"Amyotrophic Lateral Sclerosis: From Mutations to Mechanisms and Medicines"
--Robert H. Brown, Jr., MD, DPhil, Massachusetts General Hospital, Charlestown, MA
ALS is an age-dependent, lethal, paralyzing disorder of motor neurons in the brain, brainstem, and spinal cord, with a mean onset at 55 years and mean survival of 3-5 years. The hallmark of ALS at autopsy is atrophy and loss of motor neurons, sometimes with gliosis. About 5-10% of cases are transmitted as an autosomal dominant trait (familial ALS or FALS). On clinical and pathological grounds, FALS is indistinguishable from sporadic ALS (SALS). This suggests that these diseases involve similar pathogenic mechanisms and that a molecular analysis of inherited forms of ALS will provide insight into sporadic ALS. About 25% of familial ALS cases are caused by mutations in the gene for cytosolic, copper/zinc superoxide dismutase (SOD1). Several considerations indicate that the mutant SOD1 molecule is cytotoxic. While the basis for this toxicity is not definitively established, multiple cellular processes are abnormal in the presence of aberrant SOD1 including astroglial glutamate transport, axonal transport, mitochondrial ATP production, and programmed cell death signaling. Other gene defects causing simultaneous degeneration of corticospinal and spinal motor neurons have been identified. The implicated genes include VAPB (a vesicle-associated binding protein), senataxin (implicated in RNA metabolism), dynactin (implicated in axonal transport), and alsin (a multifunctional protein implicated axonal growth). While most cases of ALS are not familial, it remains plausible that normally occurring gene variants heighten ALS risk or modify the disease phenotype. Many putative risk factor genes have been considered, including VEGF, angiogenin, and ApoE. Recently, prospective studies have employed microarray technologies to screen the entire human genome to identify such DNA variants. Insights from genetic studies in FALS and SALS have permitted the generation of animal and cell-based models of ALS pathophysiology. In turn, these have facilitated multiple innovative approaches to develop ALS therapies, including high through-put drug screening, methods of inactivation of mutant genes (e.g., anti-sense oligonucleotides and inhibitory RNA), and novel methods for the delivery of proteins and complex macromolecules to the central nervous system. These considerations prompt a cautious but distinctly optimistic view of prospects for the development of treatments that will significantly attenuate the course of ALS.
Robert H. Brown, Jr., MD, DPhil, is Director of the Day Neuromuscular Research Laboratory at Massachusetts General Hospital (MGH), a staff neurologist at MGH, and Professor of Neurology at Harvard Medical School. Dr. Brown founded the Day Neuromuscular Research Laboratory in 1984 to investigate neuromuscular diseases, including amyotrophic lateral sclerosis and Miyoshi myopathy. His laboratory has focused on studies of gene defects that underlie select neuromuscular diseases and on approaches to understanding their molecular pathogenesis.
Disclosure:
Dr. Brown has received personal compensation for activities with Acceleron, Inc., Link, Inc., Biogen Idec, Genzyme Corporation, AviTx, Inc., and Cytrx, Inc. Dr. Brown has received compensation for serving on the board of directors for Link, Inc. and AviTx, Inc. He has also received royalty payments from Genzyme Corporation and research support from Cytrx, Inc. and Genzyme Corporation."Neural Interfaces to Restore Function"
--John P. Donoghue, PhD, Brown University, Providence, RI
Neurotechnology is an emerging field that is beginning to provide a range of new devices to treat nervous system disorders. Tens of thousands have already received neural interface technologies to treat symptoms of epilepsy and Parkinson's disease. While systems that sense neural signals are in early stages of development, they promise to provide a means to restore independence, communication, and, potentially, movement. In paralyzing disorders such as spinal cord injury, stroke, and ALS, a neural interface system can provide a physical means to restore communication links from the brain to the body or to assistive technologies. Early-stage clinical trials of a pilot human neural interface system, called BrainGate (Cyberkinetics Neurotechnology Systems, Inc.), indicate that individuals with paralysis can use neural activity from the motor cortex as a control signal to operate assistive technologies. The system is based upon a 4x4 mm intracortically implanted array of 100 microelectrodes that detect neural activity patterns. Signal processors located outside the body derive movement intent from neural patterns to generate a command signal that can then be used to operate technologies such as a computer, robotic hand, or powered wheelchair. Neural interface systems have the potential to significantly modify the lives of individuals with paralysis. The multi-electrode sensor itself also appears to provide a sensitive means to monitor neural function that could be useful in a range of other neurological conditions as well.
