Disability and persistent motor deficits are linked to structural crossed cerebellar diaschisis in chronic stroke.

Brain imaging has significantly contributed to our understanding of the cerebellum being involved in recovery after non-cerebellar stroke. Due to its connections with supratentorial brain networks, acute stroke can alter the function and structure of the contralesional cerebellum, known as crossed cerebellar diaschisis (CCD). Data on the spatially precise distribution of structural CCD and their implications for persistent deficits after stroke are notably limited. In this cross-sectional study, structural MRI and clinical data were analyzed from 32 chronic stroke patients, at least 6 months after the event. We quantified lobule-specific contralesional atrophy, as a surrogate of structural CCD, in patients and healthy controls. Volumetric data were integrated with clinical scores of disability and motor deficits. Diaschisis-outcome models were adjusted for the covariables age, lesion volume, and damage to the corticospinal tract. We found that structural CCD was evident for the whole cerebellum, and particularly for lobules V and VI. Lobule VI diaschisis was significantly correlated with clinical scores, that is, volume reductions in contralesional lobule VI were associated with higher levels of disability and motor deficits. Lobule V and the whole cerebellum did not show similar diaschisis-outcome relationships across the spectrum of the clinical scores. These results provide novel insights into stroke-related cerebellar plasticity and might thereby promote lobule VI as a key area prone to structural CCD and potentially involved in recovery and residual motor functioning.

Magnetothermal-based non-invasive focused magnetic stimulation for functional recovery in chronic stroke treatment.

Magnetic heat-based brain stimulation of specific lesions could promote the restoration of impaired motor function caused by chronic stroke. We delivered localized stimulation by nanoparticle-mediated heat generation within the targeted brain area via focused magnetic stimulation. The middle cerebral artery occlusion model was prepared, and functional recovery in the chronic-phase stroke rat model was demonstrated by the therapeutic application of focused magnetic stimulation. We observed a transient increase in blood-brain barrier permeability at the target site of < 4 mm and metabolic brain activation at the target lesion. After focused magnetic stimulation, the rotarod score increased by 390 ± 28% (p < 0.05) compared to the control group. Standardized uptake value in the focused magnetic stimulation group increased by 2063 ± 748% (p < 0.01) compared to the control group. Moreover, an increase by 24 ± 5% (p < 0.05) was observed in the sham group as well. Our results show that non-invasive focused magnetic stimulation can safely modulate BBB permeability and enhance neural activation for chronic-phase stroke treatment in the targeted deep brain area.

Early rise in brain damage markers and high ICOS expression in CD4+ and CD8+ T cells during checkpoint inhibitor-induced encephalomyelitis.

We report a case of rapid eradication of melanoma brain metastases and simultaneous near-fatal encephalomyelitis following double immune checkpoint blockade. Brain damage marker S-100B and C reactive protein increased before symptoms or signs of encephalomyelitis and peaked when the patient fell into a coma. At that point, additional brain damage markers and peripheral T cell phenotype was analyzed. The analyses were repeated four times during the patient's recovery. Axonal damage marker neurofilament light polypeptide (NFL) and astrocytic damage marker glial fibrillar acidic protein (GFAP) were very high in blood and cerebrospinal fluid and gradually normalized after immunosuppression and intensive care. The costimulatory receptor inducible T cell costimulatory receptor (ICOS) was expressed on a high proportion of CD4+ and CD8+T cells as encephalomyelitis symptoms peaked and then gradually decreased in parallel with clinical improvement. Both single and double immune checkpoint inhibitor-treated melanoma patients with other serious immune-related adverse events (irAE) (n=9) also expressed ICOS on a significantly higher proportion of CD4+ and CD8+T cells compared with controls without irAE (n=12). In conclusion, our results suggest a potential role for ICOS on CD4+ and CD8+T cells in mediating encephalomyelitis and other serious irAE. In addition, brain damage markers in blood could facilitate early diagnosis of encephalitis.

Impact of COVID-19 on a brain damage unit.

