DOCSLIB.ORG

Dysfunction of the Locus Coeruleus–Norepinephrine System And

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Dysfunction of the Locus Coeruleus–Norepinephrine System And J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2011-301817 on 13 October 2012. Downloaded from Neurodegeneration REVIEW Dysfunction of the locus coeruleus–norepinephrine system and related circuitry in Parkinson’s Editor's choice Scan to access more free content disease-related dementia Kelly Del Tredici, Heiko Braak Clinical Neuroanatomy, Center ABSTRACT nervous system: in an autopsy-based study, ILBD for Biomedical Research, Although resting tremor, cogwheel rigidity, hypokinesia/ cases were seen to have reduced striatal TH,36 and Department of Neurology, University of Ulm, Ulm, bradykinesia and postural instability usually dominate the subsequent reports have described abnormalities in Germany clinical picture of sporadic Parkinson’s disease (PD), both TH immunoreactivity within the LC in cases with clinical and epidemiological data reveal that a wide PD.25 37 For example, Dugger and Dickson recently Correspondence to variety of additional symptoms impair patients’ quality found that compared with controls, coeruleus pro- Professor H Braak, Clinical of life considerably, parallel to the chronic progressive jection neurones of PD patients displayed reduced Neuroanatomy Section, Center for Biomedical Research, neurodegenerative movement disorder. Autopsy based or depleted cytoplasmic immunoreactivity for TH Department of Neurology, retrospective studies have shown that α-synuclein (figure 1D) and that the melanised nerve cells there University of Ulm, immunoreactive Lewy pathology (LP) develops in the also sequestered TH within abnormal α-synuclein Helmholtzstrasse 8/1, locus coeruleus (LC) of patients with neuropathologically aggregates,37 thereby making it unavailable for Ulm 89081, Germany; fi 38 fi – [email protected] con rmed sporadic PD, as well as in individuals with essential brain functions ( gure 1D F). incidental (prodromal or premotor) Lewy body disease The LC is the largest source of noradrenergic Received 17 June 2012 but not in age and gender matched controls. Using five innervation in the human brain with ascending Revised 29 August 2012 case studies, this review discusses the possible role of projections to all regions of the cerebral cortex Accepted 3 September 2012 LP (axonopathy, cellular dysfunction and nerve cell loss) (hippocampal formation, entorhinal cortex with Published Online First in the LC, catecholaminergic tract and related circuitry adjacent mediotemporal cortex, cingulate gyrus and 13 October 2012 – in the development of PD-related dementia. The neocortex).39 41 One of the major functions of the contribution of noradrenergic deficit to cognitive LC–norepinephrine system is to maximise dysfunction in PD has been underappreciated. task-oriented performance and behaviour, particu- Noradrenergic therapeutic interventions might not only larly under challenging (novel, stressful) circum- – alleviate depressive symptoms and anxiety but also stances.42 44 In addition, together with the delay the onset of cognitive decline. gigantocellular nucleus of the pontine reticular formation and the nuclei of the lower raphé group, the LC receives supramedullary limbic (central sub- INTRODUCTION nucleus of the the amygdala) and somatomotor In sporadic Parkinson’s disease (PD), Lewy path- input (pedunculopontine tegmental nucleus ology (LP) is not only present in the brain but (PPN)). Together with the projections from the http://jnnp.bmj.com/ – throughout the entire human nervous system.1 8 lower raphé group, projections from the LC have Morphologically, LP consists of insoluble intraneur- an inhibitory effect on responses to pain in decisive onal inclusions that contain the misfolded protein situations and a facilitatory effect on the activity – α-synuclein in aggregated form9 13: immunoreac- levels of spinal cord premotor and motoneurons tive pale neurites, thread-like or spindle-shaped that receive data from the neocortex, striatal and – Lewy neurites (LNs) in axons and dendrites14 15 cerebellar circuits45 50 (figure 2). Finally, the LC (figure 1A) as well as particulate (or punctate) participates in the sympathetic innervation and on October 1, 2021 by guest. Protected copyright. – aggregates,16 pale bodies17 and Lewy bodies (LBs) modulation of the brain microcirculation.44 51 58 within neuronal cell somata10 18 19 (figure 1B, C). Thus, loss or chronic reduction of the rate limiting LP accompanied by nerve cell loss occurs in the enzyme TH for norepinephrine metabolism within locus coeruleus (LC) of the pontine tegmentum the LC and/or the ascending catecholaminergic – during PD,20 27 and there is firm evidence that tract (equivalent to the rat dorsal noradrenergic involvement of this nucleus and other regions in ascending