Tag Archives: Medical Research

Diet and Dementia (Cognitive Decline) in the Aging

“When diet is wrong medicine is of no use. When diet is correct medicine is of no need.’’ Ancient Ayurvedic Proverb

‘‘What is food to one man may be fierce poison to others.’’ Lucretius (99 B.C.-55 BC).

Précis: Last month in London, England, at the Alzheimer’s Association International Conference (AAIC) 2017, there were several presentations focused on diet and the link with dementia/cognitive decline in the elderly population.  Two reports described the effect of specific diets [Mediterranean, DASH (Dietary Approaches to Stop Hypertension), MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay), and NPDP (Nordic Prudent Dietary Pattern)] to maintain cognitive function in the aging population. In another study, the MIND diet was shown to reduce dementia in the women from the Women’s Health Initiative Memory Study (WHIMS).  Finally, it was shown that either the absence or excess of certain vitamins, minerals and other key nutrients could promote neuro-inflammation, which would be detrimental to the brain. This post reviews elements of these presentations.

“One should eat to live, not live to eat.” Moliere

A Healthy Body and Brain Combine Diet, Life-style, and Attitude: It is easy to say what it takes to be healthy; however, approaching/achieving/accomplishing it takes a concerted effort. In a minimal sense, achieving a healthy body and brain unites an efficient diet, an effective lifestyle, and a positive attitude.  Thus, a healthy body and brain requires a collective approach to living properly (and it helps to have good genes).

“Take care of your body. It’s the only place you have to live.” Jim Rohn

Inflammation and Parkinson’s: One of the many suggested causes of Parkinson’s is neuro-inflammation (see figure below).  The impact of diet promoting inflammation and cognitive decline in the aging population got my interest.  The combination of eating too much of ‘bad’ foodstuff with too little of some ‘good’ food components somehow promotes neuro-inflammation that contributes to the development of dementia. If the goal of my blog is related to Parkinson’s, what is the goal of this particular post? To present the notion that detrimental effects of neuro-inflammation could diminish brain function. And it’s this ‘possibility’ that makes the story relevant to this blog because neuro-inflammation is linked to the development of both Alzheimer’s and Parkinson’s.  Therefore, the specific pathway to how you develop that inflammation of the brain is relevant and an important topic.

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“Tell me what you eat, and I will tell you who you are.” Jean Anthelme Brillat-Savarin

Diet Linked to Neuro-inflammation: There’s an old phrase “You Are What You Eat”, which simply means it’s critical to eat good food in order to stay healthy and fit. Building on solid evidence that eating well is brain healthy, researchers are beginning to explore mechanisms through which dietary mechanisms may influence cognitive status and dementia risk. Dr. Gu and colleagues (Columbia University, New York) examined whether an inflammation-related nutrient pattern (INP) was associated with changes in cognitive function and structural changes in the brain. Gu, Y., et al. (An Inflammatory Nutrient Pattern Is Associated Both Structural and Cognitive Measures of Brain Aging in the Elderly) presented a follow-up study to earlier work using brain scans (MRI) combined with levels of inflammatory makers [C-reactive protein (CRP) and interleukin-6 (IL-6)] and cognitive function studies of >300 community-dwelling elderly people who were non-demented.

They created what was termed an “InflammatioN-related Pattern (INP) where increased levels of CRP and IL-6 were found in participants with low dietary intake of omega-3 polyunsaturated fatty acids, calcium, folate and several water- and fat-soluble vitamins (including B1, B2, B5, B6, D, and E) and increased consumption of cholesterol, beta-carotene and lutein. The INP was derived from a 61-item food frequency questionnaire that the study participants answered about their food intake during the past year. Study participants with this ‘INP-diet-pattern’ also had poorer executive function scores and smaller total brain gray matter volume compared to study participants with a healthier diet.  The strength of the study was the scientific precision and methodology; however, it was not directly comparing one diet to another.  Further studies are needed to verify the role of diet to induce neuro-inflammation-related changes in dementia (cognitive health).  Furthermore, mechanistic insight is needed to understand how a diet with either an absence or an excess of certain nutritional components promotes neuro-inflammation to alter brain function and structure. Their results imply that a poor diet promotes dementia and smaller brain volume in the aging brain through a neuro-inflammatory process.

“The food you eat can either be the safest and most powerful form of medicine, or the slowest form of poison.” Ann Wigmore

What is Good for Your Heart is Good for Your Brain: The Mediterranean diet, a diet of a type traditional in Mediterranean countries, characterized especially by a high consumption of vegetables and olive oil and moderate consumption of protein, is usually thought to confer healthy-heart benefits. The DASH (Dietary Approaches to Stop Hypertension) diet was developed to help improve cardiovascular health, especially hypertension. The DASH diet is simple: eat more fruits, vegetables, and low-fat dairy foods; cut back on foods that are high in saturated fat, cholesterol, and trans fats; eat more whole-grain foods, fish, poultry, and nuts; and limit sodium, sweets, sugary drinks, and red meats. Neurologists have merged the two diets, creating the Mediterranean-DASH Intervention for Neurodegenerative Delay, or MIND diet; testing the hypothesis that if it’s good for the heart it will be good for the brain.   The MIND diet is gaining attention for its potential positive effects on preserving cognitive function and reducing dementia risk in older individuals. In an earlier study, Morris et al. (Alzheimer’s Dement. 2015; 11:1015-22) found that  individuals on the MIND diet showed less cognitive decline as they aged.

Moving to 2017, Dr. McEvoy and colleagues (University of California, San Francisco) studied ~6000 older adults in the Health and Retirement Study. They showed that the study participants who followed either the MIND or the Mediterranean diets were more likely to maintain strong cognitive function in old age (McEvoy, C., et al. Neuroprotective Dietary Patterns Are Associated with Better Cognitive Performance in Older US Adults: The Health and Retirement Study). Their results also showed that study participants with either of these healthier diets had significant retention of cognitive function.

The doctor of the future will no longer treat the human frame with drugs, but rather will cure and prevent disease with nutrition.” Thomas A. Edison

The Nordic Prudent Dietary Pattern (NPDP) Protects Cognitive Function: The NPDP includes both more frequent and less frequent food consumption categories: More frequent consumption of non-root vegetables, apple/pears/peaches, pasta/rice, poultry, fish, vegetable oils, tea and water, and light to moderate wine intake; Less frequent intake of root vegetables, refined grains/cereals, butter/margarine, sugar/sweets/pastries, and fruit juice. Dr. Xu and colleagues (Karolinska Institute, Stockholm, Sweden) studied the relationship of diet to cognitive function in >2,200 dementia-free community-dwelling adults in Sweden (Xu,W., et al. Which Dietary Index May Predict Preserved Cognitive Function in Nordic Older Adults). During six years of evaluation, they reported that study participants with moderate loyalty to the NPDP had better cognitive function compared to study participants who deviated more frequently from the NPDP.  The scientists noted that, in the Scandinavian population studied, the NPDP was better at maintaining cognitive function compared to other diets (Mediterranean, MIND, DASH, and Baltic Sea).

“The trouble with always trying to preserve the health of the body is that it is so difficult to do without destroying the health of the mind.” Gilbert K. Chesterton

Women on the MIND Diet are Less Likely to Develop Dementia: Dr. Hayden and colleagues (Wake Forest School of Medicine, Winston-Salem, North Carolina) studied diet and dementia in >7,000 participants from the Women’s Health Initiative Memory Study (WHIMS) (Hayden, K., et al. The Mind Diet and Incident Dementia, Findings from the Women’s Health Initiative Memory Study).   The study showed that older women who followed the MIND diet were less likely to develop dementia. These results were obtained by stratification of the WHIMS  participants from very likely to very unlikely to adhere to the MIND diet; they were  assessed for almost 10 years.  Their results imply that it may not require drastic diet changes to help preserve the aging brain.

