Our results indicate a significantly higher iron deposition in GP, Put, and CN in the CSVD-S group, and a significant decline in cognitive function among subjects in this group, suggesting that iron overload may lead to more severe cognitive impairment in patients with higher total CSVD scores. As the most metabolically active organ in the body, the brain has a high demand for iron, an essential neurochemical catalyst or co-factor [22]. Nonheme brain iron is primarily stored in ferritin and plays a crucial role in influencing MRI [15]. As a paramagnetic substance, nonheme iron exhibits high susceptibility values on QSM images [23]. The distribution of these values closely corresponds to the distribution of iron accumulation in postmortem brain examinations [24], further confirming the role of nonheme iron in the QSM results [23]. Therefore, QSM may be a highly reliable tool for diagnosing and monitoring the severity of CSVD.

CSVD can be attributed to two main pathologies: arteriolosclerosis, linked to traditional vascular risk factors, and cerebral amyloid angiopathy, driven by β-amyloid protein [3]. Research on CSVD progression suggests that early endothelial dysfunction disrupts the blood-brain barrier (BBB), causing fluid and toxic plasma proteins to leak into surrounding tissues and the vascular media [2]. This leakage can adversely affect vascular reactivity, pericyte function, oligodendrocyte proliferation, and the drainage pathways of perivascular fluid. For instance, damage to oligodendrocytes, myelin-producing cells, can result in the release of iron-rich proteins, leading to the abnormal deposition of iron in other regions [2]. Additionally, the inflammatory reaction surrounding blood vessels can also lead to damage to blood vessel walls and changes in permeability [25]. Our findings reveal a significant increase in iron deposition in the GP, Put, and CN regions of the brains of CSVD-S patients, indicating a possibly more severe disruption of the BBB in local brain regions in these individuals.

The striatum comprising the neostriatum (CN and Put) and the paleostriatum (GP) plays a crucial role as a relay nucleus in the cortico-striatal-thalamo-cortical circuit, contributing to cognitive functions and the regulation of motor movements. Furthermore, the neurotoxicity of iron overload and its release in the form of free radicals within these brain areas may contribute to neuronal death and neural function impairment [26]. A high total CSVD score indicates more severe and widespread cognitive impairment, especially in information processing speed and overall cognitive function [27]. Our study showed that patients with higher total CSVD scores had more serious impaired cognitive function, and the severity of impaired cognitive function increased with the increase in iron deposition.

A higher total score in patients with CSVD is associated with more severe impairment of the cerebrovascular system and disruption of iron homeostasis in the brain, which have risk factors of age, gender, hypertension, diabetes, hyperlipidemia, smoking, and alcohol consumption are recognized as traditional risk factors for CSVD. However, local brain iron deposition in patients with CSVD is not the result of a single factor but rather the joint effect of multiple factors. Our study reveals that age is the primary factor affecting iron overload in the GP, Put, and CN of patients with CSVD, indicating a close relationship between age and the iron content increase in these brain regions. Various factors gradually manifest with age, such as decreased oxidative phosphorylation, functional decline of oligodendrocytes, and abnormal BBB permeability. Our data show that the brain iron content in the GP, Put, and CN increases with age, which is in line with previous research [28].

Another finding was that diabetes also affected the iron deposition in CN and Put in the brains of patients with CSVD. A study on the characteristics of iron deposition in deep gray matter in the elderly hypothesized that the iron deposition in T2DM patients was due to the changes in BBB permeability caused by hyperglycemia induced neuronal damage and insulin resistance [29]. Our study of patients with CSVD suggests the need for increased testing of blood glucose levels in patients with CSVD. Furthermore, there has been research indicating that smoking is a crucial determining factor for the accumulation of brain iron in normally aging individuals. Smoking has been shown to be associated with iron deposition in the basal ganglia [30], and our study has demonstrated that smoking can affect the brain iron content of patients with CSVD in the Put. These findings suggest that we need to take into account the impact of smoking when considering the management and treatment of patients with CSVD.

