关键词： axonal sprouting   diffusion tensor imaging   epidermal growth factor   oxygen-glucose deprivation   protease-inactive tPA  

摘要： Emerging evidence suggests that tissue plasminogen activator (tPA), currently the only FDA-approved medication for ischemic stroke, exerts important biological actions on the CNS besides its well-known thrombolytic effect. In this study, we investigated the role of tPA on primary neurons in culture and on brain recovery and plasticity after ischemic stroke in mice. Treatment with recombinant tPA stimulated axonal growth in culture, an effect independent of its protease activity and achieved through epidermal growth factor receptor (EGFR) signaling. After permanent focal cerebral ischemia, tPA knockout mice developed more severe sensorimotor and cognitive deficits and greater axonal and myelin injury than wildtype mice, suggesting that endogenously expressed tPA promotes long-term neurological recovery after stroke. In tPA knockout mice, intranasal administration of recombinant tPA protein 6 hours poststroke and 7 more times at 2 d intervals mitigated white matter injury, improved axonal conduction, and enhanced neurological recovery. Consistent with the proaxonal growth effects observed in vitro, exogenous tPA delivery increased poststroke axonal sprouting of corticobulbar and corticospinal tracts, which might have contributed to restoration of neurological functions. Notably, recombinant mutant tPA-S478A lacking protease activity (but retaining the EGF-like domain) was as effective as wild-type tPA in rescuing neurological functions in tPA knockout stroke mice. These findings demonstrate that tPA improves long-term functional outcomes in a clinically relevant stroke model, likely by promoting brain plasticity through EGFR signaling. Therefore, treatment with the protease-dead recombinant tPA-S478A holds particular promise as a neurorestorative therapy, as the risk for triggering intracranial hemorrhage is eliminated and tPA-S478A can be delivered intranasally hours after stroke.

关键词： Obesity   co-morbidities   neurological disorders   management   dietary aspects  

摘要： Obesity is considered a major public health concern throughout the world among children, adolescents, as well as adults and several therapeutic, preventive and dietary interventions are available. In addition to life style changes and medical interventions, significant milestones have been achieved in the past decades in the development of several functional foods and dietary regimens to reduce this menace. Being a multifactorial phenomenon and related to increased fat mass that adversely affects health, obesity has been associated with the development of several other co-morbidities. A great body of research and strong scientific evidence identifies obesity as an important risk factor for onset and progression of several neurological disorders. Obesity induced dyslipidaemia, metabolic dysfunction, and inflammation are attributable to the development of a variety of effects on central nervous system (CNS). Evidence suggests that neurological diseases such as Parkinson's disease and Alzheimer's disease could be initiated by various metabolic changes, related to CNS damage, caused by obesity. These metabolic changes could alter the synaptic plasticity of the neurons and lead to neural death, affecting the normal physiology of CNS. Dietary intervention in combination with exercise can affect the molecular events involved in energy metabolism and synaptic plasticity and are considered effective non-invasive strategy to counteract cognitive and neurological disorders. The present review gives an overview of the obesity and related neurological disorders and the possible dietary interventions.

关键词： Psychosis   schizophrenia   genetics   Niemann-Pick disease type C   registry  

摘要： Objectives: Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease that should be recognised by psychiatrists as a possible underlying cause of psychiatric abnormalities. This study describes NP-C patients who had psychiatric manifestations at enrolment in the international NPC Registry, a unique multicentre, prospective, observational disease ***: Treating physicians’ data entries describing psychiatric manifestations in NPC patients were coded and grouped by expert ***: Out of 386 NP-C patients included in the registry as of October 2015, psychiatric abnormalities were reported to be present in 34% (94/280) of those with available data. Forty-four patients were confirmed to have identifiable psychiatric manifestations, with text describing these psychiatric manifestations. In these 44 patients, the median (range) age at onset of psychiatric manifestations was 17.9 years (2.5-67.9; n = 15), while the median (range) age at NP-C diagnosis was 23.7 years (0.2-69.8; n = 34). Almost all patients (43/44; 98%) had an occurrence of ≥1 neurological manifestation at ***: These data show that substantial delays in diagnosis of NP-C are long among patients with psychiatric symptoms and, moreover, patients presenting with psychiatric features and at least one of cognitive impairment, neurological manifestations, and/or visceral symptoms should be screened for NP-C.

关键词： RNA binding protein   dementia   ALS   autism   SMA   SMN   FMRP   TDP-43   hnRNP   Repeat expansion  

摘要： RNA binding proteins are critical to the maintenance of the transcriptome via controlled regulation of RNA processing and transport. Alterations of these proteins impact multiple steps of the RNA life cycle resulting in various molecular phenotypes such as aberrant RNA splicing. transport, and stability. Disrupicion of RNA binding proteins and widespread RNA processing defects are increasingly recognized as critical determinants of neurological diseases. Here, we describe distinct mechanisms by which the homeostasis of RNA binding proteins is compromised in neurological disorders through their reduced expression level, increased propensity to aggregate or sequestration by abnormal RNAs. These mechanisms all converge toward altered neuronal function highlighting the susceptibility of neurons to deleterious changes in RNA expression and the central role of RNA binding proteins in preserving neuronal integrity. Emerging therapeutic approaches to mitigate or reverse alterations of RNA binding proteins in neurological diseases are discussed.

