Angela Trovato1, Manuela Pennisi1,5, Rosalia Crupi2*, Rosanna Di Paola2, Alice Alario1, Sergio Modafferi1, Gabriele Di Rosa1, Tito Fernandes3, Anna Signorile4, Luigi Maiolino6, Salvatore Cuzzocrea2 and Vittorio Calabrese1**

1Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
2Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
3Faculty of Veterinary Medicine, Lisbon University, Portugal
4Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy
5Spinal Unit, Emergency Hospital "Cannizzaro", Catania, Italy

Abnormal redox homeostasis and oxidative stress have been proposed to play a role in the etiology of several neuropsychiatric disorders and emerging interest has recently focused on markers of oxidative stress and neuroinflammation in neurodegenerative disorders as well as in different forms of chronic mental illness. Oxidative stress and altered antioxidant systems have been considered an important factor underlying the pathogenesis of Alzheimer’s disease (AD). Altered expression of genes related to oxidative stress, oxidative damage to DNA, protein and lipids, as well as alterations in the redox state in central and peripheral tissues could act synergistically, and contribute to the course of the disease. Specifically, we discuss the emerging role of lipoxinA4 and inflammasome in neurodegeneration. However, the notion that low levels of stress can induce responses that may be protective against the pathogenic processes is a frontier area of neurobiological research focal to understanding and developing therapeutic approaches to neurodegenerative disorders. Herein, we discuss the potenial therapeutic role of Coriolus versicolor, a mushrooom, well known in China as Yun Zhi. We propose a potentially innovative treatment for AD and, possibly, other neurodegenerative conditions associated to neuroinflammation.

DOI: 10.29245/2572.942X/2017/2.942X/2017/1.1088 View / Download Pdf

Morgan Sturgeon1, Perry Wu2, and Robert Cornell1,2*

1Molecular and Cell Biology Graduate Program, University of Iowa, Iowa City, Iowa
2Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa

Parkinson’s disease (PD) is a neurodegenerative disorder of the central nervous system with a clinically heterogeneous presentation that includes progressive loss of dopaminergic (DA) neurons in the substantia nigra. A minority of PD cases are familial and are caused by mutations in single genes. Most cases, however, are idiopathic PD, a complex multifactorial disorder with environmental and genetic contributors to etiology. Here, we first briefly summarize published evidence that among environmental contributors is dietary deficiency of magnesium. We then review genetic data suggesting that mutations in genes encoding two proteins contributing to cellular magnesium homeostasis confer risk for PD or other Parkinsonian conditions. First, the gene encoding magnesium transporter SLC41A1 is, among others, a candidate for the causative gene in the PARK16 locus where variation is associated with risk for idiopathic Parkinsonian disease. Studies of the function of SLC41A1 in animal models are needed to test whether this protein has a role in maintenance of dopaminergic neurons. Second, in a small study, a hypomorphic variant of TRPM7, a magnesium-permeable channel, was over-represented in cases of amyotrophic lateral sclerosis/ Parkinson dementia complex versus controls from the same ethnic group. Although this association was not detected in a second study, in zebrafish Trpm7 is necessary for terminal differentiation and reduction of toxin-sensitivity in dopaminergic neurons. Overall, epidemiological results support the possibility that mutations in genes relevant to magnesium homeostasis would alter PD risk, but deeper genetic analyses of PD patients are necessary to confirm whether SLC41A1 and TRPM7 are among such genes.

DOI: 10.29245/2572.942X/2016/9.1102 View / Download Pdf

Arnauld Belmer1*, Vanessa Lanoue3, Omkar L. Patkar1, and Selena E. Bartlett1,2

1Translational Research Institute, Queensland University of Technology (QUT), Brisbane, Australia
2Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology (QUT), Brisbane, Australia
3Queensland Brain Institute (QBI), The University of Queensland, Brisbane, Australia


Serotonin neurons originate from the brainstem raphe nuclei and innervate the entire brain to regulate mood, emotion, sleep, appetite and aggression. Previous electron microscopy (EM) studies have revealed that 5-HT boutons directly contact several neuronal populations via asymmetrical (excitatory) or symmetrical (inhibitory) synapses. Additionally, 5-HT boutons sometimes form “triads” with the pre and postsynaptic components of asymmetrical or symmetrical synapses to modulate their activity. However, the exact proportion and distribution of 5-HT excitatory/inhibitory synapses and triads within the entire brain remains poorly described. Recently, we have published a novel semi-quantitative approach which combines fluorescent confocal microscopy and 3D reconstruction of 5-HT fibers apposed to excitatory and inhibitory neurochemical synapses (triads). Here, we review the similarities and differences in the distribution of 5-HT asymmetrical/symmetrical synapses observed in EM and the distribution of 5-HT excitatory/inhibitory triads quantified in our recent study. We further put into perspective the possible physiological role played by 5-HT triads in the regulation of glutamate and GABA signaling in these various brain regions.

