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A role for KCC3 in maintaining cell volume of peripheral nerve fibers.
Flores B, Schornak CC, Delpire E
(2019) Neurochem Int 123: 114-124
MeSH Terms: Animals, Brain, Cell Size, Disease Models, Animal, Humans, Nerve Fibers, Symporters
Show Abstract · Added April 3, 2018
The potassium chloride cotransporter, KCC3, is an electroneutral cotransporter expressed in the peripheral and central nervous system. KCC3 is responsible for the efflux of K and Cl in neurons to help maintain cell volume and intracellular chloride levels. A loss-of-function (LOF) of KCC3 causes Hereditary Motor Sensory Neuropathy with Agenesis of the Corpus Callosum (HMSN/ACC) in a population of individuals in the Charlevoix/Lac-Saint-Jean region of Quebec, Canada. A variety of mouse models have been created to understand the physiological and deleterious effects of a KCC3 LOF. Though this KCC3 LOF in mouse models has recapitulated the peripheral neuropathy phenotype of HMSN/ACC, we still know little about the development of the disease pathophysiology. Interestingly, the most recent KCC3 mouse model that we created recapitulated a peripheral neuropathy-like phenotype originating from a KCC3 gain-of-function (GOF). Despite the past two decades of research in attempting to understand the role of KCC3 in disease, we still do not understand how dysfunction of this cotransporter can lead to the pathophysiology of peripheral neuropathy. This review focuses on the function of KCC3 in neurons and its role in human and health and disease.
Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.
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7 MeSH Terms
Inferring brain tissue composition and microstructure via MR relaxometry.
Does MD
(2018) Neuroimage 182: 136-148
MeSH Terms: Brain, Brain Chemistry, Humans, Magnetic Resonance Imaging, Models, Theoretical, Nerve Fibers, Myelinated, Neuroimaging
Show Abstract · Added March 5, 2020
MRI relaxometry is sensitive to a variety of tissue characteristics in a complex manner, which makes it both attractive and challenging for characterizing tissue. This article reviews the most common water proton relaxometry measures, T, T, and T, and reports on their development and current potential to probe the composition and microstructure of brain tissue. The development of these relaxometry measures is challenged by the need for suitably accurate tissue models, as well as robust acquisition and analysis methodologies. MRI relaxometry has been established as a tool for characterizing neural tissue, particular with respect to myelination, and the potential for further development exists.
Copyright © 2018 Elsevier Inc. All rights reserved.
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MeSH Terms
Histological validation of diffusion MRI fiber orientation distributions and dispersion.
Schilling KG, Janve V, Gao Y, Stepniewska I, Landman BA, Anderson AW
(2018) Neuroimage 165: 200-221
MeSH Terms: Animals, Brain, Diffusion Magnetic Resonance Imaging, Diffusion Tensor Imaging, Image Processing, Computer-Assisted, Imaging, Three-Dimensional, Nerve Fibers, Neuroimaging, Saimiri
Show Abstract · Added March 26, 2019
Diffusion magnetic resonance imaging (dMRI) is widely used to probe tissue microstructure, and is currently the only non-invasive way to measure the brain's fiber architecture. While a large number of approaches to recover the intra-voxel fiber structure have been utilized in the scientific community, a direct, 3D, quantitative validation of these methods against relevant histological fiber geometries is lacking. In this study, we investigate how well different high angular resolution diffusion imaging (HARDI) models and reconstruction methods predict the ground-truth histologically defined fiber orientation distribution (FOD), as well as investigate their behavior over a range of physical and experimental conditions. The dMRI methods tested include constrained spherical deconvolution (CSD), Q-ball imaging (QBI), diffusion orientation transform (DOT), persistent angular structure (PAS), and neurite orientation dispersion and density imaging (NODDI) methods. Evaluation criteria focus on overall agreement in FOD shape, correct assessment of the number of fiber populations, and angular accuracy in orientation. In addition, we make comparisons of the histological orientation dispersion with the fiber spread determined from the dMRI methods. As a general result, no HARDI method outperformed others in all quality criteria, with many showing tradeoffs in reconstruction accuracy. All reconstruction techniques describe the overall continuous angular structure of the histological FOD quite well, with good to moderate correlation (median angular correlation coefficient > 0.70) in both single- and multiple-fiber voxels. However, no method is consistently successful at extracting discrete measures of the number and orientations of FOD peaks. The major inaccuracies of all techniques tend to be in extracting local maxima of the FOD, resulting in either false positive or false negative peaks. Median angular errors are ∼10° for the primary fiber direction and ∼20° for the secondary fiber, if present. For most methods, these results did not vary strongly over a wide range of acquisition parameters (number of diffusion weighting directions and b value). Regardless of acquisition parameters, all methods show improved successes at resolving multiple fiber compartments in a voxel when fiber populations cross at near-orthogonal angles, with no method adequately capturing low to moderate angle (<60°) crossing fibers. Finally, most methods are limited in their ability to capture orientation dispersion, resulting in low to moderate, yet statistically significant, correlation with histologically-derived dispersion with both HARDI and NODDI methodologies. Together, these results provide quantitative measures of the reliability and limitations of dMRI reconstruction methods and can be used to identify relative advantages of competing approaches as well as potential strategies for improving accuracy.
