Cerebral Small Vessel Disease (CSVD): The Role of Irisin and CHIT1 in White Matter Hyperintensities and Cognitive Function

Cerebral small vessel disease (CSVD) refers to a range of clinical, imaging, and pathological syndromes caused by various factors affecting small arteries and their distal branches, microarteries, capillaries, microveins, and small veins within the brain. A common disease, CSVD poses a serious threat to the health of people in China. Due to its often-subtle nature, it is frequently overlooked by patients and even clinicians [1]. As the burden of CSVD continues to rise, patients may experience various symptoms, including cognitive impairment, motor dysfunction, emotional disturbances, and urinary and bowel dysfunction [1]. However, clinicians have traditionally lacked sufficient understanding of the chronic clinical symptoms caused by CSVD [1]. Currently, imaging examinations are the primary diagnostic method for CSVD, with cranial magnetic resonance imaging (MRI) demonstrating high sensitivity and accuracy in CSVD diagnosis. CSVD is a significant contributor to white matter lesions and cognitive impairment in the elderly. With the increasing aging population in China, the incidence of CSVD is on the rise, imposing a heavy burden on society, families, and individuals.

White matter hyperintensities (WMHs) are a key imaging marker of CSVD. In individuals over 60 years old, most show some degree of WMH on imaging, and the prevalence increases with age. Numerous studies have highlighted the crucial role of white matter damage in cognitive impairment among patients with cerebrovascular disease [2]. On MRI, WMHs exhibit two forms: periventricular white matter hyperintensities (PWMHs) and deep white matter hyperintensities (DWMHs) [3]. Research indicates that 87% of individuals aged 60 to 70 experience PWMHs, and 68% experience periventricular WMHs. In those aged 80 to 90, 100% exhibit PWMHs, and 95% exhibit periventricular WMHs [4]. Studies have revealed distinct mechanisms underlying PWMHs and DWMHs. PWMHs are primarily attributed to venous damage caused by impaired glymphatic pathway function, while DWMHs may be influenced by ischemic hypoperfusion and glymphatic pathway dysfunction [5]. The mechanisms involved in WMH formation include pathological changes such as inflammation/oxidative stress, ischemia/hypoperfusion, blood-brain barrier damage, and endothelial dysfunction. These impairments may affect cognitive function in patients.

Irisin is a newly discovered exercise-induced myokine produced by proteolytic cleavage of the FNDC5 protein by extracellular proteases, primarily secreted by skeletal muscle into peripheral circulation [6]. Irisin plays a crucial role in various chronic diseases through multiple pathways, such as regulating energy metabolism and exerting anti-inflammatory effects. Early research demonstrated that Irisin primarily promotes the conversion of white adipose tissue into brown adipose tissue by increasing energy expenditure and upregulating UCP1 expression, contributing to temperature regulation and weight management. Consequently, Irisin is considered a key regulator of energy metabolism and weight [7]. Some studies have also shown that Irisin can exert anti-inflammatory and antioxidant effects by suppressing inflammation and oxidative stress. Irisin is found in Purkinje cells, the hypothalamus, and cerebrospinal fluid in the brain, playing an important role in the central nervous system [8]. A study observed a correlation between Irisin levels and the presence of CSVD measured by MRI in Japanese men [12]. Various lines of evidence suggest that Irisin crosses the blood-brain barrier, where it induces BDNF, which is involved in regulating synaptic plasticity [7,8]. Research indicates that Irisin has neuroprotective effects in brain disorders such as Alzheimer's disease (AD) and in acute brain injuries like ischemic stroke and traumatic brain injury [9–11]. Additionally, Irisin has been shown to stimulate the cAMP/PKA/CREB pathway, thereby modulating neuronal plasticity and preventing memory impairment [10]. Studies have found that Irisin provides neuroprotective effects by activating the ERK1/2 and Akt signaling pathways [11].

The CHIT1 gene resides in the chromosome 1q31-q32 region, belonging to the glycosyl hydrolase (GH) family. It comprises two parts: an N-terminal 39 kDa catalytic domain and a C-terminal carbohydrate-binding module, connected by a highly flexible proline-rich hinge region. CHIT1 is an enzyme associated with inflammatory responses. Its increased expression in certain diseases correlates with the severity of the inflammatory reaction. Recent studies have revealed the significant role of CHIT1 in various inflammation-related neurological diseases, including Alzheimer's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, Creutzfeldt-Jakob disease, and Parkinson's disease. CHIT1 levels and activity are significantly elevated in the cerebrospinal fluid (CSF) of Alzheimer's disease patients. Research has shown that CHIT1 acts as a biomarker for macrophage activation and plays a crucial role in many inflammatory diseases.

While serum Irisin and CHIT1 levels have been linked to Alzheimer's disease and post-stroke cognitive impairment, there is currently no research reporting a correlation between serum Irisin and CHIT1 levels and white matter lesions or cognitive function in CSVD patients. Therefore, this study proposes a hypothesis: serum Irisin and CHIT1 levels in CSVD patients are associated with the severity of white matter lesions and cognitive impairment. The objective of this study is to assess the possible relationship between serum Irisin and CHIT1 levels in CSVD patients and their white matter lesion grading and cognitive dysfunction.