Poor Corticospinal Motor Neuron Health Is Associated with Increased Symptom Severity in the Acute Phase Following Repetitive Mild TBI and Predicts Early ALS Onset in Genetically Predisposed Rodents.

Traumatic brain injury (TBI) is a well-established risk factor for several neurodegenerative disorders including Alzheimer's disease and Parkinson's disease, however, a link between TBI and amyotrophic lateral sclerosis (ALS) has not been clearly elucidated. Using the SOD1G93A rat model known to recapitulate the human ALS condition, we found that exposure to mild, repetitive TBI lead ALS rats to experience earlier disease onset and shortened survival relative to their sham counterparts. Importantly, increased severity of early injury symptoms prior to the onset of ALS disease symptoms was linked to poor health of corticospinal motor neurons and predicted worsened outcome later in life. Whereas ALS rats with only mild behavioral injury deficits exhibited no observable changes in corticospinal motor neuron health and did not present with early onset or shortened survival, those with more severe injury-related deficits exhibited alterations in corticospinal motor neuron health and presented with significantly earlier onset and shortened lifespan. While these studies do not imply that TBI causes ALS, we provide experimental evidence that head injury is a risk factor for earlier disease onset in a genetically predisposed ALS population and is associated with poor health of corticospinal motor neurons.

Extended neuromuscular blockade in acute respiratory distress syndrome does not increase mortality.

BACKGROUND: Neuromuscular blockade (NMB) is often utilized in the treatment of acute respiratory distress syndrome (ARDS). Its use for a period of 48 h has been shown to improve mortality in randomized control trials. We aimed to characterize outcomes associated with a prolonged NMB. We hypothesized that the duration of NMB would not be associated with increased mortality. MATERIALS AND METHODS: This was a retrospective review from June 2014 to October 2016 of patients admitted to the surgical intensive care unit and receiving cisatracurium for ARDS. Patients paralyzed for ≤ 48 h (SHORT) were compared to those paralyzed for longer durations (LONG). Primary outcome was mortality. Parametric and nonparametric tests were utilized for the purposes of the comparison. A multivariate logistic regression model was utilized to adjust for differences. RESULTS: Of 73 patients meeting inclusion criteria, 32 (44%) were SHORT and 41 (56%) LONG. Compared to the LONG cohort, those in SHORT were older (60 versus 52 years, P = 0.04) but were comparable with respect to sex, acute physiology and chronic health evaluation IV scores, presence of concurrent pneumonia, and the use of vasopressors. SHORT patients were less likely to require rescue therapy with inhaled nitric oxide (28% versus 66%, P < 0.01). Overall mortality was 60%. There was no difference in the adjusted odds for mortality (adjusted odds ratio: 0.57, P = 0.33). Secondary outcomes including deep venous thrombosis and pneumonia did not differ between the two groups. CONCLUSIONS: Extended NMB for ARDS was not associated with increased mortality. Discontinuation of this modality should not be based solely on the duration of therapy.

Transplantation of Neural Progenitor Cells Expressing Glial Cell Line-Derived Neurotrophic Factor into the Motor Cortex as a Strategy to Treat Amyotrophic Lateral Sclerosis.

Early dysfunction of cortical motor neurons may underlie the initiation of amyotrophic lateral sclerosis (ALS). As such, the cortex represents a critical area of ALS research and a promising therapeutic target. In the current study, human cortical-derived neural progenitor cells engineered to secrete glial cell line-derived neurotrophic factor (GDNF) were transplanted into the SOD1G93A ALS rat cortex, where they migrated, matured into astrocytes, and released GDNF. This protected motor neurons, delayed disease pathology and extended survival of the animals. These same cells injected into the cortex of cynomolgus macaques survived and showed robust GDNF expression without adverse effects. Together this data suggests that introducing cortical astrocytes releasing GDNF represents a novel promising approach to treating ALS. Stem Cells 2018;36:1122-1131.

