Cognitive Functions Impairment as a Novel Paradigm for Delineating Cognitive
Dysfunction in Parkinson’s Disease (PD-CFI)

Current approaches for diagnosing cognitive dysfunction/impairment in Parkinson’s disease (PD) utilize a limited approach of classifying the patients into categories of mild cognitive impairment (abbreviated as PD-MCI) and dementia (abbreviated as PD-D), both of which are then limited to labels of either “Yes” or “No”. In sharp contrast, cognitive impairment in PD can vary for different patients in terms of severity on a continuous scale. Furthermore, cognitive impairment in PD is heterogenous in nature, given that there is selective impairment of specific cognitive functions and only a subset of patients develop it early in the disease. In addition, PD-MCI and PD-D approaches of classifying cognitive dysfunction make a rather superficial use of neuropsychological/cognitive testing data for diagnostic conclusions, and thus fail to capture the richness of these data. The categorical PD-MCI and PD-D classification also have limited ability to accurately reflect on progression, as patients can remain labelled only in either of these two categories several years despite having worsening in their cognitive function. Thus, several key aspects of cognitive dysfunction in PD are not fully addressed by the currently available classification schemes.

The PD-CFI project aims to address the above issues by developing and testing a new approach to study cognitive impairment in PD, with $1.2 million funding from the Investigator Initiated Research Award over 3 years from September 2023 to August 2026. This collaborative and interdisciplinary project is being led by the  principal investigator Deepak K. Gupta, MD, MS at the University of Vermont in collaboration with  co-investigators Satya S. Sahoo, PhD at Case Western Reserve University and Amie Hiller, MD, MCR at the Portland Veterans Affairs Medical Center. Other project personnel include two neuropsychologists (Brenna Cholerton, PhD at the Stanford University, Abigail Ryan, PhD at the University of Vermont Medical Center), a biostatistician researcher (Curtis Tatsuoka, PhD at University of Pittsburgh), a scientific advisor (Cyrus Zabetian, MD at University of Washington) and a patient advisor (Rebecca Miller, PhD at Yale University). Specifically, the project team will apply a novel statistical modelling technique, called partial ordered set (POSET), for developing the PD-CFI classification scheme (scores) using extensive data developed specifically for studying cognitive impairment in PD. They also plan to validate the PD-CFI classification scheme using an artificial intelligence (machine learning) method in a multi- center clinical research study.

Potential applications of this research in clinical care and clinical trials are, but not limited to: 1) new method of diagnosing cognitive impairment in PD in clinical care, clinical trials, and other clinical research; 2) detailed characterization of impairment of different cognitive functions; 3) identification of PD patients early on who are more likely than others to develop cognitive impairment after new diagnosis of PD; and 4) predict the rate of progression of cognitive impairment on a continuous scale. The deliverables of this project, specifically PD- CFI classification scheme for cognitive dysfunction in PD, will be ready to serve as a patient-related outcome by the end of this project. In the short term, this research project will have two major impacts: 1) address critical needs to develop novel approaches to study and classify the cognitive impairment in PD at levels of specific cognitive functions and on a continuous scale, and 2) enable computer-aided diagnosis of cognitive impairment and predict its progression for an individual patient at point- of-care. In the long term, this research project will produce data to 1) support application of PD-CFI approaches to further distinguish subtypes of PD and differentiate early on from atypical parkinsonian disorders (such as Lewy body dementia), and 2) enable development of treatments by serving as a biomarker (proxy) of progression of cognitive impairment in clinical trials.

Pictured above (from left to right and top to bottom): Dr. Ryan, Dr. Gupta, Dr. Sahoo, Dr. Cholerton, Dr. Tatsuoka, Dr. Hiller and Dr. Zabetian from the PD-CFI project virtual pre-planning meeting on Friday, August 18^th, 2023. Dr. Miller was not available to join the meeting.