A Personalized Approach to Parkinson's Disease

Parkinson's Disease (PD) is the second most common neurodegenerative disorder in the world. The cause of the disease is unknown. Parkinson's defining symptoms are motor impairments, which manifest due to damage of neurons in the substantia nigra, a structure of the basal ganglia located in the midbrain. The damage of its neurons causes a reduction in the release of dopamine, resulting in a biochemical imbalance causing poor balance and motor coordination.

The treatment of Parkinson's Disease (PD) has long consisted of imprecise medications and therapies with low degrees of efficacy. Neurologists consider Parkinson's to be a highly variable disease, resulting in starkly different clinical profiles and with symptomology progressing at vastly different rates for different patients. Indeed, patients with Parkinson's report differing responses to the traditional mode of dopamine replacement therapy (DRT) and Levodopa medication. They also vary widely in their susceptibility to medication-related side effects such as dystonia, dyskinesia or hallucinations.

As the average age of the global population continues to increase, the frequency of PD is estimated to grow by four times by 2040. With the proliferation in incidence and onset of the disease, it is necessary to consider novel methods to treat Parkinson's Disease. Personalized medicine offers the greatest potential in improving patient outcomes and health as well as supporting considerable advances within the field.

Neurologists automatically categorize PD patients into a handful of clinical subtypes. Patients presenting with a tremor, for example, tend to have a more benign treatment course than patients presenting with gait and posture symptoms. Patients with an older age of disease onset tend to develop more aggressive symptomology sooner than patients with a much younger age of diagnosis.

Bas Bloem, professor of neurological movement disorders at Radboud University Medical Center and founder of ParkinsonNet, argues that it is high time we solved this puzzle.

"So now we have...five or six Parkinson's Disease phenotypes, whereas in reality there are 5 million Parkinson Disease phenotypes: corresponding to the 5 million people worldwide with Parkinson's, each with their own individual profile."

While they are inefficient and unrealistic to develop 5 million phenotypes, the goals of Bloem and his colleagues may lead to a much more precise granular profiling and effective treatment strategies. Currently, the most common form of treatment for Parkinson's Disease is levodopa (3,4-dihydroxy-l-phenylalanine), a naturally occurring intermediate in the pathway of dopamine synthesis.

Following the oral ingestion of the drug, levodopa is transported from the upper small intestine into the circulation. As a result of ongoing metabolism and distribution throughout the body, only a small portion of levodopa reaches the brain where it takes effect. Once levodopa reaches the brain, it is rapidly formed from aromatic L-amino acid decarboxylase (AAAD), a naturally occurring enzyme. The conversion to dopamine accounts for most of the pharmacologic effect of the drug by improving diminished motor function.

Over several decades of investigation, levodopa has become the preferred treatment for Parkinson's Disease with its ability to relieve motor symptoms and provide confirmation of the disease's diagnosis. Despite levodopa therapy being the gold standard of Parkinson's treatment, tremors sometimes persist and also retropulsive imbalance rarely improves. As well, intake of the drug over time leads to lower efficiency of the drug, causing patients to discontinue its usage as soon as two years after initial treatment. There is also a litany of adverse effects, including nausea, vomiting, postural hypotension and cardiac arrhythmia. Thus, the effects of levodopa remain uncertain. While levodopa has been proven to improve motor impairments in Parkinson's patients, there has been evidence to suggest that the drug may promote the progression of the disease, yet by no means is this conclusive as scientific literature largely varies in the interpretation of this effect.

The consideration of personal needs and the specific clinical phenotype of patients before prescribing is the basis of personalized medicine (PM). The National Human Genome Research Institute (NHGRI) maintains that a personalized medicine is an approach to medicine using "an individual's genetic profile to guide decisions made in regard to the prevention, diagnosis, and treatment of disease." Personalized medicine is an important consideration for multifactorial conditions such as PD and should be prescribed based on the susceptibility of specific subtypes of PD to side effects with consideration of lifestyle, age, nutrition, health status, environmental exposure and epigenetic factors.

