Coordination Deficits Research Articles

The impact of selenium and magnesium on nigrostriatal dopaminergic neurotoxicity following paraquat exposure in mice.

Exposure to Paraquat (PQ) has been linked to Parkinsonism in both experimental animals and humans. PQ is widely used among other herbicides in developing countries, where its safe use has been proven to be impossible. This action has resulted in farmers' fatal poisonings with PQ and threatens public health. The present study was designed to investigate the role of PQ induced neurotoxicity in the sustantia Nigra, striatal and cerebellar neurons in addition to the neuroprotective potentials of Selenium (Se) and Magnesium (Mg) in abrogating PQ-induced neurotoxicity in mice. We used rotarod test to access PQinduced motor coordination deficit in mice. We also determined: PQ-induced mild cognitive impairment using Morris water maze to check for spatial memory in mice, PQ-induced oxidative stress by investigating lipid peroxidation level of malonyl dialdehyde (MDA) and glutathione peroxidase (GSH) and measuring the activities of superoxide dismutase (SOD), and catalase (CAT) in the brain of PQ-induced mice. The histomorphological outcome of the nigrostriatal neurons and cerebellum were also accessed in PQinduced experimental mice. Immunoreactivity of nigrostriatal dopaminergic neurons to thyroxine hydroxylase (TH) was accessed to determine dopamine loss in the nigrostriatal neurons. In addition, we determine selenium and magnesium's antioxidative effect on paraquat-induced Parkinsonism in mice by checking their effects on motor coordination, cognition, MDA, SOD, CAT, and GSH levels and assessing their ameliorating effect on dopaminergic neurons of the nigrostriatal system and in cerebellar neurons using both the neurons' histomorphological outline and their affinity to TH. Generally, our results showed that PQ induces Parkinsonism in mice by inducing oxidative stress, degenerative cell death in the SNpc, striatum, and cerebellum and by inducing dopamine depletion in SNpc and striatum which resulted in motor and cognitive deficits. Se and Mg also proved to be good antioxidants ameliorating PQ-induced neurodegenerative effects but combine dose of Se and Mg caused further neuronal degeneration on PQinduced mice. Se and Mg may be promising therapeutic targets for PD management in addition to L-dopa treatment since patients from developing countries may not afford deep brain stimulation (DBS) and optogenetics used in the management of PD.Keywords: Paraquat, Parkinsonism, Selenium, Magnesium, Oxidative stress, sustantia Nigra, striatum, cerebellum, motor coordination, cognition.

Daam2 Regulates Myelin Structure and the Oligodendrocyte Actin Cytoskeleton through Rac1 and Gelsolin.

Myelin is essential to neuronal health and CNS function, and oligodendrocytes (OLs) undergo a complex process of cytoskeletal remodeling to form compact myelin sheaths. We previously discovered that a formin protein, Dishevelled associated activator of morphogenesis 2 (Daam2), suppresses OL differentiation through Wnt signaling; however, its role in cytoskeletal control remains unknown. To investigate this, we used OL-specific Daam2 conditional knockout (Daam2 cKO) mice of either sex and found myelin decompaction during an active period of myelination in postnatal development and motor coordination deficits in adulthood. Using primary OL cultures, we found Daam2-depleted OLs showed morphologic dysregulation during differentiation, suggesting that Daam2 regulates the OL cytoskeleton. In vivo screening identified the actin regulators Rac1 and Gelsolin as possible effectors in Daam2-deficient OL cytoskeletal regulation. Using gain-of-function and loss-of-function (LOF) experiments in primary OLs, we found that Rac1 and Gelsolin operate downstream of Daam2 in OL differentiation, with Gelsolin and Daam2 promoting and inhibiting membrane spreading during late differentiation, respectively. In vivo experiments using Daam2 cKO mice revealed increased protein levels of Gelsolin in the developing white matter with no change in RNA levels, suggesting that Daam2 acts in a posttranslational manner to suppress Gelsolin levels. In vitro biochemical studies show Daam2 induces Gelsolin ubiquitination and degradation in OLs. Together, our studies show Daam2 is essential for formation of functional myelin through modulation of Gelsolin levels to regulate the OL cytoskeleton. These findings further demonstrate the critical role of cytoskeletal dynamics in myelination and reveal novel avenues for treatment of a variety of white matter diseases.SIGNIFICANCE STATEMENT Proper myelin formation is essential to CNS function, and oligodendrocytes (OLs) require extensive changes in the actin cytoskeleton to form myelin sheaths. Here, we show that the formin protein Dishevelled associated activator of morphogenesis 2 (Daam2) is necessary for myelin compaction during development and motor learning in adulthood. Further, we demonstrate that Daam2 regulates OL differentiation and morphology through actin regulators Rac1 and Gelsolin. Lastly, we find that Daam2 may control myelin compaction by modulating the ubiquitination and degradation of Gelsolin through recruitment of the E3 ubiquitin ligase Nedd4. These findings reveal novel pathways for regulating myelin structure and function during white matter development.

