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      Staging of Neurofibrillary Pathology in Alzheimer's Disease: A Study of the BrainNet Europe Consortium

      research-article
      , MD, PhD 1 , , MD 2 , , FRCPath 3 , , FRCPath 3 , , MD, PhD 4 , , MD 5 , , MD 6 , , MD 5 , , MD 7 , , MD 8 , , MD 6 , , MD, PhD 9 , , MD, PhD, MRCPath 10 , , MD, PhD 11 , , FRCPath 3 , , MD, PhD 12 , , MD, PhD 13 , , MD 14 , , MD 15 , , MD 16 , , MD, PhD 17 , , MD, PhD 12 , , MD 16 , , MD, PhD 18 , , MD 6 , , MD 19 , , MD 15 , , MD 14 , 20 , , FRCPath 10 , , MD 2
      Brain Pathology (Zurich, Switzerland)
      Blackwell Publishing Ltd
      Alzheimer's disease, immunohistochemistry, neurofibrillary pathology, neuropathological diagnosis, BrainNet Europe consortium

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          Abstract

          It has been recognized that molecular classifications will form the basis for neuropathological diagnostic work in the future. Consequently, in order to reach a diagnosis of Alzheimer's disease (AD), the presence of hyperphosphorylated tau (HP-tau) and β-amyloid protein in brain tissue must be unequivocal. In addition, the stepwise progression of pathology needs to be assessed. This paper deals exclusively with the regional assessment of AD-related HP-tau pathology. The objective was to provide straightforward instructions to aid in the assessment of AD-related immunohistochemically (IHC) detected HP-tau pathology and to test the concordance of assessments made by 25 independent evaluators. The assessment of progression in 7-µm-thick sections was based on assessment of IHC labeled HP-tau immunoreactive neuropil threads (NTs). Our results indicate that good agreement can be reached when the lesions are substantial, i.e., the lesions have reached isocortical structures (stage V–VI absolute agreement 91%), whereas when only mild subtle lesions were present the agreement was poorer (I–II absolute agreement 50%). Thus, in a research setting when the extent of lesions is mild, it is strongly recommended that the assessment of lesions should be carried out by at least two independent observers.

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          Most cited references13

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          Observations on the brains of demented old people.

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            Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees.

            The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-beta protein is an initiating event in Alzheimer's disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n = 5) and symptomatic (n = 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n = 2) were studied with PiB-PET imaging and compared with sporadic AD subjects (n = 12) and controls from the general population (n = 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35-49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.
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              Alpha-synuclein pathology does not predict extrapyramidal symptoms or dementia.

              Intracytoplasmic aggregation of alpha-synuclein protein as Lewy bodies in the brainstem neurons is diagnostic for Parkinson's disease, whereas if this process also occurs in the cortical neurons, it is considered pathognomonic for dementia with Lewy bodies. However, the link between alpha-synuclein incorporation into inclusions, neuronal dysfunction, and clinical symptoms needs to be clarified. Another important issue of the pathogenetic puzzle is to understand where alpha-synuclein pathology begins and how it progresses in the brain. To study this, we collected all cases from autopsy material (N = 904) that had alpha-synuclein pathology in the dorsal motor nucleus of vagus, substantia nigra, and/or basal forebrain nuclei. In this way, our study has a unique design because the selection of material is entirely based on the presence of alpha-synuclein pathology regardless of clinical phenotype. Retrospective clinical assessment then showed that only 32 (30%) of 106 alpha-synuclein-positive cases were diagnosed with a neurodegenerative disorder. The distribution or load of alpha-synuclein pathology did not permit a dependable postmortem diagnosis of extrapyramidal symptoms or cognitive impairment. Some neurologically unimpaired cases had a reasonable burden of alpha-synuclein pathology in both brainstem and cortical areas, suggesting that alpha-synuclein-positive structures are not definite markers of neuronal dysfunction.
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                Author and article information

                Journal
                Brain Pathol
                bpa
                Brain Pathology (Zurich, Switzerland)
                Blackwell Publishing Ltd
                1015-6305
                1750-3639
                October 2008
                : 18
                : 4
                : 484-496
                Affiliations
                [1 ]Department of Neuroscience and Neurology, Kuopio University Kuopio, Finland
                [2 ]Center for Neuropathology and Prion Research, München Ludwig-Maximilians-University, Munich Germany
                [3 ]Department of Clinical Neuropathology, Kings College Hospital and the Institute of Psychiatry Kings College London, UK
                [4 ]Department of Geriatrics, Karolinska Institutet Huddinge, Sweden
                [5 ]Institute fur Neuropathologie, Institute fur Clinical Neuroanatomy Frankfurt/Main, Germany
                [6 ]Fondazione IRCCS Istituto Neurologico Carlo Besta Milano, Italy
                [7 ]Institut de Neuropatologia, Universitat de Barcelona Barcelona, Spain
                [8 ]Institute of Neurology, Medical University of Vienna Vienna, Austria
                [9 ]MBG University Department of Neuropathology Hammersmith Hospitals Trust and Imperial College London, UK
                [10 ]Academic Nit of Pathology Sheffield University Medical School Sheffield, UK
                [11 ]Netherlands Brain Bank Amsterdam, the Netherlands
                [12 ]Department of Pathology, National and Capodistrian University of Athens Athens, Greece
                [13 ]OPNI, National Institute of Psychiatry and Neurology Budapest, Hungary
                [14 ]Institute for Neuropathology, University of Bonn Bonn, Germany
                [15 ]Université Lyon 1, Faculté de Médecine Laennec, Hospices Civils de Lyon, Centre de Pathologie et de Neuropathologie Est Lyon, France
                [16 ]Pathologisches Institut, Abteilung Neuropathologie der Universität Würzburg Würzburg, Germany
                [17 ]Dipartimento di Scienze Neurologiche, Università di Bologna Bologna, Italy
                [18 ]Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie and INSERM Paris, France
                [19 ]Universitätsklinikum Göttingen, Germany
                [20 ]Institute of Pathology – Laboratory of Neuropathology, University of Ulm Ulm, Germany
                Author notes
                Irina Alafuzoff, MD, PhD, Department of Clinical Medicine, Unit of Neurology, Section of Neuropathology, Kuopio University, PO Box 1627, 70211 Kuopio, Finland (E-mail: Irina.Alafuzoff@ 123456uku.fi )

                Justifications: IA, TA, HK /Design of the study, primary assessment of all cases, construction of the assessment recommendations; HB, KD-T Consultants, reference staging of the study cases together with IA, TA and HK; Each of the participating BNE centers carrying out individually staging of all cases. All authors contributed to manuscript revision.

                Article
                10.1111/j.1750-3639.2008.00147.x
                2659377
                18371174
                52dc3208-3239-4433-af53-fb2f244c246d
                © 2008 The Authors; Journal Compilation © 2008 International Society of Neuropathology

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                History
                : 20 September 2007
                : 12 December 2007
                Categories
                Research Articles

                Pathology
                neuropathological diagnosis,brainnet europe consortium,alzheimer's disease,neurofibrillary pathology,immunohistochemistry

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