Volumetric microscopy of cerebral arteries with a miniaturized optical coherence tomography imaging probe.

Endovascular interventions are increasingly becoming the preferred approach for treating strokes and cerebral artery diseases. These procedures rely on sophisticated angiographical imaging guidance, which encounters challenges because of limited contrast and spatial resolution. Achieving a more precise visualization of the underlying arterial pathology and neurovascular implants is crucial for accurate procedural decision-making. In a human study involving 32 patients, we introduced the clinical application of a miniaturized endovascular neuro optical coherence tomography (nOCT) imaging probe. This technology was designed to navigate the tortuous paths of the cerebrovascular circulation and to offer high-resolution imaging in situ. The nOCT probe is compatible with standard neurovascular microcatheters, integrating with the procedural workflow used in clinical routine. Equipped with a miniaturized optical fiber and a distal lens, the probe illuminates the tissue and collects the backscattered, near-infrared light. While rotating the fiber and the lens at high speed, the probe is rapidly retracted, creating a spiral-shaped light pattern to comprehensively capture the arterial wall and implanted devices. Using nOCT, we demonstrated volumetric microscopy of cerebral arteries in patients undergoing endovascular procedures. We imaged the anterior and posterior circulation of the brain, including distal segments of the internal carotid and middle-cerebral arteries, as well as the vertebral, basilar, and posterior cerebral arteries. We captured a broad spectrum of neurovascular pathologies, such as brain aneurysms, ischemic stroke, arterial stenoses, dissections, and intracranial atherosclerotic disease. nOCT offered artifact-free, high-resolution visualizations of intracranial artery pathology and neurovascular devices.

Assessment of thrombectomy procedure difficulty by neurointerventionalists based on vessel geometry parameters from carotid artery 3D reconstructions.

BACKGROUND: Diagnosing and treating acute ischemic stroke patients within a narrow timeframe is challenging. Time needed to access the occluded vessel and initiate thrombectomy is dictated by the availability of information regarding vascular anatomy and trajectory. Absence of such information potentially impacts device selection, procedure success, and stroke outcomes. While the cervical vessels allow neurointerventionalists to navigate devices to the occlusion site, procedures are often encumbered due to tortuous pathways. The purpose of this retrospective study was to determine how neurointerventionalists consider the physical nature of carotid segments when evaluating a procedure's difficulty. METHODS: Seven neurointerventionalists reviewed 3D reconstructions of CT angiograms of left and right carotid arteries from 49 subjects and rated the perceived procedural difficulty on a three-point scale (easy, medium, difficult) to reach the targeted M1. Twenty-two vessel metrics were quantified by dividing the carotids into 5 segments and measuring the radius of curvature, tortuosity, vessel radius, and vessel length of each segment. RESULTS: The tortuosity and length of the arch-cervical and cervical regions significantly impacted difficulty ratings. Additionally, two-way interaction between the radius of curvature and tortuosity on the arch-cervical region was significant (p < 0.0001) wherein, for example, at a given arch-cervical tortuosity, an increased radius of curvature reduced the perceived case difficulty. CONCLUSIONS: Examining the vessel metrics and providing detailed vascular data tailored to patient characteristics may result in better procedure preparation, facilitate faster vessel access time, and improve thrombectomy outcomes. Additionally, documenting these correlations can enhance device design to ensure they suitably function under various vessel conditions.

Development of an in-vitro model based on patient vessel geometry for simulated use testing in neurointerventional surgery.

