http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2013 , Hindawi Publishing Corporation . All rights reserved. Tue, 21 May 2013 08:34:16 +0000 http://www.hindawi.com/journals/nri/2013/943914/ Subarachnoid hemorrhage (SAH) is characterized by bleeding into the subarachnoid space, often caused by ruptured aneurysm. Aneurysmal rupture occurs in 700,000 individuals per year worldwide, with 40,000 cases taking place in the United States. Beyond the high mortality associated with SAH alone, morbidity and mortality are further increased with the occurrence of cerebral vasospasm, a pathologic constriction of blood vessels that can lead to delayed ischemic neurologic deficits (DIND). Treatment of cerebral vasospasm is a source of contention. One extensively studied therapy is Magnesium (Mg) as both a competitive antagonist of calcium at the N-methyl D-aspartate (NMDA) receptor, and a noncompetitive antagonist of both IP3 and voltage-gated calcium channels, leading to smooth muscle relaxation. In our literature review, several animal and human studies are summarized in addition to two Phase III trials assessing the use of intravenous Mg in the treatment of SAH (IMASH and MASH-2). Though many studies have shown promise for the use of Mg in SAH, there has been inconsistency in study design and outcomes. Furthermore, the results of the recently completed clinical trials have shown no significant benefit from using intravenous Mg as adjuvant therapy in the treatment of cerebral vasospasm. Mitchell J. Odom, Scott L. Zuckerman, and J Mocco Copyright © 2013 Mitchell J. Odom et al. All rights reserved. Tue, 21 May 2013 08:25:42 +0000 http://www.hindawi.com/journals/nri/2013/329364/ The skin acts as a complex sensory organ. The emerging new data on peripheral pain mechanisms from within the skin is presented. This data has led to new insights into the potential pain mechanisms for various pain conditions including neuropathic pain (from small fiber neuropathies) and Complex Regional Pain Syndrome. The somatosensory neurons that innervate our skin constantly update our brains on the objects and environmental factors that surround us. Cutaneous sensory neurons expressing nociceptive receptors such as transient receptor potential vanilloid 1 channels and voltage-gated sodium channels are critical for pain transmission. Epidermal cells (such as keratinocytes, Langerhans cells, and Merkel cells) express sensor proteins and neuropeptides; these regulate the neuroimmunocutaneous system and participate in nociception and neurogenic inflammation. In the past two decades, there has been widespread use of modalities such as punch skin biopsies, quantitative sensory testing, and laser-evoked potentials to evaluate small caliber nerve fibers. This paper explores these laboratory techniques as well as the phenomenon of small fiber neuropathy. Treatment using transdermal drug delivery is discussed. There is potential for these findings to predict treatment outcomes in clinical practice and to develop new therapies for different pain conditions. These findings should enhance the physician's ability to evaluate and treat diverse types of pain. Edward A. Shipton Copyright © 2013 Edward A. Shipton. All rights reserved. Mon, 15 Apr 2013 18:14:42 +0000 http://www.hindawi.com/journals/nri/2013/462491/ Cerebral vasospasm is a major source of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). Evidence suggests a multifactorial etiology and this concept remains supported by the assortment of therapeutic modalities under investigation. The authors provide an updated review of the literature for previous and recent clinical trials evaluating medical treatments in patients with cerebral vasospasm secondary to aSAH. Currently, the strongest evidence supports use of prophylactic oral nimodipine and initiation of triple-H therapy for patients in cerebral vasospasm. Other agents presented in this report include magnesium, statins, endothelin receptor antagonists, nitric oxide promoters, free radical scavengers, thromboxane inhibitors, thrombolysis, anti-inflammatory agents and neuroprotectants. Although promising data is beginning to emerge for several treatments, few prospective randomized clinical trials are presently available. Additionally, future investigational efforts will need to resolve discrepant definitions and outcome measures for cerebral vasospasm in order to permit adequate study comparisons. Until then, definitive recommendations cannot be made regarding the safety and efficacy for each of these therapeutic strategies and medical management practices will continue to be implemented in a wide-ranging manner. Peter Adamczyk, Shuhan He, Arun Paul Amar, and William J. Mack Copyright © 2013 Peter Adamczyk et al. All rights reserved. Thu, 11 Apr 2013 11:49:11 +0000 http://www.hindawi.com/journals/nri/2013/639280/ The prevalence of obesity is increasing in the industrialized world, so that the