AIM: To report on the impact of COVID-19 on a brain damage unit. METHODS: We reviewed the records of all patients admitted to our brain damage unit. The study included all the significant clinical events from the first positive qualitative real-time reverse-transcriptase-polymerase-chain-reaction assay (April 8th, 2020) for SARS-CoV-2 to the day all patients tested negative (June 8th, 2020). RESULTS: Of the 20 patients (14 men) (age 57.7 ± 14.9; 2-71 months after brain damage; all with a modified Rankin scale score > 4), 16 tested positive for SARS-CoV-2 and remained positive for a mean of 32.3 days (ranging from 26 to 61). One patient died from COVID-19, while 12 patients were asymptomatic and three suffered mild pneumonia without acute respiratory distress syndrome. All patients received prophylactic subcutaneous heparin. Intravenous methylprednisolone was prescribed for three patients with bilateral pneumonia with excellent results. CONCLUSIONS: Most positive cases (93.7%) were not severe. The good outcome was most likely due to the use of prophylactic anticoagulation therapy, the early use of methylprednisolone for pneumonia and the previously reported immunosuppression amid patients with brain damage. This study hopes to encourage further study into brain damage immunity.

Acid-Ion Sensing Channel 1a Deletion Reduces Chronic Brain Damage and Neurological Deficits after Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) causes long-lasting neurodegeneration and cognitive impairments; however, the underlying mechanisms of these processes are not fully understood. Acid-sensing ion channels 1a (ASIC1a) are voltage-gated Na+- and Ca2+-channels shown to be involved in neuronal cell death; however, their role for chronic post-traumatic brain damage is largely unknown. To address this issue, we used ASIC1a-deficient mice and investigated their outcome up to 6 months after TBI. ASIC1a-deficient mice and their wild-type (WT) littermates were subjected to controlled cortical impact (CCI) or sham surgery. Brain water content was analyzed 24 h and behavioral outcome up to 6 months after CCI. Lesion volume was assessed longitudinally by magnetic resonance imaging and 6 months after injury by histology. Brain water content was significantly reduced in ASIC1a-/- animals compared to WT controls. Over time, ASIC1a-/- mice showed significantly reduced lesion volume and reduced hippocampal damage. This translated into improved cognitive function and reduced depression-like behavior. Microglial activation was significantly reduced in ASIC1a-/- mice. In conclusion, ASIC1a deficiency resulted in reduced edema formation acutely after TBI and less brain damage, functional impairments, and neuroinflammation up to 6 months after injury. Hence, ASIC1a seems to be involved in chronic neurodegeneration after TBI.

Brain damage caused by neonatal hypoxia-ischemia and the effects of hypothermia in severe combined immunodeficient (SCID) mice.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of brain damage in newborns. Although therapeutic hypothermia has been shown to be neuroprotective against neonatal HIE in clinical trials, its effect is not satisfactory. Cell-based therapies have attracted much attention as novel treatments for HIE. Preclinical studies on a variety of human cell transplantation methods have been performed in immunodeficient/immunosuppressed animals, such as severe combined immunodeficient (SCID) mice, which lack functional T and B lymphocytes. The detailed characteristics of neonatal HIE in SCID mice, however, have not been delineated. In preclinical studies, novel therapies for neonatal HIE should be evaluated in combination with hypothermia, which has become a standard treatment for neonatal HIE. However, the effects of hypothermia in SCID mice have not been delineated. In the present study, we compared neonatal hypoxic-ischemic (HI) brain damage in SCID mice and wild-type mice treated with or without hypothermia. Male and female mouse pups were subjected to HI insult induced by unilateral common carotid artery ligation combined with systemic hypoxia on postnatal day 12. In the first 4 h after HI insult, body temperature was maintained at 36 °C for the normothermia groups or 32 °C for the hypothermia groups. The severity of brain damage in SCID mice did not differ from that in wild-type mice based on most evaluations, i.e., cerebral blood flow, hemiparesis, muscle strength, spontaneous activity, cerebral hemispheric volume, neuropathological injury, and serum cytokine levels, although spleen weight, brain weight, leukocyte counts and the levels of some cytokines in the peripheral blood were different between genotypes. The effects of hypothermia in SCID mice were comparable to those in wild-type mice based on most evaluations. Taken together, these findings indicate that SCID mice can be used as an appropriate preclinical model for cell therapies for neonatal HIE.

The interplay among education, brain metabolism, and cognitive impairment suggests a role of cognitive reserve in Amyotrophic Lateral Sclerosis.

