CNS Insults Research Articles

Dispensable regulation of brain development and myelination by the immune-related protein Serpina3n.

Serine protease inhibitor clade A member 3n (Serpina3n) or its human orthologue SERPINA3 is a secretory immune-related molecule produced primarily in the liver and brain under homeostatic conditions and up-regulated in response to system inflammation. Yet, it remains elusive regarding its cellular identity and physiological significance in the development of the postnatal brain. Here, we reported that oligodendroglial lineage cells are the major cell population expressing Serpina3n protein in the postnatal murine CNS. Using loss-of-function genetic tools, we found that Serpina3n conditional knockout (cKO) from Olig2-expressing cells does not significantly affect cognitive and motor functions in mice. Serpina3n depletion does not appear to interfere with oligodendrocyte differentiation and developmental myelination nor affects the population of other glial cells and neurons invivo. Interestingly, Serpina3n is significantly up-regulated in response to oxidative stress and its deficiency alleviates oxidative injury and diminishes cell senescence of oligodendrocytes invitro. Together, our data suggest that the immune-related molecule Serpina3n plays a minor role in neural cell development under homeostasis, yet it primes oligodendrocytes for CNS insults and regulates oligodendrocyte health under injured conditions. Our findings raise the interest in pursuing its functional significance in the CNS under disease/injury conditions.

Original Article--Risk Factors for Neurological Complications and Short-term Outcomes After Pediatric Heart Surgery: A Retrospective Analysis.

To assess the risk factors associated with neurological complications and poor short-term outcomes following pediatric heart surgery. A cross-sectional study was conducted in a cardiac intensive care unit between June 2019 and June 2022. The data of all children less than 15 years old who underwent open-heart surgery and had CT brain were extracted from hospital records. The primary outcome was the incidence of CNS insult, and secondary outcomes included death after surgery, length of stay in ICU and hospital. Data analysis was performed using SPSS version 23, and a p-value less than or equal to 0.05 was considered statistically significant. Total 1850 surgeries were performed in the specified period of time. The study included 208 children who had CT Brain, with a median age of 5 months. 2.81 % children had neurological complications, with 25 % of patients who had CT brain. The most common neurological complication was seizure (7.2 %). There were no significant differences observed between CNS insult and age, gender, syndrome, or prematurity (p > 0.05), except for a significant association between previous CNS insult and CNS insult after surgery (p = 0.001). Children with CNS insult had significantly higher ICU and hospital length of stay, mortality after surgery, and mortality within 2 weeks of surgery (p ≤ 0.05). Seizure was most common neurological manifestation after cardiac surgeries in children. CNS insult after surgery was associated with worse outcomes, including longer hospital stays and increased mortality.

A 5-year Retrospective Review Of Attention Deficit Hyperactivity Disorder In Children In Zaria, North West Nigeria

Background:Attention deficit hyperactivity disorder (ADHD) is characterized by inattention and/or hyperactivity-impulsivity that impair an individuals functioning and development. Children with ADHD are at risk of poor academic performance, dropping out of school, low self-esteem, teenage pregnancies, engaging in criminal behaviour, sustaining physical injuries and poor social skills. Objective: We carried out a 5- year retrospective review of cases of ADHD in our Paediatrics Neurology Clinic to determine the epidemiology, symptomatology and risk factors for ADHD in our setting. Materials and Methods: Case folders of all children with an established diagnosis of ADHD who were being seen at the paediatric neurology clinic of Ahmadu Bello University Teaching Hospital, Zaria from 1st January 2015 to 31st December 2019 were retrieved and relevant information such as sociodemographic characteristics, symptoms, age at presentation and perinatal or childhood central nervous system insult were extracted. Statistical analysis was done using Epi Info statistical software version 7. Results: A total of thirty (30) children were on follow-up for ADHD in the Paediatrics Neurology clinic of Ahmadu Bello University Teaching Hospital, Zaria during the study period. Twenty-four of them were males (80%) while 6 were females (20%). Their ages at presentation ranged from 2 to 15 years for boys (mean±SD =5.2 ±2.99) and from 2 to 5 years for girls (mean±SD =3.0 ±1.26). More than half (63.3% n= 19/30) were less than 5 years of age as at the time of first presentation to the clinic. Majority, (93.3% ,n= 28/30) had a history of CNS insult prior to onset of ADHD symptoms. Conclusion: Attention deficit hyperactivity disorder (ADHD) is increasingly being seen in environment, most cases occur in boys less than 5 years of age. Avoiding injuries to a childs central nervous system early in life can significantly decrease the likelihood of ADHD in them.

