Investigating the Safety and Efficacy of Therapeutic Hypothermia in Pediatric Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

BACKGROUND: Prior guidelines recommended maintaining normothermia following traumatic brain injury (TBI), but recent studies suggest therapeutic hypothermia as a viable option in pediatric cases. However, some others demonstrated a higher mortality rate. Hence, the impact of hypothermia on neurological symptoms and overall survival remains contentious. METHODS: We conducted a systematic review and meta-analysis to evaluate the effects of hypothermia on neurological outcomes in pediatric TBI patients. The PubMed/Medline, Scopus, and Web of Science databases were searched until 1 January 2024 and data were analyzed using appropriate statistical methods. RESULTS: A total of eight studies, comprising nine reports, were included in this analysis. Our meta-analysis did not reveal significant differences in mortality (RR = 1.58; 95% CI = 0.89-2.82, p = 0.055), infection (RR = 0.95: 95% CI = 0.79-1.1, p = 0.6), arrhythmia (RR = 2.85: 95% CI = 0.88-9.2, p = 0.08), hypotension (RR = 1.54: 95% CI = 0.91-2.6, p = 0.10), intracranial pressure (SMD = 5.07: 95% CI = -4.6-14.8, p = 0.30), hospital length of stay (SMD = 0.10; 95% CI = -0.13-0.3, p = 0.39), pediatric intensive care unit length of stay (SMD = 0.04; 95% CI = -0.19-0.28, p = 0.71), hemorrhage (RR = 0.86; 95% CI = 0.34-2.13, p = 0.75), cerebral perfusion pressure (SMD = 0.158: 95% CI = 0.11-0.13, p = 0.172), prothrombin time (SMD = 0.425; 95% CI = -0.037-0.886, p = 0.07), and partial thromboplastin time (SMD = 0.386; 95% CI = -0.074-0.847, p = 0.10) between the hypothermic and non-hypothermic groups. However, the heart rate was significantly lower in the hypothermic group (-1.523 SMD = -1.523: 95% CI = -1.81--1.22 p < 0.001). CONCLUSIONS: Our findings challenge the effectiveness of therapeutic hypothermia in pediatric TBI cases. Despite expectations, it did not significantly improve key clinical outcomes. This prompts a critical re-evaluation of hypothermia's role as a standard intervention in pediatric TBI treatment.

Prognostic risk factors for early outcomes of patients with myelomeningocele: a prospective study.

INTRODUCTION: Myelomeningocele (MMC) is a prevalent form of neural tube defect. Despite advancements in treatment, MMC still poses significant health risks, including complications leading to chronic disability and mortality. Identifying prognostic risk factors for early outcomes is crucial for tailored intervention strategies. METHODS: This prospective study involved newborns and infants diagnosed with MMC who underwent surgery between 2020 and 2023 at Urmia University of Medical Sciences. Demographic data and surgical outcomes were collected, and participants were followed up for six months. Statistical analyses were conducted using descriptive statistics, Chi-Square, and independent t-test. RESULTS: The study included 29 MMC cases, with an incidence rate of 1.4 per 10,000 live births. Lesions were predominantly located in the lumbar spine. Although mortality rates appeared to increase with ascending lesion sites, this trend was not statistically significant. Short-term outcomes revealed high morbidity and mortality rates, with neurological deficits being the most prevalent complication. Multivariable analysis identified head circumference as a significant predictor of adverse outcomes (IRR = 1.37, 95% CI = 1.02 to 1.86, p = 0.04). Furthermore, an increase in birth weight was associated with a reduction in the incidence of requiring a ventriculoperitoneal shunt (IRR = 0.99, 95% CI = 0.998 to 0.999, p = 0.02). CONCLUSION: This prospective study highlights prognostic risk factors for early outcomes in MMC patients, emphasizing the need for personalized intervention strategies. By addressing modifiable risk factors and implementing targeted interventions, healthcare providers can strive to improve outcomes and enhance the quality of life for MMC patients.

SIMOA-based analysis of plasma NFL levels in MCI and AD patients: a systematic review and meta-analysis.