Mediation analysis further revealed that age is a potential pathway to influence the mean susceptibility values of striatum through CSVD total score. It is found that age not only has an indirect effect on the mean susceptibility value of striatum through CSVD total score, but also has a significant direct effect on it, suggesting that iron deposition in striatum increases with age. Specifically, age has a significant positive effect on the CSVD total score, which in turn is positively associated with striatal mean susceptibility values. This suggests that with advancing age and a higher CSVD score, the severity of CSVD correlates with elevated mean susceptibility values in the striatum. This mediating effect implies that worsening CSVD with age contributes to pathological changes in the striatum region. The striatum plays a crucial role in cognitive and executive functions, especially in learning, decision-making, reward processing, inhibitory control, task switching, working memory, and error monitoring [31] Our study further supports this connection by finding significant positive correlations between the mean susceptibility values of the GP, Put, and CN with SCWT scores. Our study further supports this connection by finding significant positive correlations between the mean susceptibility values of the GP, Put, and CN with SCWT scores. Therefore, greater severity of CSVD results in reduced blood flow, and the striatum, when subjected to chronic ischemic conditions, may experience neuronal energy deficits, affecting its structure and function. The combined effects of aging and CSVD progression further exacerbate degenerative changes in the striatum.

The mediation analysis results in our study support the critical role of CSVD in age-related functional decline of the striatum, suggesting that interventions to curb CSVD progression could help protect the structure and function of the striatum, potentially slowing age-associated declines in cognitive and executive functions. This provides a theoretical basis for future intervention and mechanistic studies. Additionally, a mediation analysis conducted on age-matched subgroups also indicated a near-significant trend in the mediating role of the CSVD total score between age and striatal iron deposition, further details can be found in Supplementary Table S4 and Fig. 1.

Research has indicated that iron deposition in the GP is independently and positively correlated with the severity of WMHs, highlighting a significant link between tissue iron accumulation and the development of WMHs [6]. This aligns with our study’s findings, which similarly confirm the association between brain iron levels and WMH severity. WMHs are known to be associated with endothelial dysfunction and increased blood-brain barrier permeability [16], factors that are also implicated in the mechanisms underlying brain iron deposition [5]. Therefore, this evidence supports the idea that WMHs contribute to overall susceptibility changes seen in CSVD by influencing iron accumulation. Additionally, PVS, an important component of the brain’s glymphatic clearance system, play a key role in interstitial fluid and waste drainage, which is particularly relevant in the context of CSVD [32, 33]. Studies suggest that, in the healthy aging brain, the glymphatic system participates in iron clearance, while its dysfunction may lead to increased iron deposition [34]. In our study, patients with prominent PVS in specific brain regions, such as the Put, presented elevated susceptibility, supporting this theory and linking PVS to iron-related changes in CSVD. Further, lacunes and CMBs, which are common CSVD markers, share similar pathophysiological mechanisms. Lacunes are small, round or oval cavities in the subcortical white matter that often contain CSF-like fluid, surrounded by various levels of gliosis, axonal damage, and hemosiderin deposition. CMBs, on the other hand, are characterized by erythrocyte leakage due to small vessel damage, followed by local hemosiderin accumulation through macrophage phagocytosis [35]. Both lesions are closely related, with CMBs shown in previous studies to cause ischemic microvascular damage and subsequent blood-brain barrier disruption or inflammatory responses that may ultimately result in iron deposition [36].

Given the diagnostic limitations of using any single imaging marker, our study used the composite CSVD total score to reflect CSVD’s total burden on brain tissue, as it better captures the multi-faceted impact of CSVD on brain iron deposition. This approach accounts for both gray matter (e.g., lacunes) and white matter (e.g., WMHs) alterations [37, 38]. Our findings indicate that using the composite CSVD total score can more comprehensively depict CSVD’s cumulative influence on brain susceptibility measures, while also allowing us to recognize distinct contributions from individual CSVD features, such as WMHs and PVS, to susceptibility values. In summary, while individual CSVD components like WMHs, PVS, and CMBs contribute independently to susceptibility changes, the composite CSVD total score serves as a robust marker to reflect the overall burden of CSVD, especially as it relates to cumulative iron deposition across different brain regions.

This study has the following limitations that may be addressed in future investigations. QSM values were analyzed using ROI, which is a vast reduction of imaging information. QSM texture analyses [39] and radiomics [40] may reveal more specific information on about CSVD. QSM is sensitive to both deoxyheme iron in small veins and capillaries and nonheme iron in tissue mostly stored in ferritin, which can be separated by combining quantitative blood oxygenation level dependent modeling of mGRE magnitude signal with QSM processing of mGRE phase signal [41]. This leads to mapping of nonheme iron and oxygen extraction fraction without additional data acquisition. These further analyses may improve the accuracy in distinguishing CSVD-S patients from the HC group.