Newswise BIRMINGHAM, Ala. For decades, patients with Parkinsons disease (PD) have had the same experience. Their hands start to shake uncontrollably, their limbs become rigid and they lose their balance. Years before those movement problems set in, many begin struggling with fainting, incontinence, sexual dysfunction, anxiety and depression. Many patients are still treated with a 42-year-old drug called L-DOPA, which temporarily staves off symptoms but can itself cause heart arrhythmias, stomach bleeding and hallucinations.

This punishing experience may explain in part why patients with PD die at twice the rate of those without the disease in the years after their diagnosis. In this light, its best to tread carefully when talking about early study results that promise something better. That said, a team of researchers at the University of Alabama at Birmingham is excited.

The UAB team has identified a set of experimental drugs called LRRK2 inhibitors that may go beyond symptom relief to directly counter the inflammation and nerve cell death at the root of Parkinsons. At least, these effects have been suggested in mouse and cell culture studies meant to approximate human disease. UAB researchers reported on these findings today in a presentation at Neuroscience 2012, the annual meeting of the Society for Neuroscience in New Orleans.

We dont yet know what percentage of patients might benefit from LRKK2 inhibitors, but LRRK2 is without a doubt the most exciting target for neuroprotection to have ever been identified in Parkinsons disease, says Andrew West, Ph.D., associate professor in the Department of Neurology within the UAB School of Medicine, who gave the presentation at Neuroscience 2012. We will repeat our experiments many times before drawing final conclusions, but our ultimate goal is see our compound or something like it enter toxicology studies, and ultimately, clinical trials as soon as is prudent.

While Wests compounds are promising, they still face many crucial tests that will decide whether or not they reach human trials. But the field is excited, because this is the first time such a drug target has been found for any neurodegenerative disease. Along with evidence that LRRK2 plays a crucial role in the mechanisms of Parkinsons disease, it is a protein kinase, the same kind of enzyme (although not the same one) that has been safely and potently targeted by existing treatments for other diseases, including the cancer drugs Herceptin, Tarceva and Erbitux.

Why LRRK2? LRRK2 stands for leucine-rich repeat kinase 2. Kinases are enzymes that attach molecules called phosphates to other molecules to start, stop or adjust cellular processes. Past studies found that the most common LRRK2 mutation, called G2019S, makes LRRK2 slightly over-active. The idea is to dial LRRK2 back with drugs.

Whether its a bad version of a gene, an unlucky flu infection, a head injury or just age, something makes a protein called alpha-synuclein build up in the nerve cells of Parkinsons patients, contributing to their self-destruction. Unfortunately, alpha-synuclein and proteins like it are not part of a traditional set of drug-able targets. Once alpha-synuclein builds up, the question becomes whether the brain will handle it well or amplify the disease.

LRRK2, to Wests mind, is a critical decision-maker in the bodys answer to that question. He thinks it operates at the intersection between alpha-synuclein, neurotransmission and immune responses, which fight infectious diseases but also create disease-related inflammation when unleashed at the wrong moment, or in the wrong place or amount. Not everyone who has a LRRK2 mutation develops the disease, but Wests team thinks it becomes important when combined with other factors.

Past studies have shown that alpha-synuclein build-up in nerve cells activates nearby immune cells of the brain called microglia, and that these microglia express high levels of LRRK2. Recent cell studies in Wests lab suggest that mutated, overactive LRRK2 strengthens inflammatory responses in microglia and that inhibiting LRRK2 reduces them. Preliminary data also suggests LRRK2-driven inflammation raises the rate of nerve cell death. Its worth noting, however, that neither these mechanisms nor their relationships with each other and Parkinsons disease have been fully confirmed.

The beauty is that we dont necessarily need to confirm an exact mechanism to move drugs into clinical trials, says West. One could argue that human PD is too complex to fully model in other animals. Many predict that we will not know if we understand Parkinsons disease until we get safe, potent, specific drugs into human studies and until one of them halts or reverses the disease process.

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UAB Team Sets Sights on Neuroprotective Treatment for Parkinson's Disease

Recommendation and review posted by Fredricko

Newswise BIRMINGHAM, Ala. For decades, patients with Parkinsons disease (PD) have had the same experience. Their hands start to shake uncontrollably, their limbs become rigid and they lose their balance. Years before those movement problems set in, many begin struggling with fainting, incontinence, sexual dysfunction, anxiety and depression. Many patients are still treated with a 42-year-old drug called L-DOPA, which temporarily staves off symptoms but can itself cause heart arrhythmias, stomach bleeding and hallucinations.

This punishing experience may explain in part why patients with PD die at twice the rate of those without the disease in the years after their diagnosis. In this light, its best to tread carefully when talking about early study results that promise something better. That said, a team of researchers at the University of Alabama at Birmingham is excited.

The UAB team has identified a set of experimental drugs called LRRK2 inhibitors that may go beyond symptom relief to directly counter the inflammation and nerve cell death at the root of Parkinsons. At least, these effects have been suggested in mouse and cell culture studies meant to approximate human disease. UAB researchers reported on these findings today in a presentation at Neuroscience 2012, the annual meeting of the Society for Neuroscience in New Orleans.

