The spike glycoprotein S of SARS-CoV-2 exhibits the capability to interact with the angiotensin-converting enzyme 2 of the host, thereby mediating the amalgamation of the viral envelope with the cellular membrane of the target cell. This interaction ultimately leads to the discharge of viral RNA into the cytoplasm of the host cell, subsequently triggering a cascade of detrimental impacts on the human physiological system (64). Low levels of ACE2 expression have been detected within cerebral endothelial cells, the choroid plexus, and the ventral posterior nucleus of the thalamus (18, 19). Additionally, the presence of SARS-CoV-2 has been detected in cerebrospinal fluid via gene sequencing, indicating a potential for direct invasion and infection of the nervous system through the ACE2 receptor. Furthermore, it suggests that the virus may transform into a persistent infection within the nervous system, possibly mediated by the combined effects of immune mechanisms (20). The SARS-CoV-2 virus, by virtue of its spike protein binding to the ACE2 receptor on endothelial cells, can precipitate endothelial dysfunction, dysregulation of coagulation homeostasis, and the formation of microvascular immunothrombosis. This process may also be accompanied by complement activation, increased endothelial barrier permeability, and compromised vasodilatory capacity (21, 22). Given that ACE2 is expressed within the cerebral vasculature, the binding of the virus to this receptor may activate RhoA, a key molecule regulating the cytoskeleton and tight junctions of endothelial cells, potentially leading to the disruption of the blood-brain barrier (23). This constellation of phenomena may underpin the pathogenesis of COVID-19-induced cerebral small vessel disease.

Upon the binding of the coronavirus spike protein to ACE2, the protein is enzymatically dissected by proteases within the host cell into two distinct subunits, S1 and S2. The S1 subunit is posited as a pivotal causative agent in the induction of endothelial dysfunction, with the potential for the cleaved S1 segment to permeate the blood-brain barrier (24). In vitro experiments show that the spike protein disrupts blood-brain barrier integrity, triggering endothelial pro-inflammatory responses and upregulating matrix metalloproteinases. This disruption reduces junctional proteins and increases brain microvascular permeability. Intravenous S1 protein injection in mice causes S1 accumulation in brain endothelial cells, correlating with endothelial injury and elevated C5b-9 levels. (25). The spike protein has the capacity to be transported in the bloodstream, cross the blood-brain barrier, and ultimately enter endothelial cells via endocytosis. The spike protein can bind to a serine protease known as Furin and accumulate in the Golgi apparatus. Furin is implicated in the metabolism of the SARS-CoV-2 spike protein and is highly expressed in vascular endothelial cells, where it can regulate endothelial permeability. The intimate association and interaction between the spike protein and Furin may be related to the pathogenesis of microvascular diseases associated with COVID-19 (26). COVID-19-induced brain dysfunction correlates with TLR4 signaling in microglia driven by spike proteins. TLR4 activation elevates plasma NFL levels via spike proteins, driving delayed neuroinflammation and cognitive dysfunction. These findings mirror cerebral small vessel disease pathology and clinical features (27). Although it is currently not fully clear whether CSVD can be linked to the COVID-19 spike protein, Furin protease, and other factors, future research may focus on patients with prolonged COVID-19 infection who exhibit cognitive impairment or other neurological symptoms. Efforts should be made to investigate the potential connections through further basic experiments, clinical symptom assessments, and imaging studies.

Infection with SARS-CoV-2 can lead to the upregulation of certain pro-inflammatory cytokines and chemokines, potentially resulting in the onset of cytokine release syndrome (CRS). CRS is characterized by excessive activation of immune cells and elevated levels of circulating cytokines, representing a systemic inflammatory state that may exacerbate disease severity and pose a life-threatening risk (65). It has been reported that inflammatory biomarkers such as interleukin-6 (IL-6) and C-reactive protein (CRP) are closely associated with the severity of the novel coronavirus infection (66–70). These biomarkers are also intricately linked to the pathogenesis of cerebral small vessel disease, and in comparison to individual biomarkers, the combined assessment of multiple biomarkers associated with CSVD may offer a more comprehensive explanation of the underlying pathological processes (71, 72). SARS-CoV-2 infection may cause long COVID (LC), a prolonged condition marked by pathological persistence beyond 12 weeks post-acute infection. LC involves sustained dysfunction across respiratory, neurological, cardiovascular, metabolic, and psychosocial systems. Elevated IL-6, D-dimer, PAI-1, and sCD40L levels confirm chronic inflammation and active immunothrombosis in LC patients. These abnormalities drive endothelial dysfunction and coagulation dysregulation. (28, 73), the prolonged persistence of such aberrant states may predispose to the development of cerebral small vessel disease.

