Striatal Neurons May Help Regulate Response to Unexpected Stimuli

NEUROSCIENCE NEWS       MAY 11, 2018
Source: OIST.

Pauses in cholinergic interneuron activity could be a mechanism for controlling how animals respond to external stimuli, researchers report.

Florescent imaging of a section of the striatum showing Cholinergic Interneurons (CINs) in green, and Spiny Projection Neurons (SPNs) in red. NeuroscienceNews.com image is credited to OIST.

Changing our behavior based on unexpected cues from our environment is an essential part of survival. The ability to drop what you’re doing when circumstances demand it could mean the difference between avoiding a speeding vehicle or getting hit by it. A new study at the Okinawa Institute of Science and Technology Graduate University (OIST) has delved into a brain mechanism that may regulate such adaptation.

In the study, which was published in eLife, researchers led by Dr. Stefano Zucca at the OIST Neurobiology Research Unit investigated nerve cells in the striatum, a brain region involved in movement and motivation. Here, nerve cells called cholinergic interneurons (CINs) are in a near-constant state of activity, releasing a chemical called acetylcholine every time they fire. But if the brain gets an unexpected stimulus from outside the body – for example, a startling sound – the CINs will briefly stop firing.

“The purpose of these pauses is a mystery,” said senior author Prof. Jeff Wickens. “We wanted to know, what do these pauses do?” To find out, his team manipulated CIN activity with a method known as optogenetics. They used a virus to replace sections of these neurons’ DNA with genes encoding for light-sensitive ion channels. Optical filaments were then implanted into the striatum of mice. By shining a laser beam into the cell along the filaments, the researchers could switch the CINs into active or inactive mode as the mice moved around their cage, allowing them to generate pauses in CIN firing at will.

The next step was the most challenging: Using electrodes inserted into single nerve cells to record the electrical impulses generated during the pauses. Previous studies recorded from outside of neurons, which can only generate limited information about the impulses they generate. To get a clear recording of electrical potential, the team needed direct measurements from inside the cell. That’s easier said than done: “You have to make a hole inside an individual cell and attach a probe without damaging it”, said Wickens. “It’s extremely fine work that Dr. Zucca perfected.”

When they generated the pauses in CIN activity, the researchers observed a knock-on effect on the neurons that CINs connect to–neurons called spiny projection neurons (SPNs), which in turn send signals from the striatum to the rest of the brain. During the pauses, because SPN neurons received lower stimulation from CINs, they were less likely to fire themselves, the study showed. These pauses, then, give interrupting events significance by effectively muting the striatum’s output signals.

The stops and starts in CIN activity may be a mechanism for controlling how animals respond to stimuli from their environment, says Wickens. For example, he said, “this mechanism might regulate how an animal stops eating when it hears an unfamiliar sound”.

“The CINs only make up 1% of cells in the striatum, but they have a huge influence,” said Prof. Wickens. “They’re important in making changes in behavior, and play a part in movement disorders like Parkinson’s disease when they malfunction.”

The researchers now plan to explore the phenomenon in more detail. “Next we’d like to see if this pause is happening everywhere in the striatum at the same time, or if it’s limited to specific locations”, says Prof. Wickens. That will help reveal how it affects behaviors from moment to moment, he adds.

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

Source: Kaoru Natori – OIST
Publisher: Organized by NeuroscienceNews.com.

Image Source: NeuroscienceNews.com image is credited to OIST.

Original Research: Open access research for “Pauses in cholinergic interneuron firing exert an inhibitory control on striatal output in vivo” by Stefano Zucca, Aya Zucca, Takashi Nakano, Sho Aoki, and Jeffery Wickens in eLife. Published March 8 2018.

doi:10.7554/eLife.32510

Abstract

Pauses in cholinergic interneuron firing exert an inhibitory control on striatal output in vivo

The cholinergic interneurons (CINs) of the striatum are crucial for normal motor and behavioral functions of the basal ganglia. Striatal CINs exhibit tonic firing punctuated by distinct pauses. Pauses occur in response to motivationally significant events, but their function is unknown. Here we investigated the effects of pauses in CIN firing on spiny projection neurons (SPNs) – the output neurons of the striatum – using in vivo whole cell and juxtacellular recordings in mice. We found that optogenetically-induced pauses in CIN firing inhibited subthreshold membrane potential activity and decreased firing of SPNs. During pauses, SPN membrane potential fluctuations became more hyperpolarized and UP state durations became shorter. In addition, short-term plasticity of corticostriatal inputs was decreased during pauses. Our results indicate that, in vivo, the net effect of the pause in CIN firing on SPNs activity is inhibition and provide a novel mechanism for cholinergic control of striatal output.

