scholarly journals Disruption of orbitofrontal-hypothalamic projections in a murine ALS model and in human patients

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
David Bayer ◽  
Stefano Antonucci ◽  
Hans-Peter Müller ◽  
Rami Saad ◽  
Luc Dupuis ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Mouse Model ◽  
Lateral Hypothalamus ◽  
Large Scale ◽  
Energy Homeostasis ◽  
Diffusion Tensor ◽  
Metabolic Dysfunction ◽  
Projection Mapping ◽  
Magnetic Resonance Imaging Mri ◽  
Als Patients

Abstract Background Increased catabolism has recently been recognized as a clinical manifestation of amyotrophic lateral sclerosis (ALS). The hypothalamic systems have been shown to be involved in the metabolic dysfunction in ALS, but the exact extent of hypothalamic circuit alterations in ALS is yet to be determined. Here we explored the integrity of large-scale cortico-hypothalamic circuits involved in energy homeostasis in murine models and in ALS patients. Methods The rAAV2-based large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik software suites were used to identify and quantify projections from the forebrain to the lateral hypothalamus in the SOD1(G93A) ALS mouse model (hypermetabolic) and the FusΔNLS ALS mouse model (normo-metabolic). 3 T diffusion tensor imaging (DTI)-magnetic resonance imaging (MRI) was performed on 83 ALS and 65 control cases to investigate cortical projections to the lateral hypothalamus (LHA) in ALS. Results Symptomatic SOD1(G93A) mice displayed an expansion of projections from agranular insula, ventrolateral orbitofrontal and secondary motor cortex to the LHA. These findings were reproduced in an independent cohort by using a different analytic approach. In contrast, in the FusΔNLS ALS mouse model hypothalamic inputs from insula and orbitofrontal cortex were maintained while the projections from motor cortex were lost. The DTI-MRI data confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients. Conclusion This study provides converging murine and human data demonstrating the selective structural disruption of hypothalamic inputs in ALS as a promising factor contributing to the origin of the hypermetabolic phenotype.

scholarly journals Orbitofrontal-hypothalamic projections are disrupted in hypermetabolic murine ALS model and human patients

2020 ◽  
Author(s):  
David Bayer ◽  
Stefano Antonucci ◽  
Hans-Peter Müller ◽  
Luc Dupuis ◽  
Tobias Boeckers ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Cortex ◽  
Mouse Model ◽  
Lateral Hypothalamus ◽  
Large Scale ◽  
Energy Homeostasis ◽  
Metabolic Phenotype ◽  
Metabolic Disturbances ◽  
Als Patients ◽  
Lateral Sclerosis

AbstractIncreased catabolism is a new clinical manifestation of Amyotrophic Lateral Sclerosis. A dysfunction of lateral hypothalamus may drive hypermetabolism in ALS; however, Its causes and anatomical substrates are unknown. We hypothesize that disruption cortico-hypothalamic circuits may impair energy homeostasis in ALS. We used rAAV2 for large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik to quantify projections from the forebrain to the latera hypothalamus of the SOD1(G93A) ALS mouse model as well as of the FusΔNLS ALS mouse model. Expanded projections from agranular Insula, ventrolateral orbitofrontal and secondary motor cortex to lateral hypothalamus were found in two independent cohorts of the hypermetabolic SOD1(G93A) ALS model. The non-hypermetabolic FusΔNLS ALS mouse model display a loss of projections from motor cortex but no change in projections from insula and orbitofronal cortex. 3T DTI-MRI data on 83 ALS patients and 65 controls confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients. Converging murine and human data demonstrate the selective disruption of hypothalamic inputs in ALS as a factor contributing to the origin of hypermetabolism.Significance statementWe provide a circuit perspective of the recently identified and medically relevant hyper-metabolic phenotype of Amyotrophic Lateral Sclerosis. We demonstrate the selective involvement of orbitofrontal, insular and motor cortex projections to hypothalamus in murine ALS models and in human patients. The enhanced pipeline for large-scale registration, segmentation projections mapping, the identification of new circuits target of neurodegeneration, and the relevance of these circuits in metabolic disturbances make this work relevant not only for the investigation of ALS but also for other neurodegenerative disease as well as for all conditions characterized by systemic energy imbalances.