World Health Organization considers obesity as a “pandemia” in rich populations. The autonomic nervous system plays a crucial role in the control of energy balance and body weight. This review summarizes our own data and perspectives, emphasizing the influence exerted by autonomic nervous system on energy expenditure and food intake, which are able to determine the body weight. Activation of the sympathetic discharge causes an increase in energy expenditure and a decrease in food intake, while reduction of food intake and body weight loss determines a reduction of the sympathetic activity. On the other hand, pathophysiological mechanisms of the obesity involve alterations of the sympathetic nervous system in accordance with the “Mona Lisa Hypothesis,” an acronym for “most obesities known are low in sympathetic activity.” Furthermore, the parasympathetic influences on the energy expenditure are analyzed in this review, showing that an increase in parasympathetic activity can induce a paradoxical enhancement of energy consumption. G. Messina, V. De Luca, An. Viggiano, A. Ascione, T. Iannaccone, S. Chieffi, and M. Monda Copyright © 2013 G. Messina et al. All rights reserved. Thu, 11 Apr 2013 11:08:10 +0000 http://www.hindawi.com/journals/nri/2013/291895/ Cerebral vasospasm (CV) is a major source of morbidity and mortality in aneurysmal subarachnoid hemorrhage (aSAH). It is thought that an inflammatory cascade initiated by extravasated blood products precipitates CV, disrupting vascular smooth muscle cell function of major cerebral arteries, leading to vasoconstriction. Mechanisms of CV and modes of therapy are an active area of research. Understanding the genetic basis of CV holds promise for the recognition and treatment for this devastating neurovascular event. In our review, we summarize the most recent research involving key areas within the genetics and vasospasm discussion: (1) Prognostic role of genetics—risk stratification based on gene sequencing, biomarkers, and polymorphisms; (2) Signaling pathways—pinpointing key inflammatory molecules responsible for downstream cellular signaling and altering these mediators to provide therapeutic benefit; and (3) Gene therapy and gene delivery—using viral vectors or novel protein delivery methods to overexpress protective genes in the vasospasm cascade. Travis R. Ladner, Scott L. Zuckerman, and J Mocco Copyright © 2013 Travis R. Ladner et al. All rights reserved. Thu, 11 Apr 2013 10:47:36 +0000 http://www.hindawi.com/journals/nri/2013/580596/ Background. Despite evidence of the potential importance of the role of health and lifestyle behaviours in multiple sclerosis (MS) outcomes, there has not been a significant focus on this area of research. Aim. We aimed to recruit an international sample of people with MS at baseline and over a five-year timeframe, examine their health and lifestyle behaviours, and determine the relationship of these behaviours to self-reported disability, disease activity, and quality of life. Methods. People with MS were recruited through web 2.0 platforms including interactive websites, social media, blogs, and forums and completed a comprehensive, multifaceted online questionnaire incorporating validated and researcher-derived tools. Results. 2519 participants met inclusion criteria for this study. This paper describes the study methodology in detail and provides an overview of baseline participant demographics, clinical characteristics, summary outcome variables, and health and lifestyle behaviours. The sample described is unique due to the nature of recruitment through online media and due to the engagement of the group, which appears to be well informed and proactive in lifestyle modification. Conclusion. This sample provides a sound platform to undertake novel exploratory analyses of the association between a variety of lifestyle factors and MS outcomes. Emily J. Hadgkiss, George A. Jelinek, Tracey J. Weiland, Naresh G. Pereira, Claudia H. Marck, and Dania M. van der Meer Copyright © 2013 Emily J. Hadgkiss et al. All rights reserved. Wed, 03 Apr 2013 08:57:13 +0000 http://www.hindawi.com/journals/nri/2013/943761/ Delayed cerebral vasospasm is a significant cause of morbidity and mortality following aneurysmal subarachnoid hemorrhage (SAH). While the cellular mechanisms underlying vasospasm remain unclear, it is believed that inflammation may play a critical role in vasospasm. Matrix metalloproteinasees (MMPs) are a family of extracellular and membrane-bound proteases capable of degrading the blood-rain barrier (BBB). As such, MMP upregulation following SAH may result in a proinflammatory extravascular environment capable of inciting delayed cerebral vasospasm. This paper presents an overview of MMPs and describes existing data pertinent to delayed cerebral vasospasm. Vivek Mehta, Jonathan Russin, Alexandra Spirtos, Shuhan He, Peter Adamczyk, Arun P. Amar, and William J. Mack Copyright © 2013 Vivek