http://neurosciencenews.com/cins-striatum-stimuli-9034/

FoxFeed Blog: Ask the MD: DaTscan and Parkinson's

Posted by  Rachel Dolhun, MD,  May 11, 2018

In 2011, the U.S. Food and Drug Administration (FDA) approved a brain imaging test called DaTscan to help diagnose Parkinson's disease (PD). For some people, DaTscan can be a useful addition to the doctor's examination in diagnosing Parkinson's. But not everyone with Parkinson's symptoms needs this brain scan, and a DaTscan can't substitute for a doctor's evaluation.

How Does DaTscan Work for Parkinson's? 

In Parkinson's, dopamine cells in the brain break down and die. DaTscan uses small amounts of a radioactive drug to light up dopamine transporters, which move the chemical dopamine into cells when it's done working. In people with Parkinson's, DaTscan appears different because there are fewer dopamine cells and therefore less dopamine transporter activity.

How Can DaTscan Help Diagnose Parkinson's? 

DaTscan can differentiate Parkinson's from movement disorders that don't affect the dopamine cells such as essential tremor or drug-induced parkinsonism. When, for example, it's hard to tell whether a person's shaking is from essential tremor or Parkinson's, DaTscan may be used to separate the two conditions, which have different treatment options and prognoses.

DaTscan cannot be used on its own to diagnose Parkinson's because conditions other than Parkinson's decrease dopamine activity and cause abnormal images. Examples include the atypical parkinsonisms multiple system atrophy, corticobasal degeneration and progressive supranuclear palsy, which may look similar to Parkinson's early on.

Why Doesn't Everyone with Parkinson's Get a DaTscan? 

Doctors diagnose Parkinson's based on what you tell them (your symptoms) and what they see on examination. It's what we call a "clinical" diagnosis. Although your doctor may order certain blood tests or brain images, including a DaTscan, to exclude other conditions, there is not yet a test specifically to diagnose Parkinson's.

For many people, DaTscan offers little information above what is already known, and wouldn't change the recommended course of treatment. For a person with classic motor symptoms (tremor, slowness, stiffness) who benefits from levodopa (the most effective Parkinson's medication), the diagnosis is already made. Unless the disease progresses in a way that calls the diagnosis into question, DaTscan is likely unnecessary.

What Does a DaTscan Involve? 

If your doctor recommends a DaTscan, he or she will write a prescription for you to have the test at a hospital or clinic. You may have to stop certain medications temporarily, and the radiology department will give you specific instructions when you schedule your test. On the day of the scan, you'll be given an injection of the radioactive drug that tags the dopamine transporters, which takes several hours to work. The scan itself takes 30 to 45 minutes. The radioactive exposure, and risk associated, is somewhat small. Estimates vary -- some characterize the amount of radiation as similar to regular x-rays; others to daily environmental radiation we'd be exposed to over a year or so. Potential side effects include headache, nausea, stomach upset, dry mouth and dizziness.

Insurance coverage varies by provider, but Medicare and Medicaid typically cover the test. Always check with your insurer ahead of time.

How Is DaTscan Used in Parkinson's Research? 

Volunteers in MJFF's Parkinson's Progression Markers Initiative (PPMI) study -- people with and without Parkinson's or with PD risk factors -- have multiple DaTscans over four years to measure dopamine before motor symptoms start, at diagnosis and over time. PPMI data has shown that DaTscans change significantly in the early years after diagnosis. Although more work needs to be done to validate these measures, DaTscan could be a potential way to diagnose and track disease, and assess the impact of new therapies. Based on PPMI data, clinical trials are increasingly using DaTscan to help confirm participants' diagnosis for enrollment and some are using the images to measure therapeutic effect. 

https://www.michaeljfox.org/foundation/news-detail.php?ask-the-md-datscan-and-parkinson

Nerve Cell Signals That Guide Movement Are Complex and Dynamic, Study Finds

MAY 11, 2018 BY PATRICIA INACIO, PHD 

Rate hypothesis, a theory that Parkinson’s results from an imbalance in brain signals telling the body to start and stop moving,  may involve  “start” and “stop” signals that are more complex and intricate than initially thought, Stanford researchers report.

And, the researchers suggest, the loss of that complexity and structure might factor in the development of Parkinson’s disease.

Their study, “Diametric neural ensemble dynamics in parkinsonian and dyskinetic states,” was published in the journal Nature.

