Former MLB Player Dave Parker Shares His Perspective on Parkinson's Disease

June  29, 2018

"A reporter asked me why was I wearing the star of David. I told him my name's David and I'm a star." -Dave Parker, The Undefeated.

Many know former Pirates and Reds' player Dave Parker from his swagger and wit in the MLB. From being a forceful presence in the field to training young kids in the P&G Cincinnati MLB Youth Academy, it's safe to say that Parker has made an important mark in the history of baseball.

But, now, Parker joins a long list of athletes who have been diagnosed with Parkinson's disease. Alongside legends like the late Muhammad Ali, Kirk Gibson and Jimmy Piersall, 'The Cobra' Dave Parker is fighting this disease daily with exercise and medication, while using his foundation to help find a cure.

Dave Parker had a long and successful baseball career.

Dave Parker was drafted by the Pirates in 1970, shortly after his graduation. Parker quickly rose to fame, and his teammates looked up to him with pride. Parker batted during the 1970’s and 80’s for six Major League teams, including the Reds and the Pirates.

He ended his career as a seven-time All-Star and has won the Gold Glove and Silver Slugger award three times. However, Parker did not make it into the Baseball Hall of Fame. He was listed in the ballot alongside Luis Tiant, Steve Garvey, and Dale Murphy, among others, for 15 years.

The peak of his candidacy was in 1998 with 24.5% of the vote, and the final year in 2011 wherein he received 15.3% of the vote.

Dave Parker’s quest for the Hall of Fame is not his biggest battle. Now, he faces Parkinson's disease. Parker was diagnosed with Parkinson’s back in 2012 while he was examined for his routine physical.

He noticed the symptoms before he was diagnosed. Once while playing golf, he noticed a slight trembling in his hand. At first, he didn't take it seriously, and Parker thought it was normal until his physician noticed the same trembling. He was then referred to a neurologist, who diagnosed it as Parkinson's disease. Parker remarked, “My doctor said it looked like I had a little touch of Parkinson’s.” 

After his diagnosis, Parker had many unanswered questions. Could playing have caused him to have a slight tremor in his hands? Could it have affected his balance as well? What about his issues with speech? These questions left him frustrated and stressed, especially because it seemed that no one had the right answers.

His wife has been his biggest source of support.

Eventually, Parker learned that he had to make adjustments, especially since he started to understand how complex the disease is. But, with his family and friends in tow, Parker realized that he had a lot more support than he thought. His biggest source of support? His wife of 34 years, Kellye Crockett. His wife has been there from the very beginning, and she wasn't going to stop with this diagnosis. She helped him overcome his obstacles while playing, and now she has his back while battling Parkinson's.

In an interview with "Newsmakers" and an MLB.com podcast, Parker described his wife as "a great wife, caretaker, and grandmother." 

To him, Parkinson's disease is yet another challenge.

Since his diagnosis, Parker maintains a positive outlook, and believes that Parkinson's is nothing more than another challenge. While he manages his symptoms in the best way he can, Parker tries to educate others about the disease to raise awareness.

The Dave Parker 39 Foundation is his way to support other patients.

To show his support for other patients, he and his wife started the Dave Parker 39 Foundation. The foundation aims to raise awareness for Parkinson’s disease and has programs to educate and support patients. The Dave Parker 39 Foundation also raises money to help researchers find a cure. According to Parker, the foundation is a way for him to bring national attention to Parkinson’s. 

Parker manages his symptoms through medication and exercise

Currently, Parker takes Carbidopa and maintains an active lifestyle to maintain his symptoms. His current workout regimen includes stretching, weightlifting and using the treadmill and stationary bike. Parker also spends his evenings teaching an eight-week program at the Cincinnati Reds Urban Youth Academy, which is just a short walk from his home in Cincinnati. In this program, he teaches kids the fundamentals of baseball. 

To see more slides- Go to:

https://www.findatopdoc.com/Celebrity-Health/Former-MLB-Player-Dave-Parker-Shares-His-Perspective-on-Parkinson-s-Disease#imageref

New Method Captures Images of All Brain Areas Following Gene Therapy

 JUNE 29, 2018 BY IQRA MUMAL IN NEWS.