Biomarkers as prognostic determinants of epilepsy after post-acute central nervous system insults: a systematic review and meta-analysis (P3-5.017)

<h3>Objective:</h3> To conduct a systematic review of biofluid biomarkers to test their association with the risk of post-CNS insult epilepsy. <h3>Background:</h3> It remains unknown if there are shared common biological pathways of an epileptogenic mechanism associated with a range of cerebral insults i.e., stroke, traumatic brain injury, and infections; and if certain biological markers could predict the risk of post-CNS insult epilepsy. <h3>Design/Methods:</h3> We searched articles until January 25, 2022, in PubMed, Embase, PsycINFO, Google Scholar, and Web of Science. The primary outcome was the difference in mean biomarker levels in patients with post-CNS insult epilepsy compared to patients without post-CNS insult epilepsy. We used the modified quality score based on the Reporting Recommendations for Tumor Marker Prognostic Studies for risk of bias assessment. For each biomarker, the level difference was calculated using the pooled standardized mean difference (SMD) and 95% confidence intervals (CI). (PROSPERO CRD42021297110) <h3>Results:</h3> We included 22 studies of 1499 cases with post-CNS insult epilepsy and 7929 controls with no post-CNS insult epilepsy. They investigated 47 biomarkers in blood or cerebrospinal fluid (CSF). Of 22 studies, 21 had moderate-to-high risk of bias. A meta-analysis was possible for only 19 biomarkers. Only blood glucose levels in four studies were significantly higher in patients with post-stroke epilepsy (PSE) than in patients without PSE (SMD 0.44; CI 0.19 to 0.69). From individual studies, 15 biomarkers in blood and seven in CSF were significantly associated with post-CNS insult epilepsy. <h3>Conclusions:</h3> While several biomarkers were found to be associated with epilepsy due to CNS insults, we do not recommend using the reported biomarkers for use in clinical settings or clinical trials. A significant limitation of these studies is that they included fewer patients with CNS insults who developed post-cerebral insult epilepsy. Collaborative efforts to promote biomarker discovery are therefore warranted. <b>Disclosure:</b> Mr. Misra has nothing to disclose. Ms. Khan has nothing to disclose. The institution of Dr. Lam has received research support from NIH. Dr. Mazumder has nothing to disclose. Ms. Eldem has nothing to disclose. Dr. Gururangan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Ceribell Inc. Dr. Gururangan has stock in Ceribell Inc. The institution of Dr. Gururangan has received research support from NIH-NINDS. The institution of Dr. Gururangan has received research support from Leon Levy Foundation. Dr. Hickman has nothing to disclose. Dr. Goswami has nothing to disclose. Mrs. Funaro has nothing to disclose. The institution of Joan Montaner has received research support from spanish govt. Joan Montaner has received intellectual property interests from a discovery or technology relating to health care. Dr. Quinn has nothing to disclose. Dr. Liebeskind has received research support from Cerenovus. Dr. Liebeskind has received research support from Genentech . Dr. Liebeskind has received research support from Medtronic. Dr. Liebeskind has received research support from Stryker. Dr. Mishra has nothing to disclose.

