In the last few years I’ve watched my grandmother sink into the mysterious depths of her Alzheimer’s disease. However, as she approaches 90 years old it is not just her mind that is failing, as she struggles to regulate her cardiovascular (heart and blood pressure) and gastrointestinal (stomach, intestines) systems. Therefore, is Alzheimer’s really a disease or is it just a condition that is part of the normal human process of aging?
Although it may be tempting to call it a disease because it isn’t readily apparent in every individual, Alzheimer’s may be considered for classification as part of the aging process, similar to the slowing down and general decline of many other essential organ systems, albeit much more sad. However, much of the focus of aging is on the cognitive and behavioral aspects, perhaps because other organs may be replaced or otherwise supported functionally with treatment, or because there is a general consensus that the essence of a person is in their personality and intellect which disappear with declining mental health. While in the not-so-distant past, Grandma just became increasingly forgetful as she aged, today even the most elderly are subjected to batteries of tests looking for abnormally high levels of forgetfulness in 80 and 90 year olds. Yes, Alzheimer’s in the younger-onset demographic is most likely a disease, but once an individual is at a point where multiple organ systems aren’t functioning properly, forcing them to be on inordinately large numbers of pills per day to simply stay alive, is the mental decline of Alzheimer’s really more of a disease than the natural aging of the rest of the body?
Aging, however, is a complex equation; for example, why do people and their respective organ systems age at different rates? One aspect of rate of aging may be lifestyle. A large lifestyle concern in the US in particular, is obesity and the wide range of disease that accompany overeating and sedentary lifestyle: one of these is type 2 diabetes mellitus (T2DM). There are studies that show a connection between neuronal insulin action (part of T2DM) and the development of Alzheimer’s. This may be driven by inflammation in the central nervous system (CNS), providing the cellular processes contributing to neuroinflammation as a target for research.
Because of the natural aging process that effects the brain, this research should not focus on finding a “cure” for Alzheimer’s, but rather more productive and high-impact aspects of the condition. This is not to say that research should not be undertaken; rather, the research should focus on learning more about the etiology and pathology (for lack of a better term) of Alzheimer’s and comfort of the individual and family during the end of life stages. There should continue to be research for treatment and a possible “cure” for younger-onset versions of Alzheimer’s. Besides, to “cure” Alzheimer’s, we’d have to virtually pause or reverse aging, which is just far too ethically controversial.
ALS: What’s the best approach when the answer is not in your genes?
Amyotrophic lateral sclerosis or ALS is better known as Lou Gehrig’s disease and is a neurodegenerative disease that appears during midlife of an adult. It results in progressive motor neuron loss, making voluntary and eventually even involuntary movement impossible, eventually being fatal. The etiology or cause of ALS is not well understood although there is a focus on studying possible genes involved. This may not be the best approach because only 10% of individuals diagnosed with ALS is considered familial (or with heritable genetic origins) compared to the other 90% being sporadic. Sporadic ALS appears in an individual with no family history of the disease and is not necessarily linked to a heritable gene.
One gene that has been studied extensively (even though there isn’t a strong genetic connection to most ALS cases) is the SOD1 gene. SOD1 stands for superoxide dismutase 1 and is an enzyme (or molecule) in our cells that breaks down dangerous chemicals called reactive oxygen species (ROS) that can cause cells to age prematurely and eventually die. A mutation in the SOD1 gene causes the enzyme not to work properly which leads to an accumulation of ROS in the cell and may cause the cell to age and die from stress.
Mutations in the SOD1 gene are found in about 20% of familial ALS patients and 7% of sporadic ALS patients. Even though these numbers may seem small, they represent the largest percentage of individuals that have a similar mutation, which is why SOD1 is so widely studied. This certain mutation is also how scientists study ALS in animals. The animal model used has the mutant version of SOD1 and shows many of the symptoms of ALS.