Copyright © 2017 Elsevier Inc. All rights reserved.
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MeSH Terms
Effects of sensitivity to life stress on uncinate fasciculus segments in early adolescence.
Ho TC, King LS, Leong JK, Colich NL, Humphreys KL, Ordaz SJ, Gotlib IH
(2017) Soc Cogn Affect Neurosci 12: 1460-1469
MeSH Terms: Adolescent, Anisotropy, Anxiety, Brain Mapping, Child, Diffusion Tensor Imaging, Female, Frontal Lobe, Humans, Limbic System, Magnetic Resonance Imaging, Male, Nerve Fibers, Neural Pathways, Neuropsychological Tests, Stress, Psychological, White Matter
Show Abstract · Added March 3, 2020
Previous research suggests that exposure to early life stress (ELS) affects the structural integrity of the uncinate fasciculus (UF), a frontolimbic white matter tract that undergoes protracted development throughout adolescence. Adolescence is an important transitional period characterized by the emergence of internalizing psychopathology such as anxiety, particularly in individuals with high levels of stress sensitivity. We examined the relations among sensitivity to ELS, structural integrity of the UF, and anxiety symptoms in 104 early adolescents. We conducted structured interviews to assess exposure to ELS and obtained subjective and objective ratings of stress severity, from which we derived an index of ELS sensitivity. We also acquired diffusion MRI and conducted deterministic tractography to visualize UF trajectories and to compute measures of structural integrity from three distinct segments of the UF: frontal, insular, temporal. We found that higher sensitivity to ELS predicted both reduced fractional anisotropy in right frontal UF and higher levels of anxiety symptoms. These findings suggest that fibers in frontal UF, which are still developing throughout adolescence, are most vulnerable to the effects of heightened sensitivity to ELS, and that reduced structural integrity of frontal UF may underlie the relation between early stress and subsequent internalizing psychopathology.
© The Author (2017). Published by Oxford University Press.
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MeSH Terms
Simple, Scalable Proteomic Imaging for High-Dimensional Profiling of Intact Systems.
Murray E, Cho JH, Goodwin D, Ku T, Swaney J, Kim SY, Choi H, Park YG, Park JY, Hubbert A, McCue M, Vassallo S, Bakh N, Frosch MP, Wedeen VJ, Seung HS, Chung K
(2015) Cell 163: 1500-14
MeSH Terms: Algorithms, Animals, Female, Humans, Male, Mice, Mice, Inbred C57BL, Molecular Imaging, Nerve Fibers, Myelinated, Proteomics, Reducing Agents, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Tissue Preservation
Show Abstract · Added July 20, 2016
Combined measurement of diverse molecular and anatomical traits that span multiple levels remains a major challenge in biology. Here, we introduce a simple method that enables proteomic imaging for scalable, integrated, high-dimensional phenotyping of both animal tissues and human clinical samples. This method, termed SWITCH, uniformly secures tissue architecture, native biomolecules, and antigenicity across an entire system by synchronizing the tissue preservation reaction. The heat- and chemical-resistant nature of the resulting framework permits multiple rounds (>20) of relabeling. We have performed 22 rounds of labeling of a single tissue with precise co-registration of multiple datasets. Furthermore, SWITCH synchronizes labeling reactions to improve probe penetration depth and uniformity of staining. With SWITCH, we performed combinatorial protein expression profiling of the human cortex and also interrogated the geometric structure of the fiber pathways in mouse brains. Such integrated high-dimensional information may accelerate our understanding of biological systems at multiple levels.
Copyright © 2015 Elsevier Inc. All rights reserved.
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13 MeSH Terms
Pathogenesis of multiple sclerosis: insights from molecular and metabolic imaging.
