In 3400 BC, the Sumerians first cultivated the opium poppy plant. Since its discovery, opiates have been used medicinally to relieve pain, and more recently, to suppress coughing in patients with a “dry cough”. However, as with most pharmaceuticals, negative side effects exist to the continuous use of opiates: tolerance and dependence. The physical and psychological dependence that results from opiate use adversely impacts society. These factors make it dangerous for physicians to loosely prescribe opiates to patients (although this does not mean it doesn’t happen).
For many years, dopamine has been the focus for scientists when researching the effects of addictive drugs, though more recently, this focus has transitioned to include glutamate’s (another excitatory neurotransmitter) role in drug addiction. Glutamate exaggerates the withdrawal symptoms of opioid dependence by binding its receptors, specifically ionotropic receptors.
Learning point: There are two functionally different types of receptors that bind neurotransmitters: ionotropic and metabotropic. Ionotropic receptors are channels themselves and open in response to a neurotransmitter (i.e. glutamate). This causes an influx of ions (ionotropic) that either excites or inhibits the cell, depending on the ion moving through the channel. Metabotropic receptors are much slower than ionotropic receptors and act more indirectly in the cell. A series of proteins and second messengers interact with each other to signal a cascade of events in response to a neurotransmitter binding a metabotropic receptor.
Accumulating evidence shows that antagonists of ionotropic receptors (iGluRs) can attenuate the withdrawal symptoms of opioid dependence. One specific antagonist of interest to scientists is called MK-801. It is a glutamate antagonist that acts on NMDA receptors and protects against excitotoxicity (excessive stimulation of the neuron). Researchers are hopeful that MK-801 could suppress the psychotropic effects of prescription opiates. This is of great importance to researchers as it offers a potential way to decrease the negative side effects of opiate use. What a difference it would make if taking prescription opiates did not lead to dependence and moreover, illegal activity. Illegal activity? It is not uncommon for patients to sell their prescription drugs, such as morphine or codeine, to dependent users for a little extra cash. This is because those who are addicted to prescription opiates crave the drug due to its psychotropic effects and the withdrawal symptoms the person feels in the absence of the drug.
The ability to prescribe opiate analgesics (pain relievers) without the addictive effects (or any of the unnecessary side effects for that matter) is ideal. The illicit sale of opiates would significantly go down if this were possible. Of course, there would always be a black market sale of opiates, but at least users would not be able to obtain the drug so easily. Furthermore, the number of users addicted to opiates would drop considerably as the only people who would be addicted to opiates would be those who acquired opiates via the black market.
It is of upmost importance that scientists continue to investigate the use of glutamate antagonists as a means to subdue the negative effects associated with opiate use. It would be in the best interest of everybody to continue research in this arena. Patients would be safer, doctors would be relieved of the pressure to prescribe opiates, the community would become safer, and the stigma of prescription opiates would eventually be diminished.
Vicadin! Codeine! Oxyconton! Oh My!
You may (or may not) have heard of a class of drugs called opioids. These drugs are commonly prescribed to patients to relieve their pain after a surgery or if they are experience a chronic pain. These drugs are fantastic (as most drugs are) at making the patient feel great, however, they have one serious side effect; they are ridiculously addicting. This begs the question, “Should these drugs be used?” They are highly effective at treating the pain, but are the risks of addiction worth it? Is there something we can do to get rid of the addiction?
If you were to ask me my opinion on this issue, I would tell you to stop using opioids to treat pain. “But Brandon, why wouldn’t you use them in moderation? Or do research to relieve the side effects?” Right now, in the medical field, there are “regulations” on the prescription of opioids, but it still seems to have no effect on the problem as doctors are still handing them out like candy, and people receive an excess of what they actually need and could sell them on the streets to addicts. Even if one doctor turned down your request for a prescription, you could just as easily go and see another doctor and ask them. All in all, I don’t feel that regulation is a good solution to the problem at hand. As far as the research goes, I do see this as a possibility. There is currently research being done on opioid receptor antagonists and how they prevent the addictive property of these drugs, but in the end is it really worth the effort? To me, I see much more prevalent areas of research among medicine and drugs rather than working with pain killers. As I see it, pain killers are for wimps. Before you get mad, let me explain myself. Think back to a time way back when people didn’t go to the doctor to cure their minor pains. They weren’t prescribed opioids and thus didn’t get addicted; they just sucked it up and dealt with their pain. For more major pains, we have other pain killers which aren’t addicting such as NSAIDS (advil or aleve) which would help the patient cope with the pain without addiction side effects, which to me is worse than the side effects of NSAIDS. Therefore, I feel our government research money can be spent more responsibly.
