruited is recruiting a further 872 people from NSHD to have advanced brain imaging, detailed cognitive assessments, actigraphy, genetic testing, and sampling of their blood and spinal fluid to analyse for evidence of neurodegeneration. 250 people will undergo repeat assessments, and 100 will have at least 6 months of bed mat analysis. These repeated and prolonged assessment allow particularly detailed examination of changes in sleep and circadian rhythms over time, and how they relate to progressive changes in cognition, brain imaging, and in the blood or spinal fluid.
We will also examine the chemicals that control sleep and circadian rhythms in the spinal fluid of 375 participants, and examine how the genes that control sleep or make you more likely to develop Alzheimer's disease relate to sleep, circadian rhythms, and signs of neurodegenerative disease in old age. One fifth of those within Insight 46 already have early signs of Alzheimer's disease.
For my PhD I plan to examine how sleep and circadian rhythms relate to cognition and neurodegenerative disease. Using sleep and circadian rhythm questionnaire data from birth to the seventh decade with sleep data from actigraphy and bed mats, I will examine sleep and circadian rhythms over the human lifetime in unparalleled detail. Combining this with the advanced brain imaging, cognitive, blood and spinal fluid data already collected from Insight 46 will allow me to explore how sleep and circadian rhythms relate to cognition and neurodegenerative disease. Finally, I will examine how this process is controlled by our genes, and sleep promoting chemicals, and whether failures in this control system are related to cognition and neurodegenerative disease.
Sleep and circadian rhythms are disrupted in neurological diseases where the brain is gradually damaged over time, called neurodegenerative diseases. These diseases include Alzheimer's disease, the most common cause of dementia worldwide and a leading cause of death. Alzheimer's disease causes alterations in sleep and circadian rhythms. These changes can occur before other symptoms and may help us identify those who will develop these diseases. Early diagnosis is essential as it enables treatment before damage to the brain is too widespread. Evidence is also emerging that abnormal sleep and circadian rhythms may be part of the cause of Alzheimer's disease.
We do not know why abnormal sleep and circadian rhythms emerge, how they change over time, or how they relate to cognition in the long term. It is unclear if disturbed circadian rhythms are early signs of disease, or if they precede and cause neurodegenerative diseases.
To answer these questions we must analyse sleep and circadian rhythms in detail. Bed mats placed under the mattress, and worn devices, called actigraphy, allow us to closely monitor sleep and circadian rhythms in patients' own homes. The genes and sleep-promoting chemicals which control sleep and circadian rhythms can be detected in the blood and spinal fluid. Advanced brain imaging, blood and spinal fluid analysis allows us to detect signs of damage and neurodegenerative diseases in the brain.
The Medical Research Council National Survey for Health and Development (NSHD) offers a unique opportunity to examine the effects of abnormal sleep and circadian rhythms on cognition and neurodegenerative disease. It has followed 5362 people born in Britain on the same week in 1946, with regular questionnaires throughout their lives. The Insight 46 study has recruited is recruiting a further 872 people from NSHD to have advanced brain imaging, detailed cognitive assessments, actigraphy, genetic testing, and sampling of their blood and spinal fluid to analyse for evidence of neurodegeneration. 250 people will undergo repeat assessments, and 100 will have at least 6 months of bed mat analysis. These repeated and prolonged assessment allow particularly detailed examination of changes in sleep and circadian rhythms over time, and how they relate to progressive changes in cognition, brain imaging, and in the blood or spinal fluid.
We will also examine the chemicals that control sleep and circadian rhythms in the spinal fluid of 375 participants, and examine how the genes that control sleep or make you more likely to develop Alzheimer's disease relate to sleep, circadian rhythms, and signs of neurodegenerative disease in old age. One fifth of those within Insight 46 already have early signs of Alzheimer's disease.
For my PhD I plan to examine how sleep and circadian rhythms relate to cognition and neurodegenerative disease. Using sleep and circadian rhythm questionnaire data from birth to the seventh decade with sleep data from actigraphy and bed mats, I will examine sleep and circadian rhythms over the human lifetime in unparalleled detail. Combining this with the advanced brain imaging, cognitive, blood and spinal fluid data already collected from Insight 46 will allow me to explore how sleep and circadian rhythms relate to cognition and neurodegenerative disease. Finally, I will examine how this process is controlled by our genes, and sleep promoting chemicals, and whether failures in this control system are related to cognition and neurodegenerative disease.
Technical Summary
Aim: A comprehensive examination of the relationship between sleep and circadian measures (SACM), cognition, and biomarkers of neurodegenerative disease, in Insight 46, a subset of the British 1946 birth cohort.
Objectives: Describe SACM across the human life course and their relationship with cognition, biomarkers of AD and neurodegeneration. Explore relationships between SACM, genetic risk for AD/chronotype, and neurochemical modulators of sleep and circadian function, in relation to the above biomarker studies.
Methods: Insight 46 is recruiting 872 subjects for multimodal positron emission tomography, magnetic resonance imaging, cognitive assessment, actigraphy, genetics, an array of cerebrospinal fluid and plasma biomarkers. All subjects have extensive life course and sleep questionnaire data available, at 12 timepoints, from birth to 70 and upon enrolment in Insight 46 undergo 7 days wrist actigraphy (Philips Actiwatch) and complete the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, and Rapid Eye Movement Sleep Behaviour Disorder Questionnaire. 250 will undergo repeat assessment at 2 years, enabling longitudinal analysis. 100 will have at least 6-months sleep and circadian tracking with Withings Sleep Analyzer mats, from which the Dementia Sleep Quality Index will be calculated. 375 subjects will undergo CSF testing for orexin and prostaglandin D synthase. All subjects undergo genotype analysis, from which genetic risk scores for AD and chronotype will be calculated. SACM will be assessed in relation to each of the life course, imaging, genetic, biochemical, and cognitive measures detailed above using logistic, linear and multi-level modelling.
Opportunities: Combining SACM with the unparalleled life course, biomarker and genetic data in Insight 46 we address key questions, including whether sleep and circadian disturbance is the cause or consequence of prodromal neurodegeneration, and how sleep relates to cognition across the life course.
Objectives: Describe SACM across the human life course and their relationship with cognition, biomarkers of AD and neurodegeneration. Explore relationships between SACM, genetic risk for AD/chronotype, and neurochemical modulators of sleep and circadian function, in relation to the above biomarker studies.
Methods: Insight 46 is recruiting 872 subjects for multimodal positron emission tomography, magnetic resonance imaging, cognitive assessment, actigraphy, genetics, an array of cerebrospinal fluid and plasma biomarkers. All subjects have extensive life course and sleep questionnaire data available, at 12 timepoints, from birth to 70 and upon enrolment in Insight 46 undergo 7 days wrist actigraphy (Philips Actiwatch) and complete the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, and Rapid Eye Movement Sleep Behaviour Disorder Questionnaire. 250 will undergo repeat assessment at 2 years, enabling longitudinal analysis. 100 will have at least 6-months sleep and circadian tracking with Withings Sleep Analyzer mats, from which the Dementia Sleep Quality Index will be calculated. 375 subjects will undergo CSF testing for orexin and prostaglandin D synthase. All subjects undergo genotype analysis, from which genetic risk scores for AD and chronotype will be calculated. SACM will be assessed in relation to each of the life course, imaging, genetic, biochemical, and cognitive measures detailed above using logistic, linear and multi-level modelling.
Opportunities: Combining SACM with the unparalleled life course, biomarker and genetic data in Insight 46 we address key questions, including whether sleep and circadian disturbance is the cause or consequence of prodromal neurodegeneration, and how sleep relates to cognition across the life course.
