Human Clock-swapping: The Good, the Bad, and the Ugly

OCTOBER 5, 2018 A COLUMN BY DR. C.

Graphics by Dr. C

I hate the bad days, and what I have to say about the ugly ones is not fit for print. But the good days — well, they are delightful. I write these columns during those times.

It’s not about “Jekyll and Hyde” mood swings, but about days where the PD symptomspresent themselves as only a minor problem (the good), days when it’s a struggle to function well (the bad), and then days when the symptoms are the most disabling (the ugly). There may be a cyclicity to the good, the bad, and the ugly (see diagram, below). John D. Palmer, author of “The Living Clock,” writes about this cyclicity, saying that we are all governed by a human clock.

 (Graphic by Dr. C)

                                         

Sleep is governed by the human clock, and sleep disturbances are common with PD. Having the strong desire to go to bed when the sun is shining, and to stay awake when it is not, is the human clock swapping day for night. Think of a serious case of jet lag. But it is not just the sleep cycle function of the human clock that is swapped. With PD, there are many human biological cycles in which the normal is swapped for the abnormal.

I used to get up in the morning, jump right into projects, and go all day (16 hours). This energy helped me get four college diplomas. This is no longer the case. Those days have been swapped out for a daily cycle of times when the body and mind are available, and times when they are not (off-periods). Each day has at least three off-periods, with the one in the evening being the worst. Then, there are bad days when the off-periods are longer and more intense. In the middle of these bad days, there will be some time when it’s just plain ugly and I am bedridden. The normal human cycle of daily life has been swapped out for this PD cycle of the good, the bad, and the ugly.

Charting aspects of how PD is experienced, using a numerical scale from 1 to 10, and putting that on a calendar each day can be quite useful in getting to know your personal cycles. You can chart pain, fatigue, tremors, or any other symptom that is significantly interfering with your quality of life.

Charting can also help you to become more aware, and maybe even get to the point in which you can say to your partner “it feels like a bad day is right around the corner,” or “today is a level 5 day.” The other piece of information that comes from charting is an idea of how long it will be until the good days return. They do return, and it helps to have an idea of when that will be when you’re in the middle of the torture that accompanies the bad and the ugly days.

Communication about the good, bad, and ugly days is important for healthy relationships with family and caregivers. Using a numbering system of 1 to 10 communicates to others how the day is unfolding so that adjustments can be made. Using this system can prompt a family member to ask: “What’s your level today?” Sometimes a descriptor helps in communication, like “What’s your pain level today?” This communication helps you to adjust plans for the day and helps to put in place any compensatory strategies during the bad days. It makes life easier on everyone.

I hate bad days, and ugly ones even more, but here’s the problem: Exaggerated emotions are fuel for the bad days. Drop the anger and replace it with a practice of mental centering, even during the worst of it. I will write more on this in the columns to come. I can’t end the PD-caused human clock-swapping, but with a good rehab plan in place, I am learning how to balance the swap in my favor.

***

Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

https://parkinsonsnewstoday.com/2018/10/05/parkinsons-human-clock-swapping-good-bad-ugly/

Experts Highlight 5 NICE Guidelines for Parkinson’s Patients and Clinicians to Follow

OCTOBER 4, 2018 BY JOANA CARVALHO IN NEWS.

In 2017, the United Kingdom’s National Institute for Health and Care Excellence (NICE) published its latest guidelines on how adult patients and their caregivers should manage Parkinson’s disease (PD).

In a new commentary, four experts discuss the implications of some of these recommendations for both patients and healthcare professionals, highlighting the importance of clear communication between both parties to ensure the best management for this chronic disease.

The article, “Highlighting the goals for Parkinson’s care: commentary on NICE Guidelines for Parkinson’s in Adults (NG71),” was published in Age and Ageing.

Parkinson’s disease, the second most prevalent neurodegenerative disease in the elderly after Alzheimer’s disease, is a complex, multifactorial disorder characterized by the gradual loss of muscle control, sometimes accompanied by cognitive deficits.

So far, several models of care provision have attempted to summarize recommendations for both Parkinson’s patients and clinicians.