BACKGROUND: Neurointerventionalists use in-vitro vascular models to train for worst-case scenarios and test new devices in a simulated use environment to predict clinical performance. According to the Food and Drug Administration (FDA), any neurovascular navigation device should be able to successfully navigate two 360-degree turns and two 180-degree turns at the distal portion of the anatomical model. Here, we present a device benchmarking vascular model that complies with FDA recommendations. METHODS: Our vascular model was assembled from quantitative characterization of 49 patients who underwent CT angiography either for acute ischemic stroke caused by large vessel occlusion or for aneurysm treatment. Following complete characterization of these data, the vascular segments were 3D reconstructed from CT angiograms of 6 selected patients that presented with challenging anatomy. The curvature and total rotational angle were calculated for each segment and the anatomical parts that complied with FDA recommendations were fused together into a single in-vitro model. RESULTS: The model was constructed containing two common carotid branches arising from a type two aortic arch and the dimensions of the overall model exceeded the recommendations of the FDA. Two experienced neurointerventionalists tested the model for navigation difficulty using several devices on an in-vitro perfusion system and concluded that the model provided a realistic, challenging scenario. CONCLUSIONS: This model provides a first prototype designed according to FDA recommendations of cumulative angle while also integrating an aggregation of actual patient-specific anatomy. The availability of this clinically relevant benchmark model presents a potential standardized approach for neurovascular device testing.

Artificial Intelligence in Breast X-Ray Imaging.

This topical review is focused on the clinical breast x-ray imaging applications of the rapidly evolving field of artificial intelligence (AI). The range of AI applications is broad. AI can be used for breast cancer risk estimation that could allow for tailoring the screening interval and the protocol that are woman-specific and for triaging the screening exams. It also can serve as a tool to aid in the detection and diagnosis for improved sensitivity and specificity and as a tool to reduce radiologists' reading time. AI can also serve as a potential second 'reader' during screening interpretation. During the last decade, numerous studies have shown the potential of AI-assisted interpretation of mammography and to a lesser extent digital breast tomosynthesis; however, most of these studies are retrospective in nature. There is a need for prospective clinical studies to evaluate these technologies to better understand their real-world efficacy. Further, there are ethical, medicolegal, and liability concerns that need to be considered prior to the routine use of AI in the breast imaging clinic.

Glb1 knockout mouse model shares natural history with type II GM1 gangliosidosis patients.

GM1 gangliosidosis is a rare lysosomal storage disorder affecting multiple organ systems, primarily the central nervous system, and is caused by functional deficiency of ß-galactosidase (GLB1). Using CRISPR/Cas9 genome editing, we generated a mouse model to evaluate characteristics of the disease in comparison to GM1 gangliosidosis patients. Our Glb1-/- mice contain small deletions in exons 2 and 6, producing a null allele. Longevity is approximately 50 weeks and studies demonstrated that female Glb1-/- mice die six weeks earlier than male Glb1-/- mice. Gait analyses showed progressive abnormalities including abnormal foot placement, decreased stride length and increased stance width, comparable with what is observed in type II GM1 gangliosidosis patients. Furthermore, Glb1-/- mice show loss of motor skills by 20 weeks assessed by adhesive dot, hanging wire, and inverted grid tests, and deterioration of motor coordination by 32 weeks of age when evaluated by rotarod testing. Brain MRI showed progressive cerebellar atrophy in Glb1-/- mice as seen in some patients. In addition, Glb1-/- mice also show significantly increased levels of a novel pentasaccharide biomarker in urine and plasma which we also observed in GM1 gangliosidosis patients. Glb1-/- mice also exhibit accumulation of glycosphingolipids in the brain with increases in GM1 and GA1 beginning by 8 weeks. Surprisingly, despite being a null variant, this Glb1-/- mouse most closely models the less severe type II disease and will guide the development of new therapies for patients with the disorder.

High-frequency optical coherence tomography predictors of aneurysm occlusion following flow diverter treatment in a preclinical model.

BACKGROUND: High-frequency optical coherence tomography (HF-OCT) is an intravascular imaging method that allows for volumetric imaging of flow diverters in vivo. OBJECTIVE: To examine the hypothesis that a threshold for both volume and area of communicating malapposition can be predictive of early aneurysm occlusion. METHODS: Fifty-two rabbits underwent elastase aneurysm formation, followed by treatment with a flow diverter. At the time of implant, HF-OCT was acquired to study the rate and degree of communicating malapposition. Treated aneurysms were allowed to heal for either 90 or 180 days and euthanized following catheter angiography. Healing was dichotomized into aneurysm remnant or neck remnant/complete occlusion. Communicating malapposition was measured by HF-OCT using a semi-automatic algorithm able to detect any points where the flow diverter was more than 50 µm from the vessel wall. This was then summed across image slices to either a volume or area. Finally, a subsampled population was used to train a statistical classifier for the larger dataset. RESULTS: No difference in occlusion rate was found between device type or follow-up time (p=0.28 and p=0.67, respectively). Both volume and area of malapposition were significantly lower in aneurysms with a good outcome (p<0.001, both). From the statistical model, a volume of less than 0.56 mm3 or a normalized area less than 0.69 as quantified by HF-OCT was predictive of occlusion (p<0.001, each). CONCLUSIONS: HF-OCT allows for measurements of both volume and area of malapposition and, from these measurements, an accurate prediction for early aneurysm occlusion can be made.