Dyscoordination of non-rapid eye movement sleep oscillations in autism spectrum disorder

Converging evidence from neuroimaging, sleep, and genetic studies suggest that dysregulation of thalamocortical interactions mediated by the thalamic reticular nucleus (TRN) contribute to autism spectrum disorder (ASD). Sleep spindles assay TRN function, and their coordination with cortical slow oscillations (SOs) indexes thalamocortical communication. These oscillations mediate memory consolidation during sleep. In the present study, we comprehensively characterized spindles and their coordination with SOs in relation to memory and age in children with ASD. Nineteen children and adolescents with ASD, without intellectual disability, and 18 typically developing (TD) peers, aged 9-17, completed a home polysomnography study with testing on a spatial memory task before and after sleep. Spindles, SOs, and their coordination were characterized during stages 2 (N2) and 3 (N3) non-rapid eye movement sleep. ASD participants showed disrupted SO-spindle coordination during N2 sleep. Spindles peaked later in SO upstates and their timing was less consistent. They also showed a spindle density (#/min) deficit during N3 sleep. Both groups showed significant sleep-dependent memory consolidation, but their relations with spindle density differed. While TD participants showed the expected positive correlations, ASD participants showed the opposite. The disrupted SO-spindle coordination and spindle deficit provide further evidence of abnormal thalamocortical interactions and TRN dysfunction in ASD. The inverse relations of spindle density with memory suggest a different function for spindles in ASD than TD. We propose that abnormal sleep oscillations reflect genetically mediated disruptions of TRN-dependent thalamocortical circuit development that contribute to the manifestations of ASD and are potentially treatable.

Study of the effects of motor coordination deficits on adaptive behavior and health-related quality of life in pediatric survivors with medulloblastoma

Study of the effects of motor coordination deficits on adaptive behavior and health-related quality of life in pediatric survivors with medulloblastoma

The Estimation of the Anti-neurotoxic Effect of Costus Ethanolic Extract against Bifenthrin-Intoxication in Male Rats.

Pyrethroidsare a group of synthetic pesticides similar to the natural pesticide pyrethrum, which is produced by chrysanthemum flowers. Bifenthrin is one of the pyrethroids that are widely used pesticide in households and to control crop vectors. The main goal of this work was to investigate the possible ameliorating effect of Costus Ethanolic Extract (CEE) against neurotoxicity induced by bifenthrin in adult-male rats. Rats were arranged randomly to 4 groups (8 rats each) as next. Group 1) control rats orally received 0.5 mL water for consecutive 30 days; group 2) healthy rats orally received CEE (200 mg kg) for consecutive thirty days; group 3) rats treated orally with 7 mg kg-1 day-1 bifenthrin for consecutive 30 days and group 4) included rats treated with bifenthrin for consecutive 30 days followed by administration with CEE another consecutive 30 days. The results showed that CEE succeeded to decline the neurotoxicity-induced by bifenthrin; this was evidenced by the significant reduction in TNF-α, IL- 1β, MDA and nitric oxide levels in cortex, hippocampus and striatum concomitant with marked improvement in the values of GSH, dopamine, serotonin, AChE-ase, SOD, GPx and catalase that were diminished by bifenthrin intoxication. CEE improved also cognitive impairment and the deficits in motor coordination induced by bifenthrin. CEE was found successful, to a great extent, to counteract the bifenthrin-induced brain oxidative stress and neurochemical deteriorations and possesses a protective potential against brain-induced neurotoxicity. Therefore, it may be a promising supplement for the amelioration of BF-neurotoxicity.

