Parkinson’s Disease is a neurodegenerative disease that affects both motor and non-motor systems in the body, which is characterized by the death of neurons in the brain. There is no cure for Parkinson’s and the only form of treatment at this time is for the management of the motor symptoms, but there is currently no way to slow the progression of the disease. Dopaminergic neurons, neurons that release the neurotransmitter dopamine, are the type of neurons that are dying. By preventing the death of these neurons, we are able to relieve some of the motor symptoms associated with PD. The treatments for PD focus on increasing the amount of dopamine in the brain by inhibiting the breakdown of dopamine.
Everyone loses dopaminergic neurons throughout their life, so individuals that live longer will be more likely to develop PD since they will have a greater loss of dopaminergic neurons. Therefore, PD is largely age-related, but this does not explain why early onset PD occurs. There is evidence to suggest that PD is due to genetic factors. The neurotoxin MPTP has also been shown to play a role in the pathophysiology of PD, and can be related to environmental causes of PD. Oxidative stress, misfolded proteins, and aggregation of α-synuclein are also associated with PD. http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/parkinsons-disease/#pathophysiology
PD is diagnosed primarily because of the motor symptoms. If we were better able to detect the non-motor symptoms of PD, then maybe we could diagnose it earlier. Some of the main non-motor symptoms include depression, constipation, and troubles sleeping.
In our discussion group, the question came up that since PD is not life-threatening, does that justify why finding a cure for it is not a high priority of researchers? Although finding a cure is important, it seems logical that there is a higher priority for finding a cure for cancer since it affects more people and it is life-threatening. Despite these facts, there still needs to be more research and money donated to the cause of PD in order to find a cure.
Parkinson’s Disease: More Than Just Tremors
Parkinson’s Disease (PD) is the second most common neurodegenerative disease after Alzheimer’s. It effects about 3 in 1000 people in industrialized nations. Although PD affects less than 1% of the population, both the motor and non-motor symptoms are debilitating. The cause of PD remains unknown, however researchers believe it is caused by a combination of genetic and environmental factors. This means the disease can vary from person to person. Aging is an important risk factor with a 2 to 4% chance of developing PD over age 60.
Genetic Factors
A majority of Parkinson’s cases are not directly inherited. Around 15 to 25% of individuals with PD report having a relative with the disease. There are several gene mutations that cause the disease directly, however they only affect a small number of families.
Environmental Factors
Parkinson’s Disease is only found in industrialized nations, therefore some researchers have suggested that PD may result from exposure to an environmental toxin. Epidemiological research identifies rural living, well water, manganese, and pesticides as important factors linked to PD. Although continued environmental exposure can be linked with PD, research demonstrates that environmental factors cannot be the sole cause of PD.
Symptoms
When we hear about someone suffering from Parkinson’s Disease (PD) we automatically picture an individual with severe tremors. The motor symptoms associated with PD are the most visual symptoms however the non-motor symptoms are often the most debilitating. Patients suffering from PD state that the non-motor symptoms create more of a challenge in daily life than the motor symptoms.
