BioMed Research International: Neurology The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Cerebral Endothelial Function Determined by Cerebrovascular Reactivity to L-Arginine Thu, 17 Apr 2014 12:41:27 +0000 Endothelium forms the inner cellular lining of blood vessels and plays an important role in many physiological functions including the control of vasomotor tone. Cerebral endothelium is probably one of the most specific types but until recently it was impossible to determine its function. In this review, the role of cerebrovascular reactivity to L-arginine (CVR-L-Arg) for assessment of cerebral endothelial function is discussed. L-Arginine induces vasodilatation through enhanced production of nitric oxide (NO) in the cerebral endothelium. Transcranial Doppler sonography is used for evaluation of cerebral blood flow changes. The method is noninvasive, inexpensive, and enables reproducible measurements. CVR-L-Arg has been compared to flow-mediated dilatation as a gold standard for systemic endothelial function and intima-media thickness as a marker for morphological changes. However, it seems to show specific cerebral endothelial function. So far CVR-L-Arg has been used to study cerebral endothelial function in many pathological conditions such as stroke, migraine, etc. In addition CVR-L-Arg has also proven its usefulness in order to show potential improvement after pharmacological interventions. In conclusion CVR-L-Arg is a promising noninvasive research method that could provide means for evaluation of cerebral endothelial function in physiological and pathological conditions. Janja Pretnar-Oblak Copyright © 2014 Janja Pretnar-Oblak. All rights reserved. Prophylactic Intra-Arterial Injection of Vasodilator for Asymptomatic Vasospasm Converts the Patient to Symptomatic Vasospasm due to Severe Microcirculatory Imbalance Wed, 16 Apr 2014 12:35:40 +0000 Object. The strategy to treat asymptomatic angiographic vasospasm following subarachnoid hemorrhage (SAH) is controversial. In this study we review our consecutive vasospasm series and discuss an adequate treatment strategy for asymptomatic vasospasm. Methods. From January 2007 to December 2012 we treated 281 aneurysmal SAH cases, with postoperative angiography performed 9 ± 2 days after the onset of SAH. Four asymptomatic cases received intra-arterial (IA) injection of vasodilator due to angiographic vasospasm. All cases improved vasospasm immediately following intervention. But all cases turned symptomatic within 48 hours. We retrospectively analyzed the time-density angiography curve and calculated the time to peak (TTP), mean transit time (MTT), and relative blood flow (rBF). Relative blood flow was calculated as follows. The integration of the value of the time-density curve for the artery was divided by the same value for the internal carotid artery multiplied by the MTT. Results. The decrease in TTP and MTT for the etiologic artery was similar to that of the nonetiologic artery. But the improvement in rBF for the etiologic artery and nonetiologic artery was 10% and 17%, respectively. Blood supply to the spastic artery decreased due to iatrogenic steal. Conclusion. Prophylactic IA injection of vasodilator in cases of asymptomatic vasospasm can produce symptomatic vasospasm. Norihito Shimamura, Masato Naraoka, Naoya Matsuda, Kiyohide Kakuta, and Hiroki Ohkuma Copyright © 2014 Norihito Shimamura et al. All rights reserved. One-Year Follow-Up of a Series of 100 Patients Treated for Lumbar Spinal Canal Stenosis by Means of HeliFix Interspinous Process Decompression Device Tue, 15 Apr 2014 14:01:32 +0000 Purpose. New interspinous process decompression devices (IPDs) provide an alternative to conservative treatment and decompressive surgery for patients with neurogenic intermittent claudication (NIC) due to degenerative lumbar spinal stenosis (DLSS). HeliFix is a minimally invasive IPD that can be implanted percutaneously. This is a preliminary evaluation of safety and effectiveness of this IPD up to 12 months after implantation. Methods. After percutaneous implantation in 100 patients with NIC due to DLSS, data on symptoms, quality of life, pain, and use of pain medication were obtained for up to 12 months. Results. Early symptoms and physical function improvements were maintained for up to 12 months. Leg, buttock/groin, and back pain were eased throughout, and the use and strength of related pain medication were reduced. Devices were removed from 2% of patients due to lack of effectiveness. Conclusions. Overall, in a period of up to 12-month follow-up, the safety and effectiveness of the HeliFix offered a minimally invasive option for the relief of NIC complaints in a high proportion of patients. Further studies are undertaken in order to provide insight on outcomes and effectiveness compared to other decompression methods and to develop guidance on optimal patient selection. Alberto Alexandre, Andrea Maria Alexandre, Mario De Pretto, Luca Corò, and Raul Saggini Copyright © 2014 Alberto Alexandre et al. All rights reserved. Stem Cell Niches in Glioblastoma: A Neuropathological View Tue, 15 Apr 2014 06:25:02 +0000 Glioblastoma (GBM) stem cells (GSCs), responsible for tumor growth, recurrence, and resistance to therapies, are considered the real therapeutic target, if they had no molecular mechanisms of resistance, in comparison with the mass of more differentiated cells which are insensitive to therapies just because of being differentiated and nonproliferating. GSCs occur in tumor niches where both stemness status and angiogenesis are conditioned by the microenvironment. In both perivascular and perinecrotic niches, hypoxia plays a fundamental role. Fifteen glioblastomas have been studied by immunohistochemistry and immunofluorescence for stemness and differentiation antigens. It has been found that circumscribed necroses develop inside hyperproliferating areas that are characterized by high expression of stemness antigens. Necrosis developed inside them because of the imbalance between the proliferation of tumor cells and endothelial cells; it reduces the number of GSCs to a thin ring around the former hyperproliferating area. The perinecrotic GSCs are nothing else that the survivors remnants of those populating hyperproliferating areas. In the tumor, GSCs coincide with malignant areas so that the need to detect where they are located is not so urgent. Davide Schiffer, Marta Mellai, Laura Annovazzi, Valentina Caldera, Angela Piazzi, Tetyana Denysenko, and Antonio Melcarne Copyright © 2014 Davide Schiffer et al. All rights reserved. Controversies about Interspinous Process Devices in the Treatment of Degenerative Lumbar Spine Diseases: Past, Present, and Future Sun, 13 Apr 2014 13:11:57 +0000 A large number of interspinous process devices (IPD) have been recently introduced to the lumbar spine market as an alternative to conventional decompressive surgery in managing symptomatic lumbar spinal pathology, especially in the older population. Despite the fact that they are composed of a wide range of different materials including titanium, polyetheretherketone, and elastomeric compounds, the aim of these devices is to unload spine, restoring foraminal height, and stabilize the spine by distracting the spinous processes. Although the initial reports represented the IPD as a safe, effective, and minimally invasive surgical alternative for relief of neurological symptoms in patients with low back degenerative diseases, recent studies have demonstrated less impressive clinical results and higher rate of failure than initially reported. The purpose of this paper is to provide a comprehensive overview on interspinous implants, their mechanisms of action, safety, cost, and effectiveness in the treatment of lumbar stenosis and degenerative disc diseases. Roberto Gazzeri, Marcelo Galarza, and Alex Alfieri Copyright © 2014 Roberto Gazzeri et al. All rights reserved. Impact of Clipping versus Coiling on Postoperative Hemodynamics and Pulmonary Edema after Subarachnoid Hemorrhage Wed, 09 Apr 2014 08:52:09 +0000 Volume management is critical for assessment of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). This multicenter prospective cohort study compared the impact of surgical clipping versus endovascular coiling on postoperative hemodynamics and pulmonary edema in patients with SAH. Hemodynamic parameters were measured for 14 days using a transpulmonary thermodilution system. The study included 202 patients, including 160 who underwent clipping and 42 who underwent coiling. There were no differences in global ejection fraction (GEF), cardiac index, systemic vascular resistance index, or global end-diastolic volume index between the clipping and coiling groups in the early period. However, extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI) were significantly higher in the clipping group in the vasospasm period. Postoperative C-reactive protein (CRP) level was higher in the clipping group and was significantly correlated with postoperative brain natriuretic peptide level. Multivariate analysis found that PVPI and GEF were independently associated with high EVLWI in the early period, suggesting cardiogenic edema, and that CRP and PVPI, but not GEF, were independently associated with high EVLWI in the vasospasm period, suggesting noncardiogenic edema. In conclusion, clipping affects postoperative CRP level and may thereby increase noncardiogenic pulmonary edema in the vasospasm period. His trial is registered with University Hospital Medical Information Network UMIN000003794. Nobutaka Horie, Mitsutoshi Iwaasa, Eiji Isotani, Shunsuke Ishizaka, Tooru Inoue, and Izumi Nagata Copyright © 2014 Nobutaka Horie et al. All rights reserved. Magnesium Lithospermate B, an Active Extract of Salvia miltiorrhiza, Mediates sGC/cGMP/PKG Translocation in Experimental Vasospasm Wed, 02 Apr 2014 06:36:13 +0000 Background. Soluble guanylyl cyclases (sGCs) and Ras homolog gene family, member A (rhoA)/Ras homolog gene family kinase(rho-kinase) plays a role in vascular smooth muscle relaxation in subarachnoid hemorrhage (SAH). It is of interest to examine the effect of MLB on rhoA/ROCK and sGC/cGMP/PKG expression. Methods. A rodent SAH model was employed. Tissue samples were for sGCa1, sGCß1, PKG, rhoA, ROCK (Western blot), and cGMP (ELISA) measurement. Results. MLB morphologically improved convolution of the internal elastic lamina, distortion of endothelial wall, and necrosis of the smooth muscle in the SAH rats. Expressed cGMP, sGCa1, sGCß1, and PKG in the SAH groups were reduced (), and MLB precondition significantly induced cGMP, sGC1, sGC1, and PKG. L-NAME reversed the vasodilation effect of MLB, reduced the bioexpression of PKG and cGMP (), and tends to reduce sGC1 level and induce rhoA, ROCK level in MLB precondition + SAH groups. Conclusion. These results demonstrate that sGC/cGMP/PKG and NO/ET pathways play pivotal roles in SAH-induced vasospasm. Through activating sGC/cGMP/PKG pathway and partially by inactivating rho-kinase in a NO-dependent mechanism, MLB shows promise to be an effective strategy for the treatment of this disease entity. Chih-Zen Chang, Shu-Chuan Wu, and Aij-Lie Kwan Copyright © 2014 Chih-Zen Chang et al. All rights reserved. Postsurgical Pathologies Associated with Intradural Electrical Stimulation in the Central Nervous System: Design Implications for a New Clinical Device Tue, 01 Apr 2014 08:01:07 +0000 Spinal cord stimulation has been utilized for decades in the treatment of numerous conditions such as failed back surgery and phantom limb syndromes, arachnoiditis, cancer pain, and others. The placement of the stimulating electrode array was originally subdural but, to minimize surgical complexity and reduce the risk of certain postsurgical complications, it became exclusively epidural eventually. Here we review the relevant clinical and experimental pathologic findings, including spinal cord compression, infection, hematoma formation, cerebrospinal fluid leakage, chronic fibrosis, and stimulation-induced neurotoxicity, associated with the early approaches to subdural electrical stimulation of the central nervous system, and the spinal cord in particular. These findings may help optimize the safety and efficacy of a new approach to subdural spinal cord stimulation now under development. Katherine N. Gibson-Corley, Oliver Flouty, Hiroyuki Oya, George T. Gillies, and Matthew A. Howard Copyright © 2014 Katherine N. Gibson-Corley et al. All rights reserved. Incidence, National Trend, and Outcome of Nontraumatic Subarachnoid Haemorrhage in Taiwan: Initial Lower Mortality, Poor Long-Term Outcome Mon, 31 Mar 2014 16:11:38 +0000 To investigate the longitudinal trend of nontraumatic subarachnoid haemorrhage (SAH), we analyzed the annual population-based