Disease/Health

Parkinson's: A Disease or a Syndrome?

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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.

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Parkinsons Disease: More Than Just Meets The Eye

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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.
 

Health/Uncategorized

Parkinson's Disease

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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.

Disease/Health

Humans are not Immortal

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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.

Community/Disease/Health/Uncategorized

Mental Decline-A Societal Problem

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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.

Community/Disease/Health/Hot topics/Uncategorized

Type 3 Diabetes? The Link Between Diabetes and Alzheimer's Disease

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Alzheimer’s Disease (AD) is the most common neurodegenerative disorder diagnosed today. For a long time it was unclear as to the cause of AD, and there is still much to learn, but scientist have discovered a key player in the onset of this  disease: insulin.
Normally, insulin is associated with Diabetes. Type II Diabetes involves an inability of the pancreas to develop insulin properly, and Type I is a resistance to insulin. Both result in blood sugar (glucose) not being able to be taken up by cells, resulting in high blood sugar. In turns out, there may be something similar going on in Alzheimer’s Disease.
Cells throughout your body have insulin receptors, including your brain. The insulin receptors in your brain are the beginning to two major pathways: the PI3K pathway, and the MAPK pathway. Normally, both of these pathways get activated when insulin binds to its receptors. Both pathways balance each other out and everything works well. However, when you develop insulin resistance (similar to in Diabetes) the PI3K pathway no longer gets activated while the MAPK pathway still does. The MAPK pathway is mostly involved in vasoconstriction, whereas the PI3K pathway is involved in neuroprotection, neuron plasticity, vasodilation, and the inhibition of an enzyme called GSK3-beta among other actions as well.
As you can probably guess, the inactivation of this PI3K pathway is not a good thing. Neurons begin to die because the neuroprotective effect of PI3K is no longer occurring. Also, when GSK3-beta is not inhibited, it tends to run rampant and hyperphosphorylate things like the protein TAU. The distinguishing characteristic of AD is amyloid beta plaques and neurofibrillary tangles that develop in the brain. The hyperphosphorylation of TAU is what leads to these neurofibrillary tangles. The inhibition of the PI3K pathway is also associated with the amyloid beta plaques as well.
It has been found that treating AD patients with insulin can alleviate some of the symptoms. This is most likely because the increase in insulin is activating a few more of the receptors and the PI3K pathways. However, this treatment option has also been shown to be negative in some cases. This may be due to the person not actually having insulin resistance. If you start taking a lot of insulin when your receptors function normally, you can overwhelm them and potentially develop resistance, doing more harm than good. I think it is necessary to develop a method of determining if someone truly has insulin resistance in order to treat them properly. More research also needs to go into figuring out ways to reactivate this PI3K pathway in a safe manner. AD still does not have a cure, but scientists are well on their way.

