Publications by authors named "Rodolfo Gatto"

27 Publications

  • Page 1 of 1

Evaluation of early microstructural changes in the R6/1 mouse model of Huntington's disease by ultra-high field diffusion MR imaging.

Neurobiol Aging 2021 Feb 12;102:32-49. Epub 2021 Feb 12.

Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA.

Diffusion MRI (dMRI) has been able to detect early structural changes related to neurological symptoms present in Huntington's disease (HD). However, there is still a knowledge gap to interpret the biological significance at early neuropathological stages. The purpose of this study is two-fold: (i) establish if the combination of Ultra-High Field Diffusion MRI (UHFD-MRI) techniques can add a more comprehensive analysis of the early microstructural changes observed in HD, and (ii) evaluate if early changes in dMRI microstructural parameters can be linked to cellular biomarkers of neuroinflammation. Ultra-high field magnet (16.7T), diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI) techniques were applied to fixed ex-vivo brains of a preclinical model of HD (R6/1 mice). Fractional anisotropy (FA) was decreased in deep and superficial grey matter (GM) as well as white matter (WM) brain regions with well-known early HD microstructure and connectivity pathology. NODDI parameters associated with the intracellular and extracellular compartment, such as intracellular ventricular fraction (ICVF), orientation dispersion index (ODI), and isotropic volume fractions (IsoVF) were altered in R6/1 mice GM. Further, histological studies in these areas showed that glia cell markers associated with neuroinflammation (GFAP & Iba1) were consistent with the dMRI findings. dMRI can be used to extract non-invasive information of neuropathological events present in the early stages of HD. The combination of multiple imaging techniques represents a better approach to understand the neuropathological process allowing the early diagnosis and neuromonitoring of patients affected by HD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.02.006DOI Listing
February 2021

New molecular insights, innovative technologies, and medical approaches in the "Exploration of mechanisms in cortical plasticity".

J Integr Neurosci 2020 Dec;19(4):733-734

Department of Neurosurgery, Hamamatsu University, School of Medicine, Hamamatsu, 431-3192, Japan.

No abstract present.
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http://dx.doi.org/10.31083/j.jin.2020.04.348DOI Listing
December 2020

Molecular and microstructural biomarkers of neuroplasticity in neurodegenerative disorders through preclinical and diffusion magnetic resonance imaging studies.

J Integr Neurosci 2020 Sep;19(3):571-592

Department of Bioengineering, The University of Illinois at Chicago, Illinois, 60607, USA.

Advances in the understanding of genetic and molecular mechanisms and imaging technologies have opened a new window of research possibilities to address dynamic processes associated with neuroplasticity in physiologically intact models of neurodegenerative diseases. This review aims to: (i) establish the most relevant molecular mechanisms, as well as cellular and structural biomarkers in the study of neuroplasticity; (ii) introduce different neurodegenerative diseases in animal models that contribute to our knowledge of neuroplasticity; and (iii) illustrate the capabilities and limitations of current diffusion magnetic resonance imaging techniques to study cortical plasticity, as well as the use of alternative diffusion models.
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http://dx.doi.org/10.31083/j.jin.2020.03.165DOI Listing
September 2020

Upregulation of ASIC1a channels in an in vitro model of Fabry disease.

Neurochem Int 2020 11 22;140:104824. Epub 2020 Aug 22.

IFIBYNE-CONICET, Buenos Aires, CP1428, Argentina. Electronic address:

Neuropathic pain is one of the key features of the classical phenotype of Fabry disease (FD). Acid sensing ion channels (ASICs) are H-gated cation channels, which belong to the epithelial sodium channel/DeGenerin superfamily, sensitive to the diuretic drug Amiloride. Molecular cloning has identified several distinct ASIC subunits. In particular the ASIC1a subunit has been associated to pain and its upregulation has been documented in animal models of pain. We analyzed the expression of ASIC1a channels in cellular models that mimic the accumulation of glycosphingolipids in FD (FD-GLs) like Gb3, and LysoGb3. We used mouse primary neurons from brain cortex and hippocampus -supraspinal structures that accumulate FD-GLs-, as well as HEK293 cells. Incubation with Gb3, lysoGb3 and the inhibitor (1-deoxy-galactonojirymicin, DJG) of the enzyme α-galactosidase A (Gla) lead to the upregulation of ASIC1a channels. In addition, activation of ASIC1a results in the activation of the MAPK ERK pathway, a signaling pathway associated with pain. Moreover, accumulation of glycosphingolipids results in activation of ERK, an effect that was prevented by blocking ASIC1a channels with the specific blocker Psalmotoxin. Our results suggest that FD-GLs accumulation and triggering of the ERK pathway via ASIC channels might be involved in the mechanism responsible for pain in FD, thus providing a new therapeutic target for pain relief treatment.
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http://dx.doi.org/10.1016/j.neuint.2020.104824DOI Listing
November 2020

Assessing neuraxial microstructural changes in a transgenic mouse model of early stage Amyotrophic Lateral Sclerosis by ultra-high field MRI and diffusion tensor metrics.

Animal Model Exp Med 2020 Jun 16;3(2):117-129. Epub 2020 Apr 16.