Cumulative effect of simvastatin, L-arginine, and tetrahydrobiopterin on cerebral blood flow and cognitive function in Alzheimer's disease.

BACKGROUND AND OBJECTIVES: Vascular disease is a known risk factor for Alzheimer's disease (AD). Endothelial dysfunction has been linked to reduced cerebral blood flow. Endothelial nitric oxide synthase pathway (eNOS) upregulation is known to support endothelial health. This single-center, proof-of-concept study tested whether the use of three medications known to augment the eNOS pathway activity improves cognition and cerebral blood flow (CBF). METHODS: Subjects with mild AD or mild cognitive impairment (MCI) were sequentially treated with the HMG-CoA reductase synthesis inhibitor simvastatin (weeks 0-16), L-arginine (weeks 4-16), and tetrahydrobiopterin (weeks 8-16). The primary outcome of interest was the change in CBF as measured by MRI from baseline to week 16. Secondary outcomes included standard assessments of cognition. RESULTS: A total of 11 subjects were deemed eligible and enrolled. One subject withdrew from the study after enrollment, leaving 10 subjects for data analysis. There was a significant increase in CBF from baseline to week 8 by ~13% in the limbic and ~15% in the cerebral cortex. Secondary outcomes indicated a modest but significant increase in the MMSE from baseline (24.2±3.2) to week 16 (26.0±2.7). Exploratory analysis indicated that subjects with cognitive improvement (reduction of the ADAS-cog 13) had a significant increase in their respective limbic and cortical CBF. CONCLUSIONS: Treatment of mild AD/MCI subjects with medications shown to augment the eNOS pathway was well tolerated and associated with modestly increased cerebral blood flow and cognitive improvement. TRIAL REGISTRATION: This study is registered in https://www. CLINICALTRIALS: gov ; registration identifier: NCT01439555; date of registration submitted to registry: 09/23/2011; date of first subject enrollment: 11/2011.

Transradial access for cerebral angiography and neurointerventional procedures: A meta-analysis and systematic review.

PURPOSE: Transradial access (TRA) for diagnostic and interventional neurointerventional procedures has recently gained traction over transfemoral access (TFA) in the neurointerventional community. This meta-analysis aims to assess and summarize the utility of TRA in cerebral angiography and neurointerventional procedures. METHODS: A systematic literature review was performed utilizing Pubmed, Embase, and Scopus databases. Using PRISMA guidelines, records were extracted with the following search terms: transradial approach, transradial access, radial access, cerebral angiogram, cerebral angiography, neurointervention, and neuroendovascular. The primary outcomes assessed were case success rate, complication rate, and crossover rate from TRA to TFA. Secondary analysis was performed on procedure time, fluoroscopy time, fluoroscopy time per vessel (diagnostic procedures only), contrast dose, radial artery diameter, distal radial artery diameter, and patient preference for TRA over TFA. RESULTS: Sixty-two full-text articles were analyzed for this meta-analysis, representing 12,927 diagnostic and interventional TRA access patients. Our analysis revealed a combined diagnostic and interventional case success rate of 95.9% and complication rate of 3.5%, with crossover to TFA occurring in 4.9% of cases. CONCLUSION: This meta-analysis demonstrates that TRA access for diagnostic angiography and neurointerventional procedures is a safe and effective approach, though determining a true complication rate is challenging as the definition of TRA complications has changed in various publications over time.

