Conventional Medical Treatment
For decades, the conventional standard of care for Parkinson's disease has focused on symptomatic relief. Pharmaceutical treatments for Parkinson's accomplish this by either increasing the levels of dopamine, or mimicking its action. While conventional therapeutics are indispensible for improving quality of life in Parkinson's patients, they do not provide fundamental neuroprotection or support for neuronal mitochondria. Thus, mainstream pharmaceutical treatments cannot be expected to address the underlying cause of disease progression – neurodegeneration.
Treatment with L-DOPA causes patients to be less responsive to the medication over time, and can evoke a number of adverse side effects. However, careful dosing strategies, and utilization of ancillary medications may help limit side effects and maintain the effectiveness of conventional pharmaceutical therapies.
Pharmaceutical treatment of Parkinson's disease symptoms is usually initiated when the patient has already developed some disability for which he/she needs to be treated. This is typically referred to as the initial stage of therapy. The primary goal of treatment during the initial stage is to limit symptoms arising from progression of the disease. However, with time, adverse side effects of the medications arise, which leads into the secondary treatment stage. The aim of the secondary treatment stage is to reduce Parkinson's symptoms, as well as counterbalance the adverse side effects of levodopa.
Levodopa (L-DOPA) / Carbidopa
Since its FDA approval in 1970, Levodopa (L-DOPA) has been a staple for the management of Parkinson's disease symptoms.
L-DOPA (the precursor to dopamine) is metabolized into dopamine in the body by an enzyme called aromatic L-amino acid decarboxylase (AADC). Dopamine itself cannot pass through the protective blood-brain barrier, but L-DOPA can. When L-DOPA is administered orally, a small percentage passes into the brain and is converted into dopamine. This temporary increase in dopamine levels within the brain offers relief of Parkinson's disease symptoms for a short period.
However, the body presents many obstacles that limit the efficiency of oral L-DOPA therapy. First, AADC, exists outside the brain as well, which means that the majority of orally administered L-DOPA will be converted into dopamine peripherally (not in the central nervous system). Therefore, L-DOPA is typically administered with an inhibitor of peripheral AADC, called carbidopa. Carbidopa (or another AADC inhibitor) helps to preserve orally administered L-DOPA for conversion to dopamine in the brain.
Regrettably, the use of orally administered L-DOPA over time results in diminished production of endogenous (naturally occurring within the body) L-DOPA. L-DOPA therapy is further complicated by the development of movement disorders called dyskinesias after 5 – 10 years of use in most cases.
Dyskinesias are movement disorders in which neurological discoordination results in uncontrollable, involuntary movements. This discoordination can also affect the autonomic nervous system, resulting in, for example, respiratory irregularities (Rice 2002). Dyskinesia is the result of L-DOPA-induced synaptic dysfunction and inappropriate signaling between areas of the brain that normally coordinate movement, namely the motor cortex and the striatum (Jenner 2008).
With long-term L-DOPA use (usually after about 5 years), responsiveness declines and dose adjustment is often necessary. This phenomenon leads to fluctuations in the effectiveness of L-DOPA therapy that cause the patient to experience dyskinesia as the post-dose concentration of L-DOPA peaks, and rapid reversion to severe Parkinsonism towards the end of the dosing period.
Several strategies exist for enhancing L-DOPA effectiveness. Some of these include varying combinations of L-DOPA and other medications discussed in this section as well as altering dose timing and amount. Other strategies can involve "rest periods" or "drug holidays" during which the patient abstains from L-DOPA for a short time; as little as skipping a single dose each day may help lessen the damage caused by oxidation products of L-DOPA metabolism and maintain dopamine receptor sensitivity. A patient should never adjust their L-DOPA dose without close supervision by their physician.
Other strategies for stabilizing dopamine levels include combining L-DOPA with inhibitors of enzymes that breakdown dopamine. Medications of this type include monoamine oxidase-B (MAO-B) inhibitors, and catechol-O-methyltransferase (COMT) inhibitors. By combining L-DOPA with COMT and / or MAO-B inhibitors, a physician may be able to reduce the dose of L-DOPA required to relieve symptoms, and widen dose intervals, which is more convenient for the patient.
There are a variety of ways that pharmaceuticals can be combined to deliver optimal effects in each Parkinson's case, but the needs of each patient may vary widely. Therefore, patients should always consult an experienced physician to discuss medication combinations that may be ideal for their unique situation.