Department of Bioengineering University of Illinois at Chicago Chicago IL USA.

Objective: Cell structural changes are one of the main features observed during the development of amyotrophic lateral sclerosis (ALS). In this work, we propose the use of diffusion tensor imaging (DTI) metrics to assess specific ultrastructural changes in the central nervous system during the early neurodegenerative stages of ALS.

Methods: Ultra-high field MRI and DTI data at 17.6T were obtained from fixed, excised mouse brains, and spinal cords from ALS (G93A-SOD1) mice.

Results: Changes in fractional anisotropy (FA) and linear, planar, and spherical anisotropy ratios (C, C, and C, respectively) of the diffusion eigenvalues were measured in white matter (WM) and gray matter (GM) areas associated with early axonal degenerative processes (in both the brain and the spinal cord). Specifically, in WM structures (corpus callosum, corticospinal tract, and spinal cord funiculi) as the disease progressed, FA, C, and C values decreased, whereas C values increased. In GM structures (prefrontal cortex, hippocampus, and central spinal cord) FA and C decreased, whereas the C and C values were unchanged or slightly smaller. Histological studies of a fluorescent mice model (YFP, G93A-SOD1 mouse) corroborated the early alterations in neuronal morphology and axonal connectivity measured by DTI.

Conclusions: Changes in diffusion tensor shape were observed in this animal model at the early, nonsymptomatic stages of ALS. Further studies of C, C, and C as imaging biomarkers should be undertaken to refine this neuroimaging tool for future clinical use in the detection of the early stages of ALS.
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http://dx.doi.org/10.1002/ame2.12112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323706PMC
June 2020

Multicomponent diffusion analysis reveals microstructural alterations in spinal cord of a mouse model of amyotrophic lateral sclerosis ex vivo.

PLoS One 2020 20;15(4):e0231598. Epub 2020 Apr 20.

Research Resource Center, University of Illinois at Chicago, Chicago, IL, United States of America.

The microstructure changes associated with degeneration of spinal axons in amyotrophic lateral sclerosis (ALS) may be reflected in altered water diffusion properties, potentially detectable with diffusion-weighted (DW) MRI. Prior work revealed the classical mono-exponential model fails to precisely depict decay in DW signal at high b-values. In this study, we aim to investigate signal decay behaviors at ultra-high b-values for non-invasive assessment of spinal cord alterations in the transgenic SOD1G93A mouse model of ALS. A multiexponential diffusion analysis using regularized non-negative least squares (rNNLS) algorithm was applied to a series of thirty DW MR images with b-values ranging from 0 to 858,022 s/mm2 on ex vivo spinal cords of transgenic SOD1G93A and age-matched control mice. We compared the distributions of measured diffusion coefficient fractions between the groups. The measured diffusion weighted signals in log-scale showed non-linear decay behaviors with increased b-values. Faster signal decays were observed with diffusion gradients applied parallel to the long axis of the spinal cord compared to when oriented in the transverse direction. Multiexponential analysis at the lumbar level in the spinal cord identified ten subintervals. A significant decrease of diffusion coefficient fractions was found in the ranges of [1.63×10-8,3.70×10-6] mm2/s (P = 0.0002) and of [6.01×10-6,4.20×10-5] mm2/s (P = 0.0388) in SOD1G93A mice. Anisotropic diffusion signals persisted at ultra-high b-value DWIs of the mouse spinal cord and multiexponential diffusion analysis offers the potential to evaluate microstructural alterations of ALS-affected spinal cord non-invasively.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231598PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170503PMC
July 2020

Editorial for "Evaluating the Therapeutic Effect of Low-Intensity Transcranial Ultrasound on Traumatic Brain Injury With Diffusion Kurtosis Imaging".

Authors:
Rodolfo G Gatto

J Magn Reson Imaging 2020 08 7;52(2):532-533. Epub 2020 Feb 7.

Department of Bioengineering, University of Illinois at Chicago, Chicago, Illinois, USA.

Level Of Evidence: 1 TECHNICAL EFFICACY STAGE: 4 J. Magn. Reson. Imaging 2020;52:532-533.
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http://dx.doi.org/10.1002/jmri.27082DOI Listing
August 2020

Diffusion Tensor Imaging in Preclinical and Human Studies of Huntington's Disease: What Have we Learned so Far?

Curr Med Imaging Rev 2019 ;15(6):521-542

Insituto de Fisiología Biologia Molecular y Neurociencias-IFIBYNE-CONICET, University of Buenos Aires, Buenos Aires, Argentina.

Background: Huntington's Disease is an irreversible neurodegenerative disease characterized by the progressive deterioration of specific brain nerve cells. The current evaluation of cellular and physiological events in patients with HD relies on the development of transgenic animal models. To explore such events in vivo, diffusion tensor imaging has been developed to examine the early macro and microstructural changes in brain tissue. However, the gap in diffusion tensor imaging findings between animal models and clinical studies and the lack of microstructural confirmation by histological methods has questioned the validity of this method.

Objective: This review explores white and grey matter ultrastructural changes associated to diffusion tensor imaging, as well as similarities and differences between preclinical and clinical Huntington's Disease studies.

Methods: A comprehensive review of the literature using online-resources was performed (Pub- Med search).