incidence and mortality rate of nontraumatic subarachnoid hemorrhage in Taiwan. Logistic regression was used to identify independent predictors of mortality. The average incidence rate (IR) of nontraumatic SAH was per 100,000 per year. The prevalence of female patients was higher than in the male population (54.5% versus 45.5%). The average age of these patients was and females were older than males ( versus , ). Of these patients, 97.6% (611/626) were treated with surgical intervention with clipping procedure and 2.9% (18/626) with coiling. Total mortality of these patients was 13.4% (84/626). In adjusted analysis, age (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.98-0.98; ) and Charlson comorbidity index (OR, 0.709; 95% CI, 0.57–0.88; ) remained independent predictors of the mortality. Patients with nontraumatic SAH had a much higher prevalence in older age groups and in females than in the general population. Patients with old age and more comorbidity have higher mortality. Aggressive management of patients might reduce the initial mortality; however, patient outcome still remains poor. Hsing-Lin Lin, Kwan-Ming Soo, Chao-Wen Chen, Yen-Ko Lin, Tsung-Ying Lin, Liang-Chi Kuo, Wei-Che Lee, and Shiuh-Lin Huang Copyright © 2014 Hsing-Lin Lin et al. All rights reserved. Comment on “Vitamin D Status in Migraine Patients: A Case-Control Study” Mon, 31 Mar 2014 00:00:00 +0000 Fevzi Nuri Aydin, Ibrahim Aydin, and Mehmet Agilli Copyright © 2014 Fevzi Nuri Aydin et al. All rights reserved. Cerebral Vasospasm in Patients over 80 Years Treated by Coil Embolization for Ruptured Cerebral Aneurysms Mon, 24 Mar 2014 09:25:29 +0000 Object. The effect on clinical outcomes of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage (SAH) in patients over 80 years who underwent coil embolization was evaluated. Methods. Forty-four cases were reviewed and divided into two groups according to patient age: Group A, 79 years or younger, and Group B, 80 or older. Patient characteristics, prevalence of symptomatic vasospasm, modified Rankin Scale (mRS) scores at discharge and frequency of symptomatic vasospasm in patients with mRS scores of 3–6 were analyzed. Results. Thirty-two (73%) of the 44 cases were categorized as Group A and 12 (27%) as Group B. Group B had a significantly higher prevalence of symptomatic vasospasm compared to Group A . mRS scores at discharge were significantly higher in Group B than in Group A . Among cases with mRS scores of 3–6, there was a significantly higher frequency of symptomatic vasospasm in Group B than in Group A . Conclusions. In our cohort of aneurysmal SAH patients treated by coil embolization, patients over 80 years of age were more likely to suffer symptomatic vasospasm, which significantly correlated with worse clinical outcomes, than those 79 years and under. Tomohito Hishikawa, Yuji Takasugi, Tomohisa Shimizu, Jun Haruma, Masafumi Hiramatsu, Koji Tokunaga, Kenji Sugiu, and Isao Date Copyright © 2014 Tomohito Hishikawa et al. All rights reserved. Computed Tomography Angiography for Detection of Middle Meningeal Artery Lesions Associated with Acute Epidural Hematomas Thu, 13 Mar 2014 00:00:00 +0000 Background. The natural history of traumatic aneurysms of the middle meningeal artery (MMA) is not well known, but patients with these lesions are more likely to have delayed bleeds. In this paper, we described a series of patients with epidural hematoma who underwent angiotomography (CTA) for MMA vascular lesion diagnosis. Methods. Eleven patients admitted to our emergency unit with small acute epidural hematoma were prospectively studied. All patients with temporal acute epidural hematomas underwent CTA and cerebral angiogram at our institution for diagnosis of posttraumatic lesions of middle meningeal artery. The findings of angiotomography and digital angiography were reviewed by radiologist and angiographers, respectively, to ensure that the lesions were readily diagnosed without knowing the results of angiotomography and to compare CTA findings with standard angiogram. Results. The causes of head injury were traffic accidents, falls, and aggression. Three of these patients presented traumatic MMA pseudoaneurysm. CT angiography was able to diagnose all of them, with dimensions ranging from 1.5 to 2.8 mm. Conventional angiography confirmed the findings of CT angiography, and the lesions presented with similar dimensions at both methods. Conclusions. We believe that angiotomography can be a useful technique for diagnosis of vascular lesion associated with small epidural hematoma. Wellingson Silva Paiva, Almir Ferreira Andrade, Robson Luis Oliveira De Amorim, Edson Bor-Seng-Shu, Gabriel Gattas, Iuri Santana Neville, Jose Guilherme Caldas, Eberval Gadelha Figueiredo, and Manoel Jacobsen Teixeira Copyright © 2014 Wellingson Silva Paiva et al. All rights reserved. Therapeutic Implications of Estrogen for Cerebral Vasospasm and Delayed Cerebral Ischemia Induced by Aneurysmal Subarachnoid Hemorrhage Sun, 02 Mar 2014 13:27:52 +0000 Cerebral vasospasm (CV) remains the leading cause of delayed morbidity and mortality following aneurysmal subarachnoid hemorrhage (SAH). However, increasing evidence supports etiologies of delayed cerebral ischemia (DCI) other than CV. Estrogen, specifically 17β-estradiol (E2), has potential therapeutic implications for ameliorating the delayed neurological deterioration which follows aneurysmal SAH. We review the causes of CV and DCI and examine the evidence for E2-mediated vasodilation and neuroprotection. E2 potentiates vasodilation by activating endothelial nitric oxide synthase (eNOS), preventing increased inducible NOS (iNOS) activity caused by SAH, and decreasing endothelin-1 production. E2 provides neuroprotection by increasing thioredoxin expression, decreasing c-Jun N-terminal kinase activity, increasing neuroglobin levels, preventing SAH-induced suppression of the Akt signaling pathway, and upregulating the expression of adenosine A2a receptor. The net effect of E2 modulation of these various effectors is the promotion of neuronal survival, inhibition of apoptosis, and decreased oxidative damage and inflammation. E2 is a potentially potent therapeutic tool for improving outcomes related to post-SAH CV and DCI. However, clinical evidence supporting its benefits remains lacking. Given the promising preclinical data available, further studies utilizing E2 for the treatment of patients with ruptured intracranial aneurysms appear warranted. Dale Ding, Robert M. Starke, Aaron S. Dumont, Gary K. Owens, David M. Hasan, Nohra Chalouhi, Ricky Medel, and Chih-Lung Lin Copyright © 2014 Dale Ding et al. All rights reserved. Microbleeds in Late-Life Depression: Comparison of Early- and Late-Onset Depression Wed, 26 Feb 2014 15:58:26 +0000 Late-life depression could be classified roughly as early-onset depression (EOD) and late-onset depression (LOD). LOD was proved to be associated with cerebral lesions including white matter hyperintensities (WMH) and silent brain infarctions (SBI), differently from EOD. However, it is unclear whether similar association is present between LOD and microbleeds which are also silent lesions. In this study, 195 patients of late-life depression were evaluated and divided into EOD, presenile-onset depression (POD), and LOD groups; 85 healthy elderly controls were enrolled as controls. Subjects were scanned by MRI including susceptibility weighted images to evaluate white matter hyperintensities (WMH), silent brain infarctions (SBI), and microbleeds. The severity of depression was evaluated with 15-item Geriatric Depression Scale. Psychosocial factors were investigated with Scale of Life Events and Lubben Social Network Scale. Logistic regression and linear regression were performed to identify the independent risk factors for depression. Results showed that LOD patients had higher prevalence of microbleeds than EOD, POD, and control patients. The prevalence of lobar microbleeds and microbleeds in the left hemisphere was the independent risk factor for the occurrence of LOD; a high number of microbleeds were associated with severe state of LOD, whereas life events and lack of social support were more important for EOD and POD. All these results indicated that Microbleeds especially lobar microbleeds and microbleeds in the left hemisphere were associated with LOD but not with EOD. Chao Feng, Min Fang, Yu Xu, Ting Hua, and Xue-Yuan Liu Copyright © 2014 Chao Feng et al. All rights reserved. Stem Cell-Based Therapies for Ischemic Stroke Wed, 26 Feb 2014 13:59:45 +0000 In recent years, stem cell-based approaches have attracted more attention from scientists and clinicians due to their possible therapeutical effect on stroke. Animal studies have demonstrated that the beneficial effects of stem cells including embryonic stem cells (ESCs), inducible pluripotent stem cells (iPSCs), neural stem cells (NSCs), and mesenchymal stem cell (MSCs) might be due to cell replacement, neuroprotection, endogenous neurogenesis, angiogenesis, and modulation on inflammation and immune response. Although several clinical studies have shown the high efficiency and safety of stem cell in stroke management, mainly MSCs, some issues regarding to cell homing, survival, tracking, safety, and optimal cell transplantation protocol, such as cell dose and time window, should be addressed. Undoubtably, stem cell-based gene therapy represents a novel potential therapeutic strategy for stroke in future. Lei Hao, Zhongmin Zou, Hong Tian, Yubo Zhang, Huchuan Zhou, and Lei Liu Copyright © 2014 Lei Hao et al. All rights reserved. Perspectives on Molecular Biomarkers of Oxidative Stress and Antioxidant Strategies in Traumatic Brain Injury Thu, 13 Feb 2014 13:38:43 +0000 Traumatic brain injury (TBI) is frequently associated with abnormal blood-brain barrier function, resulting in the release of factors that can be used as molecular biomarkers of TBI, among them GFAP, UCH-L1, S100B, and NSE. Although many experimental studies have been conducted, clinical consolidation of these biomarkers is still needed to increase the predictive power and reduce the poor outcome of TBI. Interestingly, several of these TBI biomarkers are oxidatively modified to carbonyl groups, indicating that markers of oxidative stress could be of predictive value for the selection of therapeutic strategies. Some drugs such as corticosteroids and progesterone have already been investigated in TBI neuroprotection but failed to demonstrate clinical applicability in advanced phases of the studies. Dietary antioxidants, such as curcumin, resveratrol, and sulforaphane, have been shown to attenuate TBI-induced damage in preclinical studies. These dietary antioxidants can increase antioxidant defenses via transcriptional activation of NRF2 and are also known as carbonyl scavengers, two potential mechanisms for neuroprotection. This paper reviews the relevance of redox biology in TBI, highlighting perspectives for future studies. André Mendes Arent, Luiz Felipe de Souza, Roger Walz, and Alcir Luiz Dafre Copyright © 2014 André Mendes Arent et al. All rights reserved. Neuroprotective Effects of Adipose-Derived Stem Cells Are Maintained for 3 Weeks against Ischemic Damage in the Rabbit Spinal Cord Wed, 29 Jan 2014 09:05:17 +0000 In the previous study, we demonstrated that adipose-derived stem cells (ASCs) have neuroprotective effects against ischemic damage in the ventral horn of levels at 3 days after ischemia/reperfusion. In the present study, we expanded our observations for 3 weeks after ischemia/reperfusion to rule out the possibility of delayed neuronal death in several days after ischemia/reperfusion. Transient spinal cord ischemia was induced by a 15 min aortic artery occlusion in the subrenal region and rabbit ASCs were administered intrathecally into recipient rabbits () immediately after reperfusion. Transplantation of ASCs improved the neurological motor functions of the hindlimb 3 weeks after ischemia/reperfusion. Similarly, the cresyl violet-positive neurons were significantly increased at 3 weeks after ischemia/reperfusion compared to that in the vehicle (artificial cerebrospinal fluid)-treated group. The transplantation of ASCs significantly reduced reactive microglia induced by ischemia at 3 weeks after ischemia/reperfusion. In addition, transplantation of ASCs maintained the brain-derived neurotrophic factor (BDNF) levels 3 weeks after ischemia/reperfusion. These results suggest that the neuroprotective effects of ASCs are maintained 3 weeks after ischemia/reperfusion by modulating microgliosis and BDNF levels in the spinal cord. Seung Myung Moon, Woosuk Kim, Jin Young Chung, Wooseok Im, Dae Young Yoo, Hyo Young Jung, Moo-Ho Won, Jung Hoon Choi, and In Koo Hwang Copyright © 2014 Seung Myung Moon et al. All rights reserved. Primary Headache Disorders at a Tertiary Health Facility in Lagos, Nigeria: Prevalence and Consultation Patterns Thu, 23 Jan 2014 06:23:12 +0000 Background. Primary headaches are underdiagnosed and undertreated, with a significant impact on social activities and work. Aim. To determine the last-year prevalence and health care utilization pattern of primary headaches at a tertiary centre. Methods. A cross-sectional study was carried out amongst staff of the Lagos State University Teaching Hospital in Lagos, Nigeria. 