Stanley Fahn Presidential Lecture Award
Using precision medicine for Parkinson’s disease prevention
We are starting to unravel how a person’s unique biology could affect their treatment. Dr. Caroline Tanner provides updates.
I am humbled and honored to give the Stanley Fahn Presidential Lecture. Stan is a founder not only of our Society, but also of the field of Movement Disorders. I met Stan as a young neurologist through the Parkinson Study Group, another of his exceptional contributions, in the early days of the Society and the journal. He was a mentor to me, and to many others, always providing thoughtful advice and encouragement. Stan is truly a role model not just as a clinician scientist, teacher, and leader, but also as an exceptional human being.
My work includes epidemiologic studies of environmental and genetic factors, and clinical studies seeking biomarkers and disease modifying treatments. In this lecture, I will apply a combination of public health and precision medicine principles to Parkinson’s disease (PD) prevention.
Prevention includes 3 goals:
- Primary prevention identifies and removes causes so disease does not develop
- Secondary prevention identifies the disease processes and intervenes to prevent symptom onset
- Tertiary prevention reduces the burden and slows progression in manifest disease
Our understanding of prevention often stems from studies in large populations. In contrast, precision medicine focuses on the individual, providing personalized treatment taking into account genes, environment, and lifestyle to fulfill the 3 requirements of risk stratification, early detection of pathophysiologic processes, and intervention to target the specific molecular pathophysiology in that person.
For example, in population studies, we found occupational exposure to the pesticide paraquat or to the chlorinated solvent trichloroethylene (TCE) increases the risk of PD. Occupation, including specific job tasks and exposures, therefore is important for risk stratification. For paraquat, behavioral and genetic factors modify risk, adding risk stratification categories. For TCE, residential exposure (through contaminated water or concentration of this volatile organic compound in buildings) provides another risk stratum. Routinely incorporating information on occupation, residence, behavior, and lifestyle along with genotype will improve risk stratification for precision medicine in PD.
Detecting misfolded alpha-synuclein aggregates in biofluids may provide a powerful approach to identify people in the earliest stages of disease, consistent with the precision medicine requirement of early detection. In the CSF of Parkinson’s Progression Markers Initiative participants, misfolded alpha-synuclein detected by seeding amplification assay (SAA) was detected in people with hyposmia, REM Sleep Behavior Disorder, and PD, but not healthy controls. In other populations, misfolded alpha-synuclein was detected in people with DLB, but not PSP or other neurodegenerative parkinsonisms, while a different pattern was seen in MSA. Alpha-synuclein abnormalities appear to provide a sensitive and specific biomarker for a neuronal synuclein disease with a single biology, but different clinical syndromes.
Screening for alpha-synuclein abnormalities in individuals in higher risk strata (considering occupational and environmental toxicant exposures, behaviors, lifestyle, and genotype) provides an opportunity for secondary prevention. Improved biological characterization also provides a foundation for treatments targeting each person’s biology. Clinical trials – and eventually, clinical practice — can identify individuals most likely to benefit from a specific treatment based on that person’s biology.
Applying precision medicine principles, starting with population-based risk stratification, incorporating individual-specific risk and biomarker profiles, will speed progress to prevention and reducing the global burden of PD.