Mehta et al. All rights reserved. Sun, 31 Mar 2013 11:46:43 +0000 http://www.hindawi.com/journals/nri/2013/987934/ Delayed-cerebral ischemia is a major cause of morbidity and mortality in the setting of aneurysmal subarachnoid hemorrhage. Despite extensive research efforts and a breadth of collective clinical experience, accurate diagnosis of vasospasm remains difficult, and effective treatment options are limited. Classically, diagnosis has focused on imaging assessment of the cerebral vasculature. Recently, invasive and noninvasive bedside techniques designed to characterize relevant hemodynamic and metabolic alterations have gained substantial attention. Such modalities include microdialysis, brain tissue oxygenation, jugular bulb oximetry, thermal diffusion cerebral blood flow, and near-infrared spectroscopy. This paper reviews these modalities and examines data pertinent to the diagnosis and management of cerebral vasospasm. Baback Arshi, William J. Mack, and Benjamin Emanuel Copyright © 2013 Baback Arshi et al. All rights reserved. Wed, 06 Feb 2013 08:35:36 +0000 http://www.hindawi.com/journals/nri/2013/415960/ The pathophysiology of cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) is complex and is not entirely understood. Mechanistic insights have been gained through advances in the capabilities of diagnostic imaging. Core techniques have focused on the assessment of vessel caliber, tissue metabolism, and/or regional perfusion parameters. Advances in imaging have provided clinicians with a multifaceted approach to assist in the detection of cerebral vasospasm and the diagnosis of delayed ischemic neurologic deficits (DIND). However, a single test or algorithm with broad efficacy remains elusive. This paper examines both anatomical and physiological imaging modalities applicable to post-SAH vasospasm and offers a historical background. We consider cerebral blood flow velocities measured by Transcranial Doppler Ultrasonography (TCD). Structural imaging techniques, including catheter-based Digital Subtraction Angiography (DSA), CT Angiography (CTA), and MR Angiography (MRA), are reviewed. We examine physiologic assessment by PET, HMPAO SPECT, 133Xe Clearance, Xenon-Enhanced CT (Xe/CT), Perfusion CT (PCT), and Diffusion-Weighted/MR Perfusion Imaging. Comparative advantages and limitations are discussed. Jena N. Mills, Vivek Mehta, Jonathan Russin, Arun P. Amar, Anandh Rajamohan, and William J. Mack Copyright © 2013 Jena N. Mills et al. All rights reserved. Thu, 31 Jan 2013 10:24:17 +0000 http://www.hindawi.com/journals/nri/2013/571328/ Aneurysmal subarachnoid hemorrhage- (aSAH-) associated vasospasm constitutes a clinicopathological entity, in which reversible vasculopathy, impaired autoregulatory function, and hypovolemia take place, and lead to the reduction of cerebral perfusion and finally ischemia. Cerebral vasospasm begins most often on the third day after the ictal event and reaches the maximum on the 5th–7th postictal days. Several therapeutic modalities have been employed for preventing or reversing cerebral vasospasm. Triple “H” therapy, balloon and chemical angioplasty with superselective intra-arterial injection of vasodilators, administration of substances like magnesium sulfate, statins, fasudil hydrochloride, erythropoietin, endothelin-1 antagonists, nitric oxide progenitors, and sildenafil, are some of the therapeutic protocols, which are currently employed for managing patients with aSAH. Intense pathophysiological mechanism research has led to the identification of various mediators of cerebral vasospasm, such as endothelium-derived, vascular smooth muscle-derived, proinflammatory mediators, cytokines and adhesion molecules, stress-induced gene activation, and platelet-derived growth factors. Oral, intravenous, or intra-arterial administration of antagonists of these mediators has been suggested for treating patients suffering a-SAH vasospam. In our current study, we attempt to summate all the available pharmacological treatment modalities for managing vasospasm. Ioannis Siasios, Eftychia Z. Kapsalaki, and Kostas N. Fountas Copyright © 2013 Ioannis Siasios et al. All rights reserved. Wed, 19 Dec 2012 08:41:56 +0000 http://www.hindawi.com/journals/nri/2012/798028/ Brett Morrison, Kenneth Hensley, Erik P. Pioro, Susanne Petri, and Mahmoud Kiaei Copyright © 2012 Brett Morrison et al. All rights reserved. Mon, 19 Nov 2012 18:09:48 +0000 http://www.hindawi.com/journals/nri/2012/628949/ Aims. The aim of this study was to investigate the motor control and central silent period (CSP) in restless legs syndrome (RLS). Methods. Transcranial magnetic stimulation was focused on the dominant and nondominant hemispheric areas of motor cortex in six subjects with RLS and six controls. The responses were recorded on the contralateral abductor digiti minimi (ADM) and tibialis anterior (TA) muscles with intramuscular needle electrodes. Results. No significant