Background/Purpose: The central nervous system is not the primary target in rheumatoid arthritis (RA). However, neuropsychiatric symptoms including pain, depression and anxiety are common and may be critical for patients’ quality of life. The aim of the present study was to investigate how insulin-like growth factor receptor (IGF1R) signaling in RA associates with morphometric changes of the brain, and ultimately impairment of their functional ability.

Methods: Arthritis was induced in DBA/1 mice by collagen II and the RA-mice were filmed to evaluate behavioral changes. IGF1R was inhibited with short hairpin RNA. At termination, brains were analyzed by quantitative PCR and immunohistofluorescence. 15 RA patients, all of them satisfying ACR classification criteria, underwent magnetic resonance imagining (MRI) for volumetric analysis of hippocampus at 3 Tesla and processed with brain morphometry software (MAPER). Physical functioning was assessed by the Health Assessment Questionnaire (HAQ). Pain threshold was measured by algometer. Statistical analysis included the Mann-Whitney U-test and Spearman’s rank correlation coefficient.

Results: Evaluation of MRI and physical functioning in RA patients revealed that smaller hippocampus volume was linked with exaggerated response of induced pain (p=0.0006), higher functional disability (HAQ, p= 0.009), and lower serum levels of IGF1 (p=0.05). RA-mice had signs of inflammation in the hippocampus, presented by higher density of IBA1⁺ microglia and higher transcription of microglia activation marker CD68 (p= 0.0006) and interleukin-1β (p= 0.002). Enrichment of microglia was observed in the pyramidal layer of cornu ammoni (CAsp, p= 0.02) and the molecular layer of the dentate gyrus (DGmo, p= 0.02). This coincided with inhibitory phosphorylation of insulin receptor substrate-1 (IRS1) in the subgranular layer of DG (DGsg, p= 0.03) and CAsp (p= 0.05), and up-regulation of IGF1R in the CAsp (p= 0.03). These changes reproduce the molecular signature of IGF1/insulin resistance. DGsg, the site of life-long neurogenesis, became thinner (p= 0.03) and the reduced thickness correlated with a smaller number of DCX+ developing neurons in this area (r= 0.7, p= 0.005). There was also a reduction in the total hippocampus area of RA-mice (p= 0.02). Inhibition of IGF1R in RA-mice led to reduced inhibitory phosphorylation of IRS1 (p= 0.004) and partial improvement of neurogenesis, seen as an increased number of GFAP+ neuronal stem cells in DGsg (p= 0.02).

Conclusion: We offer a mechanistic link between pain perception in RA and reduced hippocampal volume. Our experimental study demonstrates that inflammation reproduce the molecular signature of IGF1/insulin resistance, which leads to inadequate maintenance of hippocampal neurons and consequently reduced hippocampal volume.