Sunday, June 14, 2009

ESSENTIAL TREMOR VS. PARKINSON'S DISEASE

Essential tremor is a progressive neurological disorder where the arms, hands head and neck shake during voluntary movements such as eating and writing. Some patients may have unsteadiness and problems with gait and balance that are above and beyond the signs of normal aging. Other diseases or conditions don't cause essential tremor, although it's sometimes confused with Parkinson's disease. It can happen at any age, but it's most common in older adults. According to the National Institutes of Health, essential tremor may affect as many as 14 percent of people over the age of 65. Essential tremor is ten to twenty times more prevalent than Parkinson's disease and is the most common of the movement disorders, affecting more than 10 million Americans.

Many people associate tremors with Parkinson's disease, but the two conditions are very different.
• Essential tremor typically occurs when hands are in use. Tremors from Parkinson's are most prominent when a person's hands are at their side or resting in their lap.
• Essential tremor doesn't cause other health problems. Parkinson's is associated with a stooped posture, slow movement and shuffling gait.
• Essential tremor can involve your hands, head and voice. Tremors from Parkinson's typically affect your hands, but not the head and voice.

DEEP BRAIN STIMULATION: For almost 50 percent of people with essential tremor, medication doesn't work or it carries debilitating side effects. That's when many consider surgery. During deep brain stimulation surgery, the patient is awake. A neurosurgeon implants an electrode into the thalamus portion of the brain. That electrode is connected to an implanted neurostimulator placed near the collarbone. During the surgery, patients are asked to perform tasks that have been difficult or impossible prior to surgery, like holding a mug and touching the point of their finger to something. As surgeons adjust the setting, they often see immediate improvement and the shaking stops. The signal emitted from the stimulator interrupts the signal in the brain that tells the body to move uncontrollably. Patients routinely go back to the doctor to have their stimulators fine-tuned. Patients also take home a remote control that can switch the device on or off. When it's in the off mode, tremors come back immediately.

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Australian researchers develop Parkinson's wristwatch monitor

Scientists at the Melbourne-based Florey Neuroscience Institute, Australia's largest brain research institute, have developed a wristwatch device that continuously monitors the health status of Parkinson's disease sufferers.

The Victorian State Minister for Innovation, Gavin Jennings, introduced the prototype wristwatch at the recent BIO2009 in Atlanta.

The new monitoring device will assist doctors treating Parkinson's patients by recording their symptoms throughout the day, and in the longer term will assist researchers in developing new drugs for the disease.

"The right dosage and correct timing of dosing has an enormous impact on the wellbeing of a person with Parkinson's disease," said Mr Jennings. "Currently, neurologists can only check dosage and timing by observing the patient during consultations, which may be at six to eight week intervals."

Parkinson's disease is a degenerative disorder of the brain that often affects speech and the body's movements. Some 80,000 people have this disease in Australia, with one in five diagnosed before the age of 50. In the US, Parkinson's is the most common neurodegenerative movement disorder, affecting around two per cent of the population.

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Saturday, June 13, 2009

Deep brain stimulation: Expanding its reach to new patients

Under the skin, a battery is surgically implanted -- generally within the upper chest. From the battery, wires snake up to the head, to tickle different targets deep inside the brain.

Such is the hardware for deep brain stimulation -- the equivalent of a cardiac pacemaker for the mind.

Until recently, deep brain stimulation was approved in the U.S. only to treat certain movement disorders, primarily those of Parkinson's disease, for which it diminishes tremors and rigidity and improves mobility. To date, more than 60,000 patients worldwide have had the devices implanted.

But now use of the technique seems set to mushroom.

This year, the Food and Drug Administration granted a so-called humanitarian device exemption for the treatment to be used in severe cases of obsessive-compulsive disorder -- the first approval of deep brain stimulation therapy for any psychiatric condition.

