It has been 200 years since Dr. James Parkinson published the An Essay On the Shaking Palsy describing the signs and symptoms of Parkinson’s disease (PD). Despite the fact that there are lots of treatment options out there to ameliorate the patient’s symptoms and to improve their quality of life, we still don’t have any neuroprotective or disease-modifying therapy to slow down disease progression. But for patients with PD, the past few years have never been so hopeful in that new candidate therapies are being developed at a very fast pace.
One of the most exciting new drugs in the pipeline is probably exenatide, a glucagon-like peptide-1 (GLP-1) agonist which is currently used to treat type II diabetes. Preclinical studies have suggested its role in inhibiting cell death, reducing oxidative stress, enhancing mitochondria function, and promoting neuronal functioning.
A recent placebo controlled trial evaluated the efficacy of exenatide. In this study, 62 patients with moderate PD received weekly injections of exenatide or placebo in conjunction with their regular medication. After 48 weeks those treated with exenatide showed improvements in motor functioning while those treated with placebo worsened. Of particular interest, 12 weeks after patients discontinued the medication the beneficial effects of exenatide remained. This study showed that a GLP-1 agonist may be able to improve symptoms and be neuroprotective.
Levodopa is a treatment for PD which increases levels of the neurotransmitter dopamine in the brain. Unfortunately, after prolonged levodopa treatment patients with PD can develop abnormal and involuntary movements referred to as dyskinesia. This suite of symptoms is referred to as levodopa-induced dyskinesia (LID) and it is an unmet need for people with PD.
The drug amantadine, specifically the immediate release form of the drug, has been used to treat LID. This form of amantadine has not been well studied and central nervous system side effects are frequent at higher doses. Recently, a clinical trial tested an extended-release form of amantadine. In this study, 126 patients with PD and sufferers from dyskinesia were randomized to receive amantadine extended-release capsules. Patients’ dyskinesia improve at 12 weeks, but more excitingly the patients’ symptoms during the time off the treatment was also less compared to the placebo.
Another challenge that faces patients with Parkinson’s disease is motor fluctuations. Motor fluctuations involve “on” periods where a patient responds positively while on a treatment and “off” periods where symptoms reemerge while the patient is still on the treatment. Currently there are better choices for adjunct therapy for patients with motor fluctuation.
A pivotal phase 3 trial tested opicapone. Opicapone could be of particular benefit for motor fluctuations since it works by preventing the breakdown of levodopa, thereby extending levels of levodopa in plasma. What’s special for this particular drug is that it has a long duration of action and can be given as a once daily regimen.
Istradefylline is another promising drug for PD with motor fluctuations. Istradefylline blocks adenosine A2A receptors. In a recent meta-analysis, istradefylline was found to be a well-tolerated drug. It decreased “off” periods and improved motor symptoms. However, since istradefylline has the potential to worsen dyskinesia it is recommended for patients in early PD who have not yet developed motor complications.
Deep Brain Stimulation
Another treatment for Parkinson’s disease is deep brain stimulation (DBS). DBS is a rather intensive treatment in which electrodes are implanted into a certain areas of the brain. DBS often targets brain areas critical for movement such as the subthalamus. The electrodes placed in the brain can then send electrical impulses to ameliorate motor dysfunction.
The beneficial effects of DBS on motor function have been well documented, but there is less attention on non-motor symptoms. Overall, DBS has shown promising effects on non-motor symptoms such as anxiety and depression. Additionally, there is also evidence that DBS can improve sleep quality, musculoskeletal pain, urinary symptoms, gastrointestinal symptoms (gastric emptying and constipation), weight loss and odor discrimination.
A new brain area is being targeted with DBS, specifically for Parkinson disease dementia. A recently published study used DBS surgery on the nucleus basalis of Meynert. The nucleus basalis of Meynert is the most important source for releasing the neurotransmitter, acetylcholine, to other brain areas critical for cognitive functioning, such as the neocortex. The rationale of this study is based on the fact that in the parkinsonian brain there is a significant deficit in brain activity related to acetylcholine. In animal models, low-frequency stimulation of the nucleus basalis of Meynert has been shown to enhance cholinergic innervation of the cortex.
Although the study using nucleus basalis of Meynert DBS surgery didn’t show improvement in the primary cognitive outcomes, the procedure was well tolerated, opening up the possibility of DBS surgery for patients with PDD. Of interest, the authors observed a significant reduction in visual hallucination in 2 patients and decreased in the severity and frequency of dyskinesia in 3 patients, which require further exploration.
Focused Ultrasound Subthalamotomy
Prior to the development of DBS, ablative neurosurgery was widely used to treat movement disorders. Ablative neurosurgery involves the removal of a specific brain area. DBS is preferred over ablative neurosurgery due to its reversibility and documented efficacy for PD treatment.
A new technique has been developed for ablating specific brain areas. Gamma-knife and MRI-guided focused ultrasound (MRgFUS), allows for deep brain ablating without opening the skull. The U.S. Food and Drug Administration have now approved MRgFUS for patients with essential tremor. A pilot study using focused ultrasound subthalatomy in patients with PD showed that it was effective, well tolerated and the adverse events seemed to be mostly mild and transient. This new technique will possibly become another treatment option in the future for patients who don’t want their brain to be opened. However, more studies with long term follow up are mandatory for confirming MRgURS’s efficacy and adverse effect.
PD is a heterogeneous disorder and every patient is unique. As more and more new drugs, devices and techniques are being developed, individualized treatment tailoring each patient’s symptoms and needs has never been so important. It is our responsibility, as physicians, to obtain the latest medical information and to select therapies that are most suitable for each patient.