BioMed Research International: Neurology The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Outcome of Elderly Patients with Meningioma after Image-Guided Stereotactic Radiotherapy: A Study of 100 Cases Tue, 26 May 2015 07:33:31 +0000 Introduction. Incidence of meningioma increases with age. Surgery has been the mainstay treatment. Elderly patients, however, are at risk of severe morbidity. Therefore, we conducted this study to analyze long-term outcomes of linac-based fractionated stereotactic radiotherapy (FSRT) for older adults (aged ≥65 years) with meningioma and determine prognostic factors. Materials and Methods. Between October 1998 and March 2009, 100 patients (≥65, median age, 71 years) were treated with FSRT for meningioma. Two patients were lost to follow-up. Eight patients each had grade I and grade II meningiomas, and five patients had grade III meningiomas. The histology was unknown in 77 cases (grade 0). Results. The median follow-up was 37 months, and 3-year, 5-year, and 10-year progression-free survival (PFS) rates were 93.7%, 91.1%, and 82%. Patients with grade 0/I meningioma showed 3- and 5-year PFS rates of 98.4% and 95.6%. Patients with grade II or III meningiomas showed 3-year PFS rates of 36%. 93.8% of patients showed local tumor control. Multivariate analysis did not indicate any significant prognostic factors. Conclusion. FSRT may play an important role as a noninvasive and safe method in the clinical management of older patients with meningioma. David Kaul, Volker Budach, Lukas Graaf, Johannes Gollrad, and Harun Badakhshi Copyright © 2015 David Kaul et al. All rights reserved. Epigenetics of Meningiomas Mon, 25 May 2015 10:08:39 +0000 Meningiomas account for one-third of all adult central nervous system tumours and are divided into three WHO grades. In contrast to the relatively well characterized genetic alterations, our current understanding of epigenetic modifications involved in the meningioma-genesis and progression is rather incomplete. Contrary to genetic alterations, epigenetic changes do not alter the primary DNA sequence and their reversible nature serves as an excellent basis for prevention and development of novel personalised tumour therapies. Indeed, growing body of evidence suggests that disturbed epigenetic regulation plays a key role in the pathogenesis of meningiomas. Altered DNA methylation, microRNA expression, histone, and chromatin modifications are frequently noted in meningiomas bearing prognostic and therapeutic relevance. In this review we provide an overview on recently identified epigenetic alterations in meningiomas and discuss their role in tumour initiation, progression, and recurrence. Balázs Murnyák, László Bognár, Álmos Klekner, and Tibor Hortobágyi Copyright © 2015 Balázs Murnyák et al. All rights reserved. From Grey Scale B-Mode to Elastosonography: Multimodal Ultrasound Imaging in Meningioma Surgery—Pictorial Essay and Literature Review Mon, 25 May 2015 06:32:18 +0000 The main goal in meningioma surgery is to achieve complete tumor removal, when possible, while improving or preserving patient neurological functions. Intraoperative imaging guidance is one fundamental tool for such achievement. In this regard, intra-operative ultrasound (ioUS) is a reliable solution to obtain real-time information during surgery and it has been applied in many different aspect of neurosurgery. In the last years, different ioUS modalities have been described: B-mode, Fusion Imaging with pre-operative acquired MRI, Doppler, contrast enhanced ultrasound (CEUS), and elastosonography. In this paper, we present our US based multimodal approach in meningioma surgery. We describe all the most relevant ioUS modalities and their intraoperative application to obtain precise and specific information regarding the lesion for a tailored approach in meningioma surgery. For each modality, we perform a review of the literature accompanied by a pictorial essay based on our routinely use of ioUS for meningioma resection. Francesco Prada, Massimiliano Del Bene, Alessandro Moiraghi, Cecilia Casali, Federico Giuseppe Legnani, Andrea Saladino, Alessandro Perin, Ignazio Gaspare Vetrano, Luca Mattei, Carla Richetta, Marco Saini, and Francesco DiMeco Copyright © 2015 Francesco Prada et al. All rights reserved. Need for Scientific Rigor in the Evaluation of Minimally Invasive Alternative Procedures Tue, 28 Apr 2015 06:45:10 +0000 Johnny Padulo and Luca Paolo Ardigò Copyright © 2015 Johnny Padulo and Luca Paolo Ardigò. All rights reserved. Multiple Sclerosis in Older Adults: The Clinical Profile and Impact of Interferon Beta Treatment Wed, 01 Apr 2015 06:45:56 +0000 Background. We examined (1) patient characteristics and disease-modifying drug (DMD) exposure in late-onset (LOMS, ≥50 years at symptom onset) versus adult-onset (AOMS, 18–<50 years) MS and (2) the association between interferon-beta (IFNβ) and disability progression in older relapsing-onset MS adults (≥50 years). Methods. This retrospective study (1980–2004, British Columbia, Canada) included 358 LOMS and 5627 AOMS patients. IFNβ-treated relapsing-onset MS patients aged ≥50 (regardless of onset age, 90) were compared with 171 contemporary and 106 historical controls. Times to EDSS 6 from onset and from IFNβ eligibility were examined using survival analyses. Results. LOMS patients (6%) were more likely to be male, with motor onset and a primary-progressive course, and exhibit faster progression and were less likely to take DMDs. Nonetheless, 57% were relapsing-onset, of which 31% were prescribed DMDs, most commonly IFNβ. Among older relapsing-onset MS adults, no significant association between IFNβ exposure and disability progression was found when either the contemporary (hazard ratio [HR]: 0.46; 95% CI: 0.18–1.22) or historical controls (HR: 0.54; 95% CI: 0.20–1.42) were considered. Conclusion. LOMS differed clinically from AOMS. One-third of older relapsing-onset MS patients were prescribed a DMD. IFNβ exposure was not significantly associated with reduced disability in older MS patients. Afsaneh Shirani, Yinshan Zhao, John Petkau, Paul Gustafson, Mohammad Ehsanul Karim, Charity Evans, Elaine Kingwell, Mia L. van der Kop, Joel Oger, and Helen Tremlett Copyright © 2015 Afsaneh Shirani et al. All rights reserved. Embolic Signals during Routine Transcranial Doppler Ultrasonography in Aneurysmal Subarachnoid Hemorrhage Sun, 29 Mar 2015 08:24:05 +0000 Introduction. Cerebral emboli may occur in subarachnoid hemorrhage (SAH) and intracranial aneurysm surgery. Although embolic signs (ES) have been reported in SAH, their origin remains unclear. The aim of this study was to report the detection of ES during routine TCD monitoring in patients with aneurysmal SAH. Methods. A total of 105 patients with aneurysmal SAH were submitted to TCD evaluation. Patients were monitored almost daily (5 times per week). In each monitoring session, one experienced operator performed TCD to detect or assess vasospasm and ES in arteries of the Willis polygon. Results. Four patients out of a total of 105 patients with aneurysmal SAH were found to present spontaneous cerebral embolization during routine TCD monitoring. The average age of the 4 patients (mean ± standard deviation) was 59.5 ± 8.34 years (range 49–68 ys); female patients predominated representing 75% (3/4) of subjects. Conclusion. Although detection of ES was relatively rare in this study, rates of emboli occurrence may be higher under systematic monitoring. The detection of ES after SAH surgery reinforces the need to study the role of embolus in this condition and may be an indicator for prophylactic antithrombotic treatment. Fernando Mendes Paschoal Jr., Karla de Almeida Lins Ronconi, Marcelo de Lima Oliveira, Ricardo de Carvalho Nogueira, Eric Homero Albuquerque Paschoal, Manoel Jacobsen Teixeira, Eberval Gadelha Figueiredo, and Edson Bor-Seng-Shu Copyright © 2015 Fernando Mendes Paschoal Jr. et al. All rights reserved. Generation of Neurospheres from Human Adipose-Derived Stem Cells Thu, 26 Feb 2015 11:28:37 +0000 Transplantation of neural stem cells (NSCs) to treat neurodegenerative disease shows promise; however, the clinical application of NSCs is limited by the invasive procurement and ethical concerns. Adipose-derived stem cells (ADSCs) are a source of multipotent stem cells that can self-renew and differentiate into various kinds of cells; this study intends to generate neurospheres from human ADSCs by culturing ADSCs on uncoated culture flasks in serum-free neurobasal medium supplemented with B27, basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF); the ADSCs-derived