Computational Model of Interstitial Transport in the Rat Brain Using Diffusion Tensor Imaging

Author(s):  
Jung Hwan Kim ◽  
Thomas H. Mareci ◽  
Malisa Sarntinoranont

In spite of the high therapeutic potential of macromolecular drugs, it has proven difficult to apply them to recovery after injury and treatment of cancer, Parkinson’s disease, and other neurodegenerative diseases. One barrier to systemic administration is low capillary permeability, i.e., the blood-brain and blood-spinal cord barrier. To overcome this barrier, convection-enhanced delivery (CED) infuses agents directly into tissue to supplement diffusion and increase the distribution of large molecules in the brain [1,2]. Predictive models of distribution during CED would be useful in treatment optimization and planning. To account for large infusion volumes, such models should incorporate tissue boundaries and anisotropic tissue properties.

2009 ◽  
Vol 131 (7) ◽  
Author(s):  
Jung Hwan Kim ◽  
Garrett W. Astary ◽  
Xiaoming Chen ◽  
Thomas H. Mareci ◽  
Malisa Sarntinoranont

Direct tissue infusion, e.g., convection-enhanced delivery (CED), is a promising local delivery technique for treating diseases of the central nervous system. Predictive models of spatial drug distribution during and following direct tissue infusion are necessary for treatment optimization and planning of surgery. In this study, a 3D interstitial transport modeling approach in which tissue properties and anatomical boundaries are assigned on a voxel-by-voxel basis using tissue alignment data from diffusion tensor imaging (DTI) is presented. The modeling approach is semi-automatic and utilizes porous media transport theory to estimate interstitial transport in isotropic and anisotropic tissue regions. Rat spinal cord studies compared predicted distributions of albumin tracer (for varying DTI resolution) following infusion into the dorsal horn with tracer distributions measured by Wood et al. in a previous study. Tissue distribution volumes compared favorably for small infusion volumes (<4 μl). The presented DTI-based methodology provides a rapid means of estimating interstitial flows and tracer distributions following CED into the spinal cord. Quantification of these transport fields provides an important step toward development of drug-specific transport models of infusion.


Author(s):  
Jung Hwan Kim ◽  
Garrett W. Astary ◽  
Thomas H. Mareci ◽  
Malisa Sarntinoranont

Despite the high therapeutic potential of many macromolecular drugs, it has proven difficult to apply them to treatment of cancer and other degenerative diseases of the central nervous system (CNS) due to low capillary permeability and low diffusivity. To overcome these barriers, recent experimental studies have shown local infusion, i.e., convection-enhanced delivery (CED), to be a promising delivery technique in the brain and spinal cord [1–3]. Predictive models of extracellular fluid flow and transport during CED would be useful for treatment optimization and planning.


Author(s):  
Jung Hwan Kim ◽  
Xiaoming Chen ◽  
Garrett W. Astary ◽  
Thomas H. Mareci ◽  
Malisa Sarntinoranont

Local infusion, i.e., convection-enhanced delivery (CED), is increasingly being considered as a means to deliver therapeutic agents to nervous tissues. These infusion techniques bypass the blood-brain barrier and overcome problems associated with slow diffusion [1, 2]. Predictive models of extracellular fluid flow and transport during and following CED would be useful in treatment optimization and planning. To account for large infusion volumes, such infusion models should incorporate tissue boundaries and anisotropic tissue properties.


Author(s):  
Jung Hwan Kim ◽  
Garrett Astary ◽  
Svetlana Kantorovich ◽  
Thomas H. Mareci ◽  
Paul R. Carney ◽  
...  

Convection enhanced delivery (CED) is a promising local delivery technique for overcoming the blood brain barrier (BBB) and treating diseases of the central nervous system (CNS). For CED, infusate is infused directly into brain tissue and the drug agent is spread through the extracellular space, which is considered highly tortuous porous media. Previous studies have indicated that the infusion of therapeutic agents into the hippocampus is a potential treatment method for epilepsy [1]. In this study, a 3D interstitial transport modeling approach is presented in which tissue properties and anatomical boundaries are assigned on a voxel-by-voxel basis using tissue alignment data from magnetic resonance (MR) diffusion tensor imaging (DTI). The developed model was used to predict CED transport in the ventral hippocampus and predicted tracer distributions were compared with experimental studies. In rat CED experiments, T1-weighted contrast-enhanced MR images were acquired to measure Gd-DTPA albumin tracer distributions after infusion into the ventral hippocampus. Similar infusate distribution patterns were obtained demonstrating the reliability and repeatability of this modeling scheme. Qualitative comparisons between predicted and measured distribution patterns, volumes and shapes were also conducted to determine the model’s proficiency.


