Parkinson's: Thinking Outside the Brain's Black Box 8 July 2011

Total Page:16

File Type:pdf, Size:1020Kb

Parkinson's: Thinking Outside the Brain's Black Box 8 July 2011 Parkinson’s: Thinking Outside the Brain’s Black Box 8 July 2011. When a German anatomist first proposed in 2003 that Parkinson’s disease (PD) begins in the gut, then slowly makes its way to the brain and spreads to different regions, his idea might have sounded like fiction. But when he and a collaborator then added that a pathogen, possibly a virus, sneaks its way into the nervous system simultaneously from the nose and gut to set off the disease process, the hypothesis became downright fantastic. After all, conventional wisdom viewed Parkinson’s as degeneration of the substantia nigra, that black-pigmented sliver of the brain. But less than a decade later, the hypothesis is gaining ground, as ongoing studies provide clues in its support. If successful, these new investigations could upend long-held views about how Parkinson’s develops. In the past decade, neuroanatomists Heiko Braak and Kelly Del Tredici, both currently at the University of Ulm in Germany, published a series of papers describing the distribution of Lewy bodies—those protein aggregates that are the hallmarks of the pathology of PD—in the central and peripheral nervous systems of deceased patients. To detect these lesions, they used an antibody to α-synuclein, the main protein component of these aggregates. α-synuclein is a normal protein found in many types of nerve cells, but something about the disease process of PD causes the protein to misfold and, as a result, clump together inside the cells. Based on painstaking observations of hundreds of tissue samples, Braak and colleagues initially proposed that the α-synuclein pathology progresses in predictable stages defined by its distribution. The pathology advances from the peripheral nervous system to the brainstem, and from there upward to the midbrain and to higher brain regions, following paths laid out by connecting neurons. This staging system resonates with that described previously by Braak and colleagues for Alzheimer’s disease ( Braak and Braak, 1991 and online seminar by H. Braak ). The pathology associated with Parkinson’s disease progresses from the peripheral nervous system to the brainstem, and from there it advances to the midbrain and higher brain regions. Image credit: H. Braak and K. Del Tredici “The breakthrough in the field was that they proposed that the process starts nowhere near the substantia nigra,” says John Duda of the Philadelphia Veteran’s Affairs Medical Center. Up until then the substantia nigra, located in the midbrain or mesencephalon, had been the main focus of PD research. The motor symptoms that constitute the diagnosis of the disease—tremor, rigidity, slowness of movement or instability while standing up— are thought to result from the loss of dopamine-producing brain cells in this region and subsequent lack of transmitter input into the striatum, an important motor control area. Current medicines for PD typically consist of the dopamine precursor levodopa and dopamine agonists, but these treatments lose effectiveness over time. Despite the focus on the substantia nigra, most PD patients have additional, non-motor symptoms, and PD is coming to be understood as a much broader disease. Chronic constipation, loss of smell, and REM sleep disorders often occur before the motor problems ( O’Sullivan et al., 2008 and ARF related news story ). A large epidemiological study, the Honolulu-Asia Aging Study, showed that men who reported less frequent bowel movements had a significantly higher risk of developing PD within the next 24 years ( Abbott et al., 2001 ; Abbott et al., 2003 ). One of the attractive features of Braak’s staging scheme is that the areas of the nervous system littered with Lewy bodies at the earliest stages of disease could account for these non-motor symptoms. The staging system, wrote Braak in an e-mail to ARF, “has drawn attention to the damage in other transmitter systems—in other words, apart from and before the nigrostriatal system. In addition, it can serve as a framework for relating the pathology in other parts of the nervous system (gastrointestinal tract, spinal cord, and so on) to that in the brain.” What the Data Show In their first paper in 2003 ( Braak et al., 2003 ), Braak, Del Tredici, and colleagues examined postmortem tissues from 168 autopsied patients belonging to one of three groups: 41 patients had been diagnosed with sporadic PD; 69 had no clinical symptoms of PD but had Lewy bodies in their brains; and 58 people had no PD and no evidence of Lewy bodies. Whereas most pathologists use tissue sections that are, at most, 10 microns thick, Braak and colleagues developed a new technique using 100 micron-thick sections, allowing them to visualize pathology over large distances, so that they would not miss any changes that would escape