关键词： Cardiac dysfunction   Immunoresponse   Neuroprotection   RP001 hydrochloride   Subarachnoid hemorrhage  

摘要： Subarachnoid hemorrhage (SAH) results in neurological damage, acute cardiac damage and has a high mortality rate. Immunoresponse in the acute phase after SAH plays a key role in mediating vasospasm, edema, inflammation and neuronal damage. The S1P/S1PR pathway impacts multiple cellular functions, exerts anti-inflammatory and anti-apoptotic effects, promotes remyelination, and improves outcome in several central nervous system (CNS) diseases. RP001 hydrochloride is a novel S1PR agonist, which sequesters lymphocytes within their secondary tissues and prevents infiltration of immune cells into the CNS thereby reducing immune response. In this study, we investigated whether RP001 attenuates neuronal injury after SAH by reducing inflammation. S1PRs, specifically S1PR(1),( 3) not only exerts anti-inflammatory effects, but also decreases heart rate and induces atrioventricular conduction abnormalities. Therefore, we also tested whether RP001 treatment of SAH regulates cardiac functional outcome. Male adult C57BL/6 mice were subjected to SAH, and neurological function tests, echocardiography, and immunohistochemical analysis were performed. SAH induces neurological deficits and acute cardiac dysfunction compared to sham control mice. Treatment of SAH with a low-dose of RP001 induces better neurological outcome and cardiac function compared to a high-dose of RP001. Low-dose-RP001 treatment significantly decreases apoptosis, white matter damage, blood brain barrier permeability, microglial/astrocyte activation, macrophage chemokine protein-1, matrix metalloproteinase-9 and NADPH oxidase-2 expression in the brain compared to SAH control mice. Our findings indicate that low-dose of RP001 alleviates neurological damage after SAH, in part by decreasing neuroinflammation.

关键词： Handwriting   Parkinson's disease   Convolutional neural networks   Visual attributes  

摘要： Parkinson's disease (PD) is a degenerative disorder that progressively affects the central nervous system causing muscle rigidity, tremors, slowed movements and impaired balance. Sophisticated diagnostic procedures like SPECT scans can detect changes in the brain caused by PD but are only effective once the disease has advanced considerably. Analysis of subtle variations in handwriting and speech can serve as potential tools for early prediction of the disease. While traditional techniques mostly rely on dynamic (kinematic and spatio-temporal) features of handwriting, in this study, we quantitatively evaluate the visual attributes in characterization of graphomotor samples of PD patients. For this purpose, Convolutional Neural Networks are employed to extract discriminating visual features from multiple representations of various graphomotor samples produced by both control and PD subjects. The extracted features are then fed to a Support Vector Machine (SVM) classifier. Evaluations are carried out on a dataset of 72 subjects using early and late fusion techniques and an overall accuracy of 83% is realized with solely visual information. (c) 2018 Published by Elsevier B.V.

关键词： Ebola virus disease   survivors   Democratic Republic of Congo   clinical findings  

摘要： Background. Clinical sequelae of Ebola virus disease (EVD) have not been described more than 3 years postoutbreak. We examined survivors and close contacts from the 1995 Ebola outbreak in Kikwit, Democratic Republic of Congo (DRC), and determined prevalence of abnormal neurological, cognitive, and psychological findings and their association with EVD survivorship. Methods. From August to September 2017, we conducted a cross-sectional study in Kikwit, DRC. Over 2 decades after the EVD outbreak, we recruited EVD survivors and close contacts from the outbreak to undergo physical examination and culturally adapted versions of the Folstein mini-mental status exam (MMSE) and Goldberg anxiety and depression scale (GADS). We estimated the strength of relationships between EVD survivorship and health outcomes using linear regression models by comparing survivors versus close contacts, adjusting for age, sex, educational level, marital status, and healthcare worker status. Results. We enrolled 20 EVD survivors and 187 close contacts. Among the 20 EVD survivors, 4 (20%) reported at least 1 abnormal neurological symptom, and 3 (15%) had an abnormal neurological examination. Among the 187 close contacts, 14 (11%) reported at least 1 abnormal neurologic symptom, and 9 (5%) had an abnormal neurological examination. EVD survivors had lower mean MMSE and higher mean GADS scores as compared to close contacts (MMSE: adjusted coefficient: -1.85;95% confidence interval [CI]: -3.63, -0.07;GADS: adjusted coefficient: 3.91;95% CI: 1.76, 6.04). Conclusions. EVD survivors can have lower cognitive scores and more symptoms of depression and anxiety than close contacts more than 2 decades after Ebola virus outbreaks.