Brain ◽  
2020 ◽  
Vol 143 (7) ◽  
pp. 2058-2072 ◽  
Author(s):  
Sea Young Yoon ◽  
Jacqueline E Hunter ◽  
Sanjeev Chawla ◽  
Dana L Clarke ◽  
Caitlyn Molony ◽  
...  

Abstract Intravascular injection of certain adeno-associated virus vector serotypes can cross the blood–brain barrier to deliver a gene into the CNS. However, gene distribution has been much more limited within the brains of large animals compared to rodents, rendering this approach suboptimal for treatment of the global brain lesions present in most human neurogenetic diseases. The most commonly used serotype in animal and human studies is 9, which also has the property of being transported via axonal pathways to distal neurons. A small number of other serotypes share this property, three of which were tested intravenously in mice compared to 9. Serotype hu.11 transduced fewer cells in the brain than 9, rh8 was similar to 9, but hu.32 mediated substantially greater transduction than the others throughout the mouse brain. To evaluate the potential for therapeutic application of the hu.32 serotype in a gyrencephalic brain of larger mammals, a hu.32 vector expressing the green fluorescent protein reporter gene was evaluated in the cat. Transduction was widely distributed in the cat brain, including in the cerebral cortex, an important target since mental retardation is an important component of many of the human neurogenetic diseases. The therapeutic potential of a hu.32 serotype vector was evaluated in the cat homologue of the human lysosomal storage disease alpha-mannosidosis, which has globally distributed lysosomal storage lesions in the brain. Treated alpha-mannosidosis cats had reduced severity of neurological signs and extended life spans compared to untreated cats. The extent of therapy was dose dependent and intra-arterial injection was more effective than intravenous delivery. Pre-mortem, non-invasive magnetic resonance spectroscopy and diffusion tensor imaging detected differences between the low and high doses, and showed normalization of grey and white matter imaging parameters at the higher dose. The imaging analysis was corroborated by post-mortem histological analysis, which showed reversal of histopathology throughout the brain with the high dose, intra-arterial treatment. The hu.32 serotype would appear to provide a significant advantage for effective treatment of the gyrencephalic brain by systemic adeno-associated virus delivery in human neurological diseases with widespread brain lesions.


2018 ◽  
Vol 25 (28) ◽  
pp. 3333-3352 ◽  
Author(s):  
Natalia Pessoa Rocha ◽  
Ana Cristina Simoes e Silva ◽  
Thiago Ruiz Rodrigues Prestes ◽  
Victor Feracin ◽  
Caroline Amaral Machado ◽  
...  

Background: The Renin-Angiotensin System (RAS) is a key regulator of cardiovascular and renal homeostasis, but also plays important roles in mediating physiological functions in the central nervous system (CNS). The effects of the RAS were classically described as mediated by angiotensin (Ang) II via angiotensin type 1 (AT1) receptors. However, another arm of the RAS formed by the angiotensin converting enzyme 2 (ACE2), Ang-(1-7) and the Mas receptor has been a matter of investigation due to its important physiological roles, usually counterbalancing the classical effects exerted by Ang II. Objective: We aim to provide an overview of effects elicited by the RAS, especially Ang-(1-7), in the brain. We also aim to discuss the therapeutic potential for neuropsychiatric disorders for the modulation of RAS. Method: We carried out an extensive literature search in PubMed central. Results: Within the brain, Ang-(1-7) contributes to the regulation of blood pressure by acting at regions that control cardiovascular functions. In contrast with Ang II, Ang-(1-7) improves baroreflex sensitivity and plays an inhibitory role in hypothalamic noradrenergic neurotransmission. Ang-(1-7) not only exerts effects related to blood pressure regulation, but also acts as a neuroprotective component of the RAS, for instance, by reducing cerebral infarct size, inflammation, oxidative stress and neuronal apoptosis. Conclusion: Pre-clinical evidence supports a relevant role for ACE2/Ang-(1-7)/Mas receptor axis in several neuropsychiatric conditions, including stress-related and mood disorders, cerebrovascular ischemic and hemorrhagic lesions and neurodegenerative diseases. However, very few data are available regarding the ACE2/Ang-(1-7)/Mas receptor axis in human CNS.