Parkinson’s is marked by the loss of dopamine neurons in a brain region called the substantia nigra, which is responsible for reward and movement, including the brain circuits that initiate and terminate movement.

“The idea was there was too much ‘stop’ and not enough ‘go,’ and that’s why there’s difficulty with movement,” Mark Schnitzer, an associate professor of biology and applied physics and the study’s lead author, said in a Stanford university news article by Nathan Collins.

Testing the rate hypothesis, however, has proven to be difficult, as the nerve cells controlling these stop and go signals are tightly interconnected. To assess that “start” neurons were suppressed and “stop” neurons hyperactive, as the hypothesis suggests, researchers need to track each type of neuron — and their activities — individually.

They used mice genetically engineered to have “stop” and “start” neurons that lit up in green whenever they were active.

The researchers then compared nerve cells dynamics in these mice under three conditions: a healthy condition,  a condition that mimics Parkinson’s disease (using a neurotoxin to damage dopamine neurons in the substantia nigra), and that same Parkinson’s-like condition but in mice also treated with L-dopa (levodopa), a common patient medication.

Tiny microscopes allowed the team to look into mice brains and track the green flashes showing when  “start” and “stop” neurons were active.

The results were surprising and contrary to what the rate hypothesis suggests: namely, that all neurons in the “start” and “stop” pathways light up at once. Rather, the researchers saw clusters of neurons firing in an activity-specific manner. For example, in healthy mice, a cluster of “start” neurons would turn on (become green) when a mouse began to turn left, while “stop” neurons would light up after that mouse finished grooming its tail.

In mice mimicking Parkinson’s disease, researchers saw a decrease in  “start” neuron activity, as the rate hypothesis predicts. But those in the “stop” pathway were suppressing all kinds of movements at once, instead of particular movements like “stop grooming” or “stop turning left.”

Treatment with L-dopa restored both “stop” and “start” neuronal activity, but that structure came undone if the dose was too high: in these conditions, mice exhibited more activity in the “start” pathway, leading to random and uncoordinated movements similar to dyskinesia — the involuntary muscle movements that are a common side effect of L-dopa treatment in patients.

Overall, these findings reveal that both neuron activity rates and levels are affected in Parkinson’s disease and potentially other diseases sharing the same mechanisms, such as Huntington’s, Tourette’s syndrome, chronic pain and schizophrenia.

Importantly, when researchers compared L-dopa to two other less effective dopamine receptor agonists, only L-dopa was capable of fully restoring activity in neurons that control movement. This, the researchers suggested, means that scans of brain activity in patients might one day help to determine the effectiveness of a medication.

“What we may have here is a new way for testing and screening new drugs by looking directly at neural circuit activity,” Schnitzer said in the article.

https://parkinsonsnewstoday.com/2018/05/11/new-cell-signals-guiding-movement-complex-and-dynamics-parkinsons-study-reports/

First Parkinson’s Patient Treated with Insightec’s Incisionless Brain Therapy

MAY 11, 2018 BY JOSE MARQUES LOPES, PHD 

Insightec has treated the first patient in a pivotal study of its non-invasive ultrasound therapy, ExAblate Neuro, for patients with advanced Parkinson’s who have not responded to medication.

The device uses focused ultrasound and magnetic resonance imaging (MRI) to destroy a target deep in the brain — the Vim nucleus of the thalamus — through an intact skull. This area has been identified as responsible for causing Parkinson’s tremors. The MRI technology enables physicians to guide treatment planning and deliver thermal feedback in real-time monitoring.

The therapy aims to improve motor function and treat the characteristic involuntary movements of arms and legs, which may occur as a side effect of medication, and impair patients’ quality of life and ability to perform daily activities.

In July 2016, Insightec’s therapy become the first focused ultrasound device approved by the U.S. Food and Drug Administration (FDA) for the treatment of medication-resistant essential tremors with non-invasive thalamus destruction. In October 2017 the FDA granted approvalto initiate the trial for these patients.

The trial (NCT03454425) evaluates the safety and effectiveness of the ExAblate System for the treatment of Parkinson’s motor features. It is currently enrolling patients who are 30 or older and have predominant motor disability from one side of the body. Insightec plans to recruit a total of 40 participants and expects to complete the research by December 2020.

“Building on the success of the incisionless focused ultrasound treatment for essential tremor, we are excited to extend its application to the debilitating effects of Parkinson’s,” Howard Eisenberg, MD, the study’s principal investigator and a neurosurgery professor at the University of Maryland School of Medicine, said in a press release.

