Does powder averaging remove dispersion bias in diffusion MRI diameter estimates within real 3D axonal architectures?

Noninvasive estimation of axon diameter with diffusion MRI holds potential to investigate the dynamic properties of the brain network and pathology of neurodegenerative diseases. Recent methods use powder averaging to account for complex white matter architectures, such as fibre crossing regions, but these have not been validated for real axonal geometries. Here, we present 120-313 μm long segmented axons from X-ray nano-holotomography volumes of a splenium and crossing fibre region of a vervet monkey brain. We show that the axons in the complex crossing fibre region, which contains callosal, association, and corticospinal connections, are larger and exhibit a wider distribution than those of the splenium region. To accurately estimate the axon diameter in these regions, therefore, sensitivity to a wide range of diameters is required. We demonstrate how the q-value, b-value, signal-to-noise ratio and the assumed intra-axonal parallel diffusivity influence the range of measurable diameters with powder average approaches. Furthermore, we show how Gaussian distributed noise results in a wider range of measurable diameter at high b-values than with Rician distributed noise, even at high signal-to-noise ratios of 100. The number of gradient directions is also shown to impose a lower bound on measurable diameter. Our results indicate that axon diameter estimation can be performed with only few b-shells, and that additional shells do not improve the accuracy of the estimate. Through Monte Carlo simulations of diffusion, we show that powder averaging techniques succeed in providing accurate estimates of axon diameter across a range of sequence parameters and diffusion times, even in complex white matter architectures. At sufficiently low b-values, the acquisition becomes sensitive to axonal microdispersion and the intra-axonal parallel diffusivity shows time dependency at both in vivo and ex vivo intrinsic diffusivities.

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High-gradient diffusion MRI reveals distinct estimates of axon diameter index within different white matter tracts in the in vivo human brain

Brain Structure and Function ◽

10.1007/s00429-019-01961-2 ◽

2019 ◽

Vol 225 (4) ◽

pp. 1277-1291 ◽

Cited By ~ 4

Author(s):

Susie Y. Huang ◽

Qiyuan Tian ◽

Qiuyun Fan ◽

Thomas Witzel ◽

Barbara Wichtmann ◽

...

Keyword(s):

White Matter ◽

Human Brain ◽

Diffusion Mri ◽

Axon Diameter ◽

White Matter Tracts ◽

High Gradient ◽

Gradient Diffusion

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Limits to anatomical accuracy of diffusion tractography using modern approaches

10.1101/392571 ◽

2018 ◽

Cited By ~ 2

Author(s):

Kurt G Schilling ◽

Vishwesh Nath ◽

Colin Hansen ◽

Prasanna Parvathaneni ◽

Justin Blaber ◽

...

Keyword(s):

White Matter ◽

Validation Studies ◽

Diffusion Mri ◽

Ex Vivo ◽

Structural Connectivity ◽

Fiber Tractography ◽

Research Groups ◽

Wide Range ◽

Modern Methods ◽

The Brain

AbstractDiffusion MRI fiber tractography is widely used to probe the structural connectivity of thebrain, with a range of applications in both clinical and basic neuroscience. Despite widespread use, tractography has well-known pitfalls that limits the anatomical accuracy of this technique. Numerous modern methods have been developed to address these shortcomings through advances in acquisition, modeling, and computation. To test whether these advances improve tractography accuracy, we organized the ISBI 2018 3D Validation of Tractography with Experimental MRI (3D-VoTEM) challenge. We made available three unique independent tractography validation datasets – a physical phantom and two ex vivo brain specimens - resulting in 176 distinct submissions from 9 research groups. By comparing results over a wide range of fiber complexities and algorithmic strategies, this challenge provides a more comprehensive assessment of tractography’s inherent limitations than has been reported previously. The central results were consistent across all sub-challenges in that, despite advances in tractography methods, the anatomical accuracy of tractography has not dramatically improved in recent years. Taken together, our results independently confirm findings from decades of tractography validation studies, demonstrate inherent limitations in reconstructing white matter pathways using diffusion MRI data alone, and highlight the need for alternative or combinatorial strategies to accurately map the fiber pathways of the brain.