We dont yet know what percentage of patients might benefit from LRKK2 inhibitors, but LRRK2 is without a doubt the most exciting target for neuroprotection to have ever been identified in Parkinsons disease, says Andrew West, Ph.D., associate professor in the Department of Neurology within the UAB School of Medicine, who gave the presentation at Neuroscience 2012. We will repeat our experiments many times before drawing final conclusions, but our ultimate goal is see our compound or something like it enter toxicology studies, and ultimately, clinical trials as soon as is prudent.

While Wests compounds are promising, they still face many crucial tests that will decide whether or not they reach human trials. But the field is excited, because this is the first time such a drug target has been found for any neurodegenerative disease. Along with evidence that LRRK2 plays a crucial role in the mechanisms of Parkinsons disease, it is a protein kinase, the same kind of enzyme (although not the same one) that has been safely and potently targeted by existing treatments for other diseases, including the cancer drugs Herceptin, Tarceva and Erbitux.

Why LRRK2? LRRK2 stands for leucine-rich repeat kinase 2. Kinases are enzymes that attach molecules called phosphates to other molecules to start, stop or adjust cellular processes. Past studies found that the most common LRRK2 mutation, called G2019S, makes LRRK2 slightly over-active. The idea is to dial LRRK2 back with drugs.

Whether its a bad version of a gene, an unlucky flu infection, a head injury or just age, something makes a protein called alpha-synuclein build up in the nerve cells of Parkinsons patients, contributing to their self-destruction. Unfortunately, alpha-synuclein and proteins like it are not part of a traditional set of drug-able targets. Once alpha-synuclein builds up, the question becomes whether the brain will handle it well or amplify the disease.

LRRK2, to Wests mind, is a critical decision-maker in the bodys answer to that question. He thinks it operates at the intersection between alpha-synuclein, neurotransmission and immune responses, which fight infectious diseases but also create disease-related inflammation when unleashed at the wrong moment, or in the wrong place or amount. Not everyone who has a LRRK2 mutation develops the disease, but Wests team thinks it becomes important when combined with other factors.

Past studies have shown that alpha-synuclein build-up in nerve cells activates nearby immune cells of the brain called microglia, and that these microglia express high levels of LRRK2. Recent cell studies in Wests lab suggest that mutated, overactive LRRK2 strengthens inflammatory responses in microglia and that inhibiting LRRK2 reduces them. Preliminary data also suggests LRRK2-driven inflammation raises the rate of nerve cell death. Its worth noting, however, that neither these mechanisms nor their relationships with each other and Parkinsons disease have been fully confirmed.

The beauty is that we dont necessarily need to confirm an exact mechanism to move drugs into clinical trials, says West. One could argue that human PD is too complex to fully model in other animals. Many predict that we will not know if we understand Parkinsons disease until we get safe, potent, specific drugs into human studies and until one of them halts or reverses the disease process.

Read the original:
UAB Team Sets Sights on Neuroprotective Treatment for Parkinson's Disease

Recommendation and review posted by Fredricko

Published: Wednesday, October 17, 2012 at 5:40 p.m. Last Modified: Wednesday, October 17, 2012 at 5:40 p.m.

A decade ago, deep-brain stimulation for Parkinsons disease was considered a risky procedure. Today, its on the cutting edge of personalized medicine, and researchers at the University of Floridas McKnight Brain Institute are at the forefront of its evolution.

When we started in 2002, there were only a handful of places in the U.S. that did it. There was a lot of skepticism about the operation from internists and neurologists, said Dr. Michael Okun, a neurologist at UF. Now it has gone from crazy to cool to completely accepted.

Okun published an article today in the New England Journal of Medicine that explains how the procedure is helping with Parkinsons disease and other neurological conditions such as obsessive compulsive disorder, Tourettes syndrome and depression.

Okun and Dr. Kelly Foote, a neurosurgeon at UF, have performed more than 800 procedures in the past decade, mostly in Parkinsons patients whose medications have become less effective, leading to complications such as on-off fluctuations.

During the off periods, the medication stops working and patients symptoms such as tremors or immobility worsen. This happens in most patients after about five years, said Okun, and patients with off periods of more than three hours a day are good candidates for deep-brain stimulation.

During the procedure, doctors first identify the part of the brain to target. For most patients, that will be either the subthalamic nucleus or the globus pallidus, two tiny sites involved in controlling movement.

Doctors then drill a dime-sized hole in the skull so they can place a lead that delivers electric current to the troublesome spot responsible for the degeneration caused by the disease.

You want to make sure that you take your time and get it right. Those leads have to be within a half-millimeter to work their magic, Okun said.

Deciding where to place the lead also depends on the patient. If you see a patient and tremors are important maybe they are a dentist or a chef, they might choose one target in the brain. If its a singer or trial litigator, they may target another part of the brain.

Continued here:
UF: Deep-brain stimulation helping with OCD, Tourette's, along with Parkinson's

Recommendation and review posted by Fredricko

Published: Wednesday, October 17, 2012 at 5:40 p.m. Last Modified: Wednesday, October 17, 2012 at 5:40 p.m.

