v
v
Warning Signs of Alzheimer’s
Dementia
Drug reverses age-related cognitive decline within days
Rapid mental rejuvenation in old mice suggests age-related losses may be broadly reversible
Just a few doses of an experimental drug can reverse age-related declines in memory and mental flexibility in mice, according to a new study by UC San Francisco scientists. The drug, called ISRIB, has already been shown in laboratory studies to restore memory function months after traumatic brain injury (TBI), reverse cognitive impairments in Down Syndrome , prevent noise-related hearing loss, fight certain types of prostate cancer , and even enhance cognition in healthy animals.
In the new study, published December 1, 2020 in the open-access journal eLife , researchers showed rapid restoration of youthful cognitive abilities in aged mice, accompanied by a rejuvenation of brain and immune cells that could help explain improvements in brain function.
“ISRIB’s extremely rapid effects show for the first time that a significant component of age-related cognitive losses may be caused by a kind of reversible physiological “blockage” rather than more permanent degradation,” said Susanna Rosi , PhD, Lewis and Ruth Cozen Chair II and professor in the departments of Neurological Surgery and of Physical Therapy and Rehabilitation Science (http://ptrehab.ucsf.edu/) .
“The data suggest that the aged brain has not permanently lost essential cognitive capacities, as was commonly assumed, but rather that these cognitive resources are still there but have been somehow blocked, trapped by a vicious cycle of cellular stress,” added Peter Walter , PhD, a professor in the UCSF Department of Biochemistry and Biophysics and a Howard Hughes Medical Institute investigator. “Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time.”
Could Rebooting Cellular Protein Production Hold the Key to Aging and Other Diseases?
Walter has won numerous scientific awards, including the Breakthrough , Lasker and Shaw prizes, for his decades-long studies of cellular stress responses. ISRIB, discovered in 2013 in Walter’s lab, works by rebooting cells’ protein production machinery after it gets throttled by one of these stress responses — a cellular quality control mechanism called the integrated stress response (ISR; ISRIB stands for ISR InhiBitor).
The ISR normally detects problems with protein production in a cell — a potential sign of viral infection or cancer-promoting gene mutations — and responds by putting the brakes on cell’s protein-synthesis machinery. This safety mechanism is critical for weeding out misbehaving cells, but if stuck in the on position in a tissue like the brain, it can lead to serious problems, as cells lose the ability to perform their normal activities, Walter and colleagues have found.
In particular, recent animal studies by Walter and Rosi, made possible by early philanthropic support from The Rogers Family Foundation, have implicated chronic ISR activation in the persistent cognitive and behavioral deficits seen in patients after TBI, by showing that, in mice, brief ISRIB treatment can reboot the ISR and restore normal brain function almost overnight.
The cognitive deficits in TBI patients are often likened to premature aging, which led Rosi and Walter to wonder if the ISR could also underlie purely age-related cognitive decline. Aging is well known to compromise cellular protein production across the body, as life’s many insults pile up and stressors like chronic inflammation wear away at cells, potentially leading to widespread activation of the ISR.
“We’ve seen how ISRIB restores cognition in animals with traumatic brain injury, which in many ways is like a sped-up version of age-related cognitive decline,” said Rosi, who is director of neurocognitive research in the UCSF Brain and Spinal Injury Center and a member of the UCSF Weill Institute for Neurosciences. “It may seem like a crazy idea, but asking whether the drug could reverse symptoms of aging itself was just a logical next step.”
ISRIB Improves Cognition, Boosts Neuron and Immune Cell Function
In the new study, researchers led by Rosi lab postdoc Karen Krukowski , PhD, trained aged animals to escape from a watery maze by finding a hidden platform, a task that is typically hard for older animals to learn. But animals who received small daily doses of ISRIB during the three-day training process were able to accomplish the task as well as youthful mice, much better than animals of the same age who didn’t receive the drug.
The researchers then tested how long this cognitive rejuvenation lasted and whether it could generalize to other cognitive skills. Several weeks after the initial ISRIB treatment, they trained the same mice to find their way out of a maze whose exit changed daily — a test of mental flexibility for aged mice who, like humans, tend to get increasingly stuck in their ways. The mice who had received brief ISRIB treatment three weeks before still performed at youthful levels, while untreated mice continued to struggle.