In this article, the authors discussed the implications of five different aspects of Parkinson’s disease highlighted in the Parkinson’s disease NICE quality standard, derived from the full NICE guidelines published previously.

First, the quality standard recommends that patients always remain in contact with a healthcare specialist to ensure continuous disease monitoring and to help with informed decision-making.

“Ensuring that a point of contact with specialist services is available for people with PD is vital for maintaining continuity of care and providing access to information, advice, care and support when people with PD, their families and carers need it,” the authors wrote.

Second, patients on dopaminergic medications should be aware of the risks of developing impulse control disorders (ICDs) — a type of personality disorder characterized by the inability to resist impulses to engage in excessive or harmful behaviors — that have been associated with levodopa and dopaminergic agonists used in the treatment of Parkinson’s.

“A better understanding of the risk of ICDs can ensure they are detected earlier and help patients understand the need to reduce their dopamine therapy and engage with cognitive behavioral therapy,” the authors wrote.

Third, patients with balance issues, severe motor symptoms, and difficulties with daily life activities, including problems with communication, swallowing, or saliva, should be referred to supportive therapies, such as physiotherapy, occupational therapy, or speech and language therapy.

“The broader impact that these symptoms have on activities of daily living requires a multi-disciplinary team approach to treatment. For clinicians this means having an awareness of the multi-system nature of the condition and the impact it can have on lifestyle. Discussing this with people with PD should prompt referral to the appropriate multi-disciplinary team member,” the authors wrote.

Fourth, patients admitted to a hospital or care home should take levodopa within 30 minutes of their usual prescribed administration time to avoid the occurrence of acute akinesia, or the inability to move voluntary muscles, and neuroleptic malignant syndrome, which is a life-threatening adverse reaction to certain anti-psychotic medications.

“The goal of current clinicians should be to take steps to … [ensure] staff training and understanding of the importance of prompt administration of levodopa,” the authors said.

Finally, healthcare professionals should provide clozapine to patients who are experiencing hallucinations and delusions that could occur as a side effect of treatment.

“The guidance advises considering quetiapine as a first line treatment as there is evidence to support that it is effective in treating hallucinations and delusions in people with PD … [and] recommends that clozapine is offered if quetiapine proves ineffective but highlights the need for services to provide access to the drug and a monitoring mechanism,” the authors said.

These different aspects highlight the importance of communication between Parkinson’s patients and clinicians and of working closely with multidisciplinary teams of healthcare professionals and services to ensure patients’ needs are being met.

“With the variety of symptoms, complex treatments and the potential for significant side effects of medications associated with PD, ensuring patients are well informed requires a point of contact and specialist clinicians to ensure that the information they give is of high quality and understandable,” the researchers concluded.

https://parkinsonsnewstoday.com/2018/10/04/parkinsons-experts-highlight-five-nice-guidelines-patients-clinicians/

Michael J. Fox Foundation Lauds Federal Funding of Data Collection for Parkinson’s, Other Diseases

OCTOBER 4, 2018 BY MARY CHAPMAN 

The new law calling for the federal government to collect data on U.S. residents with neurological conditions such as Parkinson’s will help refine disease research and make care more accessible, the Michael J. Fox Foundation (MJFF) for Parkinson’s Research said.

President Donal Trump recently signed into law the Labor, Health and Human Services, Education (LHHS) and Defense spending bill, which provides $5 million in funding to the Centers for Disease Control (CDC) for the National Neurological Conditions Surveillance System authorized in 2016 by the 21st Century Cures Act.

“We’ll finally get a more accurate number in terms of how many people live with Parkinson’s disease. But the real meat of what this system will do is provide scientists with much more comprehensive data which they can use to target research more,” Ted Thompson, MJFF senior vice president, public policy, told Parkinson’s News Today.

“We’re thrilled that this got funded.”

The signing was a major development for patient groups such as MJFF and the National Multiple Sclerosis Society (NMSS), which have fought for system authorization and funding since 2006.

