Influence of cannabis use history on the impact of acute cannabis smoking on simulated driving performance during a distraction task.

Objective: This research explores the driving performance of people who use cannabis daily or occasionally during distraction tasks performed following acute cannabis use.Methods: Healthy adults aged 25 to 45 years with different cannabis usage histories were recruited to participate in a within-subjects controlled experiment using a car-based driving simulator. Participants were classified as having daily use (n = 31), occasional use (1 or 2 times per week; n = 24), or no-use (n = 30). Participants completed a practice drive followed by four 5-10 minute driving scenarios during the baseline period. Participants then smoked self-procured cannabis flower ad libitum for up to 15 minutes. Thirty minutes later, they completed four additional 5-10 minute scenarios. Scenarios were paired according to difficulty and randomized across the baseline and post-use periods. Each scenario contained between 0 and 3 repetitions of a distraction task where the participant was prompted by an audio message to select an app from a 4 × 5 grid displayed on a mounted tablet, a step that would require briefly looking away from the roadway. Measures of driving performance (lane departures, standard deviation of lateral position) were assessed during the five-second period following the audio trigger and analyzed using generalized linear mixed models.Results: Those with a pattern of occasional use were significantly more likely to experience a lane departure during distraction periods after acute cannabis use relative to baseline (OR = 3.71, p = 0.04, CI = 1.04, 13.17), while those with daily use did not exhibit a similar increase (OR = 1.56, p = 0.43, CI = 0.52, 4.64). Changes in departure risk were significantly greater for the occasional use group compared to no-use (p = 0.02), but not for the daily use group compared to no-use (p = 0.18). However, following acute use, those who use daily exhibited decreases in speed relative to baseline in comparison to the changes observed in the no-use group (p = 0.02), while differences between occasional and no-use did not reach statistical significance (p = 0.052). Differences in standard deviation of lateral position were not statistically significant, likely due to the short duration of tasks.Conclusions: These results find the largest potential safety concerns associated with a pattern of occasional use, who displayed an increase in lane departures after acute cannabis smoking. Those in the daily use group decreased their speed, which may be interpreted as compensation for drug effects. Further research is needed to understand the effects during longer and more complex secondary tasks.

Clinical impacts of frailty, poor performance status, and advanced age in carfilzomib-containing treatment for relapsed/refractory multiple myeloma: post hoc investigation of the KOTOSG multicenter pilot prospective observational study.

We conducted a post hoc analysis of our previous pilot observational study on the efficacy and safety of carfilzomib (CFZ)-containing therapy in 50 patients with relapsed/refractory multiple myeloma in routine practice to clarify the relationships between three major criteria for vulnerability (frailty, poor performance status [PS], and advanced age [≥ 75 years]) and their clinical impact on efficacy and adverse events (AEs). Sixteen patients fulfilled at least one and five patients fulfilled all three criteria. The overall response rate was not significantly affected by frailty, poor PS, and/or advanced age; however, frailty and advanced age were significantly associated with shorter progression-free survival (PFS). In contrast, no significant difference in PFS was observed between patients with PS0-1 or PS2-4. The three criteria for vulnerability were associated with more frequent hematologic AEs: frailty, poor PS, and/or advanced age significantly increased the risk of grade 3-4 anemia and lymphopenia. However, these criteria were not associated with increased risk of other non-hematologic AEs except infection. Collectively, these results demonstrate the need to carefully manage severe hematologic AEs in vulnerable patients and perform disease-specific assessment of frailty to predict prognosis.

Subacute AMD3100 Treatment Is Not Efficient in Neonatal Hypoxic-Ischemic Rats.

BACKGROUND AND PURPOSE: Despite the advances in treating neonatal hypoxic-ischemic encephalopathy (HIE) with induced hypothermia, the rates of severe disability are still high among survivors. Preclinical studies have indicated that cell therapies with hematopoietic stem/progenitor cells could improve neurological outcomes in HIE. In this study, we investigated whether the administration of AMD3100, a CXCR4 antagonist that mobilizes hematopoietic stem/progenitor cells into the circulation, has therapeutic effects in HIE. METHODS: P10 Wistar rats of both sexes were subjected to right common carotid artery occlusion or sham procedure, and then were exposed to hypoxia for 120 minutes. Two subcutaneous injections of AMD3100 or vehicle were given on the third and fourth day after HIE. We first assessed the interindividual variability in brain atrophy after experimental HIE and vehicle treatment in a small cohort of rats. Based on this exploratory analysis, we designed and conducted an experiment to test the efficacy of AMD3100. Brain atrophy on day 21 after HIE was defined as the primary end point. Secondary efficacy end points were cognitive (T-water maze) and motor function (rotarod) on days 17 and 18 after HIE, respectively. RESULTS: AMD3100 did not decrease the brain atrophy in animals of either sex. Cognitive impairments were not observed in the T-water maze, but male hypoxic-ischemic animals exhibited motor coordination deficits on the rotarod, which were not improved by AMD3100. A separate analysis combining data from animals of both sexes also revealed no evidence of the effectiveness of AMD3100 treatment. CONCLUSIONS: These results indicate that the subacute treatment with AMD3100 does not improve structural and functional outcomes in a rat HIE model.