Ciccarelli O, Barkhof F, Bodini B, De Stefano N, Golay X, Nicolay K, Pelletier D, Pouwels PJ, Smith SA, Wheeler-Kingshott CA, Stankoff B, Yousry T, Miller DH
(2014) Lancet Neurol 13: 807-22
MeSH Terms: Animals, Humans, Magnetic Resonance Imaging, Molecular Imaging, Multiple Sclerosis, Nerve Fibers, Myelinated
Show Abstract · Added February 13, 2015
The mechanisms underlying the pathogenesis of multiple sclerosis induce the changes that underpin relapse-associated and progressive disability. Disease mechanisms can be investigated in preclinical models and patients with multiple sclerosis by molecular and metabolic imaging techniques. Many insights have been gained from such imaging studies: persisting inflammation in the absence of a damaged blood-brain barrier, activated microglia within and beyond lesions, increased mitochondrial activity after acute lesions, raised sodium concentrations in the brain, increased glutamate in acute lesions and normal-appearing white matter, different degrees of demyelination in different patients and lesions, early neuronal damage in grey matter, and early astrocytic proliferation and activation in lesions and white matter. Clinical translation of molecular and metabolic imaging and extension of these techniques will enable the assessment of novel drugs targeted at these disease mechanisms, and have the potential to improve health outcomes through the stratification of patients for treatments.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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6 MeSH Terms
Epidermal nerve fiber density, oxidative stress, and mitochondrial haplogroups in HIV-infected Thais initiating therapy.
Hulgan T, Levinson RT, Gerschenson M, Phanuphak N, Ananworanich J, Teeratakulpisarm N, Jadwattanakul T, LiButti DE, Fink H, McArthur JC, Ebenezer GJ, Hauer P, Murdock D, Shikuma CM, Samuels DC, SEARCH 003 Study Team
(2014) AIDS 28: 1625-33
MeSH Terms: Adult, Animals, Asian Continental Ancestry Group, Epidermis, Female, HIV Infections, Haplotypes, Humans, Male, Mitochondria, Nerve Fibers, Nervous System Diseases, Oxidative Stress
Show Abstract · Added May 27, 2014
OBJECTIVE - We explored associations between mitochondrial DNA (mtDNA) haplogroups, epidermal nerve fiber density (ENFD), and HIV-associated sensory neuropathy (HIV-SN) in a randomized trial of Thai patients initiating antiretroviral therapy (ART).
DESIGN - The South East Asia Research Collaboration with Hawaii 003 study evaluated toxicity of nucleoside reverse transcriptase inhibitors (stavudine vs. zidovudine vs. tenofovir). We present secondary analyses of mtDNA haplogroups and ENFD changes.
METHODS - ENFD, peripheral blood mononuclear cell mitochondrial complex I and IV, and 8-oxo-deoxyguanine (8-oxo-dG) were quantified. Peripheral blood mononuclear cell mtDNA sequences were obtained for haplogroup determination. Multivariate regression of ENFD change was performed.
RESULTS - Paired ENFD was available from 118 patients. Median age, CD4 cell count, and height at entry were 34 years, 172 cells/μl, and 162 cm, respectively. Major haplogroups included M (42%), F (21%), and B (16%). Baseline ENFD, CD4 cell count, randomized ART, and biomarkers did not differ by haplogroup. Haplogroup B patients were older (P=0.02) at baseline, and had an increase in median ENFD (+1.5 vs. -2.9 fibers/mm; P=0.03) and 8-oxo-dG break frequency (+0.05 vs. 0.00; P=0.05) compared to other haplogroups. In a multivariate model, haplogroup B was associated with increased ENFD (β=3.5, P=0.009) at week 24, whereas older age (P=0.02), higher baseline CD4 cell count, (P=0.03), higher complex I level (P=0.03), and higher ENFD (P<0.001) at baseline were all associated with decreased ENFD. Three of the six HIV-SN cases were haplogroup B (P=0.05).
CONCLUSIONS - Thai persons belonging to mtDNA haplogroup B had increased ENFD and 8-oxo-dG on ART, and were more likely to develop HIV-SN. These results suggest that mtDNA variation influences early oxidative damage and ENFD changes.
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13 MeSH Terms
Robust GM/WM segmentation of the spinal cord with iterative non-local statistical fusion.