Within the past year alone, system advocates sent 46,000 emails to lawmakers, and held hundreds of meetings. “It’s been a multi-pronged effort,” Thompson said.

Most details concerning implementation, such as how information will be collected, and for how long, is up to the CDC, which at press time had not responded to an information request for those details. However, Thompson said he “would hope” the process is underway within a year.

“I can envision a situation where they start to collect for a certain baseline to get certain data, then expanding it,” he said.

The NMSS has said that Shawna Mercer of the CDC will lead data collection. She’s chief of the Centers’ Community Guide Branch, and director of the guide to Community Preventive Services. The CDC website touts the guide as a pre-imminent source of recommendations regarding public health programs, services and policies. Mercer, who has a PhD in epidemiology from the University of Toronto, has worked in Canada and the United States as a researcher, evaluator and practitioner.

The MJFF had a preliminary meeting with the CDC in August 2017. Now that funding’s in place, Thompson expects another one soon. The meeting last year sent the message that the system will not be one-size-fits-all, he said, adding that nearly 90 percent of Parkinson’s patients are on Medicare, whereas most multiple sclerosis patients are not.

“The CDC is very open to getting it right, and we’re happy to have a good working relationship,” he said, “There are more than 400 neurological diseases.”

The NMSS also has said that those living with neurological disease won’t have to take any action regarding collection, and that information possibly will be culled from medical records and insurance claims.

As details emerge, the MJFF will apprise Parkinson’s patients initially via its blog and newletter, Thompson said.

The system is expected to significantly advance research by providing analysis of genetic and environmental neurological disease factors. In addition, it will give insight into the geography and demographics of diagnoses, variances in gender, the percentage of U.S. residents who have neurological diseases, and healthcare practices and utilization.

“It will give us a national picture and highlight whether there are disease clusters in urban or rural areas, which can lead to further discoveries regarding environment aspects,” Thompson said.

There are now estimated to be at least one million U.S. residents living with Parkinson’s, markedly more than previous approximations, which Thompson said were extrapolated from a 1970s study of a single county in Mississippi.

Many individuals don’t get diagnosed because there are no disorder specialists nearby. “So, this survey could help provide better access to high-quality care,” Thompson said.

The MJFF’s mission is to find a cure for Parkinson’s by funding research and ensuring the development of improved therapies for those living with the disease.

https://parkinsonsnewstoday.com/2018/10/04/federal-funding-data-collection-parkinsons-praised-mjff/

Parkinson’s Institute and Clinical Center and Retrotope Announce Collaboration on New Drug Treatment Therapies for Parkinson’s Disease Patients

October 04, 2018 | Source: Retrotope

SUNNYVALE and LOS ALTOS, Calif., Oct. 04, 2018 (GLOBE NEWSWIRE) -- Parkinson’s Institute and Clinical Center, which provides comprehensive patient care, while discovering new treatment options to improve the quality of life for all Parkinson’s disease (PD) patients, and Retrotope announced today a collaboration on a new drug therapy to treat patients with Progressive SupraNuclear Palsy (PSP), a type of treatment-resistant PD.

“The Parkinson’s Institute and Clinical Center brings novel therapies for PD to patients in need,” said Dr. Carrolee Barlow, M.D., Ph.D., CEO of the Institute. “Retrotope’s approach to reducing mitochondrial oxidative damage by fortifying lipids against peroxidation is truly novel and differentiated from other therapies both available and in development. Retrotope has responded to our physicians’ requests for Expanded Access, and we have initiated treatment in two PSP patients under the care of the Institute with Retrotope’s RT001. We look forward to working with Retrotope in evaluating the responses to this therapeutic candidate in these patients.”

The study is expected to help guide the design of future randomized placebo-controlled trials in PSP. RT001 is the first-in-class of a new drug category called deuterated polyunsaturated fatty acids (D-PUFAs), which are a novel approach to protect against lipid peroxidation damage resulting in cell death that is a hallmark of numerous neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, PSP, Huntington’s disease, ALS and several inherited disorders including Friedreich's ataxia (FA) and infantile neuroaxonal dystrophy (INAD) in which Retrotope is planning formal clinical trials.