John P. Donoghue, PhD, is the Henry Merritt Wriston Professor at Brown University and director of the Brain Science Program at Brown University. Donoghue is a shareholder, director, and chief scientific officer of Cyberkinetics Neurotechnology Systems, Inc.
Disclosure:
Dr. Donoghue has received personal compensation for activities with Cyberkinetics. Dr. Donoghue has served as an investigator for Cyberkinetics and holds stock and/or stock options in Cyberkinetics."Progranulin Mutations in FTDP-17: Genetic and Clinical Implications"
--Michael Hutton, PhD, Mayo Clinic, Jacksonville, FL
We recently demonstrated that mutations in Progranulin (PGRN) cause MAPT-negative FTDP-17. All pathogenic mutations in PGRN identified to date create functional null alleles implying that they cause disease by producing a deficiency of PGRN. However, the role of PGRN in neuronal survival and the explanation for why partial loss of this factor causes adult-onset neurodegenerative disease remains uncertain. What is known is that PGRN has been consistently implicated in the mechanism of wound repair. It is therefore likely significant that PGRN is upregulated in activated microglia in response to the development of multiple neurodegenerative diseases including Alzheimer's disease. In addition, the dramatic accumulation of PGRN in dystrophic neurites surrounding senile plaques suggests that PGRN is involved in the localized brain response to amyloid deposition in AD. However, whether PGRN is critical to the mechanism of brain repair and whether deficiency in this process is responsible for the development of FTD in patients with PGRN mutations remains to be determined.
Michael Hutton, PhD, is a professor in neuroscience and associate professor of biochemistry at the Mayo Clinic, Jacksonville, FL.
Disclosure:
Dr. Hutton has nothing to disclose."Waking up to Sleep: Implications for Neurology"
--Clifford B. Saper, MD, PhD, FAAN, Beth Israel Deaconess Medical Center, Boston, MA
We spend nearly one-third of our lives asleep. Recent years have seen major advances in our understanding of the brain circuitry that controls the transitions between sleep and wakefulness. A key advance in understanding sleep regulation has been the demonstration that the brain circuitry that controls sleep is organized as a series of flip-flop switches. A flip-flop switch is one in which each side inhibits the other. Electrical engineers design these switches into circuits that must make rapid
transitions between either an "on" or "off" state. This is empirically the way sleep works as well, with suddenly "falling" asleep, and rapidly snapping to wakefulness.
Recent studies have defined two flip-flop switches that control sleep. The first switch consists of the interactions between the ascending arousal systems, which keep the forebrain awake, and a sleep master-switch, the ventrolateral preoptic nucleus (VLPO). The second flip-flop switch controls the transitions between slow-wave (or non-REM) and REM (rapid eye movement) sleep. These switches can help us understand several very puzzling neurological disorders, such as narcolepsy and REM behavior disorders (RBD). Understanding these relationships will allow us to target new therapies for these conditions. Furthermore, RBD may be one of the earliest signs of parkinsonian disorders, and may allow us to identify a cohort of patients for neuro-protective therapy years before the motor disorders appear.
Clifford B. Saper, MD, PhD, FAAN, is the James Jackson Putnam Professor of Neurology and Neuroscience, Harvard Medical School Chair, Harvard Department of Neurology, Beth Israel Deaconess Medical Center, Boston.
Disclosure:
Dr. Saper has received personal compensation for activities with Merck & Co., Inc., sanofi-aventis Pharmaceuticals, Inc., Sepracor, and NuraPharmaceuticals. Dr. Saper has received personal compensation in an editorial capacity for the Journal of Comparative Neurology and has received research support from the National Institutes of Health and Merck & Co., Inc.
"Inhibition of B Cell Functions: Implications for Neurology"
--Marinos C. Dalakas, MD, FAAN, National Institutes of Health, Bethesda, MD
B cells are involved in the pathophysiology of many neurological diseases, either in a causative or contributory role, via production of autoantibodies, cytokine secretion, or by acting as antigenpresenting cells leading to T cell activation. B cells are clonally expanded in various CNS disorders, such as multiple sclerosis, paraneoplastic CNS disorders, or stiff-person syndrome and are activated to produce autoantibodies in demyelinating neuropathies and myasthenia. BAFF, a key cytokine for B cell survival, strongly unregulated in MS brain and in muscles of inflammatory myopathies. Modulation of B cell functions using monoclonal antibodies against CD20+ B cells or the molecules that increase B cell survival, such as BAFF/APRIL and their receptors BAFF-R, TACI and BCMA, provide a rational approach to the treatment of the aforementioned neurological disorders.
