Digital Motor and Cognitive Variability as Early Markers of the Prodromal Parkinson's Disease Spectrum

Understanding Parkinson's Disease: The Prodromal Stage

Parkinson's disease (PD) is a neurodegenerative disorder that affects millions worldwide, with symptoms ranging from tremors and stiffness to cognitive decline and dementia. However, the early stages of PD are often characterized by subtle motor and cognitive impairments, making diagnosis challenging. Researchers have been exploring digital tests to detect these early signs, which may serve as valuable markers for the prodromal Parkinson's disease spectrum.

Individuals with isolated REM sleep behaviour disorder (iRBD) often exhibit motor and cognitive dysfunction before developing clinical synucleinopathy, a hallmark of PD. Performance instability may represent an earlier marker of neurodegeneration, but remains underexplored using digital tests. The objectives of this study were to assess baseline and longitudinal differences in motor and cognitive performance, and examine performance variability in iRBD and related phenotypes.

Methodology and Study Design

Three PD-risk-stratified prodromal cohorts were compared with healthy controls:

• Normosmic probable RBD (pRBD): Participants with normal olfactory function and probable RBD
• Hyposmic pRBD: Participants with impaired olfactory function and probable RBD
• Polysomnography-confirmed iRBD (PSG-iRBD): Participants with confirmed iRBD through polysomnography

Participants completed the following digital tests:

• BRadykinesia Akinesia Incoordination (BRAIN) test: Assesses motor function, including kinesia, akinesia, and incoordination
• Distal Finger Tapping (DFT) test: Evaluates motor speed and coordination
• Trail Making Test (TMT): Assesses cognitive function, including executive function and processing speed

Key Findings and Data Analysis

At baseline, PSG-iRBD participants showed greater motor and cognitive impairment than controls, while hyposmic pRBD demonstrated intermediate deficits and normosmic pRBD participants showed milder but significant impairments. Linear mixed-effects models showed no change in motor trajectories across all groups, while executive function declined significantly in PSG-iRBD (p=0.001). However, variance modelling showed widespread variability.

Cognitive variability was elevated in PSG-iRBD and hyposmic pRBD participants (MSSD p<0.035), and heteroscedastic modelling captured significant visit-specific motor instability across all prodromal cohorts on the BRAIN test (all p<0.02).

Performance variability precedes measurable linear decline across PD-risk stratified groups. Remote digital testing offers a scalable framework to capture this early instability.

Implications for Early Detection and Intervention

The findings of this study have significant implications for early detection and intervention in PD. By identifying performance variability as an early marker of neurodegeneration, healthcare providers can initiate targeted interventions to slow disease progression. Remote digital testing provides a convenient and accessible means of monitoring motor and cognitive function, enabling timely diagnosis and treatment.

Future Directions

Future research should focus on validating these digital tests in larger cohorts and exploring their potential as biomarkers for PD. Additionally, studies should investigate the efficacy of targeted interventions in slowing disease progression and improving quality of life for individuals with PD.