Impact of early positive cultures in the elderly with traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in the United States, especially in the elderly, who have the highest rates of TBI-related hospitalizations and deaths among all age groups. Sepsis is one of many risk factors that is associated with higher mortality and longer length of hospital stay in this population partially due to the immunosuppressive effects of TBI. The significance of early indicators of infection, such as a positive blood, sputum, or urine culture, is not well described. The purpose of this study was to determine if early positive cultures predict higher mortality in elderly patients with TBI. METHODS: All trauma patients aged ≥65 years with TBI, admitted between January 1, 2009 and December 31, 2013 to the surgical intensive care unit, were retrospectively reviewed. Clinical data including results from sputum, blood, and urine cultures were reviewed. RESULTS: Overall, 288 elderly patients with TBI were identified, and 92 (32%) had a positive culture. Patients with positive cultures had longer intensive care unit (median 6.0 versus 2.0 days, P < 0.001) and ventilation days (median 7.0 versus 2.0 days, P < 0.001). Patients who had positive cultures within 2-3 days of admission had a higher adjusted hazard ratio for mortality than those patients who had positive cultures after 6 or more days. CONCLUSIONS: In elderly patients with TBI, early positive cultures are associated with a higher risk of mortality. Further research is required to determine the role of obtaining cultures on admission in this subpopulation of trauma patients.

Nonoperative Management of Blunt Splenic Trauma in Patients with Traumatic Brain Injury: Feasibility and Outcomes.

INTRODUCTION: Preventing secondary insult to the brain is imperative following traumatic brain injury (TBI). Although TBI does not preclude nonoperative management (NOM) of splenic injuries, development of hypotension in this setting may be detrimental and could therefore lead trauma surgeons to a lower threshold for operative intervention and a potentially higher risk of failure of NOM (FNOM). We hypothesized that the presence of a TBI in patients with blunt splenic injury would lead to a higher risk of FNOM. METHODS: Patients with blunt splenic injury were selected from the National Trauma Data Bank research datasets from 2007 to 2011. TBI was defined as AIS head ≥ 3 and FNOM as patients who underwent a spleen-related operation after 2 h from admission. TBI patients were compared to those without head injury. The primary outcome was FNOM. RESULTS: Of 47,713 patients identified, 41,436 (86.8%) underwent a trial of NOM. FNOM was identical (10.6 vs. 10.8%, p = 0.601) among patients with and without TBI. TBI patients had lower adjusted odds for FNOM (AOR 0.66, p < 0.001), even among those with a high-grade splenic injury (AOR 0.68, p < 0.001). No difference in adjusted mortality was noted when comparing TBI patients with and without FNOM (AOR 1.01, p = 0.95). CONCLUSIONS: NOM of blunt splenic trauma in TBI patients has higher adjusted odds for success. This could be related to interventions targeting prevention of secondary brain injury. Further studies are required to identify those specific practices that lead to a higher success rate of NOM of splenic trauma in TBI patients.

Patterns of vasopressor utilization during the resuscitation of massively transfused trauma patients.

BACKGROUND: The use of vasopressors (VP) in the resuscitation of massively transfused trauma patients might be considered a marker of inadequate resuscitation. We sought to characterize the utilization of VP in patients receiving massive transfusion and examine the association of their use with mortality. METHODS: Trauma patients admitted from January 2011 to October 2016 receiving massive transfusion, defined as 3 units of pRBC within the first hour from admission, were selected for analysis. Demographics, admission vital signs and labs, use of VP, surgical interventions and outcomes were collected. Standard statistical tools were utilized. RESULTS: Over the 5-year study period, 120 trauma patients met inclusion criteria. The median age was 39 years with 77% being male and 41% sustaining a penetrating injury. Patients who received VP [VP (+)] were more likely to have a lower admission GCS (median 4.5 vs. 14.0, p <0.01) and less likely to have a penetrating injury (31% vs. 54%, p=0.02). The overall mortality was 49% and significantly higher in the VP (+) cohort (60% vs. 34%, AHR: 9.9, adjusted p=0.03). Mortality increased in a stepwise fashion with increasing number of VP utilized, starting at 34% for no VP, to 78% for 3 VP, and 100% for 5 or more. The majority of deaths in the VP (-) group (88%) occurred within one day from admission. For the VP (+) group, 57% of deaths occurred within one day, with the remaining 43% occurring at a later time. CONCLUSION: In the era of massive transfusion protocols, vasopressors are commonly utilized in exsanguinating trauma patients and their use is associated with a higher mortality risk. Deaths in patients receiving vasopressors are more likely to occur later compared to those in patients who do not receive vasopressors. Further research to characterize the role of these agents in the resuscitation of trauma patients is required.