Motor Symptoms
- Resting Tremor
- Bradykinesia
- Rigidity
- Postural Instability
- Freezing Gait
- Micrographia
- Mask-like Expression
- Unwanted Accelerations
Non-Motor Symptoms
- Cognitive Impairment
- Dementia
- Psychosis
- Depression
- Fatigue
- Sleep Disturbances
- Constipation
- Sexual Dysfunction
- Vision Disturbances
Society’s perception of Parkinson’s Disease is often skewed by our lack of understanding of the non-motor symptoms. PD is characterized by the tremors, but the invisible symptoms are just as deadly. As
a society, we must make an effort to understand all aspects of PD and work to support those suffering from its symptoms. Current research is focused better understanding the genetic cause of PD and developing a more effective diagnostic and treatment plan. Knowing more about the causes and symptoms of PD, what can we do to support the fight for a cure? To learn more about the fight against Parkinson’s Disease, visit www.pdf.org
Insulin: A Sometimes Under Appreciated Key Player in the Brain
As a relatively healthy person, insulin is something that I rarely consider, I do not consider how my intake of sugar may affect my body, I also do not consider what would happen if I did not have the necessary insulin in my body. Insulin is involved in many processes in the body, more than I have ever really considered. Deficiencies in insulin lead to diabetes, and in turn obesity, but also with links to Alzheimer’s disease. Insulin is highly involved in metabolic as well as cognitive regulations. Thus, when the insulin pathway is not working properly, the brain and energy homeostasis are thrown off. Insulin is the key player in glucose homeostasis, meaning it is the thing that keeps our body’s sugar and energy levels under control. In the central nervous system, insulin is largely found, but in patients with diabetes or Alzheimer’s disease, there are lower levels of insulin or insulin receptors. Thus, we see a link of insulin to Alzheimer’s disease (which makes sense as insulin has a part in cognitive part of the brain, especially in learning and memory). We also can see a link to obesity when insulin is not functioning properly. This change in food intake is changed as within the insulin signaling pathway, we see the PI3-K pathway, which when activated will send signals for decrease of food intake. The neurons that are involved in this regulation of food intake are the AgRP/NPY neuron (which tells the body to eat more) and the POMC neuron (which sends the signals that the body is full) and if insulin is not functioning fully, then there is excess glucose, leading to these two neurons getting signals screwed up. Thus, if the insulin is not working properly, then there is no signal to decrease food intake, which will then lead to over ingestion and set the body up for obesity. Another interesting part of these neurons is that in a high fat diet, the POMC neuron is tricked, and instead of recognizing high fat food as something that should satiate our bodies, it instead still thinks we are hungry (in the figure below we see this pathway and that fatty food cause the same pathway as hunger).
It really took me by surprise learning that this is why it is so easy to eat lots of fatty foods without ever really feeling full, and explains why problems with insulin can lead to obesity.
The other pathway that insulin signals through is the MAP-K cascade, which is involved in cognition (especially learning and memory). Thus, we can see how Alzheimer’s disease has a link to poor insulin function, as there would be decreased memory when there is less signaling coming from the insulin pathway. In addition to causing the memory issues, the PI3-K pathway (from insulin pathway) causes a descrease in phosphorylated tau, so as PI3K stops functioning appropriately, phosphorylated tau increases, which is a large player in AD. In addition to the tau, we see an increase in Aβ plaques, which inhibits the insulin pathway, thus causing loss of the cognition that is gained. I find it extremely interesting that AD is linked to insulin. It is not something that I had ever considered to be related to each other. I also found myself wondering if having diabetes earlier on would pretty much mean that one will end up with AD or if there are ways to prevent AD when someone has type II diabetes. It is kind of a foreboding thought, just because a large possibility for the future of people who have this type of diabetes is AD, which is a scary thought to know that you will slowly forget who you are. However, I think it is interesting that we have found such a link, and how insulin may be the link in curing AD as effectively as it is in helping with diabetes. All in all, I found that I really should put more thought towards how insulin is working in my body and how what I may be eating may hurt the insulin or its receptors. What I am trying to get across is that insulin plays such a crucial role in our lives, and that maybe we should consider how to keep the insulin in our body functioning appropriately (by eating healthy) so we don’t have to be worried about whether our sugar will be metabolized and our body will function properly in the future.
ALS: Of Ice Buckets and Men.
Last year, the ALS ice bucket challenge went viral across the United States with millions of people joining in on the phenomena of pouring ice water onto one’s head in order to raise awareness for amyotrophic lateral sclerosis (ALS). The movement raised close to $100 million for the ALS association and was a great launching pad for bring about awareness to the little-mentioned/covered disease. This was 2014. What of this year?
This ALS association attempted to reintroduce the event again this year with the intent to make a yearly tradition, but the movement was nowhere close to as successful as the first iteration. They only raised close to $1 million this year, a significant drop in donations from only one year before. So what happened?
The problem for the ALS association is one that many major disease organizations struggle with. Consistency. Public opinion and in turn, money, is controlled by the mass media that dominates our culture. Information is delivered, controlled, and modified by the media to serve corporations and to drive personal gain on behalf of those that own these companies. They decide what the public has the right to know and if we need to know information. As a firm believe in the free trade/distribution of information, I think that this sort of behavior/deliberate acts of population manipulation is utter bullsh*t. It inhibits the ability for the public, especially those that doesn’t take full advantage of the internet, to make informed decisions without all the facts being presented.