neurospheres were terminally differentiated after growth factor withdrawal. Expression of Nestin, NeuN, MAP2, and GFAP in ADSCs and terminally differentiated neurospheres was shown by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting, and immunocytochemistry; cell proliferation in neurospheres was evaluated by cell cycle analyses, immunostaining, and flow cytometry. These data strongly support the conclusion that human ADSCs can successfully differentiate into neurospheres efficiently on uncoated culture flasks, which present similar molecular marker pattern and proliferative ability with NSCs derived from embryonic and adult brain tissues. Therefore, human ADSCs may be an ideal alternative source of stem cells for the treatment of neurodegenerative diseases. Erfang Yang, Na Liu, Yingxin Tang, Yang Hu, Ping Zhang, Chao Pan, Shasha Dong, Youping Zhang, and Zhouping Tang Copyright © 2015 Erfang Yang et al. All rights reserved. Results of Surgical Treatment of Schwannomas Arising from Extremities Sun, 22 Feb 2015 12:17:24 +0000 Schwannomas are benign neoplasms derived from Schwann cells. In this work, we present our experience in operative management of schwannomas and analyse results of treatment. Clinical material consisted of 34 patients, in whom 44 schwannomas located in extremities were excised between 1985 and 2013. Thirty-five tumours originated from major peripheral nerves and 9 from small nerve branches. Postoperatively, in the first group of tumours, pain resolved in 100%, paresthesias in 83.3%, and Hoffmann-Tinel sign in 91.6% of the patients. Improvement in motor function was noted in 28.5% of the cases, in sensory function: complete in 70%, and partial in 15%. The most frequently affected major peripheral nerves were the ulnar (11 tumours) and median (5 tumours) nerves. Schwannomas originating from small nerve branches were removed without identification of the site of origin. After their resection, definitive healing was achieved. Conclusions. (1) Schwannomas located in extremities arise predominantly from major peripheral nerves, most commonly the ulnar and median nerves. (2) Gradual tumour growth causes exacerbation of compression neuropathy, creating an indication for surgery. (3) In most cases, improvement in peripheral nerve function after excision of schwannoma is achieved. (4) The risk of new permanent postoperative neurological deficits is low. Jerzy Gosk, Olga Gutkowska, Maciej Urban, Witold Wnukiewicz, Paweł Reichert, and Piotr Ziółkowski Copyright © 2015 Jerzy Gosk et al. All rights reserved. Corrigendum to “Presymptomatic Treatment with Acetylcholinesterase Antisense Oligonucleotides Prolongs Survival in ALS (G93A-SOD1) Mice” Tue, 03 Feb 2015 09:02:41 +0000 Marc Gotkine, Leah Rozenstein, Ofira Einstein, Oded Abramsky, Zohar Argov, and Hanna Rosenmann Copyright © 2015 Marc Gotkine et al. All rights reserved. Anti-CCP Antibody Levels Are Not Associated with MS: Results from a Case-Control Study Mon, 02 Feb 2015 06:02:33 +0000 Citrullinated proteins have been suggested to play a critical role in the pathogenesis of multiple sclerosis (MS). Anticyclic citrullinated peptide (anti-CCP) antibody is used in the early diagnosis of rheumatoid arthritis (RA). The objective of this study was to investigate the presence of anti-CCP antibody in patients with MS compared to RA patients and healthy controls. Fifty patients with MS (38 females, 12 males; mean age 36.72 ± 8.82 years), 52 patients with RA (40 females, 12 males; mean age 40.87 ± 10.17 years), and 50 healthy controls (32 females, 18 males; mean age 38.22 ± 11.59 years) were included in this study. The levels of serum anti-CCP antibody were measured using an enzyme-linked immunosorbent assay (ELISA). The results of the study showed that anti-CCP antibody levels were significantly higher in RA patients versus MS or healthy controls . Moreover, anti-CCP antibody was positive in 43 (83%) patients with RA, while it was negative in all MS patients as well as in all healthy controls. Also, no significant correlation was found between the anti-CCP levels and EDSS scores . In conclusion, the results of this study did not support a positive association between serum anti-CCP antibody and MS. Mahmut Alpayci, Aysel Milanlioglu, Veysel Delen, Mehmet Nuri Aydin, Huseyin Guducuoglu, and Yasemin Bayram Copyright © 2015 Mahmut Alpayci et al. All rights reserved. Cholinergic Synaptic Transmissions Were Altered after Single Sevoflurane Exposure in Drosophila Pupa Sun, 01 Feb 2015 11:37:20 +0000 Purpose. Sevoflurane, one of the most used general anesthetics, is widely used in clinical practice all over the world. Previous studies indicated that sevoflurane could induce neuron apoptosis and neural deficit causing query in the safety of anesthesia using sevoflurane. The present study was designed to investigate the effects of sevoflurane on electrophysiology in Drosophila pupa whose excitatory neurotransmitter is acetylcholine early after sevoflurane exposure using whole brain recording technique. Methods. Wide types of Drosophila (canton-s flies) were allocated to control and sevoflurane groups randomly. Sevoflurane groups (1% sevoflurane; 2% sevoflurane; 3% sevoflurane) were exposed to sevoflurane and the exposure lasted 5 hours, respectively. All flies were subjected to electrophysiology experiment using patch clamp 24 hours after exposure. Results. The results showed that, 24 hours after sevoflurane exposure, frequency but not the amplitude of miniature excitatory postsynaptic currents (mEPSCs) was significantly reduced . Furthermore, we explored the underlying mechanism and found that calcium currents density, which partially regulated the frequency of mEPSCs, was significantly reduced after sevoflurane exposure . Conclusions. All these suggested that sevoflurane could alter the mEPSCs that are related to synaptic plasticity partially through modulating calcium channel early after sevoflurane exposure. Rongfa Chen, Tao Zhang, Liting Kuang, Zhen Chen, Dongzhi Ran, Yang Niu, Kangqing Xu, and Huaiyu Gu Copyright © 2015 Rongfa Chen et al. All rights reserved. Is There a Persistent Dysfunction of Neurovascular Coupling in Migraine? Sun, 01 Feb 2015 11:20:04 +0000 Changes in cerebral blood flow are one of the main features of migraine attack and have inspired the vascular theory of migraine. This traditional view has been reshaped with recent experimental data, which gave rise to the neural theory of migraine. In this review, we speculate that there might be an important link between the two theories, that is, the dysfunction of neurovascular coupling. Andrej Fabjan, Marjan Zaletel, and Bojana Žvan Copyright © 2015 Andrej Fabjan et al. All rights reserved. Risk Factors Associated with the Onset of Relapsing-Remitting and Primary Progressive Multiple Sclerosis: A Systematic Review Sat, 31 Jan 2015 07:36:27 +0000 Multiple sclerosis (MS) is a chronic central nervous system disease with a highly heterogeneous course. The aetiology of MS is not well understood but is likely a combination of both genetic and environmental factors. Approximately 85% of patients present with relapsing-remitting MS (RRMS), while 10–15% present with primary progressive MS (PPMS). PPMS is associated with an older onset age, a different sex ratio, and a considerably more rapid disease progression relative to RRMS. We systematically reviewed the literature to identify modifiable risk factors that may be associated with these different clinical courses. We performed a search of six databases and integrated twenty observational studies into a descriptive review. Exposure to Epstein-Barr virus (EBV) appeared to increase the risk of RRMS, but its association with PPMS was less clear. Other infections, such as human herpesvirus-6 and chlamydia pneumoniae, were not consistently associated with a specific disease course nor was cigarette smoking. Despite the vast literature examining risk factors for the development of MS, relatively few studies reported findings by disease course. This review exposes a gap in our understanding of the risk factors associated with the onset of PPMS, our current knowledge being predominated by relapsing-onset MS. Kyla A. McKay, Vivian Kwan, Thomas Duggan, and Helen Tremlett Copyright © 2015 Kyla A. McKay et al. All rights reserved. Early Aging in Chernobyl Clean-Up Workers: Long-Term Study Tue, 27 Jan 2015 11:47:41 +0000 This paper represents data of long-term open prospective study. 