The first completed controlled studies using Rituximab, a B cell-depleting monoclonal antibody, showed encouraging results in MS and paraproteinemic anti-MAG demyelinating neuropathy. Up to 65% of patients with MAGneuropathy, which is unresponsive to all therapies, improved after eight months, sometimes with long-lasting remissions. B cell depletion is a well-tolerated therapeutic option that requires further testing in autoimmune neurological disorders. The excellent safety profile of Rituximab suggests that, in spite of prolonged peripheral B cell depletion, the immune system has the plasticity to compensate for the deleted cells.
Marinos C. Dalakas, MD, FAAN, is chief of the Neuromuscular Diseases Section of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health in Bethesda, Maryland.
Disclosure:
Dr. Dalakas has nothing to disclose."Genetic Correlates of Brain Aging on MRI and Cognitive Test Measures: Genome Wide Associated Analysis in the Framingham Heart Study"
--Sudha Seshadri, MD, Boston University, Boston, MA
Age-related neurological diseases represent a substantial societal burden, and one in three persons now aged 65 will develop stroke or dementia in their lifetime. Only a few genes have been identified that increase the risk of stroke or dementia in the community. Two challenges to a more complete understanding of the genetic basis of these age-related brain diseases are the late phenotypic manifestation of these conditions and their polygenic mode of inheritance. Multiple genes interacting with each other and with environmental factors likely create complex gradients of susceptibility to disease. One novel approach is to relate genetic variation to quantitative subclinical markers of stroke and dementia risk in middle-aged adults. Recently, volumetric brain MRI and standardized cognitive tests have been used to define such heritable endophenotypes.
We performed genome-wide association analyses to explore the genetic basis of these endophenotypes in a comprehensive manner within a community-based sample of middle-aged to elderly adults. Our data identified novel genes, and also implicated some genes previously associated with clinical disease, as possible determinants of brain structure and function in a middle-aged population free of clinical disease. Our findings do require replication in other cohorts. Similarly, our database will serve as a resource for examining findings observed in other population samples, and in animal models of brain aging, stroke, and neurodegenerative diseases.
Sudha Seshadri, MD, is an assistant professor of neurology at the Boston University School of Medicine, and co-director of medical education for the residency program and an investigator at the Framingham Heart Study.
Disclosure:
Dr. Seshadri has nothing to disclose.DISCUSSANT
--John A. Hardy, PhD, National Institutes of Health, Bethesda, MD
John A. Hardy, PhD, was born in Nelson in northern England in 1954 and studied Biochemistry at Leeds University, followed by a PhD in Neurochemistry at Imperial College London in 1979. He did postdoctoral training at the MRC Neuropathogenesis Unit in Newcastle from 1979 to 1983 followed by two years working at the Swedish Brain bank in Umea. He returned to England in 1985 to join the faculty at Imperial College. He left England to take a Professorship at the University of South Florida in 1991, and then a Professorship at the Mayo Clinic in 1996 where he was the founding Chair of the Department of Neuroscience in 1999. He moved to the NIH in 2000. He has won the Allied Signal, the MetLife, the Peter Debye, the Potamkin, and the Kaul Prizes for his work dissecting the genetic causes of the dementias.
Disclosure:
Dr. Hardy has nothing to disclose."The Neurochemical Aftermath of Amateur Boxing"
--Max Albert Hietala, MD, PhD, Sahlgrenska University, Göteborg, Sweden
For this study, we wanted to determine whether amateur boxing and severity of hits are associated with elevated levels of biochemical markers for neuronal injury in cerebrospinal fluid (CSF). Despite the high prevalence of brain damage as a result of professional boxing, there is little solid information available on the possible risks for neuronal injury in amateur boxing. A total of 14 amateur boxers (11 men and three women) were enrolled in a longitudinal study conducted at a referral center specialized in evaluation of neurodegenerative disorders. The boxers underwent lumbar puncture (LP) 7?10 days and three months after their bouts. The study also included 10 healthy male non-athletic control individuals who underwent LP once. Increased CSF levels was significantly higher among boxers who had received many (greater than 15) or high impact hits to the head compared with boxers who reported few hits. Neurofilament light protein (NFL) and glial fibrillary acidic protein (GFAP), but not total tau, were significantly elevated after bout compared with the non-athletic control subjects. With the exception of NFL, there were no significant differences between boxers after three months of rest from boxing and the non-athletic control subjects. Amateur boxing is associated with acute neuronal and astroglial injury. If verified in longitudinal studies with extensive follow-up regarding the clinical outcome, CSF analyses may provide a scientific basis for medical counseling of athletes after boxing or head injury.