We tested the Cognitive Reserve (CR) hypothesis in Amyotrophic Lateral Sclerosis (ALS), enrolling 111 patients, using education as CR proxy, 18F-FDG-PET to assess brain damage, and ECAS to measure cognition. Education was regressed out against brain metabolism, including age, sex, spinal/bulbar onset, ALSFRS-R, and ECAS as covariates. Clusters showing a significant correlation were used as seed regions in an interregional correlation analysis (IRCA) in the ALS group and in 40 controls. In the ALS group, we found a negative correlation between brain metabolism and education in the right anterior cingulate and bilateral medial frontal gyrus. In the IRCA in the ALS group, the medial frontal cluster metabolism positively correlated with that of frontotemporal regions (right > left), bilateral caudate nuclei, and right insula, and negatively correlated with that of corticospinal tracts, cerebellum, and pons. In controls, the IRCA showed significant positive correlations in the same regions but less extended. Our results agree with the CR hypothesis. The negative correlation between the medial frontal cluster and the cerebellum found only in ALS patients might reflect cerebellar compensation.

Leigh syndrome in an infant: autopsy and histopathology findings

Leigh syndrome is an inherited neurodegenerative disorder of infancy that typically manifests between 3 and 12 months of age. The common neurological manifestations are developmental delay or regression, progressive cognitive decline, dystonia, ataxia, brainstem dysfunction, epileptic seizures, and respiratory dysfunction. Although the disorder is clinically and genetically heterogeneous, the histopathological and radiological features characteristically show focal and bilaterally symmetrical, necrotic lesions in the basal ganglia and brainstem. The syndrome has a characteristic histopathological signature that helps in clinching the diagnosis. We discuss these unique findings on autopsy and radiology in a young infant who succumbed to a subacute, progressive neurological illness suggestive of Leigh syndrome. Our case highlights that Leigh syndrome should be considered in the differential diagnosis of infantile-onset, subacute neuroregression with dystonia and seizures, a high anion gap metabolic acidosis, normal ketones, elevated lactates in blood, brain, and urine, and bilateral basal ganglia involvement.

Neuropsychological and neuropathological observations of a long-studied case of memory impairment.

We report neuropsychological and neuropathological findings for a patient (A.B.), who developed memory impairment after a cardiac arrest at age 39. A.B. was a clinical psychologist who, although unable to return to work, was an active participant in our neuropsychological studies for 24 y. He exhibited a moderately severe and circumscribed impairment in the formation of long-term, declarative memory (anterograde amnesia), together with temporally graded retrograde amnesia covering ∼5 y prior to the cardiac arrest. More remote memory for both facts and autobiographical events was intact. His neuropathology was extensive and involved the medial temporal lobe, the diencephalon, cerebral cortex, basal ganglia, and cerebellum. In the hippocampal formation, there was substantial cell loss in the CA1 and CA3 fields, the hilus of the dentate gyrus (with sparing of granule cells), and the entorhinal cortex. There was also cell loss in the CA2 field, but some remnants remained. The amygdala demonstrated substantial neuronal loss, particularly in its deep nuclei. In the thalamus, there was damage and atrophy of the anterior nuclear complex, the mediodorsal nucleus, and the pulvinar. There was also loss of cells in the medial and lateral mammillary nuclei in the hypothalamus. We suggest that the neuropathology resulted from two separate factors: the initial cardiac arrest (and respiratory distress) and the recurrent seizures that followed, which led to additional damage characteristic of temporal lobe epilepsy.

Induction of brain injury and depression in rats by chronic unpredictable stress associated with the augmentation of nitrosative stress and apoptosis / Inducción de lesión cerebral y depresión en ratas por estrés crónico impredecible asociado con el aumento del estrés nitrosativo y la apoptosis

SUMMARY: Repeated stress is a risk factor for memory impairment and neurological abnormalities in both humans and animals. We sought to investigate the extent of (i) brain tissue injury; (ii) nitrosative and oxidative stress in brain tissue homogenates; (iii) apoptotic and survival biomarkers in brain tissue homogenates; and (iv) immobility and climbing abilities, induced over a period of three weeks by chronic unpredictable stress (CUS). Wistar rats were either left untreated (Control group) or exposed to a variety of unpredictable stressors daily before being sacrificed after 3 weeks (model group). Assessment of depression-like behavior was performed and animals were then culled and harvested brain tissues were stained with basic histological staining and examined under light microscopy. In addition, brain tissue homogenates were prepared and assayed for these parameters; inducible nitric oxide synthase (iNOS), malondialdehyde (MDA), superoxide dismutase (SOD), caspase-3, and B-cell lymphoma 2 (Bcl-2). Histology images showed CUS induced profound damage to the cerebral cortex as demonstrated by severe neuronal damage with shrunken cells, disrupted atrophic nuclei, perineuronal vacuolation and swollen glial cells. CUS also significantly (p<0.05) induced iNOS, MDA, and caspase-3, whereas SOD and Bcl-2 brain tissue levels were inhibited by CUS. In addition, data from the depression-like behavior, forced swimming test showed significant (p<0.05) increase in animal immobility and decrease in climbing ability in the model group of rats. Thus, here we demonstrated a reliable rat model of chronic stress-induced brain injury, which can further be used to investigate beneficial drugs or agents used for a period of three weeks to protect against CUS-induced brain damage.