“It’s not about eating healthy to lose weight. It’s about eating healthy to feel good.” Demi Lovato

Diet and Dementia in the Aging Brain: Four different studies with similar results; diet can  influence dementia and cognitive function in the aging brain.  The single most important finding in these studies was simply that a good diet helps maintain a healthy brain. Strong evidence was presented in three of the studies that the Mediterranean, the MIND and NPBP are excellent diets to help maintain cognitive function as we age.  Mechanistic studies to further demonstrate the link of dietary components with an increase in neuro-inflammation  would be most interesting. A confounding issue is that overall health and a healthy brain are more than just diet alone.  To reduce the chance of cognitive decline and dementia, it’s important to remember as we get older to protect our brain by eating well, exercise regularly, and exercise our brain by becoming lifelong learners (see Word Cloud below).

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“The older I get, the more vegetables I eat. I can’t stress that more. Eating healthy really affects my work. You not only need to be physically prepared, but mentally and spiritually.” James Badge Dale

 Cover photo credit:  C.J. Reuland

 

 

Parkinson’s Disease Research: A Commentary from the Stands and the Playing Field

“You can have a very bad end with Parkinson’s, but on the other hand, you can be like me, because I’m lucky. I’m not having a bad end.” Margo MacDonald

“My age makes me think how valuable life is. How bad is something like Parkinson’s in relation to not having life at all?” Michael J. Fox

Introduction: Last month, together with Dr. Simon Stott and his team of scientists (The Science of Parkinson’s Disease), we co-published a historical timeline of Parkinson’s disease beginning with the description of the ‘shaking palsy’ from James Parkinson in 1817. My post entitled “Milestones in Parkinson’s Disease Research and Discovery” can be read here (click this link). The Science of Parkinson’s Disease post entitled “Milestones in Parkinson’s Disease Research and Discovery” can be read here (click this link).

We spent a lot of time compiling and describing what we felt were some of the most substantial findings during the past 200 years regarding Parkinson’s disease.  I learned a lot; truly amazing what has been accomplished in our understanding of  such a complex and unique disorder.  Simon posted a follow-up note entitled “Editorial: Putting 200 years into context” (click this link). I have decided to also post a commentary from the standpoint of (i) being someone with Parkinson’s and (ii) being a research scientist.

“Every strike brings me closer to the next home run.” Babe Ruth

Baseball: I want to use the analogy of a baseball game to help organize my commentary. Baseball fans sit in the stands and have fun watching the game, thinking about the strategy behind the game, eating/drinking, and sharing the experience with family/friends/colleagues.   Most baseball players begin playing early in life and the ultimate achievement would be to reach the major leagues. And this would usually have taken many years of advancing through different levels of experience on the part of the ballplayer. How does how this analogy work for me in this blog? Stands: I am a person-with-Parkinson’s watching the progress to treat and/or cure this disorder. Playing field: I am a research scientist in a medical school (click here to view my training/credentials).

“Never allow the fear of striking out keep you from playing the game!”  Babe Ruth

Observation from the stands:
I am a spectator like everyone else with Parkinson’s. I read much of the literature available online.  Like you, I think about my disorder; I think about how it’s affecting me every day of my life. Yes, I want a cure for this disease.  Yes, I’m rather impatient too.  I understand the angst and anxiety out there with many of the people with Parkinson’s. In reality, I would not be writing this blog if I didn’t have Parkinson’s. Therefore, I truly sense your frustration that you feel in the presence of Parkinson’s, I do understand.  Given below are examples of various organizations and ads and billboards in support of finding a cure for Parkinson’s.  Some even suggest that a cure must come soon.   However, the rest of my post is going to be dedicated to trying to explain why it’s taking so long; why I am optimistic and positive a cure and better treatment options are going to happen.  And it is partly based on the fact that there really are some amazing people working to cure Parkinson’s and to advance our understanding of this disorder.

“When you come to a fork in the road take it.” Yogi Berra

Observations from the playing field (NIH, war on cancer, research lab, and advancing to a cure for Parkinson’s):

National Institutes of Health (NIH) and biomedical research in the USA: Part of what you have to understand, in the United States at least, is that a large portion of biomedical research is funded by the NIH (and other federally-dependent organizations), which receives a budget from Congress (and the taxpayers). What does it mean for someone with Parkinson’s compared to someone with cancer or diabetes? The amount of federal funds committed to the many diseases studied by NIH-funded-researchers are partly divvied up by the number of people affected. I have prepared a table from the NIH giving the amount of money over the past few years for the top four neurodegenerative disorders, Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), and Huntington’s Disease, respectively [taken from “Estimates of Funding for Various Research, Condition, and Disease Categories” (click here)]. And this is compared to cancer and coronary arterial disease and a few other major diseases. Without going into the private organizations that fund research, a large amount of money comes from the NIH. Unfortunately, from 2003-2015, the NIH lost >20% of its budget for funding research (due to budget cuts, sequestration, and inflationary losses; click here to read further).   Therefore,  it is not an overstatement to say getting  funded today by the NIH is fiercely competitive.  From 1986 to 2015, my lab group was supported by several NIH grants and fellowships  (and we also received funding from the American Heart Association and Komen for the Cure).

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“In theory, there is no difference between theory and practice. But in practice, there is.” Yogi Berra

War against cancer: In 1971, Pres. Richard Nixon declared war against cancer and Congress passed the National Cancer Act.  This created a new national mandate “to support research and application of the results of research to reduce the incident, morbidity, and mortality from cancer.” Today, cancer is still the second leading cause of death in the USA; however, we’ve come such a long way to improving this statistic from when the Cancer Act was initiated.

Scientifically, in the 1970’s, we were just learning about oncogenes and the whole field of molecular biology was really in its infancy. We had not even started sequencing the human genome, or even of any organism.  We discovered genes that could either promote or suppress cellular growth.   We began to delineate the whole system of cell signaling and communications with both normal and malignant cells. We now know there are certain risk factors that allow us to identify people that may have increased risk for certain cancers. Importantly,  we came to realize that not all cancers were alike,  and it offered the notion to design treatment strategies for each individual cancer.  For example,  we now have very high cure rates for childhood acute leukemia and Hodgkin’s lymphoma and we have significantly improved survival statistics for women with breast cancer. Many might say this was a boondoggle and that we wasted billions of dollars  funding basic biomedical research on cancer; however, basic  biomedical research is expensive and translating that into clinical applications is even more expensive.  [ For a  very nice short review on cancer research please see the following article, it may be freely accessible by now: DeVita Jr, Vincent T., and Steven A. Rosenberg. “Two hundred years of cancer research.” New England Journal of Medicine 366.23 (2012): 2207-2214.]

“One of the beautiful things about baseball is that every once in a while you come into a situation where you want to, and where you have to, reach down and prove something.” Nolan Ryan

The biomedical research laboratory environment:  A typical laboratory group setting is depicted in the drawing below. The research lab usually consists of the lead scientist who has the idea to study a research topic, getting grants funded and in recruiting a lab group to fulfill the goals of the project.  Depending on the philosophy of the project leader the lab may resemble very much like the schematic below or may be altered to have primarily technicians or senior postdoctoral fellows working in the lab  (as two alternative formats). A big part of academic research laboratories is education and training the students and postdocs to go on to advance their own careers; then you replace the people that have left and you continue your own research.  Since forming my own lab group in 1986, I have helped train over 100 scientists in the research laboratory: 17 graduate students, 12 postdoctoral fellows, 17 medical students, and 64 undergraduates. The lab has been as large as 10 people and a small as it is currently is now with two people. People come to your lab group because they like what you’re doing scientifically and this is where they want to belong for their own further training and advancement.  This description is for an academic research  laboratory; and  I should also emphasize that many people get trained in federal government-supported organizations, private Pharma and other types of research environments that may differ in their laboratory structure and organizational format.