PSP is believed to be a tauopathy, which is a progressive aggregation of hyper-phosphorylated tau protein in the brain, with accompanying brain atrophy and neuronal cell death.  Symptoms include loss of balance, lunging forward when mobilizing, fast walking, bumping into objects or people, and falls. Later symptoms are dementia (typically including loss of inhibition and ability to organize information), slurring of speech, difficulty swallowing, and difficulty moving the eyes, particularly in the vertical direction. Approximately six per 100,000 people are believed to be affected with the disease. There are currently no approved treatments.

“The patients we treat with these fatal, degenerative diseases are willing to try therapies which appear safe and for which there is a mechanistic rationale that they may benefit from the treatment,” said Dr. Barlow. “Retrotope is a willing partner with a highly unique and well- studied approach to addressing neurodegenerative diseases. The Institute’s goal is to find a cure for Parkinson’s and Expanded Access programs like Retrotope’s are really at the forefront of generating hope for patients from novel therapies, and data for pharmaceutical companies to plan their drug trials.  It is a win-win for both the Institute and Retrotope.”

Peter G. Milner, M.D., Chief Medical Officer of Retrotope said, “Early results in clinical trials of RT001 and Expanded Access programs for a variety of neurodegenerative diseases have generated encouraging results along with a favorable safety profile. We look forward to providing updates on this and other studies in the coming months as we support patients and investigators exploring the utility of RT001 to block lipid peroxidation in a range of primary neurodegenerative diseases.”

Robert J. Molinari, Ph.D., Chief Executive Officer and Co-Founder of Retrotope, added, “As lipid peroxidation is believed to be involved in PSP, it makes a great deal of sense mechanistically to determine if the well-documented downregulation of lipid peroxidation by RT001 might help PSP patients. Therefore, while Retrotope initiates its pivotal studies of RT001 in INAD and Friedreich’s ataxia, the Company is willing to respond to requests of informed physicians for treatment of other diseases in which lipid peroxidation is implicated.”

About the Parkinson’s Institute and Clinical Center:

Parkinson’s Institute and Clinical Center is at the forefront of patient care and therapy development. We are the nation’s only Institute that provides patient care, basic science research, and clinical research in one integrated model. Our unique freestanding organization directly connects research to patient care – from the "bench to bedside.”  For 30 years, our team of epidemiologists, physicians, scientists, and therapists, have been at the forefront of every clinical and scientific discovery in the field of Parkinson’s research.

Since our inception, patients have come from 38 states and many foreign countries for their care. We have managed more than 135 clinical research trials, medically evaluating more than 95 different drugs and therapies for Parkinson’s. The result: our Institute has been directly involved in bringing every Parkinson’s drug currently available to the market. The Institute is at the forefront of discovering and developing the latest, most innovative treatments and therapies for people living with Parkinson's.

For more information visit www.thepi.org or call (408) 734-2800.

About Retrotope:

Retrotope, a privately held, clinical-stage pharmaceutical company is creating a new category of drugs for the treatment of neurodegenerative diseases. Composed of proprietary compounds that are chemically stabilized forms of essential nutrients, these compounds are being considered as disease-modifying drug therapies for many intractable diseases, such as Infantile Neuroaxonal Dystrophy (INAD), ALS, Late Onset Tay Sachs (LOTS), Progressive SupraNuclear Palsy (PSP), Huntington’s disease, mitochondrial myopathies, and retinopathies.  RT001, Retrotope’s first lead candidate, is being tested in placebo-controlled clinical trials for the treatment of Friedreich's ataxia, a fatal orphan disease, and in compassionate use studies for other neurodegenerative diseases such as INAD, LOTS, PSP, ALS and a genetic form of Alzheimer’s disease.  For more information about Retrotope, please visit www.retrotope.com.