RESUMEN: El estrés crónico es un factor de riesgo para el deterioro de la memoria y las anomalías neurológicas tanto en humanos como en animales. Intentamos investigar el alcance de lesión del tejido cerebral; (ii) estrés nitrosativo y oxidativo en homogeneizados de tejido cerebral; (iii) biomarcadores apoptóticos y de supervivencia en homogeneizados de tejido cerebral; y (iv) inmovilidad y habilidades de escalada, inducidas durante un período de tres semanas por estrés crónico impredecible (ECI). Se dejaron sin tratamiento (grupo control) ratas Wistar, o se expusieron a una variedad de factores estresantes impredecibles diariamente antes de ser sacrificadas después de 3 semanas (grupo modelo). Se realizó una evaluación del comportamiento similar a la depresión y luego se sacrificaron los animales y se tiñeron los tejidos cerebrales con tinción histológica básica y se examinaron con microscopía óptica. Además, se prepararon homogeneizados de tejido cerebral y se analizaron los siguientes parámetros; óxido nítrico sintasa inducible (iNOS), malondialdehído (MDA), superóxido dismutasa (SOD), caspasa- 3 y linfoma de células B 2 (Bcl-2). Las imágenes histológicas mostraron que el CUS indujo un daño profundo en la corteza cerebral como lo demuestra el daño neuronal severo con células encogidas, núcleos atróficos alterados, vacuolación perineuronal y células gliales inflamadas. ECI también indujo significativamente (p <0,05) iNOS, MDA y caspase-3, mientras que los niveles de tejido cerebral SOD y Bcl-2 fueron inhibidos por ECI. Además, los datos del comportamiento similar a la de- presión, la prueba de natación forzada mostró un aumento significativo (p <0,05) en la inmovilidad animal y una disminución en la capacidad de escalada en el grupo modelo de ratas. Por lo tanto, aquí demostramos un modelo confiable de daño cerebral crónico en rata inducido por el estrés, que se puede utilizar para investigar medicamentos o agentes beneficiosos usados durante un período de tres semanas para proteger el daño cerebral inducido por ECI.

Face-Specific Perceptual Distortions Reveal A View- and Orientation-Independent Face Template.

The spatial coordinate system in which a stimulus representation is embedded is known as its reference frame. Every visual representation has a reference frame [1], and the visual system uses a variety of reference frames to efficiently code visual information [e.g., 1-5]. The representation of faces in early stages of visual processing depends on retino-centered reference frames, but little is known about the reference frames that code the high-level representations used to make judgements about faces. Here, we focus on a rare and striking disorder of face perception-hemi-prosopometamorphopsia (hemi-PMO)-to investigate these reference frames. After a left splenium lesion, Patient A.D. perceives features on the right side of faces as if they had melted. The same features were distorted when faces were presented in either visual field, at different in-depth rotations, and at different picture-plane orientations including upside-down. A.D.'s results indicate faces are aligned to a view- and orientation-independent face template encoded in a face-centered reference frame, that these face-centered representations are present in both the left and right hemisphere, and that the representations of the left and right halves of a face are dissociable.

Preterm infants with isolated cerebellar hemorrhage show bilateral cortical alterations at term equivalent age.