A decade ago, deep-brain stimulation for Parkinsons disease was considered a risky procedure. Today, its on the cutting edge of personalized medicine, and researchers at the University of Floridas McKnight Brain Institute are at the forefront of its evolution.

When we started in 2002, there were only a handful of places in the U.S. that did it. There was a lot of skepticism about the operation from internists and neurologists, said Dr. Michael Okun, a neurologist at UF. Now it has gone from crazy to cool to completely accepted.

Okun published an article today in the New England Journal of Medicine that explains how the procedure is helping with Parkinsons disease and other neurological conditions such as obsessive compulsive disorder, Tourettes syndrome and depression.

Okun and Dr. Kelly Foote, a neurosurgeon at UF, have performed more than 800 procedures in the past decade, mostly in Parkinsons patients whose medications have become less effective, leading to complications such as on-off fluctuations.

During the off periods, the medication stops working and patients symptoms such as tremors or immobility worsen. This happens in most patients after about five years, said Okun, and patients with off periods of more than three hours a day are good candidates for deep-brain stimulation.

During the procedure, doctors first identify the part of the brain to target. For most patients, that will be either the subthalamic nucleus or the globus pallidus, two tiny sites involved in controlling movement.

Doctors then drill a dime-sized hole in the skull so they can place a lead that delivers electric current to the troublesome spot responsible for the degeneration caused by the disease.

You want to make sure that you take your time and get it right. Those leads have to be within a half-millimeter to work their magic, Okun said.

Deciding where to place the lead also depends on the patient. If you see a patient and tremors are important maybe they are a dentist or a chef, they might choose one target in the brain. If its a singer or trial litigator, they may target another part of the brain.

Continued here:
UF: Deep-brain stimulation helping with OCD, Tourette's, along with Parkinson's

Recommendation and review posted by Fredricko

Public release date: 17-Oct-2012 [ | E-mail | Share ]

Contact: Jessica Mikulski jessica.mikulski@uphs.upenn.edu 215-349-8369 University of Pennsylvania School of Medicine

PHILADELPHIA - Changes in the ability to smell and taste can be caused by a simple cold or upper respiratory tract infection, but they may also be among the first signs of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Now, new research from the Perelman School of Medicine at the University of Pennsylvania has revealed an association between an impaired sense of smell and myasthenia gravis (MG), a chronic autoimmune neuromuscular disease characterized by fluctuating fatigue and muscle weakness. The findings are published in the latest edition of PLOS ONE.

"This study demonstrates, for the first time, that myasthenia gravis is associated with profound dysfunction of the olfactory system dysfunction equivalent to that observed in Alzheimer's disease and Parkinson's disease," said senior study author Richard Doty, PhD, director of the Smell and Taste Center at Penn. "The results are the strongest evidence to date that myasthenia gravis, once thought of as solely a disorder of the peripheral nervous system, involves the brain as well."

The general notion that MG is strictly a peripheral nervous system disease stems, in part, from early observations that the disorder is not accompanied by obvious brain pathology. Behavioral and physiological evidence that has been presented in support of MG's involvement in the central nervous system (CNS) has frequently been discounted due to lack of replicability of findings. For example, while some studies have found MG-related deficits in verbal memory, relative to controls, others have not. Nevertheless, scientists have continued to report CNS-related dysfunctions in MG, including visual and auditory deficiencies in this disease. Further, EEG tests have shown abnormalities in MG patients and MG-related antibodies have been detected in cerebrospinal fluid of patients.

In order to further explore the role of the central nervous system in MG, Doty and colleagues employed a smell test that has been used to assess the underlying connection between sense of smell and other neurodegenerative diseases.

"Our sense of smell is directly linked to numerous functions of the brain," says Doty, one of the original researchers who made the connection between loss of smell and Parkinson's disease. "Olfaction is a good model system for other, more complicated, brain circuits. Understanding our sense of smell, or lack thereof, offers broader insights into brain functions and diseases stemming from the brain."

In the current study, 27 MG patients were individually matched for age and sex to 27 normal controls. Eleven patients with polymyositis, a disorder with debilitating muscle symptoms similar to those of MG, also were tested. All participants were administered the University of Pennsylvania Smell Identification Test (UPSIT) and the Picture Identification Test (PIT), a picture test that is equivalent in content and form to the UPSIT designed to control for non-olfactory cognitive deficits. The research team also monitored each patient during the UPSIT and found no impaired ability to inhale, ruling out physical impediments to sniffing the odors.

Researchers found that the UPSIT scores of the MG patients were significantly lower than those of the age- and sex-matched normal controls, as well as the patients with polymyositis. Of the MG patients, only 15 percent were even aware of a smell problem before testing.

"The marked difference in smell dysfunction between the MG patients and the controls cannot be explained by any other physical or cognitive differences," says Doty. "Although we are still exploring the physiological basis of this dysfunction in MG, it's important to note that the extent of the diminished ability to identify odors found in this study is of the same magnitude as that observed in a range of CNS-related diseases, including Alzheimer's and Parkinson's."

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Association between rare neuromuscular disorder and loss of smell, Penn Study finds

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