Results: Similar changes in fractional anisotropy as well as axial, radial and mean diffusivities were observed in white matter tracts across clinical and animal studies. However, comparative diffusion alterations in different grey matter structures were inconsistent between clinical and animal studies.

Conclusion: Diffusion tensor imaging can be related to specific structural anomalies in specific cellular populations. However, some differences between animal and clinical studies could derive from the contrasting neuroanatomy or connectivity across species. Such differences should be considered before generalizing preclinical results into the clinical practice. Moreover, current limitations of this technique to accurately represent complex multicellular events at the single micro scale are real. Future work applying complex diffusion models should be considered.
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http://dx.doi.org/10.2174/1573405614666181115113400DOI Listing
October 2020

Unveiling early cortical and subcortical neuronal degeneration in ALS mice by ultra-high field diffusion MRI.

Amyotroph Lateral Scler Frontotemporal Degener 2019 11 3;20(7-8):549-561. Epub 2019 Jun 3.

Department of Bioengineering, University of Illinois at Chicago , Chicago , IL , USA.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily characterized by the progressive impairment of motor functions. However, a significant portion of affected patients develops severe cognitive dysfunction, developing a widespread white (WM) and gray matter (GM) microstructural impairment. The objective of this study is to determine if Gaussian and non-Gaussian diffusion models gathered by ultra-high field diffusion MRI (UHFD-MRI) are an appropriate tool to detect early structural changes in brain white and gray matter in a preclinical model of ALS. ALS brains (G93A-SOD1mice) were scanned in a 16.7 T magnet. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) have shown presymptomatic decrease in axonal organization by Fractional Anisotropy (FA) and neurite content by Intracellular Volume Fraction (ICVF) across deep WM (corpus callosum) as well as superficial (cortex) and deep (hippocampus) GM. Additional diffusion kurtosis imaging (DKI) analysis demonstrated broader and earlier GM reductions in mean kurtosis (MK), possibly related to the decrease in neuronal complexity. Histological validation was obtained by an ALS fluorescent mice reporter (YFP, G93A-SOD1 mice). The combination of DTI, NODDI, and DKI models have proved to provide a more complete assessment of the early microstructural changes in the ALS brain, particularly in areas associated with high cognitive functions. This comprehensive approach should be considered as a valuable tool for the early detection of neuroimaging markers.
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http://dx.doi.org/10.1080/21678421.2019.1620285DOI Listing
November 2019

Detection of axonal degeneration in a mouse model of Huntington's disease: comparison between diffusion tensor imaging and anomalous diffusion metrics.

MAGMA 2019 Aug 15;32(4):461-471. Epub 2019 Feb 15.

Department of Bioengineering, University of Illinois at Chicago, 851 S Morgan St, 218 SEO (MC 063), Chicago, IL, 60607, USA.

Objective: The goal of this work is to study the changes in white matter integrity in R6/2, a well-established animal model of Huntington's disease (HD) that are captured by ex vivo diffusion imaging (DTI) using a high field MRI (17.6 T).

Materials And Methods: DTI and continuous time random walk (CTRW) models were used to fit changes in the diffusion-weighted signal intensity in the corpus callosum of controls and in R6/2 mice.

Results: A significant 13% decrease in fractional anisotropy, a 7% increase in axial diffusion, and a 33% increase in radial diffusion were observed between R6/2 and control mice. No change was observed in the CTRW beta parameter, but a significant decrease in the alpha parameter (- 21%) was measured. Histological analysis of the corpus callosum showed a decrease in axonal organization, myelin alterations, and astrogliosis. Electron microscopy studies demonstrated ultrastructural changes in degenerating axons, such as an increase in tortuosity in the R6/2 mice.

Conclusions: DTI and CTRW diffusion models display quantitative changes associated with the microstructural alterations observed in the corpus callosum of the R6/2 mice. The observed increase in the diffusivity and decrease in the alpha CTRW parameter providing support for the use of these diffusion models for non-invasive detection of white matter alterations in HD.
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http://dx.doi.org/10.1007/s10334-019-00742-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837609PMC
August 2019

Ultra-High Field Diffusion MRI Reveals Early Axonal Pathology in Spinal Cord of ALS mice.

Transl Neurodegener 2018 8;7:20. Epub 2018 Aug 8.

5Department of Bioengineering, University of Illinois at Chicago, Chicago, IL USA.

Background: Amyotrophic lateral sclerosis (ALS) is a disease characterized by a progressive degeneration of motor neurons leading to paralysis. Our previous MRI diffusion tensor imaging studies detected early white matter changes in the spinal cords of mice carrying the G93A-SOD1 mutation. Here, we extend those studies using ultra-high field MRI (17.6 T) and fluorescent microscopy to investigate the appearance of early structural and connectivity changes in the spinal cords of ALS mice.

Methods: The spinal cords from presymptomatic and symptomatic mice (80 to 120 days of age) were scanned (ex-vivo) using diffusion-weighted MRI. The fractional anisotropy (FA), axial (AD) and radial (RD) diffusivities were calculated for axial slices from the thoracic, cervical and lumbar regions of the spinal cords. The diffusion parameters were compared with fluorescence microscopy and membrane cellular markers from the same tissue regions.

