13 research outputs found
Single severe traumatic brain injury produces progressive pathology with ongoing contralateral white matter damage one year after injury
There is increasing recognition that traumatic brain injury (TBI) may initiate long-term neurodegenerative processes, particularly chronic traumatic encephalopathy. However, insight into the mechanisms transforming an initial biomechanical injury into a neurodegenerative process remain elusive, partly as a consequence of the paucity of informative pre-clinical models. This study shows the functional, whole brain imaging and neuropathological consequences at up to one year survival from single severe TBI by controlled cortical impact in mice. TBI mice displayed persistent sensorimotor and cognitive deficits. Longitudinal T2 weighted magnetic resonance imaging (MRI) showed progressive ipsilateral (il) cortical, hippocampal and striatal volume loss, with diffusion tensor imaging demonstrating decreased fractional anisotropy (FA) at up to one year in the il-corpus callosum (CC: − 30%) and external capsule (EC: − 21%). Parallel neuropathological studies indicated reduction in neuronal density, with evidence of microgliosis and astrogliosis in the il-cortex, with further evidence of microgliosis and astrogliosis in the il-thalamus. One year after TBI there was also a decrease in FA in the contralateral (cl) CC (− 17%) and EC (− 13%), corresponding to histopathological evidence of white matter loss (cl-CC: − 68%; cl-EC: − 30%) associated with ongoing microgliosis and astrogliosis.
These findings indicate that a single severe TBI induces bilateral, long-term and progressive neuropathology at up to one year after injury. These observations support this model as a suitable platform for exploring the mechanistic link between acute brain injury and late and persistent neurodegeneration
Current and emerging technologies for probing molecular signatures of traumatic brain injury
Traumatic brain injury (TBI) is understood as an interplay between the initial injury, subsequent secondary injuries, and a complex host response all of which are highly heterogeneous. An understanding of the underlying biology suggests a number of windows where mechanistically inspired interventions could be targeted. Unfortunately, biologically plausible therapies have to-date failed to translate into clinical practice. While a number of stereotypical pathways are now understood to be involved, current clinical characterization is too crude for it to be possible to characterize the biological phenotype in a truly mechanistically meaningful way. In this review, we examine current and emerging technologies for fuller biochemical characterization by the simultaneous measurement of multiple, diverse biomarkers. We describe how clinically available tech- niques such as cerebral microdialysis can be leveraged to give mechanistic insights into TBI pathobiology and how multiplex proteomic and metabolomic techniques can give a more complete description of the underlying biology. We also describe spatially resolved label-free multiplex techniques capable of probing structural differences in chemical signatures. Finally, we touch on the bioinformatics challenges that result from the acquisition of such large amounts of chemical data in the search for a more mechanistically complete description of the TBI phenotype.GV received a fellowship by “Associazione Amici del Mario Negri.
Induction of a transmissible tau pathology by traumatic brain injury.
Traumatic brain injury is a risk factor for subsequent neurodegenerative disease, including chronic traumatic encephalopathy, a tauopathy mostly associated with repetitive concussion and blast, but not well recognized as a consequence of severe traumatic brain injury. Here we show that a single severe brain trauma is associated with the emergence of widespread hyperphosphorylated tau pathology in a proportion of humans surviving late after injury. In parallel experimental studies, in a model of severe traumatic brain injury in wild-type mice, we found progressive and widespread tau pathology, replicating the findings in humans. Brain homogenates from these mice, when inoculated into the hippocampus and overlying cerebral cortex of naïve mice, induced widespread tau pathology, synaptic loss, and persistent memory deficits. These data provide evidence that experimental brain trauma induces a self-propagating tau pathology, which can be transmitted between mice, and call for future studies aimed at investigating the potential transmissibility of trauma associated tau pathology in humans
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Studies in Mice and Patients to Understand the Role of Tau Pathology in Driving Neurodegeneration After Traumatic Brain Injury
Traumatic brain injury (TBI) is a global public health issue that afflicts 55 million people worldwide. It represents a huge burden for the health system, and a leading cause of injury-related death and disability, with devastating impact on individuals and society. TBI is a complex disease characterised by dynamic pathophysiological adaptive and maladaptive processes that may predispose to chronic neurodegeneration and increase risk of dementia later in life including Alzheimer’s disease (AD). However, the mechanisms driving the transition from the acute biomechanical impact to late neurodegeneration still need to be fully addressed.
