Sex effects on brain structure in de novo Parkinson’s disease: a multimodal neuroimaging study

Abstract

Parkinson’s disease varies in severity and age of onset. One source of this variability is sex. Males are twice as likely as females to develop Parkinson’s disease, and tend to have more severe symptoms and greater speed of progression. However, to date, there is little information in large cohorts on sex differences in the patterns of neurodegeneration. Here we used MRI and clinical information from the Parkinson Progression Markers Initiative to measure structural brain differences between sexes in Parkinson’s disease after regressing out the expected effect of age and sex. We derived atrophy maps from deformation-based morphometry of T1-weighted MRI and connectivity from diffusion-weighted MRI in de novo Parkinson’s disease patients (149 males: 83 females) with comparable clinical severity, and healthy control participants (78 males: 39 females). Overall, even though the two patient groups were matched for disease duration and severity, males demonstrated generally greater brain atrophy and disrupted connectivity. Males with Parkinson’s disease had significantly greater tissue loss than females in 11 cortical regions including bilateral frontal and left insular lobe, right postcentral gyrus, left inferior temporal and cingulate gyrus and left thalamus, while females had greater atrophy in six cortical regions, including regions in the left frontal lobe, right parietal lobe, left insular gyrus and right occipital cortex. Local efficiency of white matter connectivity showed greater disruption in males in multiple regions such as basal ganglia, hippocampus, amygdala and thalamus. These findings support the idea that development of Parkinson’s disease may involve different pathological mechanisms and yield distinct prognosis in males and females, which may have implications for research into neuroprotection, and stratification for clinical trials.

Brain atrophy progression in Parkinson’s disease is shaped by connectivity and local vulnerability

“… 26 Pathological findings are mirrored by human imaging evidence showing that diffusion weighted MRI measures sensitive to neuritic damage are consistently abnormal in Parkinson’s disease. 49 , 96–98 Finally, synaptic and neuritic death should be associated with reduced neuropil and hence tissue loss, which should be reflected in the DBM measures used here.…”

“…Only the baseline HC data were used as a reference since only a limited number of HC had longitudinal measurements. 49 …”

“…Although sex was accounted for in the W-score calculation, we added it as a covariate in the repeated measures ANOVA to regress out its effect, as sex differences in atrophy were recently demonstrated in Parkinson’s disease. 49 Scanner site was also added as a covariate. Family-wise error (FWE) rate (threshold: P FWE < 0.05) was used to correct for multiple comparisons.…”

X-Vectors: New Quantitative Biomarkers for Early Parkinson's Disease Detection From Speech

“…The remaining differences may be explained by other factors. First, a less pronounced brain atrophy (Tremblay et al, 2020) and less network disruptions (Haaxma et al, 2007) have been observed in the first stages of PD in women. In addition, the onset of symptoms is delayed on average by 2 years in women compared to men (Haaxma et al, 2007).…”

Brain atrophy progression in Parkinson’s disease is shaped by connectivity and local vulnerability

“…26 Pathological findings are mirrored by human imaging evidence showing that diffusion weighted MRI measures sensitive to neuritic damage are consistently abnormal in Parkinson's disease. 49,[96][97][98] Finally, synaptic and neuritic death should be associated with reduced neuropil and hence tissue loss, which should be reflected in the DBM measures used here.…”