3.1 The effect of LRRK2 G2385R on clinical profile in female and male PD
Our study indicated that sex distribution was similar between carriers and non-carriers. A multi-center study in China reported similar sex distribution[13]. Consistent with a previous study, most clinical variables were similar in LRRK2 G2385R carriers and non-carriers regardless of sex[13]. But there is two exception. In male, cognitive impairment was observed less frequent in carriers than non-carriers among PD. Similar with our study, a previous research also observed higher score of Mini-Mental State Examination (MMSE) in LRRK2 G2385R carriers than that in non-carriers in China[15]. Some other studies did not find significant differences in dementia between carriers and non-carriers[13, 21]. The lack of association between LRRK2 G2385R and cognition in female may support that the effect of G2385R on cognition existed in some but not all studies. In previous study, the frequency of autonomous symptoms was similar between LRRK2-PD and idiopathic PD [13, 15, 22]. In our study, we also found no significant differences in autonomic dysfunction between LRRK2 G2385R carriers and non-carriers. However, in female, a lower risk of autonomic dysfunction was found in LRRK2 G2385R carriers compared with non-carriers. These results may indicate that the effects of LRRK2 G2385R may different between sexs.
3.2 The effect of sex on clinical profile in LRRK2 G2385R carriers and non-carriers
Female sex in PD with LRRK2 G2385R non-carriers had milder severity in motor symptoms and lower risk in EDS, autonomic dysfunction and SN hyperechogenicity but higher risk in mood disorders in this study, in agreement with most published studies[3, 10, 23-25]. Sex differences in cognition was inconsistent. Some studies found male were at risk, but others found female[3, 8, 26, 27]. Male sex among LRRK2 G2385R non-carriers had a tendency to cognitive impairment in our study. Besides, EDS, the risk factor for cognitive impairment, was observed more frequent in male. It may suggest that male is more prone to cognitive impairment in our study. Previous studies discovered significant positive correlations between the frequency of SN+ and clinical scores[24, 28, 29]. Consequently, the relatively reserved motor function in female sex may be explained by the similar trends of TCS in our study. Except TCS, the similar trends were also observed by other neuroimaging and fluid biomarker, such as declined brain dopamine binding and lower urate concentrations in male PD patients[30, 31]. Genetics such as estrogen-related gene or brain-derived neurotrophic factor gene, hormonal influences such as estrogens, immunological factors, environmental exposures, or a combination of these are likely contributors to sex differences in PD via their influence on mitochondrial function, oxidative stress and inflammation [32-36].
However, except autonomic dysfunction, the sex effects were not seen in PD with LRRK2 G2385R carriers in our study. The mechanism is still unclear. One potential explanation is that LRRK2 G2385R carriers may have a less heterogeneous phenotypic presentation than non-carriers, and this might mitigate potential sex differences due to LRRK2 G2385R mutations thus leading to a general tendency to neurodegeneration, that is not influenced by sex[19, 20].
3.3 Strength and limitation
To our best knowledge, this is the first study about the sex effects on clinical features with and without LRRK2 G2385R mutation and the role of LRRK2 G2385R on clinical features in terms sex. Assessments in this study were comprehensive, including motor symptoms, various NMS scales and neuroimaging. Besides, we found sex effects perform differently in different genetic subtype. Trials in LRRK2 and sex should consider stratification in design or analysis.
Limitations should be considered in interpreting our findings. We enrolled 613 individuals and only 79 was detected with LRRK2 G2385R mutation. The number of LRRK2 G2385R variants was relatively small. In addition, we only detect LRRK2 G2385R, and thus non-carrier might include individual with other genetic mutation. Effects of other SNPs and genes cannot be excluded in our study. Besides, for the convenience of analysis, some continuous variables are being treated as binary outcomes with arbitrary cut-offs, leading to be less powerful. The results became insignificant except lower risk of LRRK2 carriers in cognitive impairment in male patients since relatively small sample size. Some of genetic power was less than 0.05, indicating the results were not inaccurate to some extent for the relatively small sample size. Consequently, further study is needed to enlarge the sample size and add healthy control.