detection in a thinner sample. “Braak is a hugely gifted pathologist,” says Michael Schlossmacher, a neurologist at the University of Ottawa in Canada, echoing a sentiment expressed by most researchers in the field. Using this technique, Braak and colleagues found that, in samples with mild pathology, which Braak called Stage 1, the Lewy bodies are typically confined to the olfactory bulb and the dorsal motor nucleus of the vagus nerve. Because the vagus nerve connects the brain to the enteric nervous system (ENS), the authors proposed that the disease could start in the gut and move along the vagus nerve in an upstream, or retrograde, direction toward the brain. In Stage 2, Lewy bodies continue to ascend into the brainstem, reaching the medulla oblongata and pontine tegmentum, parts of the brainstem that control swallowing, sleep, and other autonomic functions sometimes affected in PD. By Stage 3, pathology starts to show up in the amygdala (an almond-shaped mass of neurons involved in processing fear and other emotions, but also the sense of smell) and in the infamous substantia nigra; this is the stage when the motor phase of the disorder begins. In Stage 4, pathology in areas affected in earlier stages worsens, and Lewy bodies progress to the forebrain and encroach on a portion of the cerebral cortex (the temporal mesocortex), whereas the neocortex, the part of the brain involved in higher functions, remains unaffected. In Stages 5 and 6, the pathology is full blown, appearing initially in the anterior association and prefrontal areas of the neocortex and then spreading to the posterior association areas, which are involved with memory and learning, and planning movement. Defects in these areas could explain many of the cognitive problems associated with advanced PD. “There is no evidence in our material for involvement of the cerebral cortex in the absence of lesions in the brainstem,” reads their 2003 paper published in the Neurobiology of Aging, essentially making the point that pathology rises up from lower to higher regions of the brain as PD gets worse. In a subsequent study, Braak applied his pathology skills to the enteric nervous system (ENS). Earlier work had indicated that Lewy bodies could be detected in the ENS, but those studies had gone largely ignored. “The [sporadic] sPD-associated involvement of the ENS initially reported two decades ago found relatively little resonance in comparison to the literature devoted to lesions in the CNS,” reads their 2006 paper published in Neuroscience Letters ( Braak et al., 2006 ). Braak and colleagues examined five autopsy patients who had Lewy bodies in the CNS—three had been diagnosed with PD and two had no clinical symptoms of the disease. In all five patients, Braak and colleagues found Lewy bodies in both the Meissner’s and Auerbach’s plexus, the two layers that make up the ENS. Because the ENS lesions were found both in PD cases and in asymptomatic individuals who only had Lewy bodies in the lower brainstem, the results confirmed the authors’ view that the disease could start off in the ENS. But Braak and colleagues went further to postulate that the disease could be set off by a yet-unidentified pathogen in the gut ( Braak et al., 2003 ). Then, Braak and Christopher Hawkes, a neurologist now at Barts and The London School of Medicine and Dentistry, U.K., revised this hypothesis to suggest that the pathogen could simultaneously enter the nose, by inhalation, and the gut, by swallowing nasal secretions, and then progress to the brain from two directions, providing a “dual-hit” ( Hawkes et al., 2009 ). Although Hawkes personally favors the explanation that the causative pathogen is a virus, he said it could also be a toxin, bacteria, or any inflammatory agent that causes α- synuclein to misfold and aggregate. Although Lewy bodies have not been found in nasal passages, the olfactory bulb is chock full of these lesions. From there, they could reach the amygdala in the temporal lobe of the brain through forward, or anterograde, motion, hopping across synapses of connecting neurons. At the same time, the pathology starting in the gut would move in a retrograde direction up the motor vagus nerve fibers, reaching the brainstem and then progressing to the amygdala and substantia nigra in Stage 3 of the disease. “These two paths meet up in the temporal lobe of the brain,” said Hawkes. “By that time, the patient is quite ill.” Although Braak and colleagues did not assign a time course to the spread of disease, the process could take several decades to occur. Not Everyone Agrees on the Interpretation While most researchers agree that α-synuclein pathology can be found in many regions of the brain, many have disagreed with Braak’s proposed staging sequence, saying that it does not apply to all patients and questioning its clinical relevance. In addition, certain aspects of the hypothesis, such as its viral origin or its spread, remain speculative.
