Mike’s Walk for Parkinson’s Disease

January 3, 2010 by mike.

On April 24, 2010, Mike Justak will join the thousands gathering in New York City’s Central Park and walk in support of those with Parkinson’s disease. The New York walk is the largest of its kind. Details on Mike’s effort can be found at:

MikesWalkforPD.com

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Progression Of Parkinson’s Disease May Be Prevented By Widely Used Cholesterol-Lowering Drug

November 13, 2009 by mike.

Simvastatin, a commonly used, cholesterol-lowering drug, may prevent Parkinson’s disease from progressing further. Neurological researchers at Rush University Medical Center conducted a study examining the use of the FDA-approved medication in mice with Parkinson’s disease and found that the drug successfully reverses the biochemical, cellular and anatomical changes caused by the disease.

“Statins are one of the most widely used cholesterol-lowering drugs throughout the world,” said study author Kalipada Pahan, PhD, professor of neurological sciences at Rush University Medical Center. “This may be a safer approach to halt the disease progression in Parkinson’s patients.”

Pahan and colleagues from Rush, along with researchers at the University of Nebraska Medical Center in Omaha published these findings in the October 28 issue of the Journal of Neurosciences.

The authors have shown that the activity of one protein called p21Ras is increased very early in the midbrain of mice with Parkinson’s pathology. Simvastatin enters into the brain and blocks the activity of the p21Ras protein and other associated toxic molecules, and goes on to protect the neurons, normalize neurotransmitter levels, and improves the motor functions in the mice with Parkinson’s.

“Understanding how the disease works is important to developing effective drugs that protect the brain and stop the progression of Parkinson’s,” said Pahan. “If we are able to replicate these results in Parkinson’s patients in the clinical setting, it would be a remarkable advance in the treatment of this devastating neurodegenerative disease.”

The study was supported by grants from National Institutes of Health and Michael J. Fox Foundation for Parkinson’s Research.

Parkinson’s is a slowly progressive disease that affects a small area of cells within the mid-brain known as the substantia nigra. Gradual degeneration of these cells causes a reduction in dopamine, which is a vital chemical neurotransmitter. The decrease in dopamine results in one or more of the classic signs of Parkinson’s disease that includes, resting tremor on one side of the body, generalized slowness of movement, stiffness of limbs, and gait or balance problems. The cause of Parkinson’s disease is unknown. Both environmental and genetic causes of the disease have been postulated.

Parkinson’s disease affects about 1.2 million patients in the United States and Canada. Although 15 percent of patients are diagnosed before age 50, it is generally considered a disease that targets older adults, affecting one of every 100 persons over the age of 60. This disease appears to be slightly more common in men than women.

Source: Deborah Song
Rush University Medical Center

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Hope For Possible Parkinson’s Disease Cure From ISU Researchers’ Findings

November 13, 2009 by mike.

Researchers at Iowa State University have found an essential key to possibly cure Parkinson’s disease and are looking for others.

Anumantha Kanthasamy, a distinguished professor of biomedical sciences and W. Eugene and Linda R. Lloyd Endowed Chair in Neurotoxicology at the ISU College of Veterinary Medicine, has been working to understand the complex mechanisms of the disease for more than a decade and thinks he has found hope for the cure.

Parkinson’s disease sufferers lack a sufficient amount of a brain chemical called dopamine.

Kanthasamy’s research shows that there is specific protein that is naturally present in human brains that — for no known reason — kills the brain cells that make dopamine.

The cells that are being killed are the ones that produce the needed dopamine.

“We have millions of cells in our brains,” said Kanthasamy, “In Parkinson’s, about 10,000 of these brain cells die; no one knows why.”

Kanthasamy discovered that a novel protein — known as protein kinase-C (specifically PKCδ) - is killing the dopamine-producing cells.

Kanthasamy and his research staff discovered a compound that neutralizes the cell-killing kinase-C and allows the dopamine-producing cells to survive and function.

“With a lot of hard work, and little bit of luck, we found something important,” he said. “And when you find something like this you say, ‘This is great because it can be a target for developing new drugs.’”

Now, Kanthasamy’s group is looking for additional compounds that also can serve to neutralize protein kinase-C. By identifying more compounds that perform the function of neutralizing kinase-C, researchers are more likely to locate one that works well and has few side effects.

This discovery is expected to provide new treatment options to stop the progression of the disease or even cure it.

The study is being funded by a Grow Iowa Values Fund grant. The goal of the grant program is to support development of technologies with commercial potential and to support the growth of companies using those technologies. Kanthasamy is working on this research with PK Biosciences Corp., an Iowa-based startup company. Funding was also provided by the National Institutes of Health.

