Cobbers on the Brain

“Hi I’m Sally and I’m about to do the ALS Ice Bucket Challenge. I’m going to nominate my three friends Jimmy, Johnny, and Hank to do the challenge as well. Do the challenge and donate to a research center in your area. Good luck!”

I’m sure we are all very familiar with this type of post. It was all over social media in 2014. For a while it was almost like you couldn’t even go online without seeing these posts littering your timeline or page. “The ALS Ice Bucket Challenge was a tremendous event in our Association’s history, raising f$115 million in the summer of 2014. Not only did it bring awareness to this devastating disease, it importantly spurred a huge increase in our research budget.” This is what was said in a statement by the ALS Association. I agree with them that it raised lots of awareness about this devastating disease, but what I think was really lacking was a knowledge of what was really happening.

http://www.alsa.org/fight-als/ice-bucket-challenge.html

What is ALS?

ALS is a fatal motor neuron disease characterized by degeneration of upper and lower motor neurons. The symptoms of ALS are initially quite varied in people, with some people having trouble gripping things and others have sudden voice cracks. Eventually these symptoms can begin in the vocal muscles as well as in the hands, arms, legs, and feet. As it progresses, progressive muscle weakness and paralysis are experienced by all suffering from ALS. However, since ALS only attacks motor neurons, these people maintain their senses of sight, touch, feeling, taste, and smell, while being confined to their body being unable to move.

https://www.ncbi.nlm.nih.gov/pubmed/27150074
http://www.alsa.org/about-als/symptoms.html

What happens in ALS?

In individuals with ALS, there is some sort of oxidative damage caused by oxidative stress. This oxidative stress leads to damaged mitochondria, protein aggregation, and impaired autophagy. There is then a mutation in several proteins that bind RNA such as FUS and TDP43.

What are some treatments for ALS?

There are several treatments used for ALS, but it is ultimately lethal so these treatments are aimed at controlling symptoms, preventing unnecessary complications, and make living with the disease easier. These treatments are:

• Medications:
  • Rilutek: decreases glutamate and reduces damage to motor neurons
  • Radicava: slows decline of daily functions
  • Pain medications, sleeping pills, and antidepressants
• Physical therapy: prevent quick muscle deterioration
• Speech therapy: computer-based speech synthesizers, eye-tracking technology
• Nutritional support: feeding tubes, meal plans
• Breathing support: respirators, oxygen masks, and breathing techniques

Much more research is needed to help improve these treatments so they target the source of the disease rather than just lessening of many of the symptoms caused by ALS.

Above are Stephen Hawking and Lou Gehrig, two of the most famous people to have suffered from ALS. There are approximately 30,000 Americans living with ALS in the United States today.

https://nypost.com/2016/05/21/whatever-happened-to-lou-gehrigs-bats/
https://usefulstoooges.com/2018/03/27/stephen-hawking-a-brilliant-scientist-a-flawed-man/

This brings me back to the Ice Bucket Challenge. I think in the future if there is some sort of foundation that is raising money by doing an event like this I would like to see it focus more on educating people of what is going on with the disease, giving money to research, and caring for those who have it, rather than just looking up funny videos of their friends trying out the challenge. This did a great job of bringing both awareness to the disease and money, but I feel like more attention was given to those who did the challenge. In the future hopefully we can both understand this disease better and ultimately treat or cure it.
http://www.alsa.org/news/media/quick-facts.html

Have you ever met someone with amyotrophic lateral sclerosis, better known as ALS? Do you know anything about it besides that it was the origins and reasons behind the “Ice Bucket Challenge”?

In 2014 the Ice Bucket Challenge was sweeping the Nation, everyone from celebrities to average individuals were challenging their friends to do this to raise not only money but awareness of this disease. Popular news sources and celebrities doing it the summer of 2014 seems to be what truly brought ALS to the knowledge of the general public. Today they use the month of August to focus on ALS via media and sources like the Ice Bucket Challenge.

However, you may have done it and not truly known what it is or where it comes from. It seemed that many didn’t know and few did their own research into the topic. General consensus seemed along the lines of ‘it is a debilitating disease that eventually steals all mobility from someone until they die.’

So then what is it?

According to the ALS association it was originally discovered in 1869 by a French neurologist, but it wasn’t until 1939 when it got national recognition by the diagnosis of baseball player Lou Gehrig. It is still commonly known today as Lou Gehrig’s disease. ALS is a progressive neurodegenerative disease affecting the motor neurons in the brain and spinal cord leading to their eventual death and therefore loss of mobility and eventual paralysis (see picture on the right). Most of the patients end up passing due to respiratory distress or failure because of these neurons.

