Cerebral small vessel disease (CSVD) is a common chronic cerebrovascular disease, that reflects a wide spectrum of pathological changes affecting capillaries, arterioles, and venules in the brain (Wardlaw et al., 2019). Though CSVD could be almost asymptomatic, it has been shown to be responsible for strokes, gait disturbances, depression, and cognitive impairment (Hamilton et al., 2021, (Pantoni, 2010, (Rensma et al., 2018), contributing to about 25% of ischemic strokes and 45% of vascular dementias (Li et al., 2018, (Pantoni, 2010). At present, the diagnosis of CSVD mainly depends on the neuroimaging features detected by magnetic resonance imaging (MRI), which includes cerebral microbleeds (CMB), lacunar infarctions (LI), perivascular spaces (PVS), and white matter hyperintensities (WMH) (Wardlaw et al., 2019, (Wardlaw et al., 2013b). Despite the considerable health burden imposed by CSVD on aging societies worldwide, due to its insidious onset and lack of typical clinical manifestations, there are currently no effective and convenient approaches to estimate CSVD other than MRI. The grim situation has incited scholars to explore simple and feasible measures to prevent and identify CSVD in its early stage (Arboix et al., 2014, (Bath, Wardlaw (2015)).

Since the pathogenesis of CSVD is still poorly understood, there are few effective means to reduce the burden of CSVD except by controlling traditional cardiovascular risk factors, such as hypertension, diabetes, and hyperlipidemia (Benavente et al., 2012, (Pearce et al., 2014, (van Norden et al., 2011, (Vivier et al., 2011). Nevertheless, recent studies have highlighted the roles of immunity and inflammation in the development of CSVD (Wardlaw et al., 2019). Prolonged elevated inflammation may be necessary for the increased risk and development of CSVD. Peripheral immune cells with different immunophenotypes and functions also have diverse associations with CSVD (Evans et al., 2021). Furthermore, there has been growing evidence that immunity and inflammation are greatly involved in neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, etc.), central nervous system autoimmune diseases (multiple sclerosis, neuromyelitis optica, etc.), and cerebrovascular diseases (Jian et al., 2020, (Li et al., 2020). Since CSVD shares common pathophysiological mechanisms with the aforementioned diseases, as one of the many possible candidates for pathogenesis, the role of immunity and inflammation in the development and progression of CSVD deserves further exploration.

It has been widely accepted that measuring peripheral immune cells could yield important information on both peripheral and central system immunity. Furthermore, ratios derived from blood cell counts, including neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR), are thought to better reflect the balance between innate and adaptive immunity (Fest et al., 2018, (Iwasaki, Medzhitov (2010), (Nøst et al., 2021). Higher NLR indicates the predominance of innate immunity, whereas higher LMR indicates the predominance of adaptive immunity. To date, emerging evidence has suggested that NLR and LMR are closely linked to the incidence and prognosis of cardiovascular diseases, dementia, and cancer (Bhat et al., 2013, (Gong et al., 2021, (Lux et al., 2020). Considering the possible pathogenesis of CSVD, it can be speculated that these peripheral indicators, which are convenient and effective, might be associated with CSVD.

Previously, no longitudinal studies and only a few cross-sectional studies have explored the relationship between NLR and CSVD (Chung et al., 2020, (Nam et al., 2017, (Wang et al., 2022), yielding inconsistent results. Thus, with large samples, the purpose of our longitudinal study is to establish the associations of peripheral immune cells and their derived indicators with CSVD neuroimaging markers. It will not only provide new insights into the pathogenesis of CSVD, but also contribute to the early identification, treatment, and prognosis of this disease.