1. Introduction
Cerebral small vascular disease (CSVD) is one of the common, chronic, and progressive cerebrovascular diseases, accounting for about 25% of ischemic strokes, and it is also an important pathogen of dementia [
1]. CSVD is caused by various pathological changes of intracranial arterioles, venules, and capillaries, with clinical manifestations of ischemic stroke, dementia, gait disturbance, urinary incontinence, depression, etc.
CSVD is one of the common causes of vascular cognitive impairment (VCI) and is associated with progressive cognitive decline and the emergence of new cognitive impairment [
2]. VCI caused by CSVD accounts for 15–30% of clinical dementia cases, second only to Alzheimer’s disease (AD) [
3,
4]. The early clinical manifestations of CSVD-related cognitive impairment (CI) (CSVD-CI) are insidious and atypical [
3,
5], often detected as executive dysfunction (ED), such as attention and inhibition function, cognitive flexibility, information processing speed, and visuospatial dysfunction [
6,
7,
8], which easily affect activities of daily living, social participation, work performance, and functional prognosis [
9], and ED is the core and first symptom of CI [
10]. The assessment of executive function (EF) is an important part of the neuropsychological assessment of the elderly, has a high sensitivity to CI, and is a vital factor affecting the functional rehabilitation in stroke [
11]. With the increase in population aging worldwide, CSVD and CI impose a significant burden on individuals and the society; therefore, early identification of EF impairment in CSVD is critical. Since the pathogenesis of CSVD and VCI remains unclear [
1,
12,
13], the search for sensitive and accurate biomarkers will provide new scientific ideas.
Migration inhibitory factor (MIF) is an evolutionarily highly conserved low molecular homotrimeric protein (about 12.5 kDa). MIF is involved in various biological functions, including leukocyte recruitment, inflammation, immune response, cell proliferation, tumorigenesis, and regulation of glucocorticoids. In order to identify detection and treatment targets, studies have detected the lineage changes of various cytokines/chemokines in the plasma of ischemic stroke patients and confirmed that MIF is significantly elevated [
14]. MIF could accelerate atherosclerosis (AS) through immune reaction, inflammation, and oxidative stress, and promote neuronal death, and thus aggravate the development of stroke [
15]. MIF is associated with biomarkers of AD pathology and predicts cognitive decline in MCI and mild dementia [
16]. CSVD is a small ischemic or bleeding lesion caused by pathological small vessels or brain degeneration [
17], and is an important cause of ischemic stroke. CSVD has similar etiology and pathological mechanisms to stroke as hypoxia, inflammation, and immunoreaction, and has a complex relationship with AD [
18,
19]. It is speculated that MIF may act on CSVD and CI through different pathogeneses and become a reliable target for the detection and treatment of CSVD. Based on these, this article mainly studies the risk factors of CSVD-CI and the relevance between MIF and white matter hyperintensity (WMH) and executive dysfunction.
4. Discussion
This is the first cohort study conducted in China to investigate the relationship between serum MIF level and WMH and EF. This study found that the total Fazekas score and serum MIF level were risk factors for CSVD-CI: compared to the NC group, an increase of one point in the Fazekas score suggested a 42.2% increased risk of CSVD-CI and an increase of 1 pg/mL MIF suggested a 0.7% increased risk of CSVD-CI in the IC group. As the Fazekas score increases, the more cognitive function is impaired, and with the increase in MIF level, the more severe the degree of WMH, the more severe the impairment to cognitive and executive function. Total Fazekas score and serum MIF level were found to be significant factors for diagnosing cognitive impairment due to CSVD.