Clinical and Imaging Analysis of Headaches in Neurological Post-acute Sequelae of SARS-CoV-2 Infection (P3-12.006)

<h3>Objective:</h3> To determine risk factors associated with headache-predominant post-acute sequelae of COVID syndrome (PASC) versus PASC without headache, as well as differences in brain MRI in these two cohorts. <h3>Background:</h3> PASC is an emerging and highly prevalent disease that frequently involves neurologic symptoms such as fatigue, “brain fog”, and headache. Currently, there is a relative paucity of data describing risk factors for development of a headache-predominant PASC phenotype. <h3>Design/Methods:</h3> This retrospective chart review study identified 56 patients referred to a neuro-immunologist for evaluation of new neurologic symptoms following confirmed COVID-19 infection. Demographic data and past medical history were collected, and white matter hyperintensities were quantified from axial T2 FLAIR images of the brain using the Schelten score. <h3>Results:</h3> PASC patients complaining of headache were more likely than their counterparts with other neurologic PASC symptoms to be younger (median age 50 vs 57), female (74% vs 63%), and have a higher BMI (median 32.9 vs 28.1) and/or sleep apnea (10/34 [29.4%] vs 2/22 [9.0%]). Interestingly, the PASC headache phenotype was more likely to occur in individuals with a prior headache condition (9/34 [26.4%] vs 2/22 [9.0%]). The non-headache PASC cohort had greater amount of periventricular white matter hyperintensities (mean Schelten score 2.42 vs 1.67). <h3>Conclusions:</h3> Patients at risk of developing the PASC-associated headache phenotype are generally at risk of developing a primary headache disorder, such as women and those with a higher BMI. The absence of changes on brain MRI suggests that PASC headache is not due to a direct CNS insult as a result of COVID, such as a demyelinating or vascular process. This study is limited by its small sample size and retrospective design; further research is needed to better characterize risk factors and long term outcomes in PASC patients with headache. <b>Disclosure:</b> Mr. Kuhns has nothing to disclose. Dr. Imitola has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis . The institution of Dr. Imitola has received research support from biogen. Dr. Imitola has a non-compensated relationship as a Board Member with National MS Society that is relevant to AAN interests or activities. Dr. Imitola has a non-compensated relationship as a Committee Member with International Society for Stem Cell Research that is relevant to AAN interests or activities. Mr. Patel has nothing to disclose.

Analysis of the GPR17 receptor in NG2-glia under physiological conditions unravels a new subset of oligodendrocyte progenitor cells with distinct functions.

NG2-glia comprise a heterogeneous population of cycling cells that give rise to mature, myelinating oligodendrocytes. The mechanisms that regulate the process of differentiation from NG2-glia into oligodendrocytes are still not fully understood but over the last years the G Protein-coupled Receptor 17 (GPR17) has been on the spotlight as a possible key regulator. Interestingly, GPR17-expressing NG2-glia show under physiological conditions a slower and lower level of differentiation compared to NG2-glia without GPR17. In contrast, after a CNS insult these react with proliferation and differentiation in a high rate, pointing towards a role in repair processes. However, the role of GPR17+ NG2-glia under healthy conditions in adulthood has not been addressed yet. Therefore, we aimed here to characterize the GPR17-expressing NG2-glia. Using transgenic mouse models, we showed restricted GPR17 expression in only some NG2-glia. Furthermore, we found that these cells constitute a distinct subset within the NG2-glia population, which shows a different gene expression profile and behavior when compared to the total NG2-glia population. Genetic depletion of GPR17+ cells showed that these are not contributing to the dynamic and continuous generation of new oligodendrocytes in the adult brain. Taken together, GPR17+ NG2-glia seem to play a distinct role under physiological conditions that goes beyond their classic differentiation control, that needs to be further elucidated. These results open new avenues for using the GPR17 receptor as a target to change oligodendrogenesis under physiological and pathological conditions, highlighting the importance of further characterization of this protein for future pharmacological studies.

Systemic immune derangements are shared across various CNS pathologies and reflect novel mechanisms of immune privilege.

The nervous and immune systems interact in a reciprocal manner, both under physiologic and pathologic conditions. Literature spanning various CNS pathologies including brain tumors, stroke, traumatic brain injury and de-myelinating diseases describes a number of associated systemic immunologic changes, particularly in the T-cell compartment. These immunologic changes include severe T-cell lymphopenia, lymphoid organ contraction, and T-cell sequestration within the bone marrow. We performed an in-depth systematic review of the literature and discussed pathologies that involve brain insults and systemic immune derangements. In this review, we propose that the same immunologic changes hereafter termed 'systemic immune derangements', are present across CNS pathologies and may represent a novel, systemic mechanism of immune privilege for the CNS. We further demonstrate that systemic immune derangements are transient when associated with isolated insults such as stroke and TBI but persist in the setting of chronic CNS insults such as brain tumors. Systemic immune derangements have vast implications for informed treatment modalities and outcomes of various neurologic pathologies.