关键词： Cerebrospinal fluid dynamics   Intracranial pressure elevation   Choroid plexus   Blood-brain barrier   Ischaemic stroke  

摘要： The fine balance between the secretion, composition, volume and turnover of cerebrospinal fluid (CSF) is strictly regulated. However, during certain neurological diseases, this balance can be disrupted. A significant disruption to the normal CSF circulation can be life threatening, leading to increased intracranial pressure (ICP), and is implicated in hydrocephalus, idiopathic intracranial hypertension, brain trauma, brain tumours and stroke. Yet, the exact cellular, molecular and physiological mechanisms that contribute to altered hydrodynamic pathways in these diseases are poorly defined or hotly debated. The traditional views and concepts of CSF secretion, flow and drainage have been challenged, also due to recent findings suggesting more complex mechanisms of brain fluid dynamics than previously proposed. This review evaluates and summarises current hypotheses of CSF dynamics and presents evidence for the role of impaired CSF dynamics in elevated ICP, alongside discussion of the proteins that are potentially involved in altered CSF physiology during neurological disease. Undoubtedly CSF secretion, absorption and drainage are important aspects of brain fluid homeostasis in maintaining a stable ICP. Traditionally, pharmacological interventions or CSF drainage have been used to reduce ICP elevation due to over production of CSF. However, these drugs are used only as a temporary solution due to their undesirable side effects. Emerging evidence suggests that pharmacological targeting of aquaporins, transient receptor potential vanilloid type 4 (TRPV4), and the Na+-K+-2Cl(-) cotransporter (NKCC1) merit further investigation as potential targets in neurological diseases involving impaired brain fluid dynamics and elevated ICP.

关键词： Spinal tuberculosis   Atlantoaxial   Neurological impairment   Surgical approach  

摘要： BackgroundSurgical treatment is mainly used for atlantoaxial tuberculosis with neurological damage. However, the anatomic structure around the atlantoaxial joint is complex, and the position of vertebral body is deep, which increases the difficulty of the operation and it is challenging for the surgeon to develop surgical strategy. The purpose of this study was to evaluate the clinical outcomes of one-stage combined anterior and posterior surgical treatment approach for atlantoaxial tuberculosis with neurological *** January 2005 to January 2015, 12 patients suffering from atlantoaxial tuberculosis with neurological impairment were surgically treated by one-stage combined anterior and posterior approach. Preoperative CT scanning and MRI imaging showed unilateral or bilateral lateral mass destruction of the atlas, and varying destruction degrees of odontoid process, loss of atlantoaxial stability, and tuberculosis focus into the spinal canal resulting in the corresponding spinal cord compression in all patients. The preoperative neurological classifications were Class C for 4 cases, D for 8 cases according to the American Spinal Injury Association (ASIA) system. Quadruple sensitive anti-TB drug treatment was used in all 12 patients preoperative and postoperative. Patients' clinical symptoms and neurological function recovery were evaluated by comparing the Visual Analogue Scale (VAS) score, Neck Disability Index (NDI), Japanese Orthopedic Association (JOA) score and ASIA grading before operation and at the final *** surgical duration was 263.343.6min. Intraoperative blood loss was averagely 529.2 +/- 169.8ml. The average fusion period was 7.3 +/- 1.5months. No instrumentation loosening, migration or breakage was observed during the follow-up of 6.5 +/- 2.9years. The VAS, NDI and JOA scores were significantly changed to 1.00 +/- 0.95, 9.50 +/- 3.34 and 15.42 +/- 1.44 at last follow-up (P<0.05). The neurological function of all 12 p

关键词： Carbon monoxide poisoning   Delayed neuropsychiatric sequelae   Epidemiological study   Sri Lanka  

摘要： BackgroundCarbon monoxide poisoning is a common emergency worldwide, which carries high morbidity and mortality. Some patients who recover from the insult of acute carbon monoxide toxicity may later develop delayed neuropsychiatric sequelae (DNS) after a lucid period in the form of cognitive impairments, a broad spectrum of neurological deficits and affective disorders. Here, we present the first case of DNS following carbon monoxide poisoning in Sri Lanka and epidemiology of the exposure of nine (9) more *** presentationA 55-year-old patient and nine other people developed effects of carbon monoxide poisoning in two different occasions after sleeping few hours in the same room in their work place in Sri Lanka. These patients developed spectrum of symptoms with the acute carbon monoxide poisoning. However, one patient developed neurological deterioration pertaining to delayed neuropsychiatric sequelae (DNS) after 1 month of lucid interval. His MRI scan of the brain showed diffuse high signal intensity involving subcortical white matter, globus pallidus on FLAIR and T2W images. These areas showed high signals in DWI images with no significant changes appreciated on ADC map. There was no abnormal contrast enhancement appreciated in the above areas. EEG showed generalized slow waves. He gradually deteriorated over next 2weeks, exhibited athetoid movements of his feet and hands and went into rigid akinetic mute state. He could not response to any stimulation and even displayed decorticated-like posture and died. Others had normal MRI brain finding at 8 weeks of acute toxicity and all were neurologically normal after 1 ***, it is uncommon in a tropical country like Sri Lanka, clinicians should have high degree of suspicion with the correct circumstances, as it is a challenge for the emergency physicians, even in countries with higher rate of CO poisoning. The exact mechanisms of acute and delayed toxicity, preventive methods and the suggested t