To understand how ISRIB might be improving brain function, the researchers studied the activity and anatomy of cells in the hippocampus, a brain region with a key role in learning and memory, just one day after giving animals a single dose of ISRIB. They found that common signatures of neuronal aging disappeared literally overnight: neurons’ electrical activity became more sprightly and responsive to stimulation, and cells showed more robust connectivity with cells around them while also showing an ability to form stable connections with one another usually only seen in younger mice.
The researchers are continuing to study exactly how the ISR disrupts cognition in aging and other conditions and to understand how long ISRIB’s cognitive benefits may last. Among other puzzles raised by the new findings is the discovery that ISRIB also alters the function of the immune system’s T cells, which also are prone to age-related dysfunction. The findings suggest another path by which the drug could be improving cognition in aged animals, and could have implications for diseases from Alzheimer’s to diabetes that have been linked to heightened inflammation caused by an aging immune system.
“This was very exciting to me because we know that aging has a profound and persistent effect on T cells and that these changes can affect brain function in the hippocampus,” said Rosi. “At the moment, this is just an interesting observation, but it gives us a very exciting set of biological puzzles to solve.
ISRIB May Have Wide-Ranging Implications for Neurological Disease
It turns out that chronic ISR activation and resulting blockage of cellular protein production may play a role in a surprisingly wide array of neurological conditions. Below is a partial list of these conditions, based on a recent review by Walter and colleague Mauro Costa-Mattioli of Baylor College of Medicine, which could potentially be treated with an ISR-resetting agent like ISRIB:
- Frontotemporal Dementia
- Alzheimer’s Disease
- Amyotrophic Lateral Sclerosis (ALS)
- Age-related Cognitive Decline
- Multiple Sclerosis
- Traumatic Brain Injury
- Parkinson’s Disease
- Down Syndrome
- Vanishing White Matter Disorder
- Prion Disease
ISRIB has been licensed by Calico, a South San Francisco, Calif. company exploring the biology of aging, and the idea of targeting the ISR to treat disease has been picked up by other pharmaceutical companies, Walter says.
One might think that interfering with the ISR, a critical cellular safety mechanism, would be sure to have serious side effects, but so far in all their studies, the researchers have observed none. This is likely due to two factors, Walter says. First, it takes just a few doses of ISRIB to reset unhealthy, chronic ISR activation back to a healthier state, after which it can still respond normally to problems in individual cells. Second, ISRIB has virtually no effect when applied to cells actively employing the ISR in its most powerful form — against an aggressive viral infection, for example.
Naturally, both of these factors make the molecule much less likely to have negative side effects — and more attractive as a potential therapeutic. According to Walter: “It almost seems too good to be true, but with ISRIB we seem to have hit a sweet spot for manipulating the ISR with an ideal therapeutic window.
Living near major roads linked to risk of dementia, Parkinson’s, Alzheimer’s and MS
Living near major roads or highways is linked to higher incidence of dementia, Parkinson’s disease, Alzheimer’s disease and multiple sclerosis (MS), suggests new research published this week in the journal Environmental Health.
Researchers from the University of British Columbia analyzed data for 678,000 adults in Metro Vancouver. They found that living less than 50 metres from a major road or less than 150 metres from a highway is associated with a higher risk of developing dementia, Parkinson’s, Alzheimer’s and MS–likely due to increased exposure to air pollution.
The researchers also found that living near green spaces, like parks, has protective effects against developing these neurological disorders.
“For the first time, we have confirmed a link between air pollution and traffic proximity with a higher risk of dementia, Parkinson’s, Alzheimer’s and MS at the population level,” says Weiran Yuchi, the study’s lead author and a PhD candidate in the UBC school of population and public health. “The good news is that green spaces appear to have some protective effects in reducing the risk of developing one or more of these disorders. More research is needed, but our findings do suggest that urban planning efforts to increase accessibility to green spaces and to reduce motor vehicle traffic would be beneficial for neurological health.”
Neurological disorders–a term that describes a range of disorders, including Alzheimer’s disease and other dementias, Parkinson’s disease, multiple sclerosis and motor neuron diseases–are increasingly recognized as one of the leading causes of death and disability worldwide. Little is known about the risk factors associated with neurological disorders, the majority of which are incurable and typically worsen over time.
For the study, researchers analyzed data for 678,000 adults between the ages of 45 and 84 who lived in Metro Vancouver from 1994 to 1998 and during a follow-up period from 1999 to 2003. They estimated individual exposures to road proximity, air pollution, noise and greenness at each person’s residence using postal code data. During the follow-up period, the researchers identified 13,170 cases of non-Alzheimer’s dementia, 4,201 cases of Parkinson’s disease, 1,277 cases of Alzheimer’s disease and 658 cases of MS.