differences were found in the motor conduction or central motor conduction time, in the latency, or in the duration of the CSPs between or within the groups, but multiple CSPs were observed in both groups. The number of the CSPs was significantly higher in both ADMs and in the dominant TA () in the RLS group compared to the controls. Conclusion. Descending motor pathways functioned correctly in both groups. The occurrence of the recurrent CSPs predominantly in the RLS group could be a sign of a change of function in the inhibitory control system. Further research is needed to clarify the role of the intramuscular recording technique and especially the role of the subcortical generators in the feedback regulation of the central nervous system in RLS. Aulikki Ahlgrén-Rimpiläinen, Hannu Lauerma, Seppo Kähkönen, Juha Markkula, and Ilpo Rimpiläinen Copyright © 2012 Aulikki Ahlgrén-Rimpiläinen et al. All rights reserved. Thu, 08 Nov 2012 08:58:43 +0000 http://www.hindawi.com/journals/nri/2012/502096/ Motor Cortex Stimulation (MCS) is less efficacious than Deep Brain Stimulation (DBS) in Parkinson's disease. However, it might be proposed to patients excluded from DBS or unresponsive to DBS. Ten patients with advanced PD underwent unilateral MCS contralaterally to the worst clinical side. A plate electrode was positioned over the motor cortex in the epidural space through single burr hole after identification of the area with neuronavigation and neurophysiological tests. Clinical assessment was performed by total UPDRS, UPDRS III total, UPDRS III-items 27–31, UPDRS IV, and UPDRS II before implantation in off-medication and on-medication states and after surgery at 1, 3, 6, 12, 18, 24, and 36 months in on-medication/on-stimulation and off-medication/on-stimulation states. We assessed changes of quality of life, throughout the Parkinson's disease quality of life scale (PDQoL-39), and the dose of anti-Parkinson's disease medications, throughout the Ldopa equivalent daily dose (LEDD). During off-medication state, we observed moderate and transitory reduction of total UPDRS and UPDRS total scores and significant and long-lasting improvement in UPDRS III items 27–31 score for axial symptoms. There was marked reduction of UPDRS IV score and LEDD. PDQL-39 improvement was also significant. No important complications and adverse events occurred. Marisa De Rose, Giusy Guzzi, Domenico Bosco, Mary Romano, Serena Marianna Lavano, Massimiliano Plastino, Giorgio Volpentesta, Rosa Marotta, and Angelo Lavano Copyright © 2012 Marisa De Rose et al. All rights reserved. Wed, 07 Nov 2012 13:41:56 +0000 http://www.hindawi.com/journals/nri/2012/853030/ Kalina Venkova-Hristova, Alexandar Christov, Zarine Kamaluddin, Peter Kobalka, and Kenneth Hensley Copyright © 2012 Kalina Venkova-Hristova et al. All rights reserved. Tue, 02 Oct 2012 14:58:34 +0000 http://www.hindawi.com/journals/nri/2012/479865/ Although fever and infection have been implicated in the causation of delayed neurological deficits (DND) and poor outcome after aneurysmal subarachnoid hemorrhage (SAH), the relationship between these two often related events has not been extensively studied. We reviewed these events through of our retrospective database of patients with SAH. Multivariate logistic regression was used to determine independent predictors of DND and poor outcome. A total of 186 patients were analyzed. DND was noted in 76 patients (45%). Fever was recorded in 102 patients (55%); infection was noted in 87 patients (47%). A patient with one infection was more likely to experience DND compared to a patient with no infections (adjusted OR 3.73, 95% CI 1.62, 8.59). For those with more than two infections the likelihood of DND was even greater (adjusted OR 4.24, 95% CI 1.55, 11.56). Patients with 1-2 days of fever were less likely to have a favorable outcome when compared to their counterparts with no fever (adjusted OR 0.19, 95% CI 0.06, 0.62). This trend worsened as the number of days febrile increased. These data suggest that the presence of infection is associated with DND, but that fever may have a stronger independent association with overall outcome. G. Logan Douds, Bi Tadzong, Akash D. Agarwal, Satish Krishnamurthy, Erik B. Lehman, and Kevin M. Cockroft Copyright © 2012 G. Logan Douds et al. All rights reserved. Thu, 20 Sep 2012 10:08:01 +0000 http://www.hindawi.com/journals/nri/2012/878030/ Nrf2 (nuclear erythroid 2-related factor 2) is a basic region leucine-zipper transcription factor which binds to the antioxidant response element (ARE) and thereby regulates the expression of a large battery of genes involved in the cellular antioxidant and anti-inflammatory defence as well as mitochondrial protection. As oxidative stress, inflammation and mitochondrial dysfunctions have been identified as important pathomechanisms in amyotrophic lateral sclerosis (ALS), this signaling cascade has gained interest both with respect