THIS SESSION was held at the 18th World Congress on Controversies in Neurology (CONy), held in London, UK, from the 21st-23rd March 2024. The integration of precision medicine in Parkinson’s disease (PD) treatment was posed as a debate in this session, with two guest speakers arguing for each side: Ray Chaudhuri, Parkinson’s Foundation Centre of Excellence, King’s College Hospital, UK, was arguing for, whilst Evžen Růžička, Department of Neurology, Charles University, and General University Hospital, Prague, Czechia, argued against.
FOR
PD is characterised by the degeneration of non-dopaminergic pathways, resulting in motor symptoms such as tremors, dystonia, and rigidity, among others. These symptoms can be present from the prodromal phase, in which the patient does not yet fulfil full diagnostic criteria, through to the palliative stage.
By definition, precision medicine is tailored treatment that factors in a patient’s genetics, environment, and lifestyle, in order to select the optimal approach. As discussed, it aims to save side effects, and optimise targeted and time interventions, based on an individual’s molecular profile. Several genetic polymorphisms were highlighted as potential therapeutic targets, namely mutation carriers of the GBA gene, encoding lysosomal enzyme glucocerebrosidase, or leucine-rich repeat kinase 2, are found to be at greater risk of PD. Genomic medicine can be used to detect this at the pridomal stage, such as histone deacetylase inhibitors or leucine-rich repeat kinase 2 kinase inhibitors, respectively.
Citing a nationwide population-based study, comprised of 248,597 current cases, Chaudhuri subsequently stressed an important association between recently raised anticholinergic burden and risk of acute cardiovascular events. From this, he emphasised the importance of clinical subtypes in PD precision medicine, in which patients are subtyped based on clinical manifestation, genetics, phenotypic biomarkers, and outcomes. The purpose of this subtyping is to better predict disease progression and treatment responses, and to identify therapeutic targets for disease modification.
Expanding further on the importance of clinical subtyping, Chaudhuri referenced stories in which patients with PD, taking pramipexole and ropinirole, had fallen asleep at the wheel whilst driving. There is now known to be a narcoleptic subtype of PD, which comprises approximately 10% of all patients. Clinical subtyping in precision medicine would therefore help identify these patients, minimising wrongful treatment administration in the future.
AGAINST
Růžička contested the adoption of precision medicine in PD treatment, citing several drawbacks. He highlighted that PD subtypes have not yielded substantial results, due to a lack of replication and validation across various cohorts and research papers. Conventional subtyping methods are static, capturing subtyping variables only in a single snapshot, while symptoms, treatments, and responses evolve over time. Furthermore, understanding of the molecular, genetic, and protein structures contributing to disease progression, especially in genetic PD subtypes, remains incomplete.
Růžička emphasised that relying solely on clinical phenotype is insufficient to predict responses to molecular or biological interventions aimed at modifying the disease. Most biomarker studies in PD have primarily focused on diagnosis rather than phenotype, resulting in biomarkers common to broad PD populations, but with unclear relevance to individual pathophysiology or subtyping.
Regarding PD biomarkers, Růžička discussed their strengths and limitations. For instance, there is a lack of evidence indicating that positive biomarkers accurately reflect protein aggregation in the brain. While identifying biomarkers related to protein misfolding in PD pathology is significant, it only addresses the pathology rather than the underlying pathogenesis, offering outcomes rather than causative factors. Lastly, PD’s clinically heterogeneous nature, stemming from various aetiologies, genetic risks, and biological factors, cannot be attributed solely to the accumulation of a single protein product.