BACKGROUND: The single-molecule array assay (SIMOA)-based detection of neurofilament light (NFL) chain could be useful in diagnosing mild cognitive impairment (MCI) and Alzheimer's disease (AD). This meta-analysis aimed to evaluate the circulating concentration of NFL in AD and MCI patients compared with healthy controls using the SIMOA technique. METHODS: To this end, Google Scholar, PubMed, Scopus, Web of Science, and the reference lists of relevant articles were systematically searched for studies reporting serum NFL chain levels in healthy controls, MCI, and AD patients. Appropriate statistical methods were employed to achieve the study purpose. RESULTS: Fifteen eligible studies including 3086 patients were pooled out of a total of 347 publications. Fixed effect model analysis showed that NFL chain level was significantly higher in the serum of patients with MCI (0.361 SMD, 95% CI, 0.286-0.435, p = 0.000, I2 = 49.179) and AD (0.808 SMD, 95% CI, 0.727-0.888, p = 0.000, I2 = 39.433) compared with healthy individuals. The analysis also showed that the NFL chain levels in plasma were significantly different between patients with MCI and AD (0.436 SMD, 95% CI, 0.359-0.513, p = 0.000, I2 = 37.44). The overall heterogeneity of the studies was modest. CONCLUSIONS: This study highlights the potential of serum NFL chain detected using SIMOA in differentiating MCI, AD, and healthy controls.

Understanding Neuromodulation Pathways in tDCS: Brain Stem Recordings in Rat During Trigeminal Nerve Direct Current Stimulation.

Background: Recent evidence suggests that transcranial direct current stimulation (tDCS) indirectly influences brain activity through cranial nerve pathways, particularly the trigeminal nerve. However, the electrophysiological effects of direct current (DC) stimulation on the trigeminal nerve (DC-TNS) and its impact on trigeminal nuclei remain unknown. These nuclei exert control over brainstem centers regulating neurotransmitter release, such as serotonin and norepinephrine, potentially affecting global brain activity. Objectives: To investigate how DC-TNS impacts neuronal activity in the principal sensory nucleus (NVsnpr) and the mesencephalic nucleus of the trigeminal nerve (MeV). Methods: Twenty male Sprague Dawley rats (n=10 each nucleus) were anesthetized with urethane. DC stimulation, ranging from 0.5 to 3 mA, targeted the trigeminal nerve's marginal branch. Simultaneously, single-unit electrophysiological recordings were obtained using a 32-channel silicon probe, comprising three one-minute intervals: pre-stimulation, DC stimulation, and post-stimulation. Xylocaine was administered to block the trigeminal nerve as a control. Results: DC-TNS significantly increased neuronal spiking activity in both NVsnpr and MeV, returning to baseline during the post-stimulation phase. When the trigeminal nerve was blocked with xylocaine, the robust 3 mA trigeminal nerve DC stimulation failed to induce increased spiking activity in the trigeminal nuclei. Conclusion: Our results offer initial empirical support for trigeminal nuclei activity modulation via DC-TNS. This discovery supports the hypothesis that cranial nerve pathways may play a pivotal role in mediating tDCS effects, setting the stage for further exploration into the complex interplay between peripheral nerves and neural modulation techniques. Highlights: Direct current stimulation of the trigeminal nerve (DC-TNS) modulates neural activity in rat NVsnpr and MeV.Xylocaine administration reversibly blocks the DC-TNS effect on neural responses.Trigeminal nerve stimulation should be considered a possible mechanism of action of tDCS.

Reinterpreting published tDCS results in terms of a cranial and cervical nerve co-stimulation mechanism.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation method that has been used to alter cognition in hundreds of experiments. During tDCS, a low-amplitude current is delivered via scalp electrodes to create a weak electric field in the brain. The weak electric field causes membrane polarization in cortical neurons directly under the scalp electrodes. It is generally assumed that this mechanism causes the observed effects of tDCS on cognition. However, it was recently shown that some tDCS effects are not caused by the electric field in the brain but rather via co-stimulation of cranial and cervical nerves in the scalp that also have neuromodulatory effects that can influence cognition. This peripheral nerve co-stimulation mechanism is not controlled for in tDCS experiments that use the standard sham condition. In light of this new evidence, results from previous tDCS experiments could be reinterpreted in terms of a peripheral nerve co-stimulation mechanism. Here, we selected six publications that reported tDCS effects on cognition and attributed the effects to the electric field in the brain directly under the electrode. We then posed the question: given the known neuromodulatory effects of cranial and cervical nerve stimulation, could the reported results also be understood in terms of tDCS peripheral nerve co-stimulation? We present our re-interpretation of these results as a way to stimulate debate within the neuromodulation field and as a food-for-thought for researchers designing new tDCS experiments.