Results: At early stages of the disease (day 80) in the lumbar region, we found, a 19% decrease in FA, a 9% decrease in AD and a 35% increase in RD. Similar changes were observed in cervical and thoracic spinal cord regions. Differences between control and ALS mice groups at the symptomatic stages (day 120) were larger. Quantitative fluorescence microscopy at 80 days, demonstrated a 22% reduction in axonal area and a 22% increase in axonal density. Tractography and quantitative connectome analyses measured by edge weights showed a 52% decrease in the lumbar regions of the spinal cords of this ALS mice group. A significant increase in ADC (23.3%) in the ALS mice group was related to an increase in aquaporin markers.

Conclusions: These findings suggest that the combination of ultra-high field diffusion MRI with fluorescent ALS mice reporters is a useful approach to detect and characterize presymptomatic white matter micro-ultrastructural changes and axonal connectivity anomalies in ALS.
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http://dx.doi.org/10.1186/s40035-018-0122-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097419PMC
August 2018

In vivo diffusion MRI detects early spinal cord axonal pathology in a mouse model of amyotrophic lateral sclerosis.

NMR Biomed 2018 08 26;31(8):e3954. Epub 2018 Jun 26.

University of Illinois at Chicago, Bioengineering, Chicago, IL, USA.

Diffusion magnetic resonance imaging (MRI) exhibits contrast that identifies macro- and microstructural changes in neurodegenerative diseases. Previous studies have shown that MR diffusion tensor imaging (DTI) can observe changes in spinal cord white matter in animals and humans affected with symptomatic amyotrophic lateral sclerosis (ALS). The goal of this preclinical work was to investigate the sensitivity of DTI for the detection of signs of tissue damage before symptoms appear. High-field MRI data were acquired using a 9.4-T animal scanner to examine the spinal cord of an ALS mouse model at pre- and post-symptomatic stages (days 80 and 120, respectively). The MRI results were validated using yellow fluorescent protein (YFP) via optical microscopy of spinal cord tissue slices collected from the YFP,G93A-SOD1 mouse strain. DTI maps of diffusion-weighted imaging (DWI) signal intensity, mean diffusivity (MD), fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) were computed for axial slices of the lumbar region of the spinal cord. Significant changes were observed in FA (6.7% decrease, p < 0.01), AD (19.5% decrease, p < 0.01) and RD (16.1% increase, p < 0.001) at postnatal day 80 (P80). These differences were correlated with changes in axonal fluorescence intensity and membrane cellular markers. This study demonstrates the value of DTI as a potential tool to detect the underlying pathological progression associated with ALS, and may accelerate the discovery of therapeutic strategies for patients with this disease.
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http://dx.doi.org/10.1002/nbm.3954DOI Listing
August 2018

Diffusion tensor imaging as a tool to detect presymptomatic axonal degeneration in a preclinical spinal cord model of amyotrophic lateral sclerosis.

Neural Regen Res 2018 Mar;13(3):425-426

Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA.

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http://dx.doi.org/10.4103/1673-5374.228723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900503PMC
March 2018

Diffusion tensor imaging identifies presymptomatic axonal degeneration in the spinal cord of ALS mice.

Brain Res 2018 01 23;1679:45-52. Epub 2017 Nov 23.

Department of Bioengineering, University of Illinois at Chicago, School of Engineering, Chicago, IL 60612, USA.

Extensive pathological evidence indicates that axonal degeneration represents an early and critical event in amyotrophic lateral sclerosis (ALS). Unfortunately, few MRI studies have focused in the early detection of white matter (WM) alterations in the spinal cord region. To unveil these WM changes, we performed high resolution diffusion tensor imaging (DTI) and correlated the results with histological analysis of adjacent slices taken from the spinal cords of presymptomatic mice. The DTI studies demonstrated a significant reduction in fractional anisotropy (FA) as well as axial diffusivities (AD) and an increase in radial diffusivity (RD), predominantly at lower segments of the spinal cord. Increases in FA and a reduction in AD and RD were observed in spinal cord (SC) gray matter (GM). Diffusion changes are associated with early and progressive alterations in axonal connectivity following a distal to proximal progression. Histological data tagging neuronal, axonal and glial cell markers demonstrated presymptomatic alterations in spinal cord WM and GM. This study demonstrates that DTI methods are optimal preclinical imaging tools to detect structural anomalies in WM and GM spinal cord during early stages of the disease.
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http://dx.doi.org/10.1016/j.brainres.2017.11.017DOI Listing
January 2018

ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation.

Sci Rep 2017 03 8;7(1):115. Epub 2017 Mar 8.

Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.