DOI: 10.29245/2572.942X/2016/9.1079 View / Download Pdf

A.H. Rajput*, MBBS, FRCPC; A. Rajput, MD, FRCPC

Saskatchewan Movement Disorders Program, University of Saskatchewan/ Saskatoon Health Region

Parkinsonism in both spouses has been reported in only 20 couples in the literature so far. Six of the studies included only one or two couples, but one study reported nine couples. Fifteen of the couples reported by others consisted of only clinical data. By contrast, our study of five couples had detailed clinical, pathological and genetic observation on all ten individuals. We found no evidence of person-to-person transmission of parkinsonism. Details of that study are provided in this review.

The literature evidence to date indicates that neither Parkinson’s disease nor other common parkinson variants – multiple system atrophy or progressive supranuclear palsy are transmitted by sexual or close personal contact in the married couples. As well, these syndromes are not based on shared environments or same genetic mutation.

The best explanation for parkinsonism in both partners of non-consanguineous couples is, that Parkinson syndrome in each spouse is a coincidental disorder

DOI: 10.29245/2572.942X/2016/9.1089 View / Download Pdf

Sonja Sucic, Ameya Kasture, H. M. Mazhar Asjad, Carina Kern, Ali El-Kasaby and Michael Freissmuth*

Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria

The human dopamine transporter (hDAT) belongs to the solute carrier 6 (SLC6) gene family. Point mutations in hDAT (SLC6A3) have been linked to a syndrome of dopamine transporter deficiency or infantile dystonia/parkinsonism. The mutations impair DAT folding, causing retention of variant DATs in the endoplasmic reticulum and subsequently impair transport activity. The folding trajectory of DAT itself is not understood, though many insights have been gained from studies of folding-deficient mutants of the closely related serotonin transporter (SERT); i.e. their functional rescue by pharmacochaperoning with (nor)ibogaine or heat-shock protein inhibitors. We recently provided a proof-of-principle that folding-deficits in DAT are amenable to rescue in vitro and in vivo. As a model we used the Drosophila melanogaster DAT mutant dDAT-G108Q, which phenocopies the fumin/sleepless DAT-knockout. Treatment with noribogaine and/or HSP70 inhibitor pifithrin-μ restored folding of, and dopamine transport by, dDAT-G108Q, its axonal delivery and normal sleep time in mutant flies. The possibility of functional rescue of misfolded DATs in living flies by pharmacochaperoning grants new therapeutic prospects in the remedy of folding diseases, not only in hDAT, but also in other SLC6 transporters, in particular mutants of the creatine transporter-1, which give rise to X-linked mental retardation.

DOI: 10.29245/2572.942X/2016/9.1098 View / Download Pdf

Mélanie H. Thomas1, Sandra Pelleieux1,2, Nicolas Vitale3, Jean Luc Olivier1,2*

1Unité de Recherche Aliment et Fonctionnalité des Produits Animaux (URAFPA), INRA USC 0340, Université de Lorraine, Nancy, France
2Service de Biochimie-Biologie Moléculaire, Hôpital Central, CHU de Nancy, Nancy, France
3Institut des Neurosciences Cellulaires et Intégratives (INCI), UPR CNRS 3212, Université de Strasbourg, Strasbourg, France