Novel Oxygen Carrier Slows Infarct Growth in Large Vessel Occlusion Dog Model Based on Magnetic Resonance Imaging Analysis.

BACKGROUND: Tissue hypoxia plays a critical role in the events leading to cell death in ischemic stroke. Despite promising results in preclinical and small clinical pilot studies, inhaled oxygen supplementation has not translated to improved outcomes in large clinical trials. Moreover, clinical observations suggest that indiscriminate oxygen supplementation can adversely affect outcome, highlighting the need to develop novel approaches to selectively deliver oxygen to affected regions. This study tested the hypothesis that intravenous delivery of a novel oxygen carrier (Omniox-Ischemic Stroke [OMX-IS]), which selectively releases oxygen into severely ischemic tissue, could delay infarct progression in an established canine thromboembolic large vessel occlusion stroke model that replicates key dynamics of human infarct evolution. METHODS: After endovascular placement of an autologous clot into the middle cerebral artery, animals received OMX-IS treatment or placebo 45 to 60 minutes after stroke onset. Perfusion-weighted magnetic resonance imaging was performed to define infarct progression dynamics to stratify animals into fast versus slow stroke evolvers. Serial diffusion-weighted magnetic resonance imaging was performed for up to 5 hours to quantify infarct evolution. Histology was performed postmortem to confirm final infarct size. RESULTS: In fast evolvers, OMX-IS therapy substantially slowed infarct progression (by ≈1 hour, P<0.0001) and reduced the final normalized infarct volume as compared to controls (0.99 versus 0.88, control versus OMX-IS drug, P<0.0001). Among slow evolvers, OMX-IS treatment delayed infarct progression by approximately 45 minutes; however, this did not reach statistical significance (P=0.09). The final normalized infarct volume also did not show a significant difference (0.93 versus 0.95, OMX-IS drug versus control, P=0.34). Postmortem histologically determined infarct volumes showed excellent concordance with the magnetic resonance imaging defined ischemic lesion volume (bias: 1.33% [95% CI, -15% to 18%). CONCLUSIONS: Intravenous delivery of a novel oxygen carrier is a promising approach to delay infarct progression after ischemic stroke, especially in treating patients with large vessel occlusion stroke who cannot undergo definitive reperfusion therapy within a timely fashion.

AAV gene therapy for Tay-Sachs disease.

Tay-Sachs disease (TSD) is an inherited neurological disorder caused by deficiency of hexosaminidase A (HexA). Here, we describe an adeno-associated virus (AAV) gene therapy expanded-access trial in two patients with infantile TSD (IND 18225) with safety as the primary endpoint and no secondary endpoints. Patient TSD-001 was treated at 30 months with an equimolar mix of AAVrh8-HEXA and AAVrh8-HEXB administered intrathecally (i.t.), with 75% of the total dose (1 × 1014 vector genomes (vg)) in the cisterna magna and 25% at the thoracolumbar junction. Patient TSD-002 was treated at 7 months by combined bilateral thalamic (1.5 × 1012 vg per thalamus) and i.t. infusion (3.9 × 1013 vg). Both patients were immunosuppressed. Injection procedures were well tolerated, with no vector-related adverse events (AEs) to date. Cerebrospinal fluid (CSF) HexA activity increased from baseline and remained stable in both patients. TSD-002 showed disease stabilization by 3 months after injection with ongoing myelination, a temporary deviation from the natural history of infantile TSD, but disease progression was evident at 6 months after treatment. TSD-001 remains seizure-free at 5 years of age on the same anticonvulsant therapy as before therapy. TSD-002 developed anticonvulsant-responsive seizures at 2 years of age. This study provides early safety and proof-of-concept data in humans for treatment of patients with TSD by AAV gene therapy.

Differential association of baseline body weight and body-weight loss with neurological deficits, histology, and death after repetitive closed head traumatic brain injury.

