Parkinson’s Disease

Posted on Dementia, Multiple Sclerosis, Parkinson's Disease

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.


Posted on Dementia, Multiple Sclerosis, neurological conditions, Parkinson's Disease

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.

Posted on Parkinson's Disease

‘Brain changes’ could provide early warning sign for Parkinson’s disease

Brain Networks and Autism
Brain Networks

“Scientists say they have identified the earliest signs of Parkinson’s disease in the brain, 15 to 20 years before symptoms appear,” BBC News reports.

Parkinson’s disease is a degenerative brain condition caused by loss of nerve cells that produce the chemical dopamine, which transmits signals between nerve cells. This leads to symptoms such as involuntary shaking, slow movement and stiff muscles.

New research aimed to see whether there could be early changes in another brain-signalling chemical serotonin, long before symptoms develop.

The researchers studied 14 people from European families who have a very rare, strong hereditary risk of Parkinson’s due to a genetic mutation called A53T SNCA. They compared brain scans from this group to brain scans from healthy people and from people with the more common form of Parkinson’s.

The researchers found that in pre-symptomatic people with a hereditary risk of Parkinson’s there was a loss of serotonin in several areas of the brain that are known to be affected in Parkinson’s. Therefore this could be a change that happens in the early stages of Parkinson’s.

Whether this has implications for Parkinson’s diagnosis or management is an entirely different question. Parkinson’s is very rarely hereditary, so this small group of 14 does not represent the majority of people with the condition.

There’s also the question of how pre-symptomatic people would be found. Screening the population with specialist, expensive brain scans seems very unlikely to happen.

As there is currently no cure or preventative treatment for Parkinson’s it’s unclear how clinically useful it would be to get an early diagnosis of Parkinson’s.

Where did the story come from?

This study was carried out by researchers from King’s College London, University of Athens in Greece, University of Salerno in Italy and other institutions in the UK and Europe. Funding was provided by the Lily Safra Hope Foundation and National Institute for Health Research (NIHR) Biomedical Research Centre at King’s College London.

The study was published in peer-reviewed The Lancet: Neurology medical journal.

Some of the media coverage is a little optimistic. For example, the Mail Online claims that the research represents “Hope for Parkinson’s as scientists spot signs of the cruel disorder in the brain YEARS before patients show any traditional symptoms.” This doesn’t recognise the very limited applicability of the research at this stage, given the unique population studied and that specialist brain scans are unlikely to be widely introduced as screening tests.

The reporting also fails to acknowledge that we currently do not know how to prevent Parkinson’s disease.

What kind of research was this?

This was a cross-sectional study that compared brain scans between people with a gene mutation putting them at high hereditary risk of Parkinson’s to healthy controls, as well as people with “typical” Parkinson’s disease where the cause is unclear.

The people at genetic risk have the A53T SNCA mutation. The SNCA proteins clump together in nerve cells and form the “Lewy bodies” (abnormal clumps of protein) that are characteristic of Parkinson’s. As people with mutations of this gene are very likely to develop Parkinson’s they form a unique population who can be studied earlier in life before they develop symptoms.

The researchers wanted to see if there could be early changes in serotonin levels in the brain, as previous research had shown that serotonin-producing nerve cells may be affected first, prior to dopamine-producing cells, which are affected as the disease progresses.

Cross-sectional studies can only inform how things look at one point in time. This study cannot tell us how long any brain changes may have been apparent for, or how they may develop over time.

What did the research involve?

The research involved 14 people with SNCA gene mutations who were recruited from specialist clinics in Greece and Italy. Their average age was around 42 years.

The researchers then recruited 25 age-matched controls without Parkinson’s and 40 people with non-hereditary Parkinson’s disease (average age 60) in London.

All participants had clinical assessments to look for signs of Parkinson’s. Of the 14 people at genetic risk, 7 had already started to develop mobility and movement problems, while 7 were still pre-symptomatic.

Participants then had several specialist positron emission tomography (PET) scans to detect a radioactive tracer that binds to the serotonin transporter and could indicate levels of serotonin in the brain. They also had other brain scans to look at dopamine activity.

What were the basic results?

The 7 people with genetic risk who had not yet developed symptoms were confirmed not to have any loss of dopamine activity. However, compared with healthy controls, the tracer showed they had loss of serotonin receptors in areas of the brain that are first affected by Parkinson’s disease.

In the 7 people who had already developed Parkinson’s, this loss of serotonin receptors was more extensive. In both people with genetic Parkinson’s and the comparison group with Parkinson’s of unknown cause, greater loss of serotonin receptors in the brainstem was linked with more muscle and movement symptoms.

How did the researchers interpret the results?

The researchers concluded that serotonin changes in people at hereditary risk of Parkinson’s precede changes in dopamine and the development of symptoms. They suggest this could have potential as an early marker of the progression of Parkinson’s.

Conclusion

This is a valuable study that furthers our understanding of the brain changes that may occur before any symptoms of Parkinson’s disease develop. However, before concluding that measuring serotonin activity is a way of detecting who’s likely to develop Parkinson’s, it’s important to set this finding in the right context.