402 staff members were selected by simple random sampling and administered a detailed structured headache assessment questionnaire. Migraine and tension-type headache were diagnosed according to the criteria of the International Headache Society (2004). Results. The participants comprised 168 males and 234 females. The mean age was years. The overall headache prevalence was 39.3% with female predominance (). Tension-type headache was the most prevalent at 72.8% and migraine at 18.9%. Unclassifiable headache constituted 8.2%. Migraine headache showed female preponderance (). 80.4% of participants did not seek medical consultation compared with 19.6% who did (). Of the latter, 83.9% consulted the general practitioner (GP), whilst 16.1% consulted the neurologist. Conclusions. Primary headache prevalence is high in our population. It is not recognised as that requiring care by most of the staff of this tertiary health facility; thus education is required to increase health care utilization. Olajumoke Oshinaike, Oluwadamilola Ojo, Njideka Okubadejo, Olaitan Ojelabi, and Akinola Dada Copyright © 2014 Olajumoke Oshinaike et al. All rights reserved. Reliability and Validity of the Migraine Disability Assessment Scale among Migraine and Tension Type Headache in Iranian Patients Thu, 16 Jan 2014 10:23:08 +0000 Introduction. MIDAS is a valid and reliable short questionnaire for assessment of headache related disability. Linguistic validation of Persian MIDAS and assessment of psychometric properties between tension type headache (TTH) and migraine were the aims of this study. Methods. Patients with migraine or TTH were included. At the first visit, we administered a headache symptom questionnaire, MIDAS, and SF-36. Patients filled out MIDAS in second and third visit within three and eight weeks after base line visit. Internal consistency (Cronbach α) and test-retest reproducibility (Spearman correlation coefficient) were used to assess reliability. Convergent validity and MIDAS capability to differentiate between chronic and episodic headaches (migraine and TTH) were also assessed. Results. The 267 participants had episodic migraine (EM-64%), chronic migraine (CM-13.5%), episodic TTH (ETTH-13.5%), and chronic TTH (CTTH-9). Internal consistency reliability was 0.8 for the entire sample, 0.72 for TTH, and 0.82 for migraine. Test-retest reliability for all questions between visit 1 and visit 2 varied from 0.54 to 0.71. Convergent validity was assessed using SF-36 as an external referent. Patients with episodic headaches (EM and ETTH) had significantly lower MIDAS scores than chronic headaches (CM and CTTH). Conclusion. Persian MIDAS is a valid and reliable questionnaire for migraine and TTH that can differentiate between episodic headache and chronic headache. Alireza Zandifar, Fatemeh Asgari, Faraidoon Haghdoost, Samaneh Sadat Masjedi, Navid Manouchehri, Mahboobeh Banihashemi, Abbas Ghorbani, Mohammad Reza Najafi, Mohammad Saadatnia, and Richard B. Lipton Copyright © 2014 Alireza Zandifar et al. All rights reserved. Acute Supratentorial Ischemic Stroke: When Surgery Is Mandatory Tue, 14 Jan 2014 08:15:10 +0000 Acute occlusion of middle cerebral artery (MCA) leads to severe brain swelling and to a malignant, often fatal syndrome. The authors summarize the current knowledge about such a condition and review the main surgical issues involved. Decompressive hemicraniectomy keeps being a valid option in accurately selected patients. Gabriele Ronchetti, Pier Paolo Panciani, Roberto Stefini, Giannantonio Spena, and Marco Maria Fontanella Copyright © 2014 Gabriele Ronchetti et al. All rights reserved. Vitamin D Status in Migraine Patients: A Case-Control Study Thu, 02 Jan 2014 15:50:10 +0000 Background. There have been few studies on the relation between vitamin D and migraine. We investigated the prevalence of vitamin D deficiency in migraine patients and compared it with a control group. We also evaluated the relationship of vitamin D deficiency with severity of migraine. Methods. 105 newly diagnosed migraine patients and 110 controls, matched for age, sex, socioeconomic status, education, and sun exposure, were enrolled during the spring of 2011. 25-Hydroxy vitamin D [25(OH)D] plasma levels were measured by chemiluminescence immunoassay. Results. The mean ± SE concentration of 25(OH)D was  ng/mL in cases and  ng/mL in controls. There was no significant difference in 25(OH)D concentration between cases and controls. We found no relationship between severity of headache and 25(OH)D status. Conclusions. We did not find any association between migraine and vitamin D status; also, severity of headaches was not related to 25(OH)D level. Further studies with larger sample sizes are required to confirm our results. Alireza Zandifar, Samaneh sadat Masjedi, Mahboobeh Banihashemi, Fatemeh Asgari, Navid Manouchehri, Homa Ebrahimi, Faraidoon Haghdoost, and Mohammad Saadatnia Copyright © 2014 Alireza Zandifar et al. All rights reserved. Description of the Vasospasm Phenomena following Perimesencephalic Nonaneurysmal Subarachnoid Hemorrhage Sat, 28 Dec 2013 10:18:19 +0000 Background. Perimesencephalic nonaneurysmal subarachnoid hemorrhage (PM-NASAH) is characterized by a benign course compared with aneurysmal SAH. While vasospasm (VS) after aneurysmal SAH is considered responsible for serious complications, VS post-PM-NASAH is not well documented. Our purpose was to characterize the incidence and course of VS among 63 patients—one of the largest databases of PM-NASAH patients with documented blood flow velocities in the literature. Methods. Data from 63 patients that were admitted with PM-NASAH from 2000 to 2012 and underwent transcranial Doppler tests to assess cranial vessel flow velocity was analyzed. Results. On average, the maximal flow velocity was measured on the 7th day after hemorrhage. Higher risk for VS was associated with younger age, female sex, and higher Hunt and Hess scores, a lower risk for patients treated with statins (). Using velocity thresholds for diagnosis of VS, 49.2% showed evidence of VS. This is the first description of blood flow velocities in PM-NASAH. VS average onset was on the 4th day, average cessation on day 15 after hemorrhage. No patients showed clinical manifestation of VS. Conclusions. VS post-PM-NASAH is not as rare as previously believed. However, its lack of clinical significance raises questions regarding the need for diagnosis and may suggest a less intensive treatment protocol. Daphna Prat, Oded Goren, Bela Bruk, Mati Bakon, Moshe Hadani, and Sagi Harnof Copyright © 2013 Daphna Prat et al. All rights reserved. Protective Effects of p38 MAPK Inhibitor SB202190 against Hippocampal Apoptosis and Spatial Learning and Memory Deficits in a Rat Model of Vascular Dementia Wed, 25 Dec 2013 16:51:21 +0000 Vascular dementia (VaD) is a common age-related neurodegenerative disease resulting from chronic hypoxia. In the present study, we examined the protective effects of p38 MAPK inhibitor SB202190 against hippocampal apoptosis and spatial learning and memory deficits in a chronic hypoperfusion rat model of VaD established by permanent bilateral carotid occlusion (2-VO). Sixty rats were randomly divided into sham-operated, VaD model, and VaD plus SB202190 groups (/group). After sham/2-VO surgery, rats were administered 0.1% DMSO (sham-operated and VaD groups) or SB202190 by intracerebroventricular injection. One week after inhibitor/vehicle treatment, hippocampal p38 MAPK phosphorylation was higher in the model group than in the SB202190 group (). Compared to the model group, the SB202190 group exhibited significantly shorter escape latencies in the Morris water maze hidden platform trials () and longer times in the original platform quadrant during probe trials (). The SB202190 group also showed significantly reduced neuronal apoptosis in the hippocampus compared to VaD model rats () as well as higher (antiapoptotic) Bcl-2 expression and lower (proapoptotic) caspase-3 expression ( for both). In conclusion, blockade of the p38 MAPK signaling pathway by SB202190 following permanent 2-OV reduced apoptosis of hippocampal neurons and rescued spatial learning and memory deficits. Shen Yang, Guangan Zhou, Hong Liu, Bo Zhang, Juan Li, Ruiting Cui, and Yifeng Du Copyright © 2013 Shen Yang et al. All rights reserved. Presymptomatic Treatment with Acetylcholinesterase Antisense Oligonucleotides Prolongs Survival in ALS (G93A-SOD1) Mice Sun, 22 Dec 2013 18:04:30 +0000 Objective. Previous research suggests that acetylcholinesterase (AChE) may be involved in ALS pathogenesis. AChE enzyme inhibitors can upregulate AChE transcription which in certain contexts can have deleterious (noncatalytic) effects, making them theoretically harmful in ALS, whilst AChE antisense-oligonucleotides (mEN101), which downregulate AChE may be beneficial. Our aim was to investigate whether downregulation of AChE using mEN101 is beneficial in an ALS mouse model. Methods. ALS (G93A-SOD1) mice received saline, mEN101, inverse-EN101, or neostigmine. Treatments were administered from 5 weeks. Disease-onset and survival were recorded. Additional mice were sacrificed for pathological analysis at 15 weeks of age. In a follow-up experiment treatment was started at the symptomatic stage at a higher dose. Results. mEN101 given at the presymptomatic (but not symptomatic) stage prolonged survival and attenuated motor-neuron loss in ALS mice. In contrast, neostigmine exacerbated the clinical parameters. Conclusions. These results suggest that AChE may be involved in ALS pathogenesis. The accelerated disease course with neostigmine suggests that any beneficial effects of mEN101 occur through a non-catalytic rather than cholinergic mechanism. Gotkine Marc, Rozenstein Leah, Einstein Ofira, Abramsky Oded, Argov Zohar, and Rosenmann Hanna Copyright © 2013 Gotkine Marc et al. All rights reserved. Cardiovascular Autonomic Neuropathy in Context of Other Complications of Type 2 Diabetes Mellitus Wed, 18 Dec 2013 14:45:02 +0000 The aim of this study was to investigate the relationship between cardiac autonomic neuropathy (CAN) and other micro- and macrovascular complications and risk factors for type 2 diabetes. We included, in this study, 149 patients with type 2 diabetes. We evaluated their cardiovascular risk factors, demographic data, and any major micro- and macrovascular complications of their diabetes. Assessments of CAN were based upon Ewing’s battery. Results. CAN was present in 38.9% of patients. In the CAN group, the duration of diabetes, BMI, systolic blood pressure, lipid levels, and HBA1c were all significantly higher than those in the other group. A significant association was found between CAN and retinopathy, peripheral neuropathy, ABI, and IMT. Multivariate logistic regression demonstrated that, in type 2 diabetes, the odds of CAN (OR (95% confidence intervals)) increase with the age of the patients (1.68 (1,4129–2.0025)), the average diabetes duration (0.57 (0.47–0.67)), cholesterol (1.009 (1.00-1.01)), HbA1c levels (1.88 (1.31–2.72)), peripheral neuropathy (15.47 (5.16–46.38)), BMI (1.12 (1.05–1.21)), and smoking (2.21 (1.08–4.53)). Conclusions. This study shows that CAN in type 2 diabetes is significantly associated with other macro- and microvascular complications and that there are important modifiable risk factors for its development. Anca Moţăţăianu, Rodica Bălaşa, Septimiu Voidăzan, and Zoltán Bajkó Copyright © 2013 Anca Moţăţăianu et al. All rights reserved. Posttraumatic Refractory Intracranial Hypertension and Brain Herniation Syndrome: Cerebral Hemodynamic Assessment before Decompressive Craniectomy Wed, 27 Nov 2013 15:53:10 +0000 Background. The pathophysiology of traumatic brain swelling remains little understood. An improved understanding of intracranial circulatory process related to brain herniation may have treatment implications. Objective. To investigate the cerebral hemodynamic changes associated with brain herniation syndrome due to traumatic brain swelling. Methods. Nineteen head-injured patients with evidence of refractory intracranial hypertension and transtentorial herniation were prospectively studied. Cerebral hemodynamic assessment by transcranial Doppler (TCD) ultrasonography was performed