Max Albert Hietala, MD, PhD, is a neurologist at the Department of Neurology at Sahlgrenska University Hospital, Göteborg, Sweden. He is also a researcher at the Institute for Clinical Neurosciences and Physiology at Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
Disclosure:
Dr. Hietala has nothing to disclose.DISCUSSANT
--James P. Kelly, MA, MD, FAAN, University of Colorado, Denver, CO
James P. Kelly, MA, MD, FAAN, a Chicago native, graduated cum laude from Western Michigan University in 1974 with a major in psychology and minor in chemistry before obtaining his MA in 1977, also at WMU, in clinical psychology. After working as a psychologist for two years, Dr. Kelly attended medical school at Northwestern University from 1979 to 1983 and completed his neurology residency and behavioral neurology fellowship at the University of Colorado where he began his academic career in 1988. He returned to his hometown in 1993 as Director of the Brain Injury Program at the Rehabilitation Institute of Chicago. After 10 years on the faculty of Northwestern University in Chicago, Dr. Kelly returned to Denver where he is Visiting Professor of Neurosurgery and Rehabilitation Medicine at the University of Colorado School of Medicine and Coordinator of Health Professions Continuing Education at the Colorado Area Health Education Center System.
Dr. Kelly is a Fellow of the American Academy of Neurology and an Examiner for the American Board of Psychiatry and Neurology. He is President of the Colorado Society of Clinical Neurologists. He is the Editor-in Chief of the American Academy of Neurology's publications AANnews and AANe-news, past member of the Board of Governors of the International Brain Injury Association, and a past member of the Board of Directors of the Brain Injury Association of America. Dr. Kelly has participated on advisory boards at the Mayo Clinic, at the Institute of Medicine in Washington, DC, and at the Centers for Disease Control. His past positions include Assistant Dean for Graduate Medical Education at the University of Colorado School of Medicine, and Neurology Residency Program Director at Northwestern University.
He continues his work in all aspects of traumatic brain injury research and clinical care, and has served on the panel of speakers at the 'First International Symposium on Concussion in Sport' in Vienna in 2001 and the 'Second International Symposium on Concussion in Sport' held in Prague in 2004 which were co-sponsored by the International Ice Hockey Federation (IIHF), the International Olympic Committee (IOC), and the Federacion Internationale de Football Associations (FIFA). He was the lead author of the Colorado and American Academy of Neurology Guidelines for the Management of Sports Concussion, and a co-author of the Standardized Assessment of Concussion (SAC) which is the most widely used sideline mental status test in sports. He co-authored works on vegetative state/minimally conscious state/coma, and has an academic interest in the determination of brain death. His scientific publications and editorials have appeared in numerous medical journals, and he is invited to speak on a variety of neurological topics across the United States and abroad. Dr. Kelly is the consulting neurologist to the National Hockey League Players Association and to the Aspen Skiing Company, and maintains an active outpatient and inpatient practice at the University of Colorado Hospital.
Disclosure:
Dr. Kelly has nothing to disclose."Secondary Analysis of Hemorrhagic Stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study"
--Larry B. Goldstein, MD, FAAN, Duke University, Durham, NC
In SPARCL, atorvastatin 80 mg/day (n=2365) reduced fatal and non-fatal stroke risk in patients with recent stroke or TIA by 16% (hazard ratio, HR, 0.84, 95% CI 0.71 to 0.99, p=0.03) vs. placebo (n=2366), a result that included a small increase in the numbers of patients having hemorrhagic stroke (n=55 for active treatment vs. n=33 for placebo, HR, 1.68, 95% CI 1.09 to 2.59).
This post-hoc analysis explores the relationships between baseline patient characteristics, most recent blood pressure and LDL-cholesterol levels, and the risk of hemorrhagic stroke.
