Imaging Net Retrograde Axonal Transport In Vivo: A Physiological Biomarker. Issue 5 (19th March 2022)

• Record Type: Journal Article
• Authors: Lee, Pin‐Tsun Justin; Kennedy, Zachary; Wang, Yuzhen; Lu, Yimeng; Cefaliello, Carolina; Uyan, Özgün; Song, Chun‐Qing; Godinho, Bruno Miguel da Cruz; Xu, Zuoshang; Rusckowski, Mary; Xue, Wen; Brown, Robert H.
• Is Part Of: Annals of neurology. Volume 91:Issue 5(2022)
• Page Start: 716
• Page End: 729
• Publication Date: 2022-03-19
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.26329
• Languages: English
• ISSNs: 0364-5134

Abstract

Abstract : Objective: The objective of this study is to develop a novel method for monitoring the integrity of motor neurons in vivo by quantifying net retrograde axonal transport. Methods: The method uses single photon emission computed tomography to quantify retrograde transport to spinal cord of tetanus toxin fragment C ( 125 I‐TTC) following intramuscular injection. We characterized the transport profiles in 3 transgenic mouse models carrying amyotrophic lateral sclerosis (ALS)‐associated genes, aging mice, and SOD1 G93A transgenic mice following CRISPR/Cas9 gene editing. Lastly, we studied the effect of prior immunization of tetanus toxoid on the transport profile of TTC. Results: This technique defines a quantitative profile of net retrograde axonal transport of TTC in living mice. The profile is distinctly abnormal in transgenic SOD1 G93A mice as young as 65 days (presymptomatic) and worsens with disease progression. Moreover, this method detects a distinct therapeutic benefit of gene editing in transgenic SOD1 G93A mice well before other clinical parameters (eg, grip strength) show improvement. Symptomatic transgenic PFN1 C71G/C71G ALS mice display gross reductions in net retrograde axonal transport, which is also disturbed in asymptomatic mice harboring a human C9ORF72 transgene with an expanded GGGGCC repeat motif. In wild‐type mice, net retrograde axonal transport declines with aging. Lastly, prior immunization with tetanus toxoid does not preclude use of this assay. Interpretation: This assay of net retrograde axonal transport has broad potential clinical applications and should be particularly valuable as a physiological biomarker that permits early detection of benefit from potential therapies for motor neuron diseases. ANN NEUROL 2022;91:716–729