Mutations in Fused in Sarcoma/Translocated in Liposarcoma (FUS) cause familial forms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive axonal degeneration mainly affecting motor neurons. Evidence from transgenic mouse models suggests mutant forms of FUS exert an unknown gain-of-toxic function in motor neurons, but mechanisms underlying this effect remain unknown. Towards this end, we studied the effect of wild type FUS (FUS WT) and three ALS-linked variants (G230C, R521G and R495X) on fast axonal transport (FAT), a cellular process critical for appropriate maintenance of axonal connectivity. All ALS-FUS variants impaired anterograde and retrograde FAT in squid axoplasm, whereas FUS WT had no effect. Misfolding of mutant FUS is implicated in this process, as the molecular chaperone Hsp110 mitigated these toxic effects. Interestingly, mutant FUS-induced impairment of FAT in squid axoplasm and of axonal outgrowth in mammalian primary motor neurons involved aberrant activation of the p38 MAPK pathway, as also reported for ALS-linked forms of Cu, Zn superoxide dismutase (SOD1). Accordingly, increased levels of active p38 MAPK were detected in post-mortem human ALS-FUS brain tissues. These data provide evidence for a novel gain-of-toxic function for ALS-linked FUS involving p38 MAPK activation.
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http://dx.doi.org/10.1038/s41598-017-00091-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428330PMC
March 2017

Anti-edema effects of rhEpo in experimental traumatic brain injury.

Restor Neurol Neurosci 2015 ;33(6):927-41

Neuroscience Research, R&D, Jesse Brown VA Medical Center, Chicago, IL, USA.

Purpose: Traumatic brain injury (TBI) is one of the leading causes of disability and death which begins with the formation of edema as the persistent primary causative factor in TBI. Although medical management of cerebral edema by hypothermia, ventriculostomy, mannitol or hypertonic saline have been effective in treating edema, many of these therapies end up with some neurologic deficits, necessitating novel treatment options for treating post-TBI edema. This study investigated edema reducing effects of recombinant human Erythropoietin (rhEPO) in reducing acute brain edema in the CCI mouse model of TBI.

Methods: Anti-edema effects of rhEpo in reducing acute brain edema after injury in the CCI mouse model of TBI were assessed by T2 weighted magnetic resonance imaging (T2wMRI) as the accurate detector of brain edema in correlation with Western blot analysis of cerebral aquaporin 4 (AQP4) index as the critical marker of edema.

Results: Results show that rhEpo treatment significantly reduced brain edema with concomitant reduction in AQP4 immunoexpression in the CCI mouse model of TBI.

Conclusion: Current results emphasize clinical utility of rhEpo in treating post-TBI edema.
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http://dx.doi.org/10.3233/RNN-150577DOI Listing
August 2016

Analysis of YFP(J16)-R6/2 reporter mice and postmortem brains reveals early pathology and increased vulnerability of callosal axons in Huntington's disease.

Hum Mol Genet 2015 Sep 29;24(18):5285-98. Epub 2015 Jun 29.

Department of Anatomy and Cell Biology, University of Illinois at Chicago, 808 S. Wood St., Rm 578 M/C 512, Chicago, IL 60612, USA,

Cumulative evidence indicates that the onset and severity of Huntington's disease (HD) symptoms correlate with connectivity deficits involving specific neuronal populations within cortical and basal ganglia circuits. Brain imaging studies and pathological reports further associated these deficits with alterations in cerebral white matter structure and axonal pathology. However, whether axonopathy represents an early pathogenic event or an epiphenomenon in HD remains unknown, nor is clear the identity of specific neuronal populations affected. To directly evaluate early axonal abnormalities in the context of HD in vivo, we bred transgenic YFP(J16) with R6/2 mice, a widely used HD model. Diffusion tensor imaging and fluorescence microscopy studies revealed a marked degeneration of callosal axons long before the onset of motor symptoms. Accordingly, a significant fraction of YFP-positive cortical neurons in YFP(J16) mice cortex were identified as callosal projection neurons. Callosal axon pathology progressively worsened with age and was influenced by polyglutamine tract length in mutant huntingtin (mhtt). Degenerating axons were dissociated from microscopically visible mhtt aggregates and did not result from loss of cortical neurons. Interestingly, other axonal populations were mildly or not affected, suggesting differential vulnerability to mhtt toxicity. Validating these results, increased vulnerability of callosal axons was documented in the brains of HD patients. Observations here provide a structural basis for the alterations in cerebral white matter structure widely reported in HD patients. Collectively, our data demonstrate a dying-back pattern of degeneration for cortical projection neurons affected in HD, suggesting that axons represent an early and potentially critical target for mhtt toxicity.
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http://dx.doi.org/10.1093/hmg/ddv248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550824PMC
September 2015

Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase.

PLoS One 2013 12;8(6):e65235. Epub 2013 Jun 12.

Depart of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois, United States of America.

Dying-back degeneration of motor neuron axons represents an established feature of familial amyotrophic lateral sclerosis (FALS) associated with superoxide dismutase 1 (SOD1) mutations, but axon-autonomous effects of pathogenic SOD1 remained undefined. Characteristics of motor neurons affected in FALS include abnormal kinase activation, aberrant neurofilament phosphorylation, and fast axonal transport (FAT) deficits, but functional relationships among these pathogenic events were unclear. Experiments in isolated squid axoplasm reveal that FALS-related SOD1 mutant polypeptides inhibit FAT through a mechanism involving a p38 mitogen activated protein kinase pathway. Mutant SOD1 activated neuronal p38 in mouse spinal cord, neuroblastoma cells and squid axoplasm. Active p38 MAP kinase phosphorylated kinesin-1, and this phosphorylation event inhibited kinesin-1. Finally, vesicle motility assays revealed previously unrecognized, isoform-specific effects of p38 on FAT. Axon-autonomous activation of the p38 pathway represents a novel gain of toxic function for FALS-linked SOD1 proteins consistent with the dying-back pattern of neurodegeneration characteristic of ALS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065235PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680447PMC
January 2014

Restoration of cognitive deficits after statin feeding in TBI.