312 male clean-up workers, who participated in elimination of the Chernobyl disaster consequences in 1986-87, were observed and examined in Moscow Research Institute of Psychiatry. The average age of patients was 57,0 ± 6,8 years. All patients were diagnosed with psychoorganic syndrome, caused by combination of different factors, which led to early cerebrovascular pathology, which was confirmed by clinical, neuropsychological, and instrumental examination. Anamnesis and the level of social adaptation were also assayed. Clinical estimation was done with the use of specially developed Clinical Psychopathological Chart. All the symptoms were divided into 4 groups (asthenic, psychovegetative, dysthymic, and cognitive symptom-complexes). No pronounced signs of dementia were observed. The control group included 44 clean-up workers without mental disorders. Predomination of various exogenous factors before and after accident was noted. Therapy included different vasotropic remedies, as well as family therapy, art therapy, and cognitive training. The possibilities of the reverse development of symptoms were statistically proved. The results allow making a conclusion that these disorders could not be explained either by radiation effects or by PTSD but connected with cerebrovascular pathology. V. Krasnov, V. Kryukov, E. Samedova, I. Emelianova, and I. Ryzhova Copyright © 2015 V. Krasnov et al. All rights reserved. Melanoma Cells Homing to the Brain: An In Vitro Model Mon, 26 Jan 2015 06:46:50 +0000 We developed an in vitro contact through-feet blood brain barrier (BBB) model built using type IV collagen, rat astrocytes, and human umbilical vein endothelial cells (HUVECs) cocultured through Transwell porous polycarbonate membrane. The contact between astrocytes and HUVECs was demonstrated by electron microscopy: astrocytes endfeet pass through the 8.0 μm pores inducing HUVECs to assume a cerebral phenotype. Using this model we evaluated transmigration of melanoma cells from two different patients (M1 and M2) selected among seven melanoma primary cultures. M2 cells showed a statistically significant higher capability to pass across the in vitro BBB model, compared to M1. Expression of adhesion molecules was evaluated by flow cytometry: a statistically significant increased expression of MCAM, αvβ3, and CD49b was detected in M1. PCR array data showed that M2 had a higher expression of several matrix metalloproteinase proteins (MMPs) compared to M1. Specifically, data suggest that MMP2 and MMP9 could be directly involved in BBB permeability and that brain invasion by melanoma cells could be related to the overexpression of many MMPs. Future studies will be necessary to deepen the mechanisms of central nervous system invasion. A. Rizzo, C. Vasco, V. Girgenti, V. Fugnanesi, C. Calatozzolo, A. Canazza, A. Salmaggi, L. Rivoltini, M. Morbin, and E. Ciusani Copyright © 2015 A. Rizzo et al. All rights reserved. Meningeal Melanomatosis: A Challenge for Timely Diagnosis Wed, 14 Jan 2015 13:26:46 +0000 Neoplastic meningitis is a central nervous system complication that occurs in 3–5% of patients with cancer. Although most commonly seen in patients with disseminated disease, in a small percentage of patients, it may be the initial manifestation of cancer or even primitive in origin. In the absence of cancer history, the diagnosis of neoplastic meningitis may be challenging even for expert neurologists. Prognosis is poor, with a median overall survival of weeks from diagnosis. In the retrospective study herein, we described three cases of meningeal melanomatosis in patients without previous cancer history. The patients were diagnosed with significant delay (17 to 47 weeks from symptom onset) mainly due to the deferral in performing the appropriate testing. Even when the diagnosis was suspected, investigations by MRI, cerebrospinal fluid, or both proved at times unhelpful for confirmation. Prognosis was dismal, with a median survival of 4 weeks after diagnosis. Our observations are a cue to analyze the main pitfalls in the diagnosis of neoplastic meningitis in patients without cancer history and emphasize key elements that may facilitate early diagnosis. Giulia Berzero, Luca Diamanti, Anna Luisa Di Stefano, Paola Bini, Diego Franciotta, Ilaria Imarisio, Paolo Pedrazzoli, Lorenzo Magrassi, Patrizia Morbini, Lisa Maria Farina, Stefano Bastianello, Mauro Ceroni, and Enrico Marchioni Copyright © 2015 Giulia Berzero et al. All rights reserved. New Prognostic Score for the Prediction of 30-Day Outcome in Spontaneous Supratentorial Cerebral Haemorrhage Thu, 08 Jan 2015 12:22:56 +0000 Aims. The purpose of the present study was to evaluate predictors of outcome in primary supratentorial cerebral haemorrhage. Furthermore, we aimed to develop a prognostic model to predict 30-day fatality. Methods. We retrospectively analyzed a database of 156 patients with spontaneous supratentorial haemorrhage to explore the relationship between clinical and CT characteristics and fatal outcome within 30 days using multiple logistic regression analysis. The analyzed factors included volumetric data assessed by neuropathological and CT volumetry. A second CT scan in survivors or neuropathological ABC/2 volumetry in nonsurvivors was used along with the baseline CT to assess the growth index of haematoma. Results. Systolic blood pressure, serum potassium and glucose levels, platelet count, absolute and relative haematoma volumes, and presence and size of intraventricular haemorrhage statistically significantly predicted the fatal outcome within 30 days. Based on our results we formulated a six-factor scoring algorithm named SUSPEKT to predict outcome. Conclusions. After validation the SUSPEKT score may be applicable in general clinical practice for early patient selection to optimize individual management or for assessment of eligibility for treatment trials. Rita Szepesi, Ibolya Katalin Széll, Tibor Hortobágyi, László Kardos, Katalin Nagy, Levente István Lánczi, Ervin Berényi, Dániel Bereczki, and László Csiba Copyright © 2015 Rita Szepesi et al. All rights reserved. Quality of Life and Migraine Disability among Female Migraine Patients in a Tertiary Hospital in Malaysia Thu, 08 Jan 2015 07:20:53 +0000 Background. Disability caused by migraine may be one of the main causes of burden contributing to poor quality of life (QOL) among migraine patients. Thus, this study aimed to measure QOL among migraine sufferers in comparison with healthy controls. Methods. Female diagnosed migraine patients () and healthy controls () completed the Malay version of the World Health Organization QOL Brief (WHOQOL-BREF) questionnaire. Only migraine patients completed the Malay version of the Migraine Disability Assessment questionnaire. Results. Females with migraines had significantly lower total WHOQOL-BREF scores (84.3) than did healthy controls (91.9, ). Similarly, physical health (23.4 versus 27.7, ) and psychological health scores (21.7 versus 23.2, ) were significantly lower than those for healthy controls. Seventy-three percent of patients experienced severe disability, with significantly higher number of days with headaches (13.8 days/3 months, ) and pain scores (7.4, ). Furthermore, migraine patients with lower total QOL scores had 1.2 times higher odds of having disability than patients with higher total QOL scores. Conclusions. The present study showed that migraine sufferers experienced significantly lower QOL than the control group from a similar population. Disability was severe and frequent and was associated with lower QOL among the migraine patients. Munvar Miya Shaik, Norul Badriah Hassan, Huay Lin Tan, and Siew Hua Gan Copyright © 2015 Munvar Miya Shaik et al. All rights reserved. Current and Future Novel Treatments for Glioblastoma Multiforme Mon, 22 Dec 2014 07:00:30 +0000 Betty Tyler, Francesco DiMeco, Rachel Grossman, and Gustavo Pradilla Copyright © 2014 Betty Tyler et al. All rights reserved. Vinpocetine and Pyritinol: A New Model for Blood Rheological Modulation in Cerebrovascular Disorders—A Randomized Controlled Clinical Study Sun, 07 Dec 2014 14:15:04 +0000 Blood and plasma viscosity are the major factors affecting blood flow and normal circulation. Whole blood viscosity is mainly affected by plasma viscosity, red blood cell deformability/aggregation and hematocrit, and other physiological factors. Thirty patients (twenty males + ten females) with age range 50–65 years, normotensive with history of cerebrovascular disorders, were selected according to the American Heart Stroke Association. Blood viscosity and other rheological parameters were measured after two-day abstinence from any medications. Dual effects of vinpocetine and pyritinol exhibit significant effects on all hemorheological parameters (), especially on low shear whole blood viscosity (), but they produced insignificant effects on total serum protein and high shear whole blood viscosity (). Therefore, joint effects of vinpocetine and pyritinol improve blood and plasma viscosity in patients with cerebrovascular disorders. Hayder M. Alkuraishy, Ali I. Al-Gareeb, and Ali K. Albuhadilly Copyright © 2014 Hayder M. Alkuraishy et al. All rights reserved. Complex Network-Driven View of Genomic Mechanisms Underlying Parkinson’s Disease: Analyses in Dorsal Motor Vagal Nucleus, Locus Coeruleus, and Substantia Nigra Wed, 26 Nov 2014 07:51:54 +0000 Parkinson’s disease (PD)—classically characterized by severe loss of dopaminergic neurons in the substantia nigra pars compacta—has a caudal-rostral progression, beginning in the dorsal motor vagal nucleus and, in a less extent, in the olfactory system, progressing to the midbrain and eventually to the basal forebrain and the neocortex. About 90% of the cases are idiopathic. To study the molecular mechanisms involved in idiopathic PD we conducted a comparative study of transcriptional interaction networks in the dorsal motor vagal nucleus (VA), locus coeruleus (LC), and substantia nigra (SN) of idiopathic PD in Braak stages 4-5 (PD) and disease-free controls (CT) using postmortem samples. Gene coexpression networks (GCNs) for each brain region (patients and controls) were obtained to identify highly connected relevant genes (hubs) and densely interconnected gene sets (modules). GCN analyses showed differences in topology and module composition between CT and PD networks for each anatomic region. In CT networks, VA, LC, and SN hub modules are predominantly associated with neuroprotection and homeostasis in the ageing brain, whereas in the patient’s group, for the three brain regions, hub modules are mostly related to stress response and neuron survival/degeneration mechanisms. Beatriz Raposo Corradini, Priscila Iamashita, Edilaine Tampellini, José Marcelo Farfel, Lea Tenenholz Grinberg, and Carlos Alberto Moreira-Filho Copyright © 2014 Beatriz Raposo Corradini et al. All rights reserved. Increased DJ-1 in Urine Exosome of Korean Males with Parkinson’s Disease Thu, 13 Nov 2014 10:08:52 +0000 Parkinson’s disease (PD) is a difficult disease to diagnose although it is the second most common neurodegenerative disease. Recent studies show that exosome isolated from urine contains LRRK2 or DJ-1, proteins whose mutations cause PD. To investigate a potential use for urine exosomes as a tool for PD diagnosis, we compared levels of LRRK2, α-synuclein, and DJ-1 in urine exosomes isolated from Korean PD patients and non-PD controls. LRRK2 and DJ-1, but not α-synuclein, were detected in the urine exosome samples, as reported previously. We initially could not detect any significant difference in these protein levels between the patient and the control groups. However, when age, disease duration, L-dopa daily dose, and gender were considered as analytical parameters, LRRK2 and DJ-1 protein levels showed clear gender-dependent differences. In addition, DJ-1 level was significantly higher (1.7-fold) in male patients with PD than that in male non-PD controls and increased in an age-dependent manner in male patients with PD. Our observation might provide a clue to lead to a novel biomarker for PD diagnosis, at least in males. Dong Hwan Ho, Sanghak Yi, Hyemyung Seo, Ilhong Son, and Wongi Seol Copyright © 2014 Dong Hwan Ho et al. All rights reserved. Subunit Composition of Neurotransmitter Receptors in the Immature and in the Epileptic Brain Thu, 11 Sep 2014 06:23:54 +0000 Neuronal activity is critical for synaptogenesis and the development of neuronal networks. In the immature brain excitation predominates over inhibition facilitating the development of normal brain circuits, but also rendering it more susceptible to seizures. In this paper, we review the evolution of the subunit composition of neurotransmitter receptors during development, how it promotes excitation in the immature brain, and how this subunit composition of neurotransmission receptors may be also present in the epileptic brain. During normal brain development, excitatory glutamate receptors peak in function and gamma-aminobutiric acid (GABA) receptors are mainly excitatory rather than inhibitory. A growing body of evidence from animal models of epilepsy and status epilepticus has demonstrated that the brain exposed to repeated seizures presents a subunit composition of neurotransmitter receptors that mirrors that of the immature brain and promotes further seizures and epileptogenesis. Studies performed in samples from the epileptic human brain have also found a subunit composition pattern of neurotransmitter receptors similar to the one found in the immature brain. These findings provide a solid rationale for tailoring antiepileptic treatments to the specific subunit composition of neurotransmitter receptors and they provide potential targets for the development of antiepileptogenic treatments. Iván Sánchez Fernández and Tobias Loddenkemper Copyright © 2014 Iván Sánchez Fernández and Tobias Loddenkemper. All rights reserved. Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage: Mechanism and Therapies Mon, 08 Sep 2014 10:44:22 +0000 Chih-Lung Lin, Aaron S. Dumont, John H. Zhang, Mario Zuccarello, and Carl Muroi Copyright © 2014 Chih-Lung Lin et al. All rights reserved. Interleukin-13 Receptor Alpha 2-Targeted Glioblastoma Immunotherapy Wed, 27 Aug 2014 10:38:31 +0000 Glioblastoma (GBM) is the most lethal primary brain tumor, and despite several refinements in its multimodal management, generally has very poor prognosis. Targeted immunotherapy is an emerging field of research that shows great promise in the treatment of GBM. One of the most extensively studied targets is the interleukin-13 receptor alpha chain variant 2 (IL13Rα2). Its selective expression on GBM, discovered almost two decades ago, has been a target for therapy ever since. Immunotherapeutic strategies have been developed targeting IL13Rα2, including monoclonal antibodies as well as cell-based strategies such as IL13Rα2-pulsed dendritic cells and IL13Rα2-targeted chimeric antigen receptor-expressing T cells. Advanced therapeutic development has led to the completion of several clinical trials with promising outcomes. In this review, we will discuss the recent advances in the IL13Rα2-targeted immunotherapy and evaluate the most promising strategy for targeted GBM immunotherapy. Sadhak Sengupta, Bart Thaci, Andrew C. Crawford, and Prakash Sampath Copyright © 2014 Sadhak Sengupta et al. All rights reserved. Newcastle Disease Virus Interaction in Targeted Therapy against Proliferation and Invasion Pathways of Glioblastoma Multiforme Wed, 27 Aug 2014 00:00:00 +0000 Glioblastoma multiforme (GBM), or grade IV glioma, is one of the most lethal forms of human brain cancer. Current bioscience has begun to depict more clearly the signalling pathways that are responsible for high-grade glioma initiation, migration, and invasion, opening the door for molecular-based targeted therapy. As such, the application of viruses such as Newcastle disease virus (NDV) as a novel biological bullet to specifically target aberrant signalling in GBM has brought new hope. The abnormal proliferation and aggressive invasion behaviour of GBM is reported to be associated with aberrant Rac1 protein signalling. NDV interacts with Rac1 upon viral entry, syncytium induction, and actin reorganization of the infected cell as part of the replication process. Ultimately, intracellular stress leads the infected glioma cell to undergo cell death. In this review, we describe the characteristics of malignant glioma and the aberrant genetics that drive its aggressive phenotype, and we focus on the use of oncolytic NDV in GBM-targeted therapy and the interaction of NDV in GBM signalling that leads to inhibition of GBM proliferation and invasion, and subsequently, cell death. Jafri Malin Abdullah, Zulkifli Mustafa, and Aini Ideris Copyright © 2014 Jafri Malin Abdullah et al. All rights reserved. Morphometric Analysis of Connective Tissue Sheaths of Sural Nerve in Diabetic and Nondiabetic Patients Thu, 24 Jul 2014 00:00:00 +0000 One of the most common complications of diabetes mellitus is diabetic neuropathy. It may be provoked by metabolic and/or vascular factors, and depending on duration of disease, various layers of nerve may be affected. Our aim was to investigate influence of diabetes on the epineurial, perineurial, and endoneurial connective tissue sheaths. The study included 15 samples of sural nerve divided into three groups: diabetic group, peripheral vascular disease group, and control group. After morphological analysis, morphometric parameters were determined for each case using ImageJ software. Compared to the control group, the diabetic cases had significantly higher perineurial index () and endoneurial connective tissue percentage (). The diabetic group showed significantly higher epineurial area (), as well as percentage of endoneurial connective tissue (), in relation to the peripheral vascular disease group. It is obvious that hyperglycemia and ischemia present in diabetes lead to substantial changes in connective tissue sheaths of nerve, particularly in peri- and endoneurium. Perineurial thickening and significant endoneurial fibrosis may impair the balance of endoneurial homeostasis and regenerative ability of the nerve fibers. Future investigations should focus on studying the components of extracellular matrix of connective tissue sheaths in diabetic nerves. Braca Kundalić, Slađana Ugrenović, Ivan Jovanović, Natalija Stefanović, Vladimir Petrović, Jasen Kundalić, Vesna Stojanović, Vladimir Živković, and Vladimir Antić Copyright © 2014 Braca Kundalić et al. All rights reserved. Upregulation of Relaxin after Experimental Subarachnoid Hemorrhage in Rabbits Wed, 16 Jul 2014 10:00:47 +0000 Background. Although relaxin causes vasodilatation in systemic arteries, little is known about its role in cerebral arteries. We investigated the expression and role of relaxin in basilar arteries after subarachnoid hemorrhage (SAH) in rabbits. Methods. Microarray analysis with rabbit basilar artery RNA was performed. Messenger RNA expression of relaxin-1 and relaxin/insulin-like family peptide receptor 1 (RXFP1) was investigated with quantitative RT-PCR. RXFP1 expression in the basilar artery was investigated with immunohistochemistry. Relaxin concentrations in cerebrospinal fluid (CSF) and serum were investigated with an enzyme-linked immunosorbent assay. Using human brain vascular smooth muscle cells (HBVSMC) preincubated with relaxin, myosin light chain phosphorylation (MLC) was investigated with immunoblotting after endothelin-1 stimulation. Results. After SAH, RXFP1 mRNA and protein were significantly downregulated on day 3, whereas relaxin-1 mRNA was significantly upregulated on day 7. The relaxin concentration in CSF was significantly elevated on days 5 and 7. Pretreatment with relaxin reduced sustained MLC phosphorylation induced by endothelin-1 in HBVSMC. Conclusion. Upregulation of relaxin and downregulation of RXFP1 after SAH may participate in development of cerebral vasospasm. Downregulation of RXFP1 may induce a functional decrease in relaxin activity during vasospasm. Understanding the role of relaxin may provide further insight into the mechanisms of cerebral vasospasm. Yuichiro Kikkawa, Satoshi Matsuo, Ryota Kurogi, Akira Nakamizo, Masahiro Mizoguchi, and Tomio Sasaki Copyright © 2014 Yuichiro Kikkawa et al. All rights reserved. Patient Outcomes following Subarachnoid Hemorrhage between the Medical Center and Regional Hospital: Whether All Patients Should Be Transferred to Medical Centers Mon, 14 Jul 2014 08:58:57 +0000 Subarachnoid hemorrhage (SAH) is a critical illness that may result in patient mortality or morbidity. In this study, we investigated the outcomes of patients treated in medical center and nonmedical center hospitals and the relationship between such outcomes and hospital and surgeon volume. Patient data were abstracted from the National Health Insurance Research Database of Taiwan in the Longitudinal Health Insurance Database 2000, which contains all claims data of 1 million beneficiaries randomly selected in 2000. The International Classification of Diseases, Ninth Revision, subarachnoid hemorrhage (430) was used for the inclusion criteria. We identified 355 patients between 11 and 87 years of age who had subarachnoid hemorrhage. Among them, 32.4% (115/355) were men. The median Charlson comorbidity index (CCI) score was 1.3 (SD ± 0.6). Unadjusted logistic regression analysis demonstrated that low mortality was associated with high hospital volume (OR = 3.21; 95% CI: 1.18–8.77). In this study, we found no statistical significances of mortality, LOS, and total charges between medical centers and nonmedical center hospitals. Patient mortality was associated with hospital volume. Nonmedical center hospitals could achieve resource use and outcomes similar to those of medical centers with sufficient volume. Tsung-Ying Lin, Chieh Hsin Wu, Wei-Che Lee, Chao-Wen Chen, Liang-Chi Kuo, Shiuh-Lin Huang, Hsing-Lin Lin, and Chih-Lung Lin Copyright © 2014 Tsung-Ying Lin et al. All rights reserved. Usefulness of Anticoagulant Therapy in the Prevention of Embolic Complications in Patients with Acute Infective Endocarditis Thu, 10 Jul 2014 08:31:24 +0000 Background. The use of anticoagulant therapy (ACT) in patients with acute infective endocarditis (IE) remains a controversial issue. Our study attempts to estimate the impact of ACT on the occurrence of embolic complications and the usefulness of ACT in the prevention of embolism in IE patients. Methods. The present authors analyzed 150 patients with left-sided IE. Embolisms including cerebrovascular events (CVE) and the use of ACT were checked at the time of admission and during hospitalization. Results. 57 patients (38.0%) experienced an embolic event. There was no significant difference in the incidence of CVE and in-hospital mortality between patients with and without warfarin use at admission, although warfarin-naïve patients were significantly more likely to have large (>1 cm) and mobile vegetation. In addition, there was no significant difference in the incidence of postadmission embolism and in-hospital death between patients with and without in-hospital ACT. On multivariate logistic regression analysis, ACT at admission was not significantly associated with a lower risk of embolism in patients with IE. Conclusions. The role of ACT in the prevention of embolism was limited in IE patients undergoing antibiotic therapy, although it seems to reduce the embolic potential of septic vegetation before treatment. Seung-Jae Lee, Sam-Sae Oh, Dal-Soo Lim, Suk-Keun Hong, Rak-Kyeong Choi, and Jin-Sik Park Copyright © 2014 Seung-Jae Lee et al. All rights reserved. Biomechanics of Interspinous Devices Wed, 09 Jul 2014 14:10:25 +0000 A number of interspinous devices (ISD) have been introduced in the lumbar spine implant market. Unfortunately, the use of these devices often is not associated with real comprehension of their biomechanical role. The aim of this paper is to review the biomechanical studies about interspinous devices available in the literature to allow the reader a better comprehension of the effects of these devices on the treated segment and on the adjacent segments of the spine. For this reason, our analysis will be limited to the interspinous devices that have biomechanical studies published in the literature. Paolo D. Parchi, Gisberto Evangelisti, Antonella Vertuccio, Nicola Piolanti, Lorenzo Andreani, Valentina Cervi, Christian Giannetti, Giuseppe Calvosa, and Michele Lisanti Copyright © 2014 Paolo D. Parchi et al. All rights reserved. Validity and Reliability of the Bahasa Melayu Version of the Migraine Disability Assessment Questionnaire Wed, 09 Jul 2014 11:01:48 +0000 Background. The study was designed to determine the validity and reliability of the Bahasa Melayu version (MIDAS-M) of the Migraine Disability Assessment (MIDAS) questionnaire. Methods. Patients having migraine for more than six months attending the Neurology Clinic, Hospital Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia, were recruited. Standard forward and back translation procedures were used to translate and adapt the MIDAS questionnaire to produce the Bahasa Melayu version. The translated Malay version was tested for face and content validity. Validity and reliability testing were further conducted with 100 migraine patients (1st administration) followed by a retesting session 21 days later (2nd administration). Results. A total of 100 patients between 15 and 60 years of age were recruited. The majority of the patients were single (66%) and students (46%). Cronbach’s alpha values were 0.84 (1st administration) and 0.80 (2nd administration). The test-retest reliability for the total MIDAS score was 0.73, indicating that the MIDAS-M questionnaire is stable; for the five disability questions, the test-retest values ranged from 0.77 to 0.87. Conclusion. The MIDAS-M questionnaire is comparable with the original English version in terms of validity and reliability and may