Dopamine neuron dependent behaviors mediated by glutamate cotransmission.

Dopamine neurons in the ventral tegmental area use glutamate as a cotransmitter. To elucidate the behavioral role of the cotransmission, we targeted the glutamate-recycling enzyme glutaminase (gene Gls1). In mice with a dopamine transporter (Slc6a3)-driven conditional heterozygous (cHET) reduction of Gls1 in their dopamine neurons, dopamine neuron survival and transmission were unaffected, while glutamate cotransmission at phasic firing frequencies was reduced, enabling a selective focus on the cotransmission. The mice showed normal emotional and motor behaviors, and an unaffected response to acute amphetamine. Strikingly, amphetamine sensitization was reduced and latent inhibition potentiated. These behavioral effects, also seen in global GLS1 HETs with a schizophrenia resilience phenotype, were not seen in mice with an Emx1-driven forebrain reduction affecting most brain glutamatergic neurons. Thus, a reduction in dopamine neuron glutamate cotransmission appears to mediate significant components of the GLS1 HET schizophrenia resilience phenotype, and glutamate cotransmission appears to be important in attribution of motivational salience.

Clinical correlates to assist with chronic traumatic encephalopathy diagnosis: Insights from a novel rodent repeat concussion model.

INTRODUCTION: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repetitive head injuries. Chronic traumatic encephalopathy symptoms include changes in mood, behavior, cognition, and motor function; however, CTE is currently diagnosed only postmortem. Using a rat model of recurrent traumatic brain injury (TBI), we demonstrate rodent deficits that predict the severity of CTE-like brain pathology. METHODS: Bilateral, closed-skull, mild TBI was administered once per week to 35 wild-type rats; eight rats received two injuries (2×TBI), 27 rats received five injuries (5×TBI), and 13 rats were sham controls. To determine clinical correlates for CTE diagnosis, TBI rats were separated based on the severity of rotarod deficits and classified as "mild" or "severe" and further separated into "acute," "short," and "long" based on age at euthanasia (90, 144, and 235 days, respectively). Brain atrophy, phosphorylated tau, and inflammation were assessed. RESULTS: All eight 2×TBI cases had mild rotarod deficiency, 11 5×TBI cases had mild deficiency, and 16 cases had severe deficiency. In one cohort of rats, tested at approximately 235 days of age, balance, rearing, and grip strength were significantly worse in the severe group relative to both sham and mild groups. At the acute time period, cortical thinning, phosphorylated tau, and inflammation were not observed in either TBI group, whereas corpus callosum thinning was observed in both TBI groups. At later time points, atrophy, tau pathology, and inflammation were increased in mild and severe TBI groups in the cortex and corpus callosum, relative to sham controls. These injury effects were exacerbated over time in the severe TBI group in the corpus callosum. CONCLUSIONS: Our model of repeat mild TBI suggests that permanent deficits in specific motor function tests correlate with CTE-like brain pathology. Assessing balance and motor coordination over time may predict CTE diagnosis.

10-Year trend in crystalloid resuscitation: Reduced volume and lower mortality.