L-DOPA can produce several adverse side effects, including:
L-DOPA-induced elevations in homocysteine, a potentially harmful amino-acid derivative, are another major concern for Parkinson's patients. High levels of homocysteine have been implicated in various cardiovascular diseases, including cerebral small vessel disease, as well as brain atrophy (Rajagopalan 2011; Kloppenborg 2011). A comprehensive review of 16 studies found that elevated homocysteine was associated with dementia and markers of neurodegeneration in patients with Parkinson's patients (Zoccolella 2010).
Parkinson's disease patients taking L-DOPA should read Life Extension's protocol on Homocysteine Reduction and strive to maintain homocysteine levels of less that 7 – 8 µmol/L.
Another method used to restore dopaminergic signaling in Parkinson's disease is medicating with a dopamine agonist. A dopamine agonist is a drug containing a molecule that binds to and activates dopamine receptors, similar to dopamine itself, thus compensating for low dopamine levels. Dopamine agonists are often used in younger patients, or in very early Parkinson's disease.
Research comparing the results of initial therapy with a dopamine agonists or L-DOPA is conflicting. Some studies suggest that initiating therapy with a dopamine agonist may delay the onset of dyskinesias as the disease progresses, while some seem to indicate that this may not be the case. Other studies suggest that initial dopamine agonist therapy delivers results similar to those seen in L-DOPA + COMT inhibitor therapy (Antonini 2009). Results from a 14-year follow up study found that initial therapy with a dopamine agonist offered no greater benefit over standard L-DOPA therapy in the long term (Katzenschlager 2008).
Dopamine agonists pose a greater risk of serious side effects than L-DOPA and are therefore not as tolerable for some patients. Some side effects of dopamine agonists include:
Selegiline and Rasagiline
Selegiline is a MAO-B inhibitor that, due to its unique chemical structure, also exerts other neuropharmacological actions via its metabolites. By blocking the breakdown of dopamine, selegiline helps compensate for the diminished production of dopamine in Parkinson's disease. This can lead to symptomatic improvement, especially in early-stage Parkinson's.
Numerous clinical trials have confirmed the efficacy of selegiline alone and in combination with L-DOPA in early Parkinson's disease (Mizuno 2010; Zhao 2011; Palhagen 2006). One study showed that selegiline was highly effective if initiated within five years of Parkinson's disease diagnosis, but less effective if initiated 10 years or more after diagnosis (Mizuno 2010).
Selegiline exerts a number of other benefits as well, including maintenance of whole-brain blood flow in depressed Parkinson's disease patients (Imamura 2011). Moreover, selegiline may reduce the formation and toxicity of alpha-synuclein aggregates (Braga 2011).
Rasagiline is a newer generation medication based upon selegiline. Laboratory studies suggest that, in addition to functioning very similarly to selegiline, rasagiline may exert a greater neuroprotective effect (dimpfel 2011).
Rasagiline was superior to placebo in slowing progression of Parkinson's disease in a cohort of 1,176 early-stage patients. In this study, subjects receiving rasagiline were less likely than those taking placebo to need additional anti-Parkinson drugs to manage symptoms (Rascol 2011). More trials need to be conducted to determine if rasagiline is significantly more effective than selegiline for treating Parkinson's disease.
Selegiline is available via prescription in a clinically studied transdermal patch called Emsam®. Selegiline and rasagiline may cause dizziness, dry mouth, sleeplessness, and an overall stimulating effect.
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 (Sawada 2010; Thomas 2004). However, in some patients, discontinuation of amantadine appears to cause a rebound worsening of dyskinesias to an even higher intensity than before its introduction (Thomas 2004).
As mentioned earlier in this protocol, at least one study suggests that amantadine may suppress side effects of L-DOPA abstinence during a drug holiday (Koziorowski 2007).
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 (Exley 2008). Moreover, loss of nAChRs accompanies many neurodegenerative disease, including Parkinson's disease, suggesting that declining cholinergic signaling be a key etiological feature (Pimlott 2004). Several studies indicate that nicotine exerts powerful neuroprotective effects via activation of nAChRs (Shimohama 2009). 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 (Hong 2009).