to ALS pathogenesis and therapy. Nrf2 and Keap1 expressions are reduced in motor neurons in postmortem ALS tissue. Nrf2-activating compounds have shown therapeutic efficacy in the ALS mouse model and other neurodegenerative disease models. Alterations in Nrf2 and Keap1 expression and dysregulation of the Nrf2/ARE signalling program could contribute to the chronic motor neuron degeneration in ALS and other neurodegenerative diseases. Therefore, Nrf2 emerges as a key neuroprotective molecule in neurodegenerative diseases. Our recent studies strongly support that the Nrf2/ARE signalling pathway is an important mediator of neuroprotection and therefore represents a promising target for development of novel therapies against ALS, Parkinson’s disease (PD), Huntington’s disease (HD), and Alzheimer’s disease (AD). Susanne Petri, Sonja Körner, and Mahmoud Kiaei Copyright © 2012 Susanne Petri et al. All rights reserved. Wed, 19 Sep 2012 15:06:07 +0000 http://www.hindawi.com/journals/nri/2012/309431/ Movement disorders are neurological conditions affecting speed, fluency, quality, and ease of movement. Deep brain stimulation (DBS) is used to treat advanced Parkinson’s disease, essential tremor, and dystonia. Possible target sites for DBS include the ventral intermediate nucleus of the thalamus, the globus pallidus internus, and the subthalamic nucleus. High-frequency DBS leads to a kind of functional deafferentation of the stimulated structure and to the modulation of cortical activity. This has a profound effect on the efficiency of movement. Indications for the use of DBS include the need to improve function, reduce medication dependency, and avoid ablative neurosurgery. Appropriate patient selection is critical for success. The implantation technique is briefly described. Programming stimulation parameters are performed via telemetry. The adverse effects of DBS are discussed. The future should see the development of “closed-loop” systems. Its use has promoted interdisciplinary team work and provided an improved understanding of the complex neurocircuitry associated with these disorders. DBS is a highly effective, safe, and reversible surgical treatment for advanced Parkinson’s disease, tremor, and dystonia. It is a useful therapeutic option in carefully selected patients that significantly improves motor symptoms, functional status, and quality of life. Edward A. Shipton Copyright © 2012 Edward A. Shipton. All rights reserved. Sun, 16 Sep 2012 09:57:05 +0000 http://www.hindawi.com/journals/nri/2012/625245/ In mammalian systems, D-serine is perhaps the most biologically active D-amino acid described to date. D-serine is a coagonist at the NMDA-receptor, and receptor activation is dependent on D-serine binding. Because D-serine binding dramatically increases receptor affinity for glutamate, it can produce excitotoxicity without any change in glutamate per se. D-serine is twofold higher in the spinal cords of mSOD1 (G93A) ALS mice, and the deletion of serine racemase (SR), the enzyme that produces D-serine, results in an earlier onset of symptoms, but with a much slower rate of disease progression. Localization studies within the brain suggest that mSOD1 and subsequent glial activation could contribute to the alterations in SR and D-serine seen in ALS. By also degrading both D-serine and L-serine, SR appears to be a prime bidirectional regulator of free serine levels in vivo. Therefore, accurate and reproducible measurements of D-serine are critical to understanding its regulation by SR. Several methods for measuring D-serine have been employed, and significant issues related to validation and standardization remain unresolved. Further insights into the intracellular transport and tissue-specific compartmentalization of D-serine within the CNS will aid in the understanding of the role of D-serine in the pathogenesis of ALS. John P. Crow, John C. Marecki, and Misty Thompson Copyright © 2012 John P. Crow et al. All rights reserved. Thu, 09 Aug 2012 14:00:38 +0000 http://www.hindawi.com/journals/nri/2012/478560/ Background. Complex diseases like amyotrophic lateral sclerosis (ALS) implicate phenotypic and genetic heterogeneity. Therefore, multiple genetic traits may show differential association with the disease. The Auto Contractive Map (AutoCM), belonging to the Artificial Neural Network (ANN) architecture, “spatializes” the correlation among variables by constructing a suitable embedding space where a visually transparent and cognitively natural notion such as “closeness” among variables reflects accurately their associations. Results. In this pilot case-control study single nucleotide polymorphism (SNP) in several genes has been evaluated with a novel data mining approach based on an AutoCM. We have divided the ALS dataset into two dataset: Cases and Control dataset; we have applied to each one, independently, the AutoCM algorithm. Six genetic variants were identified which