By Katja Shimkin
An Introduction to Parkinson's Disease
Parkinson’s Disease (PD) is the second most common neurogenic disorder, affecting over one million Americans and four million individuals worldwide (NIH, 2015). It is associated primarily with expressed motor dysfunctions; from bradykinesia and awkward gait, to postural instability and hypomimia, PD is conceptualized so classically as an illness affecting body movement that the abnormal psychological or neuropsychological consequences that also distinguish it, remain inconspicuous and, in several instances, vastly underreported. (Figure 1 depicts some common phenotypic characteristics of the disease, including the shuffling steps, muscle tremors, and poor posture that characterize the disease.) Major Depressive Disorder commonly presents as a comorbidity with PD, and cognitive dysfunctions, particularly in cortical areas pertaining to executive functions such as judgement and planning, are also frequent, and in need of further research (Disease Foundation, 2015). Additionally, investigation into the prevalence of acquiring impulse control-related disorders, or associated conditions such as punding, is now underway, and analyses are reporting these conditions to be common, despite the public’s lack of knowledge regarding them. Fortunately, recent scientific inquiries into these and other detrimental effects of PD have resulted in several discoveries that could set the foundations for novel treatments to increase quality of life for individuals afflicted by PD, and, with increasing treatment options will come increasing public awareness of the vast scope of issues related to this incurable, progressive, degenerative illness.
Currently, the most common generalized treatment for PD is administration of the drug levodopa (L-DOPA.) L-DOPA is a precursor molecule to DA (as well as all neurotransmitters in the catecholamine class) and is necessary for synthesis of the chemical within the presynaptic neuron. Unlike DA, L-DOPA is small enough to permeate the blood-brain barrier, and once through the membrane, the molecule is catalyzed by the enzyme Aromatic-L-amino-acid decarboxylase into DA (Showing Protein Aromatic…, 2015) where an increase in the quantity of the neurotransmitter may mitigate the hypokinesic symptoms characteristic of PD. Since the 1960’s, treatment with the L-DOPA drug has been the standard Parkinson’s treatment, however recent investigations have implicated several other treatment methods as potentially beneficial. Whereas L-DOPA remains an effective treatment, it frequently leads to development of hyperkinesic side effects such as tremors (Julien, 1981). Additionally, though rare, there are instances in which L-DOPA does not prove to be effective. For these reasons, additional or alternative preventative measures must be investigated. The remainder of this site will discuss several side effects of dopamine treatment medications, and present recent research into possible practical solutions. A recent discovery regarding a novel, preventative vaccine will also be emphasized. The goal is to highlight these potential treatment reforms, as well as to educate readers with regards to less-known clinical presentations associated with Parkinsonian treatment drugs.
A Basic Explanation of Parkinsonian Neurological Deficit
A 2008 review article sponsored by Duke University Medical School describes the pathophysiology of Parkinson’s Disease, emphasizing loss of dopaminergic neurons in two specific regions of the cerebral cortex: the ventral tegmental area (VTA), and the pars compacta. The major production-site of dopamine neurotransmitters, the VTA maintains an extensive neuronal projection circuit, supplying dopamine (DA) to nearly the entire brain, cortex and brainstem. Also described, the pars compacta is one of two structures that comprise the substantia nigra, a cortical region that supplies inhibitory GABA neurons to the striatum. The striatum, or striate cortex, is the source of excitatory dopamine neurons to the movement-regulating brain region called the basal ganglia, and is also a major contributor to the brain’s reward system (Ferrara, 2008). Figure 2 compares an image of a normal versus PD-afflicted substantia nigra. "Substantia nigra" translates from Latin to "black space," and the substantial lightening in the bottom image demonstrates the degradation of the brain area in a Parkinson's patient.
As a primary binder of excitatory neuroreceptors, dopamine is highly implicated in Parkinsonian pathologies, motor as well as cognitive. In an unaffected brain, DA projections from substantia nigra to the striate are abundant. PD, however, is an illness predominantly induced by degeneration of such projections. Because the striate supplies the movement-controlling basal ganglia with DA, a diminished quantity of DA neurons projecting to the striatum effectually diminishes the amount of neurotransmitter reaching the basal ganglia. This accounts for the hypokinesic symptoms frequent in those who suffer from Parkinson’s (i.e. muscle rigidity, difficulties producing self-inspired movements, hypomimia). Additionally, dopaminergic depletion in areas, such as the basal ganglia, related to the brain’s reward system may explain the biochemical aspect of much-elevated depression rates in those diagnosed with the disease (Triarhou, 2015).