Most of the patients with ALS have a sporadic variation, sporadic ALS, rather than a genetic variation, or familial ALS. The familial ALS is exceedingly more rare than the sporadic. In the genetic variation, the age of onset is about 46, ten years younger than the sporadic form at 56. The only real difference between the two is the family history, otherwise they are clinically the same with mutations in the same gene. This gene is the SOD1 gene, responsible for generating the enzyme superoxide dismutase which breaks down oxidation. The SOD1 gene mutations causes a misfolding of proteins therefore unable to provide proper function.

So what happens when someone has ALS?

ALS develops in most people between the ages of 40 and 70, averaging around 55/56. It is 20% more common in men than women and your risk increases as you age. It will start with muscle weakness, progressively worsening, then atrophy or rigidity will likely start to occur. Basic tasks that require manual dexterity will become exceedingly difficult overtime. If it is initially affecting the legs it can lead to awkwardness when walking, tripping or stumbling more frequently. Some notice in their voice first with muscle spasms in the face and throat.

Because of some of these symptoms it is hard to differentiate between ALS and multiple sclerosis or MS in the beginning. Both are neuroinflammatory disorders that affect the muscles and ability to move the body due to attacks on the brain and spinal cord. MS however is more to do with the myelination surrounding the neurons.

Eventually people with ALS will sucumb to their disease either with respiratory failure/ distress or an additional illness they will not recover from. Some of the people with these illnesses actually die from morphine overdose in hospice facilities. It is not something commonly talked about but commonly is because the patient is given so much morphine to be kept comfortable that their organs start to shut down and they die.

The Neuroscience Behind It All:

Oxidation is a key component in ALS. Oxidative stress or damage is found to damage mitochondria, aggregate proteins, impair autophagy (cell death), and impair splicing proteins. Ultimately, this is a circular system between oxidative stress/ damage and FUS/ TDP4B. As stated prior oxidative stress leads to mitochondrial damage which in turn leads to the bad splicing of RNAs for the motor neurons. The Fus/TDP4B leads to oxidative stress and mitochondrial disfunction. TDP43 inhibits FOXO, a gene that tends to protect against oxidative damage, this causes a downregulation of mitochondrial proteins leading to oxidative damage. Mutations in the TDP43 gene changes the splicing location in Mtfr-1 which leads to mitochondrial fission. Lastly Fus activates PGC-1α which transcribes proteins, when Fus is not functioning correctly it can result in DNA damage, meaning more mutations. Overall this leads to problems.

ALS is a pretty scary condition for those whose lives are impacted by it. They are slowly losing themselves, becoming trapped inside their heads if they even last that long. This August join in with the Ice Bucket Challenge in helping to raise awareness and research funding for this terrible disease.

https://www.medicalnewstoday.com/articles/321900.php

 

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive neurodegenerative disease that affects neurons in the central nervous system (CNS). There are two types of ALS; familial and sporadic, the latter being more common. The eventual death of the motor neurons causes the loss of voluntary movement. There is currently no cure for ALS and eventually progresses until death, typically occurring two to five years after initial diagnosis. Currently, there is little known about the disease in science and in the general public, it’s causes, and what to do from here. It is important to know the possible warnings signs of ALS and symptology to raise awareness about the possibility developing the disease.

Image 1: An infographic containing a range of information about ALS

Image source: http://www.alsa.org/news/public-awareness/als-awareness-month/2016/what-is-als.html

 

Early Signs and Risk Factors

Unfortunately the most common risk factors and warnings signs can be similar to symptoms, as ALS tends to be undetectable until the disease has progressed. Some of the easier warning signs that you could be developing ALS include:

• Muscle weakness
• Trouble projecting the voice
• Difficulty swallowing
• Inability to stop laughing or crying
• Twitching of cramping of muscles

In addition to this, there are several risk factors that individuals should be aware of, especially when showing any of the symptoms listed above. Several risk factors that could predispose someone to ALS are:

• Family history
• Genetic factors and gene alterations
• Smoking (a controversial claim)
• Low intake of antioxidants and vitamin E
• High physical fitness and low body mass index
• Electrical occupations such as welding
• Head trauma
• Frontotemporal dementia

Despite what appears to be an overwhelming list, it is vital to know that there are certain environmental and genetic factors that may play a role in the development of ALS.