Blockade of adenosine A2A receptor alleviates cognitive dysfunction after chronic exposure to intermittent hypoxia in mice.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is widely known for its multiple systems damage, especially neurocognitive deficits in children. Since their discovery, adenosine A2A receptors (A2ARs) have been considered as key elements in signaling pathways mediating neurodegenerative diseases such as Huntington's and Alzheimer's, as well as cognitive function regulation. Herein, we investigated A2AR role in cognitive impairment induced by chronic intermittent hypoxia (CIH). Mice were exposed to CIH 7 h every day for 4 weeks, and intraperitoneally injected with A2AR agonist CGS21680 or A2AR antagonist SCH58261 half an hour before IH exposure daily. The 8-arm radial arm maze was utilized to assess spatial memory after CIH exposures.To validate findings using pharmacology, the impact of intermittent hypoxia was investigated in A2AR knockout mice. CIH-induced memory dysfunction was manifested by increased error rates in the radial arm maze test. The behavioral changes were associated with hippocampal pathology, neuronal apoptosis, and synaptic plasticity impairment. The stimulation of adenosine A2AR exacerbated memory impairment with more serious neuropathological damage, attenuated long-term potentiation (LTP), syntaxin down-regulation, and increased BDNF protein. Moreover, apoptosis-promoting protein cleaved caspase-3 was upregulated while anti-apoptotic protein Bcl-2 was downregulated. Consistent with these findings, A2AR inhibition with SCH58261 and A2AR deletion exhibited the opposite result. Overall, these findings suggest that A2AR plays a critical role in CIH-induced impairment of learning and memory by accelerating hippocampal neuronal apoptosis and reducing synaptic plasticity. Blockade of adenosine A2A receptor alleviates cognitive dysfunction after chronic exposure to intermittent hypoxia in mice.

Administration of anti-ERMAP antibody ameliorates Alzheimer's disease in mice.

BACKGROUND: Alzheimer's disease (AD) is a devastating age-related neurodegenerative disorder and characterized by progressive loss of memory and cognitive functions, which are associated with amyloid-beta (Aß) plaques. Immune cells play an important role in the clearance of Aß deposits. Immune responses are regulated by immune regulators in which the B7 family members play a crucial role. We have recently identified erythroid membrane-associated protein (ERMAP) as a novel B7 family-related immune regulator and shown that ERMAP protein affects T cell and macrophage functions. METHODS: We produced a monoclonal antibody (mAb) against ERMAP protein and then determined the ability of the mAb to affect cognitive performance and AD pathology in mice. RESULTS:  We have shown that the anti-ERMAP mAb neutralizes the T cell inhibitory activity of ERMAP and enhances macrophages to phagocytose Aß in vitro. Administration of the mAb into AD mice improves cognitive performance and reduces Aß plaque load in the brain. This is related to increased proportion of T cells, especially IFNγ-producing T cells, in the spleen and the choroid plexus (CP), enhanced expression of immune cell trafficking molecules in the CP, and increased migration of monocyte-derived macrophages into the brain. Furthermore, the production of anti-Aß antibodies in the serum and the macrophage phagocytosis of Aß are enhanced in the anti-ERMAP mAb-treated AD mice. CONCLUSIONS: Our results suggest that manipulating the ERMAP pathway has the potential to provide a novel approach to treat AD patients.

A novel bedtime pulsatile-release caffeine formula ameliorates sleep inertia symptoms immediately upon awakening.