Time dependent alteration of locomotor behavior in rat with acute liver failure induced cerebellar neuroinflammation and neuro-astroglial damage

Hepatic encephalopathy (HE) is a neurophysiological syndrome secondary to acute or chronic liver failure. Studies showed that HE patients exhibit a deficit in motor coordination, which may result from cerebellar functional impairment. The aim of this study is to assess the time-dependent alteration of locomotor behavior and the glial and neuronal alteration in rat with acute HE induced chemically. The study was carried out in male Sprague-Dawley rats with thioacetamide (TAA) induced acute liver failure at different stages 12 h, 24 h and 36 h. Hepatic and renal functions were assessed via various biochemical and histopathological examinations, while the cerebellum and the midbrain were examined using histology and immunohistochemistry for tyrosine hydroxylase (TH), cyclooxygenase-2 (COX-2) and glial fibrillary acidic protein (GFAP). We used as well, the open field test and the Rotarod test for assessing the locomotor activity and coordination. Our data showed a progressive loss of liver function and a progressive alteration in locomotor behavior and motor coordination in acute HE rats. In the cerebellum, we noted an increase in the degeneration of cerebellar Purkinje neurons parallel to increased COX-2 immunoreactivity together with astrocytic morphology and density changes. Likewise, in substantia nigra pars compacta, TH levels were reduced. We showed through the current study, a progressive deterioration in locomotor behavior in acute HE rats, as a result of Purkinje neurons death and a deficient dopaminergic neurotransmission, together with the morpho-functional astroglial modifications involving the oxidative stress and neuroinflammation.

Walking adaptability improves after treadmill training in children with Developmental Coordination Disorder: A proof-of-concept study

BackgroundChildren with Developmental Coordination Disorder (DCD) have motor coordination deficits leading to difficulties in sports and play that require adaptations of the walking pattern. Children with DCD indeed demonstrate poorer walking adaptability (WA) compared to typically developing children, but it remains elusive whether WA can be improved by training. Research questionDoes augmented-reality treadmill training lead to improvements in WA in children with DCD? MethodsSeventeen children with DCD were included in this proof-of-concept intervention study. They received a six-session training on the C-mill, a treadmill on which gait adjustments can be evoked by projected visual context. The effect of the training was evaluated before (M1), directly after training (M2) and after 6 months follow-up (M3) using the WAL-K (single and double run) and WA-tasks on the C-mill (as a single and with concurrent visuo-motor and cognitive task). In addition, parents completed a questionnaire on their perception of the training. Linear Mixed Model analyses were performed to assess the differences in WAL-K scores and success rates on the WA-tasks between M1-M2 and M1-M3. ResultsChildren significantly improved on the WAL-K double run and on all three WA-tasks between M1-M2 and M1-M3. Children did not improve on the WAL-K single run. Parents found the training useful and fun for their child and indicated that their child fell less frequently. SignificanceThe results show that C-mill training had positive and task-specific effects on WA in children with DCD, which effects generalized to an overground task and were retained at 6 months follow-up. This may help children with DCD to better participate in daily activities. Future research should include a control group to examine the effectiveness of the training program compared to receiving no training and may also examine the effect of the training on participation in daily life.

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

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. 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. 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. These results indicate that the subacute treatment with AMD3100 does not improve structural and functional outcomes in a rat HIE model.