Repetitive Transcranial Magnetic Stimulation (rTMS)
Punding, a seemingly rare though perhaps merely underreported side effect of long-term L-DOPA intake, refers to the incidence of (a) severe, irrepressible, repetitive behavior(s), almost always importantly detrimental to the individual’s physical and social well-being. One case report describes a 68 year-old PD patient who, after medications, developed a compulsive obsession with drumming, playing for hours every day, purchasing a recording studio for his home, and shunning social interactions, food, and sleep, in order to spend more time drumming, thereby avoiding feelings of depression and anxiety. (After six months, his medication was changed and the patient no longer felt controlled by the need to drum to achieve “wellbeing and a feeling of calmness”) (Vitale, 2013). Another study, published in 2013, analyzed the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) on incidence of the strange side effect of PD medication. Researchers focused efforts specifically on the brain’s dorsolateral prefrontal cortex (DLPFC), comparing effects of left- versus right-hemisphere stimulation (Nardone, 2015). (For a depiction of what a TMS set-up might look like, refer to Figure 3.) After delivering a series of low-frequency electrical pulses over a period of 32 minutes, to a sample of patients who had demonstrated punding behaviors, it was found that score on a Punding Scale decreased after stimulation over the right, and left DLPFC. After right-sided stimulation, the score remained lower after a second measurement. At third measurement, however, regardless of hemisphere, scores were not significantly different from pre-treatment Punding Scale scores. This demonstrates rTMS over the DLPFC, especially when directed at the right hemisphere, has the potential of minimizing punding behaviors. The authors conclude by suggesting a patient undergoing repeated rTMS for several consecutive days may experience a longer-duration of benefits from the treatment (Nardone, 2015).
A second important finding regarding application of rTMS has to do with cognitive impairment in the form of executive functioning. As stated previously, the prefrontal cortex (PFC) is implicated in top-down processing activities such as decision-making, problem-solving, spatial planning, and the processing of information/creation of strategy. Deficits in such areas also impact a broad range of functions from working memory, to forming strategic decisions, to sequencing actions (Srovnalova, 2012). Based on the knowledge that information related to spacial orientation is regulated by the dorsolateral PFC, a team of researchers conducted a study applying short bursts of high-frequency rTMS over the DLPFC, measuring performance on an executive decision-making/spatial orientation task immediately before, and immediately after, stimulation. The team concluded rTMS applied to the right side of the DLPFC resulted in significant improvement in the task. This indicated statistically relevant improvements in planning, strategy, and spatial orientation in the sample of Parkinson’s-afflicted test subjects (Srovnalova, 2012). Recall the previous study also reported outcomes of rTMS over the right DLPFC, noting significant reductions in punding behaviors (Nardone, 2015). Whereas the first study cited multiple sessions of rTMS as potentially most beneficial to reducing punding behaviors, this second publication asserted the possibility of longer duration of improvements, but did not qualify this by indicating the necessity of multiple consecutive exposures (Srovnalova, 2012).
Further research into the application of rTMS is needed, in terms of its potential uses, and the economic possibilities for its implementation outside the experimental setting, but, for the time being, there seems a strong basis on which future studies may build: that rTMS has clearly-demonstrated potential to decrease symptoms of PD, and side effects of medications administered to treat it. Importantly, decreases in these symptoms may lead to vast improvements in the every-day lives of PD patients, with regards to social functioning, personal wellbeing, and maintenance of cognitive capabilities.
Whereas L-DOPA is the medication most commonly prescribed for parkinsonian symptoms, there have been several others approved for administration. Two such drugs are pramipexole (Mirapex, Sifrol), and ropinirole (Adartrel.) L-DOPA, as a medication, involves direct administration of the molecule L-DOPA (the precursor molecule of dopamine) to a patient. The L-DOPA chemicals cross the blood-brain barrier and add to the diminished number of precursor molecules present in the parkinsonian striatum. Due to the now-augmented levels of DA precursor molecules, the brain is able to produce more dopamine, elevating previously pathologically-reduced DA quantities closer to their previous, more adequate levels (Julien, 1981). Pramipexole and ropinirole effect a similar overall outcome, however they do so by different means. The two drugs induce effects in a manner much alike one another; both are direct dopamine agonists. Each drug has a high affinity for the brain’s D2, D3, and D4 (dopamine) receptors, meaning they allow binding to these spaces and, by doing so, stimulate dopaminergic neurons to release DA neurotransmitters in greater abundance. Recall the brain’s striatum projects to the body-movement-regulating basal ganglia. When DA receptors are agonized by pramipexole in the striate cortex, it follows that the PD-induced hypokinesic symptoms caused by neuronal degradation in the basal ganglia will be reduced (and movement control will be be ameliorated to closer-to-normal levels), given the medication-facilitated increase in the release of DA neurotransmitters from the striatum (the primary DA production center) to the basal ganglia. For a visual reminder, Figure 4 depicts the DA receptors of the Central Nervous System and the enzymes associated with each.