Sleep inertia is a disabling state of grogginess and impaired vigilance immediately upon awakening. The adenosine receptor antagonist, caffeine, is widely used to reduce sleep inertia symptoms, yet the initial, most severe impairments are hardly alleviated by post-awakening caffeine intake. To ameliorate this disabling state more potently, we developed an innovative, delayed, pulsatile-release caffeine formulation targeting an efficacious dose briefly before planned awakening. We comprehensively tested this formulation in two separate studies. First, we established the in vivo caffeine release profile in 10 young men. Subsequently, we investigated in placebo-controlled, double-blind, cross-over fashion the formulation's ability to improve sleep inertia in 22 sleep-restricted volunteers. Following oral administration of 160 mg caffeine at 22:30, we kept volunteers awake until 03:00, to increase sleep inertia symptoms upon scheduled awakening at 07:00. Immediately upon awakening, we quantified subjective state, psychomotor vigilance, cognitive performance, and followed the evolution of the cortisol awakening response. We also recorded standard polysomnography during nocturnal sleep and a 1-h nap opportunity at 08:00. Compared to placebo, the engineered caffeine formula accelerated the reaction time on the psychomotor vigilance task, increased positive and reduced negative affect scores, improved sleep inertia ratings, prolonged the cortisol awakening response, and delayed nap sleep latency one hour after scheduled awakening. Based on these findings, we conclude that this novel, pulsatile-release caffeine formulation facilitates the sleep-to-wake transition in sleep-restricted healthy adults. We propose that individuals suffering from disabling sleep inertia may benefit from this innovative approach.Trials registration: NCT04975360.

Mechanisms of cannabis impairment: Implications for modeling driving performance.

Past research on cannabis has been limited in scope to THC potencies lower than legally available and efforts to integrate the effects into models of driving performance have not been attempted to date. The purpose of this systematic review is to understand the implications for modeling driving performance and describe future research needs. The risk of motor vehicle crashes increases 2-fold after smoking marijuana. Driving during acute cannabis intoxication impairs concentration, reaction time, along with a variety of other necessary driving-related skills. Changes to legislation in North America and abroad have led to an increase in cannabis' popularity. This has given rise to more potent strains, with higher THC concentrations than ever before. There is also rising usage of novel ingestion methods other than smoking, such as oral cannabis products (e.g., brownies, infused drinks, candies), vaping, and topicals. The PRISMA guidelines were followed to perform a systematic search of the PubMed database for peer-reviewed literature. Search terms were combined with keywords for driving performance: driving, performance, impairment. Grey literature was also reviewed, including congressional reports, committee reports, and roadside surveys. There is a large discrepancy between the types of cannabis products sold and what is researched. Almost all studies that used inhalation as the mode of ingestion with cannabis that is around 6% THC. This pales in comparison to the more potent strains being sold today which can exceed 20%. Which is to say nothing of extracts, which can contain 60% or more THC. Experimental protocol is another gap in research that needs to be filled. Methodologies that involve naturalistic (real world) driving environments, smoked rather than vaporized cannabis, and non-lab certified products introduce uncontrollable variables. When considering the available literature and the implications of modeling the impacts of cannabis on driving performance, two critical areas emerge that require additional research: The first is the role of cannabis potency. Second is the route of administration. Does the lower peak THC level result in smaller impacts on performance? How long does potential impairment last along the longer time-course associated with different pharmacokinetic profiles. It is critical for modeling efforts to understand the answers to these questions, accurately model the effects on driver performance, and by extension understand the risk to the public.

Cannabidiol attenuates cognitive deficits and neuroinflammation induced by early alcohol exposure in a mice model.

Foetal alcohol spectrum disorder (FASD) is the umbrella term used to describe the physical and mental disabilities induced by alcohol exposure during development. Early alcohol exposure induces cognitive impairments resulting from damage to the central nervous system (CNS). The neuroinflammatory response accompanied by neurodegenerative mechanisms contribute to those detrimental alterations. Cannabidiol (CBD) has recently emerged as an anti-inflammatory drug that might be useful to treat several neuropsychiatric disorders. In our study, we assessed the effects of CBD on long-lasting cognitive deficits induced by early alcohol exposure. Furthermore, we analysed long-term pro-inflammatory and apoptotic markers within the prefrontal cortex and hippocampus. To model alcohol binge drinking during gestational and lactation periods, we used pregnant C57BL/6 female mice with time-limited access to 20% v/v alcohol solution. Following the prenatal and lactation alcohol exposure (PLAE), we treated the male and female offspring with CBD from post-natal day (PD) 25 until PD34, and we evaluated their cognitive performance at PD60. Our results showed that CBD treatment during peri-adolescence period ameliorates cognitive deficits observed in our FASD-like mouse model, without sex differences. Moreover, CBD restores the PLAE-induced increased levels of TNFα and IL-6 in the hippocampus. Thus, our study provides new insights for CBD as a therapeutic agent to counteract cognitive impairments and neuroinflammation caused by early alcohol exposure.