Contact for Parkinson’s Institute and Clinical Center:

Chris Di Salvo

Phone: (408) 506-0455

E-mail: profeff@aol.com

Contact for Retrotope: Nancie Steinberg, Burns McClellan

212-213-0006, ext. 318, NSteinberg@burnsmc.com

https://globenewswire.com/news-release/2018/10/04/1601335/0/en/Parkinson-s-Institute-and-Clinical-Center-and-Retrotope-Announce-Collaboration-on-New-Drug-Treatment-Therapies-for-Parkinson-s-Disease-Patients.html

Global burden of Parkinson’s disease is on the rise

04-10-2018 | Neurology | News | Article

The global burden of Parkinson’s disease has more than doubled over the past 26 years, show findings from the Global Burden of Disease Study 2016.

“[T]his increase was not solely due to increasing numbers of older people because age-standardised rates also increased in most regions”, note E Ray Dorsey (University of Rochester, New York, USA) and co-researchers.

The team carried out a systematic analysis and identified 127 epidemiological data sources on Parkinson’s disease, including 91 on prevalence covering 16 world regions, 34 on incidence covering nine world regions and 11 sources on mortality risk covering two world regions.

Using various methods of analysis, they estimated that between 1990 and 2016, the number of people worldwide with Parkinson’s disease increased 2.4-fold, from 2.5 million to 6.1 million.

The researchers comment in The Lancet Neurology that, while aging populations were a major contributing factor to that growth in numbers, as crude prevalence rates increased by 74.3% during the 26 years, age-standardised prevalence rates also increased by 21.7%.

Parkinson’s disease was the cause of 211,296 deaths in 2016 and was responsible for 3.2 million disability-adjusted life–years (DALY), which was 2.6 and 2.5 times higher, respectively, than in 1990. Again, these differences were not solely explained by an increasing number of older people, with age-standardised rates for both increasing by about 22% between 1990 and 2006, and they generally increased across the Socio-demographic Index.

Possible other reasons for the growth in Parkinson’s disease include longer disease duration as a result of longer life expectancy and environmental factors linked to growing industrialisation, suggest the investigators.

Indeed, they found that Parkinson’s disease prevalence and rates of death and DALY increased with time across all global regions, but most notably in China, which the team points out “has undergone rapid industrial growth since 1990.” The only regions to not show an increase in Parkinson’s disease prevalence and burden were southern Latin America, eastern Europe and Oceania.

Another possible factor contributing to the findings is the decline in rates of smoking, consider Dorsey and colleagues, as “[t]he risk of Parkinson’s disease is decreased approximately 40% among smokers.”

The study confirmed that Parkinson’s disease is about 1.4 times more frequent in men than women, which may be related to “[e]nvironmental (eg, occupational) exposures to which men are more frequently exposed”, the researchers propose, and this difference did not change substantially between 1990 and 2016.

They stress that “[a]s the population ages and life expectancy increases, the number of individuals with Parkinson’s disease will continue to increase as well as the duration of the disease, leading to more patients with advanced Parkinson’s disease. To address this burden, primary prevention strategies based on the underlying causes of Parkinson’s disease and more effective treatments than are currently available are required.”

Agreeing with this sentiment, Walter Rocca (Mayo Clinic, Rochester, Minnesota, USA) says in a related commentary: “A relatively conservative projected doubling of the number of patients over the next 30 years would yield more than 12 million worldwide by about 2050.

“However, if population aging continues, medical management keeps improving survival, and environmental or social risk factors remain stable or increase, we can expect an even greater increase in the number of patients.”

He adds that different preventive strategies might need to be considered separately for men and women and tailored to specific countries or regions of the world.

By Lucy Piper

https://www.medwirenews.com/neurology/parkinson-s-disease/global-burden-of-parkinson-s-disease-is-on-the-rise/16169610

Merck runs out of Parkinson’s disease drug Sinemet as manufacturing issues, forecasting miss lead to shortage

Oct 3, 2018 

Merck expects a shortage of its Parkinson's disease drug Sinemet to continue until next year. (Merck)

Merck & Co. is out of stock and dealing with back orders of some of its Sinemet Parkinson’s disease drug products that won't be resolved until next year. The issues have resulted from manufacturing problems at the CMO that produces the drug for Merck, and because the drugmaker badly missed its forecast for demand.