Of 4,731 patients, 66% had ischemic stroke, 30% TIA, and 2% hemorrhagic stroke as entry events. Cox regression models, including baseline factors, showed that, in addition to atorvastatin treatment, the risk of brain hemorrhage was greatest in those with brain hemorrhage as an entry event, increased with age, and was higher in men. These risks did not differ by treatment group. Controlling for these factors, there was no relationship between recent LDL-C level and hemorrhage risk in atorvastatin-treated patients. Those with Stage 2 hypertension prior to the hemorrhagic stroke were at higher risk, reinforcing the need for aggressive blood pressure control.
Larry B. Goldstein, MD, FAAN, is a professor of medicine (neurology) at Duke University and the Durham VA Medical Center, director of the Duke Center for Cerebrovascular Disease, and a senior fellow in Duke's Center for Clinical Health Policy Research.
Disclosure:
Dr. Goldstein has received personal compensation for activities with Pfizer Inc, Atorvastatin, Johnson & Johnson, Bristol-Myers Squibb/Sanofi~Synthelabo Partnership, and Organon Tibolone. Dr. Goldstein has received personal compensation in an editorial capacity for Emergency Medicine and MedCirca Clinical Updates, and has received research support from Pfizer Inc, National Institutes of Health, Dept. of Veterans Affairs, UNC Chapel Hill/CDC, AGA, Boehringer Ingelheim Pharmaceuticals, Inc., and Bristol-Myers Squibb Company.DISCUSSANT
--Bruce I. Ovbiagele, MD, University of California, Los Angeles, CA
Bruce I. Ovbiagele, MD, a board-certified vascular neurologist, is actively involved in research geared at discovering effective vascular risk reduction therapies in stroke, and developing innovative strategies for optimizing the adherence to proven secondary stroke prevention therapies. Dr. Ovbiagele is Director of the Olive View-UCLA Stroke Program, and an Assistant Professor of Neurology at University of California, Los Angeles.
Dr. Ovbiagele heads the UCLA Stroke Prevention Program, part of which comprises the UCLA PROTECT (Preventing Recurrent Thromboembolic Events through Co-ordinated Treatment) initiative: a novel hospital-based quality improvement project geared at enhancing the utilization of evidence-based medication and behavioral interventions known to reduce the risk of stroke. The results of the successful execution of this program, and its impact on longer-term patient adherence post-stroke, have been published in several journals.
Dr. Ovbiagele was Co-Chair of the 2006 NIH Stroke Progress Review: Prevention of First and Recurrent Stroke Working Group. He serves on several American Stroke Association (ASA) committees at the local, state, and national levels, and is a member of the American Heart Association (AHA) Stroke Advisory Committee, a leadership body within the AHA, which advises the AHA on national stroke policy and advocacy issues. He is also a national spokesperson for the AHA, and is involved in conveying the implications of important new stroke studies to the general public through the media. Most recently, he became national medical spokesperson for the ASA "Power to End Stroke" campaign, which is an aggressive educational campaign geared at raising awareness about the warning signs, prevention, and treatment of stroke in the African American community.
Dr. Ovbiagele serves as the Principal Investigator for two translational studies (clinical research to clinical practice), and a trial looking at the effects of intensive statin therapy on carotid plaque morphology. He is also the site Principal Investigator for a NINDS-funded stroke prevention study, a large-scale industry-sponsored secondary stroke prevention study, as well as a co-investigator in several multi-center trials in acute stroke treatment and stroke imaging. Dr. Ovbiagele has authored or co-authored over 60 peer-reviewed publications, and over 75 abstracts. He is an Editorial Consultant for The Lancet, and has served as a reviewer for The Lancet, Lancet Neurology, Stroke, Neurology, Annals of Neurology, Nature Reviews Neuroscience, European Journal of Neurology, Acta Neurologica Scandinavica, Neurotherapeutics, and abstracts for the American Stroke Association International Stroke Conference. Dr. Ovbiagele has also reviewed research grants for the National Institute for Neurological Disorders and Stroke (NINDS), American Heart Association (AHA), National Institute for Health Research of the United Kingdom Department of Health, and Health Research Board of Ireland.