“Once we find the compound, we need to make sure it’s safe. If everything goes well, it could take about 10 years, and then we might be able to see something that will truly make a difference in the lives of people with this disorder,” said Kanthasamy.

Parkinson’s disease strikes around 50,000 people each year, and there are approximately 1 million people with the disease. Parkinson’s sufferers include actor Michael J. Fox and former boxing champion Muhammad Ali.

As people grow older, the cells that produce dopamine naturally die, causing dopamine levels to fall gradually over time. When the levels continue to drop below 60 to 70 percent, the person will start to have Parkinson’s disease symptoms, according to Kanthasamy.

“Everybody has a little Parkinson’s in theory,” he said. “But you can’t see it until the level of dopamine gets too low.”

Eliminating the symptoms of Parkinson’s disease doesn’t require people to be restored to 100 percent of previous dopamine levels, but only to a fraction of that.

“If you can bring dopamine up to the 40-50 percent level, you’ll see a functioning, normal person,” he said.

Currently, there is no cure for Parkinson’s and available therapies only treat the symptoms.

Major contributing factors for getting Parkinson’s disease include prolonged exposure to metals or pesticides and other environmental chemicals, according to Kanthasamy.

Symptoms of Parkinson’s disease include trembling in hands, arms, legs, jaw, and face; rigidity or stiffness of the limbs and trunk; slowness of movement; and impaired balance and coordination. As these symptoms become more pronounced, patients may have difficulty walking, talking, or completing other simple tasks. Because the disease typically affects people over the age of 50, the National Institutes of Health anticipates the incidence of Parkinson’s will increase as the nation’s population ages.

Source: Anumantha Kanthasamy
Iowa State University

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Rasagiline Said to Delay Parkinson Progression

September 25, 2009 by mike.

By John Gever, Senior Editor, MedPage Today

Final results from a closely watched trial of rasagiline (Azilect) in Parkinson’s disease suggested the drug slowed the illness’s progression, study leaders said, but outside experts voice doubts.

Patients receiving 1 mg/day of rasagiline for 72 weeks showed a mean 2.82-point worsening of symptoms compared with a 4.52-point change among patients in a “delayed start” group who received placebo for 36 weeks followed by rasagiline for 36 weeks (P=0.02), according to a report in the Sept. 24 issue of the New England Journal of Medicine.

The difference is an indication that rasagiline did not merely alleviate Parkinson symptoms, but actually slowed the loss of neuronal function that causes the disease, wrote C. Warren Olanow, MD, of Mt. Sinai School of Medicine in New York City, and colleagues.

In a press release issued by Mt. Sinai, Olanow said the findings, if confirmed, would be “one of the biggest advances made in Parkinson’s in six years.”Action Points
Explain to interested patients that there is currently no treatment known to delay progression of the underlying pathology of Parkinson’s disease, although several therapies are available to relieve symptoms.

Explain that rasagiline is FDA-approved for symptomatic treatment of Parkinson’s disease. However, the findings of this study that it may modify the underlying pathology need confirmation in additional studies.

Explain, too, that the potential disease-modifying effect was measured indirectly and was not apparent with a higher drug dose.
The study, called ADAGIO, had strength of numbers — 1,176 patients with untreated, early-stage Parkinson’s disease. The delayed-start trial design is an attempt to detect a disease-modifying effect for a condition that doesn’t lend itself to direct measures — which in this case would likely require brain biopsies.

Because this approach is relatively new, the NEJM included a primer on the delayed-start design by Ralph B. D’Agostino Sr., PhD, a statistician at Boston University.

He wrote that Olanow and colleagues achieved “some success” with ADAGIO.

But the investigators themselves cautioned that the results were somewhat ambiguous, as no disease-modifying effect was seen with a higher rasagiline dose. Patients taking 2 mg/day in the early- and delayed-start groups had nearly identical changes on the Unified Parkinson’s Disease Rating Scale (UPDRS) scores — 3.47 points with the early start versus 3.11 points with the delayed start (P=0.60).

“Given the negative findings for the 2-mg dose, we cannot definitively conclude that rasagiline at a dose of 1 mg per day has disease-modifying effects,” Olanow and colleagues conceded.

Some of the data had been presented earlier at scientific meetings, priming the Parkinson’s disease research community for responses — much of which was critical.

Peter LeWitt, MD, a neurologist at Henry Ford Hospital in Detroit, questioned whether the disase-modifying effect seen in the trial was clinically significant, even if it was real.

On the basis of early presentations of the trial data, LeWitt wrote in Neurology in April that the reported effect barely made a dent in the expected disease progression.