Deep brain stimulation for the treatment of Alzheimer's disease: A systematic review and meta-analysis.

Background: One of the experimental neuromodulation techniques being researched for the treatment of Alzheimer's disease (AD) is deep brain stimulation (DBS). To evaluate the effectiveness of DBS in AD, we performed a systematic review and meta-analysis of the available evidence. Methods: From the inception through December 2021, the following databases were searched: Medline via PubMed, Scopus, Embase, Cochrane Library, and Web of Science. The search phrases used were "Alzheimer's disease," "AD," "deep brain stimulation," and "DBS." The information from the included articles was gathered using a standardized data-collecting form. In the included papers, the Cochrane Collaboration methodology was used to evaluate the risk of bias. A fixed-effects model was used to conduct the meta-analysis. Results: Only five distinct publications and 6 different comparisons (one study consisted of two phases) were included out of the initial 524 papers that were recruited. DBS had no impact on the cognitive ability in patients with AD [0.116 SMD, 95% confidence interval (CI), -0.236 to 0.469, p = 0.518]. The studies' overall heterogeneity was not significant (κ2 = 6.23, T 2 = 0.053, df = 5, I 2 = 19.76%, p = 0.284). According to subgroup analysis, the fornix-DBS did not improve cognitive function in patients with AD (0.145 SMD, 95%CI, -0.246 to 0.537, p = 0.467). Unfavorable neurological and non-neurological outcomes were also reported. Conclusion: The inconsistencies and heterogeneity of the included publications in various target and age groups of a small number of AD patients were brought to light by this meta-analysis. To determine if DBS is useful in the treatment of AD, further studies with larger sample sizes and randomized, double-blinded, sham-controlled designs are required.

Coenzyme Q10 ameliorates aging-induced memory deficits via modulation of apoptosis, oxidative stress, and mitophagy in aged rats.

The behavioral effects and molecular signaling mechanisms of Coenzyme Q10 (Q10) in age-related memory impairment are poorly understood. This study aimed to investigate the effects of Q10 on memory impairment, oxidative stress, apoptosis, and mitophagy in aged rats. 40 aged (24 months old) and 10 young (3 months old) male Wistar rats were randomly divided into the following groups (n = 10/group): young + vehicle, aged + vehicle, and aged + Q10 (at 100, 200, 300 mg/kg/day doses). Treatments were administrated orally by gavage for 2 weeks. The novel object recognition test was used to assess episodic memory. Oxidative stress, apoptosis, and mitophagy-related protein expressions were measured in the hippocampus. We found that Q10 reversed aging-induced memory impairment at the dose of 300 mg/kg. Moreover, aging was associated with a reduction in ATP production, decrease in mitophagy-related proteins (PINK, Parkin, and P62 levels and LC3II/I ratio), excessive generation of reactive oxygen species and lipid peroxidation, and apoptosis in the hippocampus, which were partially reversed following oral administration of Q10. These findings indicate the therapeutic potential of Q10 in aging-induced memory decline.

Cerebrolysin® and Environmental Enrichment, Alone or in Combination, Ameliorate Anxiety- and Depressive-Like Behaviors in a Post-Ischemic Depression Model in Mice.