Recommended publications
  • Spatial and Temporal Relationships Between Plaques and Tangles in Alzheimer-Pathology Bärbel Schönheit, Rosemarie Zarski, Thomas G
    Neurobiology of Aging 25 (2004) 697–711 Open peer commentary Spatial and temporal relationships between plaques and tangles in Alzheimer-pathology Bärbel Schönheit, Rosemarie Zarski, Thomas G. Ohm∗,1 Department of Clinical Cell and Neurobiology, Institute of Anatomy, Charité, 10098 Berlin, Germany Received 10 September 2002; received in revised form 29 July 2003; accepted 17 September 2003 Abstract One histological hallmark in Alzheimer’s disease is the tangle. The other is the plaque. A widely discussed hypothesis is the “amyloid cascade” assuming that tangle formation is a direct consequence of amyloid plaque formation. The aim of this study was to examine plaques and tangles in a highly defined neuronal circuitry in order to determine their detailed spatial and temporal relationships. We investigated serial sections of the whole hippocampal formation of brains with early Braak-stages (0–III) for tangles only, i.e. one case at stage 0, six at stage I, six at stage II, and nine at stage III. Most cases displayed both plaques and tangles. Four cases of stages 0 and I, three cases with stage II, and even one with stage III, however, did not display plaques. In turn, no plaque was found in the absence of tangles. The spatial relationship indicates that plaques lay in the terminal fields of tangle-bearing neurons. Our analysis suggests that tangles either antecede plaques or—less likely—are independently formed. © 2004 Elsevier Inc. All rights reserved. Keywords: Alzheimer’s disease; Amyloid plaques; ␤A4-peptide; Neurofibrillary tangles; Amyloid cascade hypothesis; Hippocampal formation; Hippocampus; Entorhinal cortex; Time course; Braak staging; Anterograde neurodegeneration; Spatial pattern 1.
    [Show full text]
  • BOOK of ABSTRACTS OXFORD ENCALS Meeting 2018
    2018 MEETING 20-22 JUNE 2018 BOOK OF ABSTRACTS OXFORD ENCALS Meeting 2018 Acknowledgements ENCALS would like to thank the following sponsors for their generous support of this year’s meeting. Gold Sponsor Silver Sponsors Bronze Sponsors 2 ENCALS Meeting 2018 Poster Session 1: Wednesday 20th June, 18:00 - 19:30 Entrance Hall: A01 Hot-spot KIF5A mutations cause familial ALS David Brenner* (1), Rüstem Yilmaz (1), Kathrin Müller (1), Torsten Grehl (2), Susanne Petri (3), Thomas Meyer (4), Julian Grosskreutz (5), Patrick Weydt (1, 6), Wolfgang Ruf (1), Christoph Neuwirth (7), Markus Weber (7), Susana Pinto (8, 9), Kristl G. Claeys (10, 11, 12), Berthold Schrank (13), Berit Jordan (14), Antje Knehr (1), Kornelia Günther (1), Annemarie Hübers (1), Daniel Zeller (15), The German ALS network MND-NET, Christian Kubisch (16, 17), Sibylle Jablonka (18), Michael Sendtner (18), Thomas Klopstock (19), Mamede de Carvalho (8, 20), Anne Sperfeld (14), Guntram Borck (16), Alexander E. Volk (16, 17), Johannes Dorst (1), Joachim Weis (10), Markus Otto (1), Joachim Schuster (1), Kelly del Tredici (1), Heiko Braak (1), Karin M. Danzer (1), Axel Freischmidt (1), Thomas Meitinger (21), Tim M. Strom (21), Albert C. Ludolph (1), Peter M. Andersen (1, 9), and Jochen H. Weishaupt (1) Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome.