Restor Neurol Neurosci 2011 ;29(1):23-34

Neuroscience Research, Research & Development, Jesse Brown VA Medical Center Chicago, Chicago, IL 60612, USA.

Purpose: Traumatic brain injury (TBI) is a global health concern and growing socio-economic burden with limited treatment options. Behavioral assessment in experimental TBI with candidate therapeutic interventions is critical in order to expedite clinical translation. Statins constitute one of the potential treatment options based on their proven beneficial effects in various models of neurotrauma. We compared functional outcome after dietary intervention with representative hydrophilic Pravastatin or lipophilic Simvastatin and Lovastatin to test if different statins will differentially affect cognitive outcomes after injury in a controlled cortical impact injury (CCI) mouse model of TBI.

Methods: Mice were subjected to TBI with a controlled cortical impact produced on the left somatosensory-parietal cortex between bregma -1.82 and -2.06, fed with Simvastatin/Lovastatin/Pravastatin (2 mg/kg) for 8 weeks, evaluated for learning, memory and spontaneous exploration behavior followed by immunocytochemistry of an axonal marker.

Results: Results indicate that feeding of TBI mice with Simvastatin and Lovastatin significantly improved spatial learning and memory, restored spontaneous exploration and restored axonal integrity (Simvastatin > Lovastatin). On the other hand, Pravastatin failed to improve spatial learning or memory or exploration or axonal damage.

Conclusions: Current findings confirm maximum benefits rendered by Simvastatin and reinforce Simvastatin as the candidate therapy for treating TBI.
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http://dx.doi.org/10.3233/RNN-2011-0573DOI Listing
January 2012

A novel method for extracting respiration rate and relative tidal volume from infrared thermography.

Psychophysiology 2011 Jul 7;48(7):877-87. Epub 2011 Jan 7.

Department of Psychiatry, Brain-Body Center, University of Illinois at Chicago, Chicago, Illinois 60608, USA.

In psychophysiological research, measurement of respiration has been dependent on transducers having direct contact with the participant. The current study provides empirical data demonstrating that a noncontact technology, infrared video thermography, can accurately estimate breathing rate and relative tidal volume across a range of breathing patterns. Video tracking algorithms were applied to frame-by-frame thermal images of the face to extract time series of nostril temperature and to generate breath-by-breath measures of respiration rate and relative tidal volume. The thermal indices of respiration were contrasted with criterion measures collected with inductance plethysmography. The strong correlations observed between the technologies demonstrate the potential use of facial video thermography as a noncontact technology to monitor respiration.
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http://dx.doi.org/10.1111/j.1469-8986.2010.01167.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107393PMC
July 2011

Synergistic benefits of erythropoietin and simvastatin after traumatic brain injury.

Brain Res 2010 Nov 15;1360:177-92. Epub 2010 Sep 15.

Jesse Brown VA Medical Center, University of Illinois, Chicago, USA.

Simvastatin and recombinant human erythropoietin (rhEpo) are implicated as potential therapeutic candidates for traumatic brain injury (TBI). Prominent effects of simvastatin include its anti-inflammatory, neurotrophic and neuroregenerative actions studied in various models of neuronal injury. On the other hand, rhEpo has been shown to promote cell survival mechanisms by producing anti-apoptotic and cell proliferative actions. Beneficial effects of rhEpo and statin monotherapies have been well studied. However, there are no reports showing combined use of rhEpo and statins after TBI. This investigation examined if combined efficacy of cell proliferative ability of rhEpo along with the neuroregenerative ability of simvastatin will render maximum recovery in a controlled cortical impact (CCI) mouse model of TBI. Results showed that compared to baseline TBI, rhEpo was more effective than simvastatin in promoting cell proliferation while simvastatin was more effective than rhEpo in restoring axonal damage following TBI. Combined treatment with simvastatin and rhEpo maximally restored axonal integrity while simultaneously inducing greater proliferation of newly formed cells resulting in better functional recovery after TBI than either alone. This is the first study showing the efficacy of erythropoietin-simvastatin combinational therapeutic approach in achieving greater structural and cognitive recovery after TBI.
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http://dx.doi.org/10.1016/j.brainres.2010.09.010DOI Listing
November 2010

Neuroanatomical correlation of behavioral deficits in the CCI model of TBI.

J Neurosci Methods 2010 Jun 10;190(1):1-9. Epub 2010 Apr 10.

Research & Development, Jesse Brown VA Medical Center Chicago, IL 60612, USA.