RADT-17. FOCUSED ULTRASOUND MEDIATED BLOOD–BRAIN BARRIER OPENING IS SAFE AND FEASIBLE CONCURRENT WITH AND ADJUVANT TO A CLINICAL RADIATION SCHEME FOR BRAINSTEM DMG

Abstract Diffuse midline gliomas (DMG) are pediatric tumors with dismal prognosis. When these tumors emerge in the brainstem, there exists no feasible method of surgical resection or systemic intervention, making ionizing radiation the sole therapeutic avenue to date. However, radiotherapy (RT) provides only marginal survival benefit as the topographically diffuse and highly infiltrative tumors spread in areas in which the blood-brain barrier (BBB) is relatively intact. Focused ultrasound (FUS) with intravenous microbubbles provides a compelling solution, transiently and non-invasively opening the BBB to allow drug delivery across the cerebrovasculature. Nonetheless, it remains unclear whether FUS can be safely administered at the brainstem in patients receiving RT. Therefore, the goal of this study was to assess the safety and feasibility of FUS administered concurrent with and adjuvant to a clinical hypofractionated radiation scheme for brainstem DMG. Non-tumor bearing B6 albino mice were randomly assorted into control, RT, FUS, and RT+FUS groups. Mice designated RT+FUS received 39Gy/13fx (hypofractionated RT scheme) to the brainstem with two sessions of FUS approximately 1 week apart. A single-element, spherical-segment FUS transducer driven by a function generator through a power amplifier was used with concomitant microbubble injection to sonicate the brainstem. Magnetic resonance imaging (MRI) was used to confirm BBB opening and cardiopulmonary measures were recorded throughout sonication. Vitals were assessed daily, and all treatment animals underwent Kondziela inverted screen testing and sequential weight lifting to assess brainstem-related strength and motor coordination deficits. In both FUS and RT+FUS mice, MRI confirmed brainstem BBB opening and subsequent closure within 96 hours. Mouse weights were stable, with slight drops (mean=5.5%) following FUS that resolved within three days. No attenuation in cardiorespiratory, strength, and motor coordination measurements was observed from FUS. FUS is a safe and feasible technique for brainstem BBB opening concurrent with and adjuvant to clinical hypofractionated RT.

Developmental Training Model for the Sport Specialized Youth Athlete: A Dynamic Strategy for Individualizing Load-Response During Maturation.

Most available data on athletic development training models focus on adult or professional athletes, where increasing workload capacity and performance is a primary goal. Development pathways in youth athletes generally emphasize multisport participation rather than sport specialization to optimize motor skill acquisition and to minimize injury risk. Other models emphasize the need for accumulation of sport- and skill-specific hours to develop elite-level status. Despite recommendations against sport specialization, many youth athletes still specialize and need guidance on training and competition. Medical and sport professionals also recommend progressive, gradual increases in workloads to enhance resilience to the demands of high-level competition. There is no accepted model of risk stratification and return to play for training a specialized youth athlete through periods of injury and maturation. In this review, we present individualized training models for specialized youth athletes that (1) prioritize performance for healthy, resilient youth athletes and (2) are adaptable through vulnerable maturational periods and injury. Nonsystematic review with critical appraisal of existing literature. Clinical review. Level 4. A number of factors must be considered when developing training programs for young athletes: (1) the effect of sport specialization on athlete development and injury, (2) biological maturation, (3) motor and coordination deficits in specialized youth athletes, and (4) workload progressions and response to load. Load-sensitive athletes with multiple risk factors may need medical evaluation, frequent monitoring, and a program designed to restore local tissue and sport-specific capacity. Load-naive athletes, who are often skeletally immature, will likely benefit from serial monitoring and should train and compete with caution, while load-tolerant athletes may only need occasional monitoring and progress to optimum loads. B.

Construct Validity of the Upper-Limb Interlimb Coordination Test in Stroke

Background Coordination impairments are under-evaluated in patients with stroke due to the lack of validated assessments resulting in an unclear relationship between coordination deficits and functional limitations. Objective Determine the construct validity of the new clinical upper-limb (UL) Interlimb Coordination test (ILC2) in individuals with chronic stroke. Methods Thirteen individuals with stroke, ≥40 years, with ≥30° isolated supination of the more-affected (MAff) arm, who could understand instructions and 13 healthy controls of similar age participated in a cross-sectional study. Participants performed synchronous bilateral anti-phase forearm rotations for 10 seconds in 4 conditions: self-paced internally-paced (IP1), fast internally-paced (IP2), slow externally-paced (EP1), and fast externally-paced (EP2). Primary (continuous relative phase-CRP, cross-correlation, lag) and secondary outcome measures (UL and trunk kinematics) were compared between groups. Results Participants with stroke made slower UL movements than controls in all conditions, except EP1. Cross-correlation coefficients were lower (i.e., closer to 0) in stroke in IP1, but CRP and lag were similar between groups. In IP1 and matched-speed conditions (IP1 for healthy and IP2 for stroke), stroke participants used compensatory trunk and shoulder movements. The synchronicity sub-scale and total scores of ILC2 were related to temporal coordination in IP2. Interlimb Coordination test total score was related to greater shoulder rotation of the MAff arm. Interlimb Coordination test scores were not related to clinical scores. Conclusion Interlimb Coordination test is a valid clinical measure that may be used to objectively assess UL interlimb coordination in individuals with chronic stroke. Further reliability testing is needed to determine the clinical utility of the scale.