Eisenberg is recognized as one of the nation’s top neurosurgeons and an expert on traumatic brain injury and the blood brain barrier.

“INSIGHTEC is committed to supporting focused ultrasound research, which is much less invasive than conventional surgery, and has the potential of improving the lives of people living with Parkinson’s,” said  Maurice R. Ferré, MD, CEO at Inisightec.

The company recently began a parallel Phase 3 trial (NCT03319485) of its MRI-guided focused ultrasound system for treating motor symptoms in Parkinson’s. It plans to recruit more than 100 patients with advanced idiopathic Parkinson’s not responding to available therapies. Patient enrollment is ongoing at sites in Maryland, New York, Ohio, Pennsylvania, and Virginia. 

https://parkinsonsnewstoday.com/2018/05/11/first-parkinsons-patient-treated-with-insightec-ultrasound-brain-therapy/

Companies Join Forces to Help Improve Clinical Trials for Neurodegenerative Diseases

 MAY 10, 2018   BY CAROLINA HENRIQUES 

Worldwide Clinical Trials and Datavant have teamed up to improve research and clinical trial design for neurodegenerative diseases like Parkinson’s disease.

The collaboration will combine Worldwide’s expertise in neurodegenerative diseases and clinical trial regimens with Datavant’s experience in organizing and structuring healthcare data.

It intends to study the challenges behind the failure of many clinical trials for neurodegenerative diseases, the impact of real-world evidence and big data on clinical trial improvement, and opportunities to use digital technology for expanded trial monitoring.

“The challenges that continue to persist in neurodegenerative diseases highlight the need for novel and evolved approaches to understanding both disease mechanics and patient progression. We believe our partnership with Worldwide takes an important step to revisiting and improving upon elements of trial design and operations that have remained stubborn barriers to progress in the field,” Travis May, co-founder and CEO of Datavant, said in a press release.

Parkinson’s disease presents a growing challenge to healthcare systems worldwide. In the United States, about 1 million Americans are estimated to have Parkinson’s, and globally, that number grows to about 10 million.

Through this partnership, the two companies aim to increase understanding of the specific challenges associated with drug discovery, development, and research for Parkinson’s and other neurodegenerative diseases.

Datavant will provide software that is capable of creating a comprehensive overview of anonymized data sets, linking traditional real-world medical data from electronic health records, claims, genomics and diagnostics, with socioeconomic data, wearables/devices, and behavioral data.

Initially, the partners will co-design a pilot study that combines traditional clinical operations with external data sets to explore opportunities to improve trial monitoring by focusing on patient compliance, adherence, and overall enrollment feasibility.

Researchers will also study the obstacles faced in current clinical trials, including slow recruitment, low patient engagement, inflexible design, and limited observations.

Goals for the new partnership include enhancing methodologies and algorithms used in clinical trials, and improving existing protocol, strategies, and methods used in the clinical trial design of neurodegenerative diseases.

“Together, Worldwide and Datavant are focused on exploring the uncommon value big data and next-generation analytics, combined with robust clinical trial experience and deep therapeutic expertise, can deliver throughout the research process. For Worldwide, the promise of advancing drug development and unlocking novel opportunities for innovative trial design and interpretation is particularly important, as we strive every day to improve the lives of patients and populations suffering from the complex ravages of neurodegenerative disease,” said Peter Benton, president and chief operations officer of Worldwide Clinical Trials.

https://parkinsonsnewstoday.com/2018/05/10/companies-partner-improve-clinical-trials-parkinsons-neurodegenerative-diseases/

Better Understanding of Parkinson’s Psychosis Needed to Develop New Therapies, Study Suggests

MAY 10, 2018 BY JOSE MARQUES LOPES, PHD 

Improved understanding of Parkinson’s disease psychosis (PDP) and a unified approach for its clinical evaluation are key for developing new therapeutics, a review study suggests.

The research, “Treating Hallucinations and Delusions Associated With Parkinson’s Disease Psychosis,” was published in the journal Current Psychiatry Reports.

PDP has been increasingly recognized as a distinct clinical symptom linked with Parkinson’s progression, dementia, and medications. Both its diagnosis and symptom management remain challenging.

PDP is a non-motor symptom that causes patients to experience hallucinations and delusions, with more than half of Parkinson’s patients developing psychosis over the course of their disease.

PDP involves diverse neurotransmitter systems. Altered functioning of serotonin 5-HT2A receptors may affect how PDP patients process what they see.

