Editor's Choice - Aquaporin-4: A Predictor and Therapeutic Target for Permanent Paraplegia after Endovascular Thoraco-abdominal Aortic Aneurysm Repair.

OBJECTIVE

Endovascular thoraco-abdominal aortic aneurysm (TAAA) repair can impair spinal cord perfusion, leading to paraplegia. The mechanisms driving this devastating complication are poorly understood. This study aimed to interrogate the cerebrospinal fluid (CSF) proteome in patients after TAAA repair to identify biomarkers that herald permanent paraplegia. It also aimed to investigate a potential therapeutic target identified by proteomics using an in vivo model of ischaemic spinal cord injury (iSCI).

METHODS

CSF was collected for proteomic analysis from patients before and following TAAA repair. A differentially expressed protein identified in human paraplegic subjects was subsequently interrogated in a rodent model of iSCI. The protein composition of CSF was analysed using tandem mass tag proteomics. Neurological examinations were carried out by a blinded neurologist and T2 weighted magnetic resonance imaging (MRI) was used to measure spinal cord volume and oedema. A rodent model of iSCI was used to investigate a clinically relevant therapeutic target informed by proteomic findings.

RESULTS

CSF analysis was taken from 37 patients, all of whom had aneurysm repair using a custom branched and or fenestrated device (median age 73.5 years, range 67 - 78 years; 27 men, ten women; Crawford classification: six type I, 11 type II, 15 type III, three type IV, and two type V). Five patients remained permanently paraplegic and seven recovered from transient paraplegia. The CSF of patients who remained paraplegic contained approximately fourfold more aquaporin-4 (AQP4) (41.8 ± 19.2 ng/mL, n = 5) than those who recovered from paraplegia (10.8 ± 1.3 ng/mL, n = 7; p = .005) or did not develop paraplegia (10.8 ± 1.2 ng/mL, n = 25; p = .004). Permanently paraplegic patients had CSF AQP4 levels > 15 ng/mL and this was associated with greater cord oedema on T2 weighted MRI (1.77 ± 0.19 vs. 1.03 ± 0.36; p = .032). In a rodent model of iSCI, AQP4 inhibition preserved spinal neurons and glia in the dorsal horn and intermediate zones of white matter (p = .004) and protected against ischaemia induced paraplegia (p < .001).

CONCLUSION

The AQP4 level in the CSF of a patient represents a prognostic marker of permanent paraplegia after TAAA repair and highlights a novel therapeutic target. These findings represent a conceptual advance in the management of iSCI.