scholarly journals Imaging Neurochemistry and Brain Structure Tracks Clinical Decline and Mechanisms of ALS in Patients

2020 ◽  
Vol 11 ◽  
Author(s):  
Ovidiu C. Andronesi ◽  
Katharine Nicholson ◽  
Kourosh Jafari-Khouzani ◽  
Wolfgang Bogner ◽  
Jing Wang ◽  
...  
Keyword(s):  
White Matter ◽  
Motor Cortex ◽  
Corticospinal Tract ◽  
Rating Scale ◽  
Diffusion Tensor ◽  
Structural Parameters ◽  
Imaging Biomarkers ◽  
Imaging Protocol ◽  
Time Motion ◽  
Als Patients

Background: Oxidative stress and protein aggregation are key mechanisms in amyotrophic lateral sclerosis (ALS) disease. Reduced glutathione (GSH) is the most important intracellular antioxidant that protects neurons from reactive oxygen species. We hypothesized that levels of GSH measured by MR spectroscopic imaging (MRSI) in the motor cortex and corticospinal tract are linked to clinical trajectory of ALS patients.Objectives: Investigate the value of GSH imaging to probe clinical decline of ALS patients in combination with other neurochemical and structural parameters.Methods: Twenty-four ALS patients were imaged at 3 T with an advanced MR protocol. Mapping GSH levels in the brain is challenging, and for this purpose, we used an optimized spectral-edited 3D MRSI sequence with real-time motion and field correction to image glutathione and other brain metabolites. In addition, our imaging protocol included (i) an adiabatic T1ρ sequence to image macromolecular fraction of brain parenchyma, (ii) diffusion tensor imaging (DTI) for white matter tractography, and (iii) high-resolution anatomical imaging.Results: We found GSH in motor cortex (r = −0.431, p = 0.04) and corticospinal tract (r = −0.497, p = 0.016) inversely correlated with time between diagnosis and imaging. N-Acetyl-aspartate (NAA) in motor cortex inversely correlated (r = −0.416, p = 0.049), while mean water diffusivity (r = 0.437, p = 0.033) and T1ρ (r = 0.482, p = 0.019) positively correlated with disease progression measured by imputed change in revised ALS Functional Rating Scale. There is more decrease in the motor cortex than in the white matter for GSH compared to NAA, glutamate, and glutamine.Conclusions: Our study suggests that a panel of biochemical and structural imaging biomarkers defines a brain endophenotype, which can be used to time biological events and clinical progression in ALS patients. Such a quantitative brain endophenotype may stratify ALS patients into more homogeneous groups for therapeutic interventions compared to clinical criteria.

scholarly journals Stage-dependent remodeling of projections to motor cortex in ALS mouse model revealed by a new variant retrograde-AAV9

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Barbara Commisso ◽  
Lingjun Ding ◽  
Karl Varadi ◽  
Martin Gorges ◽  
David Bayer ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Mouse Model ◽  
Primary Motor Cortex ◽  
Structural Basis ◽  
Progressive Degeneration ◽  
New Variant ◽  
Als Patients ◽  
The Brain ◽  
Pathogenic Process ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motoneurons in the primary motor cortex (pMO) and in spinal cord. However, the pathogenic process involves multiple subnetworks in the brain and functional MRI studies demonstrate an increase in functional connectivity in areas connected to pMO despite the ongoing neurodegeneration. The extent and the structural basis of the motor subnetwork remodeling in experimentally tractable models remain unclear. We have developed a new retrograde AAV9 to quantitatively map the projections to pMO in the SOD1(G93A) ALS mouse model. We show an increase in the number of neurons projecting from somatosensory cortex to pMO at presymptomatic stages, followed by an increase in projections from thalamus, auditory cortex and contralateral MO (inputs from 20 other structures remains unchanged) as disease advances. The stage- and structure-dependent remodeling of projection to pMO in ALS may provide insights into the hyperconnectivity observed in ALS patients.

scholarly journals Improvement of Gait Dysfunction after Applying a Hinged Ankle–Foot Orthosis in a Hemiplegic Cerebral Palsy Patient with Disrupted Medial Lemniscus: A Case Report