Alzheimer’s disease is a very complex disease in which neuroinflammation and synaptic dysfunctions play a critical role in association with the two well-known molecular agents of the disease, the Aβ1-42 peptide oligomers and the hyperphosphorylated tau protein. Arachidonic acid, the main member of the ω-6 series, is quantitatively the second polyunsaturated fatty acid in brain and is mainly esterified in membrane phospholipids. It is specifically released by the cytosolic phospholipase A2 whose inhibition or gene suppression counteract the deleterious effects of Aβ1-42 peptide oligomers on cognitive abilities. Arachidonic acid can be reincorporated under the action of the acyl-CoA synthetase 4 and lysophospholipid acyltransferases which remain to be characterized. Free arachidonic acid can be involved in Alzheimer’s disease through several mechanisms. First it is converted by cyclooxygenases-1/2 and the specific prostaglandin synthases into PGE2 and PGD2 which contributes to the occurrence and progression of neuroinflammation. Neuroinflammation has positive as well as negative effects, by favoring Aβ1-42 peptide clearance on one hand and by increasing the production of neurotoxic compounds on the other hand. Second, free arachidonic acid is also involved in synaptic functions as a retrograde messenger and as a regulator of neuromediator exocytosis. Third, some studies indicated that free arachidonic acid and its derivatives activate kinases involved in tau hyperphosphorylation. In addition, the dietary intakes of arachidonic acid in western food increased in the last period. Taken together, these various reports support the hypothesis that arachidonic acid is interesting target in nutrition-based preventive strategies against this disease.

DOI: 10.29245/2572.942X/2016/9.1086 View / Download Pdf

Ahmed Hasanin1*, Dina Zakaria1, Ahmed Allam2

1Department of anesthesia, Cairo University, Egypt
2Department of neurosurgery, Cairo University, Egypt

Neurogenic stress cardiomyopathy (NSC) is a stress induced cardiomyopathy reported in various neurological disorders. The most widely accepted theory for the mechanism of NSC is the “catecholamine hypothesis”. The available evidence suggests the presence of NSC in patients with severe TBI. The presence of cardiac injury could be a poor prognostic finding in patients with TBI. The possible cardiac injury in TBI patients would make the critical care physicians more cautious with hemodynamic management of these patients. Larger studies with more sophisticated asessment would help to confirm the presence of cardiac injury in these patients.

DOI: 10.29245/2572.942X/2016/8.1090 View / Download Pdf

Gordon J. Horn1* & Frank D. Lewis2

1Florida State University, College of Medicine, USA
2Medical College of Georgia at Augusta University, USA

The purpose of this research was to evaluate the effectiveness of post-hospital neurobehavioral intensive (NBI) programs for treating acquired brain injury survivors with significant symptoms of behavioral dyscontrol and to identify variables that predict functional outcome. Subjects were 219 adults with acquired brain injury (predominately traumatic brain injury, 81%) exhibiting moderate to severe irritability, agitation, and/or aggression (includes verbal or physical) that were discharged from six NBI programs across five states. Prior to treatment, all participants demonstrated neurobehavioral impairment preventing the individuals from living in the community. All participants were assessed using the Mayo-Portland Adaptability Inventory – 4 at admission and discharge from program. A Repeated Measures MANOVA revealed significant improvement on the three MPAI-4 subscales at time of discharge. With control for participant age, a hierarchical multiple regression analysis revealed three significant MPAI-4 predictors of outcome: initiation, impaired awareness, and fund of information. Findings demonstrated that significant functional improvement can be realized with extremely chronic behaviorally intensive brain injured adults. Treatment effects may be enhanced by early intervention focused on appropriate response initiation/ inhibition, self-awareness of behavior on others, and information integration to facilitate appropriate response formation.

DOI: 10.29245/2572.942X/2016/8.1078 View / Download Pdf

Miguel L. Concha1,2,3*, Patricio Ahumada-Galleguillos1,2

1Anatomy and Developmental Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, PO Box 70031, Santiago, Chile.
2Biomedical Neuroscience Institute, Independencia 1027, Santiago, Chile.
3Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.

The habenula (Hb) of vertebrates is a dorsal and bilateral diencephalic nuclear complex that works as an anatomical hub integrating cognitive, emotional and sensory networks to regulate mood, motivation and value-based decision-making, among other functions. Across vertebrates, the Hb organises into two conserved separate components (medial and lateral in mammals equivalent to dorsal and ventral in more basal vertebrate species), which are thought to subserve different functions based on a partial independence of their connectivity systems. As a complex, the Hb shows morphological, molecular and connectivity differences between the left and right sides in a wide range of vertebrate species, which in some cases extend to the functional and behavioural levels. Habenular asymmetries are particularly prominent in basal vertebrate species but become less evident in amniotes and particular mammals. In humans, recent evidence reveals that, under an overall symmetry morphology, the Hb shows lateral differences in volume, activation, metabolism and susceptibility to damage that suggest an asymmetric condition of this nuclear complex. Here, we review the evidence supporting this view and discuss the possible origin of this asymmetric trait in humans from an evolutionary developmental perspective.