be used for the assessment of migraine in clinical settings. Munvar Miya Shaik, Norul Badriah Hassan, Huay Lin Tan, Shalini Bhaskar, and Siew Hua Gan Copyright © 2014 Munvar Miya Shaik et al. All rights reserved. The Harmful Effects of Subarachnoid Hemorrhage on Extracerebral Organs Mon, 07 Jul 2014 09:08:12 +0000 Subarachnoid hemorrhage (SAH) is a devastating neurological disorder. Patients with aneurysmal SAH develop secondary complications that are important causes of morbidity and mortality. Aside from secondary neurological injuries, SAH has been associated with nonneurologic medical complications, such as neurocardiogenic injury, neurogenic pulmonary edema, hyperglycemia, and electrolyte imbalance, of which cardiac and pulmonary complications are most common. The related mechanisms include activation of the sympathetic nervous system, release of catecholamines and other hormones, and inflammatory responses. Extracerebral complications are directly related to the severity of SAH-induced brain injury and indicate the clinical outcome in patients. This review provides an overview of the extracerebral complications after SAH. We also aim to describe the manifestations, underlying mechanisms, and the effects of those extracerebral complications on outcome following SAH. Sheng Chen, Qian Li, Haijian Wu, Paul R. Krafft, Zhen Wang, and John H. Zhang Copyright © 2014 Sheng Chen et al. All rights reserved. The Role of Microclot Formation in an Acute Subarachnoid Hemorrhage Model in the Rabbit Mon, 07 Jul 2014 08:52:31 +0000 Background. Microvascular dysfunction and microthrombi formation are believed to contribute to development of early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (SAH). Objective. This study aimed to determine (i) extent of microthrombus formation and neuronal apoptosis in the brain parenchyma using a blood shunt SAH model in rabbits; (ii) correlation of structural changes in microvessels with EBI characteristics. Methods. Acute SAH was induced using a rabbit shunt cisterna magna model. Extent of microthrombosis was detected 24 h post-SAH () by fibrinogen immunostaining, compared to controls (). We assessed apoptosis by terminal deoxynucleotidyl transferase nick end labeling (TUNEL) in cortex and hippocampus. Results. Our results showed significantly more TUNEL-positive cells (SAH: 115 ± 13; controls: 58 ± 10; ) and fibrinogen-positive microthromboemboli (SAH: 9 ± 2; controls: 2 ± 1; ) in the hippocampus after aneurysmal SAH. Conclusions. We found clear evidence of early microclot formation in a rabbit model of acute SAH. The extent of microthrombosis did not correlate with early apoptosis or CPP depletion after SAH; however, the total number of TUNEL positive cells in the cortex and the hippocampus significantly correlated with mean CPP reduction during the phase of maximum depletion after SAH induction. Both microthrombosis and neuronal apoptosis may contribute to EBI and subsequent DCI. Lukas Andereggen, Volker Neuschmelting, Michael von Gunten, Hans Rudolf Widmer, Javier Fandino, and Serge Marbacher Copyright © 2014 Lukas Andereggen et al. All rights reserved. Inflammation, Vasospasm, and Brain Injury after Subarachnoid Hemorrhage Thu, 03 Jul 2014 07:37:39 +0000 Subarachnoid hemorrhage (SAH) can lead to devastating neurological outcomes, and there are few pharmacologic treatments available for treating this condition. Both animal and human studies provide evidence of inflammation being a driving force behind the pathology of SAH, leading to both direct brain injury and vasospasm, which in turn leads to ischemic brain injury. Several inflammatory mediators that are elevated after SAH have been studied in detail. While there is promising data indicating that blocking these factors might benefit patients after SAH, there has been little success in clinical trials. One of the key factors that complicates clinical trials of SAH is the variability of the initial injury and subsequent inflammatory response. It is likely that both genetic and environmental factors contribute to the variability of patients’ post-SAH inflammatory response and that this confounds trials of anti-inflammatory therapies. Additionally, systemic inflammation from other conditions that affect patients with SAH could contribute to brain injury and vasospasm after SAH. Continuing work on biomarkers of inflammation after SAH may lead to development of patient-specific anti-inflammatory therapies to improve outcome after SAH. Brandon A. Miller, Nefize Turan, Monica Chau, and Gustavo Pradilla Copyright © 2014 Brandon A. Miller et al. All rights reserved. Efficacy of Zonisamide in Migraineurs with Nonresponse to Topiramate Wed, 02 Jul 2014 12:06:22 +0000 This study investigated another type of carbonic anhydrase inhibitor and antiepileptic drug, zonisamide, in order to evaluate its potential effectiveness for migraine prophylaxis refractory to topiramate, and to assess intolerability to adverse events, paresthesia in particular. This is an open-labeled retrospective single center study. We included headache patients who met the requirement of migraine without aura and were refractory to topiramate. Patients were treated only with zonisamide 100 mg/day, directly switching from topiramate. Patients were monitored every month for three months. A positive response to treatment (responders) was defined as a 50% or greater reduction in headache days at three months after study commencement, compared with baseline. One hundred and twenty migraineurs who were refractory to topiramate were recruited. Compared with baseline, headache days with zonisamide showed a decrease, compared with baseline (). Two patients complained of adverse effects, such as paresthesia. These results suggest that zonisamide is effective for migraine prophylaxis refractory to topiramate, or intolerable patients due to topiramate-induced paresthesia. Jin-Young Chung, Min-Wook Kim, and Manho Kim Copyright © 2014 Jin-Young Chung et al. All rights reserved. Iron Metabolism Disturbance in a French Cohort of ALS Patients Wed, 02 Jul 2014 07:39:08 +0000 Objective. The aim of this study was to assess iron status in a cohort of amyotrophic lateral sclerosis (ALS) patients compared to controls in order to evaluate these parameters as a risk factor or a modifying factor of ALS. Methods. We collected serum iron, ferritin, transferrin, total iron-binding capacity, and transferrin saturation coefficient (TSC) from 104 ALS patients at the time of diagnosis and from 145 controls. We reported phenotypic characteristics and evolution parameters such as ALSFRS-R and forced vital capacity at diagnosis and after one year of follow-up. In a first step we compared iron status between ALS patients and controls, and then we evaluated the relation between iron status and disease evolution of ALS patients using univariate and multivariate analysis. Results. We observed increased concentrations of serum iron () and ferritin () and increased TSC () in ALS patients. We also showed an association between markers of iron status and high body weight loss in ALS patients. The multivariate analysis of survival highlighted a significant relation between ferritin level and disease duration (). Conclusion. This is the first study showing a higher concentration of serum iron in ALS patients, strengthening the involvement of a deregulation of iron metabolism in ALS. Charlotte Veyrat-Durebex, Philippe Corcia, Aleksandra Mucha, Simon Benzimra, Cindy Mallet, Chantal Gendrot, Caroline Moreau, David Devos, Eric Piver, Jean-Christophe Pagès, François Maillot, Christian R. Andres, Patrick Vourc’h, and Hélène Blasco Copyright © 2014 Charlotte Veyrat-Durebex et al. All rights reserved. Electroacupuncture at ST36-ST37 and at Ear Ameliorates Hippocampal Mossy Fiber Sprouting in Kainic Acid-Induced Epileptic Seizure Rats Sun, 22 Jun 2014 13:17:39 +0000 Our previous study showed that mossy fiber sprouting can occur in the hippocampus region in rats 6 wk after kainic acid-induced epileptic seizure, and this mossy fiber sprouting can facilitate epileptogenesis. Transcutaneous auricular vagal nerve stimulation (VNS), which is similar to cervical VNS, can reduce the occurrence of epileptic seizure in intractable epilepsy patients. Greater parasympathetic nerve activity can be caused by 2 Hz electroacupuncture (EA). Therefore, we investigated the effect of 2 Hz EA at ST-36-ST37 and at the ear on mossy fiber sprouting in kainic-treated Sprague-Dawley rats. The results indicated that applying 2 Hz EA at ST36-ST37 and at the ear for 3 d per week over 6 consecutive weeks can ameliorate mossy fiber sprouting