Disease modification and biomarker development in Parkinson disease: Revision or reconstruction?

Abstract

A fundamental question in advancing Parkinson disease (PD) research is whether it represents one disorder or many. Does each genetic PD inform a common pathobiology or represent a unique entity? Do the similarities between genetic and idiopathic forms of PD outweigh the differences? If aggregates of α-synuclein in Lewy bodies and Lewy neurites are present in most (α-synucleinopathies), are they also etiopathogenically significant in each (α-synuclein pathogenesis)? Does it matter that postmortem studies in PD have demonstrated that mixed protein-aggregate pathology is the rule and pure α-synucleinopathy the exception? Should we continue to pursue convergent biomarkers that are representative of the diverse whole of PD or subtype-specific, divergent biomarkers, present in some but absent in most? Have clinical trials that failed to demonstrate efficacy of putative disease-modifying interventions been true failures (shortcomings of the hypotheses, which should be rejected) or false failures (shortcomings of the trials; hypotheses should be preserved)? Each of these questions reflects a nosologic struggle between the lumper's clinicopathologic model that embraces heterogeneity of one disease and the splitter's focus on a pathobiology-specific set of diseases. Most important, even if PD is not a single disorder, can advances in biomarkers and disease modification be revised to concentrate on pathologic commonalities in large, clinically defined populations? Or should our efforts be reconstructed to focus on smaller subgroups of patients, distinguished by well-defined molecular characteristics, regardless of their phenotypic classification? Will our clinical trial constructs be revised to target larger and earlier, possibly even prodromal, cohorts? Or should our trials efforts be reconstructed to target smaller but molecularly defined presymptomatic or postsymptomatic cohorts? At the Krembil Knowledge Gaps in Parkinson's Disease Symposium, the tentative answers to these questions were discussed, informed by the failures and successes of the fields of breast cancer and cystic fibrosis.

Figure 1. Venn diagrams of the revision vs reconstruction models for PD

Each numbered circle represents a distinct biological entity or disease. Left, a model warranting reconstruction. While the diseases are related to one another, they are mostly unique; most biological elements are not shared. According to this model, if α-synuclein (α-syn) is common to all or most forms of PD, it cannot be pathogenic to each; genetic Parkinson disease (PD) subtypes inform about those subtypes and not others. Right, a model best served by revision. All diseases have more in common with one another; their uniqueness is mostly theoretical given the large overlap. This model does not discount a potential important role for α-syn in many or all of the diseases; a therapy that might work for a genetic PD subtype may work for others. The model also allows the explanation that PD may involve multiple pathways, and if we can fix one of them, we could delay sporadic PD by years.

Figure 2. Planned adaptation allows learning and confirming in adaptive clinical trials

Only planned adaptations can be guaranteed to avoid unknown biases resulting from the adaptation (from Kairalla et al.). GS = Group sequential; SSR = Sample-size re-estimation.

Figure 3. Platform trial example

It allows multiple drugs examined from the outset, which can be removed or combined (e.g., A + C). It also permits new drugs (D) to be examined at a later time point in the same trial.