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

## TL;DR

The study finds that sex differences in Parkinson's disease influence cognitive and behavioral symptoms, sometimes overriding motor characteristics.

## Contribution

The study is the first to investigate how sex interacts with motor phenotype and lateralization in non-motor symptoms of Parkinson's disease.

## Key findings

- Females outperformed males in verbal memory, social cognition, and naming tasks.
- RA females performed better in verbal memory than TD males, indicating sex may override motor phenotype.
- Right-sided onset, especially in females, was linked to higher depression and anxiety.

## Abstract

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.

We aimed to evaluate whether sex differences interact with motor phenotype and lateralization at the onset of cognitive and neurobehavioral symptoms.

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.

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.

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.

Patients with Parkinson's disease (PD) show variability in clinical manifestations, with symptoms depending on sex, type, and their lateralization at onset (motor phenotype and lateralization). While these factors have been investigated individually, their interaction has not. Therefore, the aim of our study was to verify how sex differences interact with motor features to affect non‐motor symptoms. To do this, we collected data from 304 patients (119 women and 185 men), who underwent assessment of motor symptoms, cognitive abilities, and mood disturbances. Statistical analyses were performed on cognitive and behavioral performance, considering sex, motor phenotype, and lateralization at onset as grouping variables. We found significant sex differences across multiple cognitive domains: women outperformed men in verbal memory and naming and emotion recognition, while men performed better in visuospatial tasks. In addition, women reported higher levels of depression and anxiety than men. We also found a significant interaction between sex and motor phenotype: females with rigidity at onset (RA onset) showed better performance than other groups in a verbal memory task. Interestingly, this group outperformed males with tremor at onset (TD onset) in verbal memory, suggesting that sex may have a stronger influence than motor phenotype in this cognitive area. Sex and motor phenotype also interact in an inhibitory control task, where TD females made more errors. Right‐side onset—in particular in women—was associated with more depression symptoms compared to the other groups. Overall, these findings show that sex interacts in a complex way with onset motor features. This aspect should be considered for patient‐tailored treatment strategies.