A new method that allows imaging of all brain areas can help researchers monitor the success of gene therapy in the treatment of neurological diseases such as Parkinson’s.

The study, “A Novel Positron Emission Tomography Reporter Gene/Reporter Probe for the Central Nervous System,” was presented recently during the SNMMI 2018 Annual Meeting in Philadelphia, and published in the Journal of Nuclear Medicine.

Gene therapy is a therapeutic approach that has the potential, by replacing a defective gene copy with a healthy one, to be a one-time treatment that fixes, rather than treats, disease.

In neurological diseases – such as Parkinson’s disease or Alzheimer’s disease – gene therapy is often limited by the lack of an adequate imaging technique that can successfully help monitor the delivery and expression of the therapeutic gene directly into the brain.

While many reporter gene systems — a construct that tags genes with fluorescent probes and allows tracking within the body— have been developed for imaging gene therapies, current systems do not allow imaging all areas of the brain.

“It is challenging to find a reporter gene and imaging agent that can be used in all areas of the brain with a high signal-to-background ratio,” Thomas Haywood, PhD, department of radiology at Stanford University, said in a press release.

Researchers now have developed a new positron emission tomography (PET) reporter gene system that allows for monitoring of gene expression (the process by which information in a gene is synthesized to create a working product, like a protein) in all areas of the brain.

PET imaging uses small amounts of radioactive materials, called radiotracers, along with a special camera and computer to help evaluate organ and tissue functions.

The newly developed system allows researchers to monitor the level and location of gene expression in all areas of the brain in a non-invasive manner, helping physicians determine the likelihood of treatment success.

To test their new method, researchers infected mice brain cells with a viral vector containing the PKM2 gene. PKM2 was considered an ideal choice for a reporter gene because the protein it produces, pyruvate kinase M2, is not expressed at very high levels in the healthy brain. As such, it can be specifically monitored and traced in an experimental setting.

Animals then were imaged with the 18F-DASA-23 radiotracer over a period of two months to observe the increase in PKM2 expression over time. Importantly, this radiotracer is able to cross the blood brain barrier (BBB), a semi-permeable membrane that protects the brain from outside circulating blood.

“18F-DASA-23 is a novel radiotracer, or reporter probe, developed in the Gambhir lab at Stanford that is capable of crossing the blood–brain barrier and targeting the pyruvate kinase M2 protein in the central nervous system with minimal endogenous [normal] expression in the brain,” Haywood explained. “This allows us to monitor reporter gene expression and ultimately therapeutic gene expression for gene therapy in all regions of the brain.”

Results showed there was an increase in 18F-DASA-23 uptake, which correlated with the levels of PKM2 in the cells. This suggests that not only was PKM2 being expressed, but that the radiotracer was correctly detecting its expression in brain tissue.

“This encouraging data suggests PKM2 has the potential to be further developed into a PET reporter gene system for the imaging of gene therapy in the CNS [central nervous system],” the authors wrote.

“Having a reporter gene/reporter probe system that allows monitoring of all areas of the brain opens the door to more accurate and less invasive imaging of the brain and of gene therapies used to tackle diseases of the brain,” Haywood said.

A Phase 1 clinical trial is currently recruiting patients to test the 18F-DASA-23 radiotracer for the early detection of therapeutic response in patients with glioblastoma, a type of brain tumor that develops in certain brain cells called astrocytes.

https://parkinsonsnewstoday.com/2018/06/29/new-method-captures-images-all-brain-areas-following-gene-therapy/

What's Causing Those Tremors?

Marvin M. Lipman, M.D.  JUNE 27, 2018

I thought I had Parkinson’s disease!” the 65-year-old stock analyst exclaimed.

Over the past six months, her handwriting had deteriorated to the point that she was having difficulty signing checks. Because a good friend of hers had recently received a Parkinson’s disease diagnosis, she feared the worst.