Changes in Brain Matrix Glycan Sulfation Associate With Reactive Gliosis and Motor Coordination in Mice With Head Trauma.

Perineuronal nets (PNNs) are extracellular matrix (ECM) structures that enmesh and regulate neurocircuits involved in motor and sensory function. Maladaptive changes to the composition and/or abundance of PNNs have been implicated in preclinical models of neuroinflammation and neurocircuit destabilization. The central nervous system (CNS) is limited in its capacity to repair and reorganize neural networks following traumatic brain injury (TBI) and little is known about mechanisms of ECM repair in the adult brain after TBI. In this study, adult male C57BL/6 mice were subjected to a TBI via a controlled cortical impact (CCI) to the right motor and somatosensory cortices. At 7 days following CCI, histological analysis revealed a loss of Wisteria floribunda agglutinin (WFA) positive PNN matrices in the ipsilateral cortex. PNNs are comprised of chondroitin sulfate (CS) and dermatan sulfate (DS)-glycosaminoglycans (GAGs), the composition of which are known to influence neuronal integrity and repair. Using an innovative liquid chromatography tandem mass spectrometry (LC-MS/MS) method, we analyzed the relative abundance of six specific CS/DS-GAG isomers (Δ4S-, Δ6S-, Δ4S6S-, Δ2S6S-, Δ0S-CS, and Δ2S4S-DS) from fixed-brain sections after CCI injury. We report a significant shift in CS/DS-GAG sulfation patterns within the rostro-caudal extent of the injury site from mice exposed to CCI at 7 days, but not at 1 day, post-CCI. In the ipsilateral thalamus, the appearance of WFA+ puncta occurred in tandem with gliosis at 7 days post-CCI, but weakly colocalized with markers of gliosis. Thalamic WFA+ puncta showed moderate colocalization with neuronal ubiquitin C-terminal hydrolase L1 (UCHL1), a clinical biomarker for TBI injury. A shift in CS/DS-GAG sulfation was also present in the thalamus including an increase of 6S-CS, which is a specific isomer that associates with the presence of glial scarring. Upregulation of the 6S-CS-specific sulfotransferase (CHST3) gene expression was accompanied by reactive gliosis in both the ipsilateral cortex and thalamus. Moreover, changes in 6S-CS extracted from the thalamus positively correlated with deficits in motor coordination after CCI. Collectively, these data argue that CCI alters CS/DS-GAG sulfation in association with the spatiotemporal progression of neurorepair. Therapeutic interventions targeting restoration of CS/DS-GAG sulfation patterns may improve outcomes from TBI.

Older age, male sex, and cerebral microbleeds predict white matter loss after traumatic brain injury.