“The small clinical improvements . . . need to be contrasted with the typical rate of progression in early Parkinson’s disease, whose annual mean change ranges from 6.31 to 10.46 UPDRS units,” LeWitt wrote.

Other experts contacted by MedPage Today and ABC News generally agreed.

“I would be reluctant to accept the conclusion that this provides compelling evidence of slowed Parkinson’s disease progression,” said J. Eric Ahlskog, MD, PhD, of the Mayo Clinic in Rochester, Minn.

Even one investigator in the trial cast doubt on the study’s importance.

William Weiner, MD, chairman of neurology at the University of Maryland, said he disagreed with the NEJM report’s emphasis on the possible disease-modifying effect.

“I was never given the opportunity to review the article and I would not have agreed to stressing the neuroprotection angle so strongly,” he wrote in an e-mail.

He said the primary outcome ended up as less than two points’ difference on the 176-point UPDRS scale. “[It is] maybe statistically significant, but it is surely not clinically meaningful,” Weiner said.

Joanne Wojcieszek, MD, of Indiana University in Indianapolis, noted that rasagiline — a monoamine oxidase B inhibitor — involves dietary precautions and a long list of other medications to avoid. “It takes a lot of time to explain this med to patients,” she said.

She also said the drug is expensive. The online pharmacy Drugs.com lists a price of $311 for a month’s supply of the 1-mg dose.

In the ADAGIO trial, patients with at least two of the three major symptoms of Parkinson’s disease — resting tremor, bradykinesia, and rigidity — not previously receiving chronic treatments were eligible to participate.

Participants were rated on the UPDRS at baseline and 10 subsequent visits during the 72-week trial.

Three primary endpoints were evaluated: average weekly change in UPDRS score over weeks 12 to 36, showing slower change in the early-start group versus placebo; less change in the early-start group in total UPDRS change from baseline to week 72, which would reflect a disease-modifying effect; and noninferiority of the early-started treatment to delayed start in the rate of change in UPDRS scores over weeks 48 to 72, when all patients were taking rasagiline.

The researchers said the 1-mg dose met all three endpoints, but the 2-mg dose met only the first and third.

Olanow and colleagues offered a possible explanation for the lack of disease-modifying effect with the 2-mg dose. They suggested it may have been so effective at reducing Parkinson symptoms in both treatment groups that the slowed progression in the underlying pathology was masked.

They said the results with the 1-mg dose “cannot be readily explained by an effect on symptoms alone, since both groups received the same treatment for the last nine months of the study.”

The possibility of a disease-modifying effect was supported by laboratory studies showing that rasagiline and its primary metabolite protect neurons from various toxins.

The researchers said they had avoided at least some of the pitfalls involved with delayed-start trials identified by D’Agostino:

Dropout rates remained low during the placebo phase, reducing the bias that dropouts introduce.
Randomization should have minimized problems associated with misdiagnosis of early-stage patients.
Although average weekly change in UPDRS score is not a standard measure of disease progression, the findings were confirmed with categorical analyses.
The finding of an apparent disease-modifying effect with the 1-mg dose provided assurance that the placebo phase was not too short.
Despite the skepticism voiced by others, one prominent neurologist told MedPage Today and ABC News that the ADAGIO results were persuasive and immediately practice-changing.

“I do believe that this constitutes a major advance in Parkinson’s,” wrote Daniel Kremens, MD, of Thomas Jefferson University in Philadelphia, in an e-mail. “From this study alone and the use of this drug, the paradigm of Parkinson’s treatment really should shift.”

He said it was no longer appropriate to initiate drug treatment only after symptoms become disabling.

“We should no longer be waiting. We should consider starting [patients] on treatment as soon as diagnosis is made with hope that we can modify the disease course. And that’s a major change in how Parkinson’s is treated currently,” Kremens wrote.

Teva supported the ADAGIO study.

Olanow and colleagues reported relationships with Teva, Lundbeck, Boehringer Ingelheim, Novartis/Orion, Solvay, Ceregene, Merck Serono, Ceregene, Eisai, Eutherapie, GlaxoSmithKline, Osmotica, Schering-Plough, Pierre Fabre, Allergan Neuroscience, Alphamedica, ApotheCom, Axis Healthcare, Bayer Schering, CNS Schering-Plough, Centopharm, Embryon, Genzyme, Impax, Ipsen, Kyowa, Merck, Ortho-McNeil, Pfizer, Prestwick, Quintiles, Santhera, Schwarz Pharma, Valeant Pharm, Vernalis, Acadia, SkyePharma, UCB Pharma, INC Research, Mentor, Asubio, i3 Research, Chelsea Therapeutics, Advanced Neuromodulation Systems, Medtronic Neurological, Neurogen, and Orion.