The cerebellum is connected to numerous regions of the contralateral side of the cerebrum. Motor and cognitive deficits following neonatal cerebellar hemorrhages (CbH) in extremely preterm neonates may be related to remote cortical alterations, following disrupted cerebello-cerebral connectivity as was previously shown within six CbH infants. In this retrospective case series study, we used MRI and advanced surface-based analyses to reconstruct gray matter (GM) changes in cortical thickness and cortical surface area in extremely preterm neonates (median age = 26; range: 24.9-26.7 gestational weeks) with large isolated unilateral CbH (N = 5 patients). Each CbH infant was matched with their own preterm infant cohort (range: 20-36 infants) based on sex and gestational age at birth. On a macro level, our data revealed that the contralateral cerebral hemisphere of CbH neonates did not show less cortical thickness or cortical surface area than their ipsilateral cerebral hemisphere at term. None of the cases differed from their matched cohort groups in average cortical thickness or average cortical surface area in the ipsilateral or contralateral cerebral hemisphere. On a micro (i.e. vertex) level, we established high variability in significant local cortical GM alteration patterns across case-cohort groups, in which the cases showed thicker or bigger volume in some regions, among which the caudal middle frontal gyrus, insula and parahippocampal gyrus, and thinner or less volume in other regions, among which the cuneus, precuneus and supratentorial gyrus. This study highlights that cerebellar injury during postnatal stages may have  widespread bilateral influence on the early maturation of cerebral cortical regions, which implicate complex cerebello-cerebral interactions to be present at term birth.

Simvastatin preconditioning confers neuroprotection against hypoxia-ischemia induced brain damage in neonatal rats via autophagy and silent information regulator 1 (SIRT1) activation.

Previous studies have shown that simvastatin (Sim) has neuroprotective effects in a neonatal model of hypoxia-ischemia (HI)-induced brain injury when administered before but not after HI, pointing to the preconditioning (PC)-like effects of the statin. The present study aimed to gain more insight into the PC-like effect of Sim by studying the role of autophagy and its modulation by mTOR and SIRT1 in neuroprotection. Sim potentiated the autophagy response induced by neonatal HI, as shown by the increased expression of both microtubule-associated protein 1 light chain 3 (LC3) and beclin 1, increased monodansylcadaverine (MDC) labeling, and reduced expression of p62. The autophagy inhibitor 3-methyladenine (3MA) completely blocked the neuroprotective effect of Sim. Two hours after HI, there was a reduction in the activity of mTORC1 and a concomitant increase in that of mTORC2. Sim preconditioning further decreased the activity of mTORC1, but did not affect that of mTORC2. However, 24 h after injury, mTORC2 activity was significantly preserved in Sim-treated rats. Sim preconditioning also prevented the depletion of SIRT1 induced by HI, an effect that was completely blocked by 3MA. These data show that Sim preconditioning may modulate autophagy and survival pathways by affecting mTORC1, mTORC2, and SIRT1 activities. This study provides further preclinical evidence of the PC-like effect of statins in brain tissue, supporting their beneficial effects in improving stroke outcome after prophylactic treatments.

Association between Diffusion Tensor Imaging Findings and Cognitive Outcomes Following Mild Traumatic Brain Injury: A PRISMA-Compliant Meta-Analysis.

Previous diffusion tensor imaging (DTI) research in mild traumatic brain injury (mTBI) patients only concentrated on a limited number of brain regions and a specific cognitive function. Thus, the study aimed to explore the association between DTI findings and cognitive function following mTBI using a meta-analysis. We conducted a search for articles exploring the associations between DTI findings and cognitive outcomes following mTBI published in English in databases (PubMed, Web of Science, EMBASE, Medline, and Google Scholar) before October 2019. The correlations were computed to explore associations between DTI findings and specific cognitive function. Finally, 9 studies (including 293 mTBI patients) were included in the meta-analysis. The study showed that higher fractional anisotropy (FA) values in the longitudinal fasciculus (LF), sagittal stratum (SS), cerebellum, and internal capsule (IC) were associated with better general cognitive function. However, the study showed that higher FA values in the cerebellar peduncles (CP) were associated with worse general cognitive function. Additionally, the present study showed that higher FA values in the mesencephalon, anterior corona radiata (ACR), forceps major (FM), uncinate fasciculus (UF), cingulum, and genu of corpus callosum (gCC) were related to better memory. Higher FA values in the ACR were associated with worse attention, processing speed, and working memory. The study indicated that higher mean diffusivity (MD)/apparent diffusion coefficient (ADC) values in the external capsule (EC) were associated with worse memory. Additionally, higher MD/ADC values in the UF were associated with worse attention, processing speed, and working memory. The present study showed that better white matter integrity (higher FA, lower MD/ADC) might be associated with better cognitive function following mTBI.