BACKGROUND: Liberal emergency department (ED) resuscitation after trauma may lead to uncontrolled hemorrhage, reduced organ perfusion, and compartment syndrome. Recent guidelines reduced the standard starting point for crystalloid resuscitation from 2 L to 1 L and emphasized "balanced" resuscitation. The purpose of this study was to characterize how an urban, Level 1 trauma center has responded to changes in crystalloid resuscitation practices over time and to describe associated patient outcomes. METHODS: This is a retrospective review of trauma patients who sustained moderate to severe injury (ISS > 9) and received crystalloid resuscitation in the ED during 1/2004-12/2013 at an urban, Level 1 trauma center. Patient data collected included age, gender, Glasgow Coma Scale (GCS) score, initial systolic blood pressure (SBP), mechanism of injury, regional Abbreviated Injury Scale (AIS) score, Injury Severity Score (ISS), volume of blood products and crystalloids administered in the ED. Patients who received <2 L of crystalloid were considered low-volume while those who received ≥2 L were high-volume patients. Clinical characteristics and outcomes were compared between high- and low-volume cohorts, and multivariate regression was used to adjust for confounders. Trend analysis examined changes in variables over time. RESULTS: 1571 moderate to severely injured patients received crystalloid resuscitation; 1282 (82%) were low-volume and 289 (18%) were high-volume. Compared to high-volume patients, low-volume patients presented with a higher median SBP (134 vs. 122 mmHg, p < 0.001) and GCS (15 vs. 14, p < 0.001). Low-volume patients also had lower median ISS (15 vs. 19, p < 0.001). Unadjusted mortality was lower in the low-volume cohort (7% vs. 19%, p < 0.001). Multivariate analysis demonstrated that high-volume patients had increased odds of mortality compared to low-volume patients (AOR 1.88, p = 0.008). Decreased rates of high-volume resuscitation and overall mortality were demonstrated over the 10-year study period. CONCLUSIONS: The observed decrease in high-volume crystalloid resuscitations in the ED paralleled a reduction in mortality over the ten-year period. In addition, adjusted mortality was higher in those receiving high-volume resuscitation.

A model of recurrent concussion that leads to long-term motor deficits, CTE-like tauopathy and exacerbation of an ALS phenotype.

BACKGROUND: Concussion injury is the most common form of traumatic brain injury (TBI). How recurrent concussions alter long-term outcomes is poorly understood, especially as related to the development of neurodegenerative disease. We evaluated the functional and pathological consequences of repeated TBI over time in wild type (WT) rats as well as rats harboring the human SOD1 mutation ("SOD1"), a model of familial amyotrophic lateral sclerosis (ALS). METHODS: A total of 42 rats, 26 WT and 16 SOD1, were examined over a study period of 25 weeks (or endpoint). At postnatal day 60, 20 WT and 7 SOD1 rats were exposed to mild, bilateral TBI once per week for either 2 weeks (2×TBI) or 5 weeks (5×TBI) using a controlled cortical impact device. Six WT and nine SOD1 rats underwent sham injury with anesthesia alone. Twenty WT rats were euthanized at 12 weeks after first injury and six WT rats were euthanized at 25 weeks after first injury. SOD1 rats were euthanized when they reached ALS disease endpoint. Weekly body weights and behavioral assessments were performed. Tauopathy in brain tissue was analyzed using immunohistochemistry. RESULTS: 2XTBI injured rats initially demonstrated recovery of motor function but failed to recover to baseline within the 12-week study period. Relative to both 2XTBI and sham controls, 5XTBI rats demonstrated significant deficits that persisted over the 12-week period. SOD1 5XTBI rats reached a peak body weight earlier than sham SOD1 rats, indicating earlier onset of the ALS phenotype. Histologic examination of brain tissue revealed that, in contrast with sham controls, SOD1 and WT TBI rats demonstrated cortical and corpus collosum thinning and tauopathy, which increased over time. CONCLUSIONS: Unlike previous models of repeat brain injury, which demonstrate only transient deficits in motor function, our concussion model of repeat, mild, bilateral TBI induced long-lasting deficits in motor function, decreased cortical thickness, shrinkage of the corpus callosum, increased brain tauopathy, and earlier onset of ALS symptoms in SOD1 rats. This model may allow for a greater understanding of the complex relationship between TBI and neurodegenerative diseases and provides a potential method for testing novel therapeutic strategies.

Heart rate in pediatric trauma: rethink your strategy.