Community/Disease/Health/Hot topics

ALS – The Science Behind the Disease

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Amyneuronsotrophic Lateral Sclerosis (ALS), or Lou Gehrig’s Disease, is a fatal neurodegenerative disorder that results in the withering away of muscles due to the malfunction of motor neurons that travel from the spinal cord to the various skeletal muscles in the body. The lateral part of the spinal cord containing these motor neurons develops “sclerosis” where it hardens due to certain glial cells conglomerating together and essentially forming a scar in the spinal cord. This disrupts the signal that the motor neurons bring to the muscles, and eventually results in the muscles not being able to contract and “atrophying,” or withering away.
There has been a recent surge in the recognition of ALS with the “Ice Bucket Challege” that I’m sure most of us either heard about or participated in. ALS is a very debilitating disease that results in requiring a wheelchair to get around and eventual death. At this point there is no cure, and I’m not sure that a true “cure” will ever be developed. However, the recent advancements in scientific research are beginning to show us the possible root cause of this disease and possible treatments to help prevent and delay the development and progression of this debilitating disease.
There are receptors on neurons throughout your body called NMDA receptors. They are usually found with another receptor called AMPA. These are both responsive to a neurotransmitter called glutamate. In ALS, and other nuerodegenerative diseases, there is too much glutamate causing these receptors to activate, letting a lot of calcium into your cells. This calcium puts stress on the organelles inside the cell, especially the mitochondria and the endoplasmic reticulum (ER). This stress signals cell death in many cells. It also causes the ER of cells still alive to not fold proteins correctly; a specific misfolded protein called SOD1 is thought to play a major role in ALS because it leads to the accumulation of Reactive Oxygen Species (ROS) that can cause a lot of damage within cells. Glial cells help out neurons, and in this case they surround the damaged motor neurons to help prevent further damage. This is what results in the hardend scars found in ALS. Scientists are still uncertain to why the motor neurons in the spinal cord are the only cells that are affected in ALS. It may have to do with the type and amount of NMDA receptors found in motor neurons, but this is still unclear.
At any rate, this further understanding had lead to new developments within the treatment of ALS. NMDA receptor blockers may potentially be able to alleviate some of the effects of ALS. This is tricky however, because these receptors are found elsewhere in the body and their normal healthy function is necessary. Also, antioxidants, even like those found in grapes and blueberries, could also help stop some of the damage caused by the ROS. The best bet is a combination of NMDA antagonists, antioxidants, and cell stress reduction through a healthy lifestyle. More research is necessary to understand the full mechanism of this disease, which is essential in creating the most efficient treatment plan. Scientists are on their way to cracking the code of ALS, but they haven’t quite found it yet.

Disease

The Surprising Relationship between Insulin and Alzheimer's

Posted on by Joseph Kennedy / 0 Comment

There exists a link between type II diabetes and Alzheimer’s. People who have type II diabetes are at a significantly higher probability of developing Alzheimer’s. This is due to numerous reasons, one of which being a resistance to insulin means that  different pathways in the brain are over activated, which can lead to cell death, or aren’t activated (because the cell requires more to activate) which will also eventually lead to cell death. Neurons dying in the brain are irreplaceable and are major contributors to Alzheimer’s. While treatment exists, like an intranasal insulin spray (Detemir) has been shown to improve memory. While memory does improve, it is merely treating a symptom of the disease and not the disease itself.
Ultimately the connection between diabetes and Alzheimer’s surprised me, it does make sense. Looking at many people who have developed type II diabetes in my life and looking at their cognitive faculties. While many of these people are also much older than I (in their sixties and seventies) so I have to take this information with a grain of salt. As a species as we age our cognitive functions decrease simply due to wear and tear. This raises the question for me: are they actually showing signs of Alzheimer’s or is it an effect of aging?
While the end result may be the same actually having a name for what is happening to them somehow makes it more… bearable. If it’s aging, or if it’s Alzheimer’s knowing which one it is, for me, would be a big deal, and not knowing if the reason I’m losing my mental faculties is because of my age or a neurodegenerative disease would bother me to my dying day. While I will probably develop Alzheimer’s or a similar neurodegenerative disease later in my life, I hope that by then some sort of pharmaceutical or therapy will be able to restore cognitive functions… Even if it’s just temporary.