For non-Alzheimer’s dementia and Parkinson’s disease specifically, living near major roads or a highway was associated with 14 per cent and seven per cent increased risk of both conditions, respectively. Due to relatively low numbers of Alzheimer’s and MS cases in Metro Vancouver compared to non-Alzheimer’s dementia and Parkinson’s disease, the researchers did not identify associations between air pollution and increased risk of these two disorders. However, they are now analyzing Canada-wide data and are hopeful the larger dataset will provide more information on the effects of air pollution on Alzheimer’s disease and MS.
When the researchers accounted for green space, they found the effect of air pollution on the neurological disorders was mitigated. The researchers suggest that this protective effect could be due to several factors.
“For people who are exposed to a higher level of green space, they are more likely to be physically active and may also have more social interactions,” said Michael Brauer, the study’s senior author and professor in the UBC school of population and public health. “There may even be benefits from just the visual aspects of vegetation.”
Brauer added that the findings underscore the importance for city planners to ensure they incorporate greenery and parks when planning and developing residential neighbourhoods.
10 Early Symptoms of Dementia You should Know
Early symptoms
Early signs of vascular dementia can include mild:
slowness of thought
difficulty with planning
trouble with understanding
problems with concentration
mood or behavioural changes
problems with memory and language (but these aren’t as common as they are in people with Alzheimer’s disease)
As this point, these problems may be barely noticeable or mistaken for something else, such as depression. But they indicate some brain damage has occurred and that treatment is needed.
Later symptoms
The symptoms often continue to get worse over time. This may happen slowly, or in sudden steps every few months or years.
The symptoms depend on the part of the brain that’s affected, but can include:
significant slowness of thought
feeling disorientated and confused
memory loss and difficulty concentrating
difficulty finding the right words
severe personality changes, such as becoming aggressive
depression, mood swings and lack of interest or enthusiasm
finding it difficult to walk and keep balance, with frequent falls
loss of bladder control (incontinence)
increasing difficulty with daily activities
Some people also have some symptoms of Alzheimer’s disease.
Getting medical advice
See your GP if you think you have early symptoms of dementia, especially if you’re over 65 years of age.
If it’s spotted at an early stage, treatment may be able to stop the vascular dementia getting worse, or at least slow it down.
If you’re worried about someone else, encourage them to make an appointment with their GP and perhaps suggest that you go with them.
Symptoms of dementia can have several causes. Your GP can do some simple checks to try to find out the cause and may refer you to a specialist for further tests.
Don’t lose sleep over reports that one bad night can spark dementia
Don’t lose sleep over reports that one bad night can spark dementia
“Just one bad night’s sleep ‘increases your chances of Alzheimer’s’,” is the misleading headline in The Sun, which the Mail Online more than matches with the baseless claim that “Just one sleepless night could spark Alzheimer’s”.
The study that prompted the claim involved only 20 people, none of whom had Alzheimer’s disease. They were tracked over the course of just two nights of monitored sleep. During that time they were allowed to sleep as much as they wanted for the first night, and then on the second night they were kept awake by a nurse.
The researchers then used brain scans to measure levels of a protein called beta-amyloid that builds up naturally in the brain. This protein is found in larger amounts in people with Alzheimer’s disease, although it is not clear if simply having higher levels of it for a short time increases the risk of Alzheimer’s.
The study showed that people had slightly higher (5%) levels of beta-amyloid in their brains after a night of sleep deprivation compared with their levels after a good night’s sleep. This brief assessment provides no proof these middle-aged people would go on to develop Alzheimer’s if they continued to have sleepless nights. We don’t know how their levels of beta-amyloid may vary over time.
We can’t draw any conclusions about the relationship between sleep and Alzheimer’s disease from this research. All we can say is that generally, getting a good night’s sleep brings other important physical and mental health benefits – you can read here about how to sleep better.
Where did the story come from?
The study was carried out by researchers from the National Institutes of Health in the US, Piramal Pharma Inc., and Yale School of Medicine. It was funded by the US National Institutes of Health and the (US) National Institute on Alcohol Abuse and Alcoholism. The study was published in the peer-reviewed journal Proceedings of the National Academy of Sciences of the United States of America.