This leads to the question: should those individuals diagnosed with ALS and their offspring be required to have genetic sequencing (testing) and counseling? Although ALS may not be consistently genetic, if it could identify even a few individuals who may have the disease early enough on to teach them about the disease before they have their own children it may be worthwhile. However, this broaches many ethical considerations. For example, what if an individual whose parent is diagnosed with ALS does not want to know if their genes are mutated? Is there an ethical responsibility on that individual if they have children even if they know they may be a “carrier” of ALS? Is there an ethical need for these individuals and any possible children to undergo genetic counseling to better understand and process their condition and possibility of fatal disease? Much of the considerations surrounding diseases as devastating as ALS turn out to be ethical, instead of medical, in the end. That is not to say however, that continuing supporting, funding, and doing research on ALS won’t help to elucidate the cause and find new treatments for the disease.
Insulin: impacting more than just diabetes
Those impacted by Alzheimer’s disease (AD) has reached an alarming number of 5 million individuals as of 2015 in the United States alone. AD has no cure, which is why the diagnosis can often be so hard on friends and family. Memory loss, general confusion, and difficulty concentrating characterize the disease, which can all be blamed on the formation of beta amyloid plaques and neurofibrillary tangles in the brain.
But wait, the Title mentioned diabetes, not Alzheimer’s disease. Where is this going?!
Type II diabetes is not categorized as a neurodegenerative disease like AD is. But Type II diabetes itself impacts 90-95% of those diagnosed with any form of diabetes. The disease is characterized with what is called “insulin resistance.” This phenomenon is where the body is unable to properly create enough insulin. Or enough insulin is being produced, but insulin in general is unable to bind to its insulin receptor.
But what in the world does Type II diabetes have to do with AD?
Calm down and let me tell you.
New research is discovering a similarity in the pathways of Type II diabetes and Alzheimer’s disease. The two major pathways have been labeled MAPK and PI3K.
Two of the major problems that differentiate AD from other neurodegenerative diseases are the formation of amyloid beta plaques and neurofibrillary tangles. These plaques and tangles can be traced back to a malfunction of insulin in the PI3K pathway.
Looking exclusively at the PI3K pathway of the cell, neurofibrillary tangles are formed when glycogen synthase kinase 3 beta (GSK3ß) is NOT inhibited. The inhibition of this particular kinase can be traced all the way back to the successful or unsuccessful binding of insulin (refer to yellow circle titled ligand below) to a specific type of receptor tyrosine kinase, in this case an insulin receptor (refer to blue prong-like image below). If insulin is successfully able to bind to its receptor, a series of excitatory or inhibitory signals occurs. As the picture below refers to, a series of excitatory signals must occur in order for GSK3ß to successfully be inhibited. Successful inhibition reduces the amount of protein (specifically tau) phosphorylation.
In a healthy neuron, tau proteins bind and support the microtubules found in the axon of a neuron. Unfortunately, in the case of those with Alzheimer’s disease, if the inhibitory signal is not received to the GSK3ß, the protein tau continues to phosphorylate, causing its normal function in binding and stabilizing microtubules to cease, dissociating the microtubule all together, leading to the neurofibrillary tangles (as can be seen by the image below).
Yes, I get it. This is a lot of information that is very easy to think has completely gone in over the head. Let me try and sum all of this up for you.
Take home message: Insulin is a hormone that plays a very important role in both diabetes and Alzheimer’s disease. Too much or too little insulin is never good. The unfortunate part of all of this is that no one really knows the exact amount of insulin needed in the body for everything to function properly. Insulin, when properly binding, has the ability to inhibit the formation of beta amyloid plaques and neurofibrillary tangles and promote neuronal growth within the brain, which can lead to improvements in cognition.
The question remains: Are those who suffer from Type II diabetes more prone to Alzheimer’s disease, as improper binding of insulin is categorized in both Type II diabetes and Alzheimer’s disease?
The discoveries researchers are finding that show how insulin plays a role in both AD and Type II diabetes will hopefully lead future researchers to something that doesn’t go over everyone’s head:
A cure.
Alzheimers Disease: When Decisions Can't Be Made
Alzheimers disease (AD) is a disease that is very prevalent in the present day. Many people know Alzheimers disease due to its effect on causing people to forget things. Alzheimers disease does in fact cause one to forget many things, but there is much going on inside the body causing this forgetfulness, loss of memory, and overall trouble of thinking. With these problems occurring, another problem usually arises and that is the fact that the patient with Alzheimers disease can no longer speak for themselves and needs a family member to do so for them. This can create many problems which will be talked about. First it is key to understand the science behind Alzheimers disease.