Health

Endocannabinoids and their Classification

Posted on by Joseph Kennedy / 0 Comment

Endocannabinoids are a group of chemicals that exist within the human brain and various drugs like marijuana (hence the endo meaning within and cannabinoids… cannabis). They are the chemicals that are able bind to our CB1 and CB2 receptors to give us the psychotropic effects of smoking marijuana. In addition to the standard psychotropic effects, there are also innumerous beneficial effects ranging from decreasing nausea to helping cancer patients eat to remain healthy. Marijuana has over 400 chemical compounds that work in tandem to cause the effects normally associated with smoking or consuming marijuana. While scientists have tried to isolate the compounds that have been shown to help with nausea/pain control (THC for example), when taken without the other 400 chemicals their effects appear mitigated, and some of the negative side effects associated with marijuana become more pronounced. Leading some to believe that nature has perfected something that scientists will never quite replicate.
Regardless of one’s opinion on marijuana, we should agree that it shouldn’t have been classified as a schedule I drug. Schedule I drugs are drugs that have a high potential for abuse and have exactly zero medical benefits associated with them. With states legalizing medical and recreational usage of marijuana more research is starting to show it has beneficial effects when used correctly. This means that it should not be a schedule I drug, and at most a schedule II drug (a drug that has a high potential for abuse but has medically relevant uses). Whatever your opinion on recreational use of the drug there is no doubt that it should be reclassified as a lower schedule drug.
It is my opinion that since the endocannabinoid system within the brain is vaguely understood the use of recreational marijuana should be postponed until more is understood. Currently the only two known receptors for endocannabinoids are CB1 and CB2, however researchers believe that there might be as many as four receptors (if not more). While not knowing how many receptors might be found within the brain is semi common, what is concerning is how readily people are willing to consume a drug that scientists don’t even understand some of the effects of. While predicating recreational use of a drug based off of complete understanding of the compound is more than a little outrageous, not to mention impossible (since scientists will rarely, if ever, claim to know everything), waiting until medically useful background is established is important. Understanding the long term impact of smoking marijuana that is quantified in cold hard statistics is the biggest factor right now in preventing me from supporting marijuana as a controlled substance (i.e. alcohol). While I honestly doubt that research will discover that long term exposure to marijuana will cause harsh, irreversible side effects like smoking cigarettes, there are already side effects that are seen when comparing cognitive faculties of people who have smoked since they were in their teens versus those who smoked after their brain completely matured.
Ultimately my opinion is exactly that, my opinion. It is no more valid, or invalid than anybody else, but ask yourself this: is the risk of being wrong about marijuana in the short term worth the possible side effects about legalizing it before it’s medically better understood?

Disease/Health/Hot topics/Uncategorized

Alzheimer’s linked to Diabetes

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Alzheimer's
The topic in our Neurochemistry class this past week was Alzheimer’s Disease and how it is linked to Type II Diabetes Mellitus, T2DM. The science behind this link is that if there is either a decreased amount of insulin in the brain or if there is insulin resistance, individuals may develop a neurodegenerative disease, such as Alzheimer’s Disease. Alzheimer’s develops because insulin is essential for memory and learning.
My great-grandmother has struggled with Type II Diabetes for many years. Last year she sent me a birthday card five months after my birthday. My entire family laughed about it, but after learning about this link between T2DM and Alzheimer’s, I am wondering if perhaps she may be developing Alzheimer’s. My dad has also recently developed T2DM, and now I am even more concerned about his future health and the possibility of him eventually developing Alzheimer’s.
When insulin binds to its receptor it can have cognitive and metabolic effects within the brain. The cognitive effects include increased memory and learning, and increased neuronal plasticity. Metabolic effects include decreased food intake, and decreased hepatic glucose production. Alzheimer’s can develop when insulin’s signaling is disrupted. For example, when inflammation occurs insulin signaling is impaired. Although inflammation occurs naturally with age, the inflammation in the brains of individuals with Alzheimer’s is significantly more pronounced.
The most recent drug being developed to treat Alzheimer’s is an intranasal insulin spray called Detemir. This drug has been successful because it has been shown to improve memory in humans. Although this drug may help with symptoms of Alzheimer’s, there is still no cure for Alzheimer’s disease.
Another point to consider is that as a society we are living longer, so maybe Alzheimer’s is only appearing now because we are living longer. Through research, we may find a cure for Alzheimer’s in the future, but until that happens the most important thing we can be doing is educating others about Alzheimer’s and other diseases it is associated with.
References:
http://www.nature.com/npp/journal/v32/n1/full/1301193a.html

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