Children ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. 81
Author(s):  
Su Min Son ◽  
Min Cheol Chang
Keyword(s):  
Knee Flexion ◽  
Diffusion Tensor ◽  
Therapeutic Option ◽  
Gait Pattern ◽  
Ankle Dorsiflexion ◽  
Medial Lemniscus ◽  
Abnormal Gait ◽  
Hemiplegic Cerebral Palsy ◽  
Genu Recurvatum ◽  
Magnetic Resonance Imaging Mri

We describe the successful application of hinged ankle−foot orthoses (AFOs) in a cerebral palsied (CP) patient with gait instability due to a disrupted medial lemniscus (ML). The patient was a 27-month-old male CP child with gait instability who presented with reduced knee flexion and ankle dorsiflexion, with severe genu recurvatum on his right lower extremity during gait. The patient had no motor weakness or spasticity. Conventional magnetic resonance imaging (MRI) revealed no definite abnormal lesion. However, diffusion tensor tractography (DTT) showed disruption of the left ML, consistent with right hemiplegic symptoms. The integrity of the major motor-related neural tracts, including the corticospinal and corticoreticulospinal tracts, was preserved. We considered that the patient’s abnormal gait pattern was related to the disrupted ML state. We applied hinged AFOs, which immediately resulted in a significantly stabilized gait. The angles of knee flexion and ankle dorsiflexion increased. Our findings indicate that the application of hinged AFOs could be a useful therapeutic option for CP patients with gait instability related to ML disruption. In addition, we showed that DTT is a useful tool for identifying the causative brain pathology in CP patients, especially when conventional brain MRIs show no specific lesion.

scholarly journals Neuroimaging, Urinary, and Plasma Biomarkers of Treatment Response in Huntington’s Disease: Preclinical Evidence with the p75NTR Ligand LM11A-31

2021 ◽  
Author(s):  
Danielle A. Simmons ◽  
Brian D. Mills ◽  
Robert R. Butler III ◽  
Jason Kuan ◽  
Tyne L. M. McHugh ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Treatment Response ◽  
Diffusion Tensor ◽  
Disease Onset ◽  
Therapeutic Effects ◽  
Plasma Cytokine ◽  
Cytokine Levels ◽  
Pharmacodynamic Biomarkers

AbstractHuntington’s disease (HD) is caused by an expansion of the CAG repeat in the huntingtin gene leading to preferential neurodegeneration of the striatum. Disease-modifying treatments are not yet available to HD patients and their development would be facilitated by translatable pharmacodynamic biomarkers. Multi-modal magnetic resonance imaging (MRI) and plasma cytokines have been suggested as disease onset/progression biomarkers, but their ability to detect treatment efficacy is understudied. This study used the R6/2 mouse model of HD to assess if structural neuroimaging and biofluid assays can detect treatment response using as a prototype the small molecule p75NTR ligand LM11A-31, shown previously to reduce HD phenotypes in these mice. LM11A-31 alleviated volume reductions in multiple brain regions, including striatum, of vehicle-treated R6/2 mice relative to wild-types (WTs), as assessed with in vivo MRI. LM11A-31 also normalized changes in diffusion tensor imaging (DTI) metrics and diminished increases in certain plasma cytokine levels, including tumor necrosis factor-alpha and interleukin-6, in R6/2 mice. Finally, R6/2-vehicle mice had increased urinary levels of the p75NTR extracellular domain (ecd), a cleavage product released with pro-apoptotic ligand binding that detects the progression of other neurodegenerative diseases; LM11A-31 reduced this increase. These results are the first to show that urinary p75NTR-ecd levels are elevated in an HD mouse model and can be used to detect therapeutic effects. These data also indicate that multi-modal MRI and plasma cytokine levels may be effective pharmacodynamic biomarkers and that using combinations of these markers would be a viable and powerful option for clinical trials.

scholarly journals Multi-modal magnetic resonance imaging in a mouse model of concussion

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Xuan Vinh To ◽  
Fatima A. Nasrallah
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Data Collection ◽  
Mouse Model ◽  
Meta Analysis ◽  
Data Repository ◽  
Resonance Imaging ◽  
Loss Of Righting Reflex ◽  
Post Impact ◽  
Magnetic Resonance Imaging Mri