Transcription factor network analysis identifies REST/NRSF as an intrinsic regulator of CNS regeneration in mice

The inability of neurons to regenerate long axons within the CNS is a major impediment to improving outcome after spinal cord injury, stroke, and other CNS insults. Recent advances have uncovered an intrinsic program that involves coordinate regulation by multiple transcription factors that can be manipulated to enhance growth in the peripheral nervous system. Here, we use a systems genomics approach to characterize regulatory relationships of regeneration-associated transcription factors, identifying RE1-Silencing Transcription Factor (REST; Neuron-Restrictive Silencer Factor, NRSF) as a predicted upstream suppressor of a pro-regenerative gene program associated with axon regeneration in the CNS. We validate our predictions using multiple paradigms, showing that mature mice bearing cell type-specific deletions of REST or expressing dominant-negative mutant REST show improved regeneration of the corticospinal tract and optic nerve after spinal cord injury and optic nerve crush, which is accompanied by upregulation of regeneration-associated genes in cortical motor neurons and retinal ganglion cells, respectively. These analyses identify a role for REST as an upstream suppressor of the intrinsic regenerative program in the CNS and demonstrate the utility of a systems biology approach involving integrative genomics and bio-informatics to prioritize hypotheses relevant to CNS repair.

Therapeutical Significance of Serpina3n Subsequent Cerebral Ischemia via Cytotoxic Granzyme B Inactivation.

Ischemic stroke is a devastating CNS insult with few clinical cures. Poor understanding of underlying mechanistic network is the primary limitation to develop novel curative therapies. Extracellular accumulation of granzyme B subsequent ischemia promotes neurodegeneration. Inhibition of granzyme B can be one of the potent strategies to mitigate neuronal damage. In present study, we investigated the effect of murine Serpina3n and human (homolog) SERPINA3 against cerebral ischemia through granzyme B inactivation. Recombinant Serpina3n/SERPINA3 were expressed by transfected 293 T cells, and eluted proteins were examined for postischemic influence both in vitro and in vivo. During in vitro test, Serpina3n was found effective enough to inhibit granzyme B, while SERPINA3 was ineffectual to counter cytotoxic protease. Treatment of hypoxic culture with recombinant Serpina3n/SERPINA3 significantly increased cell viability in dosage-dependent manner, recorded maximum at the highest concentration (4 mM). Infarct volume analysis confirmed that 50 mg/kg dosage of exogenous Serpina3n was adequate to reduce disease severity, while SERPINA3 lacked behind in analeptic effect. Immunohistochemical test, western blot analysis, and protease activity assay's results illustrated successful diffusion of applied protein to the ischemic lesion and reactivity with the target protease. Taken together, our findings demonstrate therapeutic potential of Serpina3n by interfering granzyme B-mediated neuronal death subsequent cerebral ischemia.

Microglia Drive Pockets of Neuroinflammation in Middle Age.