Upon reviewing the literature, we postulate that tumor necrosis factor (TNF) and its receptors, CD40L/CD40, along with the cell surface receptor sTREM-2, are implicated in COVID-19-induced CSVD. Firstly, CD40, a member of the TNF receptor superfamily (TNFRSF), and CD40L, a member of the TNF superfamily (TNFSF), both participate in a multitude of immunological reactions within the body. CD40 is predominantly constitutively expressed in B cells and myeloid cells, whereas CD40L is primarily derived from T cells and activated platelets (74). Soluble CD40L within platelets mediates thrombogenesis and inflammatory responses, and its levels are closely associated with an increased risk of inflammation and cardiovascular diseases related to viral infections (29). Platelet-derived sCD40L promotes CD40-positive cell activation and thrombogenesis by stabilizing integrin αIIbβ3 in COVID-19. Compared to healthy controls, COVID-19 patients show elevated sCD40L levels, which decline over time as a potential biomarker for inflammatory monitoring (75, 76). CD40 also plays a pivotal role within the central nervous system, where it is expressed in astrocytes, microglia, and vascular endothelial cells. CD40 on microglia can interact with CD40L on infiltrating T lymphocytes or other cells within the CNS, triggering intracellular signaling events and culminating in the production of a plethora of cytokines and neurotoxins (77). The level of circulating sCD40L reflects the activation status of the CD40-CD40L complex. Platelet-expressed CD40L serves as a pivotal inflammatory mediator, triggering the activation of astrocytes and microglia, a process that is intricately linked to the activation of mitogen-activated protein kinases (MAPKs), degradation of IκB-α, and the NFκB-mediated inflammatory signaling cascade. The resultant indices of glial activation may ultimately precipitate platelet aggregation, neuroinflammatory responses, and neuronal damage (78). Elevated levels of soluble CD40L are observed in the plasma of patients with inflammatory demyelinating diseases, and sCD40L has also been implicated in the disruption of the blood-brain barrier (79–81). Moreover, existing evidence suggests that the concentration of sCD40L is independently associated with an increased risk of radiological progression in cerebral small vessel disease (82). The aforementioned mechanisms of abnormal platelet deposition, neuroinflammation, and disruption of the blood-brain barrier may be one of the reasons by which SARS-CoV-2 affects CSVD through the CD40 and CD40L.

sTREM-2, a cell surface receptor and a member of the Triggering Receptors Expressed on Myeloid cells (TREM) family, is associated with the induction of type 2 immune responses following viral infections. There is evidence to suggest that the plasma concentration of sTREM-2 may be a potential independent predictor of severe disease in COVID-19 patients, which could play a crucial role in distinguishing the severity of the disease (83). TREM-2, a receptor with the capacity to discern pathogen-associated molecular patterns, has been found to engage with the M protein of SARS-CoV-2 via its extracellular immunoglobulin (Ig) domain. This interaction triggers a signaling cascade, culminating in the activation of T cells and the subsequent augmentation of pro-inflammatory cytokine production by T helper 1 (TH1) cells, including interferon-β and tumor necrosis factor. The resultant cytokine release intensifies the inflammatory response and contributes to tissue injury (30). Within the brain, the immune receptor TREM2 can be expressed in microglia. TREM2 regulates microglial proliferation and survival by activating the Wnt/β-catenin signaling pathway. Additionally, TREM2 can also activate the Akt/β-catenin pathway to promote microglial proliferation and survival following injury (84). The levels of sTREM2 in peripheral blood and cerebrospinal fluid (CSF) are closely correlated (85), an elevation in the levels of soluble TREM2 within the cerebrospinal fluid has been observed to positively correlate with the progression of CSVD, particularly in conjunction with the imaging biomarker of cerebral microbleeds. Plasma levels of soluble TREM2 have been implicated as a predictive biomarker for white matter injury associated with small vessel pathologies. The therapeutic targeting of sTREM2, particularly in the CSF, may hold significant clinical implications for the management of CSVD (86). It is, however, imperative that the relationship between cerebral small vessel disease and the aforementioned biomarkers be substantiated through more comprehensive research, especially in the context of prolonged COVID-19 infection, the concurrent validation of the effectiveness of intervention strategies and the determination of the optimal timing for such interventions are also critical issues that require resolution.