Traumatic brain injury (TBI) is the leading cause of death and disability both in combat and civilian situations with limited treatment options including surgical removal of hematoma, ventricular drainage and use of hyperosmotic agents that restrict secondary injury following TBI. Availability of appropriate model system with full-range characterization of anatomical and behavioral components correlative with brain injury provides a pre-clinical platform to test candidate therapies for clinical translation. Modeling of TBI using controlled cortical impact injury (CCI) is largely considered to be close to clinical TBI and hence CCI models have been widely used in pre-clinical TBI research. Most studies reported so far using CCI models were presented with a limited behavioral characterization and lacked its correlation with the signature histopathology of TBI. Current investigation validated a detailed sensomotor and cognitive behavioral characterization correlative with diffuse axonal injury-the signature histopathology of TBI, in the CCI mouse model of TBI. Present study offers a comprehensively characterized model of TBI that can be used to investigate cellular and molecular mechanisms underlying TBI and to test candidate therapies in developing novel and effective treatments for TBI.
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http://dx.doi.org/10.1016/j.jneumeth.2010.04.004DOI Listing
June 2010

The utility of intraoperative blood flow measurement during aneurysm surgery using an ultrasonic perivascular flow probe.

Neurosurgery 2008 Jun;62(6 Suppl 3):1346-53

Department of Neurosurgery, University of Illinois at Chicago, Chicago, Illinois 60612-5970, USA.

Objective: Inadvertent vessel compromise is one major cause of unfavorable outcome from aneurysm surgery. Existing strategies for intraoperative assessment of this complication have potential limitations and disadvantages. We assessed the utility of quantitative intraoperative flow measurements using the Transonic ultrasonic flow probe (Transonic Systems, Inc., Ithaca, NY) during aneurysm surgery.

Methods: Of all aneurysms treated surgically at our institution from 1998 to 2003, 103 patients with 106 aneurysms were identified in whom intraoperative flow measurements were available for analysis. We assessed the frequency of flow compromise and clip repositioning and correlated these with postoperative angiography and stroke.

Results: Significant (>25%) reduction in flow rate was apparent in 33 (31.1%) cases, and resulted in clip repositioning in 27 (25.5%), with return to baseline flow except for two cases with vessel thrombosis/dissection. In the other six cases, flow reduction was owing to spasm resolving with papaverine (n = 3) or responded to retractor repositioning (n = 3). In another six (5.7%) cases, unnecessary clip repositioning was avoided (n = 3) or safe occlusion of the parent vessel for trapping of the aneurysm was allowed by confirming adequate distal flow (n = 3). Aneurysms of the basilar, middle cerebral, anterior communicating, or carotid terminus were more likely to be associated with flow compromise (odds ratio, 4.3; P = 0.03). Postoperative angiography corroborated vessel patency in all cases, and no unexpected large vessel occlusions or strokes were evident.

Conclusion: Use of the ultrasonic flow probe provides real-time immediate feedback concerning vessel patency. Vessel compromise is easier to interpret than with Doppler, and faster/less invasive than intraoperative angiography. Intraoperative flow measurement is a valuable adjunct for enhancing the safety of aneurysm surgery.
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http://dx.doi.org/10.1227/01.neu.0000333799.44338.19DOI Listing
June 2008

Age effects on brain oxygenation during hypercapnia.

J Biomed Opt 2007 Nov-Dec;12(6):062113

University of Illinois at Chicago, Department of Neurosurgery, Chicago, Illinois 60612, USA.

Previous studies showed that the cerebrovasodilation response to hypercapnia is attenuated with aging. The purpose of this study was to determine if normal aging attenuates increases in brain oxygenation during hypercapnia. Prefrontal cortex oxyhemoglobin (OHb) and deoxyhemoglobin (HHb) concentrations were measured in 13 healthy subjects ages 26 to 59 years using a frequency domain tissue oximeter. Measurements were obtained under the following conditions: (1) subject awake breathing spontaneously, (2) during mask ventilation with 21% oxygen, (3) mask ventilation with 100% oxygen, (4) 100% oxygen in a rebreathing circuit to increase end-tidal CO(2). Under baseline conditions breathing room air, there was a negative correlation between baseline OHb and age (r=-0.60, P<0.05). Ventilation with 100% oxygen increased OHb without a change in total hemoglobin and no affect of age. During mask rebreathing, end-tidal CO(2) increased from 39.5+/-5.0 mm Hg (millimeters of mercury) to 56.5+/-5.7 mm Hg, which produced significant increases in OHb and total blood volume that were negatively correlated with age (r=-0.67, P<0.05) and positively correlated to baseline OHb (r=0.60, P<0.05). These results indicate that OHb concentrations decreased with age, consistent with attenuated cerebral vasodilation during hypercapnia.
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http://dx.doi.org/10.1117/1.2804705DOI Listing
March 2008

Effect of age on brain oxygenation regulation during changes in position.

J Neurosci Methods 2007 Aug 5;164(2):308-11. Epub 2007 May 5.

Department of Neurosurgery, University of Illinois at Chicago, 912 South Wood Street 4th FL, NPI building, Chicago, IL 60612, USA.

Introduction: Reports indicate that brain regulation of oxygenation is inhibited in patients with low baseline oxyhemoglobin concentrations and that brain oxyhemoglobin concentrations are decreased with aging. The purpose of this study was to determine if regulation of brain oxygenation to changes in blood pressure is inhibited by normal aging.