Now you may be asking, how does this apply to ALS and other smaller disease focused NGO’s? I said it had to do with consistency. That means that these organizations are not able to consistently get their cause out their effectively without cooperation from the media. The Susan G. Komen for the Cure Foundation has done a brilliant job of being consistently marketable and present in the news, allowing it to flourish and rake in massive amounts of donations. In 2010 alone, the foundation raked in over $400 million. That is four times the amount that the ALS foundation raised in their largest year ever. And I think this really hits on the larger issue here, which is public perception of diseases and how we feel we should be appropriating our charitable donations.
Everyone has someone in their family affected by cancer making a very real and relatable disease. When a disease personally affects your reality and your daily life, you are more inclined to take part in fundraisers and events that support a foundation that fights it. This is why cancer research gets a large portion of the donation money from the public. The more support an organization gets from the public, the more money it can put into marketing, allowing it to be more consistently present in the eyes of the public, allowing even more money to pour in, creating a cyclical flow of events.
Less common diseases like ALS are not as present in the forefront of public opinion due to their relative affliction rate and how widespread their problem is. It isn’t to say ALS isn’t as dangerous or lethal in comparison to cancer, but it affects far less people that it is often forgotten, in turn hampering the ability for scientists to find a cure and to actually help those who are in need of it. It isn’t consistent enough of disease to warrant consistent public attention, which is a rather brutal way of saying it isn’t lethal enough. And that is the sad reality of ALS.
So what can be done? A flip flop in thinking of the American public is a good place to start, but isn’t that a good place to start for everything? We as a society should care about cancer research and should put funding into that because it is important, but cancer is such a diverse and multi-faceted issue that it is sometimes hard to see a light at the end of the tunnel. ALS, while also being a complicated disease, could simply be a few years of research away from a major break through.
The point I am trying to get at here is that there isn’t enough money to go around for the amount of research that needs to be done to make major breakthroughs on these diseases. We don’t have enough charitable funds to fully support all of these wonderful foundations and charities and so we pick and choose, typically based upon those that affect us and those that the media exposes us to on a regular basis.
This blog post was intended to cover the facts on ALS and what its mechanisms of action are within the body, but I felt this was an opportunity to get real with how I felt about the commercialization of how we treat diseases and to acknowledge the fact that not all diseases were created equally. It sucks, but it is the reality we live in.
Parkinson's Not Just a Tremor
Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s effecting about 3 in 1000 people in industrialized nations. It seems that although it is very common people take it a little less seriously than Alzheimer’s or some other less common neurodegenerative disorders. I believe the general perception is that while people might have some motor neuron issues it is only a tremor, not severe memory loss, or complete loss of motor control like ALS. It is important to remember that anytime there are problems in the brain there are widespread systemic consequences.
Recently it has been determined that the effects of Parkinson’s disease go further than just a tremor and balance issues. Individuals suffering for Parkinson’s not only slowly develop a tremor that get progressively worse they can also experience the following non-motor symptoms:
- Depression
- Sleep Disturbance
- Sensory Abnormalities
- Autonomic Dysfunction
- Cognitive Decline
While people begin to suffer from motor symptoms which most likely are embarrassing but overtime may become debilitating, they also can become depressed and lose control of their sleep cycle. You can easily see how as these things pile up it can be more and more difficult for individuals to handle all of these symptoms along with the general decline of aging. It would be a lot, and the worst part would be that people only see the tremors. Your loved ones don’t know why you are tired all the time, or why you just aren’t quite yourself anymore.
Parkinson’s disease is not just a tremor. The brain is so delicate and even small disturbances can cause major problems. In Parkinson’s a whole section of the brain, the substantia nigra pars compacta essentially stops functioning because the neurons get choked up with non-functioning proteins. This could be the result of a few different problems and it seems that there isn’t one clear pathway that leads to the motor symptoms. One fairly common (30% of cases) cause is mitochondrial failure due to complex I defects. I will give a brief description of what this means just so we can see how these small issues can snowball and to demonstrate how complicated this disease really is.
