The New England Journal of MedicineParkinson’s Disease

Genetic and Environmental Factors Converge in Parkinson’s Disease Pathogenesis, Pointing to Potential New Therapeutic Targets

Parkinson’s disease (PD) continues to challenge clinicians with its complex interplay of genetic and environmental factors. Recent advances in understanding its etiology, progression, and management offer new insights for healthcare providers. This review article integrates two decades of research progress, highlighting the multifaceted nature of PD and the evolving landscape of treatment options.

Key Points:

• PD is clinically defined by motor symptoms (asymmetric bradykinesia, rigidity, tremor, and imbalance) and pathologically by neuronal degeneration and intraneuronal misfolded α-synuclein (Lewy bodies).
• Nonmotor symptoms, including hyposmia, REM sleep behavior disorder, and autonomic dysfunction, often precede motor symptoms by years.
• Genetic variants account for approximately 20% of PD cases, with LRRK2 and GBA1 being the most common causative genes.
• Environmental risk factors include exposure to pesticides, chlorinated solvents, and head injury, while physical activity may decrease risk.
• The global economic burden of PD is projected to increase from $52 billion in 2017 to $79 billion in 2037.
• Mortality adjusted for age and sex in PD patients is approximately 60% higher than in the general population.
• No current therapy definitively slows PD progression, despite numerous clinical trials.
• Levodopa remains the primary treatment for motor symptoms, but its effectiveness diminishes over time due to motor fluctuations.
• Deep brain stimulation (DBS) can significantly improve quality of life and motor fluctuations in appropriate candidates.
• Nonmotor symptoms, including cognitive decline, depression, and autonomic dysfunction, contribute substantially to disease burden but lack robust evidence-based treatments.
• Biomarkers for abnormal α-synuclein show promise in distinguishing PD from other neurological conditions with high sensitivity and specificity.
• Future directions in PD research include prevention strategies, addressing healthcare disparities, and leveraging technology for improved screening, monitoring, and treatment.

HCN Medical Memo
The landscape of Parkinson’s disease management is evolving rapidly. Although levodopa remains the cornerstone of motor symptom treatment, clinicians should be alert to early nonmotor symptoms and consider multidisciplinary care approaches. Emerging biomarkers and genetic testing may soon play a larger role in early diagnosis and personalized treatment strategies.

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