During aging, microglia produce inflammatory factors, show reduced tissue surveillance, altered interactions with synapses, and prolonged responses to CNS insults, positioning these cells to have profound impact on the function of nearby neurons. We and others recently showed that microglial attributes differ significantly across brain regions in young adult mice. However, the degree to which microglial properties vary during aging is largely unexplored. Here, we analyze and manipulate microglial aging within the basal ganglia, brain circuits that exhibit prominent regional microglial heterogeneity and where neurons are vulnerable to functional decline and neurodegenerative disease. In male and female mice, we demonstrate that VTA and SNc microglia exhibit unique and premature responses to aging, compared with cortex and NAc microglia. This is associated with localized VTA/SNc neuroinflammation that may compromise synaptic function as early as middle age. Surprisingly, systemic inflammation, local neuron death, and astrocyte aging do not appear to underlie these early aging responses of VTA and SNc microglia. Instead, we found that microglial lysosome status was tightly linked to early aging of VTA microglia. Microglial ablation/repopulation normalized VTA microglial lysosome swelling and suppressed increases in VTA microglial density during aging. In contrast, CX3CR1 receptor KO exacerbated VTA microglial lysosome rearrangements and VTA microglial proliferation during aging. Our findings reveal a previously unappreciated regional variation in onset and magnitude of microglial proliferation and inflammatory factor production during aging and highlight critical links between microglial lysosome status and local microglial responses to aging.SIGNIFICANCE STATEMENT Microglia are CNS cells that are equipped to regulate neuronal health and function throughout the lifespan. We reveal that microglia in select brain regions begin to proliferate and produce inflammatory factors in late middle age, months before microglia in other brain regions. These findings demonstrate that CNS neuroinflammation during aging is not uniform. Moreover, they raise the possibility that local microglial responses to aging play a critical role in determining which populations of neurons are most vulnerable to functional decline and neurodegenerative disease.

Acute symptomatic seizures: an educational, evidence-based review.

Acute symptomatic seizures occurring in close temporal relationship with an acute CNS insult are distinct from epilepsy and occur frequently in clinical practice. The aim of this educational review is to provide information on the most important aspects related to acute symptomatic seizures that will allow clinicians to accurately distinguish acute symptomatic seizures from epilepsy in their patients. We explain the definition of acute symptomatic seizures and we illustrate how acute symptomatic seizures differ from epilepsy. We describe acute symptomatic seizures in the context of their various underlying aetiologies and we discuss the approach to the management of patients with acute symptomatic seizures.

INCIDENCE AND RISK FACTORS OF NEONATAL SEIZURES IN LOW BIRTH WEIGHT NEONATES BORN IN RURAL TERTIARY CARE CENTRE.

BACKGROUND: To study the incidence and risk factors of neonatal seizures in low birth weight neonates born in rural tertiary care centre. METHODS: This is a prospective observational study. It was carried out in neonatal division of department Of pediatrics MMIMSR, Mullana. The study included 200 low birth weight neonates born during the study period. RESULTS: Out of 200 neonates the incidence of neonatal seizures was 4%. According to weight distribution 181(90.5%) were LBW(2499gm - 1500gm) , 14(7%) were VLBW(1499gm-1000gm) , 5(2.5%) were ELBW(&lt;1000gm) and the incidence of neonatal seizure among LBW was 3.31% , VLBW 7.1% and ELBW 20%. The incidence of neonatal seizure among term was 3.09% and preterm was 4.95%. The most common cause of neonatal seizure was birth asphyxia (37.5%) followed by meningitis (25%), hypocalcemia(12.5%), intracranial hemorrrhage(12.5%) and RDS(12.5%). CONCLUSION: Low birth weight and preterm deliveries are at higher risk for morbidity during and after the birth. Early referral of high-risk pregnancies to the tertiary care centers will greatly reduce the incidence of neonatal seizures in neonates. The incidence increases as birth weight and gestation decreases in neonates. The co morbidities causing hypoxic damage and other CNS insults should be controlled at the earliest to avoid occurance of seizures in neonates.

P0147 / #1901: TREATMENT TOXICITY IN CHILDREN WITH NON-HODGKIN LYMPHOMA

Aims & Objectives: To detect toxicity–related morbidity and mortality during the courses of therapy of Non-Hodgkin’s Lymphoma Methods: A prospective study of 43 patients with Non-Hodgkin lymphoma admitted to child welfare teaching hospital from January 1st till December 31st 2013, patients <14 years were included in the study, A modified LMB 96 regimen was employed. A complete analysis of the patient’s data was registered. The duration of observation was extended to March 31st 2014. Results: Forty patients were enrolled. The median age was 5 years, Male to female ratio was 2.6:1, Bulky disease was seen in 26(60.4%) patients, and the primary presenting site of involvement was the abdomen in 28 (65.1%) patients. Advanced stages were present in 42(97.7%) patients, and Burkitt’s subtype was diagnosed in 28(65.1%) cases. Cytological diagnosis was the tool in 25 (58%) patients. Patients were treated with modified UKCCSG LMB FAB96 protocol. Induction mortality was observed in 6(15%), another 8 patients died in the subsequent period. Deaths were mainly occurred due to tumor lysis syndrome in 3, severe infection in 2, CNS insult in 1, progressive disease in 6, iatrogenic death in 1 & unknown at home in one patient. The main toxicity was hematological in 89/189 (47%) cycles; febrile neutropenia in 74/189 (39%) episodes, followed by GIT in 51/189(27%) episodes, Tumor lysis syndrome was reported in 5 patients during COP1 Conclusions: Most of the patients presented with advanced stage. The provision of Rasbiuricase, the use of GCSF post-intensive courses, and treatment of patients by a multidisciplinary team to improve survival is crucial.