So if cell biology and biochemistry aren’t your thing here is a brief recap. You probably remember that the mitochondria are the “power plant of the cell” or something like this. This is because a ton of ATP is made there. ATP is used to supply energy for cell function. You can probably see that if that isn’t happening we will have problems. So complex I is a giant protein that is the first step in a pathway that generates a lot of ATP.
A bout 1one in three Parkinson’s patients has a genetic predisposition that leads to complex I failure which then leads to mitochondrial failure which contributes to the neuronal death that then leads to the symptoms we see. You might be wondering, what about the other two out of those three? That is a good question and the answer is complicated. So many things could go wrong and lead to neuronal death. It isn’t as simple as a single receptor being bad or a single misfolded protein. There are a multitude of small things that can pile up and lead to neuronal degradation.
Parkinson's: A Disease or a Syndrome?
One of the most important themes I’ve gathered from my time in my neurochemistry class is the theme of ambiguity when trying to determine the cause of a neurodegenerative disease. One of the best examples of this, in my opinion, is Parkinson’s Disease (PD). Last week, the scientific article we read explained the general mechanisms of Parkinson’s Disease as we know it today. However, I think the major take-away from the paper is the section toward the end titled, “Bringing it all together?” Let me explain why.
There have been major advances in the understanding of the mechanisms underlying dopaminergic cell death in PD. Some of these include, but are not limited to:
- Mitochondrial dysfunction
- Oxidative stress
- Altered protein handling
- Inflammation
- Altered proteolysis
- Excitotoxicity
The list continues to expand as we learn more and more about the disease. However, the sequence of events proposed to occur in PD has not been altered or changed in years. Furthermore, there has been a general trend of working to fit new pathological findings into the existing framework of conceptual belief. It is this trend that the section toward the end of the article brings up and questions. They argue it somewhat timidly, but I would like to state boldly that working new findings into an old framework without careful and critical thinking is not going to progress our knowledge of PD much further. In fact, it will somewhat stifle it.
There have been a number of studies in which cell death is initiated at a variety of points in the pathogenic cycle of PD. These studies themselves show the difficulty of distinguishing between “the horse and the cart” when it comes to causes and effects of PD. All of the mechanisms listed above could actually be the trigger or the effect of PD. Critically thinking about the results of these studies shows that the disease is more of a positive feedback loop rather than a linear progression of events, making it very difficult to pin point its beginning.
Because of the various starting points and effects of the disease, the author of the article was hinting at the idea that PD is less of a disease and more of a syndrome. The key mechanisms involved in PD that are listed above are would actually be separate pathogenic pathways representing different forms of what is currently known as PD. While the idea he leans toward may seem a bit radical, there are already many known forms of OD including:
- Sporadic PD
- Familial PD
- Parkin mutated PD
- Lewy body PD
Therefore, it only seems logical that, because a single trigger is not something within reach, PD is actually more of a syndrome with a handful of separate pathogenic pathways than a disease with a single cause. We are missing some key parts of the jigsaw puzzle that is PD, and are looking more closely at the downstream process that is the result of malfunctioning neuronal pathways. Because of this, I am emphasizing the idea that is presented toward the end of this article: because new findings and results do not fit perfectly into our existing framework of PD, it is important that each is taken into consideration as being a part of syndrome with multiple causes and manifestations.
Parkinsons Disease: More Than Just Meets The Eye
Parkinsons disease is a disease that is often associated with people who have motor problems as far as trouble walking around, shaking, rigidity, and slowness. These problems are being caused by the loss and death of dopamine-generating cells in the substantial nigra. Often the severity of Parkinsons is determined by the severeness of there motor issues. They will often test if the person has trouble maintaining their balance, if they can rise from a chair easily, and if they have any tremors. If someone doesn’t present with many of these problems and maybe only has little trouble with balance, then they would be determined to maybe only have mild Parkinsons or not Parkinsons at all because they may determine it to be a different disease. The point of me saying all of this is that there is something missing in this diagnosis, and that is the issue of mental problems.