    [Show full text]
  • Staging of Alzheimer Disease-Associated Neurowbrillary Pathology Using Parayn Sections and Immunocytochemistry
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Springer - Publisher Connector Acta Neuropathol (2006) 112:389–404 DOI 10.1007/s00401-006-0127-z METHODS REPORT Staging of Alzheimer disease-associated neuroWbrillary pathology using paraYn sections and immunocytochemistry Heiko Braak · Irina AlafuzoV · Thomas Arzberger · Hans Kretzschmar · Kelly Del Tredici Received: 8 June 2006 / Revised: 21 July 2006 / Accepted: 21 July 2006 / Published online: 12 August 2006 © Springer-Verlag 2006 Abstract Assessment of Alzheimer’s disease (AD)- revised here by adapting tissue selection and process- related neuroWbrillary pathology requires a procedure ing to the needs of paraYn-embedded sections (5–15 m) that permits a suYcient diVerentiation between initial, and by introducing a robust immunoreaction (AT8) for intermediate, and late stages. The gradual deposition hyperphosphorylated tau protein that can be processed of a hyperphosphorylated tau protein within select on an automated basis. It is anticipated that this neuronal types in speciWc nuclei or areas is central to revised methodological protocol will enable a more the disease process. The staging of AD-related neuroW- uniform application of the staging procedure. brillary pathology originally described in 1991 was per- formed on unconventionally thick sections (100 m) Keywords Alzheimer’s disease · NeuroWbrillary using a modern silver technique and reXected the pro- changes · Immunocytochemistry · gress of the disease process based chieXy on the topo- Hyperphosphorylated tau protein · Neuropathologic graphic expansion of the lesions. To better meet the staging · Pretangles demands of routine laboratories this procedure is Introduction This study was made possible by funding from the German Research Council (Deutsche Forschungsgemeinschaft) and BrainNet Europe II (European Commission LSHM-CT-2004- The development of intraneuronal lesions at selec- 503039).
    [Show full text]
  • Staging of Brain Pathology Related to Sporadic Parkinson's Disease
    Neurobiology of Aging 24 (2003) 197–211 Staging of brain pathology related to sporadic Parkinson’s disease Heiko Braak a,∗, Kelly Del Tredici a, Udo Rüb a, Rob A.I. de Vos b, Ernst N.H. Jansen Steur b, Eva Braak a,† a Department of Clinical Neuroanatomy, J.W. Goethe University, Theodor Stern Kai 7, D-60590 Frankfurt/Main, Germany b Department of Neurology MST Hospital Group and Laboratorium Pathologie Oost Nederland, Burg. Edo Bergsmalaan, 7512 AD Enschede, The Netherlands Received 30 January 2002; received in revised form 23 April 2002; accepted 30 April 2002 Abstract Sporadic Parkinson’s disease involves multiple neuronal systems and results from changes developing in a few susceptible types of nerve cells. Essential for neuropathological diagnosis are ␣-synuclein-immunopositive Lewy neurites and Lewy bodies. The pathological process targets specific induction sites: lesions initially occur in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus. Thereafter, less vulnerable nuclear grays and cortical areas gradually become affected. The disease process in the brain stem pursues an ascending course with little interindividual variation. The pathology in the anterior olfactory nucleus makes fewer incursions into related areas than that developing in the brain stem. Cortical involvement ensues, beginning with the anteromedial temporal mesocortex. From there, the neocortex succumbs, commencing with high order sensory association and prefrontal areas. First order sensory association/premotor areas and primary sensory/motor fields then follow suit. This study traces the course of the pathology in incidental and symptomatic Parkinson cases proposing a staging procedure based upon the readily recognizable topographical extent of the lesions.