I began to suspect that her concern was groundless when I noticed that both her hands shook and that she had a barely noticeable to-and-fro motion of her head—two signs that are uncommon in Parkinson’s disease.

And as she walked toward the examining room, her gait was normal and her arms swung freely—hardly the stiff, hesitant shuffle so often seen with Parkinson’s.

The exam turned up none of the other cardinal manifestations of Parkinson’s—the typical masklike facial expression; the slowed, monotonous speech pattern; and the ratchetlike sensation the examiner feels when alternately flexing and extending the patient’s arm.

Moreover, her hand tremors seemed to improve at rest and worsen when asked to do the “finger to nose” test.

The diagnosis was unmistakable: She had essential tremor, a nervous-system problem that causes unintentional shaking, most often starting in the hands. 

Tracking the Cause

The cause of essential tremor remains uncertain, yet it may affect as much as 1 percent of the population worldwide. It usually begins in late middle age and often worsens despite attempts to suppress the symptoms.

The limbs, head, and even the voice can shake severely enough to interfere with eating, dressing, speaking, and using the bathroom.

Essential tremor is often called benign in the sense that it is not a life-threatening disease. But many who have it consider it anything but benign.

The social stigma can lead to depression and force some into early retirement. The late Katharine Hepburn was a courageous exception; the actress continued to perform and have an active public life despite advanced and fairly severe head tremor.

Recent studies have shown a possible genetic cause. Our stock analyst managed to recall that her grandfather’s hands “shook a bit.” 

There are no laboratory or easily available tests for essential tremor, so diagnosis has to be made entirely on clinical grounds and by selective testing to rule out other diseases, mostly all too obvious, that cause tremors.

These include any long-lasting severe disease that results in muscle weakness or wasting, such as cancer. Thyroid overactivity produces a fine hand tremor (in contrast to the coarse movements seen in essential tremor), and blood tests easily confirm the diagnosis.

Some drugs, including bupropion (Wellbutrin and generic), caffeine, lithium, methylphenidate (Ritalin and generic), and pseudoephedrine, can cause tremors.

Various toxins, including lead and mercury, can also cause them. But by and large, essential tremor’s most look-alike contender is Parkinson’s disease, a progressive movement disorder caused by a neuro­transmitter deficit in a specific part of the brain. 

Treating Tremors

For those with mild essential tremor, treatment is available and can be helpful. A small amount of alcohol can diminish symptoms for an hour or two in the majority of people with the condition. Although that is not the ideal way to control the disorder on a long-term basis, it can come in handy at times.

The mainstays of medical treatment are propranolol (Inderal and generic), a beta-blocker also used to treat hypertension, chest pain, and migraine headaches; and primidone (Mysoline and generic), an epilepsy drug also helpful in movement disorders.

In addition, various tranquilizers and anti-anxiety drugs have been used because the tremor tends to worsen in tension-producing situations.

Surgical techniques, such as deep brain stimulation and heat ablation, are also now being employed in some very severe cases.

The stock analyst’s relief in learning she did not have Parkinson’s disease was almost enough to improve her tremors. She declined my offer to medicate her.

However, she has taken to having a glass of wine when out for dinner. The only continuing annoyance is getting the glass to her lips for that first sip—after which she’s fine.

Editor’s Note: This article also appeared in the August 2018 issue of Consumer Reports On Health. 

Consumer Reports is an independent, nonprofit organization that works side by side with consumers to create a fairer, safer, and healthier world. CR does not endorse products or services, and does not accept advertising. Copyright © 2018, Consumer Reports, Inc.

https://www.msn.com/en-us/health/medical/whats-causing-those-tremors/ar-AAzgevr?srcref=rss

Ultrafast neuronal imaging of dopamine dynamics with designed genetically encoded sensors

JUNE 29, 2018

Imaging dopamine release in the brain

Neuromodulator release alters the function of target circuits in poorly known ways. An essential step to address this knowledge gap is to measure the dynamics of neuromodulatory signals while simultaneously manipulating the elements of the target circuit during behavior. Patriarchi et al. developed fluorescent protein–based dopamine indicators to visualize spatial and temporal release of dopamine directly with high fidelity and resolution. In the cortex, two-photon imaging with these indicators was used to map dopamine activity at cellular resolution.