The UK media’s headlines were needlessly alarming. If it were the case that a single bad night’s sleep could, as the Mail Online suggests, “spark Alzheimer’s” then we would expect far higher rates of the disease, as hardly anyone goes through life without sleeping badly from time to time.
And for some people, such as the parents of a newborn, disturbed sleep is a daily occurrence.
What kind of research was this?
This was an experimental study in which the researchers influenced the sleeping patterns of the participants to look at the effects of sleep deprivation.
There are lots of different ways in which this study could have been improved. We would ideally need a study that assessed people’s beta-amyloid levels over time to see what they were like to start with and how they varied from day to day. You could then look at levels of beta-amyloid over several nights of good sleep followed by poor sleep and then good sleep again to get an indication of how much they are influenced by sleep.
A randomised controlled trial that compared people assigned to periods of good and bad sleep could give an even better idea of the direct effect of sleep. This study design would make sure the two groups were similar in all ways apart from the amount of sleep people had.
But even with a trial, it would be hard to see if short-term changes in beta-amyloid were associated with the risk of Alzheimer’s disease developing.
A cohort study that followed a large number of people over long periods of time, taking regular brain scans and sleep assessments, then looking at who developed Alzheimer’s, may be the best way to explore this possible link. But this is unlikely to be feasible due to both the likely costs involved and the length of follow-up time that would probably be required to make a meaningful assessment.
What did the research involve?
Just 20 healthy people aged 22 to 72 (average 40 years) had brain scans to measure the amount of beta-amyloid in their brains. The researchers had excluded people with a range of physical and mental health conditions, including any history of alcohol or substance misuse, people taking any prescription medications, and those who had recently taken sedatives, stimulants or strong painkillers.
Each person in the study was measured after a good night’s sleep and after sleep deprivation at the research centre. The good night’s sleep involved sleeping from 10pm to 7am, with a nurse checking every hour whether the person was asleep. The brain scan was scheduled for lunchtime. Sleep deprivation involved waking up at 8am the morning before, and being accompanied by a nurse who made sure they did not fall asleep at all before they were scanned the next day at 1.30pm.
The scans took around 2 hours and people were encouraged to listen to music during the scan to keep themselves awake. No caffeinated drinks were allowed for 24 hours before or during the study, and no food was allowed between midnight and breakfast.
As well as beta-amyloid, the researchers also used questionnaires to assess people’s mood, and looked at whether they had particular genes associated with a higher risk of Alzheimer’s disease.
What were the basic results?
The study showed that people had slightly higher (5%) levels of beta-amyloid in their brains following the night of sleep deprivation compared to their results following good sleep. However, there was a lot of variation from person to person. There was no association with the person’s age, gender, or genetic likelihood of getting Alzheimer’s.
The study also showed that people’s mood was worse after sleep deprivation compared to good sleep, and that people who had a bigger increase in beta-amyloid had the greatest change in their mood.
How did the researchers interpret the results?
The researchers described their study as “preliminary evidence” that sleep could be one of the factors that affects levels of beta-amyloid in the brain. They speculate that improving sleeping habits could be a potential way to prevent Alzheimer’s disease.
They noted, however, that the methods used meant it was not possible to tell the difference between beta-amyloid that had accumulated in the brain in solid plaques (insoluble), and the soluble form that could still be “flushed away” by the body.
Conclusion
This study has many limitations. While it points to some avenues for more research, we can’t draw any reliable conclusions from it regarding any possible influence of sleep on Alzheimer’s risk.
The biggest problem is that this was a tiny study of a sample of healthy middle-aged adults – none of whom had any signs of dementia. It was a very brief intervention and assessment and there was no long-term follow-up of the people involved.
We don’t know:
how their levels of beta-amyloid may normally vary from day to day
whether beta-amyloid would accumulate in greater amounts with ongoing sleep deprivation
whether any of the people in the study would develop Alzheimer’s disease or not
what the “dose effect” might be if there is any link – in other words, whether short-term increases in beta-amyloid from a few bad nights’ sleep could really affect risk of Alzheimer’s disease
It’s also worth noting that the sleep deprivation used in the study was quite extreme (people were awake for around 31 hours), which doesn’t necessarily reflect the kind of “poor sleep” that people might experience in their normal lives.
It’s probably going to be difficult to gather regular assessments of large numbers of people over time to more reliably answer the question of whether lack of sleep could influence risk of Alzheimer’s.
Unfortunately, this research brings us no further forward to answering the possible causes of Alzheimer’s.
Analysis by Bazian
Edited by NHS Choices