AbstractThis data collection contains Magnetic Resonance Imaging (MRI) data, including structural, diffusion, stimulus-evoked, and resting-state functional MRI and behavioural assessment results, including acute post-impact Loss-of-Righting Reflex time and acute, subacute, and longer-term Neural Severity Score, and Open Field Behaviour obtained from a mouse model of concussion. Four cohorts with 43 3–4 months old male mice in total were used: Sham (n = 14, n = 6 day 2, n = 3 day 7, n = 5 day 14), concussion day 2 (CON 2; n = 9), concussion day 7 (CON 7; n = 10), concussion day 14 (CON 14; n = 10). The data collection contains the aforementioned MRI data in compressed NIFTI format, data sheets on animal’s backgrounds and behavioural outcomes and is made publicly available from a data repository. The available data are intended to facility cross-study comparisons, meta-analysis, and science reproducibility.

scholarly journals Identifying a Common Functional Framework for Apathy Large-Scale Brain Network

2021 ◽  
Vol 11 (7) ◽  
pp. 679
Author(s):  
Vincenzo Alfano ◽  
Mariachiara Longarzo ◽  
Giulia Mele ◽  
Marcello Esposito ◽  
Marco Aiello ◽  
...  
Keyword(s):  
Large Scale ◽  
Brain Magnetic Resonance Imaging ◽  
Brain Network ◽  
Neural Pathways ◽  
Resonance Imaging ◽  
Daily Life Activities ◽  
Functional Differences ◽  
Central Gyrus ◽  
Magnetic Resonance Imaging Mri ◽  
Disease Specific

Apathy is a neuropsychiatric condition characterized by reduced motivation, initiative, and interest in daily life activities, and it is commonly reported in several neurodegenerative disorders. The study aims to investigate large-scale brain networks involved in apathy syndrome in patients with frontotemporal dementia (FTD) and Parkinson’s disease (PD) compared to a group of healthy controls (HC). The study sample includes a total of 60 subjects: 20 apathetic FTD and PD patients, 20 non apathetic FTD and PD patients, and 20 HC matched for age. Two disease-specific apathy-evaluation scales were used to measure the presence of apathy in FTD and PD patients; in the same day, a 3T brain magnetic resonance imaging (MRI) with structural and resting-state functional (fMRI) sequences was acquired. Differences in functional connectivity (FC) were assessed between apathetic and non-apathetic patients with and without primary clinical diagnosis revealed, using a whole-brain, seed-to-seed approach. A significant hypoconnectivity between apathetic patients (both FTD and PD) and HC was detected between left planum polare and both right pre- or post-central gyrus. Finally, to investigate whether such neural alterations were due to the underlying neurodegenerative pathology, we replicated the analysis by considering two independent patients’ samples (i.e., non-apathetic PD and FTD). In these groups, functional differences were no longer detected. These alterations may subtend the involvement of neural pathways implicated in a specific reduction of information/elaboration processing and motor outcome in apathetic patients.

scholarly journals Meyer’s Loop Anatomy Demonstrated Using Diffusion Tensor MR Imaging and Fiber Tractography at 3T

2014 ◽  
Vol 60 (5) ◽  
pp. 215-222 ◽  
Author(s):  
Cristina Goga ◽  
Zeynep Firat ◽  
Klara Brinzaniuc ◽  
Is Florian
Keyword(s):  
Diffusion Tensor Imaging ◽  
Diffusion Tensor ◽  
Region Of Interest ◽  
Fiber Tractography ◽  
Brain Images ◽  
3 Dimensional ◽  
Software Release ◽  
Magnetic Resonance Imaging Mri ◽  
Meyer’S Loop

Abstract Objective: The ultimate anatomy of the Meyer’s loop continues to elude us. Diffusion tensor imaging (DTI) and diffusion tensor tractography (DTT) may be able to demonstrate, in vivo, the anatomy of the complex network of white matter fibers surrounding the Meyer’s loop and the optic radiations. This study aims at exploring the anatomy of the Meyer’s loop by using DTI and fiber tractography. Methods: Ten healthy subjects underwent magnetic resonance imaging (MRI) with DTI at 3 T. Using a region-of-interest (ROI) based diffusion tensor imaging and fiber tracking software (Release 2.6, Achieva, Philips), sequential ROI were placed to reconstruct visual fibers and neighboring projection fibers involved in the formation of Meyer’s loop. The 3-dimensional (3D) reconstructed fibers were visualized by superimposition on 3-planar MRI brain images to enhance their precise anatomical localization and relationship with other anatomical structures. Results: Several projection fiber including the optic radiation, occipitopontine/parietopontine fibers and posterior thalamic peduncle participated in the formation of Meyer’s loop. Two patterns of angulation of the Meyer’s loop were found. Conclusions: DTI with DTT provides a complimentary, in vivo, method to study the details of the anatomy of the Meyer’s loop.