As you can see, opioids can have great success in treating our pain, but in my opinion, we should just stop using them due to their nasty addictive nature and switch to using a “safer” pain killer option such as NSAIDS.
Pill Nation?!
In the article which we read for this week, the authors investigated the roles of glutamate and its receptors play in opioid addiction. When people hear the word “opioid”, it is thought as the illegal drugs, such as opium alkaloid, morphine, and semi-synthetic alkaloid derivative, heroin. But in the world of medicine, opioid plays an important role as pain killer, which is often prescribed to people who suffer from severe pains. Most of these pain pills are classified as the semi-synthetic alkaloid derivatives, the same classification as heroin. Oxycodone and hydrocodone are two of these pain killers that are often prescribed by doctors.
Although opioid drugs do a great job relieving pain, just like heroin, they are also addictive and may be very hard to quit. And people who depend on these drugs often need to go through a long and painful withdrawal. Therefore, the prescriptions and the usage of the drug by doctors have become very important. On Wednesday, Annika talked to us about the process of prescribing opioids and the “regulations” on it. But just regulations don’t seem to be enough. In fact, prescription drug abuse has already become a severe problem in the United States. I have always enjoyed National Geographic Channel’s documentary series, one of my favorites is the show called “Drugs, Inc.” And one of its episode deals with the problems of prescription drug abuse. This film interviewed users, doctors, dealers, and the law enforcements, and went into details about this industry from different perspectives. According to this documentary, nearly 1.9 million Americans are addicted to prescription pain pills, ten thousand newborns were born with addiction each year, and dealers and rouge doctors make millions off this black market trade.
Since the regulations have already failed us, another strategy needs to be played. There are many researches being conducted on opioid receptor antagonists and how they may help avoiding the addictive characteristics of these drugs. And some of them have shown promising results. But in my opinion, getting rid of the addictive characteristics of these drugs only helps with dependence physically. Unfortunately, that is not the only part of addiction. In psychology, we learned about the concept of classical conditioning, which is basically a form of learning in which the conditioned stimulus comes to signal the occurrence of the unconditioned stimulus. In the case of pain pills, by taking the pills and removing the pain of our body, we are essentially conditioning ourselves to associate the pills with the removal of our pain (negative reinforcement). This applies to not only the opioids but all kinds of pain killers (NSAIDS, Acetometaphin, Aspirin), which means they may all be addicting if used incorrectly.
After all, pain is very subjective, difficult to measure and everybody experiences it differently. All in all, I appreciate/respect what the researchers are doing with the opioids, and I really hope it could be completed. But the real problem I see here is the prescription and usage of the pain pills by the doctors as well as the patients.
To watch “Drugs, Inc.- Pill Nation” http://www.youtube.com/watch?v=AG3qM1NXRXA&feature=related
Opioids and Addiction
I have been hearing more and more these days that doctors are handing out high-potency pain killers like they are candy and I have been wondering why, when these drugs have a history of being so addicting, doctors are so keen to prescribe then for even the most menial of pains. The drugs I am talking about are the opioids: morphine, hydrocodone, codeine…heroin, the list goes on and on. Derived from the opium plant, these drugs are the pinnacle of analgesic and anesthetic drugs, with morphine as the baseline that most analgesics are compared to. It is the fact they do their job so well that makes them so addicting. So again I ask why are they still being used?
In this weeks discussion, we talked on what we thought about how easy it was to get opioids and a few ways we thought opioids research could go in order to keep the analgesic effect but lessen or eliminate the addicting effects. Opioids have strict regulations on what factors illicit their prescription but it seems that the enforcement of their distribution is on the weak side. What one person brought up was that if a patient goes into the doctor and ends up coming back for the same exact problem, the insurance can deem the first visit ineffective in a way and refuse to pay the cost. So doctors end up “over-prescribing” in a way to make sure the patient doesn’t return for the same problem. This brought us to talking about what can be done to reduce or eliminate the dependency/addiction issue. Analgesic/anesthetic drugs are a dangerous kind of drug because even if you don’t develop a dependence for them, you can still get addicted to them. What I mean is that even if the drug was made so that you didn’t develop a resistance and you could stop taking it with no side effects, the fact that it rids you of pain and makes you feel good makes it pleasurable to take.