Merck recently let the FDA and other healthcare regulators around the globe know it expects the “constraint” for some Sinemet and Sinemet Pus products to continue into the first quarter of 2019. It suggested patients seek out levodopa products from other suppliers. Its controlled release version and other dose Sinemet products are unaffected at this time. 

But the “manufacturing-related delays” being experienced by CMO are not alone in causing the shortage, Merck explained in an emailed statement.

Biopharma is a fast-growing world where big ideas come along daily. Our subscribers rely on FiercePharma as their must-read source for the latest news, analysis and data on drugs and the companies that make them. Sign up today to get pharma news and updates delivered to your inbox and read on the go.

The drugmaker said it has only a small share of the levodopa market. But it explained that at the same time that supplies from generic makers have declined, and its own supplier ran into manufacturing issues,  “Merck has received an increase in orders for the product, far exceeding our forecast.”

Merck did not respond to a question about whether a recently announced price cut may have contributed to that surge in orders. Sinemet was among six drugs whose prices the Kenilworth, New Jersey, drugmaker in July announced would be cut by 10%. Those cuts were part of several strategies Merck made as a “responsible pricing” pledge after President Trump called on drugmakers to be more reasonable in setting drug prices.

The move included slashing the price of its hepatitis C drug Zepatier by 60% and instituting price-hike controls across its entire portfolio. At the time, Evercore ISI analyst Umer Raffat said the moves were not that dramatic. He pointed out that Zepatier’s market share was small compared to competitors.

The market share of the other drugs named in its cuts, including prostate treatment Proscar and Sinemet, “are all TINY,” Raffat wrote. That’s because they’re off-patent and losing ground to generic competitors. Combined sales of the six products amounted to less than 0.1% of Merck’s total sales last year, Raffat said.

As for the Sinemet shortage, Merck said it is committed to doing its best “to ensure a reliable supply of Sinemet for patients and prescribers” and is working to resolve the situation as quickly as possible.

https://www.fiercepharma.com/manufacturing/merck-runs-out-parkinson-s-disease-drug-sinemet-as-manufacturing-issues-unexpected

Parkinson’s disease - how much water should you drink to reduce symptoms?

 Oct 3, 2018   By MATT ATHERTON

Parkinson's disease diet: Add water to diet to prevent constipation symptoms (Image: GETTY Images)

Parkinson’s disease is a condition that causes the brain to become progressively more damaged over time, according to the NHS.

It’s caused by a loss of nerve cells in part of the brain. These nerve cells help with the production of dopamine, a hormone that sends messages between the brain and the nervous system.

Parkinson’s disease can cause a number of changes in the gut, and patients often suffer from constipation, said charity The Michael J. Fox FoundationParkinson’s disease patients can avoid constipation by increasing the amount of fluids and fibre in their diet.

Drinking between six and eight glasses of water every day could help to get rid of constipation pain, said the charity.

Drinking warm water may help to kickstart bowel movements, it added.

“Constipation is common in Parkinson's disease,” said the charity.

“Increased fluid and fibre consumption can help maintain regularity.”

“Aim to drink six to eight 8-ounce glasses of water per day. Warm liquids, especially in the morning, can stimulate bowel movements.”

To boost the amount of fibre in your diet, try eating more fruits - with the peels - vegetables, legumes and whole grain breads.

Drinking more water will also help to raise blood pressure, the charity said.

Low blood pressure is a symptom of Parkinson’s disease, and a side effect of some of the medications.

“Raising fluid and salt intake will boost blood pressure, but talk with your physician, especially if you have heart or kidney problems.

“Increase cold fluids - water - to five 8-ounce glasses per half day.”

Take all Parkinson’s medications with a full glass of water. It could help the body to break down the medication more efficiently.

Parkinson’s disease symptoms are mild in its earliest stages, but develop gradually over a period of time.

The most common signs of the brain condition include tremors, slow movement, and stiff muscles.

Speak to a GP if you’re worried about the signs or symptoms of Parkinson’s disease.