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[P2-420]: A COMPARISON OF BRAIN WHITE MATTER HYPERINTENSITY BURDEN ASSESSED IN VIVO AND EX VIVO

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.06.1076 ◽

2017 ◽

Vol 13 (7S_Part_16) ◽

pp. P794-P795

Author(s):

Arman P. Kulkarni ◽

Arnold M. Evia ◽

Julie A. Schneider ◽

David A. Bennett ◽

Konstantinos Arfanakis

Keyword(s):

White Matter ◽

Ex Vivo ◽

White Matter Hyperintensity ◽

Brain White Matter

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hPSC-Derived Enteric Ganglioids Model Human ENS Development and Function

10.1101/2022.01.04.474746 ◽

2022 ◽

Author(s):

Homa Majd ◽

Ryan M Samuel ◽

Jonathan T Ramirez ◽

Ali Kalantari ◽

Kevin Barber ◽

...

Keyword(s):

Ex Vivo ◽

Xenograft Model ◽

Developmental Relationships ◽

Drug Candidates ◽

Effective Strategies ◽

Wide Range ◽

Functional Features ◽

And Function

The enteric nervous system (ENS) plays a central role in gut physiology and mediating the crosstalk between the gastrointestinal (GI) tract and other organs. The human ENS has remained elusive, highlighting the need for an in vitro modeling and mapping blueprint. Here we map out the developmental and functional features of the human ENS, by establishing robust and scalable 2D ENS cultures and 3D enteric ganglioids from human pluripotent stem cells (hPSCs). These models recapitulate the remarkable neuronal and glial diversity found in primary tissue and enable comprehensive molecular analyses that uncover functional and developmental relationships within these lineages. As a salient example of the power of this system, we performed in-depth characterization of enteric nitrergic neurons (NO neurons) which are implicated in a wide range of GI motility disorders. We conducted an unbiased screen and identified drug candidates that modulate the activity of NO neurons and demonstrated their potential in promoting motility in mouse colonic tissue ex vivo. We established a high-throughput strategy to define the developmental programs involved in NO neuron specification and discovered that PDGFR inhibition boosts the induction of NO neurons in enteric ganglioids. Transplantation of these ganglioids in the colon of NO neuron-deficient mice results in extensive tissue engraftment, providing a xenograft model for the study of human ENS in vivo and the development of cell-based therapies for neurodegenerative GI disorders. These studies provide a framework for deciphering fundamental features of the human ENS and designing effective strategies to treat enteric neuropathies.

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Rationally Designing Simple Rod-Like Amphiphilic NIR-Emissive AIE Probes for Precise In-Vivo Detection of Aβ Fibrils/Plaques at A Super-Early Stage

10.26434/chemrxiv.13699222.v1 ◽

2021 ◽

Author(s):

Yipu Wang ◽

Dong Mei ◽

Xinyi Zhang ◽

Da-Hui Qu ◽

Ju Mei ◽

...

Keyword(s):

High Performance ◽

Ex Vivo ◽

Early Stage ◽

Signal To Noise Ratio ◽

High Signal ◽

In Vivo Detection ◽

Different Strains ◽

Aβ Fibrils

With increase of social aging, Alzheimer's disease (AD) has been one of the serious diseases threatening human health. The occurrence of Aβ fibrils or plaques is recognized as the hallmark of AD. Currently, optical imaging has stood out to be a promising technique for the imaging of Aβ fibrils/plaques and the diagnosis of AD. However, restricted by their poor blood-brain barrier (BBB) penetrability, short-wavelength excitation and emission, and aggregation-caused quenching (ACQ) effect, the clinically used gold-standard optical probes such as <a>thioflavin</a> T (ThT) and thioflavin S (ThS), are not effective enough in the early diagnosis of AD in vivo. Herein, we put forward an “all-in-one” design principle and demonstrate its feasibility in developing high-performance fluorescent probes which are specific to Aβ fibrils/plaques and promising for super-early in-vivo diagnosis of AD. As a proof of concept, a simple rod-like amphiphilic NIR fluorescent AIEgen, i.e., AIE-CNPy-AD, is developed by taking the specificity, BBB penetration ability, deep-tissue penetration capacity, high signal-to-noise ratio (SNR) into consideration. AIE-CNPy-AD is constituted by connecting the electron-donating and accepting moieties through single bonds and tagging with a propanesulfonate tail, giving rise to the NIR fluorescence, aggregation-induced emission (AIE) effect, amphiphilicity, and rod-like structure, which in turn result in high binding-affinity and excellent specificity to Aβ fibrils/plaques, satisfactory ability to penetrate BBB and deep tissues, ultrahigh SNR and sensitivity, and high-fidelity imaging capability. In-vitro, ex-vivo, and in-vivo <a>identifying of Aβ fibrils/plaques</a> in different strains of mice indicate that AIE-CNPy-AD holds the universality to the detection of Aβ fibrils/plaques. It is noteworthy that AIE-CNPy-AD is even able to trace the small and sparsely distributed Aβ fibrils/plaques in very young AD model mice such as 4-month-old APP/PS1 mice which are reported to be the youngest mice to have Aβ deposits in brains, suggesting its great potential in diagnosis and intervention of AD at a super-early stage.

