Protein tangles linked with dementia seen in patients after single head injury
September 5, 2019
Science Daily/Imperial College London
Scientists have visualised for the first time protein 'tangles' associated with dementia in the brains of patients who have suffered a single head injury.
This is the finding of a new study led by scientists from Imperial College London, published in the journal Science Translational Medicine.
In the early-stage study, researchers studied 21 patients who had suffered a moderate to severe head injury at least 18 years earlier (mostly from traffic accidents), as well as 11 healthy individuals who had not experienced a head injury.
The research, from scientists at Imperial's Dementia Research Institute as well as the University of Glasgow, showed some of these patients had clumps of protein in their brain called tau tangles.
The team, who recruited patients from the Institute of Health and Wellbeing at the University of Glasgow and from Imperial College Healthcare NHS Trust, say the research may accelerate the development of treatments that breakdown tau tangles, by enabling medics to monitor the amount of the protein.
Tau normally helps provide structural support to nerve cells in the brain - acting as a type of scaffolding, but when brain cells become damaged - for instance during a head injury, the protein may form clumps, or tangles.
Tau tangles are found in Alzheimer's disease and other forms of dementia, and associated with progressive nerve damage.
Scientists have known for some time that repeated head injury - such as those sustained in sports such as boxing, rugby and American Football - can lead to neurodegeneration and dementia in later life - with particularly strong links to a type of brain condition called chronic traumatic encephalopathy.
However, this is the first time scientists have seen the protein tangles in living patients who have suffered a single, severe head injury, explains Dr Nikos Gorgoraptis, author of the paper from Imperial's Department of Brain Sciences.
"Scientists increasingly realise that head injuries have a lasting legacy in the brain - and can continue to cause damage decades after the initial injury. However, up until now most of the research has focussed on the people who have sustained multiple head injuries, such as boxers and American Football players. This is the first time we have seen in these protein tangles in patients who have sustained a single head injury."
Dr Gorgoraptis adds that although these tangles have been detected in the brains of patients in post-mortem examination - where findings suggest around one in three patients with a single head injury develop protein tangles - they have not before been seen in the brains of living patients.
The study used a type of brain scan, called a PET scan, combined with a substance that binds to tau protein, called flortaucipir, to study the amount of tau protein in the brains of head injury patients.
The results revealed that, collectively, patients with head injury were more likely to have tau tangles. The paper also showed that patients with tau tangles had higher levels of nerve damage, particular in the white matter of the brain. None of the healthy individuals had tau tangles.
Interestingly, the results revealed patients with higher levels of tau tangles did not necessarily have any reduction in brain function, such as memory problems, compared to patients with fewer tangles.
However, Dr Gorgoraptis adds these tangles can develop years before a person starts to develop symptoms such as memory loss. He explained there are still many questions to answer about the tau tangles and brain damage.
"This research adds a further piece in the puzzle of head injury and the risk of neurodegeneration. Not all patients with head injury develop these protein tangles, and some patients can have them for many years without developing symptoms. While we know tau tangles are associated with Alzheimer's and other forms of dementia, we are only beginning to understand how brain trauma might lead to their formation. What is exciting about this study is this is the first step towards a scan that can give a clear indication of how much tau is in the brain, and where it is located. As treatments develop over the coming years that might target tau tangles, these scans will help doctors select the patients who may benefit and monitor the effectiveness of these treatments."
https://www.sciencedaily.com/releases/2019/09/190905103013.htm
Disrupted sleep in one's 50s, 60s raises risk of Alzheimer's disease
Protein tangles in the aging brain throw sleep rhythms out of sync, likely leading to memory loss
June 27, 2019
Science Daily/University of California - Berkeley
PET brain scans of healthy older adults show that those reporting lower sleep quality through their 50s and 60s have higher levels of tau protein, a risk factor for Alzheimer's disease. Previous studies link poor sleep to beta-amyloid tangles also, suggesting that protein tangles in the brain may cause some of the memory problems of AD and dementia. In addition, out-of-sync brain waves during sleep are associated with tau, providing a possible biomarker of dementia.
People who report a declining quality of sleep as they age from their 50s to their 60s have more protein tangles in their brain, putting them at higher risk of developing Alzheimer's disease later in life, according to a new study by psychologists at the University of California, Berkeley.
The new finding highlights the importance of sleep at every age to maintain a healthy brain into old age.
"Insufficient sleep across the lifespan is significantly predictive of your development of Alzheimer's disease pathology in the brain," said the study's senior author, Matthew Walker, a sleep researcher and professor of psychology. "Unfortunately, there is no decade of life that we were able to measure during which you can get away with less sleep. There is no Goldilocks decade during which you can say, 'This is when I get my chance to short sleep.'"
Walker and his colleagues, including graduate student and first author Joseph Winer, found that adults reporting a decline in sleep quality in their 40s and 50s had more beta-amyloid protein in their brains later in life, as measured by positron emission tomography, or PET. Those reporting a sleep decline in their 50s and 60s had more tau protein tangles. Both beta-amyloid and tau clusters are associated with a higher risk of developing dementia, though not everyone with protein tangles goes on to develop symptoms of dementia.
Based on the findings, the authors recommend that doctors ask older patients about changes in sleep patterns and intervene when necessary to improve sleep to help delay symptoms of dementia. This could include treatment for apnea, which leads to snoring and frequent halts in breathing that interrupt sleep, and cognitive behavioral therapy for insomnia (CBT-I), a highly effective way to develop healthy sleep habits. It may even include simple sleep counseling to convince patients to set aside time for a full eight hours of sleep and simple sleep hygiene tricks to accomplish that.