OBJECTIVES: This study examined the beneficial effects of cerebrolysin (CBL) and enriched environment (EE), alone or in combination, on the neurobehavioral and molecular changes in the post-ischemic depression (PID) model in mice. MATERIALS AND METHODS: PID was induced in male Balb/c mice (25-30 g) by combining the transient bilateral common carotid artery occlusion (bCCAO), twice for 5 min at the interval of 10 min, with spatial restraint stress (2 h/day) for 2 weeks, started 48 h following the establishment of bCCAO model. Animals in the treatment groups received CBL (2.5 ml/kg) and/or were housed in EE (2 h/day) for two weeks. Anxiety- and depressive-like behaviors and sociability were evaluated the day after the last experiment. Changes in the serum corticosterone level, the hippocampal oxidative stress status, inflammatory cytokines, brain-derived neurotrophic factor (BDNF), and phosphorylated cAMP response element-binding protein (p-CREB)/CREB ratio were also detected. RESULTS: PID model induced anxiety- and depressive-like behaviors and impaired social behavior. These behavioral changes were accompanied by increased serum corticosterone level, increased lipid peroxidation, decreased antioxidant enzyme activities, reduced BDNF levels and p-CREB/CREB ratio, and increased protein levels of NF-κB and Iba-1 in the hippocampus. However, treatment with CBL and/or EE reversed behavioral and molecular changes induced by PID. CONCLUSION: Our findings imply that the model mimics many manifestations of human PID, and CBL and EE treatments, separately or in combination, are beneficial in reducing anxiety- and- depressive-like behaviors in this model.

A systematic review and meta-analysis of transcranial direct-current stimulation effects on cognitive function in patients with Alzheimer's disease.

Transcranial direct-current stimulation (tDCS) appears to enhance cognitive function in Alzheimer's disease (AD). Accordingly, over the last two decades, the number of studies using tDCS for AD has grown. This study aimed to provide a quantitative assessment of the efficacy of tDCS in improving cognitive function in patients with AD. We systematically searched the literature until May 2021 to identify relevant publications for inclusion in our systematic review and meta-analysis. Eligible studies were sham-controlled trials assessing the impacts of anodal or cathodal tDCS on cognitive function in patients with AD. The outcome measure of this study was the effects of tDCS on distinct cognitive domains including memory, attention, and global cognitive function. The initial search yielded a total of 323 records. Five other articles were found using manual search of the databases. Of these, 13 publications (14 different studies) with a total of 211 patients of various degrees of AD severity underwent meta-analysis. Meta-analysis revealed the non-significant effects of tDCS on attention (0.425 SMD, 95% CI, -0.254 to 1.104, p = 0.220), and significant positive impacts on the amelioration of general cognitive measures (1.640 SMD, 95% CI, 0.782 to 2.498, p < 0.000), and memory (1.031 SMD, 95% CI, 0.688 to 1.373, p < 0.000) dysfunction in patients with AD. However, the heterogeneity of the studies were high in all subdomains of cognition (Ï°2 = 22.810, T2 = 0.552, d.f. = 5, I2 = 78.80%, p < 0.000 for attention, Ï°2 = 96.29, T2 = 1.727, d.f. = 10, I2 = 89.61%, p < 0.000 for general cognition, and Ï°2 = 7.253, T2 = 0.085, d.f. = 5, I2 = 31.06%, p = 0.203 for memory). Improved memory and general cognitive function in patients with AD was shown in this meta-analysis. However, due to the small number of studies and the high heterogeneity of the data, more high-quality studies using standardized parameters and measures are needed before tDCS can be considered as a treatment for AD.

Heat stress aggravates oxidative stress, apoptosis, and endoplasmic reticulum stress in the cerebellum of male C57 mice.

BACKGROUND: The current study was set to assess the effect of heat stress exposure on oxidative stress, apoptosis, and endoplasmic reticulum stress markers in the cerebellum of male mice. METHODS: Fifty male C57BL/6 mice were assigned to five groups of (I) control, (II) heat stress (HS)7, (III) HS14, (IV) HS21, and (V) HS42 groups. Animals in the control group were not exposed to HS. Mice in the II-V groups were exposed to HS once a day over 7, 14, 21, and 42 days, respectively. Cerebellar reactive oxygen species (ROS) levels, expression of heat shock protein (HSP)70 and caspase 3 as well as endoplasmic reticulum stress-related proteins (PERK, p-PERK, CHOP, and Full-length ATF-6) expression were determined on the 7th, 14th, 21st, and 42nd days. RESULTS: ROS levels and HSP70 expression increased following HS on the 14th, 21st, and 42nd days and the 7th, and 14th days with a peak level of expression on the 14th day following HS. HSP70 levels decreased afterward on the 21st and 42nd days compared with the control group. Besides, exposure to HS for 14, 21, and 42 days resulted in a significant increase in the CHOP and p-PERK levels in the cerebellum compared with the control group. Heat exposure also increased protein expression of cleaved caspase 3 and active ATF-6/Full-length ATF-6 on the 21st and 42nd days in the cerebellum compared with the control animals. CONCLUSION: These findings indicated that chronic HS augmented oxidative stress, endoplasmic reticulum stress, and apoptosis pathways in the cerebellum of mice.

