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Updated: Mar 21, 2026
Human Serum Anti-aquaporin-4 Immunoglobulin G Detection by Cell-based Assay
Published on: April 5, 2019
Clinical utility of testing AQP4-IgG in CSF: Guidance for physicians
Masoud Majed1, James P Fryer1, Andrew McKeon1
1Departments of Laboratory Medicine and Pathology (M.M., J.P.F., A.M., V.A.L., S.J.P.), Neurology (A.M., V.A.L., S.J.P.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN.
Insights
Serum is the optimal specimen for detecting aquaporin-4 immunoglobulin G (AQP4-IgG). Testing AQP4-IgG in serum is more sensitive than in cerebrospinal fluid (CSF), making it more cost-effective for diagnosing conditions like NMO.
Area of Science:
- Neuroimmunology
- Diagnostic assay development
- Autoantibody detection
Background:
- Aquaporin-4 immunoglobulin G (AQP4-IgG) is a key biomarker for neuromyelitis optica spectrum disorder (NMOSD).
- Accurate and sensitive detection of AQP4-IgG is crucial for diagnosis and management.
- Previous studies have yielded varying results regarding the optimal specimen type for AQP4-IgG testing.
Purpose of the Study:
- To determine the most sensitive and specific specimen type for detecting aquaporin-4 immunoglobulin G (AQP4-IgG).
- To compare the diagnostic utility of serum versus cerebrospinal fluid (CSF) for AQP4-IgG detection.
- To evaluate the cost-effectiveness of different specimen types for AQP4-IgG testing.
Main Methods:
- Retrospective analysis of 101,065 patient specimens tested for AQP4-IgG.
- Comparison of paired serum and CSF samples from 616 patients using cell-based assays (commercial CBA and in-house FACS).
- Sensitivity analysis of 58 time-matched paired specimens from patients with NMO or at high risk.
Main Results:
- Serum AQP4-IgG detection was more sensitive than CSF detection using both FACS and commercial CBA (p < 0.001).
- In no cases was CSF positive for AQP4-IgG while serum was negative.
- A serum titer >1:100 predicted CSF positivity, and CSF positivity was higher during attacks.
Conclusions:
- Serum is the optimal specimen for AQP4-IgG detection due to higher sensitivity and cost-effectiveness.
- Lower sensitivity in CSF suggests AQP4-IgG is primarily produced peripherally, requiring a serum/CSF gradient for CNS penetration.
- Serum testing provides a more reliable and efficient method for diagnosing AQP4-IgG-associated neurological conditions.
Objective:
To define, using assays of optimized sensitivity and specificity, the most informative specimen type for aquaporin-4 immunoglobulin G (AQP4-IgG) detection.
Methods:
Results were reviewed from longitudinal service testing for AQP4-IgG among specimens submitted to the Mayo Clinic Neuroimmunology Laboratory from 101,065 individual patients. Paired samples of serum/CSF were tested from 616 patients, using M1-AQP4-transfected cell-based assays (both fixed AQP4-CBA Euroimmun kit [commercial CBA] and live in-house flow cytometry [FACS]). Sensitivities were compared for 58 time-matched paired specimens (drawn ≤30 days apart) from patients with neuromyelitis optica (NMO) or high-risk patients.
Results:
The frequency of CSF submission as sole initial specimen was 1 in 50 in 2007 and 1 in 5 in 2015. In no case among 616 paired specimens was CSF positive and serum negative. In 58 time-matched paired specimens, AQP4-IgG was detected by FACS or by commercial CBA more sensitively in serum than in CSF (respectively, p = 0.06 and p < 0.001). A serum titer >1:100 predicted CSF positivity (p < 0.001). The probability of CSF positivity was greater around attack time (p = 0.03). No control specimen from 128 neurologic patients was positive by either assay.
Conclusions:
FACS and commercial CBA detection of AQP4-IgG is less sensitive in CSF than in serum. The data suggest that most AQP4-IgG is produced in peripheral lymphoid tissues and that a critical serum/CSF gradient is required for IgG to penetrate the CNS in pathogenic quantity. Serum is the optimal and most cost-effective specimen for AQP4-IgG testing.
Classification Of Evidence:
This study provides Class IV evidence that for patients with NMO or NMOSD, CSF is less sensitive than serum for detection of AQP4-IgG.
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