Measuring Cognition in Clinical Trials in Parkinson's Disease, Dementia with Lewy Bodies, and Related Disorders: Roundtable Proceedings and Roadmap for Research

Cognitive changes are among the most worrisome symptoms related to the clinical syndromes associated with Parkinson's disease (PD); dementia with Lewy bodies (DLB); and related disorders on the PD/DLB spectrum, such as rapid eye movement (REM) sleep behavior disorder (RBD).¹ Treatments that address the cognitive changes associated with these clinical syndromes remain an area of high unmet need because of these changes' significant impact on daily function and quality of life. While the cognitive changes experienced by individuals with PD who develop mild cognitive impairment (MCI) share some clinical characteristics with patients who have undiagnosed or prodromal DLB,² these changes are distinct from those experienced by patients with MCI attributable to other types of dementias, such as Alzheimer's disease (AD). For example, patients with early clinical DLB are less likely to experience memory loss than patients with AD.³ Cognitive assessments developed for AD thus might not be fully adaptable to the distinct clinical profiles of the PD/DLB spectrum. Despite a multitude of clinical outcome assessments (COAs) of cognition, there is no clear clinical development or regulatory path for novel therapies that address mild cognitive dysfunction in disorders on the PD/DLB spectrum.⁴

To spur the adaptation of existing cognition-focused measures and the development of new ones to underlie clinical trial endpoints in PD, DLB, and related disorders, The Michael J. Fox Foundation for Parkinson's Research (MJFF), Shake It Up Australia Foundation, Parkinson's UK, Parkinson Canada, Lewy Body Dementia Association, Cure Parkinson's, and the Critical Path for Parkinson's Consortium co-hosted the PD/DLB Cognition Roundtable on January 10 and 11, 2024, in Washington, D.C. The roundtable brought together representatives from academia and industry, as well as with representatives of regulatory agencies, community partners, patient advocates, and research funders, to build consensus and collaborate on the outcome assessment and trial design methods that will support the development of new treatments for initial or mild cognitive changes in disorders on the PD/DLB spectrum. The stated goals of the roundtable were as follows:

1. Align the field on addressing knowledge gaps in patient experience that will provide a critical foundation for developing regulatory acceptable endpoints for future clinical trials.
2. Assess trial design approaches in target populations, aligning disease biology and clinical course with cognitive measures.

The roundtable's ultimate goal was to identify and refine key opportunities to drive precompetitive, global, and patient-centered approaches to developing appropriate endpoints for early cognitive dysfunction in PD, DLB, and related disorders to accelerate drug development.

Key Takeaways

• Growing evidence supports reframing Parkinson's disease (PD) and dementia with Lewy bodies (DLB) as a single, biologically defined disease, called neuronal α-synuclein disease (NSD). Moving forward, patient populations included in clinical trials in PD and DLB may therefore increasingly be defined based on their biological features rather than their clinical presentation. This will influence the development and selection of clinical outcome assessments.
• Clinical trials that address cognitive impairment are challenging to design because competing factors influence whether a clinical outcome assessment is appropriate for use (i.e., fit for purpose). Researchers must strike a balance between defining patient populations broadly enough to encompass a wide range of individuals and ensuring that the patients within that population are homogeneous enough to detect meaningful changes in outcomes over the relatively short duration of a clinical trial. The patient population being studied must drive researchers' decisions about which clinical outcome assessment is most appropriate.
• Consensus is needed on which existing cognitive measures have the highest potential for use in clinical trials of treatments for PD and DLB, and in what context new measures are needed. The field lacks wide consensus regarding which existing measures are most appropriate for evaluating cognition in PD and DLB, introducing measure heterogeneity across treatment trials in these populations. New measures might also need to be developed and validated, and the field must align on the contexts in which this is effort would be warranted.
• Collaboration and data-sharing among academic, industry, and regulatory stakeholders will accelerate the development and validation of cognition measures to underlie clinical trial endpoints in PD and DLB. Next steps include comprehensive research syntheses of existing measures and their longitudinal performance, as well as harmonization and integration of existing datasets, particularly those that include biomarker data that can be used to characterize patients by biological stages of disease.