Asman AJ, Smith SA, Reich DS, Landman BA
(2013) Med Image Comput Comput Assist Interv 16: 759-67
MeSH Terms: Algorithms, Data Interpretation, Statistical, Diffusion Tensor Imaging, Humans, Image Enhancement, Image Interpretation, Computer-Assisted, Nerve Fibers, Myelinated, Neurons, Pattern Recognition, Automated, Reproducibility of Results, Sensitivity and Specificity, Spinal Cord, Subtraction Technique
Show Abstract · Added March 26, 2014
New magnetic resonance imaging (MRI) sequences are enabling clinical study of the in vivo spinal cord's internal structure. Yet, low contrast-to-noise ratio, artifacts, and imaging distortions have limited the applicability of tissue segmentation techniques pioneered elsewhere in the central nervous system. Recently, methods have been presented for cord/non-cord segmentation on MRI and the feasibility of gray matter/white matter tissue segmentation has been evaluated. To date, no automated algorithms have been presented. Herein, we present a non-local multi-atlas framework that robustly identifies the spinal cord and segments its internal structure with submillimetric accuracy. The proposed algorithm couples non-local fusion with a large number of slice-based atlases (as opposed to typical volumetric ones). To improve performance, the fusion process is interwoven with registration so that segmentation information guides registration and vice versa. We demonstrate statistically significant improvement over state-of-the-art benchmarks in a study of 67 patients. The primary contributions of this work are (1) innovation in non-volumetric atlas information, (2) advancement of label fusion theory to include iterative registration/segmentation, and (3) the first fully automated segmentation algorithm for spinal cord internal structure on MRI.
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13 MeSH Terms
Evaluation of dermal myelinated nerve fibers in diabetes mellitus.
Peltier AC, Myers MI, Artibee KJ, Hamilton AD, Yan Q, Guo J, Shi Y, Wang L, Li J
(2013) J Peripher Nerv Syst 18: 162-7
MeSH Terms: Adult, Aged, Biopsy, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Diabetic Neuropathies, Female, Fingers, Humans, Immunohistochemistry, Male, Middle Aged, Nerve Fibers, Myelinated, Neural Conduction, Skin
Show Abstract · Added May 20, 2014
Skin biopsies have primarily been used to study the non-myelinated nerve fibers of the epidermis in a variety of neuropathies. In this study, we have expanded the skin biopsy technique to glabrous, non-hairy skin to evaluate myelinated nerve fibers in the most highly prevalent peripheral nerve disease, diabetic polyneuropathy (DPN). Twenty patients with DPN (Type I, n = 9; Type II, n = 11) and 16 age-matched healthy controls (age 29-73) underwent skin biopsy of the index finger, nerve conduction studies (NCS), and composite neuropathy scoring. In patients with DPN, we found a statistically significant reduction of both mechanoreceptive Meissner corpuscles (MCs) and their afferent myelinated nerve fibers (p = 0.01). This myelinated nerve fiber loss was correlated with the decreased amplitudes of sensory/motor responses in NCS. This study supports the utilization of skin biopsy to quantitatively evaluate axonal loss of myelinated nerve fibers in patients with DPN.
© 2013 Peripheral Nerve Society.
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15 MeSH Terms
Vessel-encoded arterial spin labeling (VE-ASL) reveals elevated flow territory asymmetry in older adults with substandard verbal memory performance.
Donahue MJ, Hussey E, Rane S, Wilson T, van Osch M, Hartkamp N, Hendrikse J, Ally BA
(2014) J Magn Reson Imaging 39: 377-86
MeSH Terms: Adult, Aging, Blood Flow Velocity, Brain, Cerebral Angiography, Cerebrovascular Circulation, Female, Humans, Magnetic Resonance Angiography, Male, Memory, Memory Disorders, Middle Aged, Nerve Fibers, Myelinated, Reproducibility of Results, Sensitivity and Specificity, Spin Labels, Verbal Behavior
Show Abstract · Added August 21, 2014
PURPOSE - To evaluate how flow territory asymmetry and/or the distribution of blood through collateral pathways may adversely affect the brain's ability to respond to age-related changes in brain function. These patterns have been investigated in cerebrovascular disease; however, here we evaluated how flow-territory asymmetry related to memory generally in older adults.
MATERIALS AND METHODS - A multi-faceted MRI protocol, including vessel-encoded arterial spin labeling capable of flow territory mapping, was applied to assess how flow territory asymmetry; memory performance (CERAD-Immediate Recall); cortical cerebral blood flow (CBF), white matter lesion (WML) count, and cortical gray matter volume were related in older healthy control volunteers (HC; n = 15; age = 64.5 ± 7 years) and age-matched mild cognitive impairment volunteers (MCI; n = 7; age = 62.7 ± 3.7 years).
RESULTS - An inverse relationship was found between memory performance and flow territory asymmetry in HC volunteers (P = 0.04), which reversed in MCI volunteers (P = 0.04). No relationship was found between memory performance and cortical tissue volume in either group (P > 0.05). Group-level differences for HC volunteers performing above versus below average on CERAD-I were observed for flow territory asymmetry (P < 0.02) and cortical volume (P < 0.05) only.
CONCLUSION - Findings suggest that flow territory asymmetry may correlate more sensitively with memory performance than CBF, atrophy and WML count in older adults.
Copyright © 2013 Wiley Periodicals, Inc.
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18 MeSH Terms