Disclosure:
Dr. Ovbiagele has received personal compensation for activities with sanofiaventis Pharmaceuticals, Inc., Boehringer-Ingelheim Pharmaceuticals, Inc., and Briston-Myers Squibb Company and has received research support from sanofi-aventis Pharmaceuticals, Inc."Sodium Channels as Targets for Pain Management: Lessons from Inherited Pain Syndromes"
--C. Geoffrey Woods, MD, Cambridge University, Cambridge, United Kingdom
C. Geoffrey Woods, MD, trained in pediatrics in the UK, carried out research into recessive causes of neurodegeneration, and changed direction to become a Clinical Geneticist. He has worked in Melbourne-Australia, Leeds, and currently Cambridge in the UK. He is employed half time as a Clinical Geneticist, with a particular interest in neurodevelopmental disorders and the diseases of consanguineous populations. The other half of his time is spent on finding human neurodevelopmental disease genes controlling fetal brain size and pain appreciation.
Disclosure:
Dr. Woods has nothing to disclose."Idebenone Treatment for Friedreich's Ataxia"
--Kenneth H. Fischbeck, MD, FAAN, National Institutes of Health, Bethesda, M
Kenneth H. Fischbeck, MD, FAAN, received AB and AM degrees from Harvard University and an MD degree from Johns Hopkins. After a medical internship at Case Western Reserve University and a neurology residency at the University of California in San Francisco, he did postdoctoral research on muscular dystrophy at the University of Pennsylvania. In 1982, he joined the faculty in the Neurology Department at the University of Pennsylvania Medical School, advancing in academic rank to Professor of Neurology in 1995. In 1998, he moved to the National Institutes of Health as Chief of the Neurogenetics Branch at the National Institute of Neurological Disorders and Stroke. He has received the Cotzias Award from the American Academy of Neurology and the Jacoby Award from the American Neurological Association and was elected to the Institute of Medicine of the National Academy of Sciences. His research group has identified the genes for a series of hereditary neuromuscular and neurological disorders, and it is currently studying the disease mechanisms and working to develop treatment for the polyglutamine expansion neurodegenerative diseases, muscular dystrophies, hereditary neuropathies, Friedreich's ataxia, and spinal muscular atrophy.
Disclosure:
Dr. Fischbeck has nothing to disclose."How Should We Treat the Patient with Persistent Painful Lumbosacral Radiculopathy?"
--J. D. Bartleson, MD, FAAN, Mayo Clinic, Rochester, MN
J. D. Bartleson, MD, FAAN, graduated from the six-year Honors Program in Medical Education at Northwestern University and received an MD in 1971. After completing an internship at Evanston Hospital, he trained in neurology under Dr. Russell N. DeJong at the University of Michigan from 1972 through 1975. Dr. Bartleson served as a major in the Army and Head of Neurology at Ireland Army Hospital, Fort Knox, KY, from 1975 through 1977. He has been at the Mayo Clinic in Rochester, MN, since 1977.
Dr. Bartleson was certified by the American Board of Psychiatry and Neurology in neurology in 1976, in the subspecialty of pain medicine in 2003, and in the subspecialty of headache medicine in 2005. He holds medical licenses in Arizona, Florida, and Minnesota. He is a Fellow of the American Academy of Neurology and a member of the American Neurological Association.
Dr. Bartleson is currently Associate Professor of Neurology in the Mayo Clinic College of Medicine. He has served in many administrative roles at the Clinic and in state and national organizations. Although he is a full-time clinician, he has published on a broad range of topics. Most of his work has been on migraine, migraine-like headaches, and spine disease including lumbar spinal stenosis and the cauda equina syndrome in long-standing ankylosing spondylitis. With Mayo colleagues, he first described the syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL) and the syndrome of stroke-like migraine attacks after radiation therapy (SMART). Dr. Bartleson's research interests include migraine and other complicated headache disorders, neurologic manifestations of spine disease, and evidence-based evaluation and treatment of headache and spine and limb pain.
Disclosure:
Dr. Bartleson has nothing to disclose."Parkinson's Disease: Beyond the Decade of the Brain"
--Anthony E. Lang, MD, FAAN, Toronto Western Hospital, Toronto, Ontario, Canada
The AAN ushered in the "Decade of the Brain" with a plenary lecture on Parkinson's disease. Since then, almost 14,000 papers have been published on the topic reporting important advances but also critical disappointments. The great enthusiasm engendered by the serendipitous discovery of MPTP encouraged the belief that further environmental causative exposures would be discovered. However, although providing tantalizing clues, extensive epidemiological studies have failed to live up to expectations. Important breakthroughs have been made on the genetic front but these have yet to impact on therapy. So far, efforts based on genetic and other mechanisms (e.g., mitochondrial dysfunction and oxidative stress) have fallen short of producing the sorely needed progressive animal model more representative of the human disease. The past two decades have seen important advances in our basic knowledge; however, our ongoing challenge is to translate these into interventions that will have greater impact on the many features that remain refractory to current therapy.