Science, this issue p. eaat4422

Structured Abstract

INTRODUCTION

Neuromodulators, such as dopamine, norepinephrine, or serotonin, exert powerful control over neural circuit dynamics that give rise to diverse neural function and behavior. Altered neuromodulator signaling is a key feature of virtually all human neurological and psychiatric disorders, including Parkinson’s disease, schizophrenia, depression, and addiction. Hence, drugs that mimic or block neuromodulators have become important components in the treatment of these disorders. Much work is devoted to determining exactly what information neuromodulatory neurons represent, but very little is known about how these signals alter the function of their target circuits.

RATIONALE

To address this problem, scientists need to be able to monitor the spatiotemporal dynamics of neuromodulatory signals in target circuits while also measuring and manipulating the elements of the circuit during natural behavior. However, existing technologies for detecting neuromodulators, such as analytic chemical or cell-based approaches, have limited spatial or temporal resolution, thus preventing high-resolution measurement of neuromodulator release in behaving animals. We recognized the potential of combining genetically encoded indicators based on fluorescent proteins with modern microscopy to support direct and specific measurement of diverse types of neuromodulators with needed spatial and temporal resolution.

RESULTS

We report the development and validation of dLight1, a novel suite of intensity-based genetically encoded dopamine indicators that enables ultrafast optical recording of neuronal dopamine dynamics in behaving mice. dLight1 works by directly coupling the conformational changes of an inert human dopamine receptor to changes in the fluorescence intensity of a circularly permuted green fluorescent protein. The high sensitivity and temporal resolution of dLight1 permit robust detection of physiologically or behaviorally relevant dopamine transients. In acute striatum slices, dLight1 faithfully and directly reports the time course and concentration of local dopamine release evoked by electrical stimuli, as well as drug-dependent modulatory effects on dopamine release. In freely moving mice, dLight1 permits deep-brain recording of dopamine dynamics simultaneously with optogenetic stimulation or calcium imaging of local neuronal activity. We were also able to use dLight1 to chronically measure learning-induced dynamic changes within dopamine transients in the nucleus accumbens at subsecond resolution. Finally, we show that two-photon imaging with dLight1 revealed a high-resolution (cellular level) dopamine transient map of the cortex showing spatially distributed, functionally heterogeneous dopamine signals during a visuomotor learning task.

CONCLUSION

To overcome the major barriers of current methods and permit high-resolution imaging of dopamine dynamics in the mammalian brain, we developed and applied a new class of genetically encoded indicators. This work validates our sensor design platform, which could also be applied to developing sensors for other neuromodulators, including norepinephrine, serotonin, melatonin, and opioid neuropeptides. In combination with calcium imaging and optogenetics, our sensors are well poised to permit direct functional analysis of how the spatiotemporal coding of neuromodulatory signaling mediates the plasticity and function of target circuits.

High-resolution dopamine imaging in vivo.

dLight1 permits robust detection of physiologically and behaviorally relevant dopamine (DA) transients with high sensitivity and spatiotemporal resolution, including dynamic learning-induced dopamine changes in the nucleus accumbens (bottom) and task-specific dopamine transients in the cortex (top).

Neuromodulatory systems exert profound influences on brain function. Understanding how these systems modify the operating mode of target circuits requires spatiotemporally precise measurement of neuromodulator release. We developed dLight1, an intensity-based genetically encoded dopamine indicator, to enable optical recording of dopamine dynamics with high spatiotemporal resolution in behaving mice. We demonstrated the utility of dLight1 by imaging dopamine dynamics simultaneously with pharmacological manipulation, electrophysiological or optogenetic stimulation, and calcium imaging of local neuronal activity. dLight1 enabled chronic tracking of learning-induced changes in millisecond dopamine transients in mouse striatum. Further, we used dLight1 to image spatially distinct, functionally heterogeneous dopamine transients relevant to learning and motor control in mouse cortex. We also validated our sensor design platform for developing norepinephrine, serotonin, melatonin, and opioid neuropeptide indicators.