Visual hallucinations — seeing, hearing, or feeling things that do not exist — are the most frequent feature in PDP patients, but non-visual hallucinations also may occur. Delusions  — distorted interpretations of reality — are more often paranoid and related to persecution or infidelity.

Both visual hallucinations and delusions are risk factors for nursing home placement, which has been associated with a 100 percent mortality rate in a two-year follow-up study. This underscores “the severity with which psychosis correlates with the disease state,” authors wrote. PDP also may impact caregivers, who have shown greater risks for chronic illnesses, depression, and mortality.

As for risk factors underlying the development of psychotic symptoms, dementia and cognitive impairment have been demonstrated extensively. Older age, Parkinson’s duration and severity, and sleep disturbances also are associated with greater risk of PDP.

Regarding treatment, non-pharmacological approaches are an important initial option. Potential reversible medical problems and patients’ non-Parkinson’s related medications — in particular antidepressants, sedatives, and narcotics — should be assessed carefully. Clinicians should then focus on Parkinsonian medications with the greatest risk of inducing psychosis, and always be on the lookout for worsening of motor symptoms.

Regarding pharmacological options, until recently patients had no approved treatments, leading to off-label use of atypical antipsychotics, which may worsen motor symptoms. These medications differ from typical antipsychotics because they induce fewer extrapyramidal symptoms, which are drug-induced movement disorders that include acute and late symptoms.

Pharmacological approaches should be considered if non-pharmacologic strategies and reducing doses of anti-parkinsonian medications are not able to reduce PDP symptoms without affecting motor function, the authors noted.

Several studies demonstrated the safety and tolerability of low-dose Clozaril (clozapine, HLS Therapeutics), an atypical antipsychotic, in PDP patients, without worsening their motor symptoms. Supporting research included multi-center, double-blind trials, which reported benefits with doses ranging between 6.25–50 mg/day. However, patients’ white blood cell counts should be monitored.

Seroquel (quetiapine, AstraZeneca) is a more potent blocker of 5-HT2A receptors than Clozaril. Studies found better results with lower doses, but lack of superior effectiveness over placebo has been consistent.

Zyprexa (olanzapine), which has higher affinity for 5-HT2A receptors than for dopaminergic D2 receptors, showed effective reduction of psychosis, but several studies showed worsened motor function, while others failed to observe differences compared to placebo. As a result, the American Academy of Neurology concluded that olanzapine should not be routinely used for PDP.

More recently, Acadia Pharmaceuticals developed Nuplazid (pimavanserin), a selective 5-HT2A/C receptor inverse agonist with no activity on dopamine receptors, which is an important feature given Parkinson’s patients’ loss of dopaminergic neurons. Inverse agonists induce pharmacological responses opposite to agonists though binding to the same receptors. Doses between 25 and 60 mg/day showed good safety and tolerability results without worsening motor symptoms.

In a larger Phase 3 clinical trial with 199 patients taking either Nuplazid 40 mg/day or placebo over six weeks, the therapy improved both sensory hallucinations and delusions, improved sleep and cognition, and did not lead to declined motor function. Nuplazid became the first medication approved by the U.S. Food and Drug Administration to treat PDP.

Several other atypical antipsychotics and non-antipsychotic medications have been assessed for PDP, but their variable effectiveness and potential motor-worsening falls short of a recommendation for standard use. These include risperidone, ziprasidone, aripiprazole, and melperone.

“While new therapeutics and targets continue to be investigated, a more complete understanding of PDP pathology is needed to further refine drug targets,” the researchers wrote.

“Ultimately, investigation into novel agents will require exploration of not only selective receptor targets, but also a unified approach to the clinical evaluation of PDP itself,” they added.

https://parkinsonsnewstoday.com/2018/05/10/better-understanding-parkinsons-psychosis-needed-for-new-therapies/

Nextstim’s NBT Transcranial Magnetic Stimulation Coming to U.S. to Treat Major Depression

MAY 10TH, 2018   NEUROLOGY, PSYCHIATRY

Nextstim, based in Helsinki, Finland, is making its NBT Navigated Brain Therapy system available in the U.S. for treatment of Major Depressive Disorder. The device is used to deliver transcranial magnetic stimulation to the brain, a therapy that has shown to be effective for certain patients.

The system consists of the transcranial magnetic stimulator, stimulation coil, a stereo camera that’s used for tracking the location of the patient with respect to the coil, an electromyograph, computer and accompanying software, display, and a few other odds and ends.

