Professor Michael Hanna, Consultant Neurologist, highlights recent research that suggest there are complex links between disordered sleep patterns and neurodegenerative brain diseases such as Dementia and Parkinson's Disease
What are the Neurodegenerative Diseases?
Dementia and Parkinson's disease are termed "neurodegenerative diseases". In neurodegenerative diseases certain populations of brain cells (neurons) seem to age prematurely and then die. The symptoms that a patient will experience depend on the exact location and function of the brain cells that die. In Alzhemier's Disease brain cells in the cortex of a certain region of the brain called the temporal lobe die first. Since the temporal lobe has an important role in memory and language the earliest symptoms in Alzhemier's disease are often impaired recent memory and difficulty with language production and understanding. In contrast, in Parkinson's disease the brain cells that die initially are located deep within the brain in a region called the Substantia Nigra. This region is very important for the coordinated and smooth control of movement. Therefore patients with Parkinson's disease develop a movement disorder as the initial symptom. Typically, patients with Parkinson's disease develop slowing of voluntary movement, increased tone and stiffness in their muscles, hand tremor and difficulty with walking.
Neurodegenerative diseases are an important health issue for society globally
The neurodegenerative diseases typically progress slowly over 10-20 years, often resulting in significant disability with major effects on patients and their families.
They are common and are increasing in prevalence as the population ages. Neurodegenerative diseases occur in all aging populations globally are therefore a very important societal health issue. For example, it is estimated that by 2020 there will be 1million patients in the UK living with dementia.
What do we understand about the cause of Dementia and Parkinson's Disease?
The precise cause of neurodegenerative diseases is not fully understood although research in recent years has provided important evidence that abnormal protein accumulation in brain cells is an important factor. For example, there is evidence that a range of abnormal proteins accumulate in the brain cells in Alzhemier's disease and there has been particular focus on the accumulation of a protein called "amyloid beta" which seems to be toxic to brain cells. In Parkinson's disease the accumulation of a different protein called alpha synuclein seems to be important. Although amyloid beta and alpha synuclein are produced by normal brain cells and are important for normal brain function the accumulation of high amounts seems to be linked to the brain cell death that occurs in Alzheimer's and Parkinson's Disease.
Two recent studies indicate there are potentially important links between sleep and neurodegenerative diseases.
The first study examined the relationship between sleep duration and the deposition of amyloid beta in the brains of genetically engineered mice.
What is known already?
Earlier research has indicated that there might be a link in humans between sleep and amyloid-beta deposition. A 2013 paper in JAMA Neurology found that in a group of adults aged 45 and older; those with A-beta deposition also had worse sleep quality. Another 2013 paper in the same publication found a greater A-beta burden in adults with shorter sleep duration and poorer sleep quality. But these studies don't answer the question: what comes first? In other words, is poor sleep causing A-beta deposition, or is it the other way around?
How did the researchers investigate the relationship between sleep and amyloid-beta?
In order to understand the relationship between sleep and amyloid beta deposition in the brain the researchers at Washington University analysed the effect of removing (knocking out) a key gene that mice and humans have that promotes wakefulness. The so called "wakefulness gene" makes a protein called orexin. Through advanced genetic manipulations the researchers made two groups of mice. The first group were programmed to over produce beta amyloid and to produce normal amounts of orexin. The second group of mice were programmed to over produce beta amyloid and to not produce any orexin (because the orexin gene was knocked out). This research was published in The Journal of Experimental Medicine. (Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer's disease.
Roh JH, Jiang H, Finn MB, Stewart FR, Mahan TE, Cirrito JR, Heda A, Snider BJ, Li M, Yanagisawa M, de Lecea L, Holtzman DM. J Exp Med. 2014 Dec 15;211(13):2487-96. doi: 10.1084/jem.20141788. Epub 2014 Nov 24.)
What did this study find and what are the implications?
This new study showed an important difference between the two groups of mice. They found that eliminating orexin made mice sleep for longer periods of time and significantly slowed down the production of amyloid beta in the brain.
It is always important to be very cautious when extrapolating the results from a mouse study to the complex clinical problems of the human brain. However, this study does provide further evidence to suggest a link between sleep and amyloid beta accumulation in the brain. Many researchers consider that amyloid beta accumulation in the brain is an important part of the cause of Alzhemier's Dementia and therefore reducing levels may be helpful.
Since there are potentially drugs that can be developed to reduce the brain levels of orexin this research opens up new research possibilities. For example, to test if reducing orexin levels in the brain might be a possible treatment for dementia. An additional next step could also be to evaluate older adults, improve their sleep quality by addressing issues such as sleep apnea or simply changing sleeping habits, and then assess cognitive outcomes years later.
The second study assessed Rapid Eye Movement Sleep Behaviour Disorder and Neurodegenerative Disease
What is known already?
It is known that in the phase of sleep known as rapid eye movement (REM) sleep some patients can exhibit disturbed behaviour known as REM behaviour disorder (RBD). Under normal conditions, vivid dream mentation combined with skeletal muscle paralysis characterizes rapid eye movement sleep. In contrast, the behaviours of RBD are often theatrical, with complexity, aggression, and violence; fighting and fleeing actions can be injurious to patients as well as bed partners.
What did this study investigate?
Recent research has indicated that such RBD can be a common symptom in patients that are affected by Parkinson Disease. In this study the researchers asked the question –is RBD predictive of developing a neurodegenerative disease in the future?
This was a retrospective study assessing peer-reviewed articles, including case reports, case series, retrospective reviews, prospective randomized trials, and basic science investigations, were identified in a PubMed search of articles on RBD from January 1, 1986, through July 31, 2014. This research was recently published in JAMA Neurology (Rapid Eye Movement Sleep Behavior Disorder and Neurodegenerative Disease Michael Joseph Howell, MD1; Carlos Hugh Schenck, MD 1Department of Neurology, University of Minnesota, Minneapolis
2Department of Psychiatry, University of Minnesota, Minneapolis JAMA Neurol. 2015;72(6):707-712. doi:10.1001/jamaneurol.2014.4563.)
What did they find?
Approximately 50% of patients with spontaneous RBD will convert to a parkinsonian disorder within a decade. Ultimately, nearly all (81%-90%) patients with RBD develop a neurodegenerative disorder. Among patients with Parkinson disease, RBD predicts a non–tremor-predominant subtype, gait freezing, and an aggressive clinical course. The most commonly cited RBD treatments include low-dose clonazepam or high-dose melatonin taken orally at bedtime.
What is the significance and relevance?
They found that treatment of RBD can prevent injury to patients and bed partners. Because RBD is often a prodromal syndrome of neurodegeneration such as Parkinson disease (or related disorder), it represents a unique opportunity for developing and testing disease-modifying therapies.
What do these two studies tell us about the links between sleep and neurodegenerative diseases?
- These recent studies indicate that the relationship between sleep and neurodegenerative diseases are complex.
- The first study suggests sleep patterns may play a role in causing neurodegenerative diseases such as dementia. It suggests that longer sleep periods may reduce the accumulation of the amyloid beta protein in the brain that is linked to dementia.
- The first study also implies that drugs that target orexin (the "wakefulness gene") could have potential in preventing dementias like Alzheimer's Disease
- The second study suggests that sleep disorder may be a consequence of early phase neurodegenerative disease.
- The second study indicated that RBD patients are at higher risk of developing neurodegenerative disease such as Parkinson's disease and might provide an earlier opportunity to test disease modifying drugs to prevent progression.
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