Frailty is a clinical condition of increased vulnerability to physiological stressors due to a loss of homeostatic reserves. It is a major public health problem since it can lead to adverse events such as falls, disabilities, hospitalizations, and death (Fried et al., 2001). Frailty is a geriatric syndrome associated with aging (Darvin et al., 2014). With an accelerated aging population worldwide, and especially in China where the proportion of people aged 60 and over was 17.9% at the end of 2018 Jing et al. (2020) and is estimated to increase to approximately 30% by 2050 (Liu et al., 2017), the burden of frailty will increase rapidly. Therefore, it is urgent to find methods that can mitigate the risk of frailty.

In addition to having an increased risk of frailty, the older adults also have a higher risk of cerebral small vessel disease (CSVD) (de Leeuw et al., 2001). CSVD is a progressive syndrome with clinical, neuroimaging, and neuropathologic presentations related to the vessels of the brain (Wardlaw et al., 2019). The principal imaging markers of CSVD include recent small subcortical infarcts, lacunes, white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), cerebral microbleeds (CMBs), and atrophy (Wardlaw et al., 2013). Although several previous studies have demonstrated the associations between frailty and the neuroimaging markers of CSVD (Siejka et al., 2018, 2020; Kant et al., 2019; Maltais et al., 2019; Jordan et al., 2020), the underlying mechanisms of this relationship remain unclear.

Poor sleep is a common health problem among the older population (Phillips and Ancoli-Israel, 2001). Both frailty and CSVD are associated with sleep disorders (Del Brutto et al., 2015; Shih et al., 2020), but the complex relationships between CSVD, sleep quality, and frailty remain to be explored. In the present study, we hypothesized that the severe CSVD burden could be related to a higher risk of frailty, and this association might be mediated by poor sleep quality. A successful mediation could mean that the risk of frailty in patients with CSVD might occur due to sleep disorders. Our investigation could thus lead to strategies to prevent frailty.

From November 2020 to May 2021, a total of 772 community residents participated in our study. Of the participants, ten of them were excluded due to failure to complete the MRI examination or having MRI artifacts. Fifteen residents were excluded due to a lack of data in the frailty assessment. Twenty-one residents were excluded due to a history of stroke or dementia. Finally, 726 residents were enrolled in the final analysis (Figure 1). Their characteristics are shown in Table 1. The mean age of the participants was 65.5 (±6.5) years. The majority of the participants were female (434, 59.8%). The numbers (percentages) of the frail, prefrail, and robust residents were 49 (6.7%), 310 (42.7%), and 367 (50.6%), respectively.

The frail residents tended to be older, with a lower education level, poorer sleep quality, higher score of HAMD, and a higher burden of CSVD. There were no significant differences in gender, body mass index (BMI), smoking habits, hypertension, and hyperlipidemia.

Our study was the first investigation to explore the mechanism underlying the association between CSVD burden and frailty. We discovered the role of sleep quality in mediating this association in community-dwelling older adults. Our results demonstrated that older people with a higher CSVD burden were more likely to be frail. This association was partially mediated by poor sleep quality.

In this study, the prevalence of frailty was 6.7% based on Fried’s criteria. Fried’s criteria is the most widely used definition for frailty assessments. This prevalence was similar to that found in a previous study that included 5,301 community-dwelling older adults from 28 Chinese cities (7.0%, based on Fried’s criteria) (Wu et al., 2017).

Although the existed associations between imaging markers of CSVD and frailty have been reported in the past, the results are inconsistent (Siejka et al., 2018, 2020; Kant et al., 2019; Maltais et al., 2019; Jordan et al., 2020). Differences in findings might be ascribed to the differences in the measurement of frailty in different study populations. In the present study, it was found that the severity of frailty was significantly related to the CSVD burden, the WMH score, the number of lacunes, and the EPVS-BG score, but not the number of CMBs.

Several previous studies have linked WMH to frailty (Siejka et al., 2018, 2020; Kant et al., 2019; Maltais et al., 2019; Sugimoto et al., 2019; Jordan et al., 2020). Sugimoto et al. (2019) and Siejka et al. (2020) reported that the severity of the baseline WMH was associated with the progression of frailty. WMH has also been linked to slow gait, falls, cognitive decline, and depression, which might increase the risk of frailty (de Leeuw et al., 2001; Srikanth et al., 2009). However, other studies only found a weak or no correlation between WMH and frailty (Chung et al., 2016; Kant et al., 2018). Interestingly, when the severity of WMH was assessed quantitatively, most previous studies reported positive correlations (Siejka et al., 2020). The link between frailty and lacunes is controversial due to the different definitions of lacunes or infarcts. For example, in three studies that used the criteria of STRIVE to assess lacunes (Chung et al., 2016; Siejka et al., 2018; Kant et al., 2019), only one study with the largest sample size (n = 962) showed a positive correlation between lacunes and frailty (Chung et al., 2016). No former studies displayed the relationship between frailty and EPVS severity, but it was found that high degree of EPVS-BG was positively correlated with the frailty in the present study. More large-size studies are required to confirm our findings.

Consistent with previous studies, our results showed that sleep quality was associated with CSVD and frailty (Del Brutto et al., 2015; Shih et al., 2020). Several previous community-based studies revealed that subjective sleep quality was associated with WMH and EPVS (Del Brutto et al., 2015, 2019; Sexton et al., 2017). The proportion of insomnia in elderly with CSVD was far higher than that among general elders (Wang et al., 2019). The comorbidity of CSVD and a sleep disorder might be related to chronic inflammation, oxidative stress, and other common pathways (Wang et al., 2020a,b). Further, several studies have demonstrated that people with poor sleep quality have increased odds of frailty (Pourmotabbed et al., 2020; Shih et al., 2020). A longitudinal study revealed that people with sleep disturbance at the baseline had a higher risk of frailty during the follow-up period (Ensrud et al., 2012). Sleep disorders might lead to frailty through dysregulation of various hormones (e.g., insulin-like growth factor-1 and testosterone), chronic inflammation, and other factors (Alvarez-Satta et al., 2020; Shih et al., 2020; Balomenos et al., 2021).

The crucial role of sleep quality in the development of frailty in individuals with higher CSVD burden was emphasized in this community-dwelling older adults cohort. It was supposed that individuals with a heavy burden of CSVD are more likely to have sleep disorders that subsequently lead to frailty through chronic inflammation, dysregulation of hormones, and other pathways (Balomenos et al., 2021). Targeted interventions toward sleep problems (e.g., medication, cognitive behavioral therapy, sleep hygiene education) (Kaur et al., 2020) could play a positive role in the prevention and treatment of frailty, thus reducing the incidence of adverse events.

Our study has a few limitations. First, this study was a cross-sectional study and thus could not establish a causal relationship between CSVD and frailty. Our findings should thus be interpreted with caution. In the future, interventional trials and basic research studies should be conducted to validate the causal relationship. Second, due to the low prevalence of frailty in the community population, the sample size of participants with frailty was small. Third, sleep quality was measured using a self-report instead of objective measures (e.g., polysomnography), which might have resulted in bias. Finally, our research subjects were Chinese-Asian people. Whether this result could be applied to non-Asian people is unclear and requires further research.

Our study revealed that CSVD burden was associated with frailty among community-dwelling older adults. This association was partially mediated by sleep quality. Interventions targeted at sleep disorders might be a promising method to prevent physical frailty in CSVD patients.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

JZ, XZ, YG, YZ, LW, and HH collected the clinical data. JZ, ZY, and WQ processed the statistical data. JZ drafted and revised the manuscript. XL designed and guided the study. All authors read and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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