Alternative and Emerging Therapies
In addition to the conventional standard of care, which relies heavily on L-DOPA therapy, physicians may sometimes implement other pharmaceutical agents that complement the effects of L-DOPA therapy, or limit its side effects.
Amantadine is an antiviral drug that exerts a number of actions in the brain. Amantadine has been shown in some studies to benefit Parkinson's patients, primarily by reducing the side effects of L-DOPA, or as an adjuvant during L-DOPA drug holidays as mentioned above, though the mechanisms are largely unclear.
In clinical studies, amantadine has been shown to temporarily reduce L-DOPA induced dyskinesia; an effect which dissipates after about eight months.98,99 However, in some patients, discontinuation of amantadine appears to cause a rebound worsening of dyskinesias to an even higher intensity than before its introduction.99
As mentioned earlier in this protocol, at least one study suggests amantadine may suppress side effects of L-DOPA abstinence during a drug holiday.88
Amantadine may ease Parkinson's symptoms in some patients, but should only be initiated under physician supervision.
Within the brain, there exists a grand diversity of neurotransmitter interaction and overlap. One such relationship, very symbiotic in many ways, is that existing between the dopaminergic and cholinergic systems. For example, acetylcholine modulates dopaminergic signaling in the striatum, an area considerably impacted in Parkinson's disease.
Nicotine interacts with the cholinergic system by to binding sites known as nicotinic acetylcholinergic receptors (nAChRs), which influence several functions relevant in Parkinson's disease, including dopamine signaling.100 Moreover, loss of nAChRs accompanies many neurodegenerative disease, including Parkinson's disease, suggesting that declining cholinergic signaling be a key etiological feature.101 Several studies indicate that nicotine exerts powerful neuroprotective effects via activation of nAChRs.102 Recent data indicates that among the neuroprotective effects of nicotine is the ability to reduce alpha-synuclein aggregation, which may suppress the formation of Lewy bodies.103
Many epidemiological studies have confirmed that smoking tobacco confers a substantial reduction in risk for developing Parkinson's disease.104,105 Moreover, transdermal nicotine patches have been shown to improve cognitive functioning in patients with Parkinson's disease.106 Other evidence suggests a therapeutic effect of nicotine in reducing L-DOPA-induced dyskinesias.107
Nicotine appears to have potential to deliver significant and clinically meaningful benefits in Parkinson's disease. If you have Parkinson's disease, you are encouraged to speak with your physician about potentially complementing your anti-Parkinsonian therapy with transdermal nicotine. Your doctor should help you determine an appropriate dose; however, the Holms study cited above used 7mg/24hrs delivered via a transdermal nicotine patch. Newer studies aim to evaluate higher doses (eg, 90 mg/week) via transdermal patch.
Granulocyte Colony-Stimulating Factor (G-CSF)
G-CSF is a signaling glycoprotein (produced in several tissues) that stimulates the production and differentiation of white blood cells, thereby playing a significant role in immune system function. Recombinant G-CSF is frequently given to chemotherapy patients to restore levels of white blood cells that have been suppressed by treatment.
The interaction of G-CSF with the immune system is very complex. However, current evidence suggests that besides stimulating white blood cell generation, it pushes the immune system towards a less autoreactive, anti-inflammatory TH2 phenotype rich in T-regulatory cells.108 Due to this unique action, G-CSF may be of benefit in diseases in which inflammation contributes to the pathology.
Interestingly, receptors for G-CSF are expressed in neurons throughout the central nervous system and activation of those receptors (by G-CSF) stimulates neurogenesis and protects neurons from damage.108,109
In animal models of both Alzheimer 's disease and Parkinson 's disease, subcutaneous injections of recombinant human G-CSF suppressed inflammation in brain regions centrally involved in the pathology of each disease and stimulated the formation of new synapses.110-112 In these studies, mice treated with G-CSF performed much better on cognitive tests than those not treated with G-CSF. These findings are very exciting and hold promise for future research.
Stem Cells and Cell Replacement Therapy
The hallmark of Parkinson's disease is loss of dopaminergic neurons in the substantia nigra. Therefore, many therapeutic approaches have aimed at replacing lost neurons in this region using cell replacement therapy, or stem cell therapy. These therapies are largely experimental as of the current time and no large-scale clinical trials have been conducted as of yet. In fact, small-scale clinical trials have shown that benefit of replacing dopamine neurons may be questionable, and that the therapy caused severe dyskinesias in some subjects.113
Another major challenge associated with cell replacement therapy is ensuring survival of transplanted neurons. So far, this has proven extremely difficult.114 However, further studies are underway, and advancements in research may allow for widespread use of these therapies in the not-too-distant future.
Ablative Surgery and Deep-Brain Stimulation
A conventional therapy of last resort involves ablative surgery, or deep-brain stimulation, in which areas of the brain that are normally under control of dopamine are destroyed. This helps alleviate symptoms in some cases because when the regulatory actions of dopamine are absent, as in advanced Parkinson's disease, those regions of the brain can become dysregulated and dysfunctional.
Only a small percentage of Parkinson's patients are good candidates for ablative surgery or deep-brain stimulation, and there are many risks. Surgical options may be considered in advanced Parkinson's disease when other treatments are no longer able to control symptoms effectively.
However, researchers in the Netherlands have recently developed a method of dramatically improving the accuracy and reliability of deep-brain stimulation.115 This may make it a more viable option in the near future.
Parkinson's disease is often accompanied by comorbid psychological disturbances such as depression and/or anxiety, and psychosis (a potential side effect of anti-Parkinson medications). Treatment of psychological disturbances is limited, to some degree, due to potential interactions between pharmaceuticals used to treat Parkinson's and those used to treat other psychological conditions.
Cognitive-behavioral therapy offers a highly effective drug free alternative for relieving psychological disturbances in Parkinson's disease patients. In one study, depressed Parkinson's patients were either clinically monitored or engaged in cognitive-behavioral therapy for just over three years. While a mere 8% of patients undergoing clinical monitoring experienced improvements in their depressive symptoms, significant improvement was noted in 56% of those engaged in cognitive-behavioral therapy.116
In addition to the psychological benefits, cognitive-behavioral therapy may be effective for the treatment of some physical symptoms of Parkinson's disease. A 2011 study found that in patients older than 50 years, cognitive-behavioral therapy led to a significant reduction in the incidence of urinary incontinence.117
Several different types of cognitive-behavioral therapy are available and different styles may be appropriate in some cases while inappropriate in others. Patients with Parkinson's disease may benefit from cognitive-behavioral therapy and therefore, should discuss this option with their physicians.
Physical Therapy and Exercise
Parkinson's patients are prone to motor disturbances, such as poor balance and a greater chance of falling, which can lead to decreased mobility. As the disease progresses, engaging in structured physical therapy or exercise may be an effective way of maintaining balance and avoiding falls.118
Moreover, an array of studies has shown that exercise and physical activity in general exert substantial supportive effects upon brain structure and function. In fact, physical activity is associated with a decreased propensity for aging adults to develop dementia, a common problem in Parkinson's disease.119 Experimental Parkinson's disease models demonstrate that physical activity provides neuroprotection and promotes mitochondrial integrity.120
Staying active is very important for Parkinson's disease patients. Those not engaged in regular physical activity are encouraged to speak with their healthcare provider about initiating a structured exercise or physical therapy regimen. A target goal of 75% maximum age adjusted heart rate for a minimum of 20 minutes at least three times per week is ideal. However, this may not be possible for advanced Parkinson's disease patients.