Little is known on how mild traumatic brain injury affects white matter based on age at injury, sex, cerebral microbleeds, and time since injury. Here, we study the fractional anisotropy of white matter to study these effects in 109 participants aged 18-77 (46 females, age μ ± σ = 40 ± 17years) imaged within [Formula: see text] 1week and [Formula: see text] 6months post-injury. Age is found to be linearly associated with white matter degradation, likely due not only to injury but also to cumulative effects of other pathologies and to their interactions with injury. Age is associated with mean anisotropy decreases in the corpus callosum, middle longitudinal fasciculi, inferior longitudinal and occipitofrontal fasciculi, and superficial frontal and temporal fasciculi. Over [Formula: see text] 6months, the mean anisotropies of the corpus callosum, left superficial frontal fasciculi, and left corticospinal tract decrease significantly. Independently of other predictors, age and cerebral microbleeds contribute to anisotropy decrease in the callosal genu. Chronically, the white matter of commissural tracts, left superficial frontal fasciculi, and left corticospinal tract degrade appreciably, independently of other predictors. Our findings suggest that large commissural and intra-hemispheric structures are at high risk for post-traumatic degradation. This study identifies detailed neuroanatomic substrates consistent with brain injury patients' age-dependent deficits in information processing speed, interhemispheric communication, motor coordination, visual acuity, sensory integration, reading speed/comprehension, executive function, personality, and memory. We also identify neuroanatomic features underlying white matter degradation whose severity is associated with the male sex. Future studies should compare our findings to functional measures and other neurodegenerative processes.

Insights into motor performance deficits after stroke: an automated and refined analysis of the lower-extremity motor coordination test (LEMOCOT)

BackgroundThe lower-extremity motor coordination test (LEMOCOT) is a performance-based measure used to assess motor coordination deficits after stroke. We aimed to automatically quantify performance on the LEMOCOT and to extract additional performance parameters based on error analysis in persons with stroke (PwS) and healthy controls. We also aimed to explore whether these parameters provide additional information regarding motor control deficit that is not captured by the traditional LEMOCOT score. In addition, the associations between the LEMOCOT score, parameters of error and performance-based measures of lower-extremity impairment and gait were tested.MethodsTwenty PwS (age: 62 ± 11.8 years, time after stroke onset: 84 ± 83 days; lower extremity Fugl-Meyer: 30.2 ± 3.7) and 20 healthy controls (age: 42 ± 15.8 years) participated in this cross-sectional exploratory study. Participants were instructed to move their big toe as fast and accurately as possible between targets marked on an electronic mat equipped with force sensors (Zebris FDM-T, 60 Hz). We extracted the contact surface area of each touch, from which the endpoint location, the center of pressure (COP), and the distance between them were computed. In addition, the absolute and variable error were calculated.ResultsPwS touched the targets with greater foot surface and demonstrated a greater distance between the endpoint location and the location of the COP. After controlling for the number of in-target touches, greater absolute and variable errors of the endpoint were observed in the paretic leg than in the non-paretic leg and the legs of controls. Also, the COP variable error differentiated between the paretic, non-paretic, and control legs and this parameter was independent of in-target counts. Negative correlations with moderate effect size were found between the Fugl Meyer assessment and the error parameters.ConclusionsPwS demonstrated lower performance in all outcome measures than did controls. Several parameters of error indicated differences between legs (paretic leg, non-paretic leg and controls) and were independent of in-target touch counts, suggesting they may reflect motor deficits that are not identified by the traditional LEMOCOT score.

Validity of claims-based algorithms to identify neurodevelopmental disorders in children.

To validate healthcare claim-based algorithms for neurodevelopmental disorders (NDD) in children using medical records as the reference. Using a clinical data warehouse of patients receiving outpatient or inpatient care at two hospitals in Boston, we identified children (≤14 years between 2010 and 2014) with at least one of the following NDDs according to claims-based algorithms: autism spectrum disorder/pervasive developmental disorder (ASD), attention deficit disorder/other hyperkinetic syndromes of childhood (ADHD), learning disability, speech/language disorder, developmental coordination disorder (DCD), intellectual disability, and behavioral disorder. Fifty cases per outcome were randomly sampled and their medical records were independently reviewed by two physicians to adjudicate the outcome presence. Positive predictive values (PPVs) and 95% confidence intervals (CIs) were calculated. PPVs were 94% (95% CI, 83%-99%) for ASD, 88% (76%-95%) for ADHD, 98% (89%-100%) for learning disability, 98% (89%-100%) for speech/language disorder, 82% (69%-91%) for intellectual disability, and 92% (81%-98%) for behavioral disorder. A total of 19 of the 50 algorithm-based cases of DCD were confirmed as severe coordination disorders with functional impairment, with a PPV of 38% (25%-53%). Among the 31 false-positive cases of DCD were 7 children with coordination deficits that did not persist throughout childhood, 7 with visual-motor integration deficits, 12 with coordination issues due to an underlying medical condition and 5 with ADHD and at least one other severe NDD. PPVs were generally high (range: 82%-98%), suggesting that claims-based algorithms can be used to study NDDs. For DCD, additional criteria are needed to improve the classification of true cases.