in the hippocampus region of rats. These results indicated that applying 2 Hz EA at ST36-ST37 and at the ear might be beneficial for the treatment and prevention of epilepsy in humans. Chung-Hsiang Liu, Yi-Wen Lin, Hsin-Cheng Hsu, Hsu-Jan Liu, Wan-Jung Lin, and Ching-Liang Hsieh Copyright © 2014 Chung-Hsiang Liu et al. All rights reserved. Intraoperative Cerebral Glioma Characterization with Contrast Enhanced Ultrasound Thu, 12 Jun 2014 11:10:30 +0000 Background. Contrast enhanced ultrasound (CEUS) is a dynamic and continuous modality providing real-time view of vascularization and flow distribution patterns of different organs and tumors. Nevertheless its intraoperative use for brain tumors visualization has been performed few times, and a thorough characterization of cerebral glioma had never been performed before. Aim. To perform the first characterization of cerebral glioma using CEUS and to possibly achieve an intraoperative differentiation of different gliomas. Methods. We performed CEUS in an off-label setting in 69 patients undergoing surgery for cerebral glioma. An intraoperative qualitative analysis was performed comparing iCEUS with B-mode imaging. A postprocedural semiquantitative analysis was then performed for each case, according to EFSUMB criteria. Results were related to histopathology. Results. We observed different CE patterns: LGG show a mild, dotted CE with diffuse appearance and slower, delayed arterial and venous phase. HGG have a high CE with a more nodular, nonhomogeneous appearance and fast perfusion patterns. Conclusion. Our study characterizes for the first time human brain glioma with CEUS, providing further insight regarding these tumors’ biology. CEUS is a fast, safe, dynamic, real-time, and economic tool that might be helpful during surgery in differentiating malignant and benign gliomas and refining surgical strategy. Francesco Prada, Luca Mattei, Massimiliano Del Bene, Luca Aiani, Marco Saini, Cecilia Casali, Assunta Filippini, Federico Giuseppe Legnani, Alessandro Perin, Andrea Saladino, Ignazio Gaspare Vetrano, Luigi Solbiati, Alberto Martegani, and Francesco DiMeco Copyright © 2014 Francesco Prada et al. All rights reserved. Alteration of Basilar Artery Rho-Kinase and Soluble Guanylyl Cyclase Protein Expression in a Rat Model of Cerebral Vasospasm following Subarachnoid Hemorrhage Sun, 01 Jun 2014 00:00:00 +0000 Background and Purpose. The vasoconstrictor endothelin-1 (ET-1) has been implicated in the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). Previous results showed that CGS 26303, an endothelin converting enzyme (ECE) inhibitor, effectively prevented and reversed arterial narrowing in animal models of SAH. In the present study, we assessed the effect of CGS 26303 on neurological deficits in SAH rats. The involvement of vasoactive pathways downstream of ET-1 signaling in SAH was also investigated. Methods. Sprague-Dawley rats were divided into five groups (/group): (1) normal control, (2) SAH, (3) SAH+vehicle, (4) SAH+CGS 26303 (prevention), and (5) SAH+CGS 26303 (reversal). SAH was induced by injecting autologous blood into cisterna magna. CGS 26303 (10 mg/kg) was injected intravenously at 1 and 24 hr after the initiation of SAH in the prevention and reversal protocols, respectively. Behavioral changes were assessed at 48 hr after SAH. Protein expression was analyzed by Western blots. Results. Deficits in motor function were obvious in the SAH rats, and CGS 26303 significantly improved the rate of paraplegia. Expressions of rho-kinase-II and membrane-bound protein kinase C-δ and rhoA were significantly increased, while those of soluble guanylyl cyclase α1 and β1 as well as protein kinase G were significantly decreased in the basilar artery of SAH rats. Treatment with CGS 26303 nearly normalized these effects. Conclusions. These results demonstrate that the rhoA/rho-kinase and sGC/cGMP/PKG pathways play pivotal roles in cerebral vasospasm after SAH. It also shows that ECE inhibition is an effective strategy for the treatment of this disease. Chih-Jen Wang, Pei-Yu Lee, Bin-Nan Wu, Shu-Chuan Wu, Joon-Khim Loh, Hung-Pei Tsai, Chia-Li Chung, Neal F. Kassell, and Aij-Lie Kwan Copyright © 2014 Chih-Jen Wang et al. All rights reserved. Plasma Albumin Induces Cytosolic Calcium Oscilations and DNA Synthesis in Human Cultured Astrocytes Thu, 22 May 2014 15:49:12 +0000 So far, a little is known about transition from normal to focal epileptic brain, although disruption in blood-brain barrier and albumin had recently involved. The main objective of this work is to characterize the response of cultured human astrocytes to plasma albumin, including induction of DNA synthesis. Cortical tissue was obtained from 9 patients operated from temporal lobe epilepsy. Astrocytes were cultured for 3-4 weeks and cytosolic calcium concentration () was measured. Bovine and human plasma albumin were used. We observed that low albumin concentration decreases , while higher concentration, induces increase in . It was shown that increase in was mediated by inositol 1,4,5-trisphosphate and released from internal stores. Increase in was reduced to 19% by blocking the transforming growth factor-beta (TGF-βR) receptor. Albumin induces DNA synthesis in a dose-response manner. Finally, induction of DNA synthesis can be partially blocked by heparin and block of TGF-β; however, the combination of both incompletely inhibits DNA synthesis. Therefore, results suggest that mechanisms other than Ca2+ signals and TGF-β receptor activation might induce DNA synthesis in a lesser degree. These results may be important to further understand the mechanisms involved in the transition from normal to focal epileptic brain. Lorena Vega-Zelaya, Guillermo J. Ortega, Rafael G. Sola, and Jesús Pastor Copyright © 2014 Lorena Vega-Zelaya et al. All rights reserved. Body Pigmentation as a Risk Factor for the Formation of Intracranial Aneurysms Thu, 22 May 2014 11:38:45 +0000 Recent studies demonstrated pigmented cells both in the murine heart, in pulmonary veins, and in brain arteries. Moreover, a role for melanocytes in the downregulation of inflammatory processes was suggested. As there is increasing evidence that inflammation is contributing significantly to the pathogenesis of intracranial aneurysms, melanocyte-like cells may be relevant in preventing age-related impairment of vessels. As pigmentation of the heart reflects that of coat color, aspects of body pigmentation might be associated with the incidence of intracranial aneurysms. We performed a case-control study to evaluate associations between the pigmentation of hair and eyes and the formation of aneurysms. In addition to hair and eye color, constitutive and facultative skin pigmentation were assessed in a replication study as well as individual handedness which can be seen as a neurophysiological correlate of developmental pigmentation processes. Hair pigmentation was highly associated with intracranial aneurysms in both samples, whereas eye pigmentation was not. In the replication cohort, facultative but not constitutive skin pigmentation proved significant. The strongest association was observed for individual handedness. Results indicate a significant association of intracranial aneurysms with particular aspects of body pigmentation as well as handedness, and imply clinical usefulness for screening of aneurysms and possible interventions. Günter Schulter, Klaus Leber, Elke Kronawetter, Viktoria R. Rübenbauer, Peter Konstantiniuk, and Ilona Papousek Copyright © 2014 Günter Schulter et al. All rights reserved. Progesterone Induces the Growth and Infiltration of Human Astrocytoma Cells Implanted in the Cerebral Cortex of the Rat Thu, 22 May 2014 05:50:29 +0000 Progesterone (P4) promotes cell proliferation in several types of cancer, including brain tumors such as astrocytomas, the most common and aggressive primary intracerebral neoplasm in humans. In this work, we studied the effects of P4 and its intracellular receptor antagonist, RU486, on growth and infiltration of U373 cells derived from a human astrocytoma grade III, implanted in the motor cortex of adult male rats, using two treatment schemes. In the first one, fifteen days after cells implantation, rats were daily subcutaneously treated with vehicle (propylene glycol, 160 μL), P4 (1 mg), RU486 (5 mg), or P4 + RU486 (1 mg and 5 mg, resp.) for 21 days. In the second one, treatments started 8 weeks after cells implantation and lasted for 14 days. In both schemes we found that P4 significantly increased the tumor area as compared with the rest of the treatments, whereas RU486 blocked P4 