The Personalized Parkinson Project (PPP), an international collaboration involving Radboud University, ParkinsonNet and Verily Life Sciences, aims to track 650 patients with early onset Parkinson's disease diagnosis (5 years or less), for a period of two years. Researchers plan to periodically measure a plethora of biological and performance metrics through brain imaging, spinal fluids, blood serum, plasma, DNA, and stool. Trained assessors will annually conduct detailed clinical exams. And, thanks to the Verily Study Watch, participants will be followed 24/7 outside the clinic as well. The PPP hopes to gather high quality physiological and environmental data, combining it to ascertain to what extent the known Parkinson's disease genes account for the variation in symptoms and individual rates of progression.

PD is now recognized as a multi system, multi neurotransmitter, heterogeneous, dysfunction-related disorder. Biomarker-driven evidence suggests that PD is a complex disease that could also present with non dopaminergic syndromes. Therefore, in a growing number of cases, the generic prescribing of DRT and Levodopa may not be sufficient in restoring motor function and health. There is a growing awareness of the "one size does not fit all" concept regarding mass treatment of PD. Scientists, however, are still unaware as to how the disease works or the extent to which genetics plays a role in the disease. Unlike other genetic diseases such as Huntington's, there is no single genetic signal for PD.

Personalized medicine relies on the inherent genetics of PD to determine susceptibility on an individual basis. Identifying at-risk individuals by widely known genetic markers in the prodromal stage of PD could aid precision medicine's ability to delay or stop its progression. This is especially important as neurologists often remark that Parkinson's is a highly variable disease, with tremendous divergence in clinical profiles, age, lifestyle and response to dopamine replacement therapies (DRT). Genome-wide association studies have identified PD loci, but still do not explain the bulk of the heritability issues with PD.

PD is rarely monogenic. However, autosomal dominant presentations can identify specific genes and gene products. Of specific interest is alpha-synuclein, a protein whose function is unknown, but forms a major constituent of Lewy bodies, abnormal aggregates of protein that develop inside nerve cells and which form the pathological hallmark of PD. Another area of interest is the increased frequency of PD in carriers of the mutated Glucocerebrosidase gene (GBA), which approximately 5% to 10% of PD patients possess. The GBA mutation is currently the single most important known factor in predicting PD. The enzyme that gene codes for, glucocerebrosidase, has a reciprocal relationship between its regular activity and alpha-synuclein function. Gaucher's Disease, a genetic disorder in which the sphingolipid glucocerebroside accumulate in cells, has been investigated as sharing similar mutations to PD.

The treatment of Parkinson's Disease remains largely monopolized by the use of levodopa, as discussed above, along with other dopamine replacement therapies. Although these treatments have the ability to improve motor functionality of PD patients, they are also shown to have a number of unwanted adverse effects and inefficiencies. Nevertheless, the treatment offers unlimited potential due to the individual, rather than collective, nature of personalized medicine. The field has continued to make significant progress in identifying the neuropathological and genetic risk and causal factors that may underlie PD. The personal genomics company 23andMe sifted through DNA samples from more than 2 million customers, identifying more than a dozen new mutations. Technological advances in molecular profiling and neuroimaging will allow us to better dissect disease subtypes and target therapies to those most likely to benefit. Still, truly transforming PD treatment into a precision approach will require tackling key research and regulatory challenges and the effort of the entire PD community.

To reach this stage, a comprehensive strategy is needed. Firstly, biosamples must be more accessible for scientists, as 23andMe have done. We must also partner with patients and their families to create a diverse and representative picture of Parkinson's Disease to better understand its plethora of genetic variants. It is also necessary to continue to generate intensive molecular profiling from a number of cellular pathways, including neuroinflammation and oxidative stress, to attempt to create a clearer picture of PD and its causes. Finally, we must drive biomarker validation towards a personalized medicine approach, rather than one championed by traditional medicine. In this way, we can create well defined biomarkers to identify patients and prescribe drugs appropriate for their condition, genetics lifestyle, and many other factors.