During the last decades, advances in the understanding of genetic, cellular, and microstructural alterations associated to Huntington's disease (HD) have improved the understanding of this ...progressive and fatal illness. However, events related to early neuropathological events, neuroinflammation, deterioration of neuronal connectivity and compensatory mechanisms still remain vastly unknown. Ultra-high field diffusion MRI (UHFD-MRI) techniques can contribute to a more comprehensive analysis of the early microstructural changes observed in HD. In addition, it is possible to evaluate if early imaging microstructural parameters might be linked to histological biomarkers. Moreover, qualitative studies analyzing histological complexity in brain areas susceptible to neurodegeneration could provide information on inflammatory events, compensatory increase of neuroconnectivity and mechanisms of brain repair and regeneration. The application of ultra-high field diffusion-MRI technology in animal models, particularly the R6/1 mice (a common preclinical mammalian model of HD), provide the opportunity to analyze alterations in a physiologically intact model of the disease. Although some disparities in volumetric changes across different brain structures between preclinical and clinical models has been documented, further application of different diffusion MRI techniques used in combination like diffusion tensor imaging, and neurite orientation dispersion and density imaging have proved effective in characterizing early parameters associated to alteration in water diffusion exchange within intracellular and extracellular compartments in brain white and grey matter. Thus, the combination of diffusion MRI imaging techniques and more complex neuropathological analysis could accelerate the discovery of new imaging biomarkers and the early diagnosis and neuromonitoring of patients affected with HD.
Flortaucipir (FTP) PET is a key imaging technique to evaluate tau burden indirectly. However, it appears to have greater utility for 3R+4R tau found in Alzheimer's disease (AD), compared to other ...non-AD tauopathies. The purpose of this study is to determine how flortaucipir uptake links to neuropathologically determined tau burden in AD and non-AD tauopathies. We identified nine individuals who had undergone antemortem tau-PET and postmortem neuropathological analyses. The cohort included three patients with low, moderate, and high AD neuropathologic changes (ADNC), five patients with a non-AD tauopathy (one Pick's disease, three progressive supranuclear palsies, and one globular glial tauopathy), and one control without ADNC. We compared regional flortaucipir PET uptake with tau burden using an anti-AT8 antibody. There was a very good correlation between flortaucipir uptake and tau burden in those with ADNC although, in one ADNC patient, flortaucipir uptake and tau burden did not match due to the presence of argyrophilic grains disease. Non-AD patients showed lower flortaucipir uptake globally compared to ADNC patients. In the non-AD patients, some regional associations between flortaucipir uptake and histopathological tau burden were observed. Flortaucipir uptake is strongly linked to underlying tau burden in patients with ADNC but there are instances where they do not match. On-the-other hand, flortaucipir has a limited capacity to represent histopathological tau burden in non-AD patients although there are instances where regional uptake correlates with regional tau burden. There is a definite need for the development of future generations of tau-PET ligands that can detect non-AD tau.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Editorial on the Research Topic Innovative Imaging Techniques in Preclinical Models of Neurodegenerative Diseases Neurodegenerative disorders have been forecast as the next global pandemic. Besides ...the growing understanding of the basic molecular mechanisms associated to neurodegenerative diseases (NDDs), the current number of disease-modifying treatments remains quite limited. ...the authors proved ML as a useful tool to combine imaging techniques in the early detection of AD and screen for mild cognitive impairment (MCI). In this Research Topic, we found that the contribution of new computational approaches, combined imaging techniques, and animal models keeps expanding the neuroscience field and the discovery of new imaging biomarkers of NDDs. ...we provide the reader with a wide-ranging overview of current innovative imaging techniques that are sensitive to novel biological paradigms and animal models to aid translational research in the diagnosis and monitoring of patient populations suffering from these devastating illnesses.
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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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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•MRI diffusion alterations in ALS mice can be detected at early stages.•Alterations in diffusion occur from distal to proximal spinal cord segments.•Changes in diffusion are ...associated with anomalies in axonal architecture.
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.
In this Research Topic, we explore new insights brought by technological advances such as high-density EEG recordings, novel biomarkers derived from relaxometry and diffusion MRI, AI-powered image ...analysis for microbleed detection, and translatability of animal models of brain and spine injury. ...a technique may find application more widely, since neuronal loss and iron, particularly accumulation, are of potential interest in a multitude of NDDs. dMRI is among the foremost innovative imaging techniques, capable of providing distinct information on neuronal tissue microstructure and composition (Gatto et al., 2018). Increasing evidence suggests that gray-white matter organization plays an important role in the impact of TBI (Soni et al., 2020). ...Hutchinson et al. used ferrets, which have gray matter folds and extensive white matter connectivity.
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.
Magnetic resonance imaging (MRI) and diffusion tensor imaging can detect presymptomatic in vivo changes in amyotrophic lateral sclerosis (ALS) mouse spinal cord (G93A‐SOD1). A progressive distal to proximal axonal degeneration represents one of the key pathological features of the disease. Diffusion anomalies are associated with early histological alterations.
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