Acute IL-1RA treatment suppresses the peripheral and central inflammatory response to spinal cord injury

BackgroundThe acute phase response (APR) to CNS insults contributes to the overall magnitude and nature of the systemic inflammatory response. Aspects of this response are thought to drive secondary inflammatory pathology at the lesion site, and suppression of the APR can therefore afford some neuroprotection. In this study, we examined the APR in a mouse model of traumatic spinal cord injury (SCI), along with its relationship to neutrophil recruitment during the immediate aftermath of the insult. We specifically investigated the effect of IL-1 receptor antagonist (IL-1RA) administration on the APR and leukocyte recruitment to the injured spinal cord.MethodsAdult female C57BL/6 mice underwent either a 70kD contusive SCI, or sham surgery, and tissue was collected at 2, 6, 12, and 24 hours post-operation. For IL-1RA experiments, SCI mice received two intraperitoneal injections of human IL-1RA (100mg/kg), or saline as control, immediately following, and 5 hours after impact, and animals were sacrificed 6 hours later. Blood, spleen, liver and spinal cord were collected to study markers of central and peripheral inflammation by flow cytometry, immunohistochemistry and qPCR. Results were analysed by two-way ANOVA or student’s t-test, as appropriate.ResultsSCI induced a robust APR, hallmarked by elevated hepatic expression of pro-inflammatory marker genes and a significantly increased neutrophil presence in the blood, liver and spleen of these animals, as early as 2 hours after injury. This peripheral response preceded significant neutrophil infiltration of the spinal cord, which peaked 24 hours post-SCI. Although expression of IL-1RA was also induced in the liver following SCI, its response was delayed compared to IL-1β. Exogenous administration of IL-1RA during this putative therapeutic window was able to suppress the hepatic APR, as evidenced by a reduction in CXCL1 and SAA-2 expression as well as a significant decrease in neutrophil infiltration in both the liver and the injured spinal cord itself.ConclusionsOur data indicate that peripheral administration of IL-1RA can attenuate the APR which in turn reduces immune cell infiltration at the spinal cord lesion site. We propose IL-1RA treatment as a viable therapeutic strategy to minimise the harmful effects of SCI-induced inflammation.

Osmotic Demyelination Syndrome: Clinical, Neuroimaging Characteristics, and Outcomes in a Series of 18 Cases.

Objective To investigate the etiology, clinical as well as neuroimaging characteristics, and outcomes after proper treatment in a series of 18 patients with osmotic demyelination syndrome. Methods Medical records, including video records, of 18 patients with osmotic demyelination syndrome were retrospectively examined. Demographic and clinical information, imaging results, plans of management, and outcomes during the follow-up period were collected and analyzed. Results Eighteen patients, including 10 males and 8 females, were included in the present study. The mean age at diagnosis of CNS insult was 47.4 ± 13.3 years (ranged from 30 to 78 years). Etiologies included rapidly corrected hyponatremia (50%), alcoholism (27.8%), and others. Neurological manifestations included encephalopathy (61.1%), dysphonia (50%), extrapyramidal symptoms (38.9%), and seizures (22.2%). Neuroimaging results showed that 6 patients (33.3%) had central pontine myelinolysis, 5 (27.8%) had extrapontine myelinolysis, and 7 (38.9%) had both. After treatment, 12 patients showed improvement and the other 6 did not. Among these patients, those who showed symptoms of encephalopathy had a favorable outcome. The majority of those who presented with mental retardation, seizures, and no other symptoms recovered better than their counterparts who had other symptoms. Nine out of 11 patients with pseudobulbar paralysis and/or extrapyramidal symptoms showed improvement, but the other 2 did not show improvement. Five patients who did not improve after treatment during admission were followed up for 1-3 months with rehabilitation training recommended, and it was found that 3 showed significant improvement after training, and the other 2 did not respond to this training. Conclusions Osmotic demyelination syndrome is a complex disease entity due to a variety of etiologies, manifesting with symptoms involving diverse systems of the brain. Early identification and removal/correction of conditions leading to osmotic demyelination syndrome are the key to prevent and/or manage this disease.