effects. All rats treated with P4 showed tumor infiltration, while 28.6% and 42.9% of the animals treated with RU486 and P4 + RU486, respectively, presented it. Our data suggest that P4 promotes growth and migration of human astrocytoma cells implanted in the motor cortex of the rat through the interaction with its intracellular receptor. Liliana Germán-Castelán, Joaquín Manjarrez-Marmolejo, Aliesha González-Arenas, María Genoveva González-Morán, and Ignacio Camacho-Arroyo Copyright © 2014 Liliana Germán-Castelán et al. All rights reserved. Fluorescence-Guided Surgery and Biopsy in Gliomas with an Exoscope System Wed, 21 May 2014 08:51:57 +0000 Background. The introduction of fluorescence-guided resection allows a better identification of tumor tissue and its more radical resection. We describe our experience with a modified exoscope to detect 5 ALA-induced fluorescence in neuronavigation-guided brain surgery or biopsy of malignant brain tumors. Methods. Thirty-eight patients with a suspected preoperative diagnosis of high-grade astrocytoma were included. We used a neuronavigation device and a high-definition exoscope system with a built-in filter to detect 5-ALA fluorescence in all cases. Thirty patients underwent craniotomy with tumor resection and 8 underwent frameless stereotactic brain biopsy. Results. Histopathological diagnosis confirmed the presence of high-grade gliomas in 34 patients. Total resection was achieved in 23 cases and subtotal in 7. No relevant complications related to the administration of 5-ALA were detected. Conclusions. The use of the exoscope in 5-ALA fluorescence-guided tumor surgery has twofold implications: during brain tumor surgery it can be considered a valuable tool to achieve a more radical resection of the lesion, and when applied to a biopsy of a suspected brain high-grade glioma, it decreases the possibility of a negative biopsy. José Piquer, Jose L. Llácer, Vicente Rovira, Pedro Riesgo, Ruben Rodriguez, and Antonio Cremades Copyright © 2014 José Piquer et al. All rights reserved. To Look Beyond Vasospasm in Aneurysmal Subarachnoid Haemorrhage Mon, 19 May 2014 10:50:14 +0000 Delayed cerebral vasospasm has classically been considered the most important and treatable cause of mortality and morbidity in patients with aneurysmal subarachnoid hemorrhage (aSAH). Secondary ischemia (or delayed ischemic neurological deficit, DIND) has been shown to be the leading determinant of poor clinical outcome in patients with aSAH surviving the early phase and cerebral vasospasm has been attributed to being primarily responsible. Recently, various clinical trials aimed at treating vasospasm have produced disappointing results. DIND seems to have a multifactorial etiology and vasospasm may simply represent one contributing factor and not the major determinant. Increasing evidence shows that a series of early secondary cerebral insults may occur following aneurysm rupture (the so-called early brain injury). This further aggravates the initial insult and actually determines the functional outcome. A better understanding of these mechanisms and their prevention in the very early phase is needed to improve the prognosis. The aim of this review is to summarize the existing literature on this topic and so to illustrate how the presence of cerebral vasospasm may not necessarily be a prerequisite for DIND development. The various factors determining DIND that worsen functional outcome and prognosis are then discussed. Giulia Cossu, Mahmoud Messerer, Mauro Oddo, and Roy Thomas Daniel Copyright © 2014 Giulia Cossu et al. All rights reserved. Progesterone Attenuates Experimental Subarachnoid Hemorrhage-Induced Vasospasm by Upregulation of Endothelial Nitric Oxide Synthase via Akt Signaling Pathway Tue, 13 May 2014 08:12:41 +0000 Cerebral vasospasm is the leading cause of mortality and morbidity in patients after aneurysmal subarachnoid hemorrhage (SAH). However, the mechanism and adequate treatment of vasospasm are still elusive. In the present study, we evaluate the effect and possible mechanism of progesterone on SAH-induced vasospasm in a two-hemorrhage rodent model of SAH. Progesterone (8 mg/kg) was subcutaneously injected in ovariectomized female Sprague-Dawley rats one hour after SAH induction. The degree of vasospasm was determined by averaging the cross-sectional areas of basilar artery 7 days after first SAH. Expressions of endothelial nitric oxide synthase (eNOS) and phosphorylated Akt (phospho-Akt) in basilar arteries were evaluated. Prior to perfusion fixation, there were no significant differences among the control and treated groups in physiological parameters recorded. Progesterone treatment significantly attenuated SAH-induced vasospasm. The SAH-induced suppression of eNOS protein and phospho-Akt were relieved by progesterone treatment. This result further confirmed that progesterone is effective in preventing SAH-induced vasospasm. The beneficial effect of progesterone might be in part related to upregulation of expression of eNOS via Akt signaling pathway after SAH. Progesterone holds therapeutic promise in the treatment of cerebral vasospasm following SAH. Chia-Mao Chang, Yu-Feng Su, Chih-Zen Chang, Chia-Li Chung, Yee-Jean Tsai, Joon-Khim Loh, and Chih-Lung Lin Copyright © 2014 Chia-Mao Chang et al. All rights reserved. The Role of Arterioles and the Microcirculation in the Development of Vasospasm after Aneurysmal SAH Sun, 11 May 2014 13:41:30 +0000 Cerebral vasospasm of the major cerebral arteries, which is characterized by angiographic narrowing of those vessels, had been recognized as a main contributor to delayed cerebral ischemia (DCI) in subarachnoid hemorrhage (SAH) patients. However, the CONSCIOUS-1 trial revealed that clazosentan could not improve mortality or clinical outcome in spite of successful reduction of relative risk in angiographic vasospasm. This result indicates that the pathophysiology underlying DCI is multifactorial and that other pathophysiological factors, which are independent of angiographic vasospasm, can contribute to the outcome. Recent studies have focused on microcirculatory disturbance, such as microthrombosis and arteriolar constriction, as a factor affecting cerebral ischemia after SAH. Reports detecting microthrombosis and arteriolar constriction will be reviewed, and the role of the microcirculation on cerebral ischemia during vasospasm after SAH will be discussed. Masato Naraoka, Naoya Matsuda, Norihito Shimamura, Kenichiro Asano, and Hiroki Ohkuma Copyright © 2014 Masato Naraoka et al. All rights reserved. Through Diffusion Tensor Magnetic Resonance Imaging to Evaluate the Original Properties of Neural Pathways of Patients with Partial Seizures and Secondary Generalization by Individual Anatomic Reference Atlas Mon, 05 May 2014 11:31:57 +0000 To investigate white matter (WM) abnormalities in neocortical epilepsy, we extract supratentorial WM parameters from raw tensor magnetic resonance images (MRI) with automated region-of-interest (ROI) registrations. Sixteen patients having neocortical seizures with secondarily generalised convulsions and 16 age-matched normal subjects were imaged with high-resolution and diffusion tensor MRIs. Automated demarcation of supratentorial fibers was accomplished with personalized fiber-labeled atlases. From the individual atlases, we observed significant elevation of mean diffusivity (MD) in fornix (cres)/stria terminalis (FX/ST) and sagittal stratum (SS) and a significant difference in fractional anisotropy (FA) among FX/ST, SS, posterior limb of the internal capsule (PLIC), and posterior thalamic radiation (PTR). For patients with early-onset epilepsy, the diffusivities of the SS and the retrolenticular part of the internal capsule were significantly elevated, and the anisotropies of the FX/ST and SS were significantly decreased. In the drug-resistant subgroup, the MDs of SS and PTR and the FAs of SS and PLIC were significantly different. Onset age was positively correlated with increases in FAs of the genu of the corpus callosum. Patients with neocortical seizures and secondary generalisation had microstructural anomalies in WM. The changes in WM are relevant to early onset, progression, and severity of epilepsy. Syu-Jyun Peng, Tomor Harnod, Jang-Zern Tsai, Chien-Chun Huang, Ming-Dou Ker, Jun-Chern Chiou, Herming Chiueh, Chung-Yu Wu, and Yue-Loong Hsin Copyright © 2014 Syu-Jyun Peng et al. 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 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 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. 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.