prior to decompressive craniectomy. Patients and their cerebral hemispheres were classified according to TCD-hemodynamic patterns, and the data correlated with neurological status, midline shift on CT scan, and Glasgow outcome scale scores at 6 months after injury. Results. A wide variety of cerebral hemodynamic findings were observed. Ten patients (52.7%) presented with cerebral oligoemia, 3 patients (15.8%) with cerebral hyperemia, and 6 patients with nonspecific circulatory pattern. Circulatory disturbances were more frequently found in the side of maximal cerebral swelling than in the opposite side. Pulsatility index (PI) values suggested that ICP varied from acceptable to considerably high; patients with increased PI, indicating higher microvascular resistance. No correlation was found between cerebral hemodynamic findings and outcome. Conclusions. There is a marked heterogeneity of cerebral hemodynamic disturbances among patients with brain herniation syndrome. Edson Bor-Seng-Shu, Wellingson Silva Paiva, Eberval G. Figueiredo, Yasunori Fujimoto, Almir Ferreira de Andrade, Erich Talamoni Fonoff, and Manoel Jacobsen Teixeira Copyright © 2013 Edson Bor-Seng-Shu et al. All rights reserved. Abnormal Nerve Conduction Study Findings Indicating the Existence of Peripheral Neuropathy in Multiple Sclerosis and Neuromyelitis Optica Thu, 07 Nov 2013 10:11:24 +0000 Objective. Chronic inflammatory demyelinating polyneuropathy (CIDP) has been reported in patients with multiple sclerosis (MS). However, there have been limited reports of peripheral neuropathy as a complication of neuromyelitis optica (NMO). In this paper, we showed the characteristics and differences between peripheral neuropathy as a complication of MS and NMO. Method. We analyzed a series of 58 MS and 28 NMO patients and evaluated nerve conduction studies (NCS) in 21 MS and 5 NMO patients. Results. Six of the 58 MS and 3 of the 28 NMO patients revealed abnormal NCS findings. Three (5.2%) of the 58 MS patients fulfilled the criteria for CIDP. One (3.6%) of the 28 NMO patients showed peripheral neuropathy at the same time of NMO relapse, although CIDP was not seen in NMO. The other 5 (3 MS and 2 NMO) patients were complicated with neuropathy caused by concomitant diabetes mellitus and Sjögren’s syndrome. Conclusion. Frequency of abnormal NCS findings might exhibit no significant difference between MS and NMO, although the cause and pathophysiology of peripheral neuropathy were different in MS and in NMO. There might be a group of NMO who were affected simultaneously in the central and peripheral nervous tissues. Yoko Warabi, Mikihiro Yamazaki, Toshio Shimizu, and Masahiro Nagao Copyright © 2013 Yoko Warabi et al. All rights reserved. Monocyte Locomotion Inhibitory Factor Produced by E. histolytica Improves Motor Recovery and Develops Neuroprotection after Traumatic Injury to the Spinal Cord Sun, 03 Nov 2013 13:40:54 +0000 Monocyte locomotion inhibitory factor (MLIF) is a pentapeptide produced by Entamoeba histolytica that has a potent anti-inflammatory effect. Either MLIF or phosphate buffered saline (PBS) was administered directly onto the spinal cord (SC) immediately after injury. Motor recovery was evaluated. We also analyzed neuroprotection by quantifying the number of surviving ventral horn motor neurons and the persistence of rubrospinal tract neurons. To evaluate the mechanism through which MLIF improved the outcome of SC injury, we quantified the expression of inducible nitric oxide synthase (iNOS), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β) genes at the site of injury. Finally, the levels of nitric oxide and of lipid peroxidation were also determined in peripheral blood. Results showed that MLIF improved the rate of motor recovery and this correlated with an increased survival of ventral horn and rubrospinal neurons. These beneficial effects were in turn associated with a reduction in iNOS gene products and a significant upregulation of IL-10 and TGF-β expression. In the same way, MLIF reduced the concentration of nitric oxide and the levels of lipid peroxidation in systemic circulation. The present results demonstrate for the first time the neuroprotective effects endowed by MLIF after SC injury. Gabriela Bermeo, Antonio Ibarra, Elisa García, Adrian Flores-Romero, Guadalupe Rico-Rosillo, Rubén Marroquín, Humberto Mestre, Carmina Flores, Francisco Blanco-Favela, and Raúl Silva-García Copyright © 2013 Gabriela Bermeo et al. All rights reserved. Analysis of Risk Factors for First Seizure after Stroke in Chinese Patients Sat, 02 Nov 2013 14:24:42 +0000 The aim of this study is to assess related risk factors and predict early- and late-onset seizure after first-ever stroke. A total of 2474 consecutive patients with initial stroke in China from 1997 to 2007 were retrospectively investigated, in which, 24 clinical and radiological indexes were used for evaluation. Odds ratio (OR) and 95% confidence interval (CI) were calculated by logistic regression. A total of 232 (11.1%) of patients developed seizures during a mean follow-up period of 18 months, with 123 experiencing early-onset and 109 late-onset seizure. The independent risk factors for early-onset seizure were large lesion (), subarachnoid hemorrhage (), initial hyponatremia (), and cortical involvement (). The independent risk factors for late-onset seizure were cortical involvement () and large lesion (). These results demonstrated that the risk factors for early seizure after stroke are large lesion, subarachnoid hemorrhage, and cortical involvement. Surprisingly, hyponatremia also predicts seizure in stroke patients. Cortical involvement is a major risk factor for late-onset seizure after stroke. Guoqing Wang, Haiyan Jia, Chunfu Chen, Senyang Lang, Xinfeng Liu, Cheng Xia, Yan Sun, and Jun Zhang Copyright © 2013 Guoqing Wang et al. All rights reserved. Psychomotor Retardation in Depression: A Systematic Review of Diagnostic, Pathophysiologic, and Therapeutic Implications Wed, 30 Oct 2013 17:42:46 +0000 Psychomotor retardation is a central feature of depression which includes motor and cognitive impairments. Effective management may be useful to improve the classification of depressive subtypes and treatment selection, as well as prediction of outcome in patients with depression. The aim of this paper was to review the current status of knowledge regarding psychomotor retardation in depression, in order to clarify its role in the diagnostic management of mood disorders. Retardation modifies all the actions of the individual, including motility, mental activity, and speech. Objective assessments can highlight the diagnostic importance of psychomotor retardation, especially in melancholic and bipolar depression. Psychomotor retardation is also related to depression severity and therapeutic change and could be considered a good criterion for the prediction of therapeutic effect. The neurobiological process underlying the inhibition of activity includes functional deficits in the prefrontal cortex and abnormalities in dopamine neurotransmission. Future investigations of psychomotor retardation should help improve the understanding of the pathophysiological mechanisms underlying mood disorders and contribute to improving their therapeutic management. Djamila Bennabi, Pierre Vandel, Charalambos Papaxanthis, Thierry Pozzo, and Emmanuel Haffen Copyright © 2013 Djamila Bennabi et al. All rights reserved. Immunization with a Neural-Derived Peptide Protects the Spinal Cord from Apoptosis after Traumatic Injury Wed, 23 Oct 2013 09:34:10 +0000 Apoptosis is one of the most destructive mechanisms that develop after spinal cord (SC) injury. Immunization with neural-derived peptides (INDPs) such as A91 has shown to reduce the deleterious proinflammatory response and the amount of harmful compounds produced after SC injury. With the notion that the aforementioned elements are apoptotic inducers, we hypothesized that INDPs would reduce apoptosis after SC injury. In order to test this assumption, adult rats were subjected to SC contusion and immunized either with A91 or phosphate buffered saline (PBS; control group). Seven days after injury, animals were euthanized to evaluate the number of apoptotic cells at the injury site. Apoptosis was evaluated using DAPI and TUNEL techniques; caspase-3 activity was also evaluated. To further elucidate the mechanisms through which A91 exerts this antiapoptotic effects we quantified tumor necrosis factor-alpha (TNF-α). To also demonstrate that the decrease in apoptotic cells correlated with a functional improvement, locomotor recovery was evaluated. Immunization with A91 significantly reduced the number of apoptotic cells and decreased caspase-3 activity and TNF-α concentration. Immunization with A91 also improved the functional recovery of injured rats. The present study shows the beneficial effect of INDPs on preventing apoptosis and provides more evidence on the neuroprotective mechanisms exerted by this strategy. Roxana Rodríguez-Barrera, Ana M. Fernández-Presas, Elisa García, Adrian Flores-Romero, Susana Martiñón, Viridiana Yazmín González-Puertos, Humberto Mestre, Carmina Flores-Dominguez, Verónica Rodriguez-Mata, Mina Königsberg, Sandra Solano, and Antonio Ibarra Copyright © 2013 Roxana Rodríguez-Barrera et al. All rights reserved. Elevated Expression of Fractalkine (CX3CL1) and Fractalkine Receptor (CX3CR1) in the Dorsal Root Ganglia and Spinal Cord in Experimental Autoimmune Encephalomyelitis: Implications in Multiple Sclerosis-Induced Neuropathic Pain Tue, 24 Sep 2013 09:38:35 +0000 Multiple sclerosis (MS) is a central nervous system (CNS) disease resulting from a targeted autoimmune-mediated attack on myelin proteins in the CNS. The release of Th1 inflammatory mediators in the CNS activates macrophages, antibodies, and microglia resulting in myelin damage and the induction of neuropathic pain (NPP). Molecular signaling through fractalkine (CX3CL1), a nociceptive chemokine, via its receptor (CX3CR1) is thought to be associated with MS-induced NPP. An experimental autoimmune encephalomyelitis (EAE) model of MS was utilized to assess time dependent gene and protein expression changes of CX3CL1 and CX3CR1. Results revealed significant increases in mRNA and the protein expression of CX3CL1 and CX3CR1 in the dorsal root ganglia (DRG) and spinal cord (SC) 12 days after EAE induction compared to controls. This increased expression correlated with behavioural thermal sensory abnormalities consistent with NPP. Furthermore, this increased expression correlated with the peak neurological disability caused by EAE induction. This is the first study to identify CX3CL1 signaling through CX3CR1 via the DRG /SC anatomical connection that represents a critical pathway involved in NPP induction in an EAE model of MS. Wenjun Zhu, Crystal Acosta, Brian MacNeil, Claudia Cortes, Howard Intrater, Yuewen Gong, and Mike Namaka Copyright © 2013 Wenjun Zhu et al. All rights reserved. Different Levels in Orexin Concentrations and Risk Factors Associated with Higher Orexin Levels: Comparison between Detoxified Opiate and Methamphetamine Addicts in 5 Chinese Cities Thu, 12 Sep 2013 11:57:24 +0000 This study sought to explore the degree of orexin levels in Chinese opiate and methamphetamine addicts and the differences between them. The cross-sectional study was conducted among detoxified drug addicts from Mandatory Detoxification Center (MDC) in five Chinese cities. Orexin levels were assayed with radioimmunoassay (RIA). Mann-Whitney test and Kruskal-Wallis test were used to detect differences across groups, and logistic regression was used to explore the association between orexin levels and characteristics of demographic and drug abuse. Between November 2009 and January 2011, 285 opiates addicts, 112 methamphetamine addicts, and 79 healthy controls were enrolled. At drug withdrawal period, both opiate and methamphetamine addicts had lower median orexin levels than controls, and median orexin levels in opiate addicts were higher than those in methamphetamine addicts (all above ). Adjusted odds of the above median concentration of orexin were higher for injection than “chasing the dragon” (AOR = 3.1, 95% CI = 1.2–7.9). No significant factors associated with orexin levels of methamphetamine addicts were found. Development of intervention method on orexin system by different administration routes especially for injected opiate addicts at detoxification phase may be significant and was welcome. Haoran Zhang, Zhi Lian, Shiyan Yan, Yanping Bao, and Zhimin Liu Copyright © 2013 Haoran Zhang et al. All rights reserved. Neuroprotective Effects of MicroRNA-210 on Hypoxic-Ischemic Encephalopathy Mon, 09 Sep 2013 17:59:21 +0000 Objectives. To reveal the effect of microRNA-210 on cell apoptosis caused by HIE. Methods. Postnatal day 7 rats after HI injury were intraventricularly injected with microRNA-210 mimic, microRNA-210 inhibitor, or physiological saline. 