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“Hitting is 50% above the shoulders.” Ted Williams

 In search of the cure for Parkinson’s:    First, I understand the situation you’re in with Parkinson’s because I’m living through the same situation.   But when people find out I’m a research scientist they always wonder why aren’t we doing more to find a cure, and I  hear the sighs of frustration and I see the anxiety in their faces. Second, the previous three sections are not meant to be an excuse for why there is still no cure for Parkinson’s. It is presented in the reality of what biomedical research scientists must undergo to study a topic.  Third, the experiments that take place in basic biomedical research laboratory may happen over weeks to months if successful. Taking that laboratory data to the clinic and further takes months and years to succeed if at all.   The section on cancer reminds me a lot of where we are going with Parkinson’s and trying to advance new paradigms in the treatment and curative strategies.  Professionally, I have even decided  to pursue research funding in the area of Parkinson’s disease.   Why not spend the rest of my academic career studying my own disease; in the least I can help educate others about this disorder. Furthermore, I can assure you from my reading and meeting people over the last couple of years, there are many hundreds of scientists and clinicians throughout this world studying Parkinson’s and trying to advance our understanding and derive a cure.  I see their devotion, I see their commitment to helping cure our disorder.

The science behind Parkinson’s is quite complicated. These complications suggest that Parkinson’s may be more of a syndrome rather than a disease. Instead of a one-size-fits-all like a disease would be classified; Parkinson’s as a syndrome would be a group of symptoms which consistently occur together.  What this might imply is that some treatment strategy might work remarkably well on some patients but have no effect on others. However, without a detailed understanding and advancement of what Parkinson’s really is we will never reach the stage where we can cure this disorder.

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In a recent blog from the Science of Parkinson’s disease, Simon nicely summarized all the current research in 2017 in Parkinson’s disease (click here to read this post). To briefly summarize what he said is that there are multiple big Pharma collaborations occurring to study Parkinson’s.  There are more than 20 clinical trials currently being done in various stages of completion to prevent disease progression but also to try to cure the disorder.  From a search of the literature, there are literally hundreds of research projects going on that promise to advance our understanding of this disorder. With the last point, it still will take time to happen. Finally, I am a realist but I’m also optimistic and positive that we’re making incredible movement toward much better therapies, which will eventually lead to curative options for Parkinson’s.

And a final analogy to baseball and Parkinson’s, as Tommy Lasorda said “There are three types of baseball players: those who make it happen, those who watch it happen, and those who wonder what happens.”  I really want to be one of those scientists that help make it happen (or at least to help advance our understanding of the disorder).

“You can’t expect life to play fair with your heart or your brain or your health. That’s not the nature of the game we call life. You have to recognize the nature of the game and know that you can do your best to make the right choices, but life if going to do whatever the hell it pleases to you anyway. All you can control is how you react to whatever life throws at you. You can shut down or you can soar.” Holly Nicole Hoxter

Cover photo credit: PNC Park photo: i.imgur.com/32RWncK

Sign post scienceofparkinsons.com/

The Evolving Portrait of Parkinson’s

“Aging is not lost youth but a new stage of opportunity and strength.” Betty Friedane

 “If we own the story then we can write the ending.” Brené Brown

Précis:  To showcase the amazing art/photography/videography of Anders M. Leines who lives in Norway, which gives me the opportunity to voice an opinion about the emerging picture/image of Parkinson’s today.

World Parkinson Congress (WPC) Promo Video: Please watch this video, it’s powerful; “This is Parkinson’s” a WPC Promo from Anders M. Leines (either view it below or click here).  Anders is a videographer and cameraman who works in Oslo, Norway; he’s been diagnosed with young onset Parkinson’s. One of his goals is to change the view about how Parkinson’s is perceived by the world.  One look at his video reinforces this notion.  A very nice article about Mr. Leines was recently posted in “Parkinson’s Life” (click here to read this story).  Anders also shares his story with his own blog “This is Parkinson`s” – The Exhibition.  The pictures, the script, and the music accompanying the WPC 2016 Promo by Mr. Leines says more in 1 min 42 sec about Parkinson’s than someone could likely summarize by writing a blog post, but nonetheless I’m going to try.

A hero is an ordinary individual who finds the strength to persevere and endure in spite of overwhelming obstacles.” Christopher Reeve

The Historical Perception of Parkinson’s: Sir Richard Gowers, in 1886, used this drawing (below left panel) to depict a person with Parkinson’s. When you perform a Google search for a ‘picture of Parkinson’s disease’, these sorts of images are still very prevalent. Yes, the average age of someone with Parkinson’s is 60 years of age and older. And yes, Sir Gowers does accurately show the Cardinal signs of Parkinson’s: tremor, rigidity from muscle stiffness, bradykinesia (slowness of movement), postural instability, and masking (reduced facial expression).  Furthermore, Dr. Charcot’s  drawings, from 1888, also depict a typical Parkinson’s patient compared to an atypical patient with Parkinson’s (bottom right panel).  While these drawings are accurate, these images portray to many who see them that all people-with-Parkinson’s must look and act like this. 

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“In all human affairs there are efforts, and there are results, and the strength of the effort is the measure of the result.” James Allen

The Emerging Perception of Parkinson’s: The reality today is that available treatment strategy and approach to life for someone with Parkinson’s are very different than what was possible for the people portrayed by Sir Gowers and Dr. Charcot. Today, we have well-trained neurologists that are specialists in movement disorders. We have a growing appreciation and understanding of the pathology and biology of Parkinson’s disease.  We have learned about vital lifestyle changes needed to thrive in the presence of this disorder. We have a growing list of therapies [both traditional and complementary and alternative medicine (CAM)] to treat Parkinson’s; we even have deep brain surgery (this surgical technique itself is undergoing new advances and is further evolving in its attempt to control/modify symptoms). We have an increased awareness of the importance of exercise to try to slow progression of this disorder. There is clearly a subset of people with Parkinson’s that present at an earlier age than 60 years old (and this is what Mr. Leines and his exhibition is highlighting).   No doubt, we are living longer and we are likely healthier than someone from the 1880’s; however, that also implies we’re living more years with our Parkinson’s.

This is not saying that Parkinson’s today is either a benign or a tame disease; in fact, it’s an insidious disorder.  Having Parkinson’s is like trying to get rid of cockroaches in your house.  You’ve done all you can to eliminate the roaches from your home, and you don’t see them for weeks; subsequently one day, they’re back. Likewise, Parkinson’s creeps around in the background of your daily life by stealthily altering physical/movement functions, by slowly uncoupling your crucial autonomic nervous system, and surreptitiously in ~50% of people with the disorder, they can develop psychotic tendencies.  The image of Parkinson’s today is clearly evolving due to improved treatment, better understanding of the disorder itself, and improved strategies for living with it; however, under any guise it is still a disagreeable disorder.

“With everything that has happened to you, you can either feel sorry for yourself or treat what has happened as a gift. Everything is either an opportunity to grow or an obstacle to keep you from growing. You get to choose.” Wayne Dyer

A Change is Happening in Our Perspective of Parkinson’s Today:  It is my belief that the perception of Parkinson’s today has changed and is becoming much different than the historical views as described above. I truly believe that the effort most people are using to handle their disorder puts them in a healthier and better lifestyle to manage their symptoms. An emerging predominate picture of Parkinson’s today is a person striving to live strongly. They’ve embraced the appropriate lifestyle, and they are trying their hardest to not become as depicted by the images from the 1800’s. When you do a Google search for ‘images of Parkinson’s disease 2016’, you will likely find more positive and dynamic pictures of people similar to those portrayed by Mr. Leines.

