Objective/Rationale:
In Western populations, men are approximately 1.5 times more likely to develop Parkinson’s disease (PD) than women. Furthermore, epidemiologic and clinical features of PD vary between genders. These differences may be influenced by genetic, environmental, hormonal, immunological and other factors. However, there are only a limited number of studies that evaluate the effects of genetics and reproductive factors on gender differences. Evaluation of PD associated with a mutation of the LRRK2 gene provides a unique window to better evaluate the relationship between genetic determinants and gender.
Project Description:
The primary focus of this project is to evaluate the roles of gender and gene status in non-mutation PD (idiopathic PD) and LRRK2 PD. We will use information about the clinical phenotype (observed clinical characteristics) of the PD subjects in the MJFF-led LRRK2 Cohort Consortium, such that we will compare clinical features between men and women with LRRK2 PD and also between men and women with idiopathic PD. We also will screen for differences between genders in frequency of markers (suggestive characteristics) between people who carry the LRRK2 mutation but do not have PD and healthy controls. We want to determine whether there is a mutation effect acting independently from a gender effect, and to determine whether a mutation-specific effect exists (R1441G versus G2019S mutation of the LRRK2 gene).
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
It is thought that women have later onset of PD but do not differ significantly once PD is present. Milder early progression has been attributed to hormonal benefits that are most prominent early in a woman’s life but that decrease post-menopause. However, studies regarding the effects of menopause and hormone therapy are conflicting, and it is not clear whether introduction of hormone therapy in postmenopausal women with PD is beneficial or harmful. By evaluating this subgroup of people with PD, we will be able to better determine the role of hormonal factors in PD with a known genetic etiology.
Anticipated Outcome:
Evaluation of women with LRRK2 PD and women who carry a LRRK2 mutation in comparison to women without the mutation, and comparison of men and women with LRRK2 PD provides the unique opportunity to evaluate the effect of carrying the LRRK2 mutation and the role of genetics in the male predominance of PD. Findings in genetic PD may shed a light on the pathophysiology of gender differences, and whether there is a specific LRRK2 gender effect.
Final Outcome
Men and women with Parkinson’s disease (PD) are known to have differences in certain disease aspects. This project sought to examine whether those differences persist when men and women with PD due to mutation of the LRRK2 gene (LRRK2 PD) are compared to one another and to those without mutations. There is a higher proportion of men in idiopathic PD (60% men to 40% women), but this ratio is not observed within LRRK2 PD (50% to 50%). Also, within idiopathic PD, men appeared to have a more “aggressive" presentation than women. Men were slightly older, had slightly later disease onset, longer disease duration, were taking more medication, and were more severely affected, due to more stiffness. Women in turn appeared to have more complications of therapy.
Within LRRK2 PD, men and women were more similar to each other. However, there were some differences. While both had similar severity of symptoms, women had more slowness than men. As expected, LRRK2 PD was more likely to be familial than idiopathic PD. No gender differences were found in depression, cognitive function, or sleep disorders. However, LRRK2 overall had less REM sleep Behavior Disorder than non-mutation PD. Women reported worse cardiovascular autonomic function and thermoregulation, while LRRK2 PD women reported worse thermoregulation only.
When we compared LRRK2 and non-mutation PD within each gender, men with LRRK2 were slightly younger than men with idiopathic PD and had younger age at onset, better olfaction, less RBD but worse dysautonomia scores. In women, LRRK2 were similar to non-mutation PD in clinical features but were taking more medication, and had better olfaction.
In conclusion, there are differences in male/female proportions and in certain disease aspects between men and women both with LRRK2 and with non-mutation PD. Such differences in family history and male/female predominance suggest that a greater proportion of PD cases among women may be due to genetic causes. The more “aggressive” phenotype in men with idiopathic PD as compared to idiopathic PD women and LRRK2 men may reflect more environmental risk exposures.