Acute caffeine ingestion improves 3-km run performance, cognitive function, and psychological state of young recreational runners.

The current study aimed to assess the effects of caffeine administration on performance time, cognition, psychomotor state, and blood levels of oxidative stress markers following a 3-km run competition. Thirteen recreational runners performed two test sessions in a double-blind randomized order after placebo or 3 mg/kg of body mass of caffeine. At each session, subjects completed a 3-km running competition around a 400 m outdoor athletics track. Cognitive tasks (attention and reaction time), psychological tests (Feeling scale and Hooper), and blood collection were carried out before and after the run. In comparison with placebo, caffeine ingestion enhanced the 3-km performance time by 1.1% (p < 0.001) (10.13 ± 0.69 min versus 10.25 ± 0.72 min), improved attention by 15.6% (p < 0.001) and reaction-time by 5.9% (p < 0.05), increased good-feeling by 15.7% (p < 0.01), and lowered stress-feeling by 17.6% (p < 0.01) and pain-sensation by 11.3% (p < 0.05). However, no significant effects of caffeine were observed on oxidative stress markers. Only exercise resulted in increased levels of glutathione peroxidase (GPX) (12.2%, 8.8%) (p < 0.05), reduced glutathione (GSH) (17.6%, 10.1%) (p < 0.05), superoxide dismutase (SOD) (7.6%, 6.5%) (p < 0.05) and malondialdehyde (MDA) (10.3%, 9.6%) (p < 0.05), for both the placebo and caffeine groups respectively. In conclusion, our study highlighted that the consumption of 3 mg/kg caffeine could be an improving agent for the physical, cognitive, and psychological states without affecting the oxidative stress state during such a running competition.

The effects of glucagon-like peptide 1 receptor agonist (exenatide) on memory impairment, and anxiety- and depression-like behavior induced by REM sleep deprivation.

Previous investigations have shown that REM sleep deprivation impairs the hippocampus-dependent memory, long-term potentiation and causing mood changes. The aim of the present study was to explore the effects of exenatide on memory performance, anxiety- and depression like behavior, oxidative stress markers, and synaptic protein levels in REM sleep deprived rats. A total of 40 male Wistar rats were randomly divided to control, exenatide-treated control, sleep deprivation (SD), wide platform (WP) and exenatide-treated SD groups. During experiments, exenatide treatment (0.5 µg/kg, subcutaneously) was applied daily in a single dose for 9 days. Modified multiple platform method was employed to generate REM sleep deprivation for 72 h. The Morris water maze test was used to assess memory performance. Anxiety- and depression-like behaviors were evaluated by open field test (OFT), elevated plus maze (EPM) forced swimming test (FST), respectively 72 h after REMSD. The levels of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and postsynaptic density proteins 95 (PSD95) were measured in tissues of hippocampus and prefrontal cortex. The content of malondialdehyde (MDA) and reduced glutathione (GSH) were also measured. In the present study, an impairment in memory was observed in SD rats at the 24th hour of SD in compare to those of other groups. REMSD increased depression-like behavior in FST as well as the number of rearing and crossing square in OFT. Anxiety is the most common comorbid condition with depressive disorders. Contents of CaMKII and PSD95 decreased in hippocampus of SD rats. Exenatide treatment improved the impaired memory of SD rats and increased CaMKII content in hippocampus There was no difference in MDA and GSH levels among groups. Exenatide treatment also diminished locomotor activity in OFT. In conclusion, treatment with exenatide, at least in part, prevented from these cognitive and behavioral changes possibly through normalizing CaMKII levels in the hippocampus.

Recovery of post-stroke cognitive and motor deficiencies by Shuxuening injection via regulating hippocampal BDNF-mediated Neurotrophin/Trk Signaling.