differently contributed to the complexity of the system: three of the above genes/SNPs represent protective factors, APOA4, NOS3, and LPL, since their contribution to the whole complexity resulted to be as high as 0.17. On the other hand ADRB3, LIPC, and MMP3, whose hub relevancies contribution resulted to be as high as 0.13, seem to represent susceptibility factors. Conclusion. The biological information available on these six polymorphisms is consistent with possible pathogenetic pathways related to ALS. Massimo Buscema, Silvana Penco, and Enzo Grossi Copyright © 2012 Massimo Buscema et al. All rights reserved. Tue, 07 Aug 2012 13:25:22 +0000 http://www.hindawi.com/journals/nri/2012/379657/ Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by the progressive degeneration of upper and lower motor neurons (MNs), leading to muscular atrophy and eventual respiratory failure. ALS research has primarily focused on mechanisms regarding MN cell death; however, degenerative processes in the skeletal muscle, particularly involving neuromuscular junctions (NMJs), are observed in the early stages of and throughout disease progression. According to the “dying-back” hypothesis, NMJ degeneration may not only precede, but actively cause upper and lower MN loss. The importance of NMJ pathology has relatively received little attention in ALS, possibly because compensatory mechanisms mask NMJ loss for prolonged periods. Many mechanisms explaining NMJ degeneration have been proposed such as the disruption of anterograde/retrograde axonal transport, irregular cellular metabolism, and changes in muscle gene and protein expression. Neurotrophic factors, which are known to have neuroprotective and regenerative properties, have been intensely investigated for their therapeutic potential in both the preclinical and clinical setting. Additional research should focus on the potential of preserving NMJs in order to delay or prevent disease progression Dan Krakora, Corey Macrander, and Masatoshi Suzuki Copyright © 2012 Dan Krakora et al. All rights reserved. Tue, 07 Aug 2012 10:49:13 +0000 http://www.hindawi.com/journals/nri/2012/806306/ Though once believed to be a disease that was limited to the motor system, it is now apparent that amyotrophic lateral sclerosis (ALS) may be associated with cognitive changes in some patients. Changes are consistent with frontotemporal dysfunction, and may range from mild abnormalities only recognized with formal neuropsychological testing, to profound frontotemporal dementia (FTD). Executive function, behavior, and language are the most likely areas to be involved. Screening helpful in detecting abnormalities includes verbal or categorical fluency, behavioral inventories filled out by the caregiver, and evaluation for the presence of depression and pseudobulbar affect. Patients with cognitive dysfunction have shortened survival and may be less compliant with recommendations regarding use of feeding tubes and noninvasive ventilation. Evolving knowledge of genetic and pathological links between ALS and FTD has allowed us to better understand the overlapping spectrum of ALS and FTD. Eugene Y. Achi and Stacy A. Rudnicki Copyright © 2012 Eugene Y. Achi and Stacy A. Rudnicki. All rights reserved. Wed, 01 Aug 2012 08:30:51 +0000 http://www.hindawi.com/journals/nri/2012/170426/ A prominent clinical feature of ALS is muscle weakness due to dysfunction, denervation and degeneration of motoneurons (MNs). While MN degeneration is a late stage event in the ALS mouse model, muscle denervation occurs significantly earlier in the disease. Strategies to prevent this early denervation may improve quality of life by maintaining muscle control and slowing disease progression. The precise cause of MN dysfunction and denervation is not known, but several mechanisms have been proposed that involve potentially toxic intra- and extracellular changes. Many cells confront these changes by mounting a stress response that includes increased expression of heat shock protein 70 (Hsp70). MNs do not upregulate Hsp70, and this may result in a potentially increased vulnerability. We previously reported that recombinant human hsp70 (rhHsp70) injections delayed symptom onset and increased lifespan in SOD1G93A mice. The exogenous rhHsp70 was localized to the muscle and not to spinal cord or brain suggesting it modulates peripheral pathophysiology. In the current study, we focused on earlier administration of Hsp70 and its effect on initial muscle denervation. Injections of the protein appeared to arrest denervation with preserved large myelinated peripheral axons, and reduced glial activation. David J. Gifondorwa, Ramon Jimenz-Moreno, Crystal D. Hayes, Hesam Rouhani, Mac B. Robinson, Jane L. Strupe, James Caress, and Carol Milligan Copyright © 2012 David J. Gifondorwa et al. All rights reserved. Tue, 17 Jul 2012 15:34:21 +0000 http://www.hindawi.com/journals/nri/2012/498428/ Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of