Clinical observations indicate that body weight (BW) extremes are associated with worse outcome after traumatic brain injury (TBI); yet, it is uncertain whether the baseline BW (bBW) may affect outcome after mouse TBI. We retrospectively analyzed 129 similarly aged (9-12 weeks) male C57BL6/J mice that were subjected to repetitive closed head TBI (rTBI) using an established weight drop paradigm as well as 55 sham injured mice. We sought to determine whether the bBW as well as the post-TBI weight relative to baseline (%BW) were associated with a variety of post-rTBI outcomes, including acute model complications (skull fractures and macroscopic hemorrhage), impact seizures, return of the righting reflex (RR), the neurological severity score (NSS), post-rTBI BW-change, and 28-day mortality. In a subset of rTBI mice, we also assessed for potential associations between the bBW and %BW and performance in the novel object recognition (NOR) task and various histological outcomes at 28 days. We found no association between the bBW with acute model complications, impact seizure burden, RR, NSS, and NOR performance at 28 days, as well as cerebral microbleed burden, presence of hyperphosphorylated tau, and TDP-43 pathology after rTBI. However, a higher bBW was associated with a longer time to first impact seizure, a greater microglial activation, astrocytosis, and neuronal loss in the injured cerebral cortex at 28 days. A greater %BW-loss was associated with a shorter impact seizure-free survival, longer time to return of the righting reflex, greater neurological deficit severity as assessed by the NSS and NOR, and worse mortality. On multiple linear regression there was no independent association of the %BW-loss with neuronal loss and neuroinflammation after adjustment for the bBW. These observations indicate that the bBW and %BW-loss may be important biological variables in certain experimental mouse TBI investigations, depending on the outcome measures of interest.

Volume and Infusion Rate Dynamics of Intraparenchymal Central Nervous System Infusion in a Large Animal Model.

Thalamic infusion of adeno-associated viral (AAV) vectors has been shown to have therapeutic effects in neuronopathic lysosomal storage diseases. Preclinical studies in sheep model of Tay-Sachs disease demonstrated that bilateral thalamic injections of AAV gene therapy are required for maximal benefit. Translation of thalamic injection to patients carries risks in that (1) it has never been done in humans, and (2) dosing scale-up based on brain weight from animals to humans requires injection of larger volumes. To increase the safety margin of this infusion, a flexible cannula was selected to enable simultaneous bilateral thalamic infusion in infants while monitoring by imaging and/or to enable awake infusions for injection of large volumes at low infusion rates. In this study, we tested various infusion volumes (200-800 µL) and rates (0.5-5 µL/min) to determine the maximum tolerated combination of injection parameters. Animals were followed for ∼1 month postinjection with magnetic resonance imaging (MRI) performed at 14 and 28 days. T1-weighted MRI was used to quantify thalamic damage followed by histopathological assessment of the brain. Trends in data show that infusion volumes of 800 µL (2 × the volume required in sheep based on thalamic size) resulted in larger lesions than lower volumes, where the long infusion times (between 13 and 26 h) could have contributed to the generation of larger lesions. The target volume (400 µL, projected to be sufficient to cover most of the sheep thalamus) created the smallest lesion size. Cannula placement alone did result in damage, but this is likely associated with an inherent limitation of its use in a small brain due to the length of the distal rigid portion and lack of stable fixation. An injection rate of 5 µL/min at a volume ∼1/3 of the thalamus (400-600 µL) appears to be well tolerated in sheep both clinically and histopathologically.

Infarct Evolution in a Large Animal Model of Middle Cerebral Artery Occlusion.

Mechanical thrombectomy for the treatment of ischemic stroke shows high rates of recanalization; however, some patients still have a poor clinical outcome. A proposed reason for this relates to the fact that the ischemic infarct growth differs significantly between patients. While some patients demonstrate rapid evolution of their infarct core (fast evolvers), others have substantial potentially salvageable penumbral tissue even hours after initial vessel occlusion (slow evolvers). We show that the dog middle cerebral artery occlusion model recapitulates this key aspect of human stroke rendering it a highly desirable model to develop novel multimodal treatments to improve clinical outcomes. Moreover, this model is well suited to develop novel image analysis techniques that allow for improved lesion evolution prediction; we provide proof-of-concept that MRI perfusion-based time-to-peak maps can be utilized to predict the rate of infarct growth as validated by apparent diffusion coefficient-derived lesion maps allowing reliable classification of dogs into fast versus slow evolvers enabling more robust study design for interventional research.