A mild ischemic stroke may cause both debilitating locomotor and cognitive decline, for which the mechanism is not fully understood, and no therapies are currently available. In this study, a nonfatal stroke model was constructed in mice by a modified middle cerebral artery occlusion (MCAO) procedure, allowing an extended recovery period up to 28 days. The extended MCAO model successfully mimicked phenotypes of a recovery phase post-stroke, including locomotor motor and cognitive deficiencies, which were effectively improved after Shuxuening injection (SXNI) treatment. Tissue slices staining showed that SXNI repaired brain injury and reduced neuronal apoptosis, especially in the hippocampus CA3 region. Transcriptomics sequencing study revealed 565 differentially expressed genes (DEGs) in the ischemic brain after SXNI treatment. Integrated network pharmacological analysis identified Neurotrophin/Trk Signaling was the most relevant pathway, which involves 15 key genes. Related DEGs were further validated by RT-PCR. Western-blot analysis showed that SXNI reversed the abnormal expression of BDNF, TrkB, Mek3 and Jnk1after stroke. ELISA found that SXNI increased brain level of p-Erk and Creb. At sub-brain level, the expression of BDNF and TrkB was decreased and GFAP was increased on the hippocampal CA3 region in the post-stroke recovery phase and this abnormality was improved by SXNI. In vitro experiments also found that oxygen glucose deprivation reduced the expression of BDNF and TrkB, which was reversed by SXNI. In summary, we conclude that SXNI facilitates the recovery of cognitive and locomotor dysfunction by modulating Neurotrophin/Trk Signaling in a mouse model for the recovery phase of post-ischemic stroke.

The why behind the high: determinants of neurocognition during acute cannabis exposure.

Acute cannabis intoxication may induce neurocognitive impairment and is a possible cause of human error, injury and psychological distress. One of the major concerns raised about increasing cannabis legalization and the therapeutic use of cannabis is that it will increase cannabis-related harm. However, the impairing effect of cannabis during intoxication varies among individuals and may not occur in all users. There is evidence that the neurocognitive response to acute cannabis exposure is driven by changes in the activity of the mesocorticolimbic and salience networks, can be exacerbated or mitigated by biological and pharmacological factors, varies with product formulations and frequency of use and can differ between recreational and therapeutic use. It is argued that these determinants of the cannabis-induced neurocognitive state should be taken into account when defining and evaluating levels of cannabis impairment in the legal arena, when prescribing cannabis in therapeutic settings and when informing society about the safe and responsible use of cannabis.

The failings of per se limits to detect cannabis-induced driving impairment: Results from a simulated driving study.

OBJECTIVE: Many jurisdictions use per se limits to define cannabis-impaired driving. Previous studies, however, suggest that THC concentrations in biological matrices do not reliably reflect cannabis dose and are poorly correlated with magnitude of driving impairment. Here, we first review a range of concerns associated with per se limits for THC. We then use data from a recent clinical trial to test the validity of a range of extant blood and oral fluid THC per se limits in predicting driving impairment during a simulated driving task. METHODS: Simulated driving performance was assessed in 14 infrequent cannabis users at two timepoints (30 min and 3.5 h) under three different conditions, namely controlled vaporization of 125 mg (i) THC-dominant (11% THC; <1% CBD), (ii) THC/CBD equivalent (11% THC; 11% CBD), and (iii) placebo (<1% THC & CBD) cannabis. Plasma and oral fluid samples were collected before each driving assessment. We examined whether per se limits of 1.4 and 7 ng/mL THC in plasma (meant to approximate 1 and 5 ng/mL whole blood) and 2 and 5 ng/mL THC in oral fluid reliably predicted impairment (defined as an increase in standard deviation of lateral position (SDLP) of >2 cm relative to placebo). RESULTS: For all participants, plasma and oral fluid THC concentrations were over the per se limits used 30 min after vaporizing THC-dominant or THC/CBD equivalent cannabis. However, 46% of participants failed to meet SDLP criteria for driving impairment. At 3.5 h post-vaporization, 57% of participants showed impairment, despite having low concentrations of THC in both blood (median = 1.0 ng/mL) and oral fluid (median = 1.0 ng/mL). We highlight two individual cases illustrating how (i) impairment can be minimal in the presence of a positive THC result, and (ii) impairment can be profound in the presence of a negative THC result. CONCLUSIONS: There appears to be a poor and inconsistent relationship between magnitude of impairment and THC concentrations in biological samples, meaning that per se limits cannot reliably discriminate between impaired from unimpaired drivers. There is a pressing need to develop improved methods of detecting cannabis intoxication and impairment.

APOE genotype influences P3b amplitude and response to smoking abstinence in young adults.