Large clinical trials are also in the works for use of deep brain stimulation for epilepsy and depression, and experimental studies in the U.S. and elsewhere -- still in their early stages -- are exploring the treatment for obesity, traumatic brain injury, severe chronic pain, Alzheimer's disease, anorexia, tinnitus and addiction.

There are discussions too on the possible use of deep brain stimulation to treat hypertension.

"The field is taking off," says Dr. Ali Rezai, director of functional neurosurgery at the Cleveland Clinic, who has been involved in research on movement disorders, traumatic brain injury, obsessive-compulsive disorder and severe depression, among others.

Some researchers warn, however, that with all this activity -- pushed in part by the industry that makes the brain-stimulation devices -- the field may be moving too fast.

"There is so much progress that's been made and so much potential -- you would hate to lose that potential," says Dr. Joseph Fins, chief of the division of medical ethics and a professor at Weill Cornell Medical College in New York.

Here's a look at deep brain stimulation as it moves beyond Parkinson's disease. (See the related story about reservations scientists have about the growth of the field, and go online at latimes.com/health for a look at less-explored applications such as traumatic brain injury and obesity.)

Obsessive- compulsive disorder

In studies with a total of 26 patients with severe obsessive-compulsive disorder, 60% of those whose device was turned on demonstrated "very much improved" symptoms after months of deep brain stimulation as measured by interviews and questionnaires, says Dr. Benjamin Greenberg, an associate professor at Brown University Medical School and Butler Hospital in Providence, R.I., who was one of the study researchers.

The patients had previously failed on medicines as well as behavioral cognitive therapy.

Yet the data, published last year in Molecular Psychiatry, can't really nail the effect of the treatment, Greenberg says, because the patients for the most part knew whether their devices were turned on or off. Thus, researchers can't rule out that some of the observed improvements were due to a placebo effect.

Patients were stimulated in an area called ventral capsule/ventral striatum, chosen, in part, because removal of nerve fibers in that area is known to cause improvement in obsessive-compulsive symptoms.

Based largely on these findings, the FDA recently granted a limited humanitarian device exemption that permits the device to be used in as many as 4,000 of the country's most severe cases of obsessive compulsive disorder per year.

To get this kind of exemption, Medtronic -- makers of the only deep brain stimulation device that is FDA-approved -- needed only to show its safety and probable benefit.

Greenberg is now doing a randomized, double-blinded trial with 30 patients, some of whom have devices turned on right away and some who have them turned on after a delay. No one will know whose device is turned on for the first several months of the trial.

Epilepsy

Medtronic has conducted a large-scale randomized trial for deep brain stimulation on epilepsy. Data will be submitted to the FDA this year, says Paul Stypulkowski, senior director of therapy research of Medtronic.

The device was turned on, for three months, in half of the 110 volunteers, stimulating -- and thereby, paradoxically, inhibiting-- an area called the anterior nucleus of the thalamus. That area is believed to influence a circuit involved in seizures.

The data, presented in December at a meeting in Seattle, show that deep brain stimulation reduced the number of seizures by 38% compared with what was seen before implanting the device.

That is slightly better than improvement seen with vagus nerve stimulation, another FDA-approved electrical stimulation treatment, which reduces seizures by about 25%.

The control group whose device was kept turned off, also improved, by 14.5%. That could be due to a placebo effect. Or it might be because people who join trials are usually at their worst -- and often tend to improve somewhat on their own, says trial researcher Dr. Douglas Labar, of the Weill Cornell Medical College in New York.

If deep brain stimulation is approved, Labar says, patients will have the choice between a more efficient but also more risky treatment and the slightly less efficient but also less risky vagus nerve stimulation.

Depression

Medtronic and a second company, St. Paul, Minn.-based St. Jude Medical, have two large-scale randomized trials underway for severe, treatment-resistant depression. (St. Jude Medical recently received approval to sell its device for the treatment of Parkinson's disease in Europe and is now completing studies aimed at securing FDA approval for treating Parkinson's and another movement disorder in the U.S.)