In patients with COVID-19, in addition to the observed impacts of the aforementioned inflammatory responses, there is also an enhancement of oxidative stress. Long COVID patients exhibit elevated oxidative damage driven by reactive oxygen species (ROS), while oxidative stress pathways drive endothelial dysfunction and amplify inflammatory responses. (31, 87). NADPH oxidase enzymes, denoted as NOX, are the producers of reactive oxygen species, it has been documented that knocking down Nox1, a member of the NADPH oxidase family known for generating reactive oxygen species, in rats can reduce ROS production and subsequently improve cognitive impairment. Moreover, Nox2, another member of this family, has been implicated in the induction of blood-brain barrier disruption and vasomotor dysfunction under ischemic conditions (88–90). In the context of focal cerebral ischemia, mice with a deficiency in Nox4, yet another isoform of the NADPH oxidase family, exhibit reduced brain injury, underscoring the pivotal role of NOX4-derived oxidative stress in the pathophysiology of acute ischemic stroke (91). Oxidative stress has been implicated in the etiology of cerebral small vessel disease, encompassing both non-amyloidogenic and amyloidogenic subtypes, and is posited to contribute to vascular damage and cognitive dysfunction (92). Consequently, oxidative stress may also be considered a contributing factor to COVID-19-induced CSVD.

The NF-κB essential modulator is a human immunological signaling protein that, under physiological conditions, activates NF-κB within the canonical NF-κB response signaling pathway, which is a pivotal immune response against viral infections. NEMO can be cleaved by the non-structural protein 3C-like protease encoded by SARS-CoV-2, leading to the inhibition of host immune responses and contributing to the severe consequences of COVID-19 infection. The cleavage of NEMO by 3CLpro results in the disruption of the NF-κB pathway, a hallmark of chronic inflammatory diseases, suggesting that COVID-19 infection may have long-lasting effects on the human body (32, 93). Jan Wenzel and colleagues, through a series of rigorous experiments, ultimately found that the toxic effects of 3CLpro are mediated by its protease activity and the cleavage of NEMO, with capillaries being particularly vulnerable to the impact of NEMO deficiency. Furthermore, the authors observed that the absence of RIPK3 or the inhibition of RIPK1 can prevent NEMO ablation, thereby contributing to the amelioration of microvascular pathology (33). A study focusing on the genetic disorder incontinentia pigmenti (IP), which shares features with CSVD, similarly implicates NEMO as a critical component of the NF-κB signaling pathway. When NEMO is mutated and rendered inactive, IP can be induced. NEMO is indispensable for angiogenesis; mice subjected to continuous NEMO ablation to disrupt angiogenesis exhibit severe functional deficits. Compared to endothelial cells with NEMO deficiency, those with normal NEMO function exhibit higher proliferation rates. In this CSVD model, NEMO-associated angiogenesis can counteract functional deficits and improve the condition (94). The mechanisms by which COVID-19 infection leads to cerebral microvascular pathology may be related to CSVD, and therefore, reducing NEMO inactivation may confer benefits to COVID-19-infected patients by mitigating neurological complications.