incurable motor neuron diseases (MNDs) characterized by a selective loss of upper and lower motor neurons in the brain and spinal cord. Most cases of ALS are sporadic, while approximately 5–10% cases are familial. More than 16 causative genes for ALS/MNDs have been identified and their underlying pathogenesis, including oxidative stress, endoplasmic reticulum stress, excitotoxicity, mitochondrial dysfunction, neural inflammation, protein misfolding and accumulation, dysfunctional intracellular trafficking, abnormal RNA processing, and noncell-autonomous damage, has begun to emerge. It is currently believed that a complex interplay of multiple toxicity pathways is implicated in disease onset and progression. Among such mechanisms, ones that are associated with disturbances of protein homeostasis, the ubiquitin-proteasome system and autophagy, have recently been highlighted. Although it remains to be determined whether disease-associated protein aggregates have a toxic or protective role in the pathogenesis, the formation of them results from the imbalance between generation and degradation of misfolded proteins within neuronal cells. In this paper, we focus on the autophagy-lysosomal and endocytic degradation systems and implication of their dysfunction to the pathogenesis of ALS/MNDs. The autophagy-endolysosomal pathway could be a major target for the development of therapeutic agents for ALS/MNDs. Asako Otomo, Lei Pan, and Shinji Hadano Copyright © 2012 Asako Otomo et al. All rights reserved. Wed, 11 Jul 2012 17:18:46 +0000 http://www.hindawi.com/journals/nri/2012/157858/ Robin L. Haynes, Tara M. DeSilva, and Jianrong Li Copyright © 2012 Robin L. Haynes et al. All rights reserved. Mon, 09 Jul 2012 13:23:17 +0000 http://www.hindawi.com/journals/nri/2012/608501/ Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder which is incurable to date. As there are many ongoing studies with therapeutic candidates, it is of major interest to develop biomarkers not only to facilitate early diagnosis but also as a monitoring tool to predict disease progression and to enable correct randomization of patients in clinical trials. Magnetic resonance imaging (MRI) has made substantial progress over the last three decades and is a practical, noninvasive method to gain insights into the pathology of the disease. Disease-specific MRI changes therefore represent potential biomarkers for ALS. In this paper we give an overview of structural and functional MRI alterations in ALS with the focus on task-free resting-state investigations to detect cortical network failures. Katja Kollewe, Sonja Körner, Reinhard Dengler, Susanne Petri, and Bahram Mohammadi Copyright © 2012 Katja Kollewe et al. All rights reserved. Thu, 05 Jul 2012 10:41:44 +0000 http://www.hindawi.com/journals/nri/2012/187234/ Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that cannot be slowed substantially using any currently-available clinical tools. Through decades of studying sporadic and familial ALS (SALS and FALS), researchers are coming to understand ALS as a complex syndrome with diverse genetic and environmental etiologies. It is know appreciated that motor neuron degeneration in ALS requires active (gain of function) and passive (loss of function) events to occur in non-neuronal cells, especially astrocytes and microglia. These neuroinflammatory processes produce paracrine factors that detrimentally affect motor neurons, precipitating protein aggregation and compromising cytoskeletal integrity. The result is a loss of neuronal homeostasis and progressive die-back of motor axons culminating in death of the afflicted motor neurons. This review will discuss experimental therapeutics that have been tested in murine ALS models, with an emphasis on those that have progressed to human clinical trials. Reasons will be considered for the frequent failure of preclinical successes to translate into positive clinical outcomes. Finally, this review will explore current trends in experimental therapeutics for ALS with emphasis on the emerging interest in axon guidance signaling pathways as novel targets for pharmacological support of neural cytoskeletal structure and function in order to slow ALS. Kalina Venkova-Hristova, Alexandar Christov, Zarine Kamaluddin, Peter Kobalka, and Kenneth Hensley Copyright © 2012 Kalina Venkova-Hristova et al. All rights reserved. Sun, 01 Jul 2012 18:31:03 +0000 http://www.hindawi.com/journals/nri/2012/323261/ Dominant mutations in a Cu, Zn-superoxide dismutase (SOD1) gene cause a familial form of amyotrophic lateral sclerosis (ALS). While it remains controversial how SOD1 mutations lead to onset and progression of the disease, many in vitro and in vivo studies have supported a gain-of-toxicity mechanism where pathogenic mutations contribute to destabilizing a native structure of SOD1 and thus facilitate misfolding and aggregation. Indeed, abnormal accumulation