Avoidance Behavior in Adults with Developmental Coordination Disorder is Related to Quality of Life

Although it is now widely accepted that developmental co-ordination disorder (DCD) persists into adolescence and adulthood, few studies have assessed the concept of Quality of Life (QOL) within the adult DCD population. This is despite a growing recognition that children and adolescents with DCD experience poorer QOL than their typically developed peers. The small body of literature which has examined QOL in adults with DCD has reported that they also report lower levels of QOL as a result of motor coordination deficits. Little research has investigated the factors that result in adults with DCD reporting lower QOL than their typically developed counterparts. The current study explored the relationships between QOL and motor coordination, and QOL and three individual subtypes of avoidance within an adult DCD sample. Eighty-five adults (27 males; 58 females) who reported a diagnosis of, or believe that they have DCD, completed an online questionnaire that consisted of three already established questionnaires in order to measure the concepts of QOL, motor coordination and avoidance, respectively. A hierarchal multiple regression revealed that all three types of avoidance behaviors were significant predictors of QOL scores, while levels of motor coordination did not significantly predict scores of QOL. These results highlight the need for clinicians to develop interventions to help reduce avoidance behavior and social impairment, in order to improve QOL within the DCD adult population.

Neuroprotective Effect of Phoenix dactylifera (Date Palm) on Paraquat Triggered Cortico-Nigral Neurotoxicity

Background: Herbicides including paraquat (PQ) have been reported to have deleterious effects on biological systems and normal functioning of the brain, especially regions related to motor functionality and coordination like the cerebrum and substantia nigra resulting in neurodegenerative conditions such as Parkinson's disease. Phoenix dactylifera has high nutritional value and is beneficial in the management and treatment of diverse ailments. Aim: This study assessed the protective properties of Aqueous fruit extract of P. dactylifera (AFPD) on PQ-triggered cortico-nigral neurotoxicity in rats. Neuroprotective properties of AFPD were assessed using beam walking performance (BWP) for motor coordination, oxidative stress biomarkers (Malondialdehyde [MDA], superoxide dismutase [SOD], and glutathione [GSH]) and histological examination (H and E stained) for cytoarchitectural changes. BWP across the study period revealed no motor coordination deficit with PQ exposure. Materials and Methods: Twenty-five rats were categorized into five groups (n = 5); the control was administered 2 ml/kg distilled H2O, another group received 11.35 mg/kg PQ, another received 11.35 mg/kg PQ + 10 mg/kg L-dopa as reference drug, while two other groups received 11.35 mg/kg PQ + 500 mg/kg AFPD and 11.35 mg/kg PQ + 1,000 mg/kg AFPD, respectively, for 28 days. Results: PQ-treated group revealed oxidative stress by significant elevation of MDA levels and decrease in antioxidant enzymes (SOD and GSH). Remarkable cytoarchitectural distortions were observed with PQ treatment. However, AFPD treatment showed ameliorative properties by a significant decrease in MDA levels and increased SOD and GSH activities. Mild distortion-to-relatively normal neuronal cytoarchitecture relative to the control was also observed with AFPD treatment. Conclusion: AFPD possesses potential neuroprotective properties against PQ-triggered pathological changes in cortico-nigral structures of Wistar rats.