“Let me tell you the secret that has led me to my goal. My strength lies solely in my tenacity.” Louis Pasteur

A Personal Perspective of Parkinson’s Today: With the “This is Parkinson’s” video from Anders M. Leines as an inspiration, I’ve included two sets of pictures of my life with Parkinson’s (photos are below). If my disorder fully progresses, and it is a progressive neurodegenerative disorder, in advanced age (I’m currently 62 years old) I may possibly appear like the drawings above from Sir Gowers and Dr. Charcot. However, as a research scientist, I truly believe in the words of Dr. Claude Levi-Strauss who said “The scientist is not a person who gives the right answers, he is one who asks the right questions.”  I am trying to improve my own knowledge about Parkinson’s; after all, there are still so many questions I want to ask, there are so many new scientific advances that I need to better understand, and there are some emerging treatment strategies that I’d be willing to consider in the future. In other words, Parkinson’s is a reluctant and unwelcome visitor in my body and I’m doing as much as I can to manage the disorder.

With substantial effort, I’m going to do all I can to resist progression; I’m going to stay hopeful, be positive, and remain persistent for many years to come. Importantly, I will take time to stretch every few hours and really make an effort to exercise every day. I will try harder to get an adequate amount of sleep every night.  I am also trying to be mindful and live within the moment by not fretting about what the future could bring.

Thus, this is what I consider to be true of myself (many other people with Parkinson’s would also fit this description): I’m a healthy person that just happens to have Parkinson’s. As I’ve said before, we both have much left to accomplish. We are both still here. Stay focused and stay hopeful.

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“We live in a time when the words impossible and unsolvable are no longer part of the scientific community’s vocabulary. Each day we move closer to trials that will not just minimize the symptoms of disease and injury but eliminate them.” Christopher Reeve

Cover photo credit: http://epod.usra.edu/.a/6a0105371bb32c970b015438c5312a970c-pi

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Déjà Vu and Neuroplasticity in Parkinson’s

“Continuous effort – not strength or intelligence – is the key to unlocking our potential.” Winston S. Churchill

“…remember that what has once been done may be done again.” Alexandre Dumas

Introducing the terms:
D
éjà vu: “A feeling of having already experienced the present situation.” (http://www.oxforddictionaries.com/us/definition/american_english/)

Neuroplasticity: “The brain’s ability to reorganize itself by forming new neural connections throughout life. Neuroplasticity allows the neurons (nerve cells) in the brain to compensate for injury and disease and to adjust their activities in response to new situations or to changes in their environment.” (http://www.medicinenet.com/script/main/art.asp?articlekey=40362 )

Do you remember learning how to ride a bike, throw/catch a baseball, and/or hit a golf ball? Yes, yes, yes; when I was a child with my father.
Learning to ride a bicycle
–  training wheels, then two wheels with support from my dad going down the street, and then he let me go on my own; never to forget how to balance and pedal the bicycle.
Learning how to catch and throw a baseball– wrapping up the ball in the mitt to get it conditioned, the  correct throwing motion, watching the thrown ball into the mitt and working on my hand-to-eye coordination.
Learning the basics of the golf swing– the complexity and intricate timing of swinging a golf club with my dad showing me how to do it from grip, set-up, back swing to follow through.
We likely all have childhood memories of activities where our brain and body were trained/taught to do something.

“Neurons that fire together wire together. Mental states become neural traits. Day after day, your mind is building your brain. This is what scientists call experience-dependent neuroplasticity,” Rick Hanson

Déjà vu and physical activity with Parkinson’s: As someone who has loved to exercise almost every day for most of my life, Parkinson’s is a most disagreeable disorder. Why? Let me give you an example of playing golf. I think about playing golf almost every day although I play maybe once a week and try to practice a couple of times per week. It used to be, every time I addressed the golf ball, my body remembered what it’s supposed to do while waiting for the signals from the brain. Now today, approaching the golf ball I remind myself this is a golf shot. As Yogi Berra said “It’s like déjà vu, all over again” and I remember I’ve been here many times before. It’s as if a short circuit exists and I’m realigning this circuitry every time I swing the golf club. For the most part, my brain-body connection still works and I successfully hit the golf ball; but not every time (maybe I just need to practice more?). This might be analogous to a car running very low on transmission fluid (i.e., in my case low on dopamine); the gears are still working but just not working very smoothly.

“Never give up. It’s like breathing—once you quit, your flame dies letting total darkness extinguish every last gasp of hope. You can’t do that. You must continue taking in even the shallowest of breaths, continue putting forth even the smallest of efforts to sustain your dreams. Don’t ever, ever, ever give up.” Richelle E. Goodrich

Neuroplasticity and physical activity: Kleim and Jones (2008) and Petzinger et al. (2013) describe neuroplasticity as a process where the brain encodes experiences and is able to learn new behavior. They define neuroplasticity as the modification of existing neural networks by adding or modifying synapses in response to changes in behavior or environment, especially when done with exercise. Thus, neuroplasticity can help repair and strengthen the circuitry of the brain.  There is substantial evidence in human studies and in rodent-experimental models that have validated numerous exercise-associated effects on “brain health”.  A regular aerobic exercise program likely helps to promote the appropriate conditions for the injured brain to undergo neuroplasticity. 

“Among other things, neuroplasticity means that emotions such as happiness and compassion can be cultivated in much the same way that a person can learn through repetition to play golf and basketball or master a musical instrument, and that such practice changes the activity and physical aspects of specific brain areas.” Andrew Weil

Neuroplasticity and physical activity in Parkinson’s: [Please remember I am not a physician; I’m not making recommendations for you to do something.  Please talk with your neurologist and/or family practitioner before beginning any of these exercise programs.]  Balance, gait-improvement and flexibility are some of the obvious things a person with Parkinson’s needs to address on a frequent basis, in fact, on a daily basis. Clearly this needs to be self-motivated in the interest of possible neuro-rehabilitation. Most experts suggest that the exercise program should be repetitive, intense, and challenging.   Of course, you must enjoy the exercise program.   Ultimately, exercising should hopefully improve motor functions  and also assist  in improving cognitive function.

The exercises that have been most widely studied and proven to be the most beneficial in promoting neuroplasticity are  treadmill training, amplitude training, tai chi, tango dancing, boxing and cycling  (there are many other exercises to consider, don’t be limited by these above). In my opinion, it’s doing the aerobic exercise you enjoy on a daily and sustained basis,  it’s getting range of motion, and its challenging to you mentally.  As a scientist, I’m impressed by the data in rodent Parkinson’s models and the ability of exercise to promote neuroplasticity, to provide neuroprotection, and even offer neurorestoration. In human studies, the results are remarkably strong as well; showing that sustained aerobic exercise induces neuroplasticity in a damaged brain to improve overall brain health.

“Things don’t go wrong and break your heart so you can become bitter and give up. They happen to break you down and build you up so you can be all that you were intended to be.” Charles Jones

Neuroplasticity and physical activity on overall brain health in Parkinson’s. There is substantial scientific evidence that goal-directed aerobic exercise can improve and strengthen motor circuitry. This is due to structural modifications of synapses and overall improved brain health (increased blood flow, enhanced innate immune system and possibly neurogenesis). Overall brain health initiated by exercise-dependent neuroplasticity alters behavior (affecting many areas of the brain, e.g., the basal ganglia,  cortex, thalamus, and cerebellum). Ultimately, the net effect of sustained exercise and neuroplasticity results in improved motor skills, executive function, cognitive function and mood and motivation.  The diagram below illustrates the changes that can occur with exercise-induced neuroplasticity in Parkinson’s.