Image 2: Looking at the known risk factors that could lead to ALS and those that could be considered some but there remains further research into them to determine the validity of them.

Image source: https://fadavispt.mhmedical.com/Content.aspx?bookId=1895&sectionId=136495898

 

Symptoms

Some of the symptoms that are commonly present themselves in ALS, also seen in the early signs, are:

• Difficulty with voluntary movement
• Tripping and falling
• Slurred speech
• Difficulty holding head and keeping posture

The symptoms usually begin in the extremities and begin to affect the core as the disease progresses.  

 

How Physicians Diagnose ALS

Image 3: One of the ways that doctors diagnose ALS is by obtaining cerebrospinal fluid through a spinal tap, depicted in the image above. The need is inserted between vertebrae and draws the fluid out for testing.

Image source: https://www.cedars-sinai.org/health-library/diseases-and-conditions/a/amyotrophic-lateral-sclerosis-als.html

 

It is incredibly difficult to diagnose ALS, oftentimes the doctors must eliminate all other options before declaring a final diagnosis. ALS often mimics other neurological and neurodegenerative disease, which is the cause of the problem with diagnosis. There are test that exist that are able to rule out the other disease such as:

• EMG
• MRI
• Blood and urine test
• Spinal tap
• Muscle biopsy

Once diagnosed, an individual should keep track of the progression of the disease, as it worsens over time. One of the difficult aspects of ALS as well is the fact that there are no completely effective treatments.  

 

Treatment and Therapies

There is no way to repair the damage that is done by ALS but there are treatments available that aim to slow the progression of the disease and lessen the severity of some of the other symptoms. There only two drugs that are currently approved by the FDA allowed to treat ALS itself. These are: Riluzole and Edaravone. Riluzole appears to slow the progression of ALS, perhaps by lowering the amount of glutamate in the brain. Edaravone, on the other hand, appears to lower the everyday cognitive decline that some patients experience during ALS. There are adverse side effects that are associated with both drugs.

Image 4: Doctors and researchers are working on new therapies and drugs to improve the quality of life as well as increasing life expectancy of those diagnosed with ALS.

Image source: https://www.israel21c.org/als-treatment-to-begin-phase-3-clinical-trials-in-us/

 

Some therapies exist such as breathing and speech therapies that aim to increase the quality of life. Social and psychological support groups also exist for those with ALS as well, as a resource for those to remember that they are not alone.

 

What to Remember

ALS is a complex disease that much more research needs to be conducted on to fully understand. The most important aspect of ALS is not necessarily the science but rather the people who experience the disease. The education of the public is so important so those with ALS to act as a support system and resource. Learn more about ALS and become and ally!

 

Sources:

http://www.alsa.org/about-als/what-is-als.html

https://blog.ochsner.org/articles/quick-guide-to-als-warning-signs

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334292/

https://www.mayoclinic.org/diseases-conditions/amyotrophic-lateral-sclerosis/diagnosis-treatment/drc-20354027 

Amyotrophic Lateral Sclerosis (ALS)

According to the Therapy Development Institute, ALS is defined as “a motor neuron disorder attacks certain cells in the brain and spinal cord needed to keep our muscles moving.” ALS doesn’t affect any of the five senses or cognitive functioning, making the disorder particularly devastating for the individual diagnosed and family. The average life-span of an individual after being diagnosed is 2-5 years. The disease affects many, with an overall lifetime risk of 1 in 400 to develop the disease.

How does ALS work? 

While not all the mechanisms of action of ALS are known, some of the main effectors in ALS are inflammation and oxidative stress that damages the mitochondrial functions. Other information on disease epidemiology is depicted in the image above.

SOD1 influence on ALS

Certain gene mutations have been associated with ALS, including on the SOD1 gene. SOD1 translates an enzyme with the function of converting superoxide (a harmful reactive oxygen species) into the less harmful H2O2. Mutated SOD1 genes lead to buildup of SOD1 aggregates which are not able to function, leading to an increase in oxidative stress.

Video Link: Some helpful information in understanding ALS!
https://www.youtube.com/watch?v=xrIjFVMliOQ

While it is important to look deeper at the mechanism of action for ALS and why it is particularly devastating, hearing individual testimonies on the disease offers a realistic view of the disorder. The following quotes come from individuals who are diagnosed with ALS or who have family members who have/have had the disorder.

