Distinct cerebrospinal fluid profiles of astrocytic aquaporin-4 and GFAP in neuroinflammatory disorders

Aquaporin 4 (AQP4), a water channel expressed in astrocytic end feet forming the blood brain barrier, is predominantly expressed in the central nervous system. Cerebrospinal fluid (CSF) AQP4 has now been suggested as a possible fluid biomarker in Alzheimer's disease. However, its diagnostic potential in primary neuroinflammatory diseases, where also AQP4 autoantibodies can circulate, has so far not been studied. We investigated the CSF of 301 patients for AQP4 and GFAP using ELISA. The single-center cohort consisted of patients with multiple sclerosis (n = 81), chronic inflammatory demyelinating polyneuropathy (n = 23), Guillain-Barré-Syndrome (n = 13), meningitis/ encephalitis (Men/Enc) (n = 19), myelin oligodendrocyte glycoprotein antibody disease (n = 6), neuromyelitis optica spectrum disease (NMOSD) (n = 12), and non-immune mediated polyneuropathy (NIP) patients (n = 49). 98 patients without acute or chronic neuroinflammation and neurodegneration served as controls. Both CSF AQP4 (r = 0.45 (95%CI: 0.36-0.54), p < 0.0001) and GFAP (r = 0.4 (95%CI: 0.30-0.49), p < 0.0001) correlated with age in the whole cohort. CSF AQP4 levels were elevated in the NIP group compared to control, MS and Men/Enc patients (p = 0.002, p = 0.029 and 0.005, respectively). When stratified further, the hereditary NIP patients (n = 26) displayed the highest AQP4 levels of all groups. CSF GFAP was elevated in the AQP4 autoantibody positive NMOSD group but was not increased in AQP4 autoantibody negative NMOSD patients. CSF AQP4 levels were similar in both NMOSD groups. Combining AQP4 and GFAP levels or calculating their ratio did not prominently enhance diagnostic discrimination. The study highlights the diagnostic potential of AQP4 as a fluid biomarker in neurological conditions, especially in peripheral neuropathies, while confirming GFAP as marker for astrocytic injury in autoantibody positive NMOSD patients. Our findings suggest that AQP4 and GFAP reflect different astrocytic processes in neurological diseases.