Neuroplasticity_4.16.03.13

“Any man could, if he were so inclined, be the sculptor of his own brain.” Santiago Ramón y Cajal

Three comments on déjà vu, neuroplasticity  and physical activity in Parkinson’s:
#1,  Maybe you’re thinking that I’m 62 y.o. and just less coordinated on the golf course with or without Parkinson’s. No doubt this is true but I have my déjà vu feeling, there’s clearly some brain-body disconnect with Parkinson’s (I do need to keep practicing to get more consistent).
#2,  Exercise-induced neuroplasticity will not reverse the effects of Parkinson’s. However, many different studies suggest some restoration of brain circuitry due to exercise-induced neuroplasticity. This implies with time and effort to exercise one could somewhat improve motor learning and behavior performance.
#3, We have much to learn about neuroplasticity and yes even déjà vu. The brain is a powerful organ capable of many different changes when impacted by damage. As we further delineate the mechanism of exercise-induced neuroplasticity, we will better understand Parkinson’s.  Hopefully, from this research (some references are below), there exists the prospect of improved treatment of Parkinson’s. Always remember, a regular aerobic exercise program is good for both your heart and your brain.  Stay positive, be focused, remain hopeful and enjoy your daily exercise.

“Be patient toward all that is unsolved in your heart and try to love the questions themselves, like locked rooms and like books that are now written in a very foreign tongue. Do not now seek the answers, which cannot be given you because you would not be able to live them. And the point is, to live everything. Live the questions now. Perhaps you will then gradually, without noticing it, live along some distant day into the answer.” Rainer Maria Rilke

Cover Photo Credit: https://c1.staticflickr.com/9/8210/8205735122_25302e7cce_b.jpg

References-

Alberts JL, Linder SM, Penko AL, Lowe MJ, Phillips M. It is not about the bike, it is about the pedaling: forced exercise and Parkinson’s disease. Exerc Sport Sci Rev. 2011;39(4):177–86. [PubMed]

Combs SA, Diehl MD, Staples WH, et al. Boxing Training for Patients With Parkinson Disease: A Case Series. Phys Ther. 2010;91(1):132–42. [PubMed]

Corcos DM, Comella CL, Goetz CG. Tai chi for patients with Parkinson’s disease. N Engl J Med. 2012;366(18):1737–8. [PubMed]

Farley BG, Koshland GF. Training BIG to move faster: the application of the speed-amplitude relation as a rehabilitation strategy for people with Parkinson’s disease. Exp Brain Res. 2005;167(3):462–7. [PubMed]

Fisher BE, Wu AD, Salem GJ, et al. The effect of exercise training in improving motor performance and corticomotor excitability in people with early Parkinson’s disease. Arch Phys Med Rehabil. 2008;89(7):1221–9. [PMC free article] [PubMed]

Fox CM, Ramig LO, Ciucci MR, Sapir S, McFarland DH, Farley BG. The science and practice of LSVT/LOUD: neural plasticity-principled approach to treating individuals with Parkinson disease and other neurological disorders. Semin Speech Lang. 2006;27(4):283–99. [PubMed]

Gajewski PD, Falkenstein M. Physical activity and neurocognitive functioning in aging – a condensed updated review. European Review of Aging and Physical Activity. 2016;13:1. doi:10.1186/s11556-016-0161-3.

Hackney ME, Earhart GM. Effects of dance on movement control in Parkinson’s disease: a comparison of Argentine tango and American ballroom. J Rehabil Med. 2009;41(6):475–81. [PMC free article] [PubMed]

Heremans E, Nackaerts E, Vervoort G, Broeder S, Swinnen SP, Nieuwboer A. Impaired Retention of Motor Learning of Writing Skills in Patients with Parkinson’s Disease with Freezing of Gait. Allodi S, ed. PLoS ONE. 2016;11(2):e0148933. doi:10.1371/journal.pone.0148933.

Kleim JA, Jones TA. Principles of experience-dependent neural plasticity: implications for rehabilitation after brain damage. J Speech Lang Hear Res. 2008;51(1):S225–39. [PubMed]

Li F, Harmer P, Fitzgerald K, et al. Tai chi and postural stability in patients with Parkinson’s disease. N Engl J Med. 2012;366(6):511–9. [PMC free article] [PubMed]

Petzinger GM, Fisher BE, McEwen S, Beeler JA, Walsh JP, Jakowec MW. Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson’s disease. Lancet Neurol. 2013; 12(7):716–726. doi: 10.1016/S1474-4422(13)70123-6 [PMC free article] [PubMed]

Voss MW, Vivar C, Kramer AF, van Praag H. Bridging animal and human models of exercise-induced brain plasticity. Trends in cognitive sciences. 2013;17(10):525-544. doi:10.1016/j.tics.2013.08.001.

 

Importance of Model Systems in Parkinson’s Research

“Science is organized knowledge. Wisdom is organized life.” Will Duran

“The most exciting phrase to hear in science, the one that heralds new discoveries, is not ‘Eureka!’ but ‘That’s funny…’” Isaac Asimov

Introduction:  The goal of this post is to highlight several experimental model systems that have effectively been used in Parkinson’s research.  We  have gained tremendous knowledge about all aspects of Parkinson’s from the use of model systems (Please note there are many publications that could have been included here by many different outstanding scientists; this is just a sampling of the strong science in the field of Parkinson’s disease).

The alpha-synuclein story in Parkinson’s: Alpha-synuclein is  a protein found in the brain that form aggregates (clumps of protein) called Lewy bodies.   Lewy bodies accumulate inside the substantia nigra region of the brain and they are toxic to the neurons and they no longer synthesize dopamine.   Part of the toxicity of alpha-synuclein-forming Lewy bodies is linked to mitochondria inhibition,  the little energy factories found in  our cells. This is just a sampling of alpha-synuclein in Parkinson’s (here is a PubMed search: http://www.ncbi.nlm.nih.gov/pubmed/?term=alpha-synuclein+Parkinson%27s ).

“Science is the process that takes us from confusion to understanding…” Brian Greene

The need for experimental model systems:  Scientists develop and use various experimental tools to answer their research questions. The ‘strength’ of the observation is usually dependent on the ‘quality’ of the experimental model system. Described here are four of many different experimental model systems: yeast; Caenorhabditis elegans (C. elegans); human, rat or mouse neuronal cells; and the mouse (or rat). Ultimately, scientists and physicians ‘translate’ this information for use in human clinical trials, which defines the phrase “bench-to-bedside”.

PD.model.16.02..25

“I never guess. It is a capital mistake to theorize before one has data. Insensibly one begins to twist facts to suit theories, instead of theories to suit facts.” Sir Arthur Conan Doyle, Author of Sherlock Holmes stories

Advancing our understanding of Parkinson’s using experimental model systems: You must remember a couple of things about science and research in general. Asking and answering one question usually leads to another question that needs to be answered. Typically, the next questions are more complex as the story unfolds. It is kind of like peeling an onion, you start taking off the top layer and you keep going; the more questions you answer the more layers you have to peel. Let’s go peel some onions.

Rising yeast in biology:  In our everyday lives,  baker’s yeast is used to make bread and alcoholic beverages like beer.  Yeast are single cell organisms, but like human cells they are eukaryotic (defined as “…cells that contain a distinct membrane-bound nucleus and by the occurrence of DNA transcription inside the nucleus and protein synthesis in the cytoplasm….” http://www.thefreedictionary.com/eukaryote ). Yeast are easy to culture and they share many similarities to human cells;  furthermore, genetic manipulation is relatively easy to do in yeast and offers a powerful tool for biomedical science. [Also see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3213361/%5D

Use of yeast in Parkinson’s research Tardiff and others performed a really clever experiment, they expressed alpha-synuclein in yeast.  They found that yeast, just like human neuronal cells, got sick in the presence of excess amounts of alpha-synuclein.  They used the yeast expressing alpha-synuclein  and asked the following questions. Could a compound neutralize or reverse the alpha-synuclein-induced toxicity in yeast? Would this compound be able to restore normal function to the yeast?  They tested  ~190,000 compounds to see whether any of those would reverse the toxic effects and allow the yeast to rapidly grow again.  One lead compound evolved from this study, N-aryl benzimidazole (NAB).  NAB corrected the problem in yeast expressing alpha-synuclein. Using elegant genetics, they found that NAB activates a “trafficking” protein named Rsp5. The alpha-synuclein-induced toxicity  was inhibiting the function of Rsp5, which means that NAB reverses this effect. This sets the scene for new pathways to be explored for how Parkinson’s evolves, and presents a new strategy for exploring drugs to treat this disorder.
Tardiff DF, Jui NT, Khurana V, et al. Yeast reveal a “druggable” Rsp5/Nedd4 Network that Ameliorates α–Synuclein Toxicity in Neurons. Science (New York, NY). 2013;342(6161):979-983. doi:10.1126/science.1245321.