The intricate developmental, structural, and functional interplay between brain cells and the microvascular system, as well as their coordinated response to injury, is realized through the neurovascular unit (NVU) (95). The induction and maintenance of the blood-brain barrier are also closely intertwined with the NVU, with astrocytes and pericytes being key constituents that significantly impact the BBB’s normal function (96). Among the various aspects of the NVU, neurovascular coupling has been a subject of extensive research. NVC refers to the coupling between neuronal activity and the vascular system, which is orchestrated by a series of highly coordinated multicellular interactions. NVC plays a crucial role in regulating cerebral blood flow (CBF) and neuronal activity, and it also influences cognitive dysfunction (97). There is a highly consistent association between CSVD and impaired NVC, particularly in relation to white matter hyperintensities, where endothelial dysfunction plays a central role in CSVD. NVC holds promise as a clinical method for assessing disease progression and treatment response in CSVD (98). Existing evidence suggests that SARS-CoV-2 infection can induce NVC damage, leading to persistent cognitive impairment in patients. The post-infection increase in reactive oxygen species generation mediated by AT1R and AngII-induced ROS production in brain microvascular endothelium activates transcription factors (e.g., nuclear factor κB), thereby increasing the synthesis of pro-inflammatory mediators and adhesion molecules. This interplay between oxidative stress and inflammation disrupts NVC and leads to endothelial dysfunction (34). SARS-CoV-2 may potentially cause endothelial dysfunction and long-term cognitive dysfunction by disrupting NVC. Given that cognitive impairment is a prominent symptom in CSVD, it is plausible that COVID-19 may contribute to the development and progression of cerebral small vessel disease by damaging NVC.

Microparticles, cell-derived vesicles measuring between 0.1 and 1 μm in diameter, have garnered increasing recognition in the scientific community. These MPs originate from the plasma membranes of endothelial cells, platelets, leukocytes, and erythrocytes, with their formation being modulated by intracellular calcium signaling pathways, αIIβ3 integrin, and the turnover of the cytoskeleton (99). MPs are facilely transported within the vascular system, capable of conveying pro-inflammatory signals to adjacent or target cells, thereby functioning as robust carriers of biomolecular information and as pivotal mediators of intercellular communication (100, 101). Extensive research has demonstrated that elevated levels of MPs can be observed in patients suffering from acute coronary syndrome, stroke, diabetes, pulmonary and systemic hypertension, as well as hypertriglyceridemia (102), with diabetes and hyperlipidemia being potential risk factors for cerebral small vessel disease. In patients with CSVD, it has been noted that individuals with white matter hyperintensities (WMH) exhibit a marked increase in platelet-derived MPs (PDMPs), leukocyte-derived MPs (LMPs), and total MP count. Elevated MP levels in symptomatic patients may signify underlying microvascular occlusion, suggesting that circulating MPs could serve as a novel surrogate marker for white matter integrity in CVSD (103). COVID-19 infection promotes microvesicle (MP) formation, which enhances coagulation, thrombosis, and inflammation through multiple mechanisms. These MPs may drive CSVD progression with prolonged effects persisting post-pandemic, leading to occult CSVD. During the cytokine release syndrome (CRS) phase of SARS-CoV-2 infection, membrane remodeling exposes procoagulant phosphatidylserine (PS), while TNF-α may also induce ACE2-bearing microvesicle release from microvascular endothelial cells. MPs shed through these pathways may cause capillary endothelial dysfunction and microcirculatory disruption, with ACE2-carrying MPs potentially forming lung-to-brain emboli that deposit in cerebral tissues. Furthermore, MPs elevate pro-inflammatory cytokine levels (IL-1, IL-6, IL-8, and TNF-α). (Che Mohd 103–105). A potential vicious cycle between these processes provides a plausible hypothesis for SARS-CoV-2-induced CSVD.

HIV-associated neurocognitive disorders are particularly pronounced among HIV-related comorbidities, adversely affecting patients’ quality of life. Cerebral small vessel disease is a significant cause of cognitive impairment, leading us to speculate that CSVD may be an important factor contributing to HAND. HIV infection is associated with increased white matter hyperintensity burden, as HIV-positive individuals exhibit higher WMH levels than controls (111). Among HIV-positive patients with microalbuminuria, those who received combined antiretroviral therapy (cART) demonstrate impaired information processing speed, which may correlate with cerebrovascular small vessel disease. Microalbuminuria, as a rapid and inexpensive screening method, may become a model for assessing cognitive function in resource-limited countries (112). The emergence of these CSVD-related clinical symptoms and imaging changes in HIV patients highlights the importance of exploring the mechanisms by which HIV infection causes CSVD.