Developing quantitative MRI parameters to characterize host response and tissue ingrowth into collagen scaffolds.

The in vivo evaluation of soft biomaterial implant remodeling routinely requires the surgical removal of the implant for subsequent histological assessment of tissue ingrowth and scaffold remodeling. This approach is very resource intensive, often destructive, and imposes practical limitations on how effectively these materials can be evaluated. MRI has the potential to non-invasively monitor the remodeling of implanted collagen scaffolds in real time. This study investigated the development of a model system to characterize the cellular infiltration, void area fraction, and angiogenesis in collagen scaffold implants using T2 relaxation time and apparent diffusion coefficient (ADC) maps along with conventional histological techniques. Initial correlations found statistically significant relationships between the MRI and histological parameters for various regions of the implanted sponges: T2 versus cell density (r ≈ -0.83); T2 versus void area fraction (r ≈ +0.78); T2 versus blood vessel density (r ≈ +0.95); ADC versus cell density (r ≈ -0.77); and ADC versus void area fraction (r ≈ +0.84). This suggests that MRI is sensitive to specific remodeling parameters and has the potential to serve as a non-invasive tool to monitor the remodeling of implanted collagen scaffolds, and to ultimately assess the ability of these scaffolds to regenerate the functional properties of damaged tissues such as tendons, ligaments, skin or skeletal muscle.

Assessment of in vivo degradation profiles of hyaluronic acid hydrogels using temporal evolution of chemical exchange saturation transfer (CEST) MRI.

Hyaluronic acid (HA) hydrogels have found a wide range of applications in biomedicine: regenerative medicine to drug delivery applications. In vivo quantitative assessment of these hydrogels using magnetic resonance imaging (MRI) provides an effective, accurate, safe, and non-invasive translational approach to assess the biodegradability of HA hydrogels. Chemical exchange saturation transfer (CEST) is an MRI contrast enhancement technique that overcomes the concentration limitation of other techniques like magnetic resonance spectroscopy (MRS) by detecting metabolites at up to two orders of magnitude or higher. In this study, HA hydrogels were synthesized based on different crosslinking agents and assessed using CEST MRI to investigate the in vivo degradation profiles of these gels in a mouse subcutaneous injection model over a three-month period. Nature of crosslinking agents was found to influence their degradation profiles. Since CEST MRI provides a unique chemical signature to visualize HA hydrogels, our studies proved that this technique could be used as a guide in the hydrogel optimization process for drug delivery and regenerative medicine applications.

In Vivo Optical Imaging of Myelination Events in a Myelin Basic Protein Promoter-Driven Luciferase Transgenic Mouse Model.

The compact myelin sheath is important for axonal function, and its loss can lead to neuronal cell death and irreversible functional deficits. Myelin is vulnerable to a variety of metabolic, toxic, and autoimmune insults. In diseases like multiple sclerosis, there is currently no therapy to stop myelin loss, underscoring the need for neuroprotective and remyelinating therapies. Noninvasive, robust techniques are also needed to confirm the effect of such therapies in animal models. This article describes the generation, characterization, and potential uses for a myelin basic protein-luciferase (MBP-luci) transgenic mouse model, in which the firefly luciferase reporter gene is selectively controlled by the MBP promoter. In vivo bioluminescence imaging can be used to visualize and quantify demyelination and remyelination at the transcriptional level, noninvasively, and in real time. Transgenic mice were assessed in the cuprizone-induced model of demyelination, and luciferase activity highly correlated with demyelination and remyelination events as confirmed by both magnetic resonance imaging and postmortem histological analysis. Furthermore, MBP-luci mice demonstrated enhanced luciferase signal and remyelination in the cuprizone model after treatment with a peroxisome proliferator activated receptor-delta selective agonist and quetiapine. Imaging sensitivity was further enhanced by using CycLuc 1, a luciferase substrate, which has greater blood-brain barrier penetration. We demonstrated the utility of MBP-luci model in tracking myelin changes in real time and supporting target and therapeutic validation efforts.