TO READ MORE:

http://science.sciencemag.org/content/360/6396/eaat4422?rss=1

Vanderbilt licenses compound to Nashville’s Appello to advance Parkinson’s therapies

By Heidi Hall   Jun. 29, 2018

Vanderbilt University has signed a licensing agreement with Nashville-based start-up Appello Pharmaceuticals, Inc. to advance novel compounds developed by researchers in the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD) for the treatment of Parkinson’s disease.

The drug-like molecules bind to mGluR4, a glutamate receptor that is highly expressed in areas of the brain directly relevant to Parkinson’s disease. Called positive allosteric modulators (PAMs), they adjust receptor activity—and thus the brain’s activity of the neurotransmitter glutamate—like a dimmer switch in an electrical circuit.

The molecules were developed with major support from The Michael J. Fox Foundation for Parkinson’s Researchand with the help of the Nashville-based Atticus Trust, a private foundation overseen by the family of Betty and Martin Brown.

“The Michael J. Fox Foundation placed a major investment in this program from its earliest stages,” said P. Jeffrey Conn, founding director of the VCNDD and the Lee E. Limbird Professor of Pharmacology in the Vanderbilt University School of Medicine.

“Also, we are especially indebted to the Brown family, who provided more recent support for key studies that were needed to bring the program to a point where it was ready for partnering with Appello,” Conn said.

Appello was established with major investment from New York-based Deerfield Management, which specializes in accelerating drug development projects at universities and other private, non-profit institutions.

Under the terms of the agreement, Appello will have the right to develop and commercialize products resulting from Vanderbilt’s research program. In turn, Vanderbilt University will obtain an equity interest in Appello as part of the consideration for the license.

“Appello is the perfect vehicle to accelerate the translation of our mGlu4 PAMs to Parkinson’s disease patients,” said Craig W. Lindsley, director of medicinal chemistry for the VCNDD, University Professor and William K. Warren Jr. Professor of Medicine.

“The center has advanced multiple programs through licenses and philanthropy,” Lindsley said, “but the opportunity to work with investors and build a company focused on a non-dopaminergic treatment for Parkinson’s disease was a golden opportunity to ensure our compounds get to patients.”

“Strategic collaborations are key to accelerating the impact of the great basic biomedical research we do at Vanderbilt” said Padma Raghavan, vice provost for research at Vanderbilt University. “This particular collaboration with Appello serves as an essential bridge toward improving patients’ lives.”

An estimated 1 million Americans have Parkinson’s disease, a progressive brain disorder characterized by resting tremor, rigidity and slowness of movement, as well as a battery of non-motor symptoms. It is caused by the death of nerve cells in a specific brain region that produce the neurotransmitter dopamine.

Dopamine replacement therapy, today’s gold-standard treatment for Parkinson’s, relieves some motor symptoms of the disease, but over time it causes debilitating side effects such as involuntary, uncontrollable movements, called dyskinesia.

It is believed that dyskinesia is caused at least in part by the ebb and flow of dopamine levels in the brains of people who are receiving dopamine replacement therapy. Current Parkinson’s treatments also provide less and less benefit to patients as the disease worsens over the long term.

The Vanderbilt compounds work in a fundamentally different way from dopamine replacement therapy, by bypassing the dopamine system altogether and instead modulating another of the brain’s neurotransmitters, glutamate.

The compounds represent an approach to correct the dysregulated signaling observed in Parkinson’s disease. When given systemically in a preclinical model of Parkinson’s disease, they reach the brain and relieve motor symptoms, including rigidity and akinesia, a “freezing” of certain motor muscles.

In this way they pharmacologically mimic a surgical procedure that has been successful in alleviating symptoms of Parkinson’s disease.

