Increase in age at onset of moyamoya disease in China over 25 years

Abstract Background To explore whether the age at onset (AAO) of Chinese patients with moyamoya disease (MMD) increased over time due to a reduced exposure to leptospiral infection. Methods We performed an independent, multicenter, retrospective study based on data from patients with MMD who initially attended four tertiary hospitals in Hubei, China, from 1996 to 2020. After stratifying the year of MMD onset into five periods (1996–2000, 2001–2005, 2006–2010, 2011–2015, and 2016–2020), we analyzed the temporal trends in AAO and compared different classes of AAO (early‐onset, < 20 years; intermediate‐onset, 20–49 years; late‐onset, ≥ 50 years) in each period. Results We included 1858 patients in this study, with 878 women and 980 men. Their median (IQR) AAO was 47 (39‒55) years. The case AAO significantly increased at the rate of 0.94 years per year (r = 0.406, p < .0001), while no trend was observed in birth years through time (p = .512). The birth cohorts who grew up in the leptospirosis epidemic years was stably susceptible to MMD. The median (IQR) AAO has increased significantly from 26 (14–37) years (1996–2000) to 51 (43–57) years (2016–2020) (p < .0001). The proportion of early‐onset MMD was significantly higher in 1996–2000 (33.3%, p < .0001) and 2001–2005 (10.4%, p < .001). The AAO shows an aging trend that the proportion of late‐onset MMD went from 4.5% (2001–2005) to 54.5% (2016–2020) (p < .0001). Conclusions The AAO of MMD was increasing during a recent 25‐year period in China, which may reflect a birth cohort effect that resulted from environmental changes. The disparity risk of birth cohorts with MMD changed with leptospirosis epidemics, suggesting leptospiral exposure might be a potential risk factor.


INTRODUCTION
Moyamoya disease (MMD), a cerebrovascular disorder characterized by chronic progressive occlusion of the terminal internal carotid artery and dilated collateral microvessels near the base skull, developing collateral circulation like "puff of smoke" on angiography (Suzuki & Takaku, 1969). MMD is a leading cause of stroke for both children and young adult, while the etiology remains largely unclear. Genetic studies have identified RNF213, as a susceptibility gene for MMD, but the low penetrance in genetically susceptible individuals suggests that a second hit is necessary to trigger disease onset (Asselman et al., 2022).
In the second half of the 20th century, leptospirosis severely threatened public health in China. During this period, a unique neurologic disorder named leptospiral cerebral arteritis was broadly reported over China, which interestingly presented typical angiographic and pathological features of MMD (Liu et al., 1980;Liu et al., 1978). Recently, epidemiologic studies from China uncovered the onset of MMD shows a clustered regional pattern, and leptospirosis may explain a cluster observed in Hubei province (Ma et al., 2021;Zhang et al., 2022).
These findings suggested a causal link might exist between leptospiral exposure and MMD.
After entering the 21st century, leptospirosis has been controlled at a pretty low prevalence in China (Zhang et al., 2012). Taking Hubei province for example, the final wave of leptospirosis outbreak occurred in 1996, and since then, the leptospirosis maintained a sporadic level ( Figure 1) (Ma et al., 2021). In this context, if the patients with MMD were originated from leptospiral exposure, then their age at onset (AAO) might have increased over time as a reduced exposure to leptospiral infection since 1996.
In this study, we performed a multicenter, retrospective epidemiologic survey in a large real-world sample, to explore whether the AAO increased over the last 25 years  in Chinese patients with MMD.
The EO and IO MMD showed a decreased trend, while a reverse trend was observed among LO MMD over time (p < .0001) (Figure 3b).   evidence, these findings suggested changes in leptospiral exposure might be a considerable environmental factor to shape the birth cohort effect of MMD. As a result, the affected birth cohorts were diagnosed at different time, which led to the increasing trend of AAO over time.
The age distribution of MMD is not always a bimodal peak pattern.
This study observed a decreased EO MMD and an upward trend for LO over time. Similar trend has been reported in previous incidence studies. Chen et al. (2014) found adults exhibited an upward trend in incidence while children had a decreased incidence in Taiwan. Baba et al. (2008) reported that the highest peak of incidence shifted from children to adults in Japan. These studies emerge with an aging trend for MMD. One possible reason might be the declining birth rate in the 21st century, and another might be the reduced exposure to leptospiral infection for children. However, exploring the reasons goes beyond our objectives, and requires a different study design. We would instead point out a standard treatment needs to be constructed for LO MMD.
There are two limitations in this study. On one hand, the data in present study was from Hubei province, data from other provinces was absent. However, most provinces had a similar history of leptospirosis epidemic, hence we believe in our results are quite representative for China. On the other hand, the hypothesized causal link between leptospiral exposure and MMD was based on whether the susceptible birth cohorts were living in the leptospirosis outbreaks, which was lack of direct evidence.
In conclusion, this study has clearly demonstrated that the AAO in Chinese patients with MMD has increased significantly over the last 25 years. The increased AAO reflected a birth cohort effect, which was associated with changing environmental factors, and leptospiral exposure might be a potential one. MA ET AL.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.