Another question brought up was how can addiction be dealt with in a mind over matter approach. I think that the brain (mind) has the biggest role in addiction because addiction is all about dopamine release in the brain. Dopamine is the “feel good” chemical in the brain that’s in charge of rewards and such. It’s that feeling you get when you have your favorite food or when you are swarmed by a mob of playful puppies. It’s your bodies signal of what you like and what you don’t like. Back to the addiction aspect of dopamine. When you take a drug, such as heroin, dopamine is released in great quantities which results in the euphoric effects. As you continue to take it, your body compensates for the increase in dopamine release, resulting in you having to take more to feel the same effects. Now fast-forward to when you stop taking the drug. You start going through withdrawals which is what happens when you have that constant inflow of dopamine and all of a sudden its gone. You feel absolutely dead and you just can’t function without more of the drug. Could you avoid the withdrawals by conditioning your brain to not need the drug anymore? Could you associate the drug with something you don’t like and replace it with something that was not as bad for you and easier to get?
I’ll try to explain what I am talking about. Say you are taking heroin. You are addicted but want to quit and know you should. Can you start doing something not pleasurable while taking heroin to in turn make taking heroin not pleasurable? Then can you substitute heroin with something not illegal or harmful but still pleasurable so you can kick the heroin habit? I think it is possible but of course the only way to know is to actually do it but that may easier said then done.
Research Suggests Great Defense from Alzheimer's Disease could be the Dinner Plate
“What would you like to order today?” “I want two number ones, a number six, a large side of fries and a shake.” “Would you like some insulin with that?” “Insulin?”
Most who hear the word insulin think about Diabetes; perhaps have had a friend or family member who takes insulin, either the pill form or a continuous pump, and checks blood sugars before and after a meal. However, for those who do not know, Insulin is a hormone produced by the body to help regulate energy in cells throughout the body. It is involved in how the cells intake glucose, the most prevalent sugar used in the body, and therefore keeps our bodies processing normally.
This week insulin’s role in the brain was brought to light for the neurochemistry class, because research has shown a correlation between the body’s use and misuse of insulin to the symptoms of the neurodegenerative disease know as Alzheimer’s. The symptoms such as dying brain cells as well as plaques and tangles in the brain.
The outside of brain cells are covered with docking stations specialized to accept insulin; when insulin attaches itself to these receptors the cell undergoes changes that allow glucose to enter from the outside and other cellular processes result from insulin’s binding to the cell. These other processes have a profound effect of the life of the brain cell, as well as the brain’s overall health. One of the pathways after insulin binding is the an enzyme (Protein Kinase B) that stops another enzyme (Glycogen Synthase Kinase, GSK) from becoming more active in the cell’s functions than it is meant to be. The enzyme GSK, if not under control has been found to have involvement in the processes that result in the tangles in brain, as well as the buildup of plaques.
Another important pathway after insulin binding that is important for the activation of an enzyme (BAD, an antagonist to cellular apoptosis) that communicates with the cell for the prevention of cell death. As a result more brain cells stay alive which protects an individual’s mental health.
Now, where does the dinner plate come in?
Unhealthy eating and lack of physical activity dramatically increases a person’s chances of contracting of Diabetes, specifically type 2. Type 2 Diabetes, is when your body does not produce enough insulin, or the number of docking stations on the cell for insulin is low. This lack of docking stations, also called insulin resistance, slows the processes of brain cells toward defending themselves from death, and from creating plaques and tangles. This all increases the early symptoms of brain diseases like Alzheimer’s.
The next time the dinner bell happens to ring at your house, take a moment and ponder about how sneaking some healthy foods might help keep your family physically healthy; while at the same time protect your loved ones future mental health.
Sources:
http://www.sciencedirect.com/science/article/pii/S1043276005000093#bib83
Super-size Nation, Super-size Problems
The modern trend of increasing rates of obesity is a cause of concern for many. The effects of obesity range from emotional problems such as low self-esteem and bullying to health problems including cardio-pulmonary stress and diabetes mellitus (DM). Recent research points to results indicating that obesity may also be involved with mental problems such as dementia and Alzheimer’s disease (AD).
