Parkinson’s Disease Brain Rhythms Detected

A team of scientists and clinicians at UC San Francisco has discovered how to detect abnormal brain rhythms associated with Parkinson’s by implanting electrodes within the brains of people with the disease.

The work may lead to developing the next generation of brain stimulation devices to alleviate symptoms for people with the disease.

Described this week in the journal Proceedings of the National Academy of Sciences (PNAS), the work sheds light on how Parkinson’s disease affects the brain, and is the first time anyone has been able to measure a quantitative signal from the disease within the cerebral cortex – the outermost layers of the brain that helps govern memory, physical movement and consciousness.

“Normally the individual cells of the brain are functioning independently much of the time, working together only for specific tasks,” said neurosurgeon Philip Starr, MD, PhD, a professor of neurological surgery at UCSF and senior author of the paper. But in Parkinson’s disease, he said, many brain cells display “excessive synchronization,” firing together inappropriately most of the time.

“They are locked into playing the same note as everyone else without exploring their own music,” Starr explained. This excessive synchronization leads to movement problems and other symptoms characteristic of the disease.

The new work also shows how deep brain stimulation (DBS), which electrifies regions deeper in the brain, below the cortex, can affect the cortex, itself. This discovery may change how DBS is used to treat Parkinson’s and other neurologically based movement disorders, and it may help refine the technique for other types of treatment.

Scientists Identify ‘Clean-Up’ Snafu That Kills Brain Cells in Parkinson’s Disease

Researchers at Albert Einstein College of Medicine of Yeshiva University have discovered how the most common genetic mutations in familial Parkinson’s disease damage brain cells. The study, which published online in the journal Nature Neuroscience, could also open up treatment possibilities for both familial Parkinson’s and the more common form of Parkinson’s that is not inherited.

"Our study found that abnormal forms of LRRK2 protein disrupt an important garbage-disposal process in cells that normally digests and recycles unwanted proteins including one called alpha-synuclein - the main component of those protein aggregates that gunk up nerve cells in Parkinson’s patients," said study leader Ana Maria Cuervo, M.D., Ph.D., professor of  developmental and molecular biology, of anatomy and structural biology, and of medicine and the Robert and Renee Belfer Chair for the Study of Neurodegenerative Diseases at Einstein.

The name for the disrupted disposal process is chaperone-mediated autophagy (the word “autophagy” literally means “self-eating”). It involves specialized molecules that “guide” old and damaged proteins to enzyme-filled structures called lysosomes; there the proteins are digested into amino acids, which are then recycled within the cell.

"We showed that when LRRK2 inhibits chaperone-mediated autophagy,
alpha-synuclein doesn’t get broken down and instead accumulates to toxic levels in nerve cells,” said Dr. Cuervo.

The study involved mouse neurons in tissue culture from four different animal models, neurons from the brains of patients with Parkinson’s with  LRRK2 mutations, and neurons derived from the skin cells of Parkinson’s patients via induced pluripotent stem (iPS) cell technology. All the lines of research confirmed the researchers’ discovery.

"We’re now looking at ways to enhance the activity of this recycling system to see if we can prevent or delay neuronal death and disease," said Dr. Cuervo. "We’ve started to analyze some chemical compounds that look very promising."

Dr. Cuervo hopes that such treatments could help patients with familial as well as nonfamilial Parkinson’s - the predominant form of the disease that also involves the buildup of alpha-synuclein.

Dr. Cuervo is credited with discovering chaperone-mediated autophagy. She has published extensively on autophagy and its role in numerous diseases, such as cancer and Huntington’s disease, and its role in age-related conditions, including organ decline and weakened immunity. Dr. Cuervo is co-director of Einstein’s  Institute of Aging Research.