I guess I never really knew the meaning of strength. Now I do.

I pray that all those who are suffering with this condition will one day be free from the pain of this most serious of experiences.

In three years he went from being perfectly healthy to not even being able to cluck a tongue and it all happened in the blink of an eye.

Unfortunately, she never came off that respirator and we spent the next five years watching her body deteriorate while she lived on life support. Her mind was sound and her will to live was strong, but we knew she was afraid of being alone and what was to come.

Sources

https://als-ny.org/blog/patients-families-tell-us-als-stories/

http://dmm.biologists.org/content/10/5/537

https://www.cell.com/trends/neurosciences/fulltext/S0166-2236(14)00085-X

 

 

 

What is Amyotrophic Lateral Sclerosis (ALS)?

A progressive neurological degenerative disease of the upper (UMN) and lower motor neurons (LMN). Upper motor neurons in the brain send messages to the lower motor neurons in the spinal cord then to a group of muscles or a single muscle.  In ALS, UMN and LMN start to stop sending messages to the muscles. Furthering to symptoms of: muscular atrophy, muscle stiffness, slurred speech, and difficulty swallowing.

This disease is currently incurable. Treatments available are to help control the symptoms and making living with ALS easier.

Medication: Rilutek helps reduce damage to motor neurons by decreasing glutamate levels. Many medications that directly treat the symptoms such as muscle cramps, stiffness, depression, and constipation are usually prescribed. Edaravone, just FDA approved in 2017, is a known antioxidant to help with ALS.

Therapy: Physical therapy that use very low-impact exercises can help with cardiovascular health, fight fatigue, and strengthen the muscles that are still unaffected. Speech therapy to help with speaking and help improve or continue the ability to communicate.

Support: Nutritional support allows for increased ease of eating food as well as increased nourishment to continue calorie intake. With a high calorie intake, they will not lose weight as fast thus slowing down the progression of weakness. Breathing support such as a mask or other machines. This support is vital due to the weakness of the respiratory system is the common way of passing.

Unfortunately, this disease is very deadly. Most people die from respiratory failure within 3-5 of first symptoms being present. Rilutek has been found to slow down the progression and increase life expectancy by a few months.  Breathing support has also shown to prolong survival.

Rare Case: Stephen Hawking

A short video about Stephen Hawking published by the Washington Post.

Most people don’t survive 3-5 years after diagnosis of ALS; however, one man beat the odds and survived 55 years with ALS.

Stephen Hawking was a renounced theoretical physicist from Oxford, England. Throughout his life he had worked on the basic laws of the universe. His contribution to society had won him awards from Presidential Medal of Freedom to CBE. While accomplishing our further understanding of the universe, battled with ALS. At the age of 21 (1964), Stephen Hawking was diagnosed with ALS. Progressing over the years he became wheelchair-bound and used a computerized voice system. Even through the progression, he did not allow the disease to limit him. Stephen was a very rare and unique case.

Hope for a brighter future:

A discovery of the NEK-1 gene. The function of NEK1: maintaining neuron’s cytoskeleton and regulation of the membrane of mitochondria. This gene has been found to be in sporadic and familial ALS posing an opportunity for a new target for drug development for ALS. *Further research is being conducted.

Therapeutic target for C9orf72-associated ALS. A common gene mutation, C9orf72, is a genetic cause of ALS. Inhibition of Spt4 protein, was found to reduce toxicity caused by C9orf72 repeat expansion. *Further research is being conducted.

AstroRx, stem cell-gene therapy Clinical trials are recruiting after positive results in animal models with ALS. In hopes that using human embryonic stem cells to produce astrocyte progenitor cells in labs will be effective. Injecting healthy astrocytes into the spinal canal of mice had shown a delay of onset. *New Clinical Trial is being conducted.

*For more information on stem-cell research.

Positive results for NurOwn stem cell phase II trial. Mesenchymal stem cells from bone marrow are being used for cell therapy. Administered intramuscular and intrathecal injection showed to be safe and highly tolerated. *Research being continued into phase III.

*For more information on the trial

A better understanding of ALS has begun to emerge and more quickly since the Ice Bucket Challenge. This challenge has risen awareness as well as enough money to put toward research. Through the ALS foundation and remarkable researchers, a cure for the incurable is reachable in the near future.

References:

The ALS Association

National Institute of Neurological Disorders and Stroke

Stephen Hawking