Medtronic's depression trial will follow about 200 patients stimulated in an area called the anterior limb of the internal capsule for at least one year.

This brain target for depression was identified by accident: When obsessive-compulsive disorder patients who also had depression were stimulated in this area, their depression also improved.

In one case, a patient produced a one-sided smile when stimulated on one side of the brain and also expressed feelings of happiness, says study researcher Dr. Wayne Goodman of the National Institute of Mental Health.

In a recently published unblinded study, about half of 15 patients showed at least a 50% improvement in severe depression symptoms a year or more after surgery when the anterior limb of the internal capsule was stimulated, says Rezai, who was involved in the study.

St. Jude Medical chose a different brain target, area 25, for its depression trial, which will enroll more than 100 patients. Brain imaging studies have shown that area 25 is more active in depressed people.

In a study of 20 patients, 55% still responded to treatment as late as one year after surgery, says study author Dr. Helen Mayberg, professor of psychiatry and neurology at Emory University. That is an "unheard-of response rate" given that these patients had tried and failed every other treatment, including several medications and electroconvulsive therapy, Mayberg says.

By comparison, Mayberg says, stimulation of the vagus nerve in the neck, approved by the FDA for depression, has only a 15% response rate at 10 weeks in similarly severely depressed patients.

Dr. Thomas Schlaepfer, vice chairman of the department of psychiatry of the University of Bonn in Germany, has been treating severely depressed patients by stimulating yet a third brain target, the nucleus accumbens.

The nucleus accumbens doesn't show normal activity in depressed patients, which could explain why they are less able to experience pleasure.

Last year, Schlaepfer showed that deep brain stimulation in this area led to acute improvements in three severely depressed patients. He says he has extended the work to 10 patients, half of whom showed an improvement when examined a year later.

With deep brain stimulation now being tried in at least three brain areas for depression, the question is, which target is the best? All agree that it's too early to tell.

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New Parkinson's drug found

New nuclear-based research from Australian Nuclear Science and Technology Organisation (ANSTO) has focused on a protein called Alpha-Synuclein, which plays a role in the development of Parkinson’s disease when it behaves abnormally. This behavior can be stopped or even reversed using a man-made polymer called a dendrimer, also known as a ‘dense star’ polymer.

This fundamental research adds another piece in the puzzle to develop better treatments for Parkinson’s disease, which affects around one in 250 Australians.

ANSTO Researcher, Dr Agata Rekas, said that past research had shown the dendrimer – called a PAMAM dendrimer and made by Dendirtech® Inc - had positively affected a peptide involved in Alzheimer’s disease (ABeta) and a prion peptide. So Dr Rekas and Dr Seok Il Yun, an ANSTO Post Doctoral fellow, decided to see if it had a similar effect on the Parkinson’s disease.

“As all these diseases affect the brain and neuronal pathways in the body we anticipated the dendrimer’s effect would be similar, and we were right,” she said.

“The Alpha-Synuclein protein is a natural protein in the body but when it aggregates into fibrils, long insoluble strings of protein molecules stuck together, it affects transmissions to the brain, resulting in Parkinson’s disease,” Dr Rekas explained. “No one is sure of the protein’s normal role but we believe it assists cognitive function.

“It is thought that the aggregation is triggered by a dopamine deficiency and causes deposits in the brain to occur, however this could be just a factor, not the complete cause, of the disease,” she said. “There is still much to find out, but it’s all part of the puzzle. The exciting part of our results is that it most definitely provides further information as to how this dendrimer can contribute to developing better therapeutics for Parkinson’s disease,” she said.

Dr Rekas explained that a dendrimer is spherical in shape and contains chemical groups similar to those of proteins, which start branching out in the middle so the dendrimer increased in size as each layer was added, similar to the branch-like structures seen in snow flakes.

“The more layers in the dendrimer the more effective it was due to the larger surface area. In the experiments we put certain amounts of these dendrimers and a control, with no dendrimers, into a protein solution for over 120 hours and stimulated aggregation with heat and shaking,” she explained. “The control measured a lot of fibrils and different dendrimers reduced this fibrillar growth to various extents.