The key reason for Alzheimers disease that is currently under research is the role of insulin in the central nervous system. One possible way that insulin leads to AD is through impaired neuronal insulin action. The big reason impaired neuronal insulin action is bad is that insulin has a regulatory role concerning the amyloid precursor protein and its derivative beta-amyloid. This protein is associated with senile plaques which are seen in high concentration when someone has AD. So when insulin is being impaired, the degradation and trafficking of beta-amyloid is basically being interfered with and that can lead to Alzheimers disease. So possible treatment for Alzheimers disease could be done by administering insulin to a patient with AD. This is still an area that needs much research, but it provides a hopeful option to treatment for AD.
This leads me to talking about the effects that AD can have on a person. When a person gets AD, they start to lose there memory and ability to think. This causes them to often be forgetful. As the disease progresses, this issue becomes worse and often times the person isn’t able to make decisions for themselves any longer. This creates many issues because often the family has to take over for that person. If the patient didn’t set up any type of plan for themselves as far as what they want in a life where they can no longer make decisions, then the family has to step in. This often leads to a patient family conflict. The family can often be selfish when they think they are doing what is best for the patient, but they really just don’t realize what the patient wants and that is not their fault. Often the patient will be in a lot of pain and discomfort and the family will keep trying to do everything in their power to keep that patient alive when maybe the patient doesn’t want that but just can’t express that feeling. This type of issue is very common in the medical field and is one that needs to be addressed. There needs to be some type of program implemented that meets with people early in life to discuss what they want if they happen to be faced with a serious illness. Its not just AD where this issue arises, but many other diseases also see this issue. If a program can be implemented then future family and patient issues could be avoided leading to a happier party of both sides.
Overall Alzheimers disease still needs to have much research done to discover effective treatments for patients experiencing AD, but there are areas that give hope like insulin. There also needs to be a program implemented that will allow patients the opportunity to talk about what they want with their life if they are faced with a serious illness and can no longer make decisions for themselves. If this can be accomplished, then there will be less patient family issues in the medical field.
ALS: is it worthy of the public limelight?
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that kills/damages cells in the brain and the spinal column. The cells that are especially impacted are motor neurons, leading to involuntary muscle spasms. Eventually as the disease progresses control over voluntary muscles begins to decrease, eventually voluntary muscle control is lost. The disease will even claim the person’s ability to live by themselves, feed themselves and ultimately their ability to breathe for themselves. While the person’s physical abilities decrease exponentially the thinking capability of the person remains unimpeded, keeping their mind as sharp as it was previously.
ALS is a disease that affects around 30,000 people in the United States, a relatively rare neurodegenerative disease. Unfortunately global statistics on this disease are much harder to find, a quick search of the Internet leads me to the statistic that 30,000 people in the US are impacted. It is approximately as common as Huntington’s Disease, a degenerative disease that was prominently featured in the TV show House M.D.. While both diseases are incredibly damaging to families and people it is merely a small fraction of the number of people that are killed in the US (and the world) each year. In the United States 2 per 100,000 deaths are by (or are related to) ALS; while 3.5 per 100,000 deaths are related to guns/gun violence (I only use this as a framing device).
This is not meant to belittle the impact of ALS on society, it is merely meant to show how few people it impacts. Until recently I hadn’t heard of the ALS Ice Bucket Challenge (I freely admit I live under a rock when it comes to popular culture), but it surprised me. It’s raising money and awareness for a disease that is devastating and painful to watch a loved one go through; but raising awareness for a disease that impacts a mere 0.01% of the population in the US. When I quickly Googled how much money the Ice Bucket Challenge raised to research a cure for ALS over $15,000,000 (fifteen million) has been raised since it first began.
This begs the question to me: Is such a relatively rare disease deserving of the newfound public fame when diseases like Creutzfeldt-Jakob disease (CJD), a prion disease, impacts 10 people per 100,000 across the globe? In the state of Minnesota alone 13 people per 100,000 (the US as a whole is approximately 9.6 per 10,000) die from CJD with death occurring on average six months after the onset of the disease. While ALS is completely deserving of being researched and funded to the best of their ability there are also other diseases, diseases few people have heard of that impact more people than ALS and are currently without any effective treatments; like CJD.