In the present study, the results showed that the total Fazekas score was a risk factor for CI in patients with WMH, the degree of WMH was correlated with CI, and the ROC curve showed certain diagnostic value for CI in CSVD. Previous studies have shown that WMH is closely associated with the incidence of CI and dementia [
26,
27], mainly impairs EF, attention, information processing speed, memory and language function [
28,
29], and especially causes EF impairment [
30]. An increase in total WMH load could predict cognitive decline, MCI, dementia, stroke, and even death [
31], and the greater the WMH load, the more severe the cognitive impairment [
32,
33], which are consistent with the conclusion that the total Fazekas scores are negatively correlated with MoCA scores in this study. We found that in the Stroop test, with the increase in WMH load, except for the mistake number of Card D, the other indexes increased with varying degrees, especially SIE-T and SIE-M, representing the interference inhibition. Combined with the CTT test results, with the increase in WMH load, the time consumption and interference of Card A and Card B also increased, indicating that the patient’s information processing speed and fixed transfer ability were impaired, while the mistake numbers in Card A and Card B were not significantly correlated; this may because patients with CI try to extend reading time in exchange for reading correctness. These above results suggest that attention and ED may be more sensitive evaluation indexes in the early stage of CI. IADL involves complex activities related to the ability to live independently and can be monitored dynamically to assess CI [
34], and the more severe the CI, the more obvious the degree of IADL disability. This study found that WMH severity was negatively correlated with IADL, suggesting that WMH lesions can cause decreased independent living ability. Early cognitive impairment of CSVD can be preventable and controllable. MRI should be performed as early as possible to assess the severity of WMH based on Fazekas, and to infer whether the patient has cognitive impairment and the severity of it. Timely screening of cognitive function with WMH, especially assessment of EF, and early intervention are expected to play a key role in the prognosis of CSVD patients.
This study found that MIF level was a risk factor for CI in patients with CSVD, and its level was positively correlated with cognitive function and the severity of WMH. Previous studies have found that MIF could affect the development of CSVD by affecting a variety of pathophysiological processes [
35]. Arteriosclerosis is the main cause of chronic hypoxia hypoperfusion, while MIF is a key mediator of arteriosclerosis [
36], participating in the entire process of arteriosclerosis by promoting leukocyte recruitment and damaging inflammation [
37,
38]. Previous studies have found that MIF is involved in the preclinical atherosclerosis process based on low-grade inflammation [
39], and is associated with hypoendothelial function and increased vascular stiffness [
40], while arteriosclerosis may be a common pathogenesis of CSVD [
41]. Moreover, MIF can also promote the production of pro-inflammatory factors (IL-1β, IL-6, and intercellular cell adhesion molecule (ICAM)) [
42,
43]; aggravate many pathophysiological processes, including endothelial injury, blood–brain barrier(BBB) destruction, white matter lesions, etc. [
44]; and participate in the whole process of inflammatory response. At the same time, MIF can promote endothelial autophagy induction, leading to endothelial barrier dysfunction [
45], thereby increasing vascular permeability, and ultimately leading to the destruction of the BBB [
14], and the degree of increased BBB permeability is associated with higher WMH load and cognitive decline [
46]. Therefore, MIF can promote the occurrence and progression of CSVD through different pathogeneses, which in turn causes cognitive impairment.
This study showed that with the increase in MIF level, the total MoCA score decreased significantly (
p = 0.001), and thus the increased MIF level may cause cognitive function decline. MIF level is positively correlated with the time consumption of Card C, SIE-T, SIE (B-A). Card C is the most difficult in the Stroop test, which can best reflect the ability to inhibit cognitive interference. SIE-T represents the dominant inhibitor and is the core factor of EF. SIE (B-A) represents the stereotype transfer factor, which can assess well the executive ability of the patients, and its sensitivity and specificity for the diagnosis of MCI caused by CSVD were 88% and 76%, respectively [
47]. These above results show that the cognitive dysfunction influenced by MIF is mainly characterized by ED with impaired information processing speed, dominant inhibition ability, and static transfer ability, which is consistent with the characteristics of CSVD-CI, so CI caused by MIF may further affect cognitive function through cerebrovascular pathology.
Although the ROC curve analysis in the present study showed that serum MIF level has a diagnostic value for CI in CSVD, the diagnostic sensitivity and specificity are still unsatisfactory and remained at 0.723 and 0.596, respectively. Because the sequence of ischemia, hypoxia, inflammatory response, and elevated MIF level is not well defined, the sensitivity of MIF is difficult to detect. MIF can be implicated in multiple CNS diseases through the inflammatory immune responses, such as stroke, neurodegeneration, multiple sclerosis, etc. Therefore, the specificity is difficult to detect. This may be related to the fact that MIF with other neurological factors, as diagnostic markers for CNS diseases, can further improve diagnostic specificity.