Sericin protects against acute sleep deprivation-induced memory impairment via enhancement of hippocampal synaptic protein levels and inhibition of oxidative stress and neuroinflammation in mice.

Sleep deprivation (SD) induces learning and memory deficits via inflammatory responses and oxidative stress. On the other hand, sericin (Ser) possesses potent antioxidant and neuroprotective effects. We investigated the effect of different doses of Ser on the SD-induced cognitive impairment. Ser (100, 200, and 300 mg/kg) was administered to animals via oral gavage for 8 days, 5 days before to SD, and during SD. SD was induced in mice using a modified multiple platform model, starting on the 6th day for 72 h. Spatial learning and memory were assessed using the Lashley III maze. Serum corticosterone level, and hippocampal malondialdehyde (MDA), total antioxidant capacity (TAC), and the activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymes were evaluated. The expression of growth-associated protein 43 (GAP-43), post-synaptic density-95 (PSD-95), synapsin 1 (SYN-1), and synaptophysin (SYP), and inflammation markers were detected by western blotting. SD caused cognitive impairment, while Ser pretreatment prevented such an effect. Serum corticosterone also increased with SD, but its levels were suppressed in SD mice receiving Ser. Furthermore, Ser normalized SD-induced reduction in the hippocampus activity of SOD and GPx, increased TAC, and decreased MDA levels. Besides, Ser pretreatment increased GAP-34, SYP, SYN-I, and PSD-95 and reduced IL1-ß and TNF-α in the hippocampus. SD induced memory impairment and pretreatment with Ser improved memory via its antioxidant, anti-inflammation, and up-regulation of synaptic proteins in the hippocampus.

Effects of transdermal nicotine delivery on cognitive outcomes: A meta-analysis.

OBJECTIVE: By the association of nicotinic acetylcholine receptors in the brain, nicotine in the therapeutic window lowers neuronal damage and raises protective factors. These data, however, are contradicted by other findings. Here, we assessed the effects of transdermal nicotine administration on cognitive functions in healthy non-smoker adults by systematic review and meta-analysis of clinical trials. METHODS: We included reports of clinical trials comparing the effects of nicotine patches with placebo in healthy non-smoking adults. The main outcome was the impact of nicotine patches on overall cognitive function with a focus on attention and memory. Standard meta-analytic and statistical methods measured the effect of transdermal nicotine compared with placebo patches. RESULTS: We included 31 publications involving 978 subjects. Nicotine patches boosted cognitive function in healthy adults (0.233 SMD, 95%CI, 0.111-0.355, p < .001). Overall heterogeneity of the studies was found to be modest (Ï°2  = 68.24, T2  = 0.07, I2  = 50.17%, p < .001). Also, nicotine patches improved attention (0.231 SMD, 95%CI, 0.106-0.356, p < .001). We found the inter-study heterogeneity to be low (Ï°2  = 40.95, T2  = 0.03, I2  = 34.07%, p = .042). Further, the enhancement of memory by transdermal nicotine did not reach statistical significance in normal subjects (0.270 SMD, 95% CI, -0.293-0.833, p = .347). Also, high inter-study heterogeneity was found among studies (Ï°2  = 27.25, T2  = 0.43, I2  = 77.98%, p < .001). CONCLUSION: The meta-analysis showed that transdermal nicotine had statistically significant positive effects on attention, and non-significant effects on memory, in healthy non-smoking adults. The results encourage further studies of the therapeutic potential of nicotine patches in disorders of cognition.

The correlation between circulating inflammatory, oxidative stress, and neurotrophic factors level with the cognitive outcomes in multiple sclerosis patients.