bundle)59 may be anticipated to contrib- incidental Lewy body disease (ILBD) precedes the ute not only to some of the motor difficulties appearance of α-synuclein aggregates and neuronal experienced by PD patients in ‘unexpected’ situa- – loss in the nigral pars compacta.28 33 Less attention, tions (eg, no abrupt turns and hesitation at thresh- however, has been paid to the possible association olds) but also to problems with wake–arousal states of LP with noradrenergic axonal or cellular dysfunc- or redirecting attention, and to deficits in cognitive – tion there and its potential consequences. Until function and the cerebral microcirculation.38 58 60 62 recently, for instance, diminution of tyrosine hydro- During PD neuropathological stage 2, the level To cite: Del Tredici K, xylase (TH) immunoreactivity in PD and ILBD had setting nuclei (ie, LC, gigantocellular reticular Braak H. J Neurol Neurosurg only been detected in cardiac sympathetic nucleus and lower raphe nuclei) as a unit become Psychiatry 2013;84: nerves,34 35 but several groups have shown that this involved and, during the following stage, a bifurca- 774–783. phenomenon is not restricted to the peripheral tion, as it were, of the pathological process in the 774 Del Tredici K, et al. J Neurol Neurosurg Psychiatry 2013;84:774–783. doi:10.1136/jnnp-2011-301817 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2011-301817 on 13 October 2012. Downloaded from Neurodegeneration Figure 1 Lewy pathology in brains of demented patients with Parkinson’s disease. (A) Micrograph of a Lewy neurite showing immunoreactive material on the inner cellular membrane of a dendrite covered with short appendages. (B–F) Particulate α-synuclein aggregates in melanised projection neurones of the locus coeruleus (LC) (B) and substantia nigra (C, lower right). Lewy bodies are also seen (B, C), whereby in (D–F) (the LC), they clearly sequester tyrosine hydroxylase (TH, arrows) in their halos or centres. As such, the neurotransmitter presumably is not available for brain noradrenergic metabolism. (D) Compare the normal appearing melanised neurone at the left (dark blue, chromogen SK-4700) with that directly to the right: the cytoplasm of the latter nerve cell is pale, indicating reduced TH activity. Immunoreactions for α-synuclein (C) and for α-synuclein plus TH (A, B, D–F) in polyethylene glycol embedded 100 μm sections. http://jnnp.bmj.com/ brain occurs: LP develops in high order relay centres of the neuropathological substrates of cognitive decline and dementia in central autonomic network (central subnucleus of the amygdala, PD have been attributed not only to cortical (limbic and neocor- – hypothalamus and limbic circuit components)22 63 and, at the tical) LP71 83 86 89 but also to lesions compatible with Alzheimer’s – same time, it progresses into superordinate centres of the somato- disease (AD)61 72 82 83 87 90 95 and, somewhat more infrequently, – – motor system, including the PPN nucleus and striatal circuit64 66 comorbid argyrophilic grain disease (AGD).83 96 98 Potential (figure 2). The central autonomic network and PPN nucleus mechanisms that might contribute to a synergistic effect between regulate the brainstem level setting nuclei and send projections to tau and α-synuclein or between α-synuclein and amyloid-β remain on October 1, 2021 by guest. Protected copyright. – all diffusely projecting non-thalamic nuclei.48 67 In other words, the object of ongoing research and discussion.99 106 In addition, by the time the PD associated pathological process makes intracerebral vascular disease, including amyloid angiopathies and headway into cortical sites during PD neuropathological stage 4, subcortical arteriosclerotic encephalopathy (small vessel disease the LP and axonal and/or cellular dysfunction and neuronal loss with white matter lesions) are recognised as contributory in key brainstem serotonergic, noradrenergic and cholinergic factors.85 107 108 Thus the entities cognitive dysfunction and – neurones are fairly advanced22 27 37 64 68 70 (figures 2 and 6). dementia in PD are often associated with an admixture of patholo- There is now a consensus that PD patients develop dysexecutive gies—that is, PD plus AD or PD plus AD plus AGD—often – symptoms and, provided they live long enough, dementia.71 77 accompanied by a vascular component.109 However, the differential diagnosis between PD associated demen- Finally, dopamine replacement therapy can have undesirable – tia (PDD) and dementia with Lewy bodies (DLB) is still fraught effects not only on behaviour but also on cognitive function.110 112 – with difficulties.78 80 For instance, use of the 1 year rule originally proposed by McKeith et al81—that is, parkinsonism prior to cog- CASE HISTORIES AND POST MORTEM DIAGNOSES IN FIVE nitive impairment/fluctuating cognition—to
Load more

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]