For the vast majority of people who develop Parkinson’s, the cause is unclear. Families with gene mutations that place them at strong hereditary risk of the condition are very rare.

We cannot assume that the early stages of disease for people at hereditary risk would occur in exactly the same way in someone from the general population who develops Parkinson’s. Especially as the study only involved a small sample of 14 people with the hereditary risk. So we do not know how typical these serotonin patterns are.

Even if these serotonin changes were typical of all people who are developing Parkinson’s, we’d have to think about how such changes could be detected. It’s very unlikely that whole population screening would be offered using expensive, specialist scans purely to see if people had changes in serotonin in the brain. Then if you did detect changes, there would be the question of how would you stop Parkinson’s from developing?

At present we do not understand enough about the causes of Parkinson’s disease to be sure of any health or lifestyle changes that may reduce people’s risk of developing the condition. So this does bring into question how useful an early diagnosis of Parkinson’s would actually be?

Read more information about Parkinson’s disease.

Analysis by Bazian
Edited by NHS Website

‘Brain changes’ could provide early warning sign for Parkinson’s disease

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Parkinson’s disease – signs and symptoms. Do you know what to look out for?

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Parkinson's disease

Parkinson’s disease

 

Symptoms

The symptoms of Parkinson’s disease usually develop gradually and are mild at first.

There are many different symptoms associated with Parkinson’s disease. Some of the more common symptoms are described below.

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However, the order in which these develop and their severity is different for each individual. It’s unlikely that a person with Parkinson’s disease would experience all or most of these.

Main symptoms

The three main symptoms of Parkinson’s disease affect physical movement:

These main symptoms are sometimes referred to by doctors as parkinsonism as there can be causes other than Parkinson’s disease.

Other symptoms

Parkinson’s disease can also cause a range of other physical and mental symptoms.

Physical symptoms

balance problems – these can make someone with the condition more likely to have a fall and injure themselves

loss of sense of smell (anosmia) – sometimes occurs several years before other symptoms develop

nerve pain – can cause unpleasant sensations, such as burning, coldness or numbness

problems with urination – such as having to get up frequently during the night to urinate or unintentionally passing urine (urinary incontinence)

constipation

an inability to obtain or sustain an erection (erectile dysfunction) in men

difficulty becoming sexually aroused and achieving an orgasm (sexual dysfunction) in women

dizziness, blurred vision or fainting when moving from a sitting or lying position to a standing one – caused by a sudden drop in blood pressure

excessive sweating (hyperhidrosis)

swallowing difficulties (dysphagia) – this can lead to malnutrition and dehydration

excessive production of saliva (drooling)

problems sleeping (insomnia) – this can result in excessive sleepiness during the day

Cognitive and psychiatric symptoms

depression and anxiety

mild cognitive impairment – slight memory problems and problems with activities that require planning and organisation

dementia – a group of symptoms, including more severe memory problems, personality changes, seeing things that aren’t there (visual hallucinations) and believing things that aren’t true (delusions)

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When to seek medical advice

See your GP if you’re concerned you may have symptoms of Parkinson’s disease.

Your GP will ask about your symptoms and your medical history to help them decide whether it’s necessary to refer you to a specialist for further tests.

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Donna’s Story: Third Generation of Parkinson’s in the family and fears for her Daughter’s future




Parkinson's UK We Won't Wait Campaign: Donna's story

Parkinson’s UK We Won’t Wait Campaign: Donna’s story




To mark the beginning of Parkinson’s Awareness Week (10th-16th April) a new campaign has revealed a shocking lack of awareness surrounding the challenges those with Parkinson’s face trying to manage their condition.

The We Won’t Wait campaign has been launched today to highlight the urgent need to unlock the next step of research developments that could pave the way to better treatments for Parkinson’s. The main treatment  hasn’t changed in 50 years, with no current medication available to slow down or stop the condition’s spread.

Our video features Donna, the third generation of women in her family to have Parkinson’s, with both her mother and grandmother diagnosed before her.  Donna is committed to supporting research into the condition to find a cure, as she worries for her own daughter’s potential future diagnosis.

Donna is trying to avoid taking medication for as long as possible, as the side effects experienced by her mother were ‘devastating’ to see first-hand. They included hallucinations and forgetting who some of her closest family members were. Donna’s mother is now in a coma in hospital.

Donna was told in November 2016 by a private practice neurologist that she almost certainly has Parkinson’s. She is still awaiting a DAT scan via the NHS to confirm or deny her worst fears.

Parkinson’s affects almost every area of a person’s life with a range of physical and ‘hidden’ symptoms that include tremor, pain, sleep and mental health problems. Worryingly, there is a lack of public understanding of the day-to-day reality of living with the condition, with only a minority of people associating Parkinson’s with bladder or bowel problems (20%), anxiety (38%) and sleep problems, including insomnia and nightmares (32%).




The Parkinson’s UK ‘We Won’t Wait’ campaign aims to raise essential funds and awareness that will drive forward developments in Parkinson’s research and will hopefully help find more effective treatments that are desperately needed for the 127,000 people currently living with the condition.