Tagged: levodopa

Parkinson’s Disease: Current and Future Treatments

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This week’s question comes from Alex. She asks, “I saw a video on YouTube where a guy with Parkinson’s disease is able to use a machine implanted in his brain to control his shaking. Please explain this!”

The video Alex is referring to can be seen here and shows a man with the severe shaking most of us associate with Parkinson’s controlled by a device he had implanted in his brain. The effects are dramatic between when the machine is on or off; in fact, it seems that his symptoms are so severe with it off that he has moderate difficulty turning the machine back on after he had switched it off. But, before we go into detail about how that machine and other treatments for Parkinson’s work, we should first understand the disease itself and what exactly is going on in the body to cause its symptoms.

The disease itself is caused when the dopamine producing neurons in an area of the brain known as the substantia nigra begin to die. Past posts and some sources below detail the role of dopamine in the brain, so please refer back to those if you are not familiar (here). The exact reason(s) for this premature death is unknown, but evidence supports excessive oxidative stress and the inappropriate collection of certain proteins (alpha-synulcein bundles known as Lewy bodies, for the curious) in these neurons and to a lesser extent throughout the brain. In certain cases there is also a genetic cause, but for a majority of people the cause is idiopathic (without a known source).

Regardless of the reason(s) behind it, damage to the dopamine producing cells in the substantia nigra has a wide ranging effect on the body. Chief among them is parkinsonism, which is the specific name for the motor (movement) issues most visible in Parkinson’s patients. The motor issues are mainly divided into tremor, rigidity, slowness, and postural issues. Tremor is the familiar shakiness, which more often happens when not moving (resting tremor). Rigidity can come in multiple forms, but basically means the muscle is hyperactive, making it harder to move fluidly or with normal ease. Slowness is what it sounds like, preventing rapid execution of movements. Slowness is especially visible in fine motor movements, making these activities difficult since they often require multiple actions to be executed quickly and successively. Postural issues are present in more advanced stages of the disease, resulting in balance issues and frequent falls.

Beyond the motor issues, Parkinson’s can result in a whole host of issues that vary from person to person. The most common issues associated with advanced Parkinson’s are cognitive issues (ie. slowed thought, speech issues, memory issues), psychiatric issues (ie. depression, anxiety, hallucinations), and dementia. It is thought that the accumulation of the Lewy bodies mentioned earlier contribute to this loss of function. As such, these issues tend to present much later in Parkinson’s patients because it takes time for these elements to accumulate and interfere with function.

Because the symptoms of Parkinson’s are generated largely by loss of dopamine production, the logical treatment would be to try to replace that dopamine. In fact, that is exactly what the main treatment for Parkinson’s does. Known as Levodopa, this drug is converted to dopamine in the body and can increase the concentration of available dopamine in the brain. It can have significant side effects because it can also be converted to dopamine outside the brain. This peripheral dopamine can have a whole host of effects on nerves, leading to inappropriate nerve activity. To combat this, it is usually administered alongside a drug that prevents this conversion outside the brain but allows it to occur within the brain (by not being able to cross the blood-brain barrier). Even with this concurrent drugs,  levodopa can still cause disabling side effects. Ironically, the most common are dyskinesias, or involuntary movements. Other drugs exist, but with varying degrees of effectiveness and still largely have a poor side effect profile. However, on the whole these drugs only mask the symptoms. As of now, no drug in clinical use has been shown to stop progression, though some recent compounds and genetic targets (1, 2, 3) have shown promise by a variety of mechanisms.

But, what if the symptom controlling drugs cause too many side effects, don’t last long enough, or otherwise don’t work? What if a more permanent solution is needed? Enter deep brain stimulation (DBS). As you saw in the video, deep brain stimulation can be tremendously effective in regulating the motor symptoms of Parkinson’s. DBS does this by using electrical signals to block out the errant motor signals generated in the Parkinson’s affected brain. Electrodes are placed in certain parts of the brain (specifically ventral intermediate nucleus, globus pallidus, and subthalamic nucleus) and transmit their signal directly into these areas. All of these areas are involved with some portion of motor control, though the specifics are not important in this context. Despite blocking the erroneous Parkinson’s motor signals in these areas, normal motor signals can still be processed. Think of it like a freeway where a drunk driver is swerving across the road, disrupting all of the normal traffic. Once that driver is removed from the road, traffic can resume as normal. The result of DBS is a much smoother overall motor control and significant reduction of the tremors, slowness, rigidity, and posture control issues. The drawback is that DBS involves open brain surgery and implantation of foreign bodies deep into the brain. Thus it is not considered the primary treatment for Parkinson’s patients. Hopefully in the future a similar technology can be created that involves a much less invasive procedure, allowing it to be a primary treatment option for those with progressive symptoms. Until then, drug therapy continues to be the most widely used treatment for the symptoms of Parkinson’s disease.

Hope this helps, Alex! As always, thank you for the question. If you want to submit your own, feel free to do so at the top link.

Till next time,

Justin

Sources:

http://www.parkinson.org/Parkinson-s-Disease/Treatment/Surgical-Treatment-Options/Deep-Brain-Stimulation

http://www.sciencemag.org.libproxy.usc.edu/content/302/5646/819.short

http://www.psychologytoday.com/basics/dopamine

http://www.parkinson.org/Parkinson-s-Disease/Treatment/Medications-for-Motor-Symptoms-of-PD/Carbidopa-levodopa

http://www.parkinson.org/Parkinson-s-Disease/Treatment/Surgical-Treatment-Options/Deep-Brain-Stimulation

http://www.ninds.nih.gov/disorders/deep_brain_stimulation/deep_brain_stimulation.htm

http://www.nlm.nih.gov/medlineplus/ency/imagepages/19515.htm

http://www.mayoclinic.com/health/parkinsons-disease/DS00295

http://www.nejm.org/doi/full/10.1056/NEJMct1208070

http://www.neurology.org/content/61/7/919.abstract

http://www.ncbi.nlm.nih.gov/pubmed/11801431

http://www.ncbi.nlm.nih.gov/pubmed/22772329

http://brain.oxfordjournals.org/content/127/1/4.full.pdf