First it is important to have an idea of what exactly is causing Parkinsons disease. One area that is often looked at as a main factor in the cause of Parkinsons disease is that of the Ubiquitin Proteasome System (UPS). The main function of the UPS is to basically mark proteins with Ubiquitin so they can then be found by proteasome and then be degraded into amino acids. Problems in this system often arise when someone ages or when there is oxidative stress and bioenergetic failure. When there is UPS dysfunction protein aggregation begins. Protein aggregation is basically the accumulation of misfolded proteins which can lead to cell dysfunction resulting apoptosis and cell death which causes neurodegeneration. Neurodegeneration leads to the motor symptoms seen in Parkinsons disease and therefore this pathway is often linked to Parkinsons disease. Now it is not known exactly how this pathway could be effecting those with Parkinsons disease which brings me to talking about the mental aspect of Parkinsons disease.
There is still much to be learned about Parkinsons disease and one area of Parkinsons disease that has little known about it is the effect it has on a persons mental state. It has been eluded to that many times people with Parkinsons disease may have depression or something along those lines, but it will be determined that Parkinsons isn’t causing that issue and the depression will be treated separately. This may lead to issues because while the depression is being treated, there may be other ways that it should be treated due to the possible link with Parkinsons. This side of the Parkinsons story is often ignored and thats why I say that Parkinsons disease is one that is more than meets the eye. People may see people diagnosed with Parkinsons moving around fine because they don’t present with severe motor symptoms and think that they aren’t facing too many challenges with the disease. But there is the underlying mental effects that are often placed to the side. It is hard to find a way to diagnose the possible mental issues that come along with Parkinsons disease when so little is known about the mental side of Parkinsons disease, but hopefully in the future more knowledge will be gained giving insight into the aspect of Parkinsons disease that isn’t seen by the eye.
Parkinson's Disease
Parkinson’s disease is a neurodegenerative disorder that does not impact mental faculties, but instead destroys motor neurons over a period of years/decades. Ultimately there are many different causes of neuronal death, but I believe the underlying reason behind this is an increase in Fe2+, iron that has one extra electron than normal in the body. Fe2+ is able to form a complex with the copper that is in our brains (the copper there is good, it helps with oxygen transfer and a plethora of other necessary functions) which create free radicals. These free radicals are molecules that either have a free valence electron (normally molecules have “shells” of electrons which once they are filled to a certain extent become inert, and a free valence electron is an otherwise empty portion of the shell) which is frequently lost to surrounding molecules. These affected molecules in turn affect other molecules in their vicinity causing cells to die, proteins to misfold, and generally horrible things to happen within a cell.
In the spirit of full disclosure my area of focus lies in inorganic chemistry (the study of metals), which biases my opinion of what I think is happening. These complexes occur frequently in Parkinson’s affected brains, and thusly appear to be a primary cause of the disease (though the scientific consensus is out). Doing more research into controlling the Fe2+ and copper complex is important medically. This will help control the degradation of the motor neurons and possibly allow for some level of reversal of the mental degradation.
Ultimately Parkinson’s is a disease that we don’t know what causes it, and that is one of the scariest aspects of the disease. Hopefully in the future research into the dysregulation of the iron will lead to better medication and a further understanding of the underlying causes of the disease. I don’t know if we will ever cure it, since Parkinson’s appears to be related to aging, but having a functional cure of minimal degradation of motor neurons and helping with some of the nonphysical symptoms of Parkinson’s disease would be ideal.
Maybe one day, disease related to aging will be eliminated or completely under control… But until then chelating drugs appear to be an effective method of controlling/minimizing the damaging effects of Parkinson’s.
Humans are not Immortal
Biologically speaking, humans are not meant to live forever. People age for a variety of reasons; but a few of the main issues are the amount of free radicals produced by your body as you age from natural biological processes and your organs simply aging and not working well enough to complete their jobs. With old age also comes increased risk of disease. Modern medicine has done a wonderful job in treating and preventing many life threatening diseases, and overall increasing the life expectancy of the average human.