“Science is a way of thinking much more than it is a body of knowledge.” Carl Sagan

“Worm people” advancing science using C. elegans: C. elegans are non-parasitic soil nematodes that are free-living (…worms of the phylum Nematoda, having unsegmented cylindrical bodies often narrowing at each end, and including free-living species that are abundant in soil and water, and species that are parasites of plants and animals…” http://www.thefreedictionary.com/nematode ). C. elegans is a model organism due to its ability to be easily grown and manipulated genetically, which scientists use to advance complex biological principles.  [Also see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1855192/%5D

Use of worms in Parkinson’s research Advanced age is the greatest known risk factor for development of Parkinson’s.  Why this happens is not fully understood. Cooper and others proposed the following hypothesis: “…there are specific changes that take place during the aging process that make cells susceptible to disease-causing mutations that are well-tolerated at younger ages.” To begin to ‘test’ this hypothesis, they used genetics and C. elegans as a model system.  Worms containing mutations in the daf-2 gene live twice as long as control worms.  The researchers crossed  C. elegans models of Parkinson’s with daf-2 mutants.  Compared to the appropriate control worms, the Parkinson’s/daf-2 mutant worms had longer lifespan, protection of dopamine neurons, resistance to inflammatory stress, and decreased Lewy-body formation. This C. elegans genetics-aging study implies that slowing down the aging process is neuroprotective in Parkinson’s.
Jason F Cooper, Dylan J Dues, Katie K Spielbauer, Emily Machiela, Megan M Senchuk, and Jeremy M Van Raamsdonk. Delaying aging is neuroprotective in Parkinson’s disease: a genetic analysis in C. elegans models. npj Parkinson’s Disease (2015) 1, 15022; doi:10.1038/npjparkd.2015.22; published online 19 November 2015

“What we find changes who we become.” Peter Morville

Cells provide a cultivating environment to model tissues/organs:  Over the past several decades, many different types of cells have been grown in sterile plastic dishes; ranging from “primary” cell extracts obtained from different organs to “immortalized” cell types from various tumor types (i.e., cancer).  Cells grown in vitro (defined as “performed or taking place in a test tube, culture dish, or elsewhere outside a living organism” https://www.google.com/search?q=define+in+vitro&ie=utf-8&oe=utf-8) do not fully recapitulate the organ of origin; nonetheless, cell culture is a powerful model system to study both normal biological and abnormal pathological processes. [Also see http://www.biologyreference.com/Bl-Ce/Cell-Culture.html%5D

Use of neuronal cells in Parkinson’s research Proteins have unique three-dimensional shapes, which encode their biological activity.  Sometimes, proteins go bad and do things that are pathological like alpha-synuclein forming aggregates. Moree and others are testing a hypothesis that small molecules can be discovered that reverse such detrimental protein aggregation. They developed a novel screening technique to identify compounds that modulate protein conformation (which is way beyond the scope of this blog posting). They discovered a compound named BIOD303 as a novel conformational modulator of alpha-synuclein.Interestingly, these modulators reduced alpha-synuclein aggregation in an experimental neuronal cell model. This sort of study could (possibly one day) lead to a novel process for treating Parkinson’s by reversing alpha-synuclein aggregates.
Moree B, Yin G, Lázaro DF, et al. Small Molecules Detected by Second-Harmonic Generation Modulate the Conformation of Monomeric α-Synuclein and Reduce Its Aggregation in Cells. The Journal of Biological Chemistry. 2015;290(46):27582-27593. doi:10.1074/jbc.M114.636027.

“Science does not know its debt to imagination.” Ralph Waldo Emerson

The mouse (rat) provides a most important model system:  Our understanding of many human diseases (think cardiovascular, cancer, and yes, Parkinson’s) has been advanced using mice and rats as model systems. One reason why mice are used is the similarity of mouse and human genetics. Scientists have done amazing feats using mice including “gene knockout” where specific genes have been deleted or inactivated.  Another type of mouse genetically-derived is the “transgenic mice”, which usually express genes thought to promote human diseases.  Ultimately, a mouse (or rat) with a specific disease becomes a model or ‘stand-in’ for that same human disease or condition.  [Also see  http://emice.nci.nih.gov/aam%5D

Use of rats in Parkinson’s researchVolakakis and others studied how alpha-synuclein promotes changes in dopamine-producing neurons. They found that alpha-synuclein alters gene expression and that a transcription factor (a protein that binds to specific DNA sequences that modulates the genetic information being transcribed from DNA to messenger RNA) known as Nurr1 helps resist these effects. They found that nuclear substances that bind to Nurr1’s partner retinoid X receptor (RXR) also had a neuroprotective role. Their results clearly highlight Nurr1’s neuroprotective role against alpha-synuclein-induced changes in dopamine-producing neurons. Furthermore, their results imply that RXR ligands have therapeutic potential in Parkinson’s.
Volakakis N, Tiklova K, Decressac M, Papathanou M, Mattsson B, Gillberg L, Nobre A, Björklund A, Perlmann T. Nurr1 and Retinoid X Receptor Ligands Stimulate Ret Signaling in Dopamine Neurons and Can Alleviate α-Synuclein Disrupted Gene Expression. J Neurosci. 2015 Oct 21;35(42):14370-85. doi: 10.1523/JNEUROSCI.1155-15.2015. PMID:26490873

“Barry L. Jacobs and colleagues from the neuroscience program at Princeton University showed that when mice ran every day on an exercise wheel, they developed more brain cells and they learned faster than sedentary controls. I believe in mice.”  Bernd Heinrich

From bench-to-bedside: The four papers described here represent the tip-of-the-iceberg in Parkinson’s research. As with any basic science study, the next step, the next few years are key to developing/advancing/evaluating these questions and getting answers. I am optimistic that new compounds, new treatment strategies, and further understanding of Parkinson’s are coming in the near future. It just will take time, so we must remain patient while all of their research endeavors progress.

“From the standpoint of daily life, however, there is one thing we do know: that we are here for the sake of each other – above all for those upon whose smile and well-being our own happiness depends, and also for the countless unknown souls with whose fate we are connected by a bond of sympathy. Many times a day I realize how much my own outer and inner life is built upon the labors of my fellow men, both living and dead, and how earnestly I must exert myself in order to give in return as much as I have received.” Albert Einstein

Cover photo credit: http://www.boredpanda.com/beautiful-winter-photos/

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Neuroprotection by Modified-Macrophages in a Parkinson’s Model System

“Somewhere, something incredible is waiting to be known.” Carl Sagan

“You never change things by fighting the existing reality.  To change something, build a new model that makes the existing model obsolete.” R. Buckminster Fuller

Précis: Scientists at the University of North Carolina at Chapel Hill are using an innovative approach to treat Parkinson’s in a model animal system (I realize this is my University, but it’s still very cool science). Dr. Elena Batrakova’s research is focused on engineering macrophages (a key host defense cell) for delivery to and therapy in the brain.  This “Trojan Horse” therapeutic system has been used for treating Parkinson’s in an animal model (go here: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106867).