Complement C6 deficiency exacerbates pathophysiology after spinal cord injury

Historically, the membrane attack complex, composed of complement components C5b-9, has been connected to lytic cell death and implicated in secondary injury after a CNS insult. However, studies to date have utilized either non-littermate control rat models, or mouse models that lack significant C5b-9 activity. To investigate what role C5b-9 plays in spinal cord injury and recovery, we generated littermate PVG C6 wildtype and deficient rats and tested functional and histological recovery after moderate contusion injury using the Infinite Horizon Impactor. We compare the effect of C6 deficiency on recovery of locomotor function and histological injury parameters in PVG rats under two conditions: (1) animals maintained as separate C6 WT and C6-D homozygous colonies; and (2) establishment of a heterozygous colony to generate C6 WT and C6-D littermate controls. The results suggest that maintenance of separate homozygous colonies is inadequate for testing the effect of C6 deficiency on locomotor and histological recovery after SCI, and highlight the importance of using littermate controls in studies involving genetic manipulation of the complement cascade.

Meta-analysis of mouse transcriptomic studies supports a context-dependent astrocyte reaction in acute CNS injury versus neurodegeneration

BackgroundNeuronal damage in acute CNS injuries and chronic neurodegenerative diseases is invariably accompanied by an astrocyte reaction in both mice and humans. However, whether and how the nature of the CNS insult—acute versus chronic—influences the astrocyte response, and whether astrocyte transcriptomic changes in these mouse models faithfully recapitulate the astrocyte reaction in human diseases remains to be elucidated. We hypothesized that astrocytes set off different transcriptomic programs in response to acute versus chronic insults, besides a shared “pan-injury” signature common to both types of conditions, and investigated the presence of these mouse astrocyte signatures in transcriptomic studies from human neurodegenerative diseases.MethodsWe performed a meta-analysis of 15 published astrocyte transcriptomic datasets from mouse models of acute injury (n = 6) and chronic neurodegeneration (n = 9) and identified pan-injury, acute, and chronic signatures, with both upregulated (UP) and downregulated (DOWN) genes. Next, we investigated these signatures in 7 transcriptomic datasets from various human neurodegenerative diseases.ResultsIn mouse models, the number of UP/DOWN genes per signature was 64/21 for pan-injury and 109/79 for acute injury, whereas only 13/27 for chronic neurodegeneration. The pan-injury-UP signature was represented by the classic cytoskeletal hallmarks of astrocyte reaction (Gfap and Vim), plus extracellular matrix (i.e., Cd44, Lgals1, Lgals3, Timp1), and immune response (i.e., C3, Serping1, Fas, Stat1, Stat2, Stat3). The acute injury-UP signature was enriched in protein synthesis and degradation (both ubiquitin-proteasome and autophagy systems), intracellular trafficking, and anti-oxidant defense genes, whereas the acute injury-DOWN signature included genes that regulate chromatin structure and transcriptional activity, many of which are transcriptional repressors. The chronic neurodegeneration-UP signature was further enriched in astrocyte-secreted extracellular matrix proteins (Lama4, Cyr61, Thbs4), while the DOWN signature included relevant genes such as Agl (glycogenolysis), S1pr1 (immune modulation), and Sod2 (anti-oxidant). Only the pan-injury-UP mouse signature was clearly present in some human neurodegenerative transcriptomic datasets.ConclusionsAcute and chronic CNS injuries lead to distinct astrocyte gene expression programs beyond their common astrocyte reaction signature. However, caution should be taken when extrapolating astrocyte transcriptomic findings from mouse models to human diseases.

