Exploring neurodegenerative disorders using a novel integrated model of cerebral transport: Initial results.

The neurovascular unit (NVU) underlines the complex and symbiotic relationship between brain cells and the cerebral vasculature, and dictates the need to consider both neurodegenerative and cerebrovascular diseases under the same mechanistic umbrella. Importantly, unlike peripheral organs, the brain was thought not to contain a dedicated lymphatics system. The glymphatic system concept (a portmanteau of glia and lymphatic) has further emphasized the importance of cerebrospinal fluid transport and emphasized its role as a mechanism for waste removal from the central nervous system. In this work, we outline a novel multiporoelastic solver which is embedded within a high precision, subject specific workflow that allows for the co-existence of a multitude of interconnected compartments with varying properties (multiple-network poroelastic theory, or MPET), that allow for the physiologically accurate representation of perfused brain tissue. This novel numerical template is based on a six-compartment MPET system (6-MPET) and is implemented through an in-house finite element code. The latter utilises the specificity of a high throughput imaging pipeline (which has been extended to incorporate the regional variation of mechanical properties) and blood flow variability model developed as part of the VPH-DARE@IT research platform. To exemplify the capability of this large-scale consolidated pipeline, a cognitively healthy subject is used to acquire novel, biomechanistically inspired biomarkers relating to primary and derivative variables of the 6-MPET system. These biomarkers are shown to capture the sophisticated nature of the NVU and the glymphatic system, paving the way for a potential route in deconvoluting the complexity associated with the likely interdependence of neurodegenerative and cerebrovascular diseases. The present study is the first, to the best of our knowledge, that casts and implements the 6-MPET equations in a 3D anatomically accurate brain geometry.

On the Validation of a Multiple-Network Poroelastic Model Using Arterial Spin Labeling MRI Data.

The Multiple-Network Poroelastic Theory (MPET) is a numerical model to characterize the transport of multiple fluid networks in the brain, which overcomes the problem of conducting separate analyses on individual fluid compartments and losing the interactions between tissue and fluids, in addition to the interaction between the different fluids themselves. In this paper, the blood perfusion results from MPET modeling are partially validated using cerebral blood flow (CBF) data obtained from arterial spin labeling (ASL) magnetic resonance imaging (MRI), which uses arterial blood water as an endogenous tracer to measure CBF. Two subjects-one healthy control and one patient with unilateral middle cerebral artery (MCA) stenosis are included in the validation test. The comparison shows several similarities between CBF data from ASL and blood perfusion results from MPET modeling, such as higher blood perfusion in the gray matter than in the white matter, higher perfusion in the periventricular region for both the healthy control and the patient, and asymmetric distribution of blood perfusion for the patient. Although the partial validation is mainly conducted in a qualitative way, it is one important step toward the full validation of the MPET model, which has the potential to be used as a testing bed for hypotheses and new theories in neuroscience research.

Subject-specific multi-poroelastic model for exploring the risk factors associated with the early stages of Alzheimer's disease.

There is emerging evidence suggesting that Alzheimer's disease is a vascular disorder, caused by impaired cerebral perfusion, which may be promoted by cardiovascular risk factors that are strongly influenced by lifestyle. In order to develop an understanding of the exact nature of such a hypothesis, a biomechanical understanding of the influence of lifestyle factors is pursued. An extended poroelastic model of perfused parenchymal tissue coupled with separate workflows concerning subject-specific meshes, permeability tensor maps and cerebral blood flow variability is used. The subject-specific datasets used in the modelling of this paper were collected as part of prospective data collection. Two cases were simulated involving male, non-smokers (control and mild cognitive impairment (MCI) case) during two states of activity (high and low). Results showed a marginally reduced clearance of cerebrospinal fluid (CSF)/interstitial fluid (ISF), elevated parenchymal tissue displacement and CSF/ISF accumulation and drainage in the MCI case. The peak perfusion remained at 8 mm s-1 between the two cases.

Investigating cerebral oedema using poroelasticity.