Skeletal Characterization of the Fgfr3 Mouse Model of Achondroplasia Using Micro-CT and MRI Volumetric Imaging.

Achondroplasia, the most common form of dwarfism, affects more than a quarter million people worldwide and remains an unmet medical need. Achondroplasia is caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene which results in over-activation of the receptor, interfering with normal skeletal development leading to disproportional short stature. Multiple mouse models have been generated to study achondroplasia. The characterization of these preclinical models has been primarily done with 2D measurements. In this study, we explored the transgenic model expressing mouse Fgfr3 containing the achondroplasia mutation G380R under the Col2 promoter (Ach). Survival and growth rate of the Ach mice were reduced compared to wild-type (WT) littermates. Axial skeletal defects and abnormalities of the sternebrae and vertebrae were observed in the Ach mice. Further evaluation of the Ach mouse model was performed by developing 3D parameters from micro-computed tomography (micro-CT) and magnetic resonance imaging (MRI). The 3-week-old mice showed greater differences between the Ach and WT groups compared to the 6-week-old mice for all parameters. Deeper understanding of skeletal abnormalities of this model will help guide future studies for evaluating novel and effective therapeutic approaches for the treatment of achondroplasia.

MRI Simulation Study Investigating Effects of Vessel Topology, Diffusion, and Susceptibility on Transverse Relaxation Rates Using a Cylinder Fork Model.

Brain vasculature is conventionally represented as straight cylinders when simulating blood oxygenation level dependent (BOLD) contrast effects in functional magnetic resonance imaging (fMRI). In reality, the vasculature is more complicated with branching and coiling especially in tumors. Diffusion and susceptibility changes can also introduce variations in the relaxation mechanisms within tumors. This study introduces a simple cylinder fork model (CFM) and investigates the effects of vessel topology, diffusion, and susceptibility on the transverse relaxation rates R2* and R2. Simulations using Monte Carlo methods were performed to quantify R2* and R2 by manipulating the CFM at different orientations, bifurcation angles, and rotation angles. Other parameters of the CFM were chosen based on physiologically relevant values: vessel diameters (~2‒10 µm), diffusion rates (1 × 10-11‒1 × 10-9 m2/s), and susceptibility values (3 × 10-8-4 × 10-7 cgs units). R2* and R2 measurements showed a significant dependence on the bifurcation and rotation angles in several scenarios using different vessel diameters, orientations, diffusion rates, and susceptibility values. The angular dependence of R2* and R2 using the CFM could potentially be exploited as a tool to differentiate between normal and tumor vessels. The CFM can also serve as the elementary building block to simulate a capillary network reflecting realistic topological features.

Limitations in biexponential fitting of NMR inversion-recovery curves.

NMR relaxation agents have long been employed as contrast agents in MRI. In many cases, the contrast agent is confined to either (i) the vascular and/or extracellular compartment (EC), as is the case with gadolinium(III)-based agents, or (ii) the intracellular compartment (IC), as is the case with manganese(II) ions. The compartmentalization of contrast agents often results in tissue-water 1H relaxation profiles that are well modeled as biexponential. It has long been recognized that water exchange between compartments modifies the biexponential relaxation parameters (amplitudes and rate constants) from those that would be found in the absence of exchange. Nevertheless, interpretation in terms of an "apparent" two-compartment biophysical model, apparent EC vs. apparent IC, can provide insight into tissue structure and function, and changes therein, in the face of physiologic challenge. The accuracy of modeling biexponential data is highly dependent upon the amplitudes, rate constants, and signal-to-noise characterizing the data. Herein, simulated (in silico) inversion-recovery relaxation data are modeled by standard, nonlinear-least-squares analysis and the error in parameter values assessed for a range of amplitudes and rate constants characteristic of in vivo systems following administration of contrast agent. The findings provide guidance for laboratories seeking to exploit contrast-agent-driven, biexponential relaxation to differentiate MRI-based compartmental properties, including the apparent diffusion coefficient.