Conn and Lindsley’s colleagues in this effort include: Carrie Jones, assistant professor of pharmacology and director of behavioral pharmacology in the VCNDD; Colleen Niswender, research professor of pharmacology and director of molecular pharmacology in the VCNDD; Jerri Rook, research assistant professor of pharmacology (behavioral pharmacology); and Annie Blobaum, research assistant professor of pharmacology (drug metabolism and pharmacokinetics).

Media inquiries

Liz Entman, (615) 322-NEWS

Liz.Entman@Vanderbilt.edu

https://news.vanderbilt.edu/2018/06/29/vanderbilt-appello-parkinsons-therapies/

Complex brain circuitry revealed using new single-cell sequencing technology

June 29, 2018 by Steve Yozwiak, Translational Genomics Research Institute

The complexity of the human brain presents scientists with immense challenges as they try to find new treatments for a host of diseases and conditions. But the advent of a new technology known as single-cell RNA sequencing is opening a window into how the brain works.

Researchers at the Translational Genomics Research Institute (TGen), an affiliate of City of Hope, and a Silicon Valley startup called Circuit Therapeutics Inc. have combined to look deep inside the brain at a structure known as the striatum, which not only is responsible for controlling how we move, but also contributes to the brain's decision-making and the initiation of action.

Nearly 95 percent of the cells that make up the striatum are known as medium spiny neurons (MSN), whose health or malfunction is associated with many psychiatric and neurodegenerative diseases, including Parkinson's disease, Huntington's disease, schizophrenia, drug addiction and ADHD.

In one of the first investigations of its kind, TGen and Circuit Therapeutics have developed exacting methods for examining these MSN cells, and in the process identified a specific gene known as Chrm4 as one of several potential therapeutic drug targets, according to a study published June 15 in the journal Frontiers in Cellular Neuroscience.

"Understanding the molecular composition and gene expression of individual MSN cells are of critical importance to gaining insights into how they work and how we can identify drug targets to treat neurological dysfunctions," said Dr. Matt Huentelman, TGen Professor of Neurogenomics. "In this study, we analyzed and simplified methods for isolating single MSN cells in the striatum, using newly available technology to examine them with unprecedented resolution."

By using single-cell RNA sequencing, the team redefined previous understandings of how MSN cells work, and added to the list of MSN marker genes previously discovered using older technologies that analyzed gene expression by studying bulk portions of striatal tissue.

"Understanding the molecular properties of neural circuitry in the brain is of great interest to neuroscience drug discovery," said Dr. Thomas Portmann, Director of Neurobiology and Transcriptomics at Circuit Therapeutics Inc. "Being able to understand how individual cells form key neural circuits is rapidly advancing our knowledge about the molecular signatures of the brain, and about druggable targets for development of future therapies."

Provided by: Translational Genomics Research Institute

https://medicalxpress.com/news/2018-06-complex-brain-circuitry-revealed-single-cell.html

Neural implants modulate microstructures in the brain with pinpoint accuracy

June 29, 2018 by Windy Pham,   Massachusetts Institute of Technology

MiNDS probes developed at MIT cause minimal injury to brain tissue. This image shows minimal tissue scarring (green and red stains) and healthy neuron growth (purple) surrounding an implant. Credit: Khalil Ramadi

The diversity of structures and functions of the brain is becoming increasingly realized in research today. Key structures exist in the brain that regulate emotion, anxiety, happiness, memory, and mobility. These structures can come in a huge variety of shapes and sizes and can all be physically near one another. Dysfunction of these structures and circuits linking them are common causes of many neurologic and neuropsychiatric diseases. For example, the substantia nigra is only a few millimeters in size yet is crucial for movement and coordination. Destruction of substantia nigra neurons is what causes motor symptoms in Parkinson's disease.

New technologies such as optogenetics have allowed us to identify similar microstructures in the brain. However, these techniques rely on liquid infusions into the brain, which prepare the regions to be studied to respond to light. These infusions are done with large needles, which do not have the fine control to target specific regions. Clinical therapy has also lagged behind. New drug therapies aimed at treating these conditions are delivered orally, which results in drug distribution throughout the brain, or through large needle-cannulas, which do not have the fine control to accurately dose specific regions. As a result, patients of neurologic and psychiatric disorders frequently fail to respond to therapies due to poor drug delivery to diseased regions.