The development of progressive proteinopathies is a shared feature of dementia and TBI. In particular, tau pathology has sparked our interest being a hallmark of AD and pathognomonic feature of chronic traumatic encephalopathy. In the present study we document the presence of tau pathology in human brain contusion samples surgically removed early after severe TBI in patients. We provide evidence that human TBI-induced tau (tauTBI) has self-templating properties and spreads throughout the brain causing a widespread tau pathology that is associated with synaptic dysfunction and cognitive impairment. Moreover, we show that tauTBI can be horizontally transmitted to naïve mice by intracerebral inoculation, causing memory deficits. Thus, human tauTBI holds prion-like properties, suggesting a mechanism by which an acute biomechanical impact may predispose to neurodegeneration in patients. We also show an impairment of proteostatic mechanisms in chronic TBI mice, thus further contributing to tau accumulation later in life. Interestingly, tau deficiency reduces the physiological cognitive aged-related decline in mice. Finally, we exploit the C. elegans model to demonstrate that the bio-inspired multitarget hexapeptide Aβ1-6A2V(D), acting against amyloid β and tau, could represent an innovative pharmacological approach to counteract pathological aggregates formation and mitigate the progression of dementia and post-traumatic neurodegenerative processes
Longitudinal Molecular Magnetic Resonance Imaging of Endothelial Activation after Severe Traumatic Brain Injury
Traumatic brain injury (TBI) is a major cause of death and disability. Despite progress in neurosurgery and critical care, patients still lack a form of neuroprotective treatment that can counteract or attenuate injury progression. Inflammation after TBI is a key modulator of injury progression and neurodegeneration, but its spatiotemporal dissemination is only partially known. In vivo approaches to study post-traumatic inflammation longitudinally are pivotal for monitoring injury progression/recovery and the effectiveness of therapeutic approaches. Here, we provide a minimally invasive, highly sensitive in vivo molecular magnetic resonance imaging (MRI) characterization of endothelial activation associated to neuroinflammatory response after severe TBI in mice, using microparticles of iron oxide targeting P-selectin (MPIOs-α-P-selectin). Strong endothelial activation was detected from 24 h in perilesional regions, including the cortex and hippocampus, and peaked in intensity and diffusion at two days, then partially decreased but persisted up to seven days and was back to baseline 15 days after injury. There was a close correspondence between MPIOs-α-P-selectin signal voids and the P-selectin stained area, confirming maximal endothelial activation at two days. Molecular MRI markers of inflammation may thus represent a useful tool to evaluate in vivo endothelial activation in TBI and monitoring the responses to therapeutic agents targeting vascular activation and permeability
18F-FDG PET/CT Cannot Substitute Endoscopy in the Staging of Gastrointestinal Involvement in Mantle Cell Lymphoma. A Retrospective Multi-Center Cohort Analysis
The detection of gastrointestinal (GI) involvement in Mantle Cell Lymphoma is often underestimated and may have an impact on outcome and clinical management. We aimed to evaluate whether baseline 18F-FDG PET/CT presents comparable results to endoscopic biopsy in the diagnosis of GI localizations. In our retrospective cohort of 79 patients, sensitivity and specificity of 18F-FDG PET/CT were low for the stomach, with a fair concordance (k = 0.32), while higher concordance with pathologic results (k = 0.65) was detected in the colorectal tract. Thus, gastric biopsy remains helpful in the staging of MCL despite 18F-FDG PET/CT, while colonoscopy could be omitted in asymptomatic patients. The validation of our data in prospective cohorts is desirabl
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Induction of a transmissible tau pathology by traumatic brain injury.
Traumatic brain injury is a risk factor for subsequent neurodegenerative disease, including chronic traumatic encephalopathy, a tauopathy mostly associated with repetitive concussion and blast, but not well recognized as a consequence of severe traumatic brain injury. Here we show that a single severe brain trauma is associated with the emergence of widespread hyperphosphorylated tau pathology in a proportion of humans surviving late after injury. In parallel experimental studies, in a model of severe traumatic brain injury in wild-type mice, we found progressive and widespread tau pathology, replicating the findings in humans. Brain homogenates from these mice, when inoculated into the hippocampus and overlying cerebral cortex of naïve mice, induced widespread tau pathology, synaptic loss, and persistent memory deficits. These data provide evidence that experimental brain trauma induces a self-propagating tau pathology, which can be transmitted between mice, and call for future studies aimed at investigating the potential transmissibility of trauma associated tau pathology in humans