Barrier dysfunction or drainage reduction: differentiating causes of CSF protein increase

BACKGROUND Cerebrospinal fluid (CSF) protein analysis is an important element in the diagnostic chain for various central nervous system (CNS) pathologies. Among multiple existing approaches to interpreting measured protein levels, the Reiber diagram is particularly robust with respect to physiologic inter-individual variability, as it uses multiple subject-specific anchoring values. Beyond reliable identification of abnormal protein levels, the Reiber diagram has the potential to elucidate their pathophysiologic origin. In particular, both reduction of CSF drainage from the cranio-spinal space as well as blood-CNS barrier dysfunction have been suggested ρas possible causes of increased concentration of blood-derived proteins. However, there is disagreement on which of the two is the true cause. METHODS We designed two computational models to investigate the mechanisms governing protein distribution in the spinal CSF. With a one-dimensional model, we evaluated the distribution of albumin and immunoglobulin G (IgG), accounting for protein transport rates across blood-CNS barriers, CSF dynamics (including both dispersion induced by CSF pulsations and advection by mean CSF flow) and CSF drainage. Dispersion coefficients were determined a priori by computing the axisymmetric three-dimensional CSF dynamics and solute transport in a representative segment of the spinal canal. RESULTS Our models reproduce the empirically determined hyperbolic relation between albumin and IgG quotients. They indicate that variation in CSF drainage would yield a linear rather than the expected hyperbolic profile. In contrast, modelled barrier dysfunction reproduces the experimentally observed relation. CONCLUSIONS High levels of albumin identified in the Reiber diagram are more likely to originate from a barrier dysfunction than from a reduction in CSF drainage. Our in silico experiments further support the hypothesis of decreasing spinal CSF drainage in rostro-caudal direction and emphasize the physiological importance of pulsation-driven dispersion for the transport of large molecules in the CSF

Altered Diastolic Flow Patterns and Kinetic Energy in Subtle Left Ventricular Remodeling and Dysfunction Detected by 4D Flow MRI.

4D flow magnetic resonance imaging (MRI) allows quantitative assessment of left ventricular (LV) function according to characteristics of the dynamic flow in the chamber. Marked abnormalities in flow components' volume and kinetic energy (KE) have previously been demonstrated in moderately dilated and depressed LV's compared to healthy subjects. We hypothesized that these 4D flow-based measures would detect even subtle LV dysfunction and remodeling.We acquired 4D flow and morphological MRI data from 26 patients with chronic ischemic heart disease with New York Heart Association (NYHA) class I and II and with no to mild LV systolic dysfunction and remodeling, and from 10 healthy controls. A previously validated method was used to separate the LV end-diastolic volume (LVEDV) into functional components: direct flow, which passes directly to ejection, and non-ejecting flow, which remains in the LV for at least 1 cycle. The direct flow and non-ejecting flow proportions of end-diastolic volume and KE were assessed. The proportions of direct flow volume and KE fell with increasing LVEDV-index (LVEDVI) and LVESV-index (LVESVI) (direct flow volume r = -0.64 and r = -0.74, both P74 ml/m2 compared to patients with LVEDVI <74 ml/m2 and controls (both P<0.05).Direct flow volume and KE proportions diminish with increased LV volumes, while non-ejecting flow proportions increase. A decrease in direct flow volume and KE at end-diastole proposes that alterations in these novel 4D flow-specific markers may detect LV dysfunction even in subtle or subclinical LV remodeling

Hydrodynamic and Longitudinal Impedance Analysis of Cerebrospinal Fluid Dynamics at the Craniovertebral Junction in Type I Chiari Malformation

Elevated or reduced velocity of cerebrospinal fluid (CSF) at the craniovertebral junction (CVJ) has been associated with type I Chiari malformation (CMI). Thus, quantification of hydrodynamic parameters that describe the CSF dynamics could help assess disease severity and surgical outcome. In this study, we describe the methodology to quantify CSF hydrodynamic parameters near the CVJ and upper cervical spine utilizing subject-specific computational fluid dynamics (CFD) simulations based on in vivo MRI measurements of flow and geometry. Hydrodynamic parameters were computed for a healthy subject and two CMI patients both pre- and post-decompression surgery to determine the differences between cases. For the first time, we present the methods to quantify longitudinal impedance (LI) to CSF motion, a subject-specific hydrodynamic parameter that may have value to help quantify the CSF flow blockage severity in CMI. In addition, the following hydrodynamic parameters were quantified for each case: maximum velocity in systole and diastole, Reynolds and Womersley number, and peak pressure drop during the CSF cardiac flow cycle. The following geometric parameters were quantified: cross-sectional area and hydraulic diameter of the spinal subarachnoid space (SAS). The mean values of the geometric parameters increased post-surgically for the CMI models, but remained smaller than the healthy volunteer. All hydrodynamic parameters, except pressure drop, decreased post-surgically for the CMI patients, but remained greater than in the healthy case. Peak pressure drop alterations were mixed. To our knowledge this study represents the first subject-specific CFD simulation of CMI decompression surgery and quantification of LI in the CSF space. Further study in a larger patient and control group is needed to determine if the presented geometric and/or hydrodynamic parameters are helpful for surgical planning