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      Parkinson's disease: a dual‐hit hypothesis

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          Abstract

          Accumulating evidence suggests that sporadic Parkinson's disease has a long prodromal period during which several non‐motor features develop, in particular, impairment of olfaction, vagal dysfunction and sleep disorder. Early sites of Lewy pathology are the olfactory bulb and enteric plexus of the stomach. We propose that a neurotropic pathogen, probably viral, enters the brain via two routes: (i) nasal, with anterograde progression into the temporal lobe; and (ii) gastric, secondary to swallowing of nasal secretions in saliva. These secretions might contain a neurotropic pathogen that, after penetration of the epithelial lining, could enter axons of the Meissner's plexus and, via transsynaptic transmission, reach the preganglionic parasympathetic motor neurones of the vagus nerve. This would allow retrograde transport into the medulla and, from here, into the pons and midbrain until the substantia nigra is reached and typical aspects of disease commence