Prediction of Cognitive Heterogeneity in Parkinson's Disease: A 4‐Year Longitudinal Study Using Clinical, Neuroimaging, Biological and Electrophysiological Biomarkers

Objective Cognitive impairment in Parkinson's disease (PD) can show a very heterogeneous trajectory among patients. Here, we explored the mechanisms involved in the expression and prediction of different cognitive phenotypes over 4 years. Methods In 2 independent cohorts (total n = 475), we performed a cluster analysis to identify trajectories of cognitive progression. Baseline and longitudinal level II neuropsychological assessments were conducted, and baseline structural magnetic resonance imaging, resting electroencephalogram and neurofilament light chain plasma quantification were carried out. Linear mixed‐effects models were used to study longitudinal changes. Risk of mild cognitive impairment and dementia were estimated using multivariable hazard regression. Spectral power density from the electroencephalogram at baseline and source localization were computed. Results Two cognitive trajectories were identified. Cluster 1 presented stability (PD‐Stable) over time, whereas cluster 2 showed progressive cognitive decline (PD‐Progressors). The PD‐Progressors group showed an increased risk for evolving to PD mild cognitive impairment (HR 2.09; 95% CI 1.11–3.95) and a marked risk for dementia (HR 4.87; 95% CI 1.34–17.76), associated with progressive worsening in posterior‐cortical‐dependent cognitive processes. Both clusters showed equivalent clinical and sociodemographic characteristics, structural magnetic resonance imaging, and neurofilament light chain levels at baseline. Conversely, the PD‐Progressors group showed a fronto‐temporo‐occipital and parietal slow‐wave power density increase, that was in turn related to worsening at 2 and 4 years of follow‐up in different cognitive measures. Interpretation In the absence of differences in baseline cognitive function and typical markers of neurodegeneration, the further development of an aggressive cognitive decline in PD is associated with increased slow‐wave power density and with a different profile of worsening in several posterior‐cortical‐dependent tasks. ANN NEUROL 2024