BACKGROUND: The optimal heart rate (HR) for children after trauma is based on values derived at rest for a given age. As the stages of shock are based in part on HR, a better understanding of how HR varies after trauma is necessary. Admission HRs of pediatric trauma patients were analyzed to determine which ranges were associated with lowest mortality. MATERIALS AND METHODS: The National Trauma Data Bank was used to evaluate all injured patients ages 1-14 years admitted between 2007 and 2011. Patients were stratified into eight groups based on age. Clinical characteristics and outcomes were recorded, and regression analysis was used to determine mortality odds ratios (ORs) for HR ranges within each age group. RESULTS: A total of 214,254 pediatric trauma patients met inclusion criteria. The average admission HR and systolic blood pressure were 104.7 and 120.4, respectively. Overall mortality was 0.8%. The HR range associated with lowest mortality varied across age groups and, in children ages 7-14, was narrower than accepted resting HR ranges. The lowest risk of mortality for patients ages 5-14 was captured at HR 80-99. CONCLUSIONS: The HR associated with lowest mortality after pediatric trauma frequently differs from resting HR. Our data suggest that a 7y old with an HR of 115 bpm may be in stage III shock, whereas traditional HR ranges suggest that this is a normal rate for this child. Knowing when HR is critically high or low in the pediatric trauma population will better guide treatment.

Early propranolol after traumatic brain injury is associated with lower mortality.

BACKGROUND: ß-Adrenergic receptor blockers (BBs) administered after trauma blunt the cascade of immune and inflammatory changes associated with injury. BBs are associated with improved outcomes after traumatic brain injury (TBI). Propranolol may be an ideal BB because of its nonselective inhibition and ability to cross the blood-brain barrier. We determined if early administration of propranolol after TBI is associated with lower mortality. METHODS: All adults (age ≥ 18 years) with moderate-to-severe TBI (head Abbreviated Injury Scale [AIS] score, 3-5) requiring intensive care unit (ICU) admission at a Level I trauma center from January 1, 2013, to May 31, 2015, were prospectively entered into a database. Administration of early propranolol was dosed within 24 hours of admission at 1 mg intravenous every 6 hours. Patients who received early propranolol after TBI (EPAT) were compared with those who did not (non-EPAT). Data including demographics, hospital length of stay (LOS), ICU LOS, and mortality were collected. RESULTS: Over 29 months, 440 patients with moderate-to-severe TBI met inclusion criteria. Early propranolol was administered to 25% (109 of 440) of the patients. The EPAT cohort was younger (49.6 years vs. 60.4 years, p < 0.001), had lower Glasgow Coma Scale (GCS) score (11.7 vs. 12.4, p = 0.003), had lower head AIS score (3.6 vs. 3.9, p = 0.001), had higher admission heart rate (95.8 beats/min vs. 88.4 beats/min, p = 0.002), and required more days on the ventilator (5.9 days vs. 2.6 days, p < 0.001). Similarities were noted in sex, Injury Severity Score (ISS), admission systolic blood pressure, hospital LOS, ICU LOS, and mortality rate. Multivariate regression showed that EPAT was independently associated with lower mortality (adjusted odds ratio, 0.25; p = 0.012). CONCLUSION: After adjusting for predictors of mortality, early administration of propranolol after TBI was associated with improved survival. Future studies are needed to identify additional benefits and optimal dosing regimens. LEVEL OF EVIDENCE: Therapeutic study, level IV.

Thromboelastography After Murine TBI and Implications of Beta-Adrenergic Receptor Knockout.

BACKGROUND: The source of coagulopathy in traumatic brain injury (TBI) is multifactorial and may include adrenergic stimulation. The aim of this study was to assess coagulopathy after TBI using thromboelastography (TEG), and to investigate the implications of ß-adrenergic receptor knockout. METHODS: Adult male wild type c57/bl6 (WT) and ß1/ß2-adrenergic receptor knockout (BKO) mice were assigned to either TBI (WT-TBI, BKO-TBI) or sham injury (WT-sham, BKO-sham). Mice assigned to TBI were subject to controlled cortical impact (CCI). At 24 h post-injury, whole blood samples were obtained and taken immediately for TEG. RESULTS: At 24 h after injury, a trend toward increased fibrinolysis was seen in WT-TBI compared to WT-sham although this did not reach significance (EPL 8.1 vs. 0 %, p = 0.18). No differences were noted in fibrinolysis in BKO-TBI compared to BKO-sham (LY30 2.6 vs. 2.5 %, p = 0.61; EPL 3.4 vs. 2.9 %, p = 0.61). In addition BKO-TBI demonstrated increased clot strength compared to BKO-sham (MA 76.6 vs. 68.6, p = 0.03; G 18.2 vs. 11.3, p = 0.03). CONCLUSIONS: In a mouse TBI model, WT mice sustaining TBI demonstrated a trend toward increased fibrinolysis at 24 h after injury while BKO mice did not. These findings suggest ß-blockade may attenuate the coagulopathy of TBI and minimize progression of intracranial hemorrhage by reducing fibrinolysis and increasing clot strength.