DOI: 10.29245/2572.942X/2016/8.1094 View / Download Pdf

Faith C. Robertson B.S.,1,2 Hormuzdiyar H. Dasenbrock M.D., M.P.H.,1,2,3 William B. Gormley M.D., M.P.H., M.B.A.1,2,3

1Harvard Medical School, Boston, Massachusetts, USA
2Cushing Neurosurgical Outcomes Center, Brigham and Women's Hospital, Boston, Massachusetts, USA
3Department of Neurological Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA

Malignant cerebral edema is a potential consequence of large territory cerebral infarction, as the resultant elevation in intracranial pressure may progress to transtentorial herniation, brainstem compression, and death. In appropriate patients, decompressive hemicraniectomy (DHC) reduces mortality without increasing the risk of severe disability. However, as the foundational DHC randomized, controlled trials excluded patients greater than 60 years of age, the appropriateness of DHC in older adults remains controversial. Recent clinical trials among elderly participants, including DESTINY II, reported that DHC reduces mortality, but may leave patients with substantial morbidity. Nationwide analyses have demonstrated generalizability of such data. However, what constitutes an acceptable outcome − the perspective on quality of life after survival with substantial disability − varies between clinicians, patients, and caregivers. Consequently, quality of life measures are being increasingly incorporated into stroke research. This review summarizes the impact of DHC in space-occupying cerebral infarction, and the influence of patient age on postoperative survival, functional capacity, and quality of life-all key factors in the clinical decision process. Ultimately, these data underscore the inherent complexity in balancing scientific evidence, clinical expertise, and patient and family preference when pursuing hemicraniectomy among the elderly.

Abbreviations: BI: Barthel Index; DHC: decompressive hemicraniectomy; EQ-5D: European Quality of Life Scale; mRS: modified Rankin Scale; QoL: quality of life; RCT: randomized controlled trial.

DOI: 10.29245/2572.942X/2017/2.942X/2017/1.1103 View / Download Pdf

Katsuji Yoshioka*

Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan

 Axonal transport is essential for the development, function, and survival of neurons, and impaired axonal transport has been implicated in many neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. To date, however, how axonal transport is regulated, and how defective transport leads to neurodegeneration, remain largely unknown. This study by Sato et al. shows that the loss of both JSAP1 and JLP in the cerebellar Purkinje cells (PCs) of mice causes axonal dystrophy followed by gradual, progressive PC degeneration. This study also suggests that JSAP1 and JLP regulate kinesin-1-dependent axonal transport in the brain with functional redundancy, which prevents axonal degeneration and subsequent neuronal death. There is increasing evidence that in neurodegenerative diseases, axonal degeneration precedes neuronal cell death. Thus, elucidating the mechanisms of axonal degeneration may provide promising targets for therapeutic intervention. The JSAP1-null, JLP-null mouse generated in this study may provide a useful animal model for studying the molecular basis of axonal degeneration in neurodegenerative diseases, and for developing therapeutic drugs for these diseases.

DOI: 10.29245/2572.942X/2016/8.1095 View / Download Pdf

Michaela F. George, PhD1*, Calliope B. Holingue, MPH1*, Farren B.S. Briggs, PhD, ScM2, Xiaorong Shao, MA1, Kalliope H. Bellesis3, Rachel A. Whitmer, PhD3, Catherine Schaefer, PhD3, Ralph HB Benedict, PhD4, Lisa F. Barcellos, PhD, MPH1,3,5

1Division of Epidemiology, Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, CA, USA
2Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
3Kaiser Permanente Division of Research, Oakland, CA, USA
4Jacobs MS Center, SUNY Buffalo School of Medicine, Buffalo, NY, USA

Cognitive impairment is common in multiple sclerosis (MS), and affects employment and quality of life. Large studies are needed to identify risk factors for cognitive decline. Currently, a MS-validated remote assessment for cognitive function does not exist. Studies to determine feasibility of large remote cognitive function investigations in MS have not been published.

To determine whether MS patients would participate in remote cognitive studies. We utilized the Modified Telephone Interview for Cognitive Status (TICS-M), a previously validated phone assessment for cognitive function in healthy elderly populations to detect mild cognitive impairment. We identified factors that influenced participation rates. We investigated the relationship between MS risk factors and TICS-M score in cases, and score differences between cases and control individuals.

The TICS-M was administered to MS cases and controls. Linear and logistic regression models were utilized.