Methods: Brain oxyhemoglobin (OHb) and deoxyhemoglobin (HHb) concentrations were determined from the forehead using a frequency domain near infrared spectroscopy in 27 healthy volunteers. Subjects were separated into two groups by age (20-39, n=16; 40-60, n=11). Brain hemoglobin and non-invasive blood pressure were measured in (1) supine, (2) sitting, (3) supine and (4) sitting positions with 10-min equilibration intervals between each determination. Statistical differences were determined by two way repeated measures analysis of variance.

Results: Young subjects were 28+/-5 years (mean+/-S.D.) and older subjects were 48+/-6 years. In supine position, OHb and HHb were 28.4+/-8.3 and 15.4+/-2.4micromol/L, respectively, in young; 22.4+/-5.7 and 13.4+/-2.9micromol/L, respectively, in older subjects, both P<0.05 between groups. Changing position from supine to sitting decreased OHb 5% and increased HHb 5% with no difference between groups.

Conclusions: There was a small but significant decrease in OHb and an increase in HHb from supine to sitting position, and this effect was similar between young and older subjects. Regulation of brain oxygenation during modest decreases in blood pressure did not change in normal aging to 60 years compared to young adults.
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http://dx.doi.org/10.1016/j.jneumeth.2007.04.020DOI Listing
August 2007

Frequency domain near-infrared spectroscopy technique in the assessment of brain oxygenation: a validation study in live subjects and cadavers.

J Neurosci Methods 2006 Oct 24;157(2):274-7. Epub 2006 May 24.

Department of Neurosurgery, University of Illinois at Chicago, Chicago, IL 60612, USA.

Background: Studies with continuous wave near infrared spectroscopy (CW-NIRS) have shown little difference in brain oxygenation of dead compared to live subjects. We determined brain oxyhemoglobin (OHb) and deoxyhemoglobin (HHb) concentrations in healthy volunteers and cadavers using frequency domain near infrared spectroscopy (FD-NIRS).

Methods: Regional OHb and HHb, brain oxygen saturation (SO2), and total hemoglobin (tHb) were determined. Nine patients who died in the hospital were evaluated by FD-NIRS in the morgue 7-96 h after death was confirmed. Ten volunteers served as a control group.

Results: Absolute concentrations of brain tissue OHb and HHb were 24.9 +/- 9.1 uM and 13.8 +/- 32 uM, respectively, in live subjects. In dead subjects, OHb was 1.3 +/- 2.1 uM and HHb was 30.8 +/- 14.4 uM (both P < 0.05 compared to live). OHb showed a 90% decrease within 7h of death. There was a significant trend for a continued decrease in OHb from 7 to 96 h.

Conclusion: OHb decreased and HHb increased in dead patients compared to live volunteers. Depletion of OHb primarily occurred within 7 h of death but continued gradually over 96 h. FD-NIRS was a novel technique for determining OHb and HHb changes following death.
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http://dx.doi.org/10.1016/j.jneumeth.2006.04.013DOI Listing
October 2006

The utility of intraoperative blood flow measurement during aneurysm surgery using an ultrasonic perivascular flow probe.

Neurosurgery 2006 Apr;58(4 Suppl 2):ONS-305-12; discussion ONS-312

Neuropsychiatric Institute (MC 799), Department of Neurosurgery, University of Illinois at Chicago, Chicago, Illinois 60612-5970, USA.

Objective: Inadvertent vessel compromise is one major cause of unfavorable outcome from aneurysm surgery. Existing strategies for intraoperative assessment of this complication have potential limitations and disadvantages. We assessed the utility of quantitative intraoperative flow measurements using the Transonic ultrasonic flow probe (Transonic Systems, Inc., Ithaca, NY) during aneurysm surgery.

Methods: Of all aneurysms treated surgically at our institution from 1998 to 2003, 103 patients with 106 aneurysms were identified in whom intraoperative flow measurements were available for analysis. We assessed the frequency of flow compromise and clip repositioning and correlated these with postoperative angiography and stroke.

Results: Significant (>25%) reduction in flow rate was apparent in 33 (31.1%) cases, and resulted in clip repositioning in 27 (25.5%), with return to baseline flow except for two cases with vessel thrombosis/dissection. In the other six cases, flow reduction was owing to spasm resolving with papaverine (n = 3) or responded to retractor repositioning (n = 3). In another six (5.7%) cases, unnecessary clip repositioning was avoided (n = 3) or safe occlusion of the parent vessel for trapping of the aneurysm was allowed by confirming adequate distal flow (n = 3). Aneurysms of the basilar, middle cerebral, anterior communicating, or carotid terminus were more likely to be associated with flow compromise (odds ratio, 4.3; P = 0.03). Postoperative angiography corroborated vessel patency in all cases, and no unexpected large vessel occlusions or strokes were evident.

Conclusion: Use of the ultrasonic flow probe provides real-time immediate feedback concerning vessel patency. Vessel compromise is easier to interpret than with Doppler, and faster/less invasive than intraoperative angiography. Intraoperative flow measurement is a valuable adjunct for enhancing the safety of aneurysm surgery.
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http://dx.doi.org/10.1227/01.NEU.0000209339.47929.34DOI Listing
April 2006