D’Agostino reported being a special employee of the FDA, but had no relationships with industry.

Lewitt reported relationships with Allergan, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, Schwarz Pharma (now UCB), Solstice, Vernalis, Asubio, Brittania, Eisai, Impax, Kyowa, Neurim, Neuroderm, Neurologix, Orion, Prestwick, Spherics, XenoPort, Merck & Co., Santhera, Schering-Plough, Supernus, Valeant, and Chelsea Therapeutics.

Wojcieszek reported a relationship with Teva.

Ahlskog reported no potential conflicts.

Weiner reported relationships with Teva, Boehringer Ingelheim, Santhera, Biogen Idec, and Novartis.

Kremens reported a relationship with Teva.

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OLFACTORY DYSFUNCTION —AN EARLY DIAGNOSTIC FOR PARKINSON’S DISEASE

August 8, 2009 by mike.

SAN DIEGO—A simple smell test may soon be used to aid the diagnosis of Parkinson’s disease and to identify relatives and others at risk for the disease. Research on the use of smell tests in Parkinson’s disease was presented at the 58th Annual Meeting of the American Academy of Neurology.

Since at least 1955, hyposmia has been known to occur in patients with Parkinson’s disease, according to Nicolaas Bohnen, MD, Associate Professor of Radiology and Neurology at the University of Michigan in Ann Arbor. But interest in the phenomenon has grown markedly in the past few years, driven by the hope of developing neuroprotective treatment for patients in the early stage of the disorder. “The idea is to have biomarkers for early diagnosis,” said Dr. Bohnen, “and this interest is related to neuroprotective treatment.” While no definitive neuroprotective treatment has emerged, recent studies of coenzyme Q10 and rasagiline have hinted that such a therapy might be possible.

PASSING THE SMELL TEST

Dr. Bohnen’s team sought to determine whether a selective pattern of smell deficit might exist in patients with Parkinson’s disease. They used the University of Pennsylvania Smell Identification Test (UPSIT), a self-administered battery of 40 scratch-and-sniff odors ranging from turpentine to roses to pizza. The researchers compared smell ability in 26 Parkinson’s disease patients and 26 controls matched for age, sex, and smoking history.
The investigators found that patients with Parkinson’s disease did worse compared with controls on identifying eight odors (listed here in order of decreasing odor identification): licorice, coconut, banana, dill pickle, paint thinner, turpentine, cherry, and soap. Patients were better able to distinguish only one smell: lemon.

The existence of a selective deficit corroborates well with findings from a similar study in the United Kingdom, although there were some differences. In particular, British patients especially had trouble identifying wintergreen, while the American patients in Dr. Bohnen’s study had fewer difficulties in identifying this odor. “The cultural affinity for specific smells may differ between groups, as people are more exposed in daily life to specific smells,” he said. Difficulty recognizing banana was common to both groups.

“I’m unaware of any good explanation for why there is this specific deficit in Parkinson’s disease,” said Dr. Bohnen. While the disease is characterized by well-described pathology in the olfactory nucleus, “smell recognition is also a cognitive function. It’s relatively complex.”
Whatever the underlying physiology, the selective pattern may provide a reliable and easily administered biomarker for earlier diagnosis, assuming further studies confirm these results. “If a physician has a clinical suspicion, selective hyposmia could be used to help make the diagnosis,” Dr. Bohnen said. He also noted that smell testing may be more reliable than motor testing, especially for patients in the earliest stages or for those with comorbid conditions that also affect movement, such as arthritis. Early results from an ongoing study conducted by his group suggest that in first-degree relatives of patients with Parkinson’s disease, a combination of smell and cognitive testing is better at predicting a dopamine deficit than are motor tests.

CAFFEINE AND HYPOSMIA

Hyposmia in first-degree relatives of Parkinson’s disease patients also correlates with low caffeine intake, according to a third study. High caffeine consumption previously has been shown to be associated with a lower risk of Parkinson’s disease. In this study of 159 relatives of patients with Parkinson’s disease, Matthew Stern, MD, and colleagues from Pennsylvania Hospital in Philadelphia found that lifetime caffeine intake was negatively correlated with UPSIT score. Twenty-five percent of those consuming one cup or less per day of a caffeinated beverage over their lifetime were at or below the 10th percentile in UPSIT performance, compared with only 8% of those consuming more than one cup per day. “The effect may be the result of poor olfactory performance in individuals who will go on to develop Parkinson’s disease,” the researchers concluded, although they noted an alternative explanation is that hyposmia is “an intermediate phenotype” for the disease, due to the sharing of epidemiologic associations and risk factors with those for clinical Parkinson’s disease.
NR

—Richard Robinson

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