    [Show full text]
  • Staging of Brain Pathology Related to Sporadic Parkinson’S Disease Heiko Braak A,∗, Kelly Del Tredici A, Udo Rüb A, Rob A.I
    Neurobiology of Aging 24 (2003) 197–211 Staging of brain pathology related to sporadic Parkinson’s disease Heiko Braak a,∗, Kelly Del Tredici a, Udo Rüb a, Rob A.I. de Vos b, Ernst N.H. Jansen Steur b, Eva Braak a,† a Department of Clinical Neuroanatomy, J.W. Goethe University, Theodor Stern Kai 7, D-60590 Frankfurt/Main, Germany b Department of Neurology MST Hospital Group and Laboratorium Pathologie Oost Nederland, Burg. Edo Bergsmalaan, 7512 AD Enschede, The Netherlands Received 30 January 2002; received in revised form 23 April 2002; accepted 30 April 2002 Abstract Sporadic Parkinson’s disease involves multiple neuronal systems and results from changes developing in a few susceptible types of nerve cells. Essential for neuropathological diagnosis are ␣-synuclein-immunopositive Lewy neurites and Lewy bodies. The pathological process targets specific induction sites: lesions initially occur in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus. Thereafter, less vulnerable nuclear grays and cortical areas gradually become affected. The disease process in the brain stem pursues an ascending course with little interindividual variation. The pathology in the anterior olfactory nucleus makes fewer incursions into related areas than that developing in the brain stem. Cortical involvement ensues, beginning with the anteromedial temporal mesocortex. From there, the neocortex succumbs, commencing with high order sensory association and prefrontal areas. First order sensory association/premotor areas and primary sensory/motor fields then follow suit. This study traces the course of the pathology in incidental and symptomatic Parkinson cases proposing a staging procedure based upon the readily recognizable topographical extent of the lesions.
    [Show full text]
  • Seeding Propensity and Characteristics of Pathogenic
    Seeding Propensity and Characteristics of Pathogenic αSyn Assemblies in Formalin-Fixed Human Tissue from the Enteric Nervous System, Olfactory Bulb, and Brainstem in Cases Staged for Parkinson’s Disease Alexis Fenyi, Charles Duyckaerts, Luc Bousset, Heiko Braak, Kelly Del Tredici, Ronald Melki To cite this version: Alexis Fenyi, Charles Duyckaerts, Luc Bousset, Heiko Braak, Kelly Del Tredici, et al.. Seeding Propensity and Characteristics of Pathogenic αSyn Assemblies in Formalin-Fixed Human Tissue from the Enteric Nervous System, Olfactory Bulb, and Brainstem in Cases Staged for Parkinson’s Disease. Cells, MDPI, 2021, 10, pp.139. 10.3390/cells10010139. cea-03116038 HAL Id: cea-03116038 https://hal-cea.archives-ouvertes.fr/cea-03116038 Submitted on 20 Jan 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License cells Article Seeding Propensity and Characteristics of Pathogenic αSyn Assemblies in Formalin-Fixed Human Tissue from the Enteric Nervous System, Olfactory Bulb, and
    [Show full text]
  • Neuropathologic Outcome of Mild Cognitive Impairment Following Progression to Clinical Dementia
