A Prominent Elevation of Glial Fibrillary Acidic Protein in the Cerebrospinal Fluid during Relapse in Neuromyelitis Optica

Abstract

Neuromyelitis optica (NMO) is a neurologic disease characterized by severe optic neuritis, longitudinally extended, transverse myelitis and serum aquaporin-4 (AQP4) antibody. Our recent neuropathological study revealed the extensive loss of AQP4 and glial fibrillary acidic protein (GFAP), an astrocyte-specific protein, in NMO lesions, but not in MS lesions, suggesting that severe astrocytic damage or dysfunction may be related to the pathogenesis of NMO. Here we report a patient of NMO, in which the cerebrospinal fluid (CSF) levels of GFAP were measured both during relapse of myelitis and after high-dose intravenous methylprednisolone (HIMP). The patient was a 34-year old woman with two previous episodes of optic neuritis. She developed myelitis longitudinally extending from C3 to T12 with contrast enhancement, and was AQP4 antibody-positive. In the acute phase, the GFAP level in the cerebrospinal fluid (CSF) was prominently elevated (18,966.7 ng/ml) as compared with controls (0.6 ± 0.33 ng/ml). However, following HIMP, the clinical and MRI findings improved, and the CSF-GFAP level was near-normal (2.1 ng/ml). The CSF of myelin basic protein was also elevated in relapse (1,016.0 pg/ml), and became lower but still remained high (158.7 pg/ml) after HIMP compared with controls (3.36 ± 3.83 pg/ml). The prominent elevation of the CSF-GFAP level in relapse of NMO, followed by its sharp decline after therapy, suggests severe astrocytic damage with a temporal profile distinct from that of the demyelinating process in NMO. CSF-GFAP may be useful as a biomarker of NMO.glial fibrillary acidic protein (GFAP); neuromyelitis optica; cerebrospinal fluid; myelin basic protein; relapse. Neuromyelitis optica (NMO) is a neurologic disease characterized by severe, often bilateral optic neuritis and transverse myelitis. As well as the unique lesion distribution and severe functional disability in NMO, the clinical and laboratory features of NMO have been reported to be distinct from those of MS, and they include female preponderance, higher onset age, mostly

Clinical Manifestations and Spinal Cord Magnetic Resonance Imaging Findings in Chinese Neuromyelitis Optica Patients

“…Although pathogenic AQP4 antibody-positive sera and IgG purified from AQP4 antibody-negative sera did not induce NMO-like pathology in experimental studies [8], this finding requires confirmation. Analyses of central nervous tissue samples and CSF biomarkers including astrocyte-specific glial fibrillary acidic protein are expected to elucidate the pathology of seronegative NMO [29]. …”

Glial fibrillary acidic protein is a body fluid biomarker for glial pathology in human disease

“…Both, complement mediated autoimmune antibody and cellular mediated glial toxicity are hold responsible for astrocytic apoptosis (Bradl et al, 2009;Kinoshita et al, 2009;Pohl et al, 2011;Saadoun et al, 2010;Matsumoto et al, 2014). The group from Sendai was the first to report the serendipitous finding of a several magnitude increase of CSF GFAP levels in one patient with acute NMO (Takano et al, 2008). This finding has since been reproduced by different groups (Misu et al, 2009;Takano et al, 2010;Petzold et al, 2011a;Hyun et al, 2014).…”

Pathogenesis, diagnosis and treatment of neuromyelitis optica: Changing concept of an old disease

“…Such efforts detected markedly increased IL-6 and GFAP levels in NMO in contrast to MS. 19,151,152 Nerve growth factor and iodothyronines in CSF, reflecting thyroid hormones in the brain, were higher in NMO and MS compared with controls. 153 Proteome analysis of the CSF identified a unique expression profile in NMO compared with undefined controls.…”

“…8,9 Outside the CNS, AQP4 is expressed in skeletal muscles, distal collecting tubules of the kidney, parietal cells of the stomach, colon epithelium, tracheal and bronchial epithelium, and glandular epithelia of breast and salivary glands. 10,11 Several data show that anti-AQP4 antibodies are pathogenic: (i) antibodies binding to AQP4 are present in a substantial portion of patients with NMO; (ii) NMO-IgG titers in sera might correlate with clinical disease activity; 6,12 (iii) in CNS plaques of NMO characterized by antibody and complement deposition, AQP4 molecules are absent in contrast to MS, 6,[14][15][16] and glial fibrillary acidic protein (GFAP) (an astrocyte marker) immunoreactivity is lost along with increased cerebrospinal fluid (CSF) levels of soluble GFAP; [17][18][19] (iv) sera containing NMO-IgG induces complement-dependent necrosis of astrocytes in vitro; [20][21][22][23][24] (v) human NMO sera recognize an extracellular epitope of AQP4 and induce AQP4 endocytosis in transfected cell lines. 17,20,21,23,25,26 The third extracellular loop of AQP4 might be the major epitope for antibodies in NMO; 27 (vi) IgG isolated from sera or recombinant antibodies generated from CSF of NMO patients were able to transfer disease.…”