I will end this blog post with a humble request: next time when the Ice Bucket Challenge scrolls across social media (and I guarantee it will) just remember there are also other diseases that are just as worthy, if not more so, than ALS.
Heritability of ALS
What is ALS?
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that affects the motor neurons in the brain and the spinal cord. As the motor neurons die, the brain is unable to control the muscles involved. This is how the paralysis associated with ALS happens.
There are two different types of ALS, familial and sporadic affecting around 20,000 people in the United States. Only 5-10% of people have familial ALS, which means immediate family members have ALS also and it was inherited. Research suggests it is autosomal dominant inheritance in those families, so there would be a 50% chance that a child would inherit the disease. The other type, sporadic, is seen in the other 90-95% of the cases. This means that the person, to the best of our abilities, has a sporadic genetic mutation causing the disease. If a person has more than one mutation, they would have an earlier onset of the disease than someone with only one mutation. Some research is suggesting a link between concussions and ALS. Other research is just now revealing the possible genetic mutations causing ALS.
Types of Mutations
There are a lot of different mutations that can cause ALS. One of the common mutations that have been researched is the SOD1 mutation on chromosome 21 which causes abnormal protein deposits that aid in the degeneration of motor neurons. Not everyone with ALS has this mutation though. A study in Nature looking at fALS (not looking at SOD1) reported finding a faulty enzyme, Ubuiquilin-2, that is supposed to break down ubiquinated proteins. If the enzyme isn’t functioning, the proteins accumulate in the lower motor neurons and upper cortical motor neurons and block normal transmission of brain signals in the spinal cord and brain which lead to the paralysis. This build up is also seen when people have mutations in TDP-43 and C9ORF72 genes which cause the enzyme to malfunction in other ways.
As seen in the picture below, there are many ways in which the motor neuron can become damaged and die in ALS. Since there are many variations of the disease, it has been difficult to find medicines to treat it.
So… Is it inherited?
Unfortunately as with a lot of science, there is a lot of ambiguity in the research attempting to solve the genetic mechanisms of ALS and if it is inherited or not. Without the knowledge of family members with the disease, a neurological exam could not reveal if a person has the familial vs sporadic version of the disease. Both forms have been seen to have some of the same mutations. Currently, there are variants of other genes that are inherited that have been seen to cause a greater susceptibility to developing ALS, but no one “tell all” gene that can show that the disease is directly caused by inheritance. Hopefully with the new understandings of the mechanisms of the disease, researchers will be able to pinpoint ways of diagnosing and treating the disease with the specificity of that person’s genetic mutation.
The beginning of the cure for ALS.
If I say the words “ice bucket challenge”, do you know what purpose of it is? Or what it is aiming to cure? The answer is the all-too-familiar Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s Disease. ALS has been on the back-burner of recent research mainly due to the fact that it affects only 30,000 Americans today. This is in comparison to the millions of people with some form of cancer, which respectfully has been a forefront of research for decades. In recent years, ALS has captivated copious amounts of attention. We may know that finding the cure to ALS is the purpose of the ice bucket challenge, but what is ALS exactly? Although I participated in an ice-cold bath to raise money, I struggled with that very question.
ALS is a neurodegenerative disease that is physically characterized by a decrease in motor function which is an effect of a loss of motor neurons in the brain stem, spinal cord and cerebral cortex. Although the reason for loss of function in motor neurons is still under investigation, glutamate toxicity is a main suspect.
At the end of each neuron, where glutamate is released to the receiving neuron, there is a little space called the synaptic cleft housing enzymes that will terminate the glutamate action or cause it to be a factor of reuptake for use again, and to prevent over-accumulation of glutamate. If there is excessive glutamate in this cleft and/or a dysfunction of one or more of these enzymes, glutamate’s receptors may be over-activated which would lead to the undesired massive influx of calcium with the end result being toxic to the neuron. There is also the possibility that one of the glutamate receptors, NMDAR, is potentially seen to be over-activated in ALS patients. Why is this important? Well, since NMDAR is permeable to calcium, and if high calcium levels may result in neuronal death, over-activation may play a vital role in what characteristics of ALS we are seeing. Although the process is more complicated than that, this is a major area of focus.