11.5% of eligible study participants did not participate in cognitive testing. MS cases, females and individuals with lower educational status were more likely to refuse (p<0.001). Cases who did complete testing did not differ in terms of perceived cognitive deficit compared to cases that did participate. More severe disease, smoking, and being male were associated with a lower TICS-M score among cases (p<0.001). The TICS-M score was significantly lower in cases compared to controls (p=0.007).

Our results demonstrate convincingly that a remotely administered cognitive assessment is quite feasible for conducting large epidemiologic studies in MS, and lay the much needed foundation for future work that will utilize MS-validated cognitive measures.

DOI: 10.29245/2572.942X/2016/8.1084 View / Download Pdf

Karen E. Lee, Mahendra T. Bhati, Casey H. Halpern*

Department of Neurosurgery, Stanford University 300 Pasteur Dr., Edwards Bldg. Stanford, CA 94305, USA

Deep brain stimulation (DBS) has proven to be an effective treatment for neurologic disorders such as Parkinson’s disease, and is currently being investigated as a therapy for psychiatric diseases such as addiction, major depressive disorder, and obsessive compulsive disorder. In this commentary, we review and discuss the findings presented in the Letter to the Editor entitled “Attitudes towards treating addiction with deep brain stimulation,” written by Ali et al1. The survey presented in this Letter reported general approval for examining the effects of DBS on addictive disorders in a clinical trial, but highlighted critical areas of concern including informed consent, patient autonomy, appropriate medical practice, passing of clinical trial milestones, and implications on law enforcement.

DOI: 10.29245/2572.942X/2016/8.1093 View / Download Pdf

Guoyan Yang1,2, Dennis Chang1, and Jianping Liu2*

1National Institute of Complementary Medicine, Western Sydney University, NSW 2751, Australia
2Center for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China

Background: Ginkgo biloba is a natural medicine used for cognitive impairment and Alzheimer’s disease.

Methods: This is a commentary on a systematic review that we conducted to evaluate the effectives and safety of Ginkgo biloba in treating mild cognitive impairment or Alzheimer’s disease.

Results: 21 articles with 2608 patients met the inclusion criteria. The general methodological quality of included studies was moderate to poor. Compared with conventional medicine alone, Ginkgo biboba in combination with conventional medicine was superior in improving Mini-Mental State Examination (MMSE) scores at 24 weeks for patients with Alzheimer’s disease (MD 2.39, 95% CI 1.28 to 3.50, P<0.0001) and mild cognitive impairment (MD 1.90, 95% CI 1.41 to 2.39, P<0.00001), and Activity of Daily Living (ADL) scores at 24 weeks for Alzheimer’s disease (MD -3.72, 95% CI -5.68 to -1.76, P=0.0002). When compared with placebo or conventional medicine in individual trials, Ginkgo biboba demonstrated similar but inconsistent findings. Adverse events were mild.

Conclusion: Ginkgo biloba is potentially beneficial for the improvement of cognitive function, activities of daily living, and global clinical assessment in patients with mild cognitive impairment or Alzheimer’s disease. However, due to limited sample size, inconsistent findings and methodological quality of included trials, more research are warranted to confirm the effectiveness and safety of Ginkgo biloba in treating mild cognitive impairment and Alzheimer’s disease.

DOI: 10.29245/2572.942X/2016/8.1083 View / Download Pdf

Salvatore Caratozzolo*, Andrea Scalvini, Francesco Lanfranchi, Silvia Pelizzari, Marina Zanetti, Luca Rozzini, Alessandro Padovani

Department of Clinical and Experimental Science, University of Brescia, Brescia, Italy, 25123, Italy

DOI: 10.29245/2572.942X/2016/8.1092 View / Download Pdf

Hanna Choi, MD; Seo Young Choi, MD; Jae Guk Kim, MD; Sung-Yeon Sohn, MD; Do-Hyung Kim, MD; Soo Joo Lee, MD, PhD*

Department of Neurology, Eulji University Hospital, Eulji University School of Medicine, Daejeon, Republic of Korea