INTRODUCTION: Changes in the levels of circulating markers of inflammation, oxidative stress, and neurotrophic factors might be a good candidate for the prediction of cognitive impairment in multiple sclerosis (MS). Here, the correlation between the mentioned circulating markers with the Cambridge neuropsychological test automated battery (CANTAB) task outcomes was determined in MS patients. METHODS: The CANTAB (paired-associate learning (PAL), reaction time (RTI), rapid visual information processing (RVP), and spatial working memory tasks (SWM)) was completed by the patients. Accordingly, the serum levels of interferon-γ (INF-γ), C-reactive protein (CRP), ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF), malondialdehyde (MDA), total antioxidant capacity (TAC), and the acetylcholine esterase (AChE) activity were measured. Cognitive impairment status and the correlation between the circulating factors with the CANTAB outcomes were determined. RESULTS: The cognitively impaired (CI) patients appropriately differentiated from not cognitively impaired (NCI) ones using the CANTAB tasks. The serum levels of MDA, TAC, CRP, INF-γ, and GDNF correlated with the cognitive scores in MS patients (p < 0.05). After adjusting for age, sex, disease duration, and disability levels (covariates in a regression model), the MDA, INF-γ, and GDNF factors levels were statistically different between CI and NCI groups (p < 0.05). DISCUSSION: The mentioned markers might predict the cognitive impairment progress and be used as an index of its detection, in addition to neuropsychological assessments, in MS patients.

Ceftriaxone Plus Methylprednisolone Combination Therapy Versus Methylprednisolone Monotherapy in Patients With Acute Spinal Cord Injury: A Randomized, Triple-Blind Clinical Trial.

BACKGROUND: Guidelines do not suggest the routine use of methylprednisolone (MP) in patients with acute traumatic spinal cord injury (SCI). We tested the hypothesis regarding whether combination therapy with ceftriaxone and MP is superior to MP monotherapy in patients with acute traumatic SCI. METHODS: In a randomized, triple-blind clinical trial, 60 patients with acute (first 8 hours of the injury) traumatic SCI were enrolled at the Tabriz University of Medical Sciences, Tabriz, Iran, between December 2016 and June 2017. Accordingly, the patients were randomly divided into 2 case and control groups (n = 30 each). Upon admission, all included patients received a bolus dose of MP at 33 mg/kg intravenously (IV) for 15 minutes. Then, after 45 minutes, MP infusion was continued for 24 to 48 hours at a 5.4 mg/kg IV dose. The case group received an additional dose of ceftriaxone at 1 g 2 times a day for 7 days through an IV route. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were checked and compared between case and control groups upon admission and on the fourth and eighth days. Also, sensory and motor functions were evaluated according to the American Spinal Injury Association (ASIA) grading score upon admission, on the third and seventh days, upon discharge and 6 months after admission. RESULTS: Analyses showed a significant statistical difference between groups in the changes in CRP levels during days 1 and 4 (P = .001) and also during days 4 and 8 (P = .001). However, no significant statistical difference was detected in ESR levels changes between groups during days 1 and 4 (P = .073), and during days 4 and 8 (P = .069). ASIA scale was found to be significantly different between the MP plus ceftriaxone group and MP monotherapy upon admission and 6 months after treatment (P = .001 for both comparisons). However, the number of variations in the ASIA score had no significant statistical difference between groups 6 months after intervention (P = .465). CONCLUSION: The addition of ceftriaxone to the routine therapeutic protocol of acute SCI is accompanied by improved inflammation markers and functional outcomes 6 months after the intervention.