RATIONALE: There is strong evidence that nicotine can enhance cognitive functions and growing evidence that this effect may be larger in young healthy APOE ε4 carriers. However, the moderating effects of the APOE ε4 allele on cognitive impairments caused by nicotine deprivation in chronic smokers have not yet been studied with brain indices. OBJECTIVE: We sought to determine whether young female carriers of the APOE ε4 allele, relative to noncarriers, would exhibit larger abstinence-induced decreases in P3b amplitude during a two-stimulus auditory oddball task. METHODS: We compared parietal P3bs in female chronic smokers with either APOE ε3/ε3 (n = 54) or ε3/ε4 (n = 20) genotype under nicotine-sated conditions and after 12-17-h nicotine deprivation. RESULTS: Nicotine deprivation significantly reduced P3b amplitudes in APOE ε4 carriers, but not in APOE-ε3/ε3 individuals, such that the difference seen prior to nicotine deprivation was eliminated. CONCLUSIONS: The results suggest that subjects with the APOE ε4 allele are more sensitive to nicotine, which could influence smoking patterns, the risk for nicotine dependence, and the cognitive effects of nicotine use in these individuals.

Intoxication by a synthetic cannabinoid (JWH-018) causes cognitive and psychomotor impairment in recreational cannabis users.

BACKGROUND: Smoking mixtures containing synthetic cannabinoids (SCs) have become very popular over the last years but pose a serious risk for public health. Limited knowledge is, however, available regarding the acute effects of SCs on cognition and psychomotor performance. Earlier we demonstrated signs of impairment in healthy volunteers after administering one of the first SCs, JWH-018, even though subjective intoxication was low. In the current study, we aimed to investigate the acute effects of JWH-018 on several cognitive and psychomotor tasks in participants who are demonstrating representative levels of acute intoxication. METHODS: 24 healthy cannabis-experienced participants took part in this placebo-controlled, cross-over study. Participants inhaled the vapor of 75 µg JWH-018/kg body weight and were given a booster dose if needed to induce a minimum level of subjective high. They were subsequently monitored for 4 h, during which psychomotor and cognitive performance, vital signs, and subjective experience were measured, and serum concentrations were determined. RESULTS: Maximum subjective high (average 64%) was reached 30 min after administration of JWH-018, while the maximum blood concentration was shown after 5 min (8 ng/mL). JWH-018 impaired motor coordination (CTT), attention (DAT and SST), memory (SMT), it lowered speed-accuracy efficiency (MFFT) and slowed down response speed (DAT). CONCLUSION: In accordance with our previous studies, we demonstrated acute psychomotor and cognitive effects of a relatively low dose of JWH-018.

Subcutaneous anti-CD20 antibody treatment delays gray matter atrophy in human myelin oligodendrocyte glycoprotein-induced EAE mice.

BACKGROUND: The human myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (huMOG-EAE) model, generates B-cell driven demyelination in mice, making it a suitable multiple sclerosis model to study B cell depletion. OBJECTIVES: We investigated the effect of subcutaneous anti-CD20 antibody treatment on huMOG-EAE gray matter (GM) pathology. METHODS: C57Bl/6, 8-week old mice were immunized with 200 huMOG1-125 and treated with 50 µg/mouse of anti-CD20 antibody (n = 16) or isotype control (n = 16). Serial brain volumetric 9.4 T MRI scans was performed at baseline, 1 and 5 wkPI. Disease severity was measured by clinical disability score (CDS) and performance on rotarod test. RESULTS: Anti-CD20 antibody significantly reduced brain volume loss compared with the isotype control across all timepoints longitudinally in the basal ganglia (p = 0.01), isocortex (p = 0.025) and thalamus (p = 0.023). The CDS was reduced significantly with anti-CD20 antibody vs. the isotype control at 3 (p = 0.003) and 4 (p = 0.03) wkPI, while a trend was observed at 5 (p = 0.057) and 6 (p = 0.086) wkPI. Performance on rotarod was also improved significantly at 3 (p = 0.007) and 5 (p = 0.01) wkPI compared with the isotype control. At cellular level, anti-CD20 therapy suppressed the percentage of proliferative nuclear antigen positive microglia in huMOG-EAE isocortex (p = 0.016). Flow cytometry confirmed that anti-CD20 antibody strongly depleted the CD19-expressing B cell fraction in peripheral blood mononuclear cells, reducing it from 39.7% measured in isotype control to 1.59% in anti-CD20 treated mice (p < 0.001). CONCLUSIONS: Anti-CD20 antibody treatment delayed brain tissue neurodegeneration in GM, and showed clinical benefit on measures of disease severity in huMOG-EAE mice.

