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

bjective: Cell structural changes are one of the main features observed during the development of amyotrophic lateral sclerosis (ALS). In this work, we propose the useof 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 (CL, CP, and CS, 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, CL, and CP values decreased, whereas CS values increased.In GM structures (prefrontal cortex, hippocampus, and central spinal cord) FA and CP decreased, whereas the CL a nd 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 CL, CP, and CSas imaging biomarkers should be undertaken to refine this neuroimaging tool for future clinical use in the detection of the early stages of ALSFil: Gatto, Rodolfo G.. University Of Illinois. Deparment Of Biological Science; Estados UnidosFil: Weissmann, Carina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Amin, Manish. University of Florida; Estados UnidosFil: Finkielsztein, Ariel. Northwestern University; Estados UnidosFil: Sumagin, Ronen. Northwestern University; Estados UnidosFil: Mareci, Thomas H.. University of Florida; Estados UnidosFil: Uchitel, Osvaldo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Magin, Richard L.. University Of Illinois. Deparment Of Biological Science; Estados Unido

Evaluation of Early Microstructural Changes in the R6/1 Mouse Model of Huntington's Disease by Ultra-High Field Diffusion MR Imaging

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.Fil: Segatto, Rodolfo Guillermo. University Of Illinois. Deparment Of Biological Science; Estados UnidosFil: Weissmann, Carina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Amin, Manish. University of Florida. Department of Microbiology and Cell Science; Estados UnidosFil: Angeles López, Quetzalli D.. Consejo Nacional de Ciencia y Tecnologia de Mexico. Centro de Investigacion Cientifica y de Educacion Superior de Ensenada Baja California.; MéxicoFil: García Lara, Lucia. Consejo Nacional de Ciencia y Tecnologia de Mexico. Centro de Investigacion Cientifica y de Educacion Superior de Ensenada Baja California.; MéxicoFil: Salinas Castellanos, Libia Catalina. Consejo Nacional de Ciencia y Tecnologia de Mexico. Centro de Investigacion Cientifica y de Educacion Superior de Ensenada Baja California.; MéxicoFil: Deyoung, Daniel. University of Florida. Department of Microbiology and Cell Science; Estados UnidosFil: Segovia, Jose Manuel. Consejo Nacional de Ciencia y Tecnologia de Mexico. Centro de Investigacion Cientifica y de Educacion Superior de Ensenada Baja California.; MéxicoFil: Mareci, Thomas H.. University of Florida. Department of Microbiology and Cell Science; Estados UnidosFil: Uchitel, Osvaldo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Magin, Richard L.. University Of Illinois. Deparment Of Biological Science; Estados Unido

Better Brain and Cognition Prior to Surgery Is Associated With Elevated Postoperative Brain Extracellular Free-Water in Older Adults

For adults age 65 and older, the brain shows acute functional connectivity decreases after total knee arthroplasty with the severity of change predicted by preoperative cognitive function and brain disease burden. The extent of acute structural microstructural brain changes acutely after surgery remains unknown within the literature. For the current study, we report on the severity of acute post-surgery microstructural brain changes as measured by diffusion imaging and free-water analysis. Participants who underwent total knee arthroplasty under general anesthesia and non-surgery peers were part of a federally funded prospective cohort investigation involving participants. Recruitment occurred between 2013 and 2017. Data were collected in outpatient and inpatient settings within a university-affiliated medical center. A total of 232 TKA patients were referred by the study surgeon and contacted for study inclusion. Of these, 78 met inclusion and exclusion criteria and completed assessment. Five participants were excluded due to anesthetic protocol changes (spinal instead of general) with an additional 12 excluded for imaging-related complications. The total included sample size was 61. A total of 127 non-surgery participants were screened with 66 enrolled. One non-surgery participant was excluded for an imaging-related complication. Total knee arthroplasty and general anesthetic protocols were standardized. Participants received preoperative neurocognitive assessment and brain magnetic resonance imaging, with repeat imaging 48 h after surgery or pseudo surgery. Free-water analyses were performed using diffusion weighted images and tract-based spatial statistics with baseline cognitive data used to predict free-water changes. Surgery participants had widespread increases in white matter free-water. Surgery participants with higher cognitive functions as measured by immediate memory and less evidence of brain atrophy and disease (i.e., brain integrity) had greater free-water increase. Non-surgery peers had no free-water change. We interpret the surgery group’s free-water change as indicating widespread brain white matter glial response, with greater change indicative of better brain response to the acute surgery/anesthesia experience

Across‐vendor standardization of semi‐LASER for single‐voxel MRS at 3T

The semi‐adiabatic localization by adiabatic selective refocusing (sLASER) sequence provides single‐shot full intensity signal with clean localization and minimal chemical shift displacement error and was recommended by the international MRS Consensus Group as the preferred localization sequence at high‐ and ultra‐high fields. Across‐vendor standardization of the sLASER sequence at 3 tesla has been challenging due to the B1 requirements of the adiabatic inversion pulses and maximum B1 limitations on some platforms. The aims of this study were to design a short‐echo sLASER sequence that can be executed within a B1 limit of 15 μT by taking advantage of gradient‐modulated RF pulses, to implement it on three major platforms and to evaluate the between‐vendor reproducibility of its perfomance with phantoms and in vivo. In addition, voxel‐based first and second order B0 shimming and voxel‐based B1 adjustments of RF pulses were implemented on all platforms. Amongst the gradient‐modulated pulses considered (GOIA, FOCI and BASSI), GOIA‐WURST was identified as the optimal refocusing pulse that provides good voxel selection within a maximum B1 of 15 μT based on localization efficiency, contamination error and ripple artifacts of the inversion profile. An sLASER sequence (30 ms echo time) that incorporates VAPOR water suppression and 3D outer volume suppression was implemented with identical parameters (RF pulse type and duration, spoiler gradients and inter‐pulse delays) on GE, Philips and Siemens and generated identical spectra on the GE ‘Braino’ phantom between vendors. High‐quality spectra were consistently obtained in multiple regions (cerebellar white matter, hippocampus, pons, posterior cingulate cortex and putamen) in the human brain across vendors (5 subjects scanned per vendor per region; mean signal‐to‐noise ratio [less than] 33; mean water linewidth between 6.5 Hz to 11.4 Hz). The harmonized sLASER protocol is expected to produce high reproducibility of MRS across sites thereby allowing large multi‐site studies with clinical cohorts

Modeling direct injection of drugs into the brain

The World Health Organization (WHO) estimates that one billion people worldwide suffer from central nervous system (CNS) disorders [1]. One major issue in treating these disorders is inadequate drug penetration which can be attributed to an effective blood-brain-barrier that limits passage across blood vessels. Low diffusivity of large classes of drug compounds restricts transport across blood vessel walls and subsequent passage through surrounding brain tissues. Tissue transport is emerging as an increasingly important area of research in drug delivery since the vast majority of therapeutic agents must traverse this space before reaching their targets

Modeling direct injection of drugs into the brain

The World Health Organization (WHO) estimates that one billion people worldwide suffer from central nervous system (CNS) disorders [1]. One major issue in treating these disorders is inadequate drug penetration which can be attributed to an effective blood-brain-barrier that limits passage across blood vessels. Low diffusivity of large classes of drug compounds restricts transport across blood vessel walls and subsequent passage through surrounding brain tissues. Tissue transport is emerging as an increasingly important area of research in drug delivery since the vast majority of therapeutic agents must traverse this space before reaching their targets