Acute Traumatic Brain Injury Does Not Exacerbate Amyotrophic Lateral Sclerosis in the SOD1 (G93A) Rat Model

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease in which upper and lower motor neurons degenerate, leading to muscle atrophy, paralysis, and death within 3 to 5 years of onset. While a small percentage of ALS cases are genetically linked, the majority are sporadic with unknown origin. Currently, etiological links are associated with disease onset without mechanistic understanding. Of all the putative risk factors, however, head trauma has emerged as a consistent candidate for initiating the molecular cascades of ALS. Here, we test the hypothesis that traumatic brain injury (TBI) in the SOD1 (G93A) transgenic rat model of ALS leads to early disease onset and shortened lifespan. We demonstrate, however, that a one-time acute focal injury caused by controlled cortical impact does not affect disease onset or survival. Establishing the negligible involvement of a single acute focal brain injury in an ALS rat model increases the current understanding of the disease. Critically, untangling a single focal TBI from multiple mild injuries provides a rationale for scientists and physicians to increase focus on repeat injuries to hopefully pinpoint a contributing cause of ALS.

Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice.

Genetic pharmacotherapy is an early drug development strategy for the identification of novel CNS targets in mouse models prior to the development of specific ligands. Here for the first time, we have implemented this strategy to address the potential therapeutic value of a glutamate-based pharmacotherapy for schizophrenia involving inhibition of the glutamate recycling enzyme phosphate-activated glutaminase. Mice constitutively heterozygous for GLS1, the gene encoding glutaminase, manifest a schizophrenia resilience phenotype, a key dimension of which is an attenuated locomotor response to propsychotic amphetamine challenge. If resilience is due to glutaminase deficiency in adulthood, then glutaminase inhibitors should have therapeutic potential. However, this has been difficult to test given the dearth of neuroactive glutaminase inhibitors. So, we used genetic pharmacotherapy to ask whether adult induction of GLS1 heterozygosity would attenuate amphetamine responsiveness. We generated conditional floxGLS1 mice and crossed them with global CAG(ERT2cre∕+) mice to produce GLS1 iHET mice, susceptible to tamoxifen induction of GLS1 heterozygosity. One month after tamoxifen treatment of adult GLS1 iHET mice, we found a 50% reduction in GLS1 allelic abundance and glutaminase mRNA levels in the brain. While GLS1 iHET mice showed some recombination prior to tamoxifen, there was no impact on mRNA levels. We then asked whether induction of GLS heterozygosity would attenuate the locomotor response to propsychotic amphetamine challenge. Before tamoxifen, control and GLS1 iHET mice did not differ in their response to amphetamine. One month after tamoxifen treatment, amphetamine-induced hyperlocomotion was blocked in GLS1 iHET mice. The block was largely maintained after 5 months. Thus, a genetically induced glutaminase reduction-mimicking pharmacological inhibition-strongly attenuated the response to a propsychotic challenge, suggesting that glutaminase may be a novel target for the pharmacotherapy of schizophrenia. These results demonstrate how genetic pharmacotherapy can be implemented to test a CNS target in advance of the development of specific neuroactive inhibitors. We discuss further the advantages, limitations, and feasibility of the wider application of genetic pharmacotherapy for neuropsychiatric drug development.

Delayed disease onset and extended survival in the SOD1G93A rat model of amyotrophic lateral sclerosis after suppression of mutant SOD1 in the motor cortex.