Pharmacotherapy in multiple sclerosis-induced cognitive impairment: A systematic review and meta-analysis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) commonly complicated by cognitive impairment. Unfortunately, no medical therapy has been proved to improve cognitive problems in these patients. This meta-analysis investigated the effectiveness of different categories of drugs on the minimal assessment of cognitive function in MS (MACFIMS)-related tasks outcome in MS patients. To this end, a systematic evaluation was conducted using PubMed, Google Scholar, and Scopus databases. Among a total of 128 publications, 31 studies met our inclusion criteria, and 22 included in the meta-analysis. We found that symbol digit modalities test (SDMT), paced auditory serial addition test (PASAT), controlled oral word association test (COWAT), and California verbal learning test (CVLT) were the most frequently reported tasks in included studies. The frequently reported drugs were classified into five main groups of acetylcholine esterase inhibitors, CNS stimulants, fampridine, herbal remedies, and miscellaneous. Overall heterogeneity of the studies was modest. The treatments did not affect cognitive function in any of the tasks (p>0.05). However, in subgroup analysis, we found significant improvement in SDMT task outecomes after treatment by fampridine (0.283 SMD, 95%CI, 0.015 to 0.550, p = 0.039, I2=11.7%). Our meta-analysis highlighted that the currently proposed therapeutic agents had no beneficial effects on the alleviation of MS-induced cognitive impairment.

Cotinine ameliorates memory and learning impairment in senescent mice.

This study aimed to assess the effects of cotinine on age-induced memory and learning impairment and related downstream pathways in mice. Thirty aged (18-month old) and 10 young mice (8-week old) were randomly divided into 4 groups (n = 10 each) and subjected to cotinine at 5 mg/kg dose and/or methyllycaconitine (MLA) at 1 mg/kg, i.p. dose (α7 nAChRs antagonist) for 4 weeks. Morris water maze (MWM) and novel object recognition (NOR) tasks were used to assess spatial and recognition learning and memories of the mice, respectively. Levels of oxidative stress, apoptosis, neuroinflammation, and structural synaptic plasticity, and also neurotrophic factors and α7 nAChRs were assessed in the hippocampus using either ELISA or Western blotting. Aging was associated with learning and memory disabilities and dysregulation of the assessed pathways in the hippocampus of mice. Chronic cotinine treatment improved learning and memory in aged animals, indicated by decreased latency time, and increased time spent in the target quadrant and discrimination index (DI) in the MWM and NOR tasks. Also, chronic cotinine injection increased total antioxidant capacity (TAC), SOD and GSH-px activity, PSD-95, GAP-43, SYN, brain-derived neurotrophic factor, and neural growth factor levels and decreased malondialdehyde, TNF-α, and IL-1ß in the hippocampus of aged mice. Conversely, MLA treatment reversed most of the mentioned effects via the blockade of α7 nAChRs. Cotinine improves age-induced memory and learning impairment via its modulatory effects on α7 nAChRs and subsequent activation/deactivation of the mentioned pathways in the hippocampus of aged mice.

Neutrophil-to-Lymphocyte Ratio and Traumatic Brain Injury: A Review Study.

Traumatic brain injury (TBI) is the leading cause of morbidity and mortality worldwide. Several prognostic factors have been developed to predict functional outcomes and mortality rate in patients with TBI. Neutrophil-to-lymphocyte ratio (NLR) is an objective, available, low-cost, and reproducible indicator of inflammation. It is also a marker of extensive secondary damage caused by neutrophils and their products to the cerebral tissue. Accordingly, NLR has been proposed as a valuable outcome predictor in patients with TBI. Evidence emerging from several studies shows that higher NLR value is an independent predictor of poorer functional outcomes and higher mortality rate in patients with severe TBI. Further, higher NLR value is in correlation with lower Glasgow Coma Scale scores. Thus its role as a complementary index to other factors, such as Glasgow Coma Scale, in predicting outcomes after TBI is under investigation. This review aims at gathering the most recent data on the prognostic value of NLR in patients with TBI.

The Cambridge Neuropsychological Test Automated Battery (CANTAB) Versus the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) for the Assessment of Cognitive Function in Patients with Multiple Sclerosis.