72 h after the injection, rats were sacrificed and the left hemispheres were collected. The expression level of microRNA-210 was identified by quantitative real-time PCR analysis. Apoptosis in brain sections was investigated by TUNEL assay. Apoptosis-related protein expressions were studied by Western blot analysis. Results. The results showed that microRNA-210, whose expression was downregulated in the brain 72 h after HI injury, suppressed neuronal apoptosis by inhibiting caspase activity and regulating the balance between bcl-2 and bax levels. Discussion. Recent study demonstrated that microRNA-210 has neuroprotective effects through inhibiting apoptosis in a murine model of HIE. It represents a potential novel therapeutic approach for the treatment of HIE. Jie Qiu, Xiao-yu Zhou, Xiao-guang Zhou, Rui Cheng, Hai-ying Liu, and Yong Li Copyright © 2013 Jie Qiu et al. All rights reserved. Immunocytochemical Characterization of Alzheimer Disease Hallmarks in APP/PS1 Transgenic Mice Treated with a New Anti-Amyloid-β Vaccine Mon, 09 Sep 2013 17:52:08 +0000 APP/PS1 double-transgenic mouse models of Alzheimer’s disease (AD), which overexpress mutated forms of the gene for human amyloid precursor protein (APP) and presenilin 1 (PS1), have provided robust neuropathological hallmarks of AD-like pattern at early ages. This study characterizes immunocytochemical patterns of AD mouse brain as a model for human AD treated with the EB101 vaccine. In this novel vaccine, a new approach has been taken to circumvent past failures by judiciously selecting an adjuvant consisting of a physiological matrix embedded in liposomes, composed of naturally occurring phospholipids (phosphatidylcholine, phosphatidylglycerol, and cholesterol). Our findings showed that administration of amyloid-β1−42 (Aβ) and sphingosine-1-phosphate emulsified in liposome complex (EB101) to APP/PS1 mice before onset of Aβ deposition (7 weeks of age) and/or at an older age (35 weeks of age) is effective in halting the progression and clearing the AD-like neuropathological hallmarks. Passive immunization with EB101 did not activate inflammatory responses from the immune system and astrocytes. Consistent with a decreased inflammatory background, the basal immunological interaction between the T cells and the affected areas (hippocampus) in the brain of treated mice was notably reduced. These results demonstrate that immunization with EB101 vaccine prevents and attenuates AD neuropathology in this type of double-transgenic mice. Iván Carrera, Ignacio Etcheverría, Yi Li, Lucía Fernández-Novoa, Valter Lombardi, Carmen Vigo, Hector H. Palacios, Valery V. Benberin, Ramón Cacabelos, and Gjumrakch Aliev Copyright © 2013 Iván Carrera et al. All rights reserved. Endostatin/Collagen XVIII Is Increased in Cerebrospinal Fluid after Severe Traumatic Brain Injury Sun, 08 Sep 2013 15:29:43 +0000 Recent studies have suggested that endogenous angiogenesis inhibitor endostatin/collagen XVIII might play an important role in the secondary brain injury following traumatic brain injury (TBI). In this study, we measured endostatin/collagen XVIII concentrations serially for 1 week after hospitalization by using the enzyme-linked immunosorbent assay method in the cerebrospinal fluid (CSF) of 30 patients with TBI and a Glasgow Coma Scale (GCS) score of 8 or less on admission. There was a significant trend toward increased CSF levels of endostatin after TBI versus control from 72 h after injury. In patients with GCS score of 3–5, CSF endostatin concentration was substantially higher at 72 h after injury than that in patients with GCS score of 6–8 () and peaked rapidly at day 5 after injury, but decreased thereafter. The CSF endostatin concentration in 12 patients with an unfavorable outcome was significantly higher than that in 18 patients with a favorable outcome at day 5 () and day 7 () after trauma. Receiver operating characteristic curve analysis suggested a reliable operating point for the 7-day CSF endostatin concentration predicting poor prognosis to be 67.29 pg/mL. Our preliminary findings provide new evidence that endostatin/collagen XVIII concentration in the CSF increases substantially in patients with sTBI. Its dynamic change may have some clinical significance on the judgment of brain injury severity and the assessment of prognosis. This trial is registered with the Identifier: NCT01846546. Hao Chen, Li-Xia Xue, He-Li Cao, Shi-Wen Chen, Yan Guo, Wen-Wei Gao, Shi-Ming Ju, and Heng-Li Tian Copyright © 2013 Hao Chen et al. All rights reserved. Schwannoma in the Upper Limbs Wed, 04 Sep 2013 10:50:25 +0000 Schwannomas are the commonest tumours of peripheral nerves. Despite the classical description that schwannomas are well encapsulated and can be completely enucleated during excision, a portion of them have fascicular involvement and could not be completely shelled out. A retrospective review for 8 patients was carried out over 10 years. 75% of schwannoma occurred over the distal region of upper limb (at elbow or distal to it). It occurs more in the mixed nerve instead of pure sensory or motor nerve. 50% of patients had mixed nerve involvement. Fascicular involvement was very common in schwannoma (75% of patients). Removal of the tumour with fascicles can cause functional deficit. At present, there is no method (including preoperative MRI) which can predict the occurrence of fascicular involvement; the authors therefore proposed a new system to stratify patients who may benefit from interfascicular nerve grafts. In this group of patients, the authors strongly recommend that the possibility and option of nerve graft should be discussed with patients prior to schwannoma excision, so that nerve grafting could be directly proceeded with patient consent in case there is fascicular involvement of tumour found intraoperatively. Chris Yuk Kwan Tang, Boris Fung, Margaret Fok, and Janet Zhu Copyright © 2013 Chris Yuk Kwan Tang et al. All rights reserved. Nosology of Juvenile Muscular Atrophy of Distal Upper Extremity: From Monomelic Amyotrophy to Hirayama Disease—Indian Perspective Mon, 26 Aug 2013 14:49:11 +0000 Since its original description by Keizo Hirayama in 1959, “juvenile muscular atrophy of the unilateral upper extremity” has been described under many nomenclatures from the east. Hirayama disease (HD), also interchangeably referred to as monomelic amyotrophy, has been more frequently recognised in the west only in the last two decades. HD presents in adolescence and young adulthood with insidious onset unilateral or bilateral asymmetric atrophy of hand and forearm with sparing of brachioradialis giving the characteristic appearance of oblique amyotrophy. Symmetrically bilateral disease has also been recognized. Believed to be a cervical flexion myelopathy, HD differs from motor neuron diseases because of its nonprogressive course and pathologic findings of chronic microcirculatory changes in the lower cervical cord. Electromyography shows features of acute and/or chronic denervation in C7, C8, and T1 myotomes in clinically affected limb and sometimes also in clinically unaffected contralateral limb. Dynamic forward displacement of dura in flexion causes asymmetric flattening of lower cervical cord. While dynamic contrast magnetic resonance imaging is diagnostic, routine study has high predictive value. There is a need to lump all the nomenclatures under the rubric of HD as prognosis in this condition is benign and prompt diagnosis is important to institute early collar therapy. Kaukab Maqbool Hassan and Hirdesh Sahni Copyright © 2013 Kaukab Maqbool Hassan and Hirdesh Sahni. All rights reserved. Sporadic Cerebral Cavernous Malformations: Report of Further Mutations of CCM Genes in 40 Italian Patients Thu, 22 Aug 2013 08:23:35 +0000 Cerebral cavernous malformations (CCMs) are vascular lesions characterized by abnormally enlarged capillary cavities, affecting the central nervous system. CCMs can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes: CCM1 (K-Rev interaction trapped 1 (KRIT1)), CCM2 (MGC4607), and CCM3 (PDCD10). CCMs occur as a single or multiple malformations that can lead to seizures, focal neurological deficits, hemorrhagic stroke, and headache. However, patients are frequently asymptomatic. In our previous mutation screening, performed in a cohort of 95 Italian patients, both sporadic and familial, we have identified several mutations in CCM genes, three of which in three distinct sporadic patients. In this study, representing further molecular screening of the three CCM genes, in a south Italian cohort of CCM patients enrolled by us in the last three years, we report the identification of other four new mutations in 40 sporadic patients with either single or multiple CCM. Rosalia D’Angelo, Concetta Alafaci, Concetta Scimone, Alessia Ruggeri, Francesco Maria Salpietro, Placido Bramanti, Francesco Tomasello, and Antonina Sidoti Copyright © 2013 Rosalia D’Angelo et al. All rights reserved. Quality of Life in Parkinson's Disease Caregivers: The Contribution of Personality Traits Mon, 19 Aug 2013 08:16:16 +0000 Parkinson's disease imposes significant demands not only on patients but also on those people living and caring for them, who often have a reduction in their quality of life. The factors that may ameliorate these effects, such as an individual's personality, are not understood. Therefore, the aim of this study was to look at the relative contribution of caregiver personality on their quality of life, specifically attempting to identify those traits, which may be protective or harmful. Two hundred and seventy-four caregivers of patients with Parkinson's disease were included in this study. Caregivers were given questionnaires to complete, including the Big Five Inventory and the World Health Organisation Quality of Life BREF version. Univariate correlations demonstrated that depression and anxiety were the largest predictors of reduced quality of life amongst caregivers. However, after controlling for these potential confounds, conscientiousness was associated with enhanced psychological quality of life and openness positively predicted benefits in the environmental domain. Neuroticism was associated with reduced quality of life in the psychological domain. Thus, screening for neuroticism may help identify those caregivers who would benefit from intervention strategies, which could in the long term help reduce the need for nursing home placement of Parkinson's disease patients. Eloise H. Tew, Sharon L. Naismith, Marilia Pereira, and Simon J. G. Lewis Copyright © 2013 Eloise H. Tew et al. All rights reserved. The Influence of Hemocoagulation Disorders on the Development of Posttraumatic Cerebral Infarction and Outcome in Patients with Moderate or Severe Head Trauma Sun, 04 Aug 2013 10:42:10 +0000 Posttraumatic cerebral infarction (PTCI) is a severe secondary insult of head injury and often leads to a poor prognosis. Hemocoagulation disorder is recognized to have important effects on hemorrhagic or ischemic damages. We sought to assess if posttraumatic hemocoagulation disorders were associated with cerebral infarction, and evaluate their influence on outcome among patients with moderate or severe head trauma. In this study, PTCI was observed in 28 (10.57%) of the 265 patients within the first week after injury. In multivariate analysis, the thrombocytopenia (odds ratio (OR) 2.210, 95% confidence interval (CI) 1.065–4.674), abnormal prothrombin time (PT) (OR 3.241, 95% CI 1.090–7.648), D-dimer (>2 mg/L) (OR 7.260, 95% CI 1.822–28.076), or disseminated intravascular coagulation (DIC) scores (≥5) (OR 4.717, 95% CI 1.778–12.517) were each independently associated with an increased risk of PTCI. Admission Glasgow Coma Scale (GCS) score, abnormal activated partial thromboplastin time (APTT) and fibrinogen, and D-dimer (>2 mg/L) and DIC scores (≥5) showed an independent predictive effect on poor outcome. In conclusion, recognition of this important treatable cause of PTCI and the associated risk factors may help identify the group at risk and tailor management of patients with TBI. Hao Chen, Li-Xia Xue, Yan Guo, Shi-Wen Chen, Gan Wang, He-Li Cao, Jiong Chen, and Heng-Li Tian Copyright © 2013 Hao Chen et al. All rights reserved. Calcifications of Vertebrobasilar Arteries on CT: Detailed Distribution and Relation to Risk Factors in 245 Ischemic Stroke Patients Sun, 04 Aug 2013 10:34:30 +0000 Introduction. Intracranial atherosclerosis is responsible for a substantial proportion of strokes worldwide but its detailed morphology in the vertebrobasilar arteries (VBA) is unknown. Subject and Methods. Cases with ischemic strokes were retrospectively sought from the hospital database. Native CT scans were assessed for vessel area and intracranial artery calcifications (ICACs) in VBA. The calcifications were classified as focal (FCs), crescent, and circular. Results. 