Sporadic amyotrophic lateral sclerosis (ALS) is a fatal disease with unknown etiology, characterized by a progressive loss of motor neurons leading to paralysis and death typically within 3-5 years of onset. Recently, there has been remarkable progress in understanding inherited forms of ALS in which well defined mutations are known to cause the disease. Rodent models in which the superoxide dismutase-1 (SOD1) mutation is overexpressed recapitulate hallmark signs of ALS in patients. Early anatomical changes in mouse models of fALS are seen in the neuromuscular junctions (NMJs) and lower motor neurons, and selective reduction of toxic mutant SOD1 in the spinal cord and muscle of these models has beneficial effects. Therefore, much of ALS research has focused on spinal motor neuron and NMJ aspects of the disease. Here we show that, in the SOD1(G93A) rat model of ALS, spinal motor neuron loss occurs presymptomatically and before degeneration of ventral root axons and denervation of NMJs. Although overt cell death of corticospinal motor neurons does not occur until disease endpoint, we wanted to establish whether the upper motor neuron might still play a critical role in disease progression. Surprisingly, the knockdown of mutant SOD1 in only the motor cortex of presymptomatic SOD1(G93A) rats through targeted delivery of AAV9-SOD1-shRNA resulted in a significant delay of disease onset, expansion of lifespan, enhanced survival of spinal motor neurons, and maintenance of NMJs. This datum suggests an early dysfunction and thus an important role of the upper motor neuron in this animal model of ALS and perhaps patients with the disease.

Traumatic brain injury reveals novel cell lineage relationships within the subventricular zone.

The acute response of the rodent subventricular zone (SVZ) to traumatic brain injury (TBI) involves a physical expansion through increased cell proliferation. However, the cellular underpinnings of these changes are not well understood. Our analyses have revealed that there are two distinct transit-amplifying cell populations that respond in opposite ways to injury. Mash1+ transit-amplifying cells are the primary SVZ cell type that is stimulated to divide following TBI. In contrast, the EGFR+ population, which has been considered to be a functionally equivalent progenitor population to Mash1+ cells in the uninjured brain, becomes significantly less proliferative after injury. Although normally quiescent GFAP+ stem cells are stimulated to divide in SVZ ablation models, we found that the GFAP+ stem cells do not divide more after TBI. We found, instead, that TBI results in increased numbers of GFAP+/EGFR+ stem cells via non-proliferative means-potentially through the dedifferentiation of progenitor cells. EGFR+ progenitors from injured brains only were competent to revert to a stem cell state following brief exposure to growth factors. Thus, our results demonstrate previously unknown changes in lineage relationships that differ from conventional models and likely reflect an adaptive response of the SVZ to maintain endogenous brain repair after TBI.

The past, present and future of stem cell clinical trials for ALS.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that is characterized by progressive degeneration of motor neurons in the cortex, brainstem and spinal cord. This leads to paralysis, respiratory insufficiency and death within an average of 3 to 5 years from disease onset. While the genetics of ALS are becoming more understood in familial cases, the mechanisms underlying disease pathology remain unclear and there are no effective treatment options. Without understanding what causes ALS it is difficult to design treatments. However, in recent years stem cell transplantation has emerged as a potential new therapy for ALS patients. While motor neuron replacement remains a focus of some studies trying to treat ALS with stem cells, there is more rationale for using stem cells as support cells for dying motor neurons as they are already connected to the muscle. This could be through reducing inflammation, releasing growth factors, and other potential less understood mechanisms. Prior to moving into patients, stringent pre-clinical studies are required that have at least some rationale and efficacy in animal models and good safety profiles. However, given our poor understanding of what causes ALS and whether stem cells may ameliorate symptoms, there should be a push to determine cell safety in pre-clinical models and then a quick translation to the clinic where patient trials will show if there is any efficacy. Here, we provide a critical review of current clinical trials using either mesenchymal or neural stem cells to treat ALS patients. Pre-clinical data leading to these trials, as well as those in development are also evaluated in terms of mechanisms of action, validity of conclusions and rationale for advancing stem cell treatment strategies for this devastating disorder.