Product page: NBT Navigated Brain Therapy System…:

https://www.nexstim.com/healthcare-professionals/nbt-system/?tx_siweiche_showweichelinks%5Baction%5D=redirectTo&tx_siweiche_showweichelinks%5Bcontroller%5D=Weiche&cHash=aa610b2649e918f87e49f8e80232ed6b

https://www.medgadget.com/2018/05/nextstims-nbt-transcranial-magnetic-stimulation-coming-to-u-s-to-treat-major-depression.html?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+Medgadget+%28Medgadget%29

UAB researchers unravel brain neuron dysfunction in Parkinson’s disease and dementia with Lewy bodies

May 11, 2018

A decay of brain function is a hallmark of Parkinson's disease and dementia with Lewy bodies, or DLB. Specifically, cognitive dysfunction defines DLB, and nearly eight of every 10 Parkinson's patients develop dementia.

In both of these neuro-degenerative diseases, aggregates of misfolded alpha-synuclein protein develop in brain neurons, including the hippocampus, the region of the brain that plays a vital role in the formation of memories.

These aggregates eventually lead to cell death. However, knowledge of how the abnormal aggregates affect hippocampal neuron structure and function in Parkinson's and DLB before cell death is lacking.

Laura Volpicelli-Daley, Ph.D., assistant professor of neurology at the University of Alabama at Birmingham School of Medicine, and colleagues have now described changes in hippocampal neurons early after the pathogenic alpha-synuclein aggregates begin to appear. This understanding, combined with further exploration of the mechanisms underlying the neuronal changes, could point to novel therapeutic treatments to prevent or reverse neuronal defects and halt development of dementia.

"In Parkinson's disease, you can give levodopa to improve motor function; but there is nothing to stop the non-motor symptoms," Volpicelli-Daley said.

About 1 million Americans live with Parkinson's disease, and DLB is the second-most-common form of dementia in the elderly after Alzheimer's.

Volpicelli-Daley's study took advantage of a novel experimental model of alpha-synuclein aggregates in neurons developed by Volpicelli-Daley and colleagues at the University of Pennsylvania eight years ago. Fibrils resembling those found in PD and DLB brains can be made by putting synthetic alpha-synuclein in a test tube and shaking the solution for several days to allow alpha-synuclein to take on a fibrillary, pathologic conformation. These fibrils can be broken up and added to neurons that are grown in culture. The nerve cells take up some of the fibrils. Inside the cells, the fibrils attract the soluble alpha-synuclein that naturally is present in the cells to form the pathological, insoluble aggregates of alpha-synuclein.

These grow to form the typical inclusions emblematic of Parkinson's and DLB. As the pathologic alpha-synuclein inclusions continue to form, they increasingly impair neuronal excitability and connectivity, and eventually lead to neuron death.

In the present study, UAB researchers and a Yale University colleague looked at changes in mouse excitatory hippocampal neuronal function seven days after exposure to the fibrils, a time point before any of the neurons die. At seven days, alpha-synuclein inclusions are abundant in axons of the cells -- the part of the nerve cell that sends a chemical signal to another nerve cell as part of nerve circuit functioning across the synapses between neurons. These neuronal circuits throughout the brain give rise to perception, action, thought, learning and memories.

The researchers found several significant changes in the hippocampal neurons. Formation of the pathological alpha-synuclein inclusions created multiple defects in both pre-synaptic and post-synaptic functions before neurodegeneration had begun.

"Something is clearly going on with the neurons before they die," Volpicelli-Daley said. "There is increased activity at the presynaptic terminal, the site of the neuron that releases chemicals called neurotransmitters. On the other hand, there is decreased activity post-synaptically, the site of the neighboring neuron where these released chemicals activate messenger systems. This may suggest that there is plasticity in the neurons, that is, the neurons are adapting to the increased activity."

"Over time, this abnormal activity may eventually lead to neuron death," she said. "The next step will be looking at how alpha-synuclein increases presynaptic activity and whether this is a loss of alpha-synuclein function in this neuron compartment or it is caused by formation of toxic alpha-synuclein aggregates."

"This is a groundbreaking study and one of the first to address critical and previously elusive questions regarding how toxic alpha-synuclein affects the structure and physiology of memory neurons," said Jeremy Herskowitz, Ph.D., assistant professor in the UAB Department of Neurology and the Patsy W. and Charles A. Collat Scholar of Neuroscience.

"Our team was able to move the field forward by applying a truly multidisciplinary approach," said Linda Overstreet-Wadiche, Ph.D., associate professor in the UAB Department of Neurobiology. "We combined anatomical, biochemical and functional assays to understand how inclusions alter neuronal function prior to cell death, and this approach yielded the unexpected finding that loss of postsynaptic structure was accompanied by enhanced presynaptic function."