Anthony E. Lang, MD, FRCPC, FAAN, is Professor and Director of the Division of Neurology at the University of Toronto and Director of the Movement Disorders Center at the Toronto Western Hospital, which has developed into the largest Movement Disorders Clinic in Canada and one of the most reputable units in the world for the investigation, assessment, and treatment of patients with movement disorders. He is the Jack Clark Chair for Parkinson's Disease Research at the University of Toronto and a Fellow of the American Academy of Neurology. In 2004, Dr. Lang received the AAN Movement Disorders Research Award. Dr. Lang's research has included clinical studies of poorly recognized neurological disorders; clinical trials of new therapeutic modalities; and collaborative basic and clinical studies involving molecular biology, neurophysiology, neuropsychology, and imaging. He has published over 300 peerreviewed papers, was a founding member and initial Executive Committee member of the Parkinson Study Group (PSG) and CoEditor-in-Chief of the international journal Movement Disorder, and is the current President of the international Movement Disorder Society (MDS).
Disclosure:
Dr. Lang has received personal compensation for activities with Amgen Inc, Novartis, Boerhinger Ingelheim Pharmaceuticals, Inc., Pfizer Inc, GlaxoSmithKline, Inc., Teva Neuroscience, Solvay S.A., Neose, Biogen Idec, Valeant Pharmaceuticals International, Vernalis, and Medtronic, Inc. Dr. Lang has received research support from Novartis, Amgen Inc, Boerhinger Ingelheim Pharmaceuticals, Inc., AstraZeneca Pharmaceuticals, and Medtronic, Inc."Channels, Genes, Hormones, and Migraine"
--Michael A. Moskowitz, MD, FAAN, Massachusetts General Hospital, Charlestown, MA
The molecular and cellular origins of migraine headache are among the most complex problems in contemporary neurology. To meet these challenges, researchers have successfully applied the tools of neuroimaging, neurogenetics, neuropharmacology, and neurophysiology. With recent advances, we now have a clearer description of cellular events that characterize the migraine visual aura such as cortical spreading depression, and emerging knowledge about how these events promote the development of headache. This presentation will review translational advances with special emphasis on the evidence implicating genes regulating ion channels and pumps, sex hormones, and migraine prophylactic drugs as modulators of cortical spreading depression. The translational relevance and congruence of this body of work to the phenotype of common forms of migraine will be discussed.
Michael A. Moskowitz, MD, MSc (Hon), FAAN, is Professor of Neurology at Harvard Medical School and an affiliate in the Harvard-MIT Division of Health Science & Technology. His research interests focus on translational mechanisms of importance in migraine and stroke. He is board certified in internal medicine as well as in neurology and psychiatry, and his bibliography includes 430 scientific publications. Dr. Moskowitz is listed among the most highly cited scientists in neuroscience. He holds more than a dozen patents and is Director of Stroke and Neurovascular Regulation Laboratory at MGH. He trained more than 90 postdoctoral fellows and served as thesis advisor to six PhD candidates at MIT and Harvard Medical School. Among his awards are: the KJ Zülch Prize from the Max Planck Society; Thomas Willis Award, American Stroke Association; Decade of the Brain Lecture, American Academy of Neurology; the Ottorino Rossi Award; Bristol-Myers Research Award in Pain and Neuroscience; Soriano Lecturer, American Neurological Association; and the 2007 recipient of the William Silen Award for Lifetime Achievement in Mentoring from Harvard Medical School. He served as president of the International Society for Cerebral Blood Flow and Metabolism and is the incumbent President of the International Headache Society. He serves as Associate Editor, Basic Science, for the journal Stroke.
Disclosure:
Dr. Moskowitz has received personal compensation from activities with Astra-Zeneca, personal compensation for his role as basic science editor for Stroke, compensation in the form of stock options as the founder of Contego Pharmaceutcals, and personal compensation in the form of royalties from Massachusetts General Hospital."The Alzheimer-Frontotemporal Spectrum:A Molecular Approach"
--Christine Van Broeckhoven, PhD, DSc, University of Antwerp, Antwerp, Belgium
In the last three decades, molecular genetic techniques have contributed significantly to the unraveling of biological mechanisms underlying neurological diseases. While initial efforts were directed towards finding genes for pure genetic diseases, later the same technologies were used for complex multifactorial diseases like in aging man. Here the disease results from the interplay of genetic and environmental factors; however, in some very rare families the disease is also inherited as a monogenic trait. Therefore, the first results were obtained in these pure genetic forms. For the majority of patients with the complex form of disease, however, not many susceptibility genes have been identified. One reason is likely that each one of these genetic variants contributes a small fraction of the risk and that not yet the right instruments are available for finding these small effects contributed by several distinct genes.