245 patients (mean age: years, 57.6% females) had visible ICACs. Calcifications were found in 75.9%, 63.3%, and 17.1% in the left vertebral artery (LVA), the right vertebral artery (RVA), and the basilar artery (BA), respectively. FCs were present in 91.0%, 90.3%, and 100.0%; crescents in 30.3%, 29.0%, and 7.1%, and circulars in 6.4%, 4.8%, and 0.0% of the RVA, LVA, and BA, respectively. FCs in dorsolateral quadrant were least prevalent in both vertebral arteries (VAs): 46 (29.8%) and 46 (27.4%) for RVA and LVA, respectively. Risk factors associated with vertical dispersion of ICACs were male gender (OR : 2.69, 1.38–5.28) and diabetes (OR : 2.28, 1.04–4.99). Conclusions. FCs in VAs are least prevalent in dorsolateral quadrants. The vertical dispersion of ICACs seems to be associated with the male gender and diabetes. Slaven Pikija, Jožef Magdič, and Tanja Hojs-Fabjan Copyright © 2013 Slaven Pikija et al. All rights reserved. CYP3A5*3 and C3435T MDR1 Polymorphisms in Prognostication of Drug-Resistant Epilepsy in Children and Adolescents Thu, 01 Aug 2013 08:42:31 +0000 Drug-resistant epilepsies still remain one of the most profound problems of contemporary epileptology. Several mechanisms of drug resistance are possible; among them, genetic factors have a prominent place. Much importance is attached to genes, which encode enzymes that metabolize antiepileptic drugs CYP 3A, which belong to the family of cytochromes P450 and the genome of multidrug resistance, such as multidrug resistance 1 (MDR1) that expresses P-glycoprotein (P-gp), a drug transporter protein. The aim of the study was to assess the relation between polymorphism of gene CYP3A5 and polymorphism C3435T of MDR1 gene with the occurrence of focal, drug-resistant epilepsy in children and youths up to 18 years of age. The study comprised 85 patients, and their age range was from 33 months to 18 years of age, suffering from epilepsy, partly responding well to treatment, partly drug resistant. The polymorphism of both genes has been analysed using the PCR-RFLP method. The study failed to corroborate association between polymorphism CYP3A5*3 and C3435T polymorphism in MDR1 gene and pharmacoresistant epilepsy. The results of our research do not confirm the prognostic value of the polymorphisms examined in the prognostication of drug resistance in epilepsies. Ewa Emich-Widera, Wirginia Likus, Beata Kazek, Paweł Niemiec, Anna Balcerzyk, Aleksander L. Sieroń, and Iwona Żak Copyright © 2013 Ewa Emich-Widera et al. All rights reserved. Rotenone Upregulates Alpha-Synuclein and Myocyte Enhancer Factor 2D Independently from Lysosomal Degradation Inhibition Tue, 30 Jul 2013 09:23:30 +0000 Dysfunctions of chaperone-mediated autophagy (CMA), the main catabolic pathway for alpha-synuclein, have been linked to the pathogenesis of Parkinson’s disease (PD). Since till now there is limited information on how PD-related toxins may affect CMA, in this study we explored the effect of mitochondrial complex I inhibitor rotenone on CMA substrates, alpha-synuclein and MEF2D, and effectors, lamp2A and hsc70, in a human dopaminergic neuroblastoma SH-SY5Y cell line. Rotenone induced an upregulation of alpha-synuclein and MEF2D protein levels through the stimulation of their de novo synthesis rather than through a reduction of their CMA-mediated degradation. Moreover, increased MEF2D transcription resulted in higher nuclear protein levels that exert a protective role against mitochondrial dysfunction and oxidative stress. These results were compared with those obtained after lysosome inhibition with ammonium chloride. As expected, this toxin induced the cytosolic accumulation of both alpha-synuclein and MEF2D proteins, as the result of the inhibition of their lysosome-mediated degradation, while, differently from rotenone, ammonium chloride decreased MEF2D nuclear levels through the downregulation of its transcription, thus reducing its protective function. These results highlight that rotenone affects alpha-synuclein and MEF2D protein levels through a mechanism independent from lysosomal degradation inhibition. Gessica Sala, Alessandro Arosio, Giovanni Stefanoni, Laura Melchionda, Chiara Riva, Daniele Marinig, Laura Brighina, and Carlo Ferrarese Copyright © 2013 Gessica Sala et al. All rights reserved. Relationship between Vitamin D Receptor Gene Polymorphisms and Migraine without Aura in an Iranian Population Thu, 25 Jul 2013 12:55:47 +0000 Background. Inflammation has a key role in migraine pathophysiology. Vitamin D is an effective anti-inflammatory agent. The aim of this study was to investigate the association between migraine and two vitamin D receptor (VDR) polymorphisms (TaqI and FokI) and also the relationship between VDR polymorphisms and headache severity. Methods. In this case-control study we assessed 103 patients with newly diagnosed migraine without aura and 100 healthy subjects. Patients filled headache impact test-6 (HIT-6) as a tool to assess headache severity. Results. Genotype frequencies of VDR were significantly different between control and migraine patients. Heterozygote genotypes (Ff and Tt) were statistically more frequent in the migraine patients than the control subjects both for TaqI gene (; OR = 1.81, 95% CI = 1.03–3.18) and FokI gene polymorphisms (; OR = 2.91, 95% CI = 1.47–5.77). Also f and t alleles were more frequent in the migraine patients. Total HIT-6 score was significantly different between FokI heterozygote and homozygote patients ( versus , resp., ). Conclusions. In conclusion our results showed that TaqI and FokI gene polymorphisms are associated with migraine without aura in Iranians patients. Also headache severity in FokI heterozygote patients was significantly greater than in the homozygote patients. Mohammad Motaghi, Shaghayegh Haghjooy Javanmard, Faraidoon Haghdoost, Mohamadhasan Tajadini, Mohammad Saadatnia, Laleh Rafiee, and Alireza Zandifar Copyright © 2013 Mohammad Motaghi et al. All rights reserved. Relationship between Pulsatility Index and Clinical Course of Acute Ischemic Stroke after Thrombolytic Treatment Thu, 25 Jul 2013 10:24:04 +0000 Background. The relationship between the arterial recanalization after intravenous recombinant tissue plasminogen activator (rtPA) and outcomes is still uncertain. The aim of our study was to evaluate whether there is an association between the pulsatility indexes (PI) of the middle cerebral artery (MCA) measured by transcranial Doppler (TCD) after iv rtPA treatment and short- and long-term outcomes in ischemic stroke patients. Methods. Forty-eight patients with acute ischemia in the MCA territory who achieved complete recanalization after the administration of intravenous thrombolytic treatment were included in the study. The TCD was applied to patients after the iv rtPA treatment. Clinical and functional outcomes were assessed by National Institutes of Health Stroke Scale (NIHSS) scores and modified Rankin Scores (mRS), respectively. Results. Significant positive correlations were found between the PI value and NIHSS score at 24 hours, NIHSS score at 3 months, and mRS at 3 months ( for all). The cut-off value for PI in predicting a favorable prognosis and a good prognosis might be less than or equal to 1.1 and less than or equal to 1.4, respectively. Conclusions. PI may play a role in predicting the functional and clinical outcome after thrombolytic therapy in acute ischemic stroke patients. Nevzat Uzuner, Özcan Özdemir, and Gülnur Tekgöl Uzuner Copyright © 2013 Nevzat Uzuner et al. All rights reserved. Endoplasmic Reticulum Stress-Mediated Hippocampal Neuron Apoptosis Involved in Diabetic Cognitive Impairment Wed, 24 Apr 2013 13:09:33 +0000 Poor management of DM causes cognitive impairment while the mechanism is still unconfirmed. The aim of the present study was to investigate the activation of C/EBP Homology Protein (CHOP), the prominent mediator of the endoplasmic reticulum (ER) stress-induced apoptosis under hyperglycemia. We employed streptozotocin- (STZ-) induced diabetic rats to explore the ability of learning and memory by the Morris water maze test. The ultrastructure of hippocampus in diabetic rats and cultured neurons in high glucose medium were observed by transmission electron microscopy and scanning electron microscopy. TUNEL staining was also performed to assess apoptotic cells while the expression of CHOP was assayed by immunohistochemistry and Western blot assay in these hippocampal neurons. Six weeks after diabetes induction, the escape latency increased and the average frequency in finding the platform decreased in diabetic rats (). The morphology of neuron and synaptic structure was impaired; the number of TUNEL-positive cells and the expression of CHOP in hippocampus of diabetic rats and high glucose medium cultured neurons were markedly altered (). The present results suggested that the CHOP-dependent endoplasmic reticulum (ER) stress-mediated apoptosis may be involved in hyperglycemia-induced hippocampal synapses and neurons impairment and promote the diabetic cognitive impairment. Xiaoming Zhang, Linhao Xu, Daqiang He, and Shucai Ling Copyright © 2013 Xiaoming Zhang et al. All rights reserved. The Use of Fuzzy BackPropagation Neural Networks for the Early Diagnosis of Hypoxic Ischemic Encephalopathy in Newborns Sun, 24 Jul 2011 08:20:09 +0000 Objective. To establish an early diagnostic system for hypoxic ischemic encephalopathy (HIE) in newborns based on artificial neural networks and to determine its feasibility. Methods. Based on published research as well as preliminary studies in our laboratory, multiple noninvasive indicators with high sensitivity and specificity were selected for the early diagnosis of HIE and employed in the present study, which incorporates fuzzy logic with artificial neural networks. Results. The analysis of the diagnostic results from the fuzzy neural network experiments with 140 cases of HIE showed a correct recognition rate of 100% in all training samples and a correct recognition rate of 95% in all the test samples, indicating a misdiagnosis rate of 5%. Conclusion. A preliminary model using fuzzy backpropagation neural networks based on a composite index of clinical indicators was established and its accuracy for the early diagnosis of HIE was validated. Therefore, this method provides a convenient tool for the early clinical diagnosis of HIE. Liu Li, Huo Liqing, Lu Hongru, Zhang Feng, Zheng Chongxun, Shami Pokhrel, and Zhang Jie Copyright © 2011 Liu Li et al. All rights reserved. Reduction of Ischemic and Oxidative Damage to the Hypothalamus by Hyperbaric Oxygen in Heatstroke Mice Thu, 17 Jun 2010 15:37:57 +0000 The aims of the present paper were to ascertain whether the heat-induced ischemia and oxidative damage to the hypothalamus and lethality in mice could be ameliorated by hyperbaric oxygen therapy. When normobaric air-treated mice underwent heat treatment, the fractional survival and core temperature at 4 hours after heat stress were found to be 0 of 12 and 34∘C±0.3∘C, respectively. In hyperbaric oxygen-treated mice, when exposed to the same treatment, both fractional survival and core temperature values were significantly increased to new values of 12/12 and 37.3∘C±0.3∘C, respectively. Compared to normobaric air-treated heatstroke mice, hyperbaric oxygen-treated mice displayed lower hypothalamic values of cellular ischemia and damage markers, prooxidant enzymes, proinflammatory cytokines, inducible nitric oxide synthase-dependent nitric oxide, and neuronal damage score. The data indicate that hyperbaric oxygen may improve outcomes of heatstroke by normalization of hypothalamic and thermoregulatory function in mice. Po-An Tai, Chen-Kuei Chang, Ko-Chi Niu, Mao-Tsun Lin, Wen-Ta Chiu, and Jia-Wei Lin Copyright © 2010 Po-An Tai et al. All rights reserved. Biological Role of Dystroglycan in Schwann Cell Function and Its Implications in Peripheral Nervous System Diseases Tue, 15 Jun 2010 08:36:43 +0000 Dystroglycan is a central component of the dystrophin-glycoprotein complex (DGC) that links extracellular matrix with cytoskeleton, expressed in a variety of fetal and adult tissues. Dystroglycan plays diverse roles in development and homeostasis including basement membrane formation, epithelial morphogenesis, membrane stability, cell polarization, and cell migration. In this paper, we will focus on biological role of dystroglycan in Schwann cell function, especially myelination. First, we review the molecular architecture of DGC in Schwann cell abaxonal membrane. Then, we will review