scholarly journals Demyelination and remyelination detected in an alternative cuprizone mouse model of multiple sclerosis with 7.0 T multiparameter magnetic resonance imaging

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shuang Ding ◽  
Yu Guo ◽  
Xiaoya Chen ◽  
Silin Du ◽  
Yongliang Han ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Multiple Sclerosis ◽  
Magnetic Resonance ◽  
Mouse Model ◽  
Diffusion Tensor ◽  
Mean Diffusivity ◽  
Blue Staining ◽  
Resonance Imaging ◽  
The Mean ◽  
Underlying Mechanisms

AbstractThe aim of this study was to investigate the mechanisms underlying demyelination and remyelination with 7.0 T multiparameter magnetic resonance imaging (MRI) in an alternative cuprizone (CPZ) mouse model of multiple sclerosis (MS). Sixty mice were divided into six groups (n = 10, each), and these groups were imaged with 7.0 T multiparameter MRI and treated with an alternative CPZ administration schedule. T2-weighted imaging (T2WI), susceptibility-weighted imaging (SWI), and diffusion tensor imaging (DTI) were used to compare the splenium of the corpus callosum (sCC) among the groups. Prussian blue and Luxol fast blue staining were performed to assess pathology. The correlations of the mean grayscale value (mGSV) of the pathology results and the MRI metrics were analyzed to evaluate the multiparameter MRI results. One-way ANOVA and post hoc comparison showed that the normalized T2WI (T2-nor), fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) values were significantly different among the six groups, while the mean phase (Φ) value of SWI was not significantly different among the groups. Correlation analysis showed that the correlation between the T2-nor and mGSV was higher than that among the other values. The correlations among the FA, RD, MD, and mGSV remained instructive. In conclusion, ultrahigh-field multiparameter MRI can reflect the pathological changes associated with and the underlying mechanisms of demyelination and remyelination in MS after the successful establishment of an acute CPZ-induced model.

scholarly journals In vivo genome editing in mouse restores dystrophin expression in Duchenne muscular dystrophy patient muscle fibers

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Menglong Chen ◽  
Hui Shi ◽  
Shixue Gou ◽  
Xiaomin Wang ◽  
Lei Li ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Model ◽  
Genome Editing ◽  
Large Scale ◽  
Gene Editing ◽  
High Efficiency ◽  
Muscle Fibers ◽  
Muscle Cells

Abstract Background Mutations in the DMD gene encoding dystrophin—a critical structural element in muscle cells—cause Duchenne muscular dystrophy (DMD), which is the most common fatal genetic disease. Clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene editing is a promising strategy for permanently curing DMD. Methods In this study, we developed a novel strategy for reframing DMD mutations via CRISPR-mediated large-scale excision of exons 46–54. We compared this approach with other DMD rescue strategies by using DMD patient-derived primary muscle-derived stem cells (DMD-MDSCs). Furthermore, a patient-derived xenograft (PDX) DMD mouse model was established by transplanting DMD-MDSCs into immunodeficient mice. CRISPR gene editing components were intramuscularly delivered into the mouse model by adeno-associated virus vectors. Results Results demonstrated that the large-scale excision of mutant DMD exons showed high efficiency in restoring dystrophin protein expression. We also confirmed that CRISPR from Prevotella and Francisella 1(Cas12a)-mediated genome editing could correct DMD mutation with the same efficiency as CRISPR-associated protein 9 (Cas9). In addition, more than 10% human DMD muscle fibers expressed dystrophin in the PDX DMD mouse model after treated by the large-scale excision strategies. The restored dystrophin in vivo was functional as demonstrated by the expression of the dystrophin glycoprotein complex member β-dystroglycan. Conclusions We demonstrated that the clinically relevant CRISPR/Cas9 could restore dystrophin in human muscle cells in vivo in the PDX DMD mouse model. This study demonstrated an approach for the application of gene therapy to other genetic diseases.

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