Abstract
BackgroundDeveloping 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.MethodsComplete 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.ResultsComparison 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.ConclusionWhile 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.
Highlights
Developing novel therapeutic agents to treat amyotrophic lateral sclerosis (ALS) has been difficult due to multifactorial pathophysiologic processes at work
Other differences in spectral harmonic content and geometric comparisons may support an overall decrease in intrathecal compliance in the ALS group
Our study shows the potential for Magnetic resonance imaging (MRI) based measurements of cerebrospinal fluid (CSF) geometry and flow to provide information about the hydrodynamic environment of the spinal subarachnoid space
Summary
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. Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease, is a devastating neurological disorder of predominately sporadic origin [1] that leads to severe disability and death. Neurodegeneration in ALS typically advances in a sequential fashion to the point of phrenic nerve involvement resulting in failure of respiratory effort and death before degenerative changes are seen elsewhere [3]. ALS affects approximately 3.9 in 100,000 people within the United States [4] with approximately equal occurrence worldwide and does not appear to be linked with environmental toxins. Studies indicate that ALS incidence is approximately 1.8 times greater in males than females for unknown reasons [5]
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