Chronic Pharmacological Increase of Neuronal Activity Improves Sensory-Motor Dysfunction in Spinal Muscular Atrophy Mice.

Dysfunction of neuronal circuits is an important determinant of neurodegenerative diseases. Synaptic dysfunction, death, and intrinsic activity of neurons are thought to contribute to the demise of normal behavior in the disease state. However, the interplay between these major pathogenic events during disease progression is poorly understood. Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a deficiency in the ubiquitously expressed protein SMN and is characterized by motor neuron death, skeletal muscle atrophy, as well as dysfunction and loss of both central and peripheral excitatory synapses. These disease hallmarks result in an overall reduction of neuronal activity in the spinal sensory-motor circuit. Here, we show that increasing neuronal activity by chronic treatment with the FDA-approved potassium channel blocker 4-aminopyridine (4-AP) improves motor behavior in both sexes of a severe mouse model of SMA. 4-AP restores neurotransmission and number of proprioceptive synapses and neuromuscular junctions (NMJs), while having no effects on motor neuron death. In addition, 4-AP treatment with pharmacological inhibition of p53-dependent motor neuron death results in additive effects, leading to full correction of sensory-motor circuit pathology and enhanced phenotypic benefit in SMA mice. Our in vivo study reveals that 4-AP-induced increase of neuronal activity restores synaptic connectivity and function in the sensory-motor circuit to improve the SMA motor phenotype.SIGNIFICANCE STATEMENT Spinal muscular atrophy (SMA) is a neurodegenerative disease, characterized by synaptic loss, motor neuron death, and reduced neuronal activity in spinal sensory-motor circuits. However, whether these are parallel or dependent events is unclear. We show here that long-term increase of neuronal activity by the FDA-approved drug 4-aminopyridine (4-AP) rescues the number and function of central and peripheral synapses in a SMA mouse model, resulting in an improvement of the sensory-motor circuit and motor behavior. Combinatorial treatment of pharmacological inhibition of p53, which is responsible for motor neuron death and 4-AP, results in additive beneficial effects on the sensory-motor circuit in SMA. Thus, neuronal activity restores synaptic connections and improves significantly the severe SMA phenotype.

Coffee effectively attenuates impaired attention in ADORA2A C/C-allele carriers during chronic sleep restriction.

Many people consume coffee to attenuate increased sleepiness and impaired vigilance and attention due to insufficient sleep. We investigated in genetically caffeine sensitive men and women whether 'real world' coffee consumption during a simulated busy work week counteracts disabling consequences of chronically restricted sleep. We subjected homozygous C-allele carriers of ADORA2A (gene encoding adenosine A2A receptors) to five nights of only 5 h time-in-bed. We administered regular coffee (n = 12; 200 mg caffeine at breakfast and 100 mg caffeine after lunch) and decaffeinated coffee (n = 14) in double-blind fashion on all days following sleep restriction. At regular intervals four times each day, participants rated their sleepiness and performed the psychomotor vigilance test, the visual search task, and the visuo-spatial and letter n-back tasks. At bedtime, we quantified caffeine and the major caffeine metabolites paraxanthine, theobromine and theophylline in saliva. The two groups did not differ in age, body-mass-index, sex-ratio, chronotype and mood states. Subjective sleepiness increased in both groups across consecutive sleep restriction days and did not differ. By contrast, regular coffee counteracted the impact of repeated sleep loss on sustained and selective attention, as well as executive control when compared to decaffeinated coffee. The coffee also induced initial or transient benefits on different aspects of baseline performance during insufficient sleep. All differences between the groups disappeared after the recovery night and the cessation of coffee administration. The data suggest that 'real world' coffee consumption can efficiently attenuate sleep restriction-induced impairments in vigilance and attention in genetically caffeine sensitive individuals. German Clinical Trial Registry: # DRSK00014379.

Effect of Cannabidiol and Δ9-Tetrahydrocannabinol on Driving Performance: A Randomized Clinical Trial.