Despite the continuous advancement of combined antiretroviral therapy, a significant proportion of chronically HIV-infected individuals—ranging from 18% to 50%—still develop HIV-associated neurocognitive disorders (113). Among middle-aged individuals, even with sustained immunovirological control, the prevalence of asymptomatic cerebral small vessel disease in infected individuals is found to be twice that of their uninfected counterparts (114). Certain components of highly active antiretroviral therapy (HAART) based on protease inhibitors (PIs) may exert toxic effects on the cerebral microvascular endothelial and smooth muscle cells, leading to vascular wall degeneration. Additionally, these medications may indirectly increase the risk of CSVD and exacerbate cognitive impairment by inducing metabolic abnormalities such as dyslipidemia and insulin resistance (36). However, it remains unclear whether HIV and its associated treatments invariably induce neurocognitive dysfunction. Some studies have found no adverse effects of antiretroviral therapy class exposure on CSVD in treated middle-aged HIV-infected individuals, suggesting that HIV infection and CSVD may be independent processes that cumulatively contribute to cognitive impairment (115, 116).

Neopterin, a pyrazine-pyrimidine compound produced by cells of the monocyte-macrophage lineage and astrocytes, functions in response to interferon-γ stimulation and may serve as a biomarker for HIV-associated central nervous system damage (37, 117). Neopterin is closely associated with monocytes, the activation of which has been linked to cognitive decline in HIV+ individuals (118), and it is plausible that these monocytes may migrate into the brain and exert influence. Furthermore, neopterin can activate nuclear factor-κB, enhancing the expression of adhesion molecules (119). Endothelial activation drives blood-brain barrier (BBB) disruption and neuroinflammation, contributing to small vessel damage in CSVD. Neopterin levels are elevated in CSVD patients compared to non-CSVD individuals (120), suggesting its potential as a biomarker for HIV-associated CSVD.

The scavenger receptor CD163, expressed by monocytes and macrophages, upon shedding, transforms into its soluble form, sCD163 (121). sCD163 serves as a biomarker of HIV activity, linking viral replication to monocyte and macrophage activation. (38). CD163 may also play a role in the pathomechanisms of cerebral small vessel disease. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a subtype of CSVD, has been investigated through comparative analysis of the inflammatory and immune responses in CADASIL patients versus controls, revealing a pronounced accumulation of microglia/macrophages around microvessels.CD163-positive cells were associated with a specific perivascular inflammatory cell response (122). In early hypertension, detailed analysis of cellular subpopulations identified a subpopulation of microglia expressing CD163, with altered microglial function implicated in blood-brain barrier leakage and responsiveness to vascular dysfunction, factors that may collectively contribute to the progression of CSVD (123).

High-mobility group box-1 protein, a nuclear factor and secreted protein, is implicated in the maintenance of the nucleosome structure as well as in DNA replication, transcription, and recombination (124, 125). HMGB1 can be actively secreted during stress and passively released by damaged or necrotic cells, engaging in the production of pro-inflammatory cytokines (126). High HMGB1 levels in plasma correlate with viral loads in HIV-1 infection, suggesting that HMGB1-containing immune complexes may participate in the pathogenesis of HIV-1 (39). Concurrently, HMGB1 emerges as a risk factor for cognitive impairment in patients with CSVD, as increased levels of HMGB1 promote the activation of microglia, leading to a sustained inflammatory response that disrupts the neurovascular unit and the blood-brain barrier, resulting in neurodegenerative necrosis and ultimately cognitive impairment and cerebral microbleeds (127). This may account for the cognitive decline observed in HIV patients and those afflicted with CSVD.

Hepatitis C virus infection can manifest a variety of extrahepatic manifestations, which diminish the quality of life of patients and augment their economic and health burdens (133–135). HCV infection may precipitate acute and subacute involvement of white matter, elicit inflammatory diseases of the central nervous system, and present with cognitive impairment, alterations in consciousness, as well as sensory and motor dysfunction (136). By virtue of viral localization within the lesions of HCV seropositive patients’ plaques, it has been observed that HCV infection factors might penetrate target cells through LDL receptors or scavenger receptor B1, thereby enhancing lipoprotein oxidation. The local effects of this process are believed to play a role in the pathogenesis of carotid atherosclerosis (137), potentially influencing cerebrovascular function as a consequence. Chronic hepatitis C virus infection correlates with cerebrovascular lesion development, supported by evidence that elevated serum HCV RNA levels associate with increased cerebrovascular mortality risk (138). However, the literature on the relationship between HCV and cerebral small vessel disease is limited, prompting us to investigate this association. Both HCV and HIV infections can present with mild neurocognitive impairment, exhibiting similar patterns of injury. While these diseases may share a common pathogenic mechanism, co-infected HIV and HCV patients exhibit poorer cognitive function than those with HIV alone. (139). As a common comorbidity of HIV, HCV infection not only results in more severe cognitive impairment but also manifests with higher HIV RNA levels and increased levels of MCP-1, an inflammatory chemokine, in cerebrospinal fluid (140). In light of the presence of cognitive impairment and inflammation, we postulate that HCV may induce the occurrence and progression of CSVD through a unique mechanism.