COVID-19 Vasculitis: A Case Report with Complicated Course

Coronavirus disease 2019 (COVID-19) is a viral infection caused by the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), it spreads from person to person rapidly and presents with multi systemic manifestations namely respiratory symptoms, similar to prior SARS viruses. Neurologic manifestations of COVID-19 are uncommon; those include encephalopathy, strokes, and polyneuropathy. Here we report a unique neurologic complication of COVID-19 in a patient who had extensive cerebral small-vessel ischemic lesions resembling those of cerebral vasculitis. This case report supports the fact that neurologic complications from CVOID 19 could be more debilitating than the respiratory illness itself, especially for those patients who were eventually able to survive the complicated course of being on mechanical ventilation but unfortunately end up with this extensive CNS insult.

Suppression of microglial activation and monocyte infiltration ameliorates cerebellar hemorrhage induced-brain injury and ataxia

Ataxia, characterized by uncoordinated movement, is often found in patients with cerebellar hemorrhage (CH), leading to long-term disability without effective management. Microglia are among the first responders to CNS insult. Yet the role and mechanism of microglia in cerebellar injury and ataxia after CH are still unknown. Using Ki20227, an inhibitor for colony-stimulating factor 1 receptor which mediates the signaling responsible for the survival of microglia, we determined the impact of microglial depletion on cerebellar injury and ataxia in a murine model of CH. Microglial depletion reduced cerebellar lesion volume and alleviated gait abnormality, motor incoordination, and locomotor dysfunction after CH. Suppression of CH-initiated microglial activation with minocycline ameliorated cerebellum infiltration of monocytes/macrophages, as well as production of proinflammatory cytokines and chemokine C–C motif ligand-2 (CCL-2) that recruits monocytes/macrophages. Furthermore, both minocycline and bindarit, a CCL-2 inhibitor, prevented apoptosis and electrophysiological dysfunction of Purkinje cells, the principal neurons and sole outputs of the cerebellar cortex, and consequently improved ataxia-like motor abnormalities. Our findings suggest a detrimental role of microglia in neuroinflammation and ataxic motor symptoms after CH, and pave a new path to understand the neuroimmune mechanism underlying CH-induced cerebellar ataxia.

RNA Binding Motif 5 (RBM5) in the CNS-Moving Beyond Cancer to Harness RNA Splicing to Mitigate the Consequences of Brain Injury.

Gene splicing modulates the potency of cell death effectors, alters neuropathological disease processes, influences neuronal recovery, but may also direct distinct mechanisms of secondary brain injury. Therapeutic targeting of RNA splicing is a promising avenue for next-generation CNS treatments. RNA-binding proteins (RBPs) regulate a variety of RNA species and are prime candidates in the hunt for druggable targets to manipulate and tailor gene-splicing responses in the brain. RBPs preferentially recognize unique consensus sequences in targeted mRNAs. Also, RBPs often contain multiple RNA-binding domains (RBDs)—each having a unique consensus sequence—suggesting the possibility that drugs could be developed to block individual functional domains, increasing the precision of RBP-targeting therapies. Empirical characterization of most RBPs is lacking and represents a major barrier to advance this emerging therapeutic area. There is a paucity of data on the role of RBPs in the brain including, identification of their unique mRNA targets, defining how CNS insults affect their levels and elucidating which RBPs (and individual domains within) to target to improve neurological outcomes. This review focuses on the state-of-the-art of the RBP tumor suppressor RNA binding motif 5 (RBM5) in the CNS. We discuss its potent pro-death roles in cancer, which motivated our interest to study it in the brain. We review recent studies showing that RBM5 levels are increased after CNS trauma and that it promotes neuronal death in vitro. Finally, we conclude with recent reports on the first set of RBM5 regulated genes identified in the intact brain, and discuss how those findings provide new clues germane to its potential function(s) in the CNS, and pose new questions on its therapeutic utility to mitigate CNS injury.