Differences in the Presentation and Progression of Parkinson's Disease by Sex

Abstract

Background Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. Objectives We examined sex associations to PD phenotypes cross‐sectionally and longitudinally in large‐scale data. Methods We tested 40 clinical phenotypes, using longitudinal, clinic‐based patient cohorts, consisting of 5946 patients, with a median follow‐up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex‐associated differences in presentation, and linear mixed‐effects models to test sex‐associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non‐PD participants from an online‐only, self‐assessment PD cohort were cross‐sectionally evaluated to determine whether the sex‐associated differences identified in the primary analyses were consistent and unique to PD. Results Female PD patients had a higher risk of developing dyskinesia early during the follow‐up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic‐based cohorts were mostly consistent with the results of the online‐only cohort. Conclusions We observed sex‐associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management. © 2020 International Parkinson and Movement Disorder Society

Differential effects of sex on longitudinal patterns of cognitive decline in Parkinson’s disease

“…Importantly, studies have noted sex as a risk variable in the onset of cognitive impairment, both in PD and in other populations. However, there have been few previous comprehensive investigations of sex-based differences in individual cognitive domains over time [31], as in the present study. Some prior studies have been purely cross sectional in nature [5,9,10,12,[17][18][19], while longitudinal studies have not examined the sex-specific differences in various cognitive domains [20], or have not focussed primarily on elucidating the impact of sex on cognition [32].…”

“…Furthermore, sex differences in microglial and astrocytic cells, such as their heightened sensitivity to inflammatory stimuli [42][43][44] and their anatomical distribution [45,46], have been postulated to mediate sex differences in cognition and memory [47,48]. It is worthwhile considering that such results may be reflective of the superior baseline performance of females in cognitive measures than males or may be exacerbated by disease process, though prior research has found that sexspecific progression to cognitive impairment cannot be fully explained by this baseline performance, nor disease duration [31].…”

Investigation of Autosomal Genetic Sex Differences in Parkinson's Disease

“…27 Where on the phenotype level slight differences are observed between men and women in PD, DLB, and AD and overall men have a faster progression/ cognitive decline and shorter lifespan after diagnosis. 6,27 Sex-dependent autosomal effects on clinical progression of AD have been observed 28 and data on sex-dependent autosomal effects for other neurodegenerative diseases is lacking. Here, we assessed whether an autosomal genetic difference explains these differences by performing GWAS using several large case-control datasets and separating these by men and women.…”

“…[2][3][4][5] There are also differences in the clinical presentation of PD by sex, female patients are more likely to experience dyskinesia and a slower decline in performance of activities of daily living, whereas it has been shown that male patients have a higher risk of developing cognitive impairment. 6 Symptoms that present into the earliest phases of PD also differ by sex; rapid eye movement (REM) sleep behavior disorder (RBD) is much more common in men, and depression and anxiety appear to be more common in women. 7,8 PD is a genetically complex disease, with a substantial genetic component explained by rare and common variants.…”

Investigation of Autosomal Genetic Sex Differences in Parkinson’s disease

“…Possible explanations might include different degrees of exposure to environmental risk factors (such as pesticides and heavy metals), putative risk and protective factors (head trauma, caffeine and urate), the influence of sex-specific hormones, differential aging and life expectancy, or potential genetic factors, either linked or independent of these other factors (Nandipati and Litvan 2016;Gao et al 2016;Ascherio et al 2004;Taylor, Cook, and Counsell 2007). There are also differences in the clinical presentation of PD by sex, female patients are more likely to experience dyskinesia and a slower decline in performance of activities of daily living, while it has been shown that male patients have a higher risk of developing cognitive impairment (Iwaki et al 2020). Symptoms that present into the earliest phases of PD also differ by sex; REM sleep behaviour disorder (RBD) is much more common in males, and depression and anxiety appear to be more common in females (Postuma et al 2019;Shiba et al 2000).…”