Much of this conversation begins with insulin. Type II diabetes is a form of DM that occurs when the body begins to exhibit characteristics of insulin resistance. The body may also stop producing insulin properly. Insulin is needed to bring blood sugar into cells to be used as an energy source. Once called adult-onset diabetes, views about this disease are changing because it is now developing at a much younger age than previously observed. View the Centers for Disease Control and Prevention’s website for more information on type II diabetes and children: http://www.cdc.gov/diabetes/projects/cda2.htm
In addition to cell energy demands, insulin functions in cell signaling. When insulin is recognized by a receptor on the cell membrane, a chain reaction phosphorylation cascade occurs. Energy is used to continue the signaling pathway. At the end of the signaling process, gene expression can be influenced. Cell proliferation and growth is also a result. A blockade in this pathway, associated with aging, leads to cell death. Neuronal cell death is one characteristic of AD.
As early as 1999 a study in the Netherlands showed that DM was a risk factor associated with dementia. Over 6000 adults aged 55 and over participated in the Rotterdam Study, which included complete health screenings and follow-up either in person or using the individual’s health record. They found that the percent of dementia in that population that could be traced back to DM was 8.8% and most of those exhibiting dementia were also diagnosed with AD (Ott A, Stolk RP, Hofman A, et al. Diabetes mellitus and risk of dementia: the Rotterdarm Study. Neurology. 1999; 53: 1907–9.). Those with newly diagnosed or untreated diabetes had a lower risk factor for dementia than those that were insulin treated. In sum, those with more severe diabetes had a greater risk of developing dementia.
If type II diabetes is developing in adolescence rather than middle age, what does this say about Alzheimer’s disease? A trend often referred to as an “epidemic” by popular usage and the media, obesity is influencing health on a variety of fronts. Type II diabetes is strongly associated with obesity and so, therefore, is insulin. Findings of type II diabetes in children rather than middle aged adults is a twenty, thirty, even forty or more year advance in the disease. Could this “fast-forward” in deterioration translate to diseases that are associated with DM, such as AD? Granted, DM is a risk factor associated with AD, not a necessary cause, but this alarming trend may have far-reaching effects that cannot yet be foreseen.
Could too much fast-food lead to Alzheimer’s Disease?
Imagine sitting down to dinner with family and friends to enjoy a nice, healthy meal. Now snap back to reality and think of how busy your life is and how often you decide to go out to eat. In today’s society eating seems to be more like a distraction, interrupting people from their fast-paced lives. As a result, people are looking for the quickest options for breakfast, lunch, and dinner. However, by eating out too often people are developing unhealthy eating habits. At times these eating habits might exceed what is optimal leading to obesity.
You may be thinking “ok yeah I gained a few pounds but what’s the problem with that?”. One of the main problems is the rise in the number of cases of type 2 diabetes caused by obesity. In fact the number of cases of diabetes is rising at an alarming rate worldwide. According to WebMD Health news the number of people diagnosed this diabetes has double to a reported 350 million cases since 1980. Type 2 diabetes occurs when the body produces insulin, but either not enough insulin is produced or the body does not properly use the insulin which is produced. This is called insulin resistance. Since the purpose of insulin is to transport glucose (sugar) into the body’s cells to use as energy, a result of insulin resistance is too high of glucose levels in the blood and not enough sugar in the cells. Therefore, your body is basically starving. Although type 2 diabetes has been around awhile, new research has hinted at a link between type 2 diabetes and Alzheimer’s disease dementia.
The key link between type 2 diabetes and Alzheimer’s disease appears to be the affects of insulin resistance in the brain. According to the article discusses in class, insulin acts through a series of important processes to regulate neuron survival, aging, as well as memory and learning. However, when people have type 2 diabetes insulin found in the brain may not properly regulate these important biological processes. This can lead to improper regulation of the biological processes resulting in overproduction of beta-amyloid and tau proteins. When beta-amyloid protein builds up forming plaques, the brain is more susceptible to oxidative stress which can result in the death of brain cells. Likewise, if too many tau proteins are constructed they begin to bunch up causing a deficiency of nutrient transport in the brain and therefore the death of brain cells. So what can be done to help fix this situation?