So what can we do so far? We know that excessive levels of glutamate in aforementioned clefts were a bad thing, so how can we prevent that? Today, there is a drug, called Riluzole, that remains the only disease-modifying drug for treatment of ALS. It does so by controlling by reducing glutamate release, uptake and glutamate receptor function. Although it hasn’t had significant improvements on patient lives (only extending ventilator-free living for a couple months for roughly $10 a pill), it still is a step in the right direction.
With more research, like all diseases, a better way can be found. Although a minority of the population is being affected, it is roughly 15 new diagnoses in the United States alone. That is 15 new families impacted by this debilitating disease which could be prevented if this research were carried out farther.
ALS… Why Do We Care?
ALS is a neurodegenerative disease that quickly kills motor neuron functioning in the body. In most cases, patients afflicted with the disease die within five years. Although a specific cause has not been identified, however, multiple factors have been attributed to the onset of this disease. This may sound insensitive, but why do we care about the disease? Only 3.9 out of every 100,000 Americans are affected, which is only 0.0039%. Even in the targeted age group (70-79), only 0.017% suffer from the disease. Compare these statistics with cancer. In American citizen has a 39.6% chance of getting cancer in their lifetime. There are many other first world diseases with higher prevalence than ALS as well. So again, why do we care about this disease?
ALS has recently gained a lot of publicity through the Ice Bucket Challenge frenzy that occurred last year. This event helped to spread the word about the disease, it also raised about 100 million dollars for research of the disease. My question is; were people really concerned about finding a cure for ALS, or just participating in the newest social media craze? Before this fundraising, ALS did not receive significant amounts of donations for research. In fact, the only reason this disease received as much attention as it did was likely because it ended a very famous baseball player’s career (Lou Gehrig). Personally, I don’t think the disease needs more attention or increased funding. Not only because it is extremely uncommon, but also because it affects mostly the elderly. There are a limited number of resources in the research world; these resources being researchers and funding. I believe more research and funding needs to go towards diseases with a higher prevalence among the whole population. Once more prevalent diseases are cured, more attention can be given to more obscure diseases. Also, research on the common diseases like cancer may even provide knowledge necessary to find a cure to related, but less prevalent diseases. An applicable analogy of this idea relates to homework. If I have homework due in all four of my classes one night, what is the best way to complete it all? I’ll probably start with either the most difficult class or whichever homework is due the soonest. Once I complete that assignment, I go onto the next most important assignment and so on, until all my work is done. This method is much more effective than attempting to work on all the assignments at the same time. You may even learn something from the early assignments that help you complete the latter ones.
With that being said, research should still be conducted on ALS. However, with limited resources the research needs to be specifically directed. There are too many potential physiological causes to narrow down with the limited amount of funding researchers have. I think research should be directed towards gene therapy; this could have a high potential of limiting the prevalence of familial ALS. There are a few known proteins that cause some of the symptoms of ALS, errors in the SOD-1 protein in particular, that could potentially be corrected for with directed funds and research. All in all, ALS should remain one of the lower priority diseases because of its low prevalence and primarily affected age group.
Is there enough money?
Amyotrophic lateral sclerosis or ALS is a neurodegenerative disease that affects motor neurons in the brain and in the spinal cord. ALS affects approximately 30,000 Americans at a given time. That means that 15 different people are diagnosed every single day in America. In the past few years ALS has received massive media attention through the campaign Ice Bucket challenge. The Ice bucket challenge has been a huge help for the ALS Association (ALSA) in terms of raising money for awareness and research. But the real question is if whether or not that is enough?