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Fixel-based Analysis of Diffusion MRI: Methods, Applications, Challenges and Opportunities

10.31219/osf.io/zu8fv ◽

2020 ◽

Author(s):

Thijs Dhollander ◽

Adam Clemente ◽

Mervyn Singh ◽

Frederique Boonstra ◽

Oren Civier ◽

...

Keyword(s):

Diffusion Mri ◽

State Of The Art ◽

Specific Information ◽

Analysis Framework ◽

Wide Range ◽

Challenges And Opportunities ◽

P Diffusion ◽

Modelling Techniques ◽

The Rich

Diffusion MRI has provided the neuroimaging community with a powerful tool to acquire in-vivo data sensitive to microstructural features of white matter, up to 3 orders of magnitude smaller than typical voxel sizes. The key to extracting such valuable information lies in complex modelling techniques, which form the link between the rich diffusion MRI data and various metrics related to the microstructural organisation. Over time, increasingly advanced techniques have been developed, up to the point where some diffusion MRI models can now provide access to properties specific to individual fibre populations in each voxel in the presence of multiple "crossing" fibre pathways. While highly valuable, such fibre-specific information poses unique challenges for typical image processing pipelines and statistical analysis. In this work, we review the "fixel-based analysis" (FBA) framework that implements bespoke solutions to this end, and has recently seen a stark increase in adoption for studies of both typical (healthy) populations as well as a wide range of clinical populations. We describe the main concepts related to fixel-based analyses, as well as the methods and specific steps involved in a state-of-the-art FBA pipeline, with a focus on providing researchers with practical advice on how to interpret results. We also include an overview of the scope of current fixel-based analysis studies (until August 2020), categorised across a broad range of neuroscientific domains, listing key design choices and summarising their main results and conclusions. Finally, we critically discuss several aspects and challenges involved with the fixel-based analysis framework, and outline some directions and future opportunities.

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In vitro-transcribed antigen receptor mRNA nanocarriers for transient expression in circulating T cells in vivo

Nature Communications ◽

10.1038/s41467-020-19486-2 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

N. N. Parayath ◽

S. B. Stephan ◽

A. L. Koehne ◽

P. S. Nelson ◽

M. T. Stephan

Keyword(s):

T Cells ◽

Ex Vivo ◽

Human Leukemia ◽

Antigen Receptors ◽

Wide Range ◽

Engineered T Cells ◽

Circulating T Cells ◽

The Cost

AbstractEngineering chimeric antigen receptors (CAR) or T cell receptors (TCR) helps create disease-specific T cells for targeted therapy, but the cost and rigor associated with manufacturing engineered T cells ex vivo can be prohibitive, so programing T cells in vivo may be a viable alternative. Here we report an injectable nanocarrier that delivers in vitro-transcribed (IVT) CAR or TCR mRNA for transiently reprograming of circulating T cells to recognize disease-relevant antigens. In mouse models of human leukemia, prostate cancer and hepatitis B-induced hepatocellular carcinoma, repeated infusions of these polymer nanocarriers induce sufficient host T cells expressing tumor-specific CARs or virus-specific TCRs to cause disease regression at levels similar to bolus infusions of ex vivo engineered lymphocytes. Given their ease of manufacturing, distribution and administration, these nanocarriers, and the associated platforms, could become a therapeutic for a wide range of diseases.