The effectiveness of intravenous tissue plasminogen activator (t-PA) is well established in hyperacute ischemic stroke. Despite its efficacy, spontaneous intracranial hemorrhage after t-PA is a severe complication associated with poor prognosis. We evaluated the role of blood pressure (BP) and BP variability, measured before and after injection of t-PA within 24 hours. Herein, 116 patients were enrolled in this study. BP (systolic blood pressure, diastolic blood pressure, and pulse pressure) were recorded before t-PA and every hour after t-PA for 24 hours. The BP profiles were characterized by initial, mean, maximum (max), minimum (min), max-min, and standard deviation (sd). The intracranial hemorrhage was assessed via computed tomography, 24-36 hours after injection of t-PA. The hemorrhagic transformation was classified using clinical and radiological criteria as follows: hemorrhagic transformation (HT), parenchymal hemorrhage (PH), and symptomatic hemorrhage (SH). The intracranial hemorrhage occurred as follows: HT 25.52% (n=25), PH 10.81% (n=12), SH 3.60% (n=4). The PPsd during the 24-hour period post-injection (24h PPsd) was significantly higher in patients with HT (14.57±0.76 vs. 11.84±0.39, 95% confidence interval [CI] 1.07-4.40, p<0.001) and PH (16.74±4.17 vs. 11.93±3.48, 95% CI 2.65-6.97, p<0.001). The odds ratio per 5 mmHg of 24h-PPsd was 2.41 (95% CI 1.23-4.72) in HT and 4.76 (95% CI 1.60-12.17) in PH. The variability in pulse pressure during the first 24 hours may be associated with hemorrhagic transformation after thrombolytic therapy with t-PA in hyperacute infarction.

DOI: 10.29245/2572.942X/2016/8.1085 View / Download Pdf

Wolf-Dieter Heiss

Max Planck Institute for Metabolism Research, Cologne, Germany

Ischemic stroke is caused by interruption or significant impairment of blood supply to the brain, which leads to a cascade of metabolic and molecular alterations resulting in functional disturbance and morphological damage. The changes in regional cerebral blood flow and in regional metabolism can be assessed by radionuclide imaging, especially single photon emission tomography (SPECT) and positron emission tomography (PET). SPECT and PET have broadened our understanding of flow and metabolic thresholds critical for maintenance of brain function and morphology: PET was essential in the transfer of the concept of the penumbra to clinical stroke and thereby had a great impact on developing treatment strategies. Receptor-ligands can be applied as early markers of irreversible neuronal damage and can predict the size of the final infarcts, which is important for decisions of invasive therapy in large (“malignant”) infarction. With SPECT and PET the reserve capacity of blood supply can be tested in obstructive arteriosclerosis, which is essential for planning interventions. The effect of a stroke on surrounding and contralateral primarily not-affected tissue can be investigated helping to understand symptoms caused by disturbance in functional networks. Activation studies are useful to demonstrate alternative pathways to compensate for lesions and to test the effect of rehabilitative therapy. Radioisotope studies help to detect neuroinflammation and its effect on extension of tissue damage. Despite the limitations of broad clinical application of radionuclide imaging, this technology has a great impact on research in cerebrovascular diseases and still has various applications in the management of stroke. In this short review the contributions of PET- and SPECT-studies to the understanding of the pathophysiology of ischemic stroke are described.

DOI: 10.29245/2572.942X/2016/8.1087 View / Download Pdf

Wang Liang1, Xu Min2, Sun Yiming3, Zhang Cheng1*

1Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, P.R. China
2Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 Yanjiang West Road, Guangzhou 510120, P.R. China
3Department of Health Care, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, P.R. China

Objective: To report a misdiagnosed case in order to avoid similar misdiagnosis of atypical juvenile dermatomyositis as muscular dystrophy in neurological clinics.

Methods: The process of misdiagnosis was first described. Thereafter, the patient’s diagnosis and treatment effect at the six-month follow-up were evaluated, and reported here.

Results: The patient presented an atypical course of juvenile dermatomyositis. The rashes, which mainly presented as erythema and wheals, were subsequently followed by the appearance of muscle weakness. However, the rashes were inconspicuous at first consult. The misdiagnosis of Duchenne muscular dystrophy was made due to the age of onset, distribution of muscle weakness, a high creatine kinase level, and other serum enzymatic changes. Upon further analysis, however, a diagnosis of juvenile dermatomyositis was definitively confirmed and the disease was controlled following systematic treatment for five months.

Conclusion: Although atypical juvenile dermatomyositis has a manifestation similar to that of muscular dystrophy, the considerations outlined in this case report will be helpful to avoid similar misdiagnosis.