As of now there is only one medically approved drug by the FDA and that is the drug riluzole. Riluzole works by slowing the progression of the disease. The process of which riluzole works through the molecular level has not actually be discovered or agreed upon, it is just accepted to say that the drugs works by reducing the levels of the chemical messenger glutamate in the brain. Glutamate in reasonable concentrations is very common and helpful in a normal and healthy human but when there is prolonged over expression of glutamate it becomes extremely toxic and detrimental to nerve cells. This over expression is what eventually leads to the motor neurons being damaged and ultimately the progression of ALS. So the whole purpose of riluzole is to prevents the release of glutamate in the brain along with promoting the uptake of it. While riluzole has had some success in delaying the progression of the disease it by no means reverse the effects or stop the disease. The most common results from the drug is two to three month life expectancy increase along with a 9% increase in the probability of making it to one year.
With riluzole being the only approved drug for treating ALS you may begin to wonder why there is not other treatments. There are two reasons to why I believe that there are not more treatments for ALS and I also believe the first is a result of the the second. The first reason is that our knowledge of what is causing ALS is very limited and that is preventing the development of a successful drug. The second reason is that there is not sufficient money to fund more research into ALS. According to the ALSA they were able to generate $13.6 million dollars for research and of the research that is shown on their website only one of the six research programs they provided information about was directed towards finding a drug to help treat the disease. When comparing the money ALSA was able to provide, it is almost nothing compared to Susan G. Komen’s $49.5 million. Although breast cancer does affect more people than ALS it is just sad to see such a gap in funding because an ALS diagnosisis a death sentence where as a breast cancer diagnosis has a change for survival due to more successful trements regiments. Another cancer organization that does not support just one type of cancer but was almost able to raise more total money then the ALS Association as a whole is Livestrong. Livestrong was able to raise $35.5 million and ALSA was only able to raise $39.2 million.
With ALS lacking a highly successful treatment it is very sad to see that the disease’s association is really lacking when looking at the funding for research compared to other diseases, cancers or organizations. I’m very thankful for this class because it gave me more information about ALS and it also gave me the realization that ALSA needs help with funding to help develop a more successful treatment. I’m sure there are other organizations that also lack the funding and treatments just like ALS and as a society I think we need to step up and help these organizations, not just the major ones. Going forward I’m definitely going to donate money to different cancer and disease organizations because they all need help and I want to be apart of making peoples lives better. So I challenge you to do the same.
Sources:
http://www.alsa.org
http://ww5.komen.org
http://www.livestrong.org
ALS: More Than Just an Ice Bucket Challenge
Recently ALS has been on the radar of many because of something called the ALS ice bucket challenge. The challenge composes of people dumping a bucket of ice on their head and then saying that they will donate money to research for ALS. I’m not trying to make assumptions but my guess would be that most of the people doing the challenge don’t have a great knowledge of what ALS is. Instead they did the challenge to post a video on Facebook because everyone was doing it and that was the extent of it for him or her. By no means am I saying that this cause is bad because this challenge did actually raise quite a bit of money for research and raise a lot of awareness for ALS, but I feel that it shifts the spotlight from what ALS truly is and how devastating it can be. This brings me to explaining the science behind ALS and why there is a need for funds raised by the ice bucket challenge.
ALS is characterized as an adult onset neurodegenerative disease that is caused by the degeneration of motor neurons in the brain stem, spinal cord and cerebral cortex. There are multiple pathways that have been suggested to be degenerated by ALS, but more research needs to be done to see which ones are leading to the effects induced by ALS. Glutamate toxicity as of now has been the most researched pathway being the underlying cause of ALS. Another pathway under discussion deals with low calcium buffering. This leads to the mitochondria and endoplasmic reticulum becoming engulfed with calcium leading to misfolding of proteins and triggering of the unfolded protein response. This in turn leads to cell death and degeneration of motor neurons. The reason that the symptoms associated with ALS are loss of motor function and paralysis is due to the degradation of the motor neurons. Motor neurons take a signal in and transfer it down its axon. It then releases synaptic vesicles containing a neurotransmitter that speaks with the muscle and tells it to move. That is being said in a very simplistic manner but that is the basic function of motor neurons, so when they are degraded that is why you lose function.
Overall there are many pathways that have been proposed to be leading to the degeneration of motor neurons and causing ALS. With the ALS ice bucket challenge, a large sum of money was raised that will help in finding the pathway causing the degeneration of the motor neurons in ALS. Once again, the ice bucket challenge is a good thing, but just know why and what ALS is before you feel that sensation of cold water spill over your head.