"The idea that there are distinct sleep windows across the lifespan is really exciting. It means that there might be high-opportunity periods when we could intervene with a treatment to improve people's sleep, such as using a cognitive behavioral therapy for insomnia," Winer said. "Beyond the scientific advance, our hope is that this study draws attention to the importance of getting more sleep and points us to the decades in life when intervention might be most effective."
The 95 subjects in the study were part of the Berkeley Aging Cohort Study (BACS), a group of healthy older adults -- some as old as 100 years of age -- who have had their brains scanned with PET, the only technique capable of detecting both beta-amyloid tangles and, very recently, tau tangles, in the brain.
Winer, Walker and their colleagues reported their results online last week in the Journal of Neuroscience.
Brain waves out of sync
The team also made a second discovery. They found that people with high levels of tau protein in the brain were more likely to lack the synchronized brain waves that are associated with a good night's sleep. The synchronization of slow brain waves throughout the cortex of the sleeping brain, in lockstep with bursts of fast brain waves called sleep spindles, takes place during deep or non-rapid eye movement (NREM) sleep. The team reported that the more tau protein older adults had, the less synchronized these brain waves were. This impaired electrical sleep signature may therefore act as a novel biomarker of tau protein in the human brain.
"There is something special about that synchrony," given the consequences of this tau protein disruption of sleep, Walker said. "We believe that the synchronization of these NREM brain waves provides a file-transfer mechanism that shifts memories from a short-term vulnerable reservoir to a more permanent long-term storage site within the brain, protecting those memories and making them safe. But when you lose that synchrony, that file-transfer mechanism becomes corrupt. Those memory packets don't get transferred, as well, so you wake up the next morning with forgetting rather than remembering."
Indeed, last year, Walker and his team demonstrated that synchronization of these brain oscillations helps consolidate memory, that is, hits the "save" button on new memories.
Several years ago, Walker and his colleagues initially showed that a dip in the amplitude of slow wave activity during deep NREM sleep was associated with higher amounts of beta-amyloid in the brain and memory impairment. Combined with these new findings, the results help identify possible biomarkers for later risk of dementia.
"It is increasingly clear that sleep disruption is an underappreciated factor contributing to Alzheimer's disease risk and the decline in memory associated with Alzheimer's," Walker said. "Certainly, there are other contributing factors: genetics, inflammation, blood pressure. All of these appear to increase your risk for Alzheimer's disease. But we are now starting to see a new player in this space, and that new player is called insufficient sleep."
The brain rhythms were recorded over a single eight-hour night in Walker's UC Berkeley sleep lab, during which most of the 31 subjects wore a cap studded with 19 electrodes that recorded a continual electroencephalogram (EEG). All had previously had brain scans to assess their burdens of tau and beta-amyloid that were done using a PET scanner at the Lawrence Berkeley National Laboratory and operated by study co-author William Jagust, professor of public health and a member of Berkeley's Helen Wills Neuroscience Institute.
Is sleep a biomarker for dementia?
Doctors have been searching for early markers of dementia for years, in hopes of intervening to stop the deterioration of the brain. Beta-amyloid and tau proteins are predictive markers, but only recently have they become detectable with expensive PET scans that are not widely accessible.
Yet, while both proteins escalate in the brain in old age and perhaps to a greater extent in those with dementia, it is still unknown why some people with large burdens of amyloid and tau do not develop symptoms of dementia.
"The leading hypothesis, the amyloid cascade hypothesis, is that amyloid is what happens first on the path to Alzheimer's disease. Then, in the presence of amyloid, tau begins to spread throughout the cortex, and if you have too much of that spread of tau, that can lead to impairment and dementia," Winer said.
Walker added that, "A lack of sleep across the lifespan may be one of the first fingers that flicks the domino cascade and contributes to the acceleration of amyloid and tau protein in the brain."
The hypothesis is supported, in part, by Jagust's PET studies, which have shown that higher levels of beta-amyloid and tau protein tangles in the brain are correlated with memory decline, tau more so than amyloid. Tau occurs naturally inside the brain's neurons, helping to stabilize their internal skeleton. With age, tau proteins seem to accumulate inside cells of the medial temporal lobe, including the hippocampus, the seat of short-term memory. Only later do they spread more widely throughout the cortex.
While Jagust has run PET scans on the brains of many healthy people, as well as those with dementia, many more subjects are needed to confirm the relationship between protein tangles and dementias like Alzheimer's disease. Because PET scanners are currently expensive and rare, and because they require injection of radioactive tracers, other biomarkers are needed, Walker said.
The new study suggests that sleep changes detectable in a simple overnight sleep study may be less intrusive biomarkers than a PET scan.
"As wearable technology improves, this need not be something you have to come to a sleep laboratory for," said Walker. "Our hope is that, in the future, a small head device could be worn by people at home and provide all the necessary sleep information we'd need to assess these Alzheimer's disease proteins. We may even be able to track the effectiveness of new drugs aimed at combating these brain proteins by assessing sleep."
"I think the message is very clear," Walker added. "If you are starting to struggle with sleep, then you should go and see your doctor and find ways, such as CBT-I, that can help you improve your sleep. The goal here is to decrease your chances of Alzheimer's disease."
https://www.sciencedaily.com/releases/2019/06/190627114105.htm