Clinical Updates, Awareness Efforts During Parkinson's Awareness Month

PATHOPHYSIOLOGY

Parkinson disease (PD) is a progressive neurodegenerative movement disorder. It results from the depletion of dopaminergic neurons in the substantia nigra; dopamine deficits may be the result of neuronal impairment or death.

The substantia nigra within the central nervous system serves as the coordination center for movement, motor initiation and structuring, as well as postural regulation and reflexes. Depletion of these cells affects the extrapyramidal motor system, thus resulting in the debilitating symptoms associated with PD.^1,2

ETIOLOGY AND DIAGNOSIS

The specific etiology of PD is unknown. A primary risk factor is increasing age. The average age at onset of symptoms for PD is around 60 years. Some will have early-onset PD, which presents prior to 50 years of age.

Other risk factors include family history, environmental or toxin exposure, the male gender, and Caucasian race.³ There are currently no blood or laboratory tests to diagnose PD, but there are criteria that exist to either include or exclude PD in a presenting patient.

Some positive PD criteria include unilateral onset, resting tremor, bradykinesia, rigidity, progressive onset, and levodopa (L-DOPA) response. PD can be further characterized by severity level using the Hoehn and Yahr scale, provided in Table 1.1:^4-6

SYMPTOMS

PD may be difficult to diagnose due to the insidious onset of symptoms often attributed to the natural aging process, leading to diagnostic negligence.^1,3 The 4 main clinical manifestations of PD are resting tremor, bradykinesia, muscular rigidity, and impaired posture or gait (typically presenting later on).³

Although these are the most distinguishable symptoms of PD, they are not all-encompassing of the other symptoms that may affect a patient’s activities of daily living, such as depression, anxiety, pain, fatigue, urinary problems, constipation, diminished speaking volume, and cognitive impairment.⁴

MANAGEMENT OF PD

PHARMACOLOGICAL MANAGEMENT OF PD

Guideline-directed pharmacologic management of PD is sparce and rarely updated due to the limited therapeutic options and developments over the years. The goal of pharmacological management in PD is to control both the patient’s motor symptoms and non-motor symptoms that affect daily living.⁶

Table 1.2 is provided to serve as a guide in understanding the pharmacotherapies available for PD, as well as their use, benefits, and complications:^1,3,6

There is little evidence to support effective uses of natural medicines for either the prevention or progression of PD. Some neuroprotective drug candidates may include caffeine, co-enzyme Q10, creatine, nicotine (although not recommended), and antioxidants such as vitamins C and E.⁶

MOTOR COMPLICATIONS

There are multiple motor complications that can present from either the disease progression or treatment options utilized. Almost all patients on long-term L-DOPA treatment will lose motor control, which commonly present as “early wearing off” or fluctuations in “on-off” states.³

Thus, initiation of L-DOPA should begin with the lowest effective dose to further delay dyskinesia manifestations. Another motor complication, defined as start hesitation, or “freezing,” is typically managed by the addition of MAO-B inhibitors or dopamine agonists.^3,6

NON-PHARMACOLOGICAL MANAGEMENT OF PD

Physical activity has been associated with both functional and motor benefits. Exercise strategies may include balance therapy, tai chi, resistance training, and physical therapy. For patients whose symptoms are refractory to drug therapy or limited by drug adverse effects, treatment of motor symptoms may include the following:⁷

• Deep Brain Stimulation—a surgical procedure to reduce movement-related symptoms²
• Low-frequency repetitive transcranial magnetic stimulation (rTMS)⁷
• Magnetic resonance imaging (MRI)-guided focused ultrasound thalamotomy⁷

CLINICAL RESEARCH

Although there have been few new developments of pharmacologic options for patients with PD in the past few years, clinical research is continuously underway for better therapeutic management and etiologic understanding.

A recent study in 2019 first demonstrated that administration of Ibogaine, an atypical psychedelic alkaloid, altered expression of glial cell-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor, and nerve growth factor transcripts in areas of rat brains relative to dopamine neurotransmission.

This is a potential area of interest for PD research due to the involvement of the nigrostriatal pathway in neurodegenerative diseases. If Ibogaine could be analyzed using an experimental model of PD, its potential to attenuate cell loss in the substantia nigra, as well as its biochemical changes at the striatum, could be determined.⁸

As of March 26, 2021, Forest Hills Lab announced their plans to apply for phase 2 of a clinical trial evaluating the tolerability and efficacy of FHL-301 in PD patients. FHL-301 is reported to be a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, which binds to peroxisome proliferator response elements located in the promoter region of GDNF.

This would lead to an upregulation in GDNF gene transcription, which may work to restore damaged nerve cells, specifically dopamine producing cells. However, GDNF’s role in PD treatment is still misunderstood.^9,11

WHAT CAN WE DO?

There are multiple ways to promote involvement in PD research and understanding. What better way to begin your involvement than during Parkinson’s Awareness Month? Below are common, reputable organizations that strive to dedicate their time to such causes.^9-12

Parkinson's Foundation

The Michael J. Fox Foundation

American Parkinson Disease Association

Parkinson's News Today

Below is a quiz created by the Parkinson’s Foundation to test your knowledge of PD in a fun way:¹⁰

#KnowMorePD

Whether it be through volunteering or staying up-to-date on the latest research endeavors in PD, each effort taken can lead to a raised awareness in discovering the cause and cure for PD.

REFERENCES

1. Pahwa R, Lyons KE. Early diagnosis of Parkinson's disease: recommendations from diagnostic clinical guidelines. Am J Manag Care. 2010;16 Suppl Implications:S94-S99.
2. National Institute on Aging. 2021. Parkinson's Disease. (online) Available at: https://www.nia.nih.gov/health/parkinsons-disease (Accessed 26 March 2021).
3. Lang AE et al. New England Journal of Medicine 1998;339(15):1044, 1049-50. Olanow CW et al. Neurology. 2001;56(supplementary 5):51
4. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol. 1999;56(1):33-39. doi:10.1001/archneur.56.1.33
5. National Institute for Health and Care Excellence (UK). Parkinson’s disease in adults: diagnosis and management. London: National Institute for Health and Care Excellence (UK); July 2017.
6. National Collaborating Centre for Chronic Conditions (UK). Parkinson's Disease: National Clinical Guideline for Diagnosis and Management in Primary and Secondary Care. London: Royal College of Physicians (UK); 2006.
7. Reference: Homayoun H. Parkinson Disease. Ann Intern Med. 2018;169(5):ITC33-ITC48. doi:10.7326/AITC201809040
8. Marton S, González B, Rodríguez-Bottero S, et al. Ibogaine Administration Modifies GDNF and BDNF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits. Front Pharmacol. 2019;10:193. Published 2019 Mar 5. doi:10.3389/fphar.2019.00193
9. Parkinson's News Today. 2021. Parkinson’s News Today Home. (online) Available at: https://parkinsonsnewstoday.com (Accessed 26 March 2021).
10. Parkinson's Foundation. 2021. Parkinson's Foundation | Better Lives. Together.. (online) Available at: https://www.parkinson.org (Accessed 26 March 2021).
11. The Michael J. Fox Foundation for Parkinson's Research | Parkinson's Disease. 2021. The Michael J. Fox Foundation for Parkinson's Research. (online) Available at: https://www.michaeljfox.org (Accessed 26 March 2021).
12. APDA. 2021. American Parkinson's Disease Association. (online) Available at: https://www.apdaparkinson.org (Accessed 26 March 2021).