(Image: Shutterstock)

Parkin protects from neuronal cell death

Parkinson’s disease is the most common movement disorder and the second most common neurodegenerative disease after Alzheimer’s disease. It is characterized by the loss of dopamin-producing neurons in the substantia nigra, a region in the midbrain, which is implicated in motor control. The typical clinical signs include resting tremor, muscle rigidity, slowness of movements, and impaired balance. In about 10% of cases Parkinson’s disease is caused by mutations in specific genes, one of them is called parkin.

“Parkinson-associated genes are particularly interesting for researchers, since insights into the function and dysfunction of these genes allow conclusions on the pathomechanisms underlying Parkinson’s disease”, says Dr. Konstanze Winklhofer of the Adolf Butenandt Institute at the LMU Munich, who is also affiliated with the German Center for Neurodegenerative Diseases (DZNE). Winklhofer and her colleagues had previously observed that parkin can protect neurons from cell death under various stress conditions. In the course of this project, it became obvious that a loss of parkin function impairs the activity and integrity of mitochondria, which serve as the cellular power stations. In their latest publication, Winklhofer and coworkers uncovered the molecular mechanism that accounts for parkin’s neuroprotective action.

“We discovered a novel signaling pathway that is responsible for the neuroprotective activity of parkin,” Winklhofer reports. The central player of this pathway is a protein called NEMO, which is activated by the enzymatic attachment of a linear chain of ubiquitin molecules. This reaction is promoted by parkin, thereby enabling NEMO to activate a signal cascade, which ultimately leads to the expression of a specific set of genes. Winklhofer’s team identified one essential gene targeted by this pathway, which turned out to code for the mitochondrial protein OPA1. OPA1 maintains the integrity of mitochondria and prevents stress-induced neuronal cell death.

“These findings suggest that strategies to activate this signal pathway or to enhance the synthesis of OPA1 in cells exposed to stress could be of therapeutic benefit,” Winklhofer points out.

The newly identified signal pathway may also be relevant in the context of other neurological conditions that are characterized by the loss of specific neurons. Konstanze Winklhofer and her group are already engaged in further projects designed to determine whether other molecules regulated by this pathway might provide targets for therapeutic interventions.

New therapy uses electricity to cancel out Parkinson tremors

A new therapy could help suppress tremors in people with Parkinson’s disease, an Oxford University study suggests.

The technique – called transcranial alternating current stimulation or TACS – cancels out the brain signal causing the tremors by applying a small, safe electric current across electrodes on the outside of a patient’s head.

The preliminary study, conducted with 15 people with Parkinson’s disease at Oxford’s John Radcliffe Hospital, is published in the journal Current Biology. The researchers showed a 50 per cent reduction in resting tremors among the patients.

Physical tremors are a significant and debilitating symptom of Parkinson’s disease, but do not respond well to existing drug treatments.

Tremors can be successfully treated with deep brain stimulation, a technique that involves surgery to insert electrodes deep into the brain itself to deliver electrical impulses. But this invasive therapy is expensive and carries some health risks, including bleeding in to the brain, which means it is not suitable for all patients.

In TACS in contrast, the electrode pads are placed on the outside of the patient’s head, so it does not carry the risks associated with deep brain stimulation.

Professor Peter Brown of the Nuffield Department of Clinical Neurosciences, who led the study, said: ‘Tremors experienced by Parkinson’s sufferers can be devastating and any therapy that can suppress or reduce those tremors significantly improves quality of life for patients.

'We are very hopeful this research may, in time, lead to a therapy that is both successful and carries reduced medical risks. We have proved the principle, now we have to optimise it and adapt it so it is able to be used in patients. Often that is the hardest part.'

Parkinson’s patients advised to seek Deep Brain Stimulation treatment in early stages

People with Parkinson’s disease who receive Deep Brain Stimulation (DBS) therapy in the early stages of the condition will benefit from a significant increase in quality of life, a revolutionary study from The New England Journal of Medicine has found.

World-leading neurologist and lead clinician Professor Peter Silburn from the Asia-Pacific Centre for Neuromodulation (APCN), a joint initiative of The University of Queensland (UQ) and St Andrew’s Hospital, said the results published today in the medical journal would transform the way we treat people with Parkinson’s disease.