“We used an electron microscope to look at what was physically happening and verified the results using small angle neutron scattering, where a neutron beam passes through the sample onto a detector giving information as to what’s occurring at the molecular level, “she said. “The neutron experiments were conducted by Dr Yun.

“The results clearly showed that the larger dendrimer inhibited the abnormal activity of the protein best. This information can now be used by drug companies focussed on treating Parkinson’s so the next stage would be for such companies to develop this research further,” she concluded.

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Friday, June 12, 2009

Deep Brain Stimulation (DBS) in Parkinson's Disease

Overweight after deep brain stimulation of the subthalamic nucleus in Parkinson disease

OBJECTIVE: To assess the occurrence of weight gain in patients with Parkinson's disease, with an average 16 months of follow-up after subthalamic nucleus deep brain stimulation.
METHODS: We used dual x ray absorptiometry to evaluate changes in body weight and body composition in 22 patients with Parkinson's disease (15 men and seven women) before surgery, 3 months after surgery and on average 16 months after surgery. RESULTS: No patient was underweight before surgery and 50% were overweight. By contrast, 68% were overweight or obese 3 months after surgery and 82% after 16 months (p<0.001). For men, the mean increase in body mass index (BMI) was 1.14 (0.23) kg/m(2) 3 months after surgery and 2.02 (0.36) kg/m(2) 16 months after surgery. For women, the mean increases in BMI at the same evaluation times were 1.04 (0.30) kg/m(2) and 2.11 (0.49) kg/m(2). This weight gain was mainly secondary to an increase in fat mass in both men and women. Three months after surgery, acute subthalamic deep brain stimulation induced an improvement in parkinsonian symptoms (evaluated by the Unified Parkinson Disease Rating Scale (UPDRS) part III) by 60.7 (2.9)% in the "off" dopa condition and a dramatic improvement of motor complications (dyskinesia duration: 82.8 (12.8)%, p<0.0001; off period duration: 92.7 (18.8)%, p<0.0001).
CONCLUSION: Although subthalamic nucleus deep brain stimulation significantly improved parkinsonian symptoms and motor complications, many patients became overweight or obese. This finding highlights the necessity to understand the underlying mechanisms and to provide a diet management with a physical training schedule appropriate for patients with Parkinson's disease.

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Predictors of cognitive and psychosocial outcome after STN DBS in Parkinson Disease.

OBJECTIVE: To find predictors of cognitive decline and quality of life one year after bilateral subthalamic nucleus stimulation (STN DBS) in Parkinson's disease (PD).
METHODS: A total of 105 patients were evaluated with a comprehensive neuropsychological assessment before and 12 months after surgery. A control group of 40 PD patients was included to control for effects of repeated testing and disease progression. We determined individual changes in cognition, mood and quality of life using a statistical method that controls for multiple comparisons. We performed logistic regression analyses to assess predictors of cognitive changes and quality of life.
RESULTS: Twelve months after surgery, the improvement in motor function was 41% (UPDRS3 score in off). The STN group showed a large improvement in quality of life compared to the control group (Cohen's d=0.9). At the individual level, 32 percent (95% CI: 22 - 40) of the STN group showed a substantial improvement in quality of life. Thirty six percent (95% CI: 27 - 46) of the STN patients showed a profile of cognitive decline compared to the control group. Mood improved in 16 STN patients and declined in 16 subjects. Impaired attention, advanced age and a low levodopa response at baseline predicted cognitive decline, whereas a high levodopa response at baseline predicted improvement in quality of life. Postoperative decrease in dopaminergic medication was not related to cognitive decline.
CONCLUSIONS: STN DBS improves quality of life. However, a profile of cognitive decline can be found in a significant number of patients. Levodopa response, age and attention at baseline are predictors of cognitive and psychosocial outcome.

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