amyotrophic lateral sclerosis

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Drug reverses age-related cognitive decline within days


Rapid mental rejuvenation in old mice suggests age-related losses may be broadly reversible 

"Limiting children's screen time linked to better cognition," reports BBC News.


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.


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Motor Neurone Disease or Lou Gehrig’s disease. What are the signs and symptoms?




Lou Gehrig ALS MND

Lou Gehrig ALS MND

The initial symptoms of motor neurone disease often affect certain areas of the body before eventually becoming more widespread.

It’s important to visit your GP as soon as possible if you have the typical early symptoms of motor neurone disease. There’s evidence that specialist care can improve overall survival.

The symptoms usually follow a pattern that falls into three stages:

the initial stage

the advanced stage

the end stage


Initial symptoms

The initial symptoms of motor neurone disease usually develop slowly and subtly over time. It can be easy to mistake early symptoms for those of several unrelated conditions that affect the nervous system.

Limb-onset disease

In about two-thirds of people with motor neurone disease, the first symptoms occur in the arm or leg. This is sometimes called limb-onset disease. These symptoms include:

a weakened grip, which can cause difficulties picking up or holding objects

weakness at the shoulder, making lifting the arm above the head difficult

tripping up over a foot because of weakness at the ankle or hip

These symptoms are usually painless and may be accompanied by widespread twitching of the muscles (fasciculations) or muscle cramps, and there may be visible wasting of the muscles with significant weight loss.

Bulbar-onset disease

In a quarter of cases, problems initially affect the muscles used for speech and swallowing. Increasingly slurred speech (dysarthria) is usually the first sign of this type of motor neurone disease, and may be misdiagnosed as a stroke.

As the condition progresses, it may become increasingly difficult to swallow (dysphagia), and be misdiagnosed as a blockage in the throat.

Respiratory-onset disease

In extremely rare cases, motor neurone disease starts by affecting the lungs, rather than affecting them at the end of the condition. This is called respiratory-onset disease.

In some cases the initial symptoms are obvious, such as breathing difficulties and shortness of breath.




In other cases the symptoms are less noticeable, such as waking up frequently during the night because the brain is temporarily starved of oxygen when lying down. This can make the person feel very tired and unrefreshed the next morning, sometimes with a headache.

Advanced symptoms

As motor neurone disease becomes more advanced, the differences between the various types of disease are less noticeable as more parts and functions of the body are affected. The rate at which the condition spreads varies, but generally remains the same for an individual (that is, it doesn’t speed up, but doesn’t slow down either).

Muscular symptoms

The limbs become gradually weaker and the muscles in the limbs may appear progressively wasted. As a result, the person will find it increasingly difficult to move the affected limbs.

The muscles may also become stiff. This is known as spasticity. Both muscle wasting and stiffness can also cause joint aches and pains.

Speaking and swallowing difficulties

At least two-thirds of people with motor neurone disease find that speaking and swallowing become increasingly difficult as the condition progresses. However, although choking episodes can be distressing they aren’t the cause of death.

Saliva problems

Reduced swallowing can cause an excess of saliva, sometimes with drooling. Thicker saliva may sometimes be difficult to clear from the chest or throat due to weakening of the muscles that control coughing.

Excessive yawning

Some people with motor neurone disease have episodes of uncontrollable, excessive yawning, even when they’re not tired. This can sometimes cause jaw pain.

Emotional changes

Motor neurone disease can lead to changes in a person’s ability to control their emotions, particularly when there’s weakness in the muscles that control speech and swallowing.

One of the most common signs is when a person has episodes of sudden uncontrollable crying or, more rarely, laughter. Doctors may call this emotional lability or emotionality.

Changes to mental abilities

Occasionally, people with motor neurone disease may have significant difficulties with concentration, planning and use of language. This is known as cognitive change and overlaps with a condition called frontotemporal dementia.

The changes are usually quite subtle, making it difficult to tell them apart from the normal ageing process, and they don’t normally affect a person’s capacity to make their own decisions.

Up to 15% of people with motor neurone disease develop more profound frontotemporal dementia, usually soon after, or sometimes before, their first muscle-related symptoms. The affected person may not be aware that there are problems with their behaviour or personality.

Breathing difficulties

As the nerves and muscles that help control the lungs become progressively more damaged, the person’s breathing will become less efficient.

This may be a feeling of being very short of breath after doing everyday tasks, such as walking up the stairs. However, over time, the person may even become short of breath when they’re resting.

Shortness of breath may be particularly troublesome at night. Some people find it difficult to breathe when they’re lying down. Others may wake up in the night because of breathlessness.