    ORIGINAL CONTRIBUTION Neuropathologic Outcome of Mild Cognitive Impairment Following Progression to Clinical Dementia Gregory A. Jicha, MD, PhD; Joseph E. Parisi, MD; Dennis W. Dickson, MD; Kris Johnson, RN; Ruth Cha, MS; Robert J. Ivnik, PhD; Eric G. Tangalos, MD; Bradley F. Boeve, MD; David S. Knopman, MD; Heiko Braak, MD; Ronald C. Petersen, PhD, MD Background: The pathologic outcome of patients di- pathologic abnormalities. All of the cases were found to agnosed with mild cognitive impairment (MCI) follow- have sufficient pathologic abnormalities in mesial tem- ing progression to dementia is poorly understood. poral lobe structures to account for their amnestic symp- toms regardless of the cause. Most subjects were found Objective: To determine the pathologic substrates of to have secondary contributing pathologic abnormali- dementia in cases with prior diagnosis of amnestic MCI. ties in addition to primary pathologic diagnoses. No sig- nificant differences between subjects with and without Design and Setting: Community-based cohort. neuropathologically proven AD were detected in demo- graphic variables, apolipoprotein E genotype, or cogni- Patients: Thirty-four subjects followed up prospec- tive test measures at onset of MCI, onset of dementia, or tively as part of a community-based study who were di- last clinical evaluation. agnosed with amnestic MCI, progressed to clinical de- mentia, and underwent subsequent postmortem brain analysis. Conclusions: The neuropathologic outcome of amnes- tic MCI following progression to dementia is heterog- Main Outcome Measures: Neuropathologic analy- eneous, and it includes AD at a high frequency. Com- ses resulted in assignment of a primary pathologic diag- plex neuropathologic findings including 2 or more distinct nosis and included staging of Alzheimer pathologic ab- pathologic entities contributing to dementia may be com- normalities and identification of contributing vascular mon in community-based cohorts.
    [Show full text]
  • Neuropathological Staging of Brain Pathology in Sporadic Parkinson's Disease
    Journal of Parkinson’s Disease 7 (2017) S71–S85 S71 DOI 10.3233/JPD-179001 IOS Press Review Neuropathological Staging of Brain Pathology in Sporadic Parkinson’s disease: Separating the Wheat from the Chaff Heiko Braak∗ and Kelly Del Tredici Department of Neurology, Clinical Neuroanatomy Section, Center for Biomedical Research, University of Ulm, Ulm, Germany Prof. Heiko Braak, M.D., A native of Kiel, Germany, Braak completed medical school at the University of Kiel, receiving his doctorate in 1964. After the habilitation in anatomy (1970), he became Professor of Anatomy there (1974). As Visiting Professor of Neurology at Harvard Medical School (1978/79), he worked with Norman Geschwind and published the monograph Architectonics of the Human Telencephalic Cortex (1980). From 1980 until 2002, Braak directed the Institute for Clinical Neuroanatomy at the Dr. Senckenberg Anatomical Institute of the Goethe University Frank- furt/Main. After retiring from university teaching, he was appointed Guest Researcher (2002) at the Goethe University until moving to Ulm University (2009), where he is a Senior Professor. He is recipient of the Robert A. Pritzker Prize for Leadership in Parkinson’s Disease Research, awarded by the Michael J. Fox Foundation (2014), and of the Annemarie Opprecht Parkinson Prize (2015). Interests: tauopathies, PD pathogenesis, ALS, pathoarchitectonics of the human brain. Kelly Del Tredici, M.D., Ph.D., A native of San Francisco, Del Tredici came to Germany on a Fredrick Sheldon Traveling Fellowship from Harvard University (1989) after studying classical lan- guages at Loyola University of Chicago (1970–1974) and Fordham University in New York City (1976–1982).