Cerebral Damage after Carbon Monoxide Poisoning: A Longitudinal Diffusional Kurtosis Imaging Study.

BACKGROUND AND PURPOSE: Previous DTI cross-sectional studies have showed the cerebral damage feature was different in the three clinical stages after carbon monoxide poisoning. Diffusional kurtosis imaging (DKI) is an advanced diffusion imaging model and considered to better provide microstructural contrast in comparison with DTI parameters. The primary aim of this study was to assess microstructural changes in gray and white matter with diffusional kurtosis imaging in the acute, delayed neuropsychiatric, and chronic phases after acute carbon monoxide (CO) poisoning. The secondary aim was to relate diffusional kurtosis imaging measures to neuropsychiatric outcomes of acute carbon monoxide poisoning. MATERIALS AND METHODS: In all, 17 patients with acute carbon monoxide poisoning and 30 sex- and age-matched healthy volunteers were enrolled in the study. Patients were scanned within 1 week, 3-8 weeks, and 6 months after acute carbon monoxide poisoning. Diffusional kurtosis imaging metrics including mean kurtosis, mean diffusivity, fractional anisotropy, and kurtosis fractional anisotropy were measured in 11 ROIs and then further correlated with neuropsychiatric scores. RESULTS: In WM, mean kurtosis tended to increase from the acute-to-delayed neuropsychiatric phases and then decrease in the chronic phase, while in GM mean kurtosis showed a constant decline. Contrary to mean kurtosis, mean diffusivity first decreased then tended to increase in WM, while in GM, from the acute to chronic phases, mean diffusivity showed a constant increase. In both WM and GM, the fractional anisotropy and kurtosis fractional anisotropy values progressively declined with time. Kurtosis fractional anisotropy showed the best diagnostic efficiency with an area under the curve of 0.812 (P = .000). Along with neuropsychiatric scores, kurtosis fractional anisotropy of the centrum semiovale and Digit Span Backward were most relevant (r = 0.476, P = .000). CONCLUSIONS: Longitudinally, microstructural changes were inconsistent in WM and GM with time after acute carbon monoxide poisoning. Diffusional kurtosis imaging metrics provided important complementary information to quantify the damage to cognitive impairment.

The role of DKK1 in Alzheimer's disease: A potential intervention point of brain damage prevention?

Dickkopf-1 (DKK1), a secretory glycoprotein discovered for 'inducing generation of head', is an endogenous inhibitor of the canonical Wnt/ß-catenin signaling pathway. It was found to be involved in many pathophysiological processes in vivo. Abnormal expression of DKK1 will alter expressions of related proteins and genes not only in canonical Wnt/ß-catenin signaling pathway but also in other signaling pathways. Previous studies of DKK1 focused on its function in tumors. In recent years, a large number of studies have shown that it plays an important role in embryonic development, neural regeneration, synaptogenesis and so on. Therefore, its role in neuropsychiatric disorders, such as neurodysplasia, cognitive impairment and emotional disorder, has attracted increasing attention. At present, the role of DKK1 in Alzheimer's disease (AD) is one of the research hot topics. This article reviewed the research progress of its role in AD in order to provide new ideas and directions for further studies on the pathogenesis and treatment of AD.

Exosomes Secreted by the Cocultures of Normal and Oxygen-Glucose-Deprived Stem Cells Improve Post-stroke Outcome.

Emerging stroke literature suggests that treatment of experimentally induced stroke with stem cells offered post-stroke neuroprotection via exosomes produced by these cells. Treatment with exosomes has great potential to overcome the limitations associated with cell-based therapies. However, in our preliminary studies, we noticed that the exosomes released from human umbilical cord blood-derived mesenchymal stem cells (MSCs) under standard culture conditions did not improve the post-stroke neurological outcome. Because of this apparent discrepancy, we hypothesized that exosome characteristics vary with the conditions of their production. Specifically, we suggest that the exosomes produced from the cocultures of regular and oxygen-glucose-deprived (OGD) MSCs in vitro would represent the exosomes produced from MSCs that are exposed to ischemic brain cells in vivo, and offer similar therapeutic benefits that the cell treatment would provide. We tested the efficacy of therapy with exosomes secreted from human umbilical cord blood (HUCB)-derived MSCs under in vitro hypoxic conditions on post-stroke brain damage and neurological outcome in a rat model of transient focal cerebral ischemia. We performed the TTC staining procedure as well as the neurological tests including the modified neurological severity scores (mNSS), the modified adhesive removal (sticky-tape), and the beam walking tests before ischemia and at regular intervals until 7 days reperfusion. Treatment with exosomes obtained from the cocultures of normal and OGD-induced MSCs reduced the infarct size and ipsilateral hemisphere swelling, preserved the neurological function, and facilitated the recovery of stroke-induced rats. Based on the results, we conclude that the treatment with exosomes secreted from MSCs at appropriate experimental conditions attenuates the post-stroke brain damage and improves the neurological outcome.