Ceruloplasmin deletion in myelinating glial cells induces myelin disruption and oxidative stress in the central and peripheral nervous systems

Ceruloplasmin (Cp) is a ferroxidase enzyme that is essential for cell iron efflux and has been postulated to have a neuroprotective role. During the myelination process, oligodendrocytes (OLs) and Schwann cells (SCs) express high levels of Cp, but the role of this enzyme in glial cell development and function is completely unknown. To define the function of Cp in the myelination of the central and peripheral nervous systems, we have conditionally knocked-out Cp specifically in OLs and SCs during early postnatal development as well as in aged mice. Cp ablation in early OLs (postnatal day 2, P2) significantly affects the differentiation of these cells and the synthesis of myelin through the first four postnatal weeks. The total number of mature myelinating OLs was reduced, and the density of apoptotic OLs was increased. These changes were accompanied with reductions in the percentage of myelinated axons and increases in the g-ratio of myelinated fibers. Cp ablation in young myelinating OLs (P30 or P60) did not affect myelin synthesis and/or OL numbers, however, Cp loss in aged OLs (8 months) induced cell iron overload, apoptotic cell death, brain oxidative stress, neurodegeneration and myelin disruption. Furthermore, Cp deletion in SCs affected postnatal SC development and myelination and produced motor coordination deficits as well as oxidative stress in young and aged peripheral nerves. Together, our data indicate that Cp ferroxidase activity is essential for OLs and SCs maturation during early postnatal development and iron homeostasis in matured myelinating cells. Additionally, our results suggest that Cp expression in myelinating glial cells is crucial to prevent oxidative stress and neurodegeneration in the central and peripheral nervous systems.

Ccdc134 deficiency impairs cerebellar development and motor coordination.

Coiled-coil domain containing 134 (CCDC134) has been shown to serve as an immune cytokine to exert antitumor effects and to act as a novel regulator of hADA2a to affect PCAF acetyltransferase activity. While Ccdc134 loss causes abnormal brain development in mice, the significance of CCDC134 in neuronal development in vivo is controversial. Here, we report that CCDC134 is highly expressed in Purkinje cells (PCs) at all developmental stages and regulates mammalian cerebellar development in a cell type-specific manner. Selective deletion of Ccdc134 in mouse neural stem cells (NSCs) caused defects in cerebellar morphogenesis, including a decrease in the number of PCs and impairment of PC dendritic growth, as well as abnormal granule cell development. Moreover, loss of Ccdc134 caused progressive motor dysfunction with deficits in motor coordination and motor learning. Finally, Ccdc134 deficiency inhibited Wnt signaling but increased Ataxin1 levels. Our findings provide evidence that CCDC134 plays an important role in cerebellar development, possibly through regulating Wnt signaling and Ataxin1 expression levels, and in controlling cerebellar function for motor coordination and motor learning, ultimately making it a potential contributor to cerebellar pathogenesis.

Pharmacological activities of Asclepias curassavica L. (Apocynaceae) aerial parts

Ethnopharmacological relevanceAsclepias curassavica L. (Apocynaceae) is a perennial shrub used in the folk treatment of parasitism, pain, and inflammation. Aim of the studyThis work assessed the antiparasitic, anti-inflammatory, antinociceptive, and sedative effects of an ethanol extract from the aerial parts of Asclepias curassavica (ACE). Materials and methodsThe antiparasitic activity against Trichomonas vaginalis was evaluated using the trypan blue exclusion test. The in vitro anti-inflammatory actions of ACE (1–200 μg/ml) were analyzed using LPS-stimulated primary murine macrophages. The in vivo pharmacological activity of ACE (50–200 mg/kg p.o.) was evaluated using animal models of inflammation (TPA-induced ear edema test and carrageenan-induced paw edema test) and nociception (acetic acid-induced writhing test, formalin-induced licking test, and hot plate test). ResultsACE showed poor antiparasitic effects against Trichomonas vaginalis (IC50 = 302 μg/ml). ACE increased the production of IL-10 in both in vitro assays (EC50 = 3.2 pg/ml) and in vivo assays (ED50 = 111 mg/kg). ACE showed good antinociceptive actions (ED50 = 158 mg/kg in phase 1 and ED50 = 83 mg/kg in phase 2) in the formalin test. Pre-treatment with naloxone blocked the antinociceptive response induced by ACE. In addition, ACE did not induce sedative effects or motor coordination deficits in mice. ConclusionFindings showed that the anti-inflammatory activity of ACE is associated with increasing levels of IL-10 in both in vitro and in vivo assays, whereas the antinociceptive effect is associated with the participation of the opioidergic system, without inducing sedation or motor coordination impairment.