By Claire E. O’Hanlon, Shannon D. Donofry, Cheryl Coon, David Dexter, Sonya Eremenco, Catherine Kopil, Helen Matthews, Vicki Miller, Diane Stephenson, Angela Taylor, and Yuge Xiao

Cognitive changes are common among people with Parkinson’s disease (PD), and people with PD have an increased risk of developing dementia, which affects over 55 million people worldwide. While Alzheimer’s disease is the most common cause of dementia, approximately 10-15% of people with dementia have dementia with Lewy bodies (DLB). Doctors and researchers are optimistic about the potential of future treatments for PD and DLB, but available measures to test the efficacy of such treatments  on cognition are lacking.

Dementia is often characterized by the accumulation of proteins in the brain, including amyloid, tau, and synuclein. People with PD and DLB often share the common underlying feature of the buildup of alpha-synuclein. Recent scientific advances that enable detection of alpha-synuclein have led to a new unified way that scientists look at PD and DLB, a single disease with varying signs and symptoms. When PD and DLB are caused by the buildup of alpha-synuclein, they are now sometimes referred to collectively as Neuronal Synuclein Disease (NSD).

Currently, available treatments for PD and DLB have limited effects on the cognitive changes experienced by many patients.

New drugs that target the buildup of alpha-synuclein and could slow or halt progression of PD and DLB may be on the horizon. But even if such treatments were developed, the tools currently available to measure cognition in people with PD and DLB may not be suited for the job.

Many of the tools available to measure cognitive changes have been designed and tested in people with Alzheimer’s disease, but people with PD and DLB tend to have different experiences of cognitive changes. For example, people with DLB are less likely to experience memory loss early on than patients with Alzheimer’s disease.

If cognitive changes are in other domains, like ability to concentrate or navigate, measuring cognitive changes in a person with PD or DLB with a tool that primarily assesses memory would not make sense. Further, many cognitive measures are best suited to measuring cognitive changes in people with significant levels of impairment and do not detect subtle or intermittent changes very well.

Measuring cognitive change is complex and can be done in many ways. Patients can report on their own experiences of cognitive change; loved ones may also be able to observe and report on such changes, as can health care professionals. In addition to their experiences of cognition, patients and their loved ones may report on how these cognitive changes affect ability to work, drive, manage money, and communicate. Patients can also undergo tests and assessments of their cognitive abilities, which could be as simple as a paper-and-pencil test and as complex as a virtual reality game simulating activities like preparing a grocery list and navigating to a store.

Given the multitude of potential ways cognitive changes can be measured, it has been difficult to determine which measures are the most appropriate for assessing whether new treatments effectively improve cognition. Choosing a cognitive measure that is not well-suited for this purpose can lead to a treatment being rejected for approval by regulatory agencies, creating significant delays in getting effective treatments to patients.

To tackle these issues, a recent roundtable hosted by seven international PD and DLB advocacy organizations convened experts to discuss and advance development of cognitive measurement tools for PD and DLB. This event, part of ongoing efforts to improve measurement tools for clinical trials since 2022, brought together a diverse group of stakeholders, including researchers, clinicians, patients, and representatives from regulatory agencies.

Discussions at the meeting concerned tradeoffs in the design of clinical trials, appropriateness of existing cognitive measures for use in such trials, and efforts to adapt existing cognitive measures or develop new cognitive measures better suited for detecting cognitive changes in people with PD and DLB. Key takeaways include the need for strong alignment between the patient population a new treatment was developed for, domains of cognition that the treatment intends to target, domains covered by the cognitive measure chosen, and meaningfulness of the measures to patients and their loved ones. Steps to improve communication, collaboration, and data sharing among stakeholders were outlined, including an assessment of how existing cognition measures change over time and integration of datasets, especially those with biomarker indicators of disease stage.

People with PD and DLB cannot afford for potential new treatments to be rejected by regulators because the measurement tools used to evaluate cognitive changes were not appropriate.

At this point, there is no single path forward, as no single measure has yet emerged as the best option for measuring cognitive changes in people with PD and DLB, especially for patients at the earliest stages of disease. For now, multiple paths will need to be pursued in parallel to generate the evidence necessary for successful clinical trials of future treatments.

Claire E. O’Hanlon is an associate policy researcher and Shannon D. Donofry is a behavioral scientist at RAND. Catherine Kopil is senior vice president of clinical research and Yuge Xiao is associate director of clinical research at The Michael J. Fox Foundation for Parkinson’s Research. David Dexter is director of research at Parkinson’s UK. Diane Stephenson is executive director of the Critical Path for Parkinson’s Consortium, Sonya Eremenco is executive director of the Patient Reported Outcome Consortium, and Cheryl Coon is vice president of the Clinical Outcome Assessment Program, all at the Critical Path Institute. Vicki Miller is chief executive officer of the Shake It Up Australia Foundation. Helen Matthews is chief executive officer of Cure Parkinson’s. Angela Taylor is vice president of strategic partnerships at the Lewy Body Dementia Association.