Volpicelli-Daley, Herskowitz and Overstreet-Wadiche are co-senior authors of the study.

In detail, they found that synaptic activity in the absence of action potentials -- specifically, miniature excitatory post-synaptic potentials -- increased, even though there was a major reduction in spine density on the dendrites of the neurons. Electron microscopy also showed an increased number of docked presynaptic vesicles. Spontaneous synaptic activity driven by action potentials remained normal, but there was a major impairment in spontaneous influxes of calcium ions downstream of the synapse.

Source:

https://www.uab.edu/news/research/item/9435-untangling-brain-neuron-dysfunction-in-parkinson-s-disease-and-dementia-with-lewy-bodies

FDA targets clinics offering unapproved stem cell therapies

May 11, 2018

(HealthDay)—The U.S. Food and Drug Administration has launched legal action to stop two stem cell clinics from providing unapproved treatments that have caused serious, long-term harm to some patients.

On Wednesday, the FDA filed complaints in federal court seeking permanent injunctions against U.S. Stem Cell Clinic LLC of Sunrise, Fla., and California Stem Cell Treatment Center Inc./Cell Surgical Network Corporation and their executives. Along with marketing unapproved stem cell treatments, inspections of the clinics revealed improper manufacturing practices, which could affect the sterility of their products and put patients at risk, the FDA said.

The agency said U.S. Stem Cell Clinic did not correct violations outlined in a warning letter sent in August 2017. The clinic claims its unapproved therapies can treat a number of serious diseases and conditions, including Parkinson's disease, amyotrophic lateral sclerosis (ALS), chronic obstructive pulmonary disease (COPD), heart disease, and pulmonary fibrosis. California Stem Cell Treatment Center Inc./Cell Surgical Network Corporation markets its unapproved stem cell therapies as treatments for cancer, arthritis, stroke, ALS, multiple sclerosis, macular degeneration, Parkinson's disease, COPD, and diabetes.

"Cell-based regenerative medicine holds significant medical opportunity, but we've also seen some bad actors leverage the scientific promise of this field to peddle unapproved treatments that put patients' health at risk," FDA Commissioner Scott Gottlieb, M.D., said in an agency news release. "In some instances, patients have suffered serious and permanent harm after receiving these unapproved products."

https://medicalxpress.com/news/2018-05-fda-clinics-unapproved-stem-cell.html

Please read the following:

FDA seeks permanent injunctions against two stem cell clinics

Actions part of a comprehensive approach to the oversight of regenerative medicine products  

                  May 9, 2018

Release

The U.S. Food and Drug Administration, in two complaints filed today in federal court, is seeking permanent injunctions to stop two stem cell clinics from marketing stem cell products without FDA approval and for significant deviations from current good manufacturing practice requirements.

“Cell-based regenerative medicine holds significant medical opportunity, but we’ve also seen some bad actors leverage the scientific promise of this field to peddle unapproved treatments that put patients’ health at risk. In some instances, patients have suffered serious and permanent harm after receiving these unapproved products. In the two cases filed today, the clinics and their leadership have continued to disregard the law and more importantly, patient safety. We cannot allow unproven products that exploit the hope of patients and their loved ones,” said FDA Commissioner Scott Gottlieb, M.D. “We support sound, scientific research and regulation of cell-based regenerative medicine, and the FDA has advanced a comprehensive policy framework to promote the approval of regenerative medicine products. But at the same time, the FDA will continue to take enforcement actions against clinics that abuse the trust of patients and endanger their health with inadequate manufacturing conditions or by purporting to have treatments that are being manufactured and used in ways that make them drugs under the existing law but have not been proven safe or effective for any use.”

A permanent injunction is being sought against US Stem Cell Clinic LLC of Sunrise, Florida, its Chief Scientific Officer Kristin Comella and its co-owner and managing officer Theodore Gradel for marketing to patients stem cell products without FDA approval and while violating current good manufacturing practice requirements, including some that could impact the sterility of their products, putting patients at risk. The FDA is taking this action because US Stem Cell Clinic did not address the violations outlined in a warning letter to the clinic and failed to come into compliance with the law. The FDA is seeking an order of permanent injunction requiring US Stem Cell and the individual defendants to cease marketing their stem cell products until, among other things, they obtain necessary FDA approvals and correct their violations of current good manufacturing practice requirements.