The best way to help with this situation is to try and avoid developing type 2 diabetes by eating healthy and working out regularly. Eating healthy and working out will help fight off obesity and therefore type 2 diabetes. However, as stated in the introduction everyone is very busy and working out regularly may not be possible. This raises other, broader questions about American society and its eating behavior like, “Should it be the government’s responsibility to step in and regulate the food industry to force the general public to eat healthier?” and “If the link between Alzheimer’s disease and type 2 diabetes is true, what actions should be taken to help children and young adults who are developing type 2 diabetes at younger ages than normal?”.
Although, it is extremely unlike that everyone who eats out will develop unhealthy will develop type 2 diabetes and therefore Alzheimer’s disease, it is important to be aware of the possible implications your everyday decision may be having on you, your body, and possibly American society as a whole.
Sources:
http://onlinelibrary.wiley.com/doi/10.1111/j.1582-4934.2011.01318.x/full
http://diabetes.webmd.com/news/20110627/diabetes-rates-double-since-1980
http://vegetarian.procon.org/files/1-vegetarian-images/usda_food_pyramid_large.jpg
Insulin and Alzheimer's
5.4 million people of all ages have Alzheimer’s Disease (AD) in the US, 5.2 million of that 5.4 million are ages 65 and older, according to Alz.org. This statistic means that 1 in every 8 older American has Alzheimer’s. Alzheimer’s is the 6th leading cause of death in the US and payment for care of those with AD is estimated to be $200 billion. The following link goes to a site with lots of information on Alzheimer’s Disease symptoms, diagnosis, statistics, treatment…etc.
http://www.alz.org/downloads/facts_figures_2012.pdf
Recent findings have led experts to consider AD to be Type 3 Diabetes. The findings have been based on insulin’s effect (or lack thereof) on aging and brain cell death. Experts have found a correlation between people who have type 2 diabetes and those who develop AD. In fact, the correlation goes all the way back to weight gain: weight gain (chronic) leads to obesity, which sometimes leads to Type 2 diabetes which now is found to lead to AD.
Experts think that a decrease of insulin in the brain or a decrease in the “potency” of insulin in the brain is what leads to cell death and then to all the effects of AD including memory loss, inability to do simple task or tasks once able to do, time or place confusion and changes in mood and personality. What they are finding as the cause of AD is a lowering of insulin effect in the brain which causes an enzyme to activate far more often than it should, which leads to hyperphosphorylation of a protein labeled as the τ (tau) protein. Hyperphosphorylation of tau leads to the proteins aggregating, which blocks functions of brain cells and causes them to be broken down, leading to lower brain functions. Sorry for the neurochemical jargon. Basically what all that mumbo-jumbo means is that insulin stops the “bunching up” of tau proteins and keeping the brain cells from breaking down.
One thing we talked about in our group discussions is whether research should be focused on how to prevent AD or to creating a “quick fix” drug with minimal side effects. And the overall consensus was that prevention was the best route because preventing AD also can help prevent type-2 diabetes. Also messing with insulin in the body is risky because insulin has other jobs besides blood glucose control and brain cell survival.
Another topic was the ethics of trying to end the aging process and whether or not it is worth all the time and effort and money that would go into it. Again we had a general consensus that it wasn’t worth all the time and effort because the older you get the more chance you have of developing numerous age-related illnesses and disabilities. Another aspect is if we slow the aging process, will we age differently in terms of brain vs. body. What I mean by this is if slowing the aging process works, will it slow body aging, brain aging or both? Will our brains be “younger” than our bodies, vice versa, and what effect on the individual will this have?
As you can see, there still remains a lot of work in order to understand exactly what AD is and how we can go about preventing or treating it.
Next week is glutamate and its role on opioid addiction.
Aging, Diabetes, Alzheimer's and Insulin
In class this week, we talked about the connection between Insulin, Diabetes, and Alzheimer’s Disease. In type 1 diabetes, the cells of the pancreas that create insulin stop producing it. One of the most common ways of combating this disease is to give regular insulin shots. Type 2 diabetes is characterized by insulin resistance: although the body may have regular levels of insulin, the effect of insulin is decreased, usually from fewer receptors. Alzheimer’s disease is characterized by dementia: as state where the patient suffers impairments to cognition, reasoning and communication skills as well as confusion about the time and place and delirium for a prolonged period of time. Connections seen between Alzheimer’s disease and diabetes or insulin resistance has caused some to call it type 3 diabetes.