“Before the release of this study, a typical patient with Parkinson’s disease would need to wait around 10 years or until their motor complications could no longer be treated successfully with medicine alone, before DBS surgery was considered an option,” Professor Silburn said.

“This study has confirmed the best medical practice for a person with Parkinson’s disease is to perform DBS surgery around 4 to 7 years into the condition, as opposed to waiting until the medications stop working.”

Blood-Based Biomarkers May Lead to Earlier Diagnosis of Parkinson’s Disease

Pilot Study Published in the Journal of Parkinson’s Disease

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"The ideal biomarker should be minimally-invasive, cost efficient, quantifiable, reproducible, specific, and sensitive," explains lead investigator Sok Kean Khoo, PhD, of the Center for Neurodegenerative Science and Genomic Microarray Core Facility at the Van Andel Institute, Grand Rapids, Michigan. "Biofluids such as plasma could provide an ideal resource for development of such desirable biomarkers. However, clinical diagnostic tests based on biochemical analysis of biofluids from PD patients have yet to be established," she continues.

Investigators hypothesized that specific miRNAs related to PD can be detected in plasma. It is known that miRNAs detected in various cells and tissues can also be found in biofluids such as blood plasma and serum. A preliminary study using miRNA microarrays showed that approximately 4% (35/866) of miRNAs from healthy brain tissues could also be detected in the plasma of healthy controls.

In an initial study they obtained the global miRNA expressions in plasma of an initial discovery set of 32 PD patients and 32 normal controls and identified nine pairs of PD-predictive classifiers and 13 most-differentially expressed miRNAs as potential biomarkers to discriminate PD patients from normal controls. They then used a quantitative real-time Polymerase Chain Reaction technique (qRT-PCR) to validate and evaluate the performance of these biomarkers in a new replication set of 42 PD patients and 30 controls from the same clinical site.

They then identified a combination of biomarkers that achieved the highest predictive performance and applied this panel of biomarkers to a new, independent validation set of samples from 30 PD patients from a different clinical site, which showed lower biomarker performance.

The investigators acknowledge that there are still challenges to be overcome in validating biomarker candidates due to clinical and sample variability and factors that influence miRNA expression such as comorbidities and other medication the patient is taking. However, explains Dr Khoo, “This is a proof-of-concept study to demonstrate the feasibility of using plasma-based circulating miRNAs, and the hypothesis that miRNA expression changes are associated with the neurodegenerative disease process, either directly or as part of positive feedback loops, is emerging rapidly. This study opens new opportunities to the exploration of circulating miRNAs for diagnostic, prognostic, and therapeutic interventions for PD and possibly other neurodegenerative diseases.”

"A diagnostic test to determine the status of a patient’s disease onset would provide crucial data for more timely, efficient, and successful therapeutic interventions," said Patrik Brundin, MD, PhD, Director of Van Andel Institute’s Center for Neurodegenerative Science. "There is an urgent need to develop objective, measureable biomarkers to improve PD diagnostics and help define its subtypes, and Dr. Khoo’s interesting study is an important step in that direction."

(Image: Wikipedia)

Parkinson’s Treatment Can Trigger Creativity

Parkinson’s experts across the world have been reporting a remarkable phenomenon — many patients treated with drugs to increase the activity of dopamine in the brain as a therapy for motor symptoms such as tremors and muscle rigidity are developing new creative talents, including painting, sculpting, writing, and more.

Prof. Rivka Inzelberg of Tel Aviv University’s Sackler Faculty of Medicinefirst noticed the trend in her own Sheba Medical Center clinic when the usual holiday presents from patients — typically chocolates or similar gifts — took a surprising turn. “Instead, patients starting bringing us art they had made themselves,” she says.

