Non-invasive MRI quantification of cerebrospinal fluid dynamics in amyotrophic lateral sclerosis patients

Abstract

Background: Developing novel therapeutic agents to treat amyotrophic lateral sclerosis (ALS) has been difficult due to multifactorial pathophysiologic processes at work. Intrathecal drug administration shows promise due to close proximity of cerebrospinal fluid (CSF) to affected tissues. Development of effective intrathecal pharmaceuticals will rely on accurate models of how drugs are dispersed in the CSF. Therefore, a method to quantify these dynamics and a characterization of differences across disease states is needed. Methods: Complete intrathecal 3D CSF geometry and CSF flow velocities at six axial locations in the spinal canal were collected by T2-weighted and phase-contrast MRI, respectively. Scans were completed for eight people with ALS and ten healthy controls. Manual segmentation of the spinal subarachnoid space was performed and coupled with an interpolated model of CSF flow within the spinal canal. Geometric and hydrodynamic parameters were then generated at 1 mm slice intervals along the entire spine. Temporal analysis of the waveform spectral content and feature points was also completed. Results: Comparison of ALS and control groups revealed a reduction in CSF flow magnitude and increased flow propagation velocities in the ALS cohort. Other differences in spectral harmonic content and geometric comparisons may support an overall decrease in intrathecal compliance in the ALS group. Notably, there was a high degree of variability between cases, with one ALS patient displaying nearly zero CSF flow along the entire spinal canal. Conclusion: While our sample size limits statistical confidence about the differences observed in this study, it was possible to measure and quantify inter-individual and cohort variability in a non-invasive manner. Our study also shows the potential for MRI based measurements of CSF geometry and flow to provide information about the hydrodynamic environment of the spinal subarachnoid space. These dynamics may be studied further to understand the behavior of CSF solute transport in healthy and diseased states.

In vitro and numerical simulation of blood removal from cerebrospinal fluid: comparison of lumbar drain to Neurapheresis therapy

“…These parameters should be investigated in a larger cohort to determine the potential impact of age, sex, and disease states on CSF solute transport. However, the consistency of CSF dynamics across humans in the healthy state and with ALS has been studied by our group and we found relatively small differences across subjects [67]. Therefore, we expect our results would hold true for other human cases with slightly different CSF space geometry.…”

In vitro and Numerical Simulation of Blood Removal from Cerebrospinal Fluid: Comparison of Lumbar Drain to Neurapheresis Therapy

“…However, the consistency of CSF dynamics across humans in the healthy state and with ALS has been studied by our group and we found relatively small differences across subjects (67). Therefore, we expect our results would hold true for other human cases with slightly different CSF space geometry.…”

Intrathecal catheter implantation decreases cerebrospinal fluid dynamics in cynomolgus monkeys

“…Thus, although catheter placement in the cervical spine may result in decreased CSF flow, drug delivery in this region may still allow more rapid mixing compared to the lumbar spine. Catheter implantation location may also need to be taken into account alongside potentially diminished CSF flow dynamics in disease states, such as ALS (30).…”

“…Optimal catheter implantation location can be explored in future work in combination with the potential role of catheter implantation on CSF flow dynamics, but was outside the scope of the present research. Based on the results, it can be hypothesized that the impact of catheter implantation on CSF dynamics would potentially be greater in cynomolgus monkeys compared to adult humans due to relatively smaller SAS cross-sectional area in NHPs compared to humans (10X greater (19,30)).…”