of SOD1-positive inclusions in spinal motor neurons is a pathological hallmark in SOD1-related familial ALS. Furthermore, similarities in clinical phenotypes and neuropathology of ALS cases with and without mutations in sod1 gene have implied a disease mechanism involving SOD1 common to all ALS cases. Although pathogenic roles of wild-type SOD1 in sporadic ALS remain controversial, recent developments of novel SOD1 antibodies have made it possible to characterize wild-type SOD1 under pathological conditions of ALS. Here, I have briefly reviewed recent progress on biochemical and immunohistochemical characterization of wild-type SOD1 in sporadic ALS cases and discussed possible involvement of wild-type SOD1 in a pathomechanism of ALS. Yoshiaki Furukawa Copyright © 2012 Yoshiaki Furukawa. All rights reserved. Thu, 28 Jun 2012 11:56:18 +0000 http://www.hindawi.com/journals/nri/2012/582075/ Objectives. To determine if therapy with pioglitazone HCl and tretinoin could slow disease progression in patients with ALS. Levels of tau and pNFH in the cerebrospinal fluid were measured to see if they could serve as prognostic indicators. Methods. 27 subjects on stable doses of riluzole were enrolled. Subjects were randomized to receive pioglitazone 30 mg/d and tretinoin 10 mg/BID for six months or two matching placebos. ALSFRS-R scores were followed monthly. At baseline and at the final visit, lumbar punctures (LPs) were performed to measure cerebrospinal fluid (CSF) biomarker levels. Results. Subjects treated with tretinoin, pioglitazone, and riluzole had an average rate of decline on the ALSFRS-R scale of −1.02 points per month; subjects treated with placebo and riluzole had a rate of decline of −.86 (𝑃=.18). Over six months of therapy, CSF tau levels decreased in subjects randomized to active treatment and increased in subjects on placebo. Further higher levels of pNF-H at baseline correlated with a faster rate of progression. Conclusion. ALS patients who were treated with tretinoin and pioglitazone demonstrated no slowing on their disease progression. Interestingly, the rate of disease progression was strongly correlated with levels of pNFH in the CSF at baseline. Todd D. Levine, Robert Bowser, Nicole C. Hank, Stephen Gately, Dietrich Stephan, David S. Saperstein, and Kendall Van Keuren-Jensen Copyright © 2012 Todd D. Levine et al. All rights reserved. Sun, 17 Jun 2012 09:41:48 +0000 http://www.hindawi.com/journals/nri/2012/278725/ In the last years, numerous studies have focused on understanding the metabolism of RNA and its implication in disease processes but abnormal RNA metabolism is still unknown. RNA plays a central role in translating genetic information into proteins and in many other catalytic and regulatory tasks. Recent advances in the study of RNA metabolism revealed complex pathways for the generation and maintenance of functional RNA in amyotrophic lateral sclerosis (ALS). Interestingly, perturbations in RNA processing have been described in ALS at various levels such as gene transcription, mRNA stabilization, transport, and translational regulations. In this paper, we will discuss the alteration of RNA profile in ALS disease, starting from transcription, the first step leading to gene expression, through the posttranscriptional regulation, including RNA/DNA binding proteins and aberrant exon splicing to protein noncoding RNAs, as lncRNA and microRNA. Stella Gagliardi, Pamela Milani, Valentina Sardone, Orietta Pansarasa, and Cristina Cereda Copyright © 2012 Stella Gagliardi et al. All rights reserved. Sun, 03 Jun 2012 11:32:41 +0000 http://www.hindawi.com/journals/nri/2012/781512/ Understanding the evolution of neonatal hypoxic/ischemic is essential for novel neuroprotective approaches. We describe the neuropathology and glial/inflammatory response, from 3 hours to 100 days, after carotid occlusion and hypoxia (8% O2, 55 minutes) to the C57/BL6 P7 mouse. Massive tissue injury and atrophy in the ipsilateral (IL) hippocampus, corpus callosum, and caudate-putamen are consistently shown. Astrogliosis peaks at 14 days, but glial scar is still evident at day 100. Microgliosis peaks at 3–7 days and decreases by day 14. Both glial responses start at 3 hours in the corpus callosum and hippocampal fissure, to progressively cover the degenerating CA field. Neutrophils increase in the ventricles and hippocampal vasculature, showing also parenchymal extravasation at 7 days. Remarkably, delayed milder atrophy is also seen in the contralateral (CL) hippocampus and corpus callosum, areas showing astrogliosis and microgliosis during the first 72 hours. This detailed and long-term cellular response characterization of the ipsilateral and contralateral hemisphere after H/I may help in the design of better therapeutic strategies. Kalpana Shrivastava, Mariela Chertoff, Gemma Llovera, Mireia Recasens, and Laia Acarin Copyright © 2012 Kalpana Shrivastava et al. All rights reserved.