What is a Trojan Horse therapeutic system?  From Greek mythology:The Trojan Horse is a tale from the Trojan War about the subterfuge that the Greeks used to enter the city of Troy and win the war. In the canonical version, after a fruitless 10-year siege, the Greeks constructed a huge wooden horse, and hid a select force of men inside.” (https://en.wikipedia.org/wiki/Trojan_Horse).  From  modern neuroscience and molecular engineering: The Trojan Horse therapeutic system is to use a naturally occurring cell (macrophage) that fools the body (to get into and past the blood brain barrier) into accepting the cell as self. After being accepted as self, it allows the material housed inside the macrophage to be released directly at the site of injury (mid-brain region called substantia nigra that has dopamine producing cells). The drawing below illustrates the science of this study and the depiction of the Trojan Horse.

Macrophages+Parkinsons.160208

“Everything is theoretically impossible, until it is done.” Robert A. Heinlein

What are macrophages (in this study they are the Trojan horse)? Bone marrow makes many different cell types including red blood cells, white blood cells (WBC), and platelets. Macrophages are derived from the WBC named monocyte. Monocytes released from the bone marrow circulate in the bloodstream for a couple of days and leave and go to the various organs and tissues where they mature and become macrophages.  Macrophages are incredibly versatile and important cells in our host defense system; including a role as a sentinel, a role as a  General in a bunker giving out orders to all the other soldiers, and even a role functioning as a garbage collector. Let me explain. Macrophages live in our tissues and they stand guard ready to attack invading microorganisms.  Macrophages generate many different substances (growth factors and  cytokines)  that recruit and activate WBC’s both to enhance the attack against invading microorganisms  and to initiate the immune system.  Macrophages also help out by cleanup debris and cellular waste products. Macrophages can be activated when  exposed to different kinds of inflammatory cytokines and they become what are called M1 and M2 macrophages.  M1 macrophages have a role being pro-inflammatory while M2 macrophages have a role being regenerative.

“The good thing about science is that it’s true whether or not you believe in it.” Neil deGrasse Tyson

What is GDNF (in this study it is the Greek soldiers)? GDNF  stands for glial cell-line derived neurotrophic factor  (neurotrophic substances regulate the growth, survival, and differentiation of nerve cells/nervous tissue).  There is evidence in the scientific literature of the positive impact of neurotrophic factors in experimental treatment of Parkinson’s. The idea behind using GDNF is to promote survival of dopamine producing neurons and also to reduce inflammation in the mid-brain area. One of the major obstacles to this research area in general has been delivering the neurotrophic factor through the blood brain barrier and to the damaged tissue. The study here gets around this by using the macrophage as the carrier to deliver GDNF, the neurotrophic factor, directly to the brain.

“Nothing in life is to be feared, it is only to be understood. Now is the time to understand more, so that we may fear less.” Marie Curie

Is this research similar to regenerative medicine?  Ultimately, if this science translates from bench-to-bedside, it satisfies elements of what is called regenerative medicine.  By definition, “regenerative medicine is a branch of translational research in tissue engineering and molecular biology which deals with the ‘process of replacing, engineering or regenerating human cells, tissues or organs to restore or establish normal function.'” (https://www.google.com/search?q=personalized+medicine&ie=utf-8&oe=utf-8#q=regenerative+medicine+definition).  The approach used in this study was first, to use the macrophage as the protective cell carrier and as the decoy in the Trojan horse model. And second, to express GDNF in the macrophage and have the macrophages deliver the neurotrophic factor directly to the brain. This idea is partially based on the hypothesis that macrophages would migrate toward areas of inflammation; there is substantial evidence linking inflammation in the mid-brain region to someone with Parkinson’s.

“Wonder is the seed of knowledge” Francis Bacon

 Was there good news using GDNF-expressing macrophages in the experimental mouse model of Parkinson’s?   There were several notable positive results from the study, including: 1)  macrophages were able to be transfected with GDNF; 2)  macrophages were activated to the M2 regenerative state; 3) injecting GDNF-expressing macrophages into the Parkinson’s disease mouse showed significant  improvement in both neuroinflammation and  neurodegeneration; 4) behavioral studies confirmed the neuroprotective effect in the mouse model; and 5) these results indicate successful   delivery of GDNF by macrophages, release of GDNF into the affected area, and transfer of the neurotrophic factor to the appropriate targeted neurons.

“The scientist is not a person who gives the right answers, he’s one who asks the right questions.” Claude Lévi-Strauss

Of ‘Mice and Men’, what do the results mean for the future treatment of Parkinson’s?  The results of this paper are both elegant and straightforward.  Their overall goal is to use cell-mediated delivery of therapeutic substances that either stop or slow progression of Parkinson’s. Doing this successfully in a mouse model is one thing; however, getting it translated into a human study is another. We must remain positive that scientists of this caliber continue to get their research funded, continue to train scientists in the neurodegenerative field, and continue to publish their results.  We must remain persistent in managing our own disorder because there are several important studies going on right now; and some of them could reverse and/or slow down the progression of Parkinson’s.  Is this really possible? Time will tell whether this study translates from mice to men.  Finally, I am hopeful that in the near-future a strategy will emerge to slow/halt the progression of Parkinson’s; allowing our return to normalcy.

“The important thing is to not stop questioning. Curiosity has its own reason for existence. One cannot help but be in awe when he contemplates the mysteries of eternity, of life, of the marvelous structure of reality. It is enough if one tries merely to comprehend a little of this mystery each day. Albert Einstein —”Old Man’s Advice to Youth: ‘Never Lose a Holy Curiosity.'” LIFE Magazine (2 May 1955) p. 64”

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Potential New Parkinson’s Drug Highlight: the Leukemia Drug Nilotinib

“With Parkinson’s you have two choices: You can let it control you, or you can control it. And I’ve chosen to control it.” US Senator Isakson

“Learn from yesterday, live for today, hope for tomorrow. The important thing is to not stop questioning.” Albert Einstein

Introduction: In my academic career to-date, my research group and I have presented over 170 abstracts at international science, medical and education meetings.  These abstracts have been poster presentations, short-program talks or invited plenary session presentations (to view a sample of my research group presentations, click here:Church.Frank_SelectedAbstracts.2015).  Abstracts represent the best science from research laboratories; they are like invitations to look over what we study science-wise.

Presenting abstracts could  result in a news organization describing it to the public.  At the recent Neuroscience 2015 meeting, the following abstract was presented (click here to read it: Abstract.GeorgetownStudy): “Nilotinib significantly alters blood and CSF α-Synuclein and p-Tau levels, inhibits dopamine breakdown and increases neuro-restorative markers in an open-labelled Parkinson’s disease with dementia and Lewy body dementia trial.”  Over the past few weeks (Google search “Leukemia drug and Parkinson’s” or “Nilotinib and Parkinson’s”), several news and science organizations have written about this study with much fanfare and with necessary reservations.  Below are my observations on the science of Nilotinib [Pronunciation: nye LOE ti nib (Brand Name: Tasigna)] for treating Parkinson’s; hopeful for its potential combined with concerns.

“Not many appreciate the ultimate power and potential usefulness of basic knowledge accumulated by obscure, unseen investigators who, in a lifetime of intensive study, may never see any practical use for their findings but who go on seeking answers to the unknown without thought of financial or practical gain.” Eugenie Clark

Science of Gleevec and Nilotinib in treating chronic myelocytic leukemia (CML), the “Philadelphia Story”:  CML is a leukemia (blood cancer) from a deranged bone marrow stem cell, the progeny expand to displace all normal bone marrow. CML is characterized by the presence of the Philadelphia chromosome (Ph) in the leukemic cells. Clonal expansion leads to deranged overproduction of white blood cells by subordinate cell lines. Each year in the USA, there are ~5800 new CML cases with ~600 deaths; CML accounts for ~10% of all new cases of leukemia.