A new study addressing this problem has been published in Proceedings of the National Academy of Sciences. The lead author is Khalil Ramadi, a medical engineering and medical physics (MEMP) Ph.D. candidate in the Harvard-MIT Program in Health Sciences and Technology (HST). For this study, Khalil and his thesis advisor, Michael Cima, the David H. Koch Professor of Engineering within the Department of Materials Science and Engineering and the Koch Institute for Integrative Cancer Research, and associate dean of innovation in the School of Engineering, collaborated with Institute Professors Robert Langer and Ann Graybiel to tackle this issue.

The team developed tools to enable targeted delivery of nanoliters of drugs to deep brain structures through chronically implanted microprobes. They also developed nuclear imaging techniques using positron emission tomography (PET) to measure the volume of the brain region targeted with each infusion. "Drugs for disorders of the central nervous system are nonspecific and get distributed throughout the brain," Cima says. "Our animal studies show that volume is a critical factor when delivering drugs to the brain, as important as the total dose delivered. Using microcannulas and microPET imaging, we can control the area of brain exposed to these drugs, improving targeting accuracy double time comparing to the traditional methods used today."

The researchers were also able to design cannulas that are MRI-compatible and implanted up to one year in rats. Implanting these cannulas with micropumps allowed the researchers to remotely control the behavior of animals. Significantly, they found that varying the volume infused alone had a profound effect on behavior induced, even if the total drug dose delivered stayed constant. These results show that regulation of volume delivery to brain region is extremely important in influencing brain activity. This technology could potentially enable precise investigation of neurological disease pathology in preclinical models, and more effective treatment in human patients.

More information: Khalil B. Ramadi et al. Focal, remote-controlled, chronic chemical modulation of brain microstructures, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1804372115 

Journal reference: Proceedings of the National Academy of Sciences 

Provided by: Massachusetts Institute of Technology 

https://medicalxpress.com/news/2018-06-neural-implants-modulate-microstructures-brain.html

DBS treatment may slow the progression of Parkinson's tremor in early-stage patients

June 29, 2018, Vanderbilt University Medical Center

DBS

Deep brain stimulation (DBS) may slow the progression of tremor for early-stage Parkinson's disease patients, according to a Vanderbilt University Medical Center study released in the June 29 online issue of Neurology, the medical journal of the American Academy of Neurology.

The study is the first evidence of a treatment that slows the progression of one of the cardinal features of Parkinson's, but a larger-scale clinical trial across multiple investigational centers is needed to confirm the finding.

"The finding concerning tremor progression is truly exceptional," said senior author David Charles, MD, professor and vice-chairman of Neurology. "It suggests that DBS applied in early-stage Parkinson's disease may slow the progression of tremor, which is remarkable because there are no treatments for Parkinson's that have been proven to slow the progression of any element of the disease."

Patients in the Vanderbilt study were randomized to receive DBS plus drug therapy or drug therapy alone; the drug therapy alone group was seven times more likely to develop new rest tremor after two years in comparison to the DBS plus drug therapy group.

The trial, which began in 2006, was controversial because it recruited patients with early-stage Parkinson's disease for DBS brain surgery. At that time, DBS was approved for only advanced-stage Parkinson's disease when symptoms were no longer adequately controlled by medication.

"Since this was the first early DBS trial, it was unknown whether there were individual motor symptoms very early in Parkinson's disease that may be more potently improved by DBS," said lead author Mallory Hacker, Ph.D., research assistant professor of Neurology.

The post hoc analysis showed that 86 percent of the drug therapy patients developed rest tremor in previously unaffected limbs over the course of the two-year period, while that occurred in only 46 percent of patients who had received DBS therapy in addition to drug therapy. Four of the DBS patients had rest tremor improvement and rest tremor completely disappeared from all affected limbs for one DBS patient.