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Sequential average segmented microscopy for high signal-to-noise ratio motion-artifact-free in vivo heart imaging

Biomedical Optics Express ◽

10.1364/boe.4.002095 ◽

2013 ◽

Vol 4 (10) ◽

pp. 2095 ◽

Cited By ~ 12

Author(s):

Claudio Vinegoni ◽

Sungon Lee ◽

Paolo Fumene Feruglio ◽

Pasquina Marzola ◽

Matthias Nahrendorf ◽

...

Keyword(s):

Signal To Noise Ratio ◽

Motion Artifact ◽

High Signal ◽

Signal To Noise ◽

Heart Imaging ◽

Noise Ratio

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A Novel PET Imaging Using64Cu-Labeled Monoclonal Antibody against Mesothelin Commonly Expressed on Cancer Cells

Journal of Immunology Research ◽

10.1155/2015/268172 ◽

2015 ◽

Vol 2015 ◽

pp. 1-15 ◽

Cited By ~ 15

Author(s):

Kazuko Kobayashi ◽

Takanori Sasaki ◽

Fumiaki Takenaka ◽

Hiromasa Yakushiji ◽

Yoshihiro Fujii ◽

...

Keyword(s):

Monoclonal Antibody ◽

Cancer Cells ◽

Pet Imaging ◽

Ex Vivo ◽

Chelating Agent ◽

Pancreatic Cancer Cells ◽

Positron Emission ◽

Wide Range

Mesothelin (MSLN) is a 40-kDa cell differentiation-associated glycoprotein appearing with carcinogenesis and is highly expressed in many human cancers, including the majority of pancreatic adenocarcinomas, ovarian cancers, and mesotheliomas, while its expression in normal tissue is limited to mesothelial cells lining the pleura, pericardium, and peritoneum. Clone 11-25 is a murine hybridoma secreting monoclonal antibody (mAb) against human MSLN. In this study, we applied the 11-25 mAb toin vivoimaging to detect MSLN-expressing tumors. Inin vitroandex vivoimmunochemical studies, we demonstrated specificity of 11-25 mAb to membranous MSLN expressed on several pancreatic cancer cells. We showed the accumulation of Alexa Fluor 750-labeled 11-25 mAb in MSLN-expressing tumor xenografts in athymic nude mice. Then, 11-25 mAb was labeled with64Cu via a chelating agent DOTA and was used in bothin vitrocell binding assay andin vivopositron emission tomography (PET) imaging in the tumor-bearing mice. We confirmed that64Cu-labeled 11-25 mAb highly accumulated in MSLN-expressing tumors as compared to MSLN-negative ones. The64Cu-labeled 11-25 mAb is potentially useful as a PET probe capable of being used for wide range of tumors, rather than18F-FDG that occasionally provides nonspecific accumulation into the inflammatory lesions.

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Mesenchymal Stromal/Stem Cells in Regenerative Medicine and Tissue Engineering

Stem Cells International ◽

10.1155/2018/8031718 ◽

2018 ◽

Vol 2018 ◽

pp. 1-16 ◽

Cited By ~ 96

Author(s):

Ross E. B. Fitzsimmons ◽

Matthew S. Mazurek ◽

Agnes Soos ◽

Craig A. Simmons

Keyword(s):

Tissue Engineering ◽

Stem Cells ◽

Regenerative Medicine ◽

Ex Vivo ◽

Therapeutic Effects ◽

Wide Range ◽

History Of ◽

Initial Discovery ◽

Stromal Stem Cells

As a result of over five decades of investigation, mesenchymal stromal/stem cells (MSCs) have emerged as a versatile and frequently utilized cell source in the fields of regenerative medicine and tissue engineering. In this review, we summarize the history of MSC research from the initial discovery of their multipotency to the more recent recognition of their perivascular identity in vivo and their extraordinary capacity for immunomodulation and angiogenic signaling. As well, we discuss long-standing questions regarding their developmental origins and their capacity for differentiation toward a range of cell lineages. We also highlight important considerations and potential risks involved with their isolation, ex vivo expansion, and clinical use. Overall, this review aims to serve as an overview of the breadth of research that has demonstrated the utility of MSCs in a wide range of clinical contexts and continues to unravel the mechanisms by which these cells exert their therapeutic effects.

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