Temporal and age-dependent effects of haptoglobin deletion on intracerebral hemorrhage-induced brain damage and neurobehavioral outcomes.

Intracerebral hemorrhage (ICH) is a devastating stroke subtype and the presence of extracorpuscular hemoglobin (Hb) exacerbates brain damage. Haptoglobin (Hp) binds Hb, which prevents its oxidation and participation in neurotoxic reactions. Multiple studies have investigated the role of Hp under conditions of intravascular hemolysis, but little is known about its role in the brain and following ICH where extravascular hemolysis is rampant. Young and aged wildtype and Hp-/- mice underwent the autologous blood or collagenase ICH model. Early after ICH, Hp-/- mice display 58.0 ±â€¯5.6% and 36.7 ±â€¯6.9% less brain damage in the autologous blood and collagenase ICH models, respectively. In line with these findings, Hp-/- mice display less neurological deficits on several neurobehavioral tests. Hp-/- mice have less Perl's iron content, HO1 expression, and blood brain barrier dysfunction, but no difference in brain Hb content, astrogliosis and angiogenesis/neovascularization. At the later endpoint, the young cohort displays 27.8 ±â€¯9.3% less brain damage, while no difference is seen with the aged cohort. For both cohorts, no differences are seen in HO1 levels or iron accumulation, but young Hp-/- mice display less thalamic astrogliosis and striatal microgliosis. This study reveals that the presence or absence of Hp exerts important time- and age-dependent influences on ICH outcomes.

Sports-Related Concussion: Neurometabolic Aspects.

Concussion is a transitory brain injury resulting from a blow to the head. Concussion is considered a mild traumatic brain injury (mTBI), which is self-limited. Repetitive mTBI has been associated with chronic, progressive neurological damage. Extreme biochemical changes occur in neuron cells as a result of mTBI. These metabolic disturbances may reflect the symptoms observed in patients who had suffered concussions. However, it has been difficult to correlate clinical signs and symptoms. Currently, there are no laboratory tests to diagnose concussion, though several biomarkers are being investigated. Further studies are needed to elucidate the biochemical details of the metabolic cascade and the associated time frame, which will help determine when an athlete can safely return to the game.

Magnetic resonance spectroscopy of fiber tracts in children with traumatic brain injury: A combined MRS - Diffusion MRI study.

Traumatic brain injury can cause extensive damage to the white matter (WM) of the brain. These disruptions can be especially damaging in children, whose brains are still maturing. Diffusion magnetic resonance imaging (dMRI) is the most commonly used method to assess WM organization, but it has limited resolution to differentiate causes of WM disruption. Magnetic resonance spectroscopy (MRS) yields spectra showing the levels of neurometabolites that can indicate neuronal/axonal health, inflammation, membrane proliferation/turnover, and other cellular processes that are on-going post-injury. Previous analyses on this dataset revealed a significant division within the msTBI patient group, based on interhemispheric transfer time (IHTT); one subgroup of patients (TBI-normal) showed evidence of recovery over time, while the other showed continuing degeneration (TBI-slow). We combined dMRI with MRS to better understand WM disruptions in children with moderate-severe traumatic brain injury (msTBI). Tracts with poorer WM organization, as shown by lower FA and higher MD and RD, also showed lower N-acetylaspartate (NAA), a marker of neuronal and axonal health and myelination. We did not find lower NAA in tracts with normal WM organization. Choline, a marker of inflammation, membrane turnover, or gliosis, did not show such associations. We further show that multi-modal imaging can improve outcome prediction over a single modality, as well as over earlier cognitive function measures. Our results suggest that demyelination plays an important role in WM disruption post-injury in a subgroup of msTBI children and indicate the utility of multi-modal imaging.