The FDA has approved Vanderbilt to lead a large-scale, Phase III multicenter study that will enroll 280 people with very early-stage Parkinson's disease, beginning in 2019, and 17 other U.S. medical centers have joined the DBS in Early Stage Parkinson's Disease Study Group to participate.

"The field of DBS therapy for Parkinson's disease is moving toward earlier stages of treatment, therefore, we must conduct the pivotal trial to ensure patient safety and provide the Parkinson's community with the best possible medical evidence to guide treatment," Charles said.

Journal reference: Neurology

Provided by: Vanderbilt University Medical Center 

https://medicalxpress.com/news/2018-06-dbs-treatment-parkinson-tremor-early-stage.html

Parkinson's may soon be treated with blood pressure drug

Ana Sandoiu  June 29, 2018

Isradipine, an antihypertensive drug, is emerging as a potential new treatment for Parkinson's disease due to promising results of in vitro tests. Until now, it was unclear whether administering the drug in vivo would yield the same benefits — new research shows that it does.

If human trials are successful, we could have the first drug that slows down the progression of Parkinson's disease.

Isradipine is a calcium-channel inhibitor used to treat hypertension.

Previous studies have found that people who took the drug had lower rates of Parkinson's disease, so scientists wanted to examine it closely.

Further tests showed that the drug protects the dopamine-producing neurons that are affected in Parkinson's disease.

Now, a new study shows that treating mice with the drug protects the rodents' dopaminergic neurons as well.

D. James Surmeier, Ph.D., who is the Nathan Smith Davis Professor of Physiology at Northwestern Medicine in Chicago, IL, led the study, and the findings were published in the Journal of Clinical Investigation.

Isradipine affects the neurons' mitochondria

Prof. Surmeier and team administered isradipine to mice for 7–10 days. Then, using a quantitative imaging technique called two-photon laser scanning microscopy, they measured the levels of calcium inside the dopamine-producing neurons.

The tests found that the drug had lowered calcium levels inside these cells. This is important since calcium channels stimulate the mitochondria of dopaminergic neurons, sometimes making these brain cells overly active.

Prof. Surmeier says that this occurs due to the evolutionary role of dopaminergic neurons. These cells are key for activating brain regions responsible for quick motor responses, which is very useful in "fight-or-flight" situations, such as being confronted by a predator.

However, to fulfill this high-energy role, these neurons need to keep their mitochondria working at full capacity at all times. Mitochondria are tiny organelles inside of cells that are responsible for turning fats and nutrients into energy, or the cells' fuel.

Working to such a high capacity at all times is not only no longer necessary in our society, but it can create toxic byproducts. Such toxic compounds ultimately kill neurons, which is what happens in Parkinson's disease.

But in this study, isradipine inhibited calcium channels, which slowed the activity of mitochondria and lowered the production of toxic compounds.

Toward human clinical trials

Also, after treatment with isradipine, the mitochondria of the dopamine-producing neurons had a lower level of oxidative stress than untreated cells.

The scientists also found that high oxidative stress in dopaminergic neurons damaged the cells' mitochondria.

However, treating mice with isradipine lowered this mitochondrial damage. "We diminished the damage being done to mitochondria enough that dopaminergic neurons looked the same as neurons that are not lost in Parkinson's disease," says Prof. Surmeier.

Last but not least, the drug did not induce any side effects, and the rodents continued to behave normally.

The researchers say that the findings reinforce the efforts of a nationwide clinical trial that is now testing isradipine in humans.

The trial, called STEADY-PD, is now in its third phase, and it is being carried out at Northwestern Medicine and 50 other sites in the United States.

Dr. Tanya Simuni, who is the chief of movement disorders in the Ken & Ruth Davee Department of Neurology at Northwestern University, is the primary investigator of this trial. She is hopeful about the results of this study in rodents.

"These data provide additional strong preclinical rationale for the ongoing phase III study of isradipine in human patients [...] We are cautious as so many drugs have failed, but if successful, isradipine will be the first drug to demonstrate the ability to slow progression of Parkinson's disease."

Dr. Tanya Simuni

https://www.medicalnewstoday.com/articles/322312.php