For the first time in almost 20 years, molecular and epidemiological geneticists are aiming at identifying the genetic variations that underlie the disease process. I will focus on recent genotype-phenotype correlative studies in presenile frontotemporal dementia complex of disorders, including studies on the primary genetic role of the microtubule associated protein tau in the frontotemporal dementia complex of disorders and the potential role of tau in tau-negative frontotemporal dementia.
Christine Van Broeckhoven, PhD, DSc,
is a professor in molecular biology and genetics at the University of Antwerp; scientific director of the Department of Molecular Genetics of VIB, group leader of the department's Neurodegenerative Brain Diseases Group; and research director of the Laboratory of Neurogenetics at the Institute Born-Bunge. Her team specializes in the molecular genetics of Alzheimer's disease, frontotemporal dementia, and Parkinson's disease. Dr. Van Broeckhoven has been awarded several scientific prizes for her molecular genetics work including the Potamkin Prize, the five-yearly Joseph Maisin Prize by the Belgian Fund for Scientific Research, the Belgian Honor Award, and the International Award for Women in Science by L'Oréal/UNESCO. She is a member of the Royal Flemish Academy of Sciences and the Arts of Belgium and in 2006 was honored by the King of Belgium with the title of Grand Officer in the Order of Léopold.Disclosure:
Dr. Van Broeckhoven has nothing to disclose."Autonomic Neuropathy: Progress in Pathogenesis and Treatment"
--Phillip A. Low, MBBS, MD, FRACP, FRCP (Hon), FAAN, Mayo Clinic, Rochester, MN
Autoimmune autonomic ganglionopathy (AAG) typically consists of severe generalized sympathetic and parasympathetic autonomic failure. The most common manifestations are orthostatic hypotension (OH), anhidrosis, and neurogenic bladder and bowel involvement. An autoimmune pathogenesis is suggested by the demonstration of ganglionic nicotinic acetylcholine receptor (3 AChR) antibodies in high titers in about 50 percent of patients, and a correlation between severity and antibody levels. Immunization of rabbits with an 3 AChR subunit fusion protein leads to production of these antibodies, and these rabbits develop experimental AAG. It has been possible to passively transfer experimental autoimmune autonomic neuropathy from the rabbit to mice and reproduce key features of AAG. Recently, it has also been possible to demonstrate direct effects of IgG from patients with AAG on the function of ganglionic AChR.
Midodrine, the only approved drug to treat OH, increases supine BP more than it improves OH. Pyridostigmine, by enhancing ganglionic transmission, could potentially ameliorate OH without worsening supine hypertension. We demonstrated efficacy in an open study and followed this with an inpatient double-blind, randomized four-way cross-over study of pyridostigmine in 58 patients with neurogenic OH. No significant differences were seen in the supine BP measures. Diastolic BP decrement was significantly reduced (p=0.023) with treatment (pyrido, p0.040 and pyrido +5, p=0.002). Enhancement of ganglionic neurotransmission appears to be important in both sympathetic and parasympathetic ganglia. In a study of 18 patients with POTS, we demonstrated that 60 mg pyridostigmine significantly improved orthostatic symptoms, orthostatic tachycardia, orthostatic norepinephrine increment, and baroreflex sensitivity. Improvement in symptoms paralleled improvement in heart rate.
Phillip A. Low, MBBS, MD, FRACP, FRCP (Hon), FAAN, is the Robert D. and Patricia E. Kern Professor of Neurology at the Mayo Clinic College of Medicine. He heads the Mayo Autonomic Laboratory and is Director of the Autonomic Disorders Program Project. Dr. Low is board certified in Neurology and Clinical Neurophysiology and is the author of over 300 publications and three books, including Clinical Autonomic Disorders. His research and academic pursuits include: pathophysiology of autonomic disorders, development of autonomic function tests in humans, treatment of autonomic failure, peripheral nerve ischemia and oxidative injury, and mentorship.