    [Show full text]
  • From the Entorhinal Region Via the Prosubiculum to the Dentate Fascia: Alzheimer Disease-Related Neurofibrillary Changes in the Temporal Allocortex
    J Neuropathol Exp Neurol Vol. 79, No. 2, February 2020, pp. 163–175 doi: 10.1093/jnen/nlz123 ORIGINAL ARTICLE From the Entorhinal Region via the Prosubiculum to the Dentate Fascia: Alzheimer Disease-Related Neurofibrillary Changes in the Temporal Allocortex Heiko Braak, MD and Kelly Del Tredici, MD, PhD without manifest heritability. Particularly, susceptible are late- Abstract developing and late-maturing projection neurons that gener- The pathological process underlying Alzheimer disease (AD) ate—in relation to the size of their cell body—a long and unfolds predominantly in the cerebral cortex with the gradual appear- sparsely myelinated axon (3, 8). With minor exceptions, local ance and regional progression of abnormal tau. Intraneuronal tau pa- circuit neurons are resistant (3). The predictable pattern of the thology progresses from the temporal transentorhinal and entorhinal tau lesions makes it possible to track the progression and to regions into neocortical fields/areas of the temporal allocortex. Here, distinguish different neuropathological stages (9–12). The based on 95 cases staged for AD-related neurofibrillary changes, we lesions include AT8-immunopositive nonargyrophilic pretan- propose an ordered progression of abnormal tau in the temporal allo- gles (13–15) that convert into argyrophilic filamentous accu- cortex. Initially, abnormal tau was limited to distal dendritic segments mulations of abnormal tau in dendrites (neuropil threads followed by tau in cell bodies of projection neurons of the transento- [NTs]) (16, 17), and cell somata (neurofibrillary tangles rhinal/entorhinal layer pre-a. Next, abnormal distal dendrites accumu- [NFTs]) (9, 18). Abnormal tau in axons generally resists con- lated in the prosubiculum and extended into the CA1 stratum oriens version into argyrophilic tau except in terminal axons of neu- and lacunosum.
    [Show full text]
  • Research and Perspectives in Alzheimer's Disease
    research and perspectives in alzheimer’s disease Fondation Ipsen Editor Yves Christen, Fondation Ipsen, Paris (France) Editorial Board Yves Agid, Hôpital Pitié Salpêtrière, Paris (France) Albert Aguayo, McGill University, Montreal (Canada) Brian H. Anderton, Institute of Psychiatry, London (GB) Raymond T. Bartus, Alkermes, Cambridge (USA) Anders Björklund,UniversityofLund(Sweden) Floyd Bloom, Scripps Clinic and Research Foundation, La Jolla (USA) François Boller, Inserm U 324, Paris (France) Carl Cotman, University of California, Irvine (USA) Peter Davies, Albert Einstein College of Medicine, New York (USA) Andre Delacourte, Inserm U 422, Lille (France) Steven Ferris, New York University Medical Center, New York (USA) Jean-François Foncin, Hôpital Pitié Salpêtrière, Paris (France) Françoise Forette, Hôpital Broca, Paris (France) Fred Gage, Salk Institute, La Jolla (USA) Dmitry Goldgaber, State University of New York Stone Brook (USA) John Hardy, National Institute of Health, Bethesda (USA) Jean-Jacques Hauw, Hôpital Pitié Salpêtrière, Paris (France) Claude Kordon, Inserm U 159, Paris (France) Kenneth S. Kosik, Harvard Medical School, Center for Neurological Diseases and Brigham and Women’s Hospital, Boston (USA) Jacques Mallet, Hôpital Pitié Salpêtrière, Paris (France) Colin L. Masters, University of Melbourne, Parkville (Australia) Stanley I. Rapoport, National Institute on Aging, Bethesda (USA) Barry Reisberg, New York University Medical Center, New York (USA) Allen Roses, Duke University Medical Center, Durham (USA) Dennis J. Selkoe, Harvard Medical School, Center of Neurological Diseases and Brigham and Women’s Hospital, Boston (USA) Michael L. Shelanski, Columbia University, New York (USA) Pierre-Marie Sinet, Hôpital Necker, Paris (France) Peter St. George-Hyslop,UniversityofToronto,Toronto(Canada) Robert Terry, University of California, La Jolla (USA) Edouard Zarifian, Centre Hospitalier Universitaire, Caen (France) M.
