When Sex Overcomes Motor Phenotype: New Evidence on Cognitive and Neurobehavioral Symptoms in Parkinson's Disease

Background Sex‐based differences in cognitive and behavioral symptoms have been previously reported in Parkinson's disease (PD), as well as the effects of motor lateralization and phenotypes at onset. However, no studies investigated the interaction between these variables. Objective We aimed to evaluate whether sex differences interact with motor phenotype and lateralization at the onset of cognitive and neurobehavioral symptoms. Methods: Data from 304 PD patients (119 women and 185 men) were retrospectively examined, including comprehensive neurologic, neuropsychological, and neurobehavioral assessments. MANCOVAs on tests divided based on the results of a principal component analysis were performed to compare cognitive and behavioral performance, considering sex, motor phenotype at onset, and onset lateralization as grouping variables. Analyses were also performed on a subsample of patients ( n = 200) in which subgroups were balanced in terms of motor and demographic features. Results: Significant sex effects were found, with females showing higher performance compared to males in verbal long‐term memory ( p = 0.00003), social cognition ( p = 0.0001), and naming tasks ( p = 0.03009). Significant interactions between motor phenotype and sex were found: rigid‐akinetic (RA) females showed higher performance than other groups in a verbal memory task ( p = 0.0183), and tremor‐dominant (TD) females made more errors than the other groups in an inhibitory control task ( p = 0.03853). Interestingly, RA females performed better on verbal learning than tremor‐dominant (TD) males ( p = 0.00911), suggesting that sex effects overcome motor phenotype in this cognitive function. No significant interactions were found between sex and lateralization at onset concerning cognitive variables. However, patients with right‐sided onset, in particular females, self‐reported higher levels of behavioral symptoms. Conclusions: These results emphasize the complex relationship between demographic and PD motor features in delineating the clinical phenotype, which should be considered in designing patient‐tailored strategies for disease monitoring and intervention.