Both pramipexole and ropinirole have been shown to effectively diminish symptoms in Parkinson’s Disease. As with all drugs, however, a large number of side effects ranging from mild to severe has been documented. One adverse effect was the development of punding behaviors. It is established above that rTMS stimulation over the DLPFC may hold answers for punding PD patients, however, this second study regarding treatments for the condition may hold a different type of answer. Although advances in rTMS do appear promising, the existence of multiple potential treatments is essential, as individuals’ reactions to methods may vary; a treatment may be life-changing for one patient, yet ineffective for another. Multiple treatment types increases the possibility of each patient discovering a method that effectively minimizes their personal symptoms.
Based on the unfortunate reality that drugs such as L-DOPA, pramipexole, and ropinirole may induce severe side effects such as punding behaviors, a team of researchers investigated the potential implementation of antipsychotics in the reduction of such detrimental unintended effects. Specifically, the study retrospectively analyzed three case studies from 2007-2009, in each of which punding behaviors developed after long-term administration of one of the aforementioned medications. Each patient was treated with the drug clozapine, and each patient reported disappearance of punding behaviors. (One subject even stated that, in addition to loss of his punding behaviors soon after starting clozapine, his symptoms actually return if he is ever noncompliant with the neuroleptic.)
Clozapine is a second-generation antipsychotic (also neuroleptic) medication, distinguished from first-generation antipsychotic drugs in that it does not induce extrapyramidal effects (motor-related symptoms such as tardive dyskinesia, tremors, and dystonia). This lack is critical if the medication is to be used in treating patients diagnosed with Parkinson’s Disease, as such individuals are already afflicted by motor-related issues similar to those often caused by first-generation antipsychotics. Clozapine directly antagonizes dopamine by binding to D1, D2, D3, and D4 receptors. In other words, the clozapine chemical attaches itself to receptors that would otherwise receive dopamine, effectively preventing DA from binding. Clozapine is similar enough to DA in shape and chemical structure to allow the drug to bind to dopamine’s receptors, yet clozapine is not chemically identical to dopamine, and therefore, unlike the neurotransmitter, does not stimulate the receptors when binding, a process which would cause their neurons to release excitatory stimuli. This mechanism of action is vital as a large portion of the pathophysiological cause of diseases commonly treated by antispcyhotics (ex. schizophrenia) is an over-binding of DA to its receptors. In the case of punding behaviors, it is suggested that clozapine is particularly effective in blocking dopamine receptors in the limbic system. This system, part of the striatum, contains the rewards circuit, and influences mood, emotion, and subconscious, as well as cognitive, drives. Because of the aspects it regulates, the limbic system is highly connected to issues related to impulse control (ex. punding), and it is by this principle that greater binding by clozapine in this area induces a reduction in punding symptoms (Hardwick, 2013).
The current study established that the most frequent method of treating punding symptoms caused by a medication such as L-DOPA has been to decrease the dose of that medication. Although this lowered quantity of drug may diminish or even entirely eradicate punding behaviors, the initial problem (hypokinesic parkinsonian symptoms) is no longer being treated. Therefore, the study proposed another option: administration of antipsychotic medications (Hardwick, 2013). Whereas previously-discussed studies have suggested great hopes in the field of rTMS at treating parkinsonian drug side effects, this proposal of prescribing neuroleptics, specifically clozapine, could set the foreground for a second novel treatment possibility in the future.
Preventative Measures: a Microbial Direction
Thus far, this page has concentrated on treatment measures post- development of Parkinson’s Disease. The best treatment, however, is ultimately pro-, not retro-active, and so a discussion of potential preventative techniques seems in order. In the last few years, a new aspect in the field of immunovaccinations has appeared: DNA vaccines. A Chinese study published in 2013 analyzed the effects of the optimized DNA vaccine pVAX1-IL-4/SYN-B, and found that it posed significant beneficial effects in mouse models.