Almost 150,000 people in the UK have been diagnosed with Parkinson’s disease.

https://www.express.co.uk/life-style/health/1026543/parkinsons-disease-diet-water-symptoms-constipation

Fly protein has protective effect on dopaminergic neurons

 October 3, 2018, Lehigh University

Cunningham works in the lab of Daniel T. Babcock, an assistant professor in the Department of Biological Sciences whose research focuses on neuroscience. Credit: Christa Neu, Lehigh University Communications + Public Affairs

Parkinson's disease is a neurodegenerative disorder that affects dopamine-producing or dopaminergic neurons. The progressive loss of these neurons is what leads to impairment in movement coordination in those suffering from the illness.

Identifying the genes that underlie the loss of these neurons is important to understanding how the disease functions, according to Patrick Cunningham, a Ph.D. student at Lehigh University in Bethlehem, Pennsylvania, where he is investigating the loss of dopaminergic neurons in Drosophila in a model for Parkinson's disease.

Cunningham works in the lab of Daniel T. Babcock, an assistant professor in the Department of Biological Sciences whose research focuses on neuroscience. Among the inquiries that Babcock and his team are focused: Why are certain populations of neurons vulnerable to a particular disease?

"So people who have a mutation that might render them vulnerable to Parkinson's disease tend to lose dopaminergic neurons," Babcock says. "But why are dopaminergic neurons the ones that are lost? We don't have an answer for why that is."

In trying to answer this question, Babcock and his team focus on why dopamine-producing neurons selectively die in patients with Parkinson's disease.

The team recently identified the fruit fly protein known as Scarlet as a target gene whose function is required to prevent age-dependent loss of dopaminergic neurons in fruit flies, or Drosophila melanogaster. They found that loss of Scarlet activity causes a progressive loss of dopaminergic neurons, induces locomotor defects, shortens lifespan and functions cell autonomously within dopaminergic neurons. 

Additionally, they found that this neurodegeneration can be modified by genetically and pharmacologically manipulating levels of metabolites within the kynurenine pathway—a metabolic pathway in cells— and that Scarlet has a neuroprotective role in a model of Parkinson's disease. These results were recently published and highlighted in The Journal of Cell Science in an article called: "Neurodegeneration and locomotor dysfunction in Drosophila scarlet mutants."

Researchers at Lehigh University discover that the Scarlet protein -- associated with eye color -- in fruit flies has a neuroprotective effect on dopaminergic neurons -- those lost in Parkinson's disease sufferers and responsible for impairment of movement coordination. Credit: Christa Neu, Lehigh University Communications + Public Affairs

In an interview for the journal's "First Person" section, first author Cunningham says: "When I was looking at the rescue experiment to see if Scarlet was neuroprotective in a Parkinson's disease model I counted the dopaminergic neurons, and, in brain after brain, I saw that they survived."

He adds: "This was amazing to observe, because the experiment demonstrated that Scarlet was sufficient in preventing dopaminergic neuron loss, suggesting a neuroprotective function. Showing the neuroprotective property of Scarlet really stuck with me because it was my first experience that what we do in lab can be directly applied to a disease."

First author Cunningham shares credit with his mentor and senior author, Professor Babcock. In the article, they discuss the discovery's potential to impact future treatment and prevention of Parkinson's disease.

They write: "Future studies aimed at identifying genes that interact with scarlet, either directly or indirectly, should further aid in understanding why dopaminergic neurons are particularly vulnerable to degeneration. Identifying additional genes that are required to maintain dopaminergic neurons will help further research into therapeutic and preventative treatments for PD patients."

More information: Patrick C. Cunningham et al, Neurodegeneration and locomotor dysfunction in Drosophila scarlet mutants, Journal of Cell Science (2018). DOI: 10.1242/jcs.216697

https://medicalxpress.com/news/2018-10-protein-effect-dopaminergic-neurons.html

Studies show connection between diet, cognitive function

October 2, 2018 by Laura Wright, University of Kentucky

Dr. Ai-Ling Lin (L) has recently published two studies that demonstrate that the Ketogenic Diet, caloric restriction, or the pharmaceutical rapamycin can prevent cognitive decline in animals. Credit: Mark Mahan

We've all experienced a "gut feeling"—when we know deep down inside that something is true. That phenomenon and others, aptly describe what scientists have now demonstrated: that the gut and the brain are more closely connected than we once thought, and in fact the health of one can affect the other.