the loss-of-function studies using targeted mutagenesis, which have revealed biological functions of each component of DGC in Schwann cells. Based on these findings, roles of dystroglycan in Schwann cell function, in myelination in particular, and its implications in diseases will be discussed in detail. Finally, in view of the fact that understanding the role of dystroglycan in Schwann cells is just beginning, future perspectives will be discussed. Toshihiro Masaki and Kiichiro Matsumura Copyright © 2010 Toshihiro Masaki and Kiichiro Matsumura. All rights reserved. The Role of Apolipoprotein E in Guillain-Barré Syndrome and Experimental Autoimmune Neuritis Tue, 16 Feb 2010 13:33:40 +0000 Apolipoprotein E (apoE) is a 34.2 kDa glycosylated protein characterized by its wide tissue distribution and multiple functions. ApoE has been widely studied in lipid metabolism, cardiocerebrovascular diseases, and neurodegenerative diseases like Alzheimer's disease and mild cognitive impairment, and so forth. Recently, a growing body of evidence has pointed to nonlipid related properties of apoE, including suppression of T cell proliferation, regulation of macrophage function, facilitation of lipid antigen presentation by CD1 molecules to natural killer T (NKT) cells, and modulation of inflammation and oxidation. By these properties, apoE impacts physiology and pathophysiology at multiple levels. The present paper summarizes updated studies on the immunoregulatory function of apoE, with special focus on isoform-specific effects of apoE on Guillain-Barré syndrome (GBS) and its animal model experimental autoimmune neuritis (EAN). Hong-liang Zhang, Jiang Wu, and Jie Zhu Copyright © 2010 Hong-liang Zhang et al. All rights reserved. Diagnosis of Charcot-Marie-Tooth Disease Thu, 08 Oct 2009 12:21:48 +0000 Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN) is a genetically heterogeneous group of conditions that affect the peripheral nervous system. The disease is characterized by degeneration or abnormal development of peripheral nerves and exhibits a range of patterns of genetic transmission. In the majority of cases, CMT first appears in infancy, and its manifestations include clumsiness of gait, predominantly distal muscular atrophy of the limbs, and deformity of the feet in the form of foot drop. It can be classified according to the pattern of transmission (autosomal dominant, autosomal recessive, or X linked), according to electrophysiological findings (demyelinating or axonal), or according to the causative mutant gene. The classification of CMT is complex and undergoes constant revision as new genes and mutations are discovered. In this paper, we review the most efficient diagnostic algorithms for the molecular diagnosis of CMT, which are based on clinical and electrophysiological data. Isabel Banchs, Carlos Casasnovas, Antonia Albertí, Laura De Jorge, Mónica Povedano, Jordi Montero, Juan Antonio Martínez-Matos, and Victor Volpini Copyright © 2009 Isabel Banchs et al. All rights reserved. Ischemia Alters the Expression of Connexins in the Aged Human Brain Wed, 23 Sep 2009 15:42:50 +0000 Although the function of astrocytic gap junctions under ischemia is still under debate, increased expression of connexin 43 (Cx43) has been observed in ischemic brain lesions, suggesting that astrocytic gap junctions could provide neuronal protection against ischemic insult. Moreover, different connexin subtypes may play different roles in pathological conditions. We used immunohistochemical analysis to investigate alterations in the expression of connexin subtypes in human stroke brains. Seven samples, sectioned after brain embolic stroke, were used for the analysis. Data, evaluated semiquantitatively by computer-assisted densitometry, was compared between the intact hemisphere and ischemic lesions. The results showed that the coexpression of Cx32 and Cx45 with neuronal markers was significantly increased in ischemic lesions. Cx43 expression was significantly increased in the colocalization with astrocytes and relatively increased in the colocalization with neuronal marker in ischemic lesions. Therefore, Cx32, Cx43, and Cx45 may respond differently to ischemic insult in terms of neuroprotection. Taizen Nakase, Tetsuya Maeda, Yasuji Yoshida, and Ken Nagata Copyright © 2009 Taizen Nakase et al. All rights reserved. Neurodegenerative Diseases: Mechanisms and Therapies Thu, 14 Sep 2006 00:00:00 +0000 Mark A. Smith, George Perry, Xiongwei Zhu, and Abdelali Haoudi Copyright © 2006 Mark A. Smith et al. All rights reserved. Targeting Gonadotropins: An Alternative Option for Alzheimer Disease Treatment Mon, 28 Aug 2006 00:00:00 +0000 Recent evidence indicates that, alongside oxidative stress, dysregulation of the cell cycle in neurons susceptible to degeneration in Alzheimer disease may play a crucial role in the initiation of the disease. As such, the role of reproductive hormones, which are closely associated with the cell cycle both during development and after birth, may be of key import. While estrogen has been the primary focus, the protective effects of hormone replacement therapy on cognition and dementia only during a “crucial period” led us to expand the study of hormonal influences to other members of the hypothalamic pituitary axis. Specifically, in this review, we focus on luteinizing hormone, which is not only increased in the sera of patients with Alzheimer disease but, like estrogen, is modulated by hormone replacement therapy and also influences cognitive behavior and pathogenic processing in animal models of the disease. Targeting gonadotropins may be a useful treatment strategy for disease targeting multiple pleiotropic downstream consequences. Gemma Casadesus, Emma Ramiro Puig, Kate M. Webber, Craig S. Atwood, Margarida Castell Escuer, Richard L. Bowen, George Perry, and Mark A. Smith Copyright © 2006 Gemma Casadesus et al. All rights reserved. Screening Pesticides for Neuropathogenicity Wed, 19 Jul 2006 00:00:00 +0000 Pesticides are routinely screened in studies that follow specific guidelines for possible neuropathogenicity in laboratory animals. These tests will detect chemicals that are by themselves strong inducers of neuropathogenesis if the tested strain is susceptible relative to the time of administration and methodology of assessment. Organophosphate induced delayed neuropathy (OPIDN) is the only known human neurodegenerative disease associated with pesticides and the existing study guidelines with hens are a standard for predicting the potential for organophosphates to cause OPIDN. Although recent data have led to the suggestion that pesticides may be risk factors for Parkinsonism syndrome, there are no specific protocols to evaluate this syndrome in the existing study guidelines. Ideally additional animal models for human neurodegenerative diseases need to be developed and incorporated into the guidelines to further assure the public that limited exposure to pesticides is not a risk factor for neurodegenerative diseases. John D. Doherty Copyright © 2006 John D. Doherty. All rights reserved. Roles of Cholesterol and Lipids in the Etiopathogenesis of Alzheimer's Disease Wed, 05 Jul 2006 00:00:00 +0000 Alzheimer's disease is the principal cause of dementia throughout the world and the fourth cause of death in developed economies.This brain disorder is characterized by the formation of brain protein aggregates, namely, the paired helical filaments and senile plaques. Oxidative stress during life, neuroinflamamtion, and alterations in neuron-glia interaction patterns have been also involved in the etiopathogenesis of this disease. In recent years, cumulative evidence has been gained on the involvement of alteration in neuronal lipoproteins activity, as well as on the role of cholesterol and other lipids in the pathogenesis of this neurodegenerative disorder. In this review, we analyze the links between changes in cholesterol homeostasis, and the changes of lipids of major importance for neuronal activity and Alheimer's disease. The investigation on the fine molecular mechanisms underlying the lipids influence in the etiopathogenesis of Alzheimer's disease may shed light into its treatment and medical management. Leonel Rojo, Marcela K. Sjöberg, Paula Hernández, Cristian Zambrano, and Ricardo B. Maccioni Copyright © 2006 Leonel Rojo et al. All rights reserved. Heme Deficiency in Alzheimer's Disease: A Possible Connection to Porphyria Sun, 25 Jun 2006 00:00:00 +0000 Mechanisms that cause Alzheimer's disease (AD), an invariably fatal neurodegenerative disease, are unknown. Important recent data indicate that neuronal heme deficiency may contribute to AD pathogenesis. If true, factors that contribute to the intracellular heme deficiency could potentially alter the course of AD. The porphyrias are metabolic disorders characterized by enzyme deficiencies in the heme biosynthetic pathway. We hypothesize that AD may differ significantly in individuals possessing the genetic trait for an acute hepatic porphyria. We elaborate on this hypothesis and briefly review the characteristics of the acute hepatic porphyrias that may be relevant to AD. We note the proximity of genes encoding enzymes of the heme biosynthesis pathway to genetic loci linked to sporadic, late-onset AD. In addition, we suggest that identification of individuals carrying the genetic trait for acute porphyria may provide a unique resource for investigating AD pathogenesis and inform treatment and management decisions. Barney E. Dwyer, Meghan L. Stone, Xiongwei Zhu, George Perry, and Mark A. Smith Copyright © 2006 Barney E. Dwyer et al. All rights reserved. Parkinson's Disease in Relation to Pesticide Exposure and Nuclear Encoded Mitochondrial Complex I Gene Variants Mon, 12 Jun 2006 00:00:00 +0000 Parkinson's disease (PD) is a common age-related neurodegenerative disorder thought to result from the integrated effects of genetic background and exposure to neuronal toxins. Certain individual nuclear-encoded mitochondrial complex I gene polymorphisms were found to be associated with ∼2-fold risk variation in an Australian case-control sample. We further characterized this sample of 306 cases and 321 controls to determine the mutual information contained in the 22 SNPs and, additionally, level of pesticide exposure: five distinct risk sets were identified using grade-of-membership analysis. Of these, one was robust to pesticide exposure (I), three were vulnerable (II, III, IV), and another (V) denoted low risk for unexposed persons. Risk for individual subjects varied >16-fold according to level of membership in the vulnerable groups. We conclude that inherited variation in mitochondrial complex I genes and pesticide exposure together modulate risk for PD. Elizabeth H. Corder and George D. Mellick Copyright © 2006 Elizabeth H. Corder and George D. Mellick. All rights reserved. Gaucher Disease and the Synucleinopathies Sun, 28 May 2006 00:00:00 +0000 Several recent observations suggest a connection between Gaucher disease, the inherited deficiency of glucocerebrosidase, and the synucleinopathies. Rare patients have been observed who develop both Gaucher disease and parkinsonism. Autopsy studies on these subjects reveal synuclein-positive Lewy bodies and inclusions. An increased incidence of synucleinopathies also has been noted in relatives of Gaucher probands. In complementary studies, screening of patients with parkinsonism has identified a greater than expected frequency of glucocerebrosidase mutations. These glucocerebrosidase mutation carriers have a wide spectrum of associated parkinsonian phenotypes, ranging from classic L-dopa-responsive Parkinson disease to a phenotype more characteristic of Lewy body dementia. Despite this association, the vast majority of Gaucher carriers and patients with Gaucher disease never develop parkinsonism. However, mutations in this gene are likely to be a contributing risk factor in subjects otherwise prone to developing synucleinopathies. Kathleen S. Hruska, Ozlem Goker-Alpan, and Ellen Sidransky Copyright © 2006 Kathleen S. Hruska et al. All rights reserved. Oxidative Damage to RNA in Neurodegenerative Diseases Thu, 25 May 2006 00:00:00 +0000 Since 1999, oxidative damage to RNA molecules has been described in several neurological diseases including Alzheimer's disease, Parkinson's disease, Down syndrome, dementia with Lewy bodies, prion disease, subacute sclerosing panencephalitis, and xeroderma pigmentosum. An early involvement of RNA oxidation of vulnerable neuronal population in the neurodegenerative diseases has been demonstrated, which is strongly supported by a recent observation of increased RNA oxidation in brains of subjects with mild cognitive impairment. Until recently, little is known about consequences and