Many epidemiological studies have confirmed that smoking tobacco confers a substantial reduction in risk for developing Parkinson's disease (Tanaka 2010; Tan 2003). Moreover, transdermal nicotine patches have been shown to improve cognitive functioning in patients with Parkinson's disease (Holms 2011). Other evidence suggests a therapeutic effect of nicotine in reducing L-DOPA-induced dyskinesias (Quik 2008). as of August 2011, at least one larger clinical trial is currently recruiting subjects to assess the efficacy of transdermal nicotine on motor symptoms in advanced Parkinson's disease (ClinicalTrials.gov 2011).
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 (e.g. 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 autoreative, anti-inflammatory TH2 phenotype rich in T-regulatory cells (Xiao 2007). 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 (Xiao 2007; Khatibi 2011).
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 (Song 2011; McCollum 2010; Sanchez-Ramos 2009). 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. While no human clinical trials for G-CSF in Parkinson's disease have been completed as of September 2011, a phase II clinical trial is currently underway in Taiwan (ClinicalTrials.gov 2011). Results of this trial are expected sometime in 2013. If they are positive, they may lead to even larger-scale clinical trials and eventually to clinical use of G-CSF in Parkinson's disease patients.
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 (Freed 2001).
Another major challenge associated with cell replacement therapy is ensuring survival of transplanted neurons. So far, this has proven extremely difficult (Kim 2011). 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 (ScienceDaily 2011). This may make it a more viable option in the near future.
Cognitive – Behavioral Therapy
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 (Dobkin 2011).
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 (Vaughan 2011).
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 (Allen 2011).
Moreover, an array of studies have 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 (Jak 2011). Experimental Parkinson's disease models demonstrate that physical activity provides neuroprotection and promotes mitochondrial integrity (Lau 2011).
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.
Low-Protein Diet / Protein Meal Redistribution
L-DOPA therapy is hindered by many obstacles, one of which is excess protein (specifically, aromatic amino acids) competing with L-DOPA for transport into the brain. Therefore, some studies have evaluated the effects of engaging in protein meal redistribution, involving eating dietary protein separate from dosing with L-DOPA.
Current research indicates that protein meal redistribution may be favorable with a low protein diet. It appears that protein meal redistribution reduces fluctuations, or "on-off periods" in response to L-DOPA therapy (Cereda 2010). Taking L-DOPA at least 30-minutes before consuming protein and/or having your highest protein meal at a time when L-DOPA is not needed may be an effective strategy. However, patients should speak with their physician to determine which dieting approach is appropriate for them.
Coffee contains a multitude of pharmacologically active compounds, some of which have been shown to suppress oxidative stress and protect against diabetes, cancer, cognitive decline, and so on (Butt 2011). Additionally, several epidemiological studies have found that those who consume large amounts of coffee are much less likely to develop Parkinson's disease (Hu 2007; Saaksjarvi 2008; Tan 2003).
Coffee constituents (compounds) protect brain cells which can be extremely beneficial for Parkinson's disease patients. Coffee extracts have been shown to inhibit MAO-A and -B enzymes, a mechanism similar to that of some pharmaceutical Parkinson's therapies (Herraiz 2006). Experimental models suggest that coffee constituents promote neuronal development and increase antioxidant defense systems in the brain (Abreu 2011; Tohda 1999).
Green coffee extract contains more of the active antioxidant compounds than brewed coffee, and may be a promising option for Parkinson's disease patients (Farah 2008). However, clinical trials have yet to confirm this potential benefit.
Intriguing research suggests that caffeine itself may be a potent anti-Parkinson agent. Upon ingestion, caffeine readily crosses the blood-brain barrier and blocks adenosine receptors, an effect responsible for many of its pharmacologic actions. The adenosine receptor system interacts with the dopaminergic system in several ways (Xie 2007). Experimental studies have shown that caffeine binds to presynaptic adenosine receptors causing an increase in dopamine release, thereby temporarily ameliorating some symptoms of Parkinson's disease (Hauser 2005). In fact, some data from non-human primate studies indicate that adenosine receptor antagonists, like caffeine, may allow for a reduced dosage of L-DOPA. Data in mice also supports this notion, but more studies need to be done (Kanda 2000; Matsuya 2007).
In a clinical trial, a daily caffeine dose of 100 mg was shown to reduce "freezing." However, it appeared the subjects developed a tolerance after a few months. The researchers went on to suggest that caffeine might have therapeutic potential, but a periodic 2-week abstinence period may be required to maintain long term effectiveness (Kitagawa 2007).
Current evidence suggests that coffee consumption may provide some neuroprotection and pharmacologic support, with very little potential downside for Parkinson's patients.