BACKGROUND: We determined how the Cambridge Neuropsychological Test Automated Battery (CANTAB) compared to the Minimal Assessment of Cognitive Function in multiple sclerosis (MACFIMS) in terms of sensitivity, specificity, and predictive values in detecting cognitive impairment in multiple sclerosis (MS) patients. METHODS: Sixty MS patients were recruited, 2 of whom were lost to follow-up. On the first day of the neuropsychological examination, the standard MACFIMS battery and the day after, the CANTAB (paired-associate learning (PAL), reaction time (RTI), rapid visual information processing (RVP), and spatial working memory tasks (SWM)) were completed by the patients. The sensitivity, specificity, and predictive values of the CANTAB in the differentiation of cognitively impaired (CI) patients from not cognitively impaired (NCI) ones were compared with those of the MACFIMS battery using appropriate statistical tests. RESULTS: Fifty-eight patients were categorized into two groups of CI (n=16 (27.58%)) and NCI (n=42 (72.41%)) based on the MACFIMS battery standard criteria. The best reporter indices and their cut-off scores for differentiation of CI from NCI patients in each task of the CANTAB were "total errors=13" for PAL, "between errors=26" for SWM, "five-choice reaction time=368.57" for RTI, and "mean latency=522.14" for RVP. The optimal cut-off point for distinguishing CI from NCI in the CANTAB was found to be an impaired function in 3 or more tasks [(AUC (95% CI): 0.97 (0.94-1.00); p<0.001)]. Accordingly, 36.20% of the patients were CI based on the CANTAB criteria. The inter-test agreement (CANTAB and MACFIMS batteries) was found to be the highest (Cohen's κ (95% CI): 0.80 (0.64-0.96)). CONCLUSION: Results confirm that the CANTAB can discriminate CI from NCI MS patients with high accuracy, and its results are comparable to those of the MACFIMS battery; thus, they might be interchangeably used in the clinical practice.

Serotonergic system modulation holds promise for L-DOPA-induced dyskinesias in hemiparkinsonian rats: A systematic review.

The alleged effects of serotonergic agents in alleviating levodopa-induced dyskinesias (LIDs) in parkinsonian patients are debatable. To this end, we systematically reviewed the serotonergic agents used for the treatment of LIDs in a 6-hydroxydopamine model of Parkinson's disease in rats. We searched MEDLINE via PubMed, Embase, Google Scholar, and Proquest for entries no later than March 2018, and restricted the search to publications on serotonergic agents used for the treatment of LIDs in hemiparkinsonian rats. The initial search yielded 447 citations, of which 49 articles and one conference paper met our inclusion criteria. The results revealed ten different categories of serotonergic agents, including but not limited to 5-HT1A/BR agonists, 5-HT2AR antagonists, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitor (SNRIs), and tricyclic antidepressants (TCAs), all of which improved LIDs without imposing considerable adverse effects. Although there is promising evidence regarding the role of these agents in relieving LIDs in hemiparkinsonian rats, further studies are needed for the enlightenment of hidden aspect of these molecules in terms of mechanisms and outcomes. Given this, improving the quality of the pre-clinical studies and designing appropriate clinical trials will help fill the bench-to-bedside gap.

Amyloid-ß, tau, and the cholinergic system in Alzheimer's disease: seeking direction in a tangle of clues.

The link between histopathological hallmarks of Alzheimer's disease (AD), i.e. amyloid plaques, and neurofibrillary tangles, and AD-associated cognitive impairment, has long been established. However, the introduction of interactions between amyloid-beta (Aß) as well as hyperphosphorylated tau, and the cholinergic system to the territory of descriptive neuropathology has drastically changed this field by adding the theory of synaptic neurotransmission to the toxic pas de deux in AD. Accumulating data show that a multitarget approach involving all amyloid, tau, and cholinergic hypotheses could better explain the evolution of events happening in AD. Various species of both Aß and tau could be traced in cholinergic neurons of the basal forebrain system early in the course of the disease. These molecules induce degeneration in the neurons of this system. Reciprocally, aberrant cholinergic system modulation promotes changes in amyloid precursor protein (APP) metabolism and tau phosphorylation, resulting in neurotoxicity, neuroinflammation, and neuronal death. Altogether, these changes may better correlate with the clinical findings and cognitive impairment detected in AD patients. Failure of several of Aß- and tau-related therapies further highlights the need for special attention to molecules that target all of these mentioned pathologic changes. Another noteworthy fact here is that none of the popular hypotheses of AD such as amyloidopathy or tauopathy seem to be responsible for the changes observed in AD alone. Thus, the main culprit should be sought higher in the stream somewhere in APP metabolism or Wnt signaling in the cholinergic system of the basal forebrain. Future studies should target these pathological events.