Insulin controls the uptake of glucose into cells so that they can be active and use energy. In the case of insulin resistance, insulin is unable to fully perform its job of having cells take in glucose. This has been theorized to be part of why Alzheimer’s patients have cognitive defects: in the dearth of glucose, they are less responsive which leads to mental impairment. To deal with low levels of energy, sometimes the cell will also consume important molecules for the cell’s integrity or be unable to produce important molecules leading to cell death; which, in the case of the brain leads to even more irreversible mental impairment.
Another key function of insulin is the role that it plays in aging. In all animals, insulin controls the expression of age related characteristics (think about things like grey hair, facial hair, and so on); insulin levels are responsible in part for the age of our bodies. One of the defining characteristics of the aging brain is that it develops insulin resistance and consequently becomes mentally impaired. This supports the belief that all brains will eventually develop dementia like symptoms and that Alzheimer’s disease only brings it about sooner. One implication of that is that this will lead to sooner onset of dementia in people who have diabetes. This could prove to be a problem for our nation as generations with higher levels of diabetes get older.
A Frightening Proposition
If one were to list the most common fears of people today, they would likely come up with a conglomerate including things like death, heights, spiders, and clowns. My biggest fear, however, is perhaps not so run-of-the-mill: dementia is something that’s all too common and all too detrimental to overlook as a serious life issue. Many young people probably don’t consider it a major concern in their lives – that it would happen years down the road and that it wasn’t really something they could control. Recent research, however, has drawn some surprising connections from dementia and Alzheimer’s to diabetes, particularly type II, which is mostly dependent on lifestyle. When they say that the decisions you make today affect you down the road, this is no exception.
Type II diabetes is characterized by high blood sugar caused by insulin resistance or insulin deficiency. It accounts for 90% of diabetes cases and correlates highly with obesity; both diseases have been growing tremendously in recent years. As serious a disease diabetes is already, there is evidence to show that it is a significant risk factor for developing Alzheimer’s later in life. The link between the two disorders seems to be insulin resistance. Cells resistant to insulin uptake don’t take in as much glucose either, leading to a deficit in energy. This makes the cell vulnerable to oxidation, which is a main cause of neurodegeneration. Another suggested pathway involving insulin resistance involves the dysregulation of lipid metabolism; improper disposal of lipids from brain cells promotes ceramide (a lipid class) accumulation, causing inflammation and toxicity as well as beta-amyloid accumulation, which leads to amyloid plaques and neurofibrillary tangles, resulting in neurodegeneration. Although the causes of type II diabetes include genetic factors, lifestyle is a main contributor, involving obesity, lack of physical activity, and poor diet.
Another risk factor greatly associated with Alzheimer’s development is a dysfunctionality of apolipoprotein E (ApoE). This is largely a genetic risk factor, but recently has been associated with vascular health. ApoE normally works against inflammation and plaque formation in the brain, but certain isoforms of the protein that translate to dysfunctional alleles of the gene. ApoE4 has been found to be the largest known genetic risk factor for developing Alzheimer’s disease; this isoform does not efficiently bind lipids for transport out of the brain, leading to inflammation and beta-amyloid accumulation as mentioned before. There is a mechanism involving vascular health, however, where ApoE4 does not control the inflammatory molecule cyclophilin A in the brain; the resulting increase in cyclophilin A activates the enzyme MMP-9, which causes damage to the blood brain barrier (BBB). Damaging the BBB can lead to many adverse effects, such as allowing neurotoxic chemicals that wouldn’t otherwise be able to cross the BBB into the brain, as well as increasing vulnerability to beta-amyloid deposit and accumulation. Although this is mostly a genetic risk factor via ApoE4, increasing vascular health can possibly counter the damage caused to the BBB, lessening the adverse effects of ApoE4 and lessening the risk for developing Alzheimer’s.
Although there are definitely genetic risk factors that play a significant role in the development of Alzheimer’s, the fact that there is growing evidence for lifestyle contributors should not be ignored. Lifestyle plays a huge role in the development of type II diabetes, which is now linked via insulin resistance to Alzheimer’s. The possible role of vascular health in maintaining the BBB and countering the damaging effects of ApoE4 is a fairly promising one as well, and hopefully there will be more research done to confirm this relationship. Losing the ability to think clearly for myself is one of my greatest fears in life. Taking into consideration these new studies, my lifestyle choices will definitely take a turn for the better. I hope others do the same.