Cultured HCV infects brain microvascular endothelial cells (BMECs), which express HCV entry-required factors and mediate viral entry and replication. This infection increases endothelial permeability, induces apoptosis in BMECs, and damages the blood-brain barrier. (40, 41). These phenomena are linked to cerebral small vessel disease. A tissue-based study of brain small artery disease identifies HCV as an independent CSVD risk factor. HCV-induced small artery injury may arise from lipid/glucose metabolic disorders, elevated inflammatory burden, and endothelial dysfunction. (141). Moreover, HCV may increase the levels of CXCL10 released by HBMECs through the phosphorylation of NF-κB. The receptor for CXCL10 is CXCR3, which ultimately leads to the recruitment of CXCR3-positive leukocytes to the damaged central nervous system, thereby affecting it. Consequently, inhibiting lymphocyte migration might mitigate the harm caused by neuroinflammatory diseases, potentially intervening in the development of CSVD (42).

Following the acute phase of ZIKV infection, the virus can persist, indicating that it may have established an equilibrium for cell survival and viral replication within cellular reservoirs, while also exhibiting the capacity to evade both innate and adaptive immune responses. Human brain microvascular endothelial cells (hBMECs) act as reservoirs for ZIKV, enabling basolateral release into neurons and causing chronic neurological damage. Prolonged persistence in hBMECs promotes cerebrovascular small vessel disease (150).

ZIKV infection of endothelial cells, pericytes, and astrocytes in the blood-brain barrier may contribute to CSVD pathogenesis by disrupting BBB integrity. Additionally, ZIKV is capable of upregulating the levels of inflammatory cytokines (IL-6 and IL-8), chemokines (CCL5 and CXCL10), and cell adhesion molecules (CAMs), ultimately resulting in immune cell infiltration and neuroinflammation within the central nervous system (151). ZIKV can also infect monocytes in the circulation, enhancing their adhesive and migratory capabilities, and thereby facilitating their recruitment to the CNS (43). Furthermore, the non-structural protein NS1 of ZIKV influences the adherens junction proteins crucial to the endothelial barrier of human brain microvascular endothelial cells through the hsa-miR-29b-3p/DNMT3b/MMP-9 pathway, thereby compromising the barrier function of human cerebral vascular endothelial cells (44). These alterations may also be manifest in the pathological changes of CSVD, including the disruption of the BBB, the upregulation of inflammatory mediators, and the infiltration of inflammatory cells.

The sodium-dependent lysophosphatidylcholine symporter, known as Mfsd2a, serves as a membrane transport protein and is primarily expressed in the endothelial cells of the blood-brain barrier (152). In experimental research, Jia Zhou and colleagues demonstrated that ZIKV glycoprotein E interacts with Mfsd2a to promote its ubiquitination, causing BBB disruption and establishing a mechanistic link between Mfsd2a and ZIKV-induced neurovascular abnormalities (45). Current reports suggest a decline in cognitive function during the acute phase of ZIKV infection (153, 154). Despite the lack of long-term, large-scale follow-up studies on cognitive outcomes post-infection and direct evidence linking ZIKV to cerebrovascular small vessel disease, the prolonged replication of ZIKV could potentially impair BBB integrity through the ubiquitination of Mfsd2a, resulting in cognitive decline and the induction of CSVD.