The FDA is also seeking a permanent injunction to stop California Stem Cell Treatment Center Inc., with locations in Rancho Mirage and Beverly Hills, California; Cell Surgical Network Corporation of Rancho Mirage, California; and Elliot B. Lander, M.D. and Mark Berman, M.D., from marketing to patients stem cell products without FDA approval. Berman and Lander control the operations of approximately 100 for-profit affiliate clinics, including the California Stem Cell Treatment Center. The FDA is seeking an order of permanent injunction requiring California Stem Cell Treatment Center Inc. and Cell Surgical Network Corporation and the individual defendants to cease marketing their stem cell products until, among other things, they obtain necessary FDA approvals and correct their violations of current good manufacturing practice requirements.

US Stem Cell Clinic

The FDA issued a warning letter to US Stem Cell Clinic in August 2017 for marketing stem cell products without FDA approval and for significant deviations from current good manufacturing practice requirements, including some that could impact the sterility of their products. The warning letter also cited an FDA inspection of the clinic which found that it was processing adipose tissue (body fat) into stromal vascular fraction (a cellular product derived from body fat) and administering the product both intravenously or directly into the spinal cord of patients to treat a variety of serious diseases or conditions, including Parkinson’s disease, amyotrophic lateral sclerosis (ALS), chronic obstructive pulmonary disease (COPD), heart disease and pulmonary fibrosis. The FDA has not approved any biological products manufactured by US Stem Cell Clinic for any use.

During the inspection of US Stem Cell Clinic in April and May 2017, FDA investigators also documented evidence of significant deviations from current good manufacturing practices in the manufacture of at least 256 lots of stem cell products by the clinic. For example, the clinic was cited for its failure to establish and follow appropriate written procedures designed to prevent microbiological contamination of products purporting to be sterile, which puts patients at risk for infections.

The complaint for permanent injunction against US Stem Cell Clinic was filed by the U.S. Department of Justice on behalf of the FDA in the U.S. District Court for the Southern District of Florida.

California Stem Cell Treatment Center, Inc. and Cell Surgical Network Corporation

In August 2017, the FDA took action to prevent the use of a potentially dangerous and unproven treatment belonging to StemImmune Inc. in San Diego, California and administered to patients at the California Stem Cell Treatment Centers in Rancho Mirage and Beverly Hills. On behalf of the FDA, the U.S. Marshals Service seized five vials of Vaccinia Virus Vaccine (Live) – a vaccine that is reserved only for people at high risk for smallpox, such as some members of the U.S. military. The seizure came after FDA inspections at StemImmune and the California Stem Cell Treatment Centers confirmed that the vaccine was used to create an unapproved stem cell product (a combination of excess amounts of vaccine and stromal vascular fraction – a cellular product derived from body fat). The product was then administered to cancer patients with potentially compromised immune systems and for whom the vaccine posed a potential for harm, including the possibility of inflammation and swelling of the heart and surrounding tissues. The unproven and potentially dangerous treatment was being injected intravenously and directly into patients’ tumors.

California Stem Cell Treatment Center products are also being used for the experimental treatment of patients who suffer from a variety of serious diseases or conditions, including cancer, arthritis, stroke, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), macular degeneration, Parkinson’s disease, chronic obstructive pulmonary disease (COPD) and diabetes. The FDA has not approved any biological products manufactured by California Stem Cell Treatment Center for any use.

During inspections of California Stem Cell Treatment Center’s Beverly Hills and Rancho Mirage facilities in July 2017, FDA investigators documented, among other violations, evidence of significant deviations from current good manufacturing practice requirements. For example, the clinics were cited for failing to establish and follow appropriate written procedures designed to prevent microbiological contamination of products purporting to be sterile, which puts patients at risk for infections.

The complaint for permanent injunction was filed by the U.S. Department of Justice on behalf of the FDA in the U.S. District Court for the Central District of California.

Regenerative medicine regulatory framework

These cases support the FDA’s comprehensive policy framework for the development and oversight of regenerative medicine products, including novel cellular therapies. The FDA issued four guidance documents in November 2017, two final and two draft, that build upon the FDA’s existing risk-based regulatory approach. Under this framework the FDA detailed its efficient, science-based process for helping to ensure the safety and effectiveness of these therapies, while supporting development in this area. One of the two draft guidance documents laid out a novel and efficient clinical development model by which promising cell-based products could pursue review and approval by the FDA. The suite of guidance documents also describes a risk-based framework for how the FDA intends to focus its enforcement actions against those products that raise reported safety concerns or potential significant safety concerns.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm607257.htm