DOI: 10.29245/2572.942X/2016/7.1072 View / Download Pdf

Anika M. Helferich1, Pamela J. McLean2, Jochen H. Weishaupt1 and Karin M. Danzer1*

1Department of Neurology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany
2Mayo Clinic, Jacksonville, Florida, USA

Alpha-synuclein and Cu, Zn superoxide dismutase (SOD1) are both aggregation-prone proteins that are associated with Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), respectively. Recently, we showed that alpha-synuclein interacts with SOD1 in various cell types and tissues. Using a cell culture model, we also found that alpha-synuclein nucleates the polymerization of SOD1. Here, we discuss the current literature regarding their interaction and their co-localization in aggregates of human post-mortem tissue. Furthermore we comment on the reported alpha-synuclein-induced SOD1 polymerization in terms of cross-seeding effects in neurodegeneration.

DOI: 10.29245/2572.942X/2016/7.1065 View / Download Pdf

Eri Kawashita1, Daisuke Tsuji2, Kohji Itoh2*

1Department of Pathological Biochemistry, Kyoto Pharmaceutical University, Kyoto, Kyoto, Japan
2Department of Medicinal Biotechnology, Institute for Medicinal Research, Graduate School of Pharmaceutical Sciences, Tokushima University, Tokushima, Tokushima, Japan

 Sandhoff disease (SD) is an inherited lysosomal storage disease caused by a β-hexosaminidase deficiency involving excessive accumulation of undegraded substrates, including GM2 ganglioside, which leads to neurological symptoms, such as mental retardation, spasms and quadriplegia. Macrophage inflammatory protein-1α (MIP-1α) is a crucial factor for microglia-mediated neuroinflammation in the onset or progression of SD. However, there was no therapeutic approach to control the abnormal production of MIP-1α in the brain of SD, and the mechanisms underlying the MIP-1α production by microglia, especially the transmitter-mediated production, remains unclear.

Extracellular nucleotides, including uridine diphosphate (UDP), are leaked by injured or damaged neurons. It has been shown that the nucleotide leakage activates microglia to trigger chemotaxis, phagocytosis, macropinocytosis and cytokine production, suggesting that extracellular nucleotides may be important neurotransmitters for microglia to regulate their functions physiologically and pathologically.

In the present study, we review the essential roles of extracellular nucleotides in the microglial functions and the UDP-enhanced MIP-1α production by microglia in SD model mice, providing a potential therapeutic approach for SD.

DOI: 10.29245/2572.942X/2016/7.1074 View / Download Pdf

Alexandra E. Oxford, Cheryl L. Jorcyk, Julia Thom Oxford*

Boise State University, Department of Biological Sciences, Biomolecular Research Center, 1910 University Drive, Boise State University, Boise, ID 83725

 Stüve-Wiedemann syndrome (STWS; OMIM #610559) is a rare disease that results in dysfunction of the autonomic nervous system, which controls involuntary processes such as breathing rate and body temperature. In infants, this can result in respiratory distress, feeding and swallowing difficulties, and hyperthermic episodes. Individuals may sweat excessively when body temperature is not elevated. Additionally, individuals have reduced ability to feel pain and may lose reflexes such as the corneal reflex that normally causes one to blink, and the patellar reflex resulting in the knee-jerk. STWS usually results in infant mortality, yet some STWS patients survive into early adulthood. STWS is caused by a mutation in the leukemia inhibitory factor receptor (LIFR) gene, which is inherited in an autosomal-recessive pattern. Most LIFR mutations resulting in STWS cause instability of the mRNA due to frameshift mutations leading to premature stop codons, which prevent the formation of LIFR protein. STWS is managed on a symptomatic basis as no treatment is currently available.

DOI: 10.29245/2572.942X/2016/7.1068 View / Download Pdf

Claudia Barzago1, Pia Bernasconi1, Raffaele A. Calogero2, Carlo Antozzi1, Francesca Zolezzi3, Renato Mantegazza1# and Lucia Mori4*

1Neurology IV - Neuroimmunology and Neuromuscular Diseases Unit, Foundation Neurological Institute "Carlo Besta", 20133 Milan, Italy
2Molecular Biology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy
3GALDERMA R&D, 06902 Sophia Antipolis Cedex, France
4Experimental Immunology, Department of Biomedicine, University Hospital Basel and University of Basel, 4031, Basel, Switzerland

Early-onset acetylcholine receptor-positive myasthenia gravis is the most studied and better-characterized clinical subgroup of myasthenia gravis. Here we discuss the results of the first comprehensive and unbiased transcriptome sequencing analysis performed on circulating cells of a clinically homogeneous cohort of patients affected by this disease form.