Patients with early neurosyphilis may exhibit symptoms such as altered mental status, cranial nerve involvement, motor and sensory deficits, meningitis, or stroke. The clinical manifestations of late neurosyphilis may include progressive cognitive dysfunction, sensory deficits, gait abnormalities, and severe radicular pain (159). In addition to these symptoms, syphilis infection may also increase the risk of ischemic stroke in patients, although the exact mechanism remains elusive. Vascular inflammation leading to stenosis or occlusion of blood vessels is a convincing explanation; a retrospective study revealed that among patients with ischemic stroke, those with positive syphilis serology frequently had intracranial arterial stenosis. Poorly controlled syphilis infection may be closely associated with intracranial arterial stenosis (160), suggesting that syphilis infection may have potential mechanisms that affect the intracranial vasculature. A study conducted a follow-up on neurosyphilis patients diagnosed with acute ischemic stroke and ultimately found that, compared to patients without syphilis infection, those with neurosyphilis exhibited a closer relationship with the imaging manifestations of cerebral small vessel disease and lower cognitive function scores (161). Therefore, syphilis infection may be associated with CSVD through a variety of mechanisms.

Firstly, cerebrospinal fluid analysis in syphilis patients may reveal lymphocytosis or elevated protein concentrations, suggesting the presence of neurological infiltration (162). Secondly, lipoprotein Tp0751, as one of the complex pathogenic proteins of Treponema pallidum, may affect cerebral vascular endothelial cells through the MAPK pathway and the NF-κB pathway, and Tp0751 can stimulate the production of IL-6 in cerebral vascular endothelial cells, thereby disrupting the tight junction proteins in the blood-brain barrier (46). The aforementioned disruption of the blood-brain barrier, neurological infiltration, and upregulation of inflammatory factors may also link syphilis to CSVD. Neurofilament light subunit (NF-L) and phosphorylated neurofilament heavy subunit (pNF-H) serve as biomarkers for assessing the extent of neuronal damage in neurodegenerative diseases. In patients with symptomatic neurosyphilis, elevated concentrations of NF-L and pNF-H in cerebrospinal fluid have been observed, and their levels significantly decreased following treatment (47). Elevated blood NfL levels correlate with CSVD severity and serve as a marker for disease burden. (163). Moreover, axonal pNfH is typically concentrated around small penetrating arteries, which corresponds to the location of CSVD arterial lesions, potentially representing the result of subcortical white matter axonal damage due to CSVD arterial pathology (164). Consequently, NF-L and pNF-H hold promise as biomarkers for assessing the burden of CSVD in patients with syphilis.

It is currently established that dysbiosis of the gut microbiota can elevate the risk of cerebrovascular diseases through diverse mechanisms (173). These include immune activation, lipid dysregulation, and platelet hyperactivity (mediated by TMAO, PAGln, and PAGly), which not only trigger atherosclerosis but also exacerbate cerebrovascular disease. (174). Furthermore, there is a correlation between the intricate composition of the gut microbiota and the observed decline in cognitive abilities among middle-aged and elderly individuals. Consequently, investigating the interplay between the gut microbiota and cerebral small vessel disease assumes significant clinical relevance.

In an animal study, it was observed that the gut microbiota might contribute to the transformation of inflammation from a localized intestinal condition to a systemic inflammatory response through the actions of bacterial toxins and the translocation of bacteria themselves, leading to invasion of the brain and disruption of the blood-brain barrier. The loss of BBB integrity is frequently detected in the early stages of cerebral small vessel disease (175). A study linking gut microbiota to CSVD patients reveals a significant correlation between Barnesiella intestinihominis and CSVD biomarkers. Differences in bacterial gene abundance associate with molecules including AMP/GMP-activated kinases, xanthine, tyrosine, phenylpyruvate, and dicarboxylic acid-hydroxybutyrates—compounds implicated in neurodegenerative diseases. Notably, AMP-activated kinases and hydroxybutyrates demonstrate neuroinflammatory suppressive effects, suggesting that gut microbiota-CSVD associations may be regulated via neuroinflammatory pathways (48). Parasutterella, a pivotal genus within the human gut microbiota, has been demonstrated to exhibit a significant correlation with cognitive assessments such as the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) in patients with cerebral small vessel disease. Additionally, the relative abundance of Parasutterella is associated with the amplitude of low-frequency fluctuation (ALFF) within the bilateral middle frontal gyrus, these findings suggest a potential contribution of Parasutterella to the etiology of cognitive dysfunction in CSVD. Moreover, the relative abundance of Parasutterella is positively associated with plasma levels of S100β, a peripheral marker of blood-brain barrier functionality, suggesting that Parasutterella may contribute to the degradation of BBB integrity in the context of CSVD. The study also reports a positive correlation between the levels of the gut bacterium Collinsella in CSVD patients and white matter hyperintensity scores, with an increase in Collinsella being linked to inflammatory activity and tumor necrosis factor-alpha (TNF-α) levels, which may participate in neuroinflammatory responses and reflect the severity of CSVD (49).

