Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by significant deficits in social communication and interaction, repetitive behaviors, and the presence of restricted interests (First, 2013). The prevalence of autism in the United States was reported as 1/54 in the 2020 report published by the Centers for Disease Control and Prevention (CDC) (Maenner, Shaw, & Baio, 2020).
Although the etiology of ASD has not been fully elucidated, many mechanisms, such as advanced parental age, pregnancy-related complications, drug use during pregnancy, exposure to toxins, epigenetics, oxidative stress, hypoxic damage, neurotransmitter anomalies, and neuroinflammation, have been proposed in the literature (Eissa et al., 2018). Neuroinflammation is a process that involves the continuous activity and proliferation of glial cells (microglia and astrocytes) and leads to changes in brain functions (Zhao, Li, Yang, Ge, & Cui, 2022). A significant increase in neuroglial response has been identified in individuals with ASD (Vargas, Nascimbene, Krishnan, Zimmerman, & Pardo, 2005). Moreover, the expression of proinflammatory factors such as cytokines and chemokines has been reported to increase in the brain and cerebrospinal fluid in ASD (Masi, 2017).
Neuronal connectivity and impaired synaptogenesis are perhaps the most validated hypotheses that can adequately explain the pathogenesis of ASD. In order to increase the activity of neurons in a healthy developing brain and thus to create functional neuronal connections, non-functional, unnecessary neurons are disabled. Thus, the total number of neurons decreases, while the connectivity and functionality between the remaining neurons increase every day. There is evidence that this process is impaired in children with ASD (Paolicelli & Ferretti, 2017). When the cellular-molecular disorders suggested in autism studies are taken together, it is believed that the synaptic transmission from other neurons cannot be regulated in the affected neurons; in other words, synaptic plasticity is impaired. For the normal functioning of the systems, the synaptic infrastructure must be regulated according to the demands of the functional synaptic circuits. When this regulation fails, disorders in the synaptic molecular system may result in neuronal damage. Eventually, the cells respond in a way that is triggered by stress signals and does not conform to synaptic reorganization, thereby activating the glial cells. Activation of glial cells, on the other hand, leads to the production of proinflammatory signals with the participation of local defense systems and initiates neuroinflammatory processes, which is an important mechanism in ASD (Matta, Hill-Yardin, & Crack, 2019).
Visinin-like protein 1 (VILIP-1) is a cytoplasmic protein of low molecular weight (approximately 22 kDa) consisting of 191 amino acids. This protein is a member of the neuronal calcium sensor protein family and is involved in calcium-mediated signal transduction in neurons (Spilker & Braunewell, 2003). VILIP-1 has been described as a marker in CSF and serum for some neurodegenerative and neuroinflammatory diseases. For instance, VILIP-1 plays a critical role in linking pathological changes in the brain with calcium-mediated neuronal damage in Alzheimer's disease (Halbgebauer et al., 2022). It is predicted that neuronal damage secondary to the deterioration of synaptic plasticity in ASD patients will affect VILIP-1 levels.
Cluster of differentiation 163 (CD163) is a 130-kDa transmembrane protein belonging to group B of the scavenger receptor cysteine-rich (SRCR) superfamily. CD163 can be detected both as a cell surface receptor and as a serum-soluble form of sCD163 (soluble CD163). sCD163 is a marker that is expressed in microglial cells and shows microglial activation. It has been suggested that CD163 plays a role in the regulation of adaptive immune response and that its measurement in tissue or serum in inflammatory diseases might be a guide for the severity and prognosis of inflammatory diseases (H. J. Møller, Peterslund, N. A., Graversen, J. H. and Moestrup, S. K., 2012)
YKL-40, considered chitinase 3-like protein 1 (YKL-40) or human cartilage glycoprotein 39 (HC-gp39), is a chitin-binding lectin belonging to the glycosyl hydrolase family. YKL-40 protein is expressed by various cell types, including macrophages, chondrocytes, neutrophils, and synovial fibroblasts (Johansen, 2006). Its expression has been reported to increase in neuroinflammatory conditions. YKL-40 has been shown to have the capacity to regulate the plasticity or regenerative processes of neurons (Dafna Bonneh-Barkay, Wang, Starkey, Hamilton, & Wiley, 2010). YKL-40 is also thought to potentially have the capacity to negatively modulate neurotrophic factor-related changes in neuronal repair and regeneration (D. Bonneh-Barkay et al., 2010).
A relationship has been shown between the language-cognitive levels of children diagnosed with ASD and the severity and prognosis of the disease (Mawhood, Howlin, & Rutter, 2000; Nitzan et al., 2022). Clinical examination best determines the cognitive level of children with ASD. In addition, many developmental tests can be applied to these children in line with their age and developmental levels (White, 2009). It has been shown that any disruption that affects microglial physiological function during critical developmental periods can cause defective maturation of synaptic circuits, disruptions in neuronal connections, synaptogenesis damage and neuronal damage, leading to neurodevelopmental disorders (eg ASD and schizophrenia) and cognitive impairments in children (Paolicelli & Ferretti, 2017). For this reason, the relationship between cognitive impairment and the course of the disease in children with ASD was investigated via CD163, YKL-40 and VILIP-1 markers.
Given the literature, the role of CD163, YKL-40, and VILIP-1 has been investigated in the etiology of schizophrenia, depression, and other neuroinflammatory diseases but not in the group of patients with ASD, the etiology of which has not yet been clarified (Anderson et al., 2022; K. Braunewell et al., 2011; North, 2021; Purves-Tyson et al., 2020; Rymo et al., 2017). In order to close this gap in the literature, this study was planned to examine the serum levels of CD163, YKL-40, and VILIP-1 in children with ASD aged 1–6 years. In addition, the study aimed to investigate the correlation of these biomarkers with the language-cognitive development levels of children with ASD.