Capitalizing on this relatively new scientific concept, Ai-Ling Lin, and her colleagues at the University of Kentucky Sanders-Brown Center on Aging, have published two studies that demonstrate the effect of diet on cognitive health in animals.

The first, in Scientific Reports, demonstrated that neurovascular function improved in mice who followed a Ketogenic Diet regimen.

"Neurovascular integrity, including cerebral blood flow and blood-brain barrier function, plays a major role in cognitive ability," Lin said. "Recent science has suggested that neurovascular integrity might be regulated by the bacteria in the gut, so we set out to see whether the Ketogenic Diet enhanced brain vascular function and reduced neurodegeneration risk in young healthy mice."

Lin et al considered The Ketogenic Diet—characterized by high levels of fat and low levels of carbohydrates—a good candidate for the study, as it has previously shown positive effects for patients with other neurological disorders, including epilepsy, Parkinson's disease, and autism. Two groups of nine mice, aged 12-14 weeks, were given either the Ketogenic Diet (KD) or a regular diet. After 16 weeks, Lin et al saw that the KD mice had significant increases in cerebral blood flow, improved balance in the microbiome in the gut, lower blood glucose levels and body weight, and a beneficial increase in the process that clears amyloid-beta from the brain—a hallmark of Alzheimer's disease. 

"While diet modifications, the Ketogenic Diet in particular, has demonstrated effectiveness in treating certain diseases, we chose to test healthy young mice using diet as a potential preventative measure," Lin said. "We were delighted to see that we might indeed be able to use diet to mitigate risk for Alzheimer's disease."

According to Lin, the beneficial effects seen from the Ketogenic Diet are potentially due to the inhibition of a nutrient sensor called mTOR (mechanistic target of rapamycin), which has shown to affect lifespan extension and health promotion. In addition to the Ketogenic Diet, Lin said, mTOR can also be inhibited by simple caloric restriction or the pharmaceutical rapamycin.

The second study, published in Frontiers in Aging Neuroscience, used neuroimaging techniques to explore in vivo the effects of rapamycin, the Ketogenic Diet or simple caloric restriction on the cognitive function of both young and aging mice.

"Our earlier work already demonstrated the positive effect rapamycin and caloric restriction had on neurovascular function," Lin said. "We speculated that neuroimaging might allow us to see those changes in the living brain."

Even more tantalizing: her data suggested that caloric restriction functioned as a sort of "fountain of youth" for aging rodents, whose neurovascular and metabolic functions were better than those of young mice on an unrestricted diet. 

Lin emphasizes that it's too early to know whether the regimens will confer the same benefit in humans, but since rapamycin and other mTOR inhibitors have already been approved by the FDA and are widely prescribed for other diseases, it's realistic to think that study in humans could follow relatively quickly.

Linda Van Eldik, Ph.D., director of the UK Sanders-Brown Center on Aging, said that Lin's work justifies a transition to similar studies in humans, since all of the methods Lin used in animal models can be readily applied to humans. 

"Ai-Ling's lab was one of the first to use neuroimaging to see these changes in a living brain, and the potential link to changes in the gut microbiome," she said. "Her work has tremendous implications for future clinical trials of neurological disorders in aging populations." 

Lin and her lab are already doing just that; designing a clinical trial to understand the role of the gut microbiome in neurovascular dysfunction (a risk factor for AD) and in healthy aging.

"We will use neuroimaging to identify the association between gut microbiome balance and brain vascular function in individuals over 50 years of age, with an ultimate goal to design and test nutritional and pharmacological interventions that will prevent Alzheimer's disease," she said.

Journal reference: Scientific Reports

Provided by: University of Kentucky 

https://medicalxpress.com/news/2018-10-diet-cognitive-function.html