I think with increased life expectancy people have become lazier, more conservative, and less adventurous. Often subconsciously, people feel that one of the goals in life is to live as long as possible. This makes sense from a evolutionary standpoint; you want to pass on your genes to your offspring and make sure they successfully mate and pass on your genes again. Staying alive longer can help ensure the continuation of your genes. This is important in keeping the human race alive, but do you really need to live to 90 or 100 to complete that goal? Back to the original point; people in today’s society want to save all their money so they can someday do all these bucket list activities when they retire someday. The problem? Retirement age is increasing at a scary rate. Today the average American plans to retire at 66 years of age, as compared to 57 two decades ago (http://www.cnbc.com/id/100744474). By the time you reach retirement age, you won’t be able to do most of the activities you put off when you were younger.
Alzheimer’s disease is a devastating neurodegenerative disease commonly associated with old age. It has been a popular disease for research because of its prevalence and paradoxical nature. Previous research has found that insulin signaling in aging brain decreases to help prevent neurodegenerative diseases such as Alzheimer’s. However, more recently it has been found that decreased insulin signaling in the brain due to insulin resistance can actually lead to the common causes of Alzheimer’s, neurofibrillary tangles (http://www.sciencedirect.com/science/article/pii/S1552526013029221). So the question is: do you give more insulin to Alzheimer’s patients to combat insulin resistance? Or not interfere with the biological processes meant to protect the brain?
The Takeaway Message
There is no cure for Alzheimer’s, and medications do little to slow the progress of the disease. The prevalence of Alzheimer’s in the elderly nowadays is staggering. 1 in 9 adults over 65 years old (about the average age of retirement) have the disease. 1 in 3 adults over 85 years old are affected by the disease. What does this say? Maybe Alzheimer’s is just your bodies way of telling you its not meant to live this long.
Everyone has to die of something, and the longer you live, the greater chance you have of getting Alzheimer’s. My advice; save less and live more, because humans are not meant to live forever.
Mental Decline-A Societal Problem
Modern medicine is nothing short of a miracle. If you take a moment to stop and appreciate just how good we have become at not dying it is pretty mind blowing. This is clearly a great thing. Without it, and without our modern lifestyle we would all still be running around throwing stones at deer and dying at the age of 45. For just a moment think about our lives compared to the lives of our ancestors, those who were nearly genetically identical to us, but living lives that we would recognize more as animal than human. Fast forward just a handful of millennia, a blink of the eye in evolutionary time, and we can get a 5000 calorie meal for just a few dollars which we most likely earned by staring at a computer screen. Now with technology we can have this life. We can get more than enough to eat and we live much, much longer. Again, this is clearly a good thing, I honestly think so. You would have to be crazy to disagree. I just have one problem, one small issue, so here we go.
This may sound a bit crazy but just try to hang, I promise this makes sense. We now live much longer mainly because over the centuries through trial and error, as well as rigorous study we came to understand our bodies very well. We know what are bones are made from, we know how to heal broken limbs, we know how to replace snapped or strained ligaments, we can replace a faulty organ with a good one from a dead person, we can even replace our aging bones and joints with artificial ones made from space age alloys. Unfortunately, while we understand our bodies, we still don’t at all fully understand our brains. Our current understandings of the interworkings of the human brain is honestly rudimentary at best. It isn’t for lack of trying, we know a ton about it, the problem is there is way too much to know. It is so complicated.
So now we have reached the issue. We have managed to make our bodies last twice as long, but for most of us our brains can’t make it that long. There is so much going on, and everything is delicately balanced. It only takes one gene being incorrectly replicated, or a receptor failing to bind its ligand consistently, or cells being unable to get rid of old proteins, and it all comes crashing down. For instance, to the best of our knowledge Alzheimer’s disease is the result of insulin receptors in the brain not being sensitive enough to insulin. This is most likely the result of too much insulin in the brain for too long. Or in other words eating too much fatty food for too long.
Obviously there is a lot more going on but this is just an example of how, in a sense, neurodegenerative disorders are as much the result of our society as they are a disorder. I think it would be more accurate to think of this as the natural process of aging and not something that needs to or can even be cured or eliminated. Even if we can prevent our minds from declining in one way they will only fail by some other inevitable route.