As motor neurone disease progresses, a non-invasive breathing mask may be recommended at night to improve sleep quality and help reduce drowsiness during the day.

End-stage symptoms

As motor neurone disease progresses to its final phase, a person with the condition will probably experience:

increasing body paralysis, which means they’ll need help with most daily activities

significant shortness of breath

Eventually, non-invasive breathing assistance won’t be enough to compensate for the loss of normal lung function. At this stage, most people with motor neurone disease become increasingly drowsy before falling into a deep sleep, where they usually die peacefully.

Secondary symptoms

Some people with motor neurone disease have additional symptoms that aren’t directly caused by the condition but are related to the stress of living with it. These may include depression, insomnia and anxiety.

Although many people with motor neuron disease may think about ending their life at some point, this isn’t a common outcome, particularly with strong family and community support.

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The LATbelt – a great new tool for people with Multiple Sclerosis




LATBelt

LATBelt

Dr. Chris Glibert DPT, a pediatric physical therapist, has developed and brought to market a patent-pending manual assistance transfer device. Glibert utilized his Northwestern University educational background to solve a problem he frequently encountered as a full-time school-based physical therapist.




Glibert found himself training and assisting staff in a variety of dependent transfers so that students would have the opportunity to learn in a multitude of environments and positions throughout the school day. Glibert soon discovered that both manual and mechanical transfers had their drawbacks. Mechanical transfers were cumbersome, expensive, and time consuming; additionally, many classrooms and restrooms could not accommodate the space these lifts required. Manual transfers were quick and efficient, but Glibert felt that the educational staff did not always abide by proper body mechanics, reducing the safety and increasing the chance of injury during transfers.

After designing and testing several prototypes, Glibert developed the Lift and Transfer Belt (LATbelt) as a compromise between mechanical and manual transfers. This easy-to-use, compact, cost-effective solution is a heavy duty gait belt that seamlessly connects to secured thigh straps. With this belt, two staff members can complete side-by-side or front-to-back dependent transfers in a standardized, safe manner.

The LATbelt is commonly used in conjunction with diagnoses of muscular dystrophy, cerebral palsy, spinal muscular atrophy, multiple sclerosis, amyotrophic lateral sclerosis, and various spinal cord injuries. With this device, transfers can be conducted between the following: mat tables, wheelchairs, beds, vehicles, gait trainers, chairs, changing tables, standers, and toilets.

The LATbelt is currently being utilized by school districts across the United States. It also has implication for use in hospitals, skilled nursing facilities, acute rehabilitation centers, home healthcare, adaptive sports, and recreational therapy.

To learn more, visit LATbelt.com.




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Have you taken the Ice Bucket Challenge yet? What do you think of it as a way of raising awareness of ALS (Motor Neurone Disease)?


President Bush and the Ice Bucket Challenge

President Bush and the Ice Bucket Challenge

The Ice Bucket challenge had gone far more than viral by the time I picked up on it. I was away on holiday so was not really looking at social media.

But by the time we got home it was in full swing. And as with all good thing it seemed to have become very controversial.

Now as some readers will know amyotrophic lateral sclerosis (ALS), which is the most common form of Motor Neurone Disease was the medical condition from which my mother-in-law passed way some four years ago! If you wish to make a donation to her local ALS charity you can do so here.

What interests me is how many of us have done the ice bucket challenge so far. Please share in the poll below. If you could tell us which cause you donated to and a link in the comments box that would be great!


Many thanks in advance.


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Motor Neurone Disease Awareness Month 2014 – please like and share to help raise awareness of MND, ALS or Lou Gehrig’s Disease #MND


Motor Neurone Awareness Month 2014 - Lou Gehrig

Motor Neurone Awareness Month 2014 – Lou Gehrig

This man was Lou Gehrig. He gave his name to the most common type of Motor Neurone Disease called Amyotrophic lateral sclerosis or ALS.

While , of course, famous people so get MND, so do the rest of us. This post is dedicated to the memory of my late mother in law who died this month five years ago after battling ALS for three years.

A few months ago on old friend told me that his mother had just been diagnosed with MND. So this is a cause very dear to my heart.

So far there is no cure just therapies for easing the effects on the condition. So for many people with MND and their loved ones the situation can feel very hopeless.

I would be very grateful if you could share this page and image to help raise awareness of Motor Neurone Disease.

For more information on the month itself please go to the web site of the Motor Neurone Disease Association.

Many thanks in advance and just to let you know that the hashtag for the month is #MND