Inspired by the discovery, Prof. Inzelberg sought out evidence of this rise in creativity in current medical literature. Bringing together case studies from around the world, she examined the details of each patient to uncover a common underlying factor — all were being treated with either synthetic precursors of dopamine or dopamine receptor agonists, which increase the amount of dopamine activity in the brain by stimulating receptors. Her report published in the journal Behavioral Neuroscience.

Giving in to artistic impulse

Dopamine is involved in several neurological systems, explains Prof. Inzelberg. Its main purpose is to aid in the transmission of motor commands, which is why a lack of dopamine in Parkinson’s patients is associated with tremors and a difficulty in coordinating their movements.

But it’s also involved in the brain’s “reward system” — the satisfaction or happiness we experience from an accomplishment. This is the system which Prof. Inzelberg predicts is associated with increasing creativity. Dopamine and artistry have long been connected, she points out, citing the example of the Vincent Van Gogh, who suffered from psychosis. It’s possible that his creativity was the result of this psychosis, thought to be caused by a spontaneous spiking of dopamine levels in the brain.

There are seemingly no limits to the types of artistic work for which patients develop talents, observes Prof. Inzelberg. Cases include an architect who began to draw and paint human figures after treatment, and a patient who, after treatment, became a prize-winning poet though he had never been involved in the arts before.

It’s possible that these patients are expressing latent talents they never had the courage to demonstrate before, she suggests. Dopamine-inducing therapies are also connected to a loss of impulse control, and sometimes result in behaviors like excessive gambling or obsessional hobbies. An increase in artistic drive could be linked to this lowering of inhibitions, allowing patients to embrace their creativity. Some patients have even reported a connection between their artistic sensibilities and medication dose, noting that they feel they can create more freely when the dose is higher.

Therapeutic value

Prof. Inzelberg believes that such artistic expressions have promising therapeutic potential, both psychologically and physiologically. Her patients report being happier when they are busy with their art, and have noted that motor handicaps can lessen significantly. One such patient is usually wheelchair-bound or dependent on a walker, but creates intricate wooden sculptures that have been displayed in galleries. External stimuli can sometimes bypass motor issues and foster normal movement, she explains. Similar types of art therapy are already used for dementia and stroke patients to help mitigate the loss of verbal communication skills, for example.

The next step is to try to characterize those patients who become more creative through treatment through comparing them to patients who do not experience a growth in artistic output. “We want to screen patients under treatment for creativity and impulsivity to see if we can identify what is unique in those who do become more creative,” says Prof. Inzelberg. She also believes that such research could provide valuable insights into creativity in healthy populations, too.

Pesticides and Parkinson’s: UCLA researchers uncover further proof of a link

For several years, neurologists at UCLA have been building a case that a link exists between pesticides and Parkinson’s disease. To date, paraquat, maneb and ziram — common chemicals sprayed in California’s Central Valley and elsewhere — have been tied to increases in the disease, not only among farmworkers but in individuals who simply lived or worked near fields and likely inhaled drifting particles.

Now, UCLA researchers have discovered a link between Parkinson’s and another pesticide, benomyl, whose toxicological effects still linger some 10 years after the chemical was banned by the U.S. Environmental Protection Agency.

Even more significantly, the research suggests that the damaging series of events set in motion by benomyl may also occur in people with Parkinson’s disease who were never exposed to the pesticide, according to Jeff Bronstein, senior author of the study and a professor of neurology at UCLA, and his colleagues.

Benomyl exposure, they say, starts a cascade of cellular events that may lead to Parkinson’s. The pesticide prevents an enzyme called ALDH (aldehyde dehydrogenase) from keeping a lid on DOPAL, a toxin that naturally occurs in the brain. When left unchecked by ALDH, DOPAL accumulates, damages neurons and increases an individual’s risk of developing Parkinson’s.

The investigators believe their findings concerning benomyl may be generalized to all Parkinson’s patients. Developing new drugs to protect ALDH activity, they say, may eventually help slow the progression of the disease, whether or not an individual has been exposed to pesticides.

The research is published in the current online edition of Proceedings of the National Academy of Sciences.