CNS Spectrums ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 178-179
Author(s):  
John L. Sherman ◽  
Laurence J. Adams ◽  
Christen F. Kutz ◽  
Deborah York ◽  
Mitchell S. Szymczak

AbstractTraumatic brain injury (TBI) is a complex phenomenon affecting multiple areas of the brain in multiple ways. Both right and left hemispheres are affected as well as supratentorial and infratentorial compartments. These multifocal injuries are caused by many factors including acute mechanical injury, focal intracranial hemorrhage, blunt and rotational forces, epidural and subdural hematoma, hypoxemia, hypotension, edema, axonal damage, neuronal death, gliosis and blood brain barrier disruption. Clinicians and patients benefit by precise information about the neuroanatomical areas that are affected macroscopically, microscopically and biochemically in an individual patient.Standard imaging studies are frequently negative or grossly underestimate the severity of TBI and may exacerbate and prolong patient suffering with an imaging result of “no significant abnormality”. Specifically, sophisticated imaging tools have been developed which reveal significant damage to the brain structure including atrophy, MRI spectroscopy showing variations in neuronal metabolite N-acetyl-aspartate, elevations of membrane related Choline, and the glial metabolite myo-inositol is often observed to be increased post injury. In addition, susceptibility weighted imaging (SWI) has been shown to be more reliable for detecting microbleeds versus calcifications.We have selected two TBI patients with diffuse traumatic brain injury.The first patient is a 43-year-old male who suffered severe traumatic brain injury from a motorcycle accident in 2016. Following the accident, the patient was diagnosed with seizures, major depression, and intermittent explosive disorder. He has attempted suicide and has neurobehavioral disinhibition including severe anger, agitation and irritability. He denies psychiatric history prior to TBI and has negative family history. Following the TBI, he became physically aggressive and assaultive in public with minimal provocation. He denies symptoms of thought disorder and mania. He is negative for symptoms of  cognitive decline or encephalopathy.The second patient is a 49-year-old male who suffered at least 3 concussive blasts in the Army and a parachute injury. Following the last accident, the patient was diagnosed with major depressive disorder, panic disorder, PTSD and generalized anxiety disorder. He denies any psychiatric history prior to TBI including negative family history of psychiatric illness. In addition, he now suffers from nervousness, irritability, anger, emotional lability and concurrent concentration issues, problems completing tasks and alterations in memory.Both patients underwent 1.5T multiparametric MRI using standard T2, FLAIR, DWI and T1 sequences, and specialized sequences including susceptibility weighted (SWAN/SWI), 3D FLAIR, single voxel MRI spectroscopy (MRS), diffusion tensor imaging (DTI), arterial spin labeling perfusion (ASL) and volumetric MRI (NeuroQuant). Importantly, this exam can be performed in 30–45 minutes and requires no injections other than gadolinium in some patients. We will discuss the insights derived from the MRI which detail the injured areas, validate the severity of the brain damage, and provide insight into the psychological, motivational and physical disabilities that afflict these patients. It is our expectation that this kind of imaging study will grow in value as we link specific patterns of injury to specific symptoms and syndromes resulting in more targeted therapies in the future.


Neurology ◽  
2018 ◽  
Vol 91 (23 Supplement 1) ◽  
pp. S17.1-S17
Author(s):  
Haruo Nakayama ◽  
Yu Hiramoto ◽  
Yuriko Numata ◽  
Satoshi Fujita ◽  
Nozomi Hirai ◽  
...  

ObjectiveTo evaluate the relationship between functional anisotropy (FA) and neuropsychological evaluation in concussion.MethodsDiffusion tensor MRI included FA of the Brain and neuropsychological evaluation were conducted on 10 patients with concussion who were diagnosed from April 2017 to March 2018. FA was extracted from 2 regions of interest in Corpus callosum (CC) and corticospinal tract (CT). Detailed neuropsychological testing with an emphasis on Working memory (WM) and Processing speed (PS) was also conducted. The FA value in that 2 regions were compared between the 2 groups of 5 patients (group F) who failed either in WM or PS and 5 cases (group NF) who did not admit it.ResultsMean FA values in CC and CT in the Group F were 0.70 and 0.52. Mean FA values in CC and CT in the Group NF were 0.48 and 0.55.ConclusionsOur result suggests that the FA value of CC did not explain the significant fluctuation of the neuropsychological function. However, FA value in CT were shown to explain the fluctuation of WM and PS.


2012 ◽  
Vol 1 (1) ◽  
pp. 57-65 ◽  
Author(s):  
Mingming Huang ◽  
Lifeng Gao ◽  
Liqin Yang ◽  
Fuchun Lin ◽  
Hao Lei

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