PD is characterized by an increased quantity of a-synuclein (a-syn) proteins which leads to a build-up of Lewy bodies (Parkinson's Protein Causes Disease…,2015). (These are the same Lewy bodies implicated in Lewy body dementia, the second most common cause of dementia, after Alzheimer’s Disease.) In fact, a-syn protein malfunction has been implicated in most of the common neurodegerative diseases. Through increased levels of these proteins, as well as by way of abnormal folding of its structures, a-syn causes microglia (essentially the macrophages of the Central Nervous System) to signal production and release of inflammatory molecules. (In Parkinson’s, this process is most extreme in the substantia nigra.) It is these repeated, localized inflammations caused by glial stimulation from excess quantities of/misfolded proteins that ultimately lead to DA neuronal degeneration (Maguire-Zeiss, 2010).
The Maguire-Zeiss study compares a-syn levels in mice administered the optimized vaccine to those given the full vaccine and found mice that had received the optimized vaccine showed lower levels of a-syn protein post-vaccination. There was also a decrease in destructive cellular inflammation in mice receiving the optimized vaccine. These results support administering the optimized vaccine over the full one; it appears safer, as well as more effective. When analyzing the effects of the optimized vaccine, the research team found that it could cause B cells to produce more antibodies which in turn elevated a mouse’s level of humoral immunity. This heightened humoral immunity was made possible by the optimized DNA vaccine facilitating Th2 cytokines. The vaccine also appeared to have a negative effect on Th1 cells which usually allow for cellular immunity. This could be extremely beneficial to a patient at risk for Parkinson’s because cellular immunity is correlated with an increase in inflammation and inflammation is, in turn, correlated with Parkinson’s development (Chen, 2013). Figure 5 shows a simplified version of the inflammatory process which is associated with a diagnosis of PD, and which the novel vaccine may indirectly act upon.
Although these results alone appear promising, further data analysis revealed a second benefit of the optimized vaccine: significant decrease in presentation of the COX-2 enzyme. Cyclooxygenase (COX) enzymes allow for inflammatory effects, and it is these same inflammatory effects that are associated with Parkinson’s. As such, by minimizing COX-2 levels, specifically in the pars compacta and substantia nigra brain areas, the vaccine may provide neuroprotection to an individual (or at least a mouse) at risk for developing PD (Chen, 2013). Further research into this and other similar vaccines is of course needed, but the results of this study demonstrate important possibilities for the future of Parkinson’s prevention.
Parkinson’s Disease is a progressive, neurodegenerative illness currently diagnosed in over 1.5 million U.S. Americans. Despite its prevalence, however, the disease is thus far incurable, and treatment is minimal, and often presents with side effects. Several drugs have been developed to minimize the hypokinesic symptoms characteristic of PD, the most common of these being levodopa. L-DOPA, as with other PD drugs, though reasonably effective at reducing severity of otherwise-debilitating symptoms, induces many chronic, adverse effects if taken long-term. Recent studies have analyzed ways by which to mitigate these side effects, other than ceasing administration of the drug altogether. There seems to be future direction in the application of rTMS treatment, namely rTMS pulses over the right dorsolateral prefrontal cortex. Additionally, co-administration of antipsychotics such as clozapine has also been suggested, though further research is needed in order to determine the degree to which this strategy may be sufficiently effective in the general population. Although these retroactive measures are vital to investigate further, in order to increase possibilities in treating PD symptoms once they have developed, the approval of a preventative strategy would be revolutionary. There will be no need to treat PD if no one develops it in the first place. Recently, there has been research into the possibility of a novel vaccine, developed in order to reduce cellular inflammation caused by excessive levels of the protein a-syn, and the maladaptive folding it displays in the brains of patients afflicted with neurodegenerative diseases (Maguire-Zeiss, 2010). This cellular inflammation contributes largely to the neuronal degeneration that ultimately induces symptoms of Parkinson’s Disease and so, this newly-created vaccine may have the potential to greatly reduce the likelihood of an at-risk individual developing PD. Thought there is evidence to support each of these new treatment possibilities, further research is needed into each before one of these novel strategies can be added to the currently-small number of approved regimens. Much improvement has been made in the last few years in terms of knowledge regarding Parkinson’s Disease, and development of potential new treatments, however, there is still much to be discovered and research must continue until the devastating illness no longer poses a threat to any citizen of the world.
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