DOI: 10.29245/2572.942X/2016/7.1081 View / Download Pdf

Aaron Dadas1,2 Jolewis Washington4, Damir Janigro1,3*

1Flocel Inc., Cleveland, OH, USA
2The Ohio State University, Columbus, OH, USA
3Case Western Reserve University, Cleveland, OH, USA
4John Carroll University, University Heights, OH, USA

The brain is a complex system that requires continual regulation of parenchymal pressure, osmolarity, and waste removal for optimal function; despite this, human brain lacks any obvious extension of lymphatic circulation for moderating fluid and waste regulation. We recapitulate herein a recent analysis of proteinaceous waste deposition in the human brain, its observed route of clearance, and the implications of abnormal accumulation along this clearance pathway as a potential mechanism of neurological diseases. This study uncovered an analogous staining pattern of cerebral phosphorylated tau in temporal lobe epilepsy (TLE) and chronic traumatic encephalopathy (CTE). Regardless of the underlying physiopathology, p-tau elimination occurred via circulation through the perivenous space, as predicted by a glymphatic route of clearance. Remarkably, we demonstrated that p-tau is associated with a neurological disease that can develop independent of head trauma, since in both CTE and TLE: 1) Extracellular p-tau followed unidirectional, fluid-driven pathways that led toward the space bordering large (>100 µm diameter) blood vessels; 2) Tau-positive staining occurred within astroglial cells adjacent to blood vessels, which signified transcellular transport of p-tau as a potential secondary efflux route; 3) P-tau frequently appeared clustered within the perivenous space. This waste aggregation bears significant implications in the disruption of interstitial fluid circulation, which may contribute to exacerbation of disease states. A better understanding of waste elimination in the human brain may prove significant as a therapeutic target to improve parenchymal fluid circulation, and consequently, mitigate the hydrostatic, osmotic and oncotic imbalances that often cause or exacerbate brain diseases.

DOI: 10.29245/2572.942X/2016/7.1082 View / Download Pdf

Víctor Danelon1, Andrea B. Cragnolini1, Daniel Masco1*

1Laboratorio de Neurobiología, Instituto de Investigaciones Biológicas y Tecnológicas, IIByT-CONICET-FCEFyN, Universidad Nacional de Córdoba, Av. Vélez Sarsfield 1611, Córdoba, Argentina.

Several neurological conditions share a characteristic feature: an increase in intracellular calcium levels ([Ca2+]i). It has been demonstrated that calcium influx induces changes ranging from an increase in the expression levels of several genes to the activation of proteases such as calpains. Calpains are a family of Ca2+-dependent non-lysosomal cysteine proteases, whose substrates include several proteins that play critical roles in several cellular functions including synaptic plasticity and neuronal apoptosis.

TrkB is a type of tyrosine related kinase receptor that can promote neuronal survival and differentiation upon ligand binding. It has been recently shown that in several neurological diseases, the level of full-length TrkB protein decreases before the onset of neuronal death due to one of two different processes: a) a reverse regulation of TrkB isoforms mRNA, or b) calpain-mediated processing of TrkB full-length, which yields a truncated form of TrkB (Tc-TrkB). Because the most notorious feature of calpain proteolytic activity is that the products of calpain-mediated cleavage may have biological activity, here we review the hypotheses by which calpain-generated isoform Tc-TrkB may perform biological functions.

DOI: 10.29245/2572.942X/2016/7.1076 View / Download Pdf

Simon Wing Fai Mok, Vincent Kam Wai Wong, Betty Yuen Kwan Law*

State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China

Chronic diseases are the leading causes of physical impairments and mortality in the world. The functional role of autophagy in maintaining cellular homeostasis implies that the molecular machinery is a compelling pharmaceutical target for such disorders involving overall body imbalance. Therefore, autophagy modulators appeared to be the ideal source for hunting of novel and effective pharmaceutical interventions. Law et al., have performed a systematic review on more than 30 different Chinese herbal medicine (CHM)-derived bioactive compounds capable of regulating autophagy activity. The successful experimental and clinical applications of these compounds which have not been previously documented have been discussed. Notably, most of the reported novel applications are associated with chronic dysfunctions.

DOI: 10.29245/2572.942X/2016/7.1070 View / Download Pdf