Cerebral oedema can be classified as the tangible swelling produced by expansion of the interstitial fluid volume. Hydrocephalus can be succinctly described as the abnormal accumulation of cerebrospinal fluid (CSF) within the brain which ultimately leads to oedema within specific sites of parenchymal tissue. Using hydrocephalus as a test bed, one is able to account for the necessary mechanisms involved in the interaction between oedema formation and cerebral fluid production, transport and drainage. The current state of knowledge about integrative cerebral dynamics and transport phenomena indicates that poroelastic theory may provide a suitable framework to better understand various diseases. In this work, Multiple-Network Poroelastic Theory (MPET) is used to develop a novel spatio-temporal model of fluid regulation and tissue displacement within the various scales of the cerebral environment. The model is applied through two formats, a one-dimensional finite difference - Computational Fluid Dynamics (CFD) coupling framework, as well as a two-dimensional Finite Element Method (FEM) formulation. These are used to investigate the role of endoscopic fourth ventriculostomy in alleviating oedema formation due to fourth ventricle outlet obstruction (1D coupled model) in addition to observing the capability of the FEM template in capturing important characteristics allied to oedema formation, like for instance in the periventricular region (2D model).

A fully dynamic multi-compartmental poroelastic system: Application to aqueductal stenosis.

This study proposes the implementation of a fully dynamic four-network poroelastic model which is underpinned by multiple-network poroelastic theory (MPET), in order to account for the effects of varying stages of aqueductal stenosis and atresia during acute hydrocephalus. The innovation of the fully dynamic MPET implementation is that it avoids the commonplace assumption of quasi-steady behaviour; instead, it incorporates all transient terms in the casting of the equations and in the numerical solution of the resulting discrete system. It was observed that the application of mild stenosis allows for a constant value of amalgamated ventricular displacement in under 2.4h, whereas the application of a severe stenosis delays this settlement to approximately 10h. A completely blocked aqueduct does not show a clear sign of reaching a steady ventricular displacement after 24h. The increasing ventricular pressure (complemented with ventriculomegaly) during severe stenosis is causing the trans-parenchymal tissue region to respond, and this coping mechanism is most attenuated at the regions closest to the skull and the ventricles. After 9h, the parenchymal tissue shows to be coping well with the additional pressure burden, since both ventriculomegaly and ventricular CSF (cerebrospinal fluid) pressure show small increases between 9 and 24h. Localised swelling in the periventricular region could also be observed through CSF fluid content, whilst dilation results showed stretch and compression of cortical tissue adjacent to the ventricles and skull.

Exploring the efficacy of endoscopic ventriculostomy for hydrocephalus treatment via a multicompartmental poroelastic model of CSF transport: a computational perspective.

This study proposes the implementation of a Multiple-Network Poroelastic Theory (MPET) model coupled with finite-volume computational fluid dynamics for the purpose of studying, in detail, the effects of obstructing CSF transport within an anatomically accurate cerebral environment. The MPET representation allows the investigation of fluid transport between CSF, brain parenchyma and cerebral blood, in an integral and comprehensive manner. A key novelty in the model is the amalgamation of anatomically accurate choroid plexuses with their feeding arteries and a simple relationship relaxing the constraint of a unique permeability for the CSF compartment. This was done in order to account for the Aquaporin-4-mediated swelling characteristics. The aim of this varying permeability compartment was to bring to light a feedback mechanism that could counteract the effects of ventricular dilation and subsequent elevations of CSF pressure through the efflux of excess CSF into the blood system. This model is used to demonstrate the impact of aqueductal stenosis and fourth ventricle outlet obstruction (FVOO). The implications of treating such a clinical condition with the aid of endoscopic third (ETV) and endoscopic fourth (EFV) ventriculostomy are considered. We observed peak CSF velocities in the aqueduct of the order of 15.6 cm/s in the healthy case, 45.4 cm/s and 72.8 cm/s for the mild and severe cases respectively. The application of ETV reduced the aqueductal velocity to levels around 16-17 cm/s. Ventricular displacement, CSF pressure, wall shear stress (WSS) and pressure difference between lateral and fourth ventricles (ΔP) increased with applied stenosis, and subsequently dropped to nominal levels with the application of ETV. The greatest reversal of the effects of atresia come by opting for ETV rather than the more complicated procedure of EFV.