    [Show full text]
  • Cshperspect.A023630.Full.Pdf
    Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Potential Pathways of Abnormal Tau and a-Synuclein Dissemination in Sporadic Alzheimer’s and Parkinson’s Diseases Heiko Braak and Kelly Del Tredici Clinical Neuroanatomy Section/Department of Neurology, Center for Biomedical Research, University of Ulm, Helmholtzstrasse 8/1, 89081 Ulm, Germany Correspondence: [email protected] Experimental data indicate that transneuronal propagation of abnormal protein aggregates in neurodegenerative proteinopathies, such as sporadic Alzheimer’s disease (AD) and Parkinson’s disease (PD), is capable of a self-propagating process that leads to a progression of neurodegeneration and accumulation of prion-like particles. The mechanisms by which misfolded tau and a-synuclein possibly spread from one involved nerve cell to the next in the neuronal chain to induce abnormal aggregation are still unknown. Based on findings from studies of human autopsy cases, we review potential pathways and mechanisms related to axonal and transneuronal dissemination of tau (sporadic AD) and a-synuclein (sporadic PD) aggregates between anatomically interconnected regions. poradic Alzheimer’s disease (AD) and Par- protein tau (Goedert et al. 2006; Iqbal et al. Skinson’s disease (PD) are human neurode- 2009) and, thereafter gradually, by extracellular generative disorders that do not occur in other deposits of the b-amyloid protein (Ab) (Ala- vertebrate species. Pathological hallmark lesions fuzoff et al. 2009; Haass et al. 2012; Masters and in AD and PD involve only a few types of nerve Selkoe 2012). In mature nerve cells, the highest cells, mainly projection neurons. These lesions concentrations of the protein tau usually are develop at predetermined predilection sites and found in the axon.
    [Show full text]
  • FULLTEXT01.Pdf
    http://www.diva-portal.org This is the published version of a paper published in Brain. Citation for the original published paper (version of record): Brenner, D., Yilmaz, R., Müller, K., Grehl, T., Petri, S. et al. (2018) Hot-spot KIF5A mutations cause familial ALS Brain, 141: 688-697 https://doi.org/10.1093/brain/awx370 Access to the published version may require subscription. N.B. When citing this work, cite the original published paper. Permanent link to this version: http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-146237 doi:10.1093/brain/awx370 BRAIN 2018: 141; 688–697 | 688 Hot-spot KIF5A mutations cause familial ALS David Brenner,1 Ru¨stem Yilmaz,1 Kathrin Mu¨ller,1 Torsten Grehl,2 Susanne Petri,3 Thomas Meyer,4 Julian Grosskreutz,5 Patrick Weydt,1,6 Wolfgang Ruf,1 Christoph Neuwirth,7 Markus Weber,7 Susana Pinto,8,9 Kristl G. Claeys,10,11,12,13 Berthold Schrank,14 Berit Jordan,15 Antje Knehr,1 Kornelia Gu¨nther,1 Annemarie Hu¨bers,1 Daniel Zeller,16 The German ALS network MND-NET,* Christian Kubisch,17,18 Sibylle Jablonka,19 Michael Sendtner,19 Thomas Klopstock,20,21,22 Mamede de Carvalho,8,23 Anne Sperfeld,15 Guntram Borck,17 Alexander E. Volk,17,18 Johannes Dorst,1 Joachim Weis,10 Markus Otto,1 Joachim Schuster,1 Kelly Del Tredici,1 Heiko Braak,1 Karin M. Danzer,1 Axel Freischmidt,1 Thomas Meitinger,24,25 Tim M. Strom,24,25 Albert C. Ludolph,1 Peter M. Andersen1,9 and Jochen H.
    [Show full text]