Importance: Cannabis use has been associated with increased crash risk, but the effect of cannabidiol (CBD) on driving is unclear. Objective: To determine the driving impairment caused by vaporized cannabis containing Δ9-tetrahydrocannabinol (THC) and CBD. Design, Setting, and Participants: A double-blind, within-participants, randomized clinical trial was conducted at the Faculty of Psychology and Neuroscience at Maastricht University in the Netherlands between May 20, 2019, and March 27, 2020. Participants (N = 26) were healthy occasional users of cannabis. Interventions: Participants vaporized THC-dominant, CBD-dominant, THC/CBD-equivalent, and placebo cannabis. THC and CBD doses were 13.75 mg. Order of conditions was randomized and balanced. Main Outcomes and Measures: The primary end point was standard deviation of lateral position (SDLP; a measure of lane weaving) during 100 km, on-road driving tests that commenced at 40 minutes and 240 minutes after cannabis consumption. At a calibrated blood alcohol concentration (BAC) of 0.02%, SDLP was increased relative to placebo by 1.12 cm, and at a calibrated BAC of 0.05%, SDLP was increased relative to placebo by 2.4 cm. Results: Among 26 randomized participants (mean [SD] age, 23.2 [2.6] years; 16 women), 22 (85%) completed all 8 driving tests. At 40 to 100 minutes following consumption, the SDLP was 18.21 cm with CBD-dominant cannabis, 20.59 cm with THC-dominant cannabis, 21.09 cm with THC/CBD-equivalent cannabis, and 18.28 cm with placebo cannabis. SDLP was significantly increased by THC-dominant cannabis (+2.33 cm [95% CI, 0.80 to 3.86]; P < .001) and THC/CBD-equivalent cannabis (+2.83 cm [95% CI, 1.28 to 4.39]; P < .001) but not CBD-dominant cannabis (-0.05 cm [95% CI, -1.49 to 1.39]; P > .99), relative to placebo. At 240 to 300 minutes following consumption, the SDLP was 19.03 cm with CBD-dominant cannabis, 19.88 cm with THC-dominant cannabis, 20.59 cm with THC/CBD-equivalent cannabis, and 19.37 cm with placebo cannabis. The SDLP did not differ significantly in the CBD (-0.34 cm [95% CI, -1.77 to 1.10]; P > .99), THC (0.51 cm [95% CI, -1.01 to 2.02]; P > .99) or THC/CBD (1.22 cm [95% CI, -0.29 to 2.72]; P = .20) conditions, relative to placebo. Out of 188 test drives, 16 (8.5%) were terminated due to safety concerns. Conclusions and Relevance: In a crossover clinical trial that assessed driving performance during on-road driving tests, the SDLP following vaporized THC-dominant and THC/CBD-equivalent cannabis compared with placebo was significantly greater at 40 to 100 minutes but not 240 to 300 minutes after vaporization; there were no significant differences between CBD-dominant cannabis and placebo. However, the effect size for CBD-dominant cannabis may not have excluded clinically important impairment, and the doses tested may not represent common usage. Trial Registration: EU Clinical Trials Register: 2018-003945-40.

Bexarotene normalizes chemotherapy-induced myelin decompaction and reverses cognitive and sensorimotor deficits in mice.

Frequently reported neurotoxic sequelae of cancer treatment include cognitive deficits and sensorimotor abnormalities that have long-lasting negative effects on the quality of life of an increasing number of cancer survivors. The underlying mechanisms are not fully understood and there is no effective treatment. We show here that cisplatin treatment of mice not only caused cognitive dysfunction but also impaired sensorimotor function. These functional deficits are associated with reduced myelin density and complexity in the cingulate and sensorimotor cortex. At the ultrastructural level, myelin abnormalities were characterized by decompaction. We used this model to examine the effect of bexarotene, an agonist of the RXR-family of nuclear receptors. Administration of only five daily doses of bexarotene after completion of cisplatin treatment was sufficient to normalize myelin density and fiber coherency and to restore myelin compaction in cingulate and sensorimotor cortex. Functionally, bexarotene normalized performance of cisplatin-treated mice in tests for cognitive and sensorimotor function. RNAseq analysis identified the TR/RXR pathway as one of the top canonical pathways activated by administration of bexarotene to cisplatin-treated mice. Bexarotene also activated neuregulin and netrin pathways that are implicated in myelin formation/maintenance, synaptic function and axonal guidance. In conclusion, short term treatment with bexarotene is sufficient to reverse the adverse effects of cisplatin on white matter structure, cognitive function, and sensorimotor performance. These encouraging findings warrant further studies into potential clinical translation and the underlying mechanisms of bexarotene for chemobrain.