cellular handling of the RNA damage. However, increasing body of evidence suggests detrimental effects of the RNA damage in protein synthesis and the existence of several coping mechanisms including direct repair and avoiding the incorporation of the damaged ribonucleotides into translational machinery. Further investigations toward understanding of the consequences and cellular handling mechanisms of the oxidative RNA damage may provide significant insights into the pathogenesis and therapeutic strategies of the neurodegenerative diseases. Akihiko Nunomura, Kazuhiro Honda, Atsushi Takeda, Keisuke Hirai, Xiongwei Zhu, Mark A. Smith, and George Perry Copyright © 2006 Akihiko Nunomura et al. All rights reserved. Signaling, Polyubiquitination, Trafficking, and Inclusions: Sequestosome 1/p62's Role in Neurodegenerative Disease Wed, 24 May 2006 00:00:00 +0000 Aggregated misfolded proteins are hallmarks of most neurodegenerative diseases. In a chronic disease state, including pathologic situations of oxidative stress, these proteins are sequestered into inclusions. Accumulation of aggregated proteins can be prevented by chaperones, or by targeting their degradation to the UPS. If the accumulation of these proteins exceeds their degradation, they may impair the function of the proteasome. Alternatively, the function of the proteasome may be preserved by directing aggregated proteins to the autophagy-lysosome pathway for degradation. Sequestosome 1/p62 has recently been shown to interact with polyubiquitinated proteins through its UBA domain and may direct proteins to either the UPS or autophagosome. P62 is present in neuronal inclusions of individuals with Alzheimer's disease and other neurodegenerative diseases. Herein, we review p62's role in signaling, aggregation, and inclusion formation, and specifically as a possible contributor to Alzheimer's disease. The use of p62 as a potential target for the development of therapeutics and as a disease biomarker is also discussed. Marie W. Wooten, Xiao Hu, J. Ramesh Babu, M. Lamar Seibenhener, Thangiah Geetha, Michael G. Paine, and Michael C. Wooten Copyright © 2006 Marie W. Wooten et al. All rights reserved. Mechanisms of Neuronal Death in Synucleinopathy Wed, 24 May 2006 00:00:00 +0000 α-synuclein is a key molecule in the pathogenesis of synucleinopathy including Parkinson's disease and multiple system atrophy. In this mini-review, we mainly focus on recent data obtained from cellular models of synucleinopathy and discuss the possible mechanisms of neurodegeneration. Recent progress suggests that the aggregate formation of α-synuclein is cytoprotective and that its precursor oligomer (protofibril) may be cytotoxic. The catechol-derived quinones are the candidate molecules that facilitate the oligomer formation of α-synuclein. Furthermore, the cellular membranes are shown to be the primary targets injured by mutant α-synucleins, and the mitochondrial dysfunction seems to be an initial step in the neuronal death. Atsushi Takeda, Takafumi Hasegawa, Michiko Matsuzaki-Kobayashi, Naoto Sugeno, Akio Kikuchi, Yasuto Itoyama, and Katsutoshi Furukawa Copyright © 2006 Atsushi Takeda et al. All rights reserved. Mitochondrial Oxidative Damage in Aging and Alzheimer's Disease: Implications for Mitochondrially Targeted Antioxidant Therapeutics Tue, 11 Apr 2006 00:00:00 +0000 The overall aim of this article is to review current therapeutic strategies for treating AD, with a focus on mitochondrially targeted antioxidant treatments. Recent advances in molecular, cellular, and animal model studies of AD have revealed that amyloid precursor protein derivatives, including amyloid beta (Aβ) monomers and oligomers, are likely key factors in tau hyperphosphorylation, mitochondrial oxidative damage, inflammatory changes, and synaptic failure in the brain tissue of AD patients. Several therapeutic strategies have been developed to treat AD, including anti-inflammatory, antioxidant, and antiamyloid approaches. Among these, mitochondrial antioxidant therapy has been found to be the most efficacious in reducing pathological changes and in not producing adverse effects; thus, mitochondrial antioxidant therapy is promising as a treatment for AD patients. However, a major limitation in applying mitochondrial antioxidants to AD treatment has been the inability of researchers to enhance antioxidant levels in mitochondria. Recently, however, there has been a breakthrough. Researchers have recently been able to promote the entry of certain antioxidants—including MitoQ, MitoVitE, MitoPBN, MitoPeroxidase, and amino acid and peptide-based SS tetrapeptides—into mitochondria, several hundred-fold more than do natural antioxidants. Once in the mitochondria, they rapidly neutralize free radicals and decrease mitochondrial toxicity. Thus, mitochondrially targeted antioxidants are promising candidates for treating AD patients. P. Hemachandra Reddy Copyright © 2006 P. Hemachandra Reddy. All rights reserved. β-Amyloid Degradation and Alzheimer's Disease Thu, 06 Apr 2006 00:00:00 +0000 Extensive β-amyloid (Aβ) deposits in brain parenchyma in the form of senile plaques and in blood vessels in the form of amyloid angiopathy are pathological hallmarks of Alzheimer's disease (AD). The mechanisms underlying Aβ deposition remain unclear. Major efforts have focused on Aβ production, but there is little to suggest that increased production of Aβ plays a role in Aβ deposition, except for rare familial forms of AD. Thus, other mechanisms must be involved in the accumulation of Aβ in AD. Recent data shows that impaired clearance may play an important role in Aβ accumulation in the pathogenesis of AD. This review focuses on our current knowledge of Aβ-degrading enzymes, including neprilysin (NEP), endothelin-converting enzyme (ECE), insulin-degrading enzyme (IDE), angiotensin-converting enzyme (ACE), and the plasmin/uPA/tPA system as they relate to amyloid deposition in AD. Deng-Shun Wang, Dennis W. Dickson, and James S. Malter Copyright © 2006 Deng-Shun Wang et al. All rights reserved. The Creatine Kinase/Creatine Connection to Alzheimer's Disease: CK Inactivation, APP-CK Complexes and Focal Creatine Deposits Tue, 04 Apr 2006 00:00:00 +0000 Cytosolic brain-type creatine kinase (BB-CK), which is coexpressed with ubiquitous mitochondrial uMtCK, is significantly inactivated by oxidation, in Alzheimer's disease (AD) patients. Since CK has been shown to play a fundamental role in cellular energetics of the brain, any disturbance of this enzyme may exasperate the AD disease process. Mutations in amyloid precursor protein (APP) are associated with early onset AD and result in abnormal processing of APP, and accumulation of Aβ peptide, the main constituent of amyloid plaques in AD brain. Recent data on a direct interaction between APP and the precursor of uMtCK support an emerging relationship between AD, cellular energy levels and mitochondrial function. In addition, recently discovered creatine (Cr) deposits in the brain of transgenic AD mice, as well as in the hippocampus from AD patients, indicate a direct link between perturbed energy state, Cr metabolism and AD. Here, we review the roles of Cr and Cr-related enzymes and consider the potential value of supplementation with Cr, a potent neuroprotective substance. As a hypothesis, we consider whether Cr, if given at an early time point of the disease, may prevent or delay the course of AD-related neurodegeneration. Tanja S. Bürklen, Uwe Schlattner, Ramin Homayouni, Kathleen Gough, Margaret Rak, Adriana Szeghalmi, and Theo Wallimann Copyright © 2006 Tanja S. Bürklen et al. All rights reserved. The TGF-β1/Upstream Stimulatory Factor-Regulated PAI-1 Gene: Potential Involvement and a Therapeutic Target in Alzheimer's Disease Wed, 29 Mar 2006 00:00:00 +0000 Amyloid peptide (Aβ) aggregates, derived from initial β-site proteolytic processing of the amyloid precursor protein (APP), accumulate in the brains of Alzheimer's disease patients. The plasmin-generating cascade appears to serve a protective role in the central nervous system since plasmin-mediated proteolysis of APP utilizes the α site, eventually generating nontoxic peptides, and plasmin also degrades Aβ. The conversion of plasminogen to plasmin by tissue-type plasminogen activator in the brain is negatively regulated by plasminogen activator inhibitor type-1 (PAI-1) resulting in attenuation of plasmin-dependent substrate degradation with resultant accumulation of Aβ. PAI-1 and its major physiological inducer TGF-β1, moreover, are increased in models of Alzheimer's disease and have been implicated in the etiology and progression of human neurodegenerative disorders. This review highlights the potential role of PAI-1 and TGF-β1 in this process. Current molecular events associated with TGF-β1-induced PAI-1 transcription are presented with particular relevance to potential targeting of PAI-1 gene expression as a molecular approach to the therapy of neurodegenerative diseases associated with increased PAI-1 expression such as Alzheimer's disease. Paul J. Higgins Copyright © 2006 Paul J. Higgins. All rights reserved. HIV Neurotoxicity: Potential Therapeutic Interventions Wed, 29 Mar 2006 00:00:00 +0000 Individuals suffering from human immunodeficiency virus type 1 (HIV-1) infection suffer from a wide range of neurological deficits. The most pronounced are the motor and cognitive deficits observed in many patients in the latter stages of HIV infection. Gross postmortem inspection shows cortical atrophy and widespread neuronal loss. One of the more debilitating of the HIV-related syndromes is AIDS-related dementia, or HAD. Complete understanding of HIV neurotoxicity has been elusive. Both direct and indirect toxic mechanisms have been implicated in the neurotoxicity of the HIV proteins, Tat and gp120. The glutamatergic system, nitric oxide, calcium, oxidative stress, apoptosis, and microglia have all been implicated in the pathogenesis of HIV-related neuronal degeneration. The aim of this review is to summarize the most recent work and provide an overview to the current theories of HIV-related neurotoxicity and potential avenues of therapeutic interventions to prevent the neuronal loss and motor/cognitive deficits previously described. David R. Wallace Copyright © 2006 David R. Wallace. All rights reserved. Interplay Between Oxidative Damage, Protein Synthesis, and Protein Degradation in Alzheimer's Disease Wed, 22 Mar 2006 00:00:00 +0000 Protein synthesis and protein degradation are highly regulated cellular processes that are essential to maintaining cell viability. Numerous studies now indicate that protein synthesis and protein degradation are significantly altered in Alzheimer's disease (AD), with impairments in these two processes potentially contributing to AD pathogenesis. Alterations in steady state protein regulation may be a particularly important factor in regulating whether cells maintain homeostasis in response to oxidative damage, or conversely whether oxidative stress is induced by oxidative damage. The focus of this review is to discuss recent findings on each of these topics, and to discuss their importance to the onset and progression of AD. Jeffrey N. Keller Copyright © 2006 Jeffrey N. Keller. All rights reserved. Dysregulation of Protein Phosphorylation/Dephosphorylation in Alzheimer's Disease: A Therapeutic Target Mon, 20 Mar 2006 00:00:00 +0000 Studies during the last two decades have provided new insights into the molecular mechanism of Alzheimer's disease (AD). One of the milestone findings in AD research was the demonstration that neurofibrillary degeneration characterized by tau pathology is central to the pathogenesis of AD and other tauopathies and that abnormal hyperphosphorylation of tau is pivotal to neurofibrillary degeneration. This article reviews the recent research advances in tau pathology and the underlying dysregulation of the protein phosphorylation/dephosphorylation system. An updated model of the mechanism of neurofibrillary degeneration is also presented, and a promising therapeutic target to treat AD by correcting dysregulation of protein phosphorylation/dephosphorylation is discussed. Cheng-Xin Gong, Fei Liu, Inge Grundke-Iqbal, and Khalid Iqbal Copyright © 2006 Cheng-Xin Gong et al. All rights reserved. Tau Phosphorylation, Aggregation, and Cell Toxicity Tue, 03 Jan 2006 00:00:00 +0000 Protein aggregation takes place in many neurodegenerative disorders. However, there is a controversy about the possible toxicity of these protein aggregates. In this review, this controversy is discussed, focussing on the tau aggregation that takes place in those disorders known as tauopathies. J. Avila, I. Santa-María, M. Pérez, F. Hernández, and F. Moreno Copyright © 2006 J. Avila et al. All rights reserved.