There is a close association between oral bacteria and periodontal disease, with current knowledge suggesting that periodontal disease may induce cerebral small vessel disease, and lacunar infarction may be related to periodontal disease. Moreover, the progression of periodontal disease often portends an increase in the number of lacunar infarctions (187). Despite adjusting for risk factors of lacunar stroke, chronic periodontitis remains independently associated with the presence of lacunar infarcts (188). Chronic periodontal disease is considered to potentially induce a chronic systemic inflammatory response and endothelial dysfunction (189). Chronic periodontitis leads to the production of a significant amount of circulating pro-inflammatory mediators (IL-1β, IL-6, TNFα), C-reactive protein (CRP), etc. (190–192). It is known that inflammatory factors such as IL-6, TNFα, and CRP are associated with an increased risk of cognitive decline in patients with cerebral small vessel disease (193). The amassing of a substantial quantity of inflammatory mediators could potentially offer a mechanistic nexus between periodontitis and cerebral small vessel disease, this prompted us to explore additional clues.

Porphyromonas gingivalis, a member of the oral microbiota, directly infects human endothelial cells, activates p38 MAPK phosphorylation and NF-κB nuclear translocation, and enhances endothelial adhesion molecule expression, thereby inducing endothelial damage and inflammatory responses. (52). Furthermore, the bacterial-induced autoimmune response may also result in endothelial injury, as the interaction between oral bacterial antigens and endogenous molecular structures may elicit an autoimmune response; the immunological cross-reaction of antibodies and T cells between endogenous heat shock proteins and the molecular chaperone factor GroEL of Porphyromonas gingivalis may lead to endothelial dysfunction, ultimately triggering cerebral small vessel disease (53). In addition to endothelial damage, the abnormal aggregation of platelets is also of note, as the cysteine protease produced by Porphyromonas gingivalis can activate protease-activated receptors (PAR)-1 and -4 expressed on the platelet surface, ultimately causing abnormal platelet aggregation (54), which may affect the small vessels of the brain. Moreover, Porphyromonas gingivalis is present in atherosclerotic plaques, and systemic exposure to this bacterium may increase the risk of ischemic stroke (194). Intracranial atherosclerosis is also crucial for patients with CSVD (195).

CNM is a collagen-binding protein located on the cell surface of Streptococcus mutans. The presence of CNM-positive S. mutans in the oral cavity is strongly linked to severe dental caries. Infection of carious teeth with S. mutans raises the risk of bacteremia and cerebral dissemination. Additionally, S. mutans adheres to tooth surfaces, and even routine activities like brushing or flossing may trigger bacteremia. Once in the bloodstream, CNM-positive S. mutans induces blood-brain barrier inflammation by binding to cerebral vascular basal membranes (BM), causing cerebrovascular damage (55). A population-based study revealed that individuals infected with collagen-binding protein-positive Streptococcus mutans exhibited a higher incidence of cerebral microbleeds, suggesting that CNM-positive Streptococcus mutans may elevate the risk of cerebral microbleeds and, consequently, demonstrate an association with cerebral small vessel disease (196). Following oral infection with Streptococcus mutans, the bacteria bind to exposed collagen layers due to the expressed collagen-binding protein and anionic cell surface conditions, activating matrix metalloproteinase (MMP-9) and inhibiting platelet aggregation at injured blood vessels induced by collagen, potentially leading to persistent bleeding, which may be a contributing factor to cerebral microbleeds in CSVD (197). Another study evaluated nine periodontal pathogens and identified Campylobacter rectus as being associated with cerebral microbleeds (198). In conclusion, certain oral microorganisms may be implicated in systemic inflammatory responses, disruption of vascular endothelial function, and platelet abnormalities, inducing the occurrence and progression of CSVD through a variety of mechanisms.