The Philadelphia chromosome (Ph) was first described in 1960; yes, it was discovered in Philadelphia. The Ph chromosome is a reciprocal translocation involving chromosomes 9 and 22: t(9;22) (q34;q11) [cutting and pasting together chromosomes, not a good thing to happen]. The chromosomal rearrangement of Ph brings two cell-signaling substances together (they are named Bcr and Abl); the fused-chimeric Bcr-Abl gene has “unnregulated” tyrosine kinase activity. Bcr-Abl is necessary and sufficient to cause CML. This fusion Bcr-Abl interacts with many signaling pathways and it keeps the cell proliferation (growth) machinery on and cell differentiation (maturation) machinery off.   The action of Bcr-Abl would be like having both feet on the car’s accelerator (go-go-go) with no control of the brakes. Ultimately, the result of the Bcr-Abl fusion is to speed up cell division.

Imatinib (Gleevec) was found to be a novel and potent inhibitor of Bcr-Abl. Gleevec inhibits growth of Bcr-Abl positive cancer cells; it is orally bioavailable and well tolerated by most CML patients. Gleevec was the first drug of its kind used for directed-chemotherapy. Nilotinib is a second-generation Bcr-Abl inhibitor used to treat CML; including those people whose disease could not be treated successfully with Gleevec or people who cannot take Gleevec.

“It would be possible to describe everything scientifically, but it would make no sense; it would be without meaning, as if you described a Beethoven symphony as a variation of wave pressure.” Albert Einstein

Science of Nilotinib in treating Parkinson’s: The cell signaling protein c-Abl (tyrosine kinase) is involved in numerous cellular processes. Its cancer-related fusion counterpart, Bcr–Abl protein, promotes leukemia. In 2010, Johns Hopkins scientists reported that c-Abl was up-regulated in Parkinson’s; which led to a build-up of denatured proteins that promoted neuronal cell death and the progression of Parkinson’s (http://www.ncbi.nlm.nih.gov/pubmed/20823226).

Here is a plausible pathway for the development of Parkinson’s and the use of CML (Bcr-Abl) inhibitors to treat this disorder:
1. Parkinson’s develops from a loss of dopamine-producing brain cells.
2. These cells accumulate a protein named alpha (α)-synuclein that aggregates in the cell, which stresses and ultimately leads to death of the cell.
3. The physiological process responsible for clearing out this cellular debris is known as autophagy (see schematic below for an overview of autophagy).
4. A protein named parkin protects brain cells by enabling autophagy, (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2592826/). The action of autophagy is kind of analogous to the garbage disposal in your kitchen sink.
5. c-Abl ‘labels’ parkin and this modification  inhibits parkin function.
6. c-Abl up-regulation in Parkinson’s would leads to parkin dysfunction; Without autophagy activation, toxic parkin substrates (AIMP2 and FBP1) and denatured forms of α-synuclein accumulate and the dopamine-synthesizing cell dies.
7. This implies that inhibition of c-Abl could be neuroprotective.
8. To recap: over-activation of c-Abl prevents parkin from promoting autophagy, allowing for a build-up of toxic substances that can kill brain cells to begin the progression of Parkinson’s.
9.Two newer studies using animal models of Parkinson’s showed that brain-penetrating c-Abl inhibitors were neuroprotective (see http://www.ncbi.nlm.nih.gov/pubmed/23741470 and http://www.ncbi.nlm.nih.gov/pubmed/24786396 ).

AutophagyScheme.151129

“All trials are not the reason to give up, but a challenge to improve ourselves. Our pain is not an excuse to back out, but an inspiration to move on.” Anonymous/unknown

Nilotinib may be a molecular Drāno in treating Parkinson’s:  With this background story, let’s visit the Georgetown abstract/results. Dr. Charbel Moussa and Dr. Fernando Pagan led the pre-clinical research study. Reminder: Nilotinib is a second-generation Bcr-Abl inhibitor used to treat the blood cancer CML.  Thus, their initial goal was to test the safety of Nilotinib in treating patients with Parkinson’s and Lewy body dementia.  If Nilotinib was safe and well-tolerated, a second goal was to measure motor skills and cognitive function. This was a small phase I clinical trial with 11-12 patients receiving Nilotinib for 6 months (150-300 mg/day).

Why was there so much excitement in this preliminary drug study? Because treatment with Nilotinib actually improved and, in some patients, reversed impaired motor skills, non-motor functions, and cognitive functions  in Parkinson’s and Lewy body dementia patients. Some of the more remarkable changes from 6 months of treatment with Nilotinib included three individuals unable to speak before could now hold conversations, and one individual previously confined to a wheelchair could now walk again.

Nilotinib was used at a lower dose (150-300 mg/day) then recommended for treating CML (800 mg/day).  The higher dose would promote cell death during treatment of Bcr-Abl-positive CML cells. By contrast, the lower dose would inhibit (not kill) c-Abl-positive neuronal cells. They hypothesize that the lower dose initiates  autophagy to remove toxic proteins in the absence of cell death. It would be analogous to Nilotinib being a molecular Drāno.  In household use,  you pour Drāno into a clogged drain, wait a few hours, wash with hot water, and the result is an unclogged drain.

MolecDrano151213

There were several issues with this study that all have noted.  Besides being a very small clinical trial, limitations were as follows:  lack of a control group for comparison, and Nilotinib was not compared to a placebo or any existing Parkinson’s drugs. We must also remember the primary goal of this study was that of a Phase I Clinical trial.  “Phase I: Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.” (https://www.nlm.nih.gov/services/ctphases.html )

“Getting diagnosed has made me want to grab life and squeeze every last ounce of fun and opportunity from it.” Emma Lawton

Closing comments from a scientist with Parkinson’s: This study using the cancer drug Nilotinib to treat individuals with Parkinson’s and Lewy body dementia both excites me and worries me.  First, the results were very preliminary; let’s see how the planned 2016 studies turn out (this time with controls). Second, there are potential adverse side effects of Nilotinib (http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm218929.htm), which when added to the side effects of the existing arsenal of Parkinson’s therapies, it could be somewhat problematic. Third, Novartis claims the cost of Nilotinib for CML chemotherapy (800 mg/day) is  ~$10,000/month. While the dose used in this study was less (150 and 300 mg/day), off-label use and cost could be problematic for many individuals.  Fourth,  the idea of re-engaging autophagy to clear out toxic substances to rejuvenate the neuron is intriguing; however, much basic science is needed to validate this hypothesis.

Finally, if there was ever a “good time” to have Parkinson’s, it may be now. We have taken giant strides in our understanding of the pathophysiology of Parkinson’s.  There are numerous clinical trials currently underway testing novel therapies.  I can’t wait to read these innovative biomedical and clinical trial abstracts in 2016-2017. We must remain hopeful that we are on the cusp of several new treatment strategies to halt the progression of Parkinson’s.

 “With the support of my family and friends, I will meet this challenge with the same determination and unwavering intensity that I have displayed in all of my endeavors in life.” Kirk Gibson

A few examples of other reports:
https://gumc.georgetown.edu/news/Cancer-Drug-Improved-Cognition-and-Motor-Skills-in-Small-Parkinsons-Clinical-Trial
https://scienceofpd.wordpress.com/2015/12/11/parkinsons-disease-and-the-cancer-drug/
http://www.medicalnewstoday.com/articles/301144.php
http://www.forbes.com/sites/emilymullin/2015/10/21/could-a-cancer-drug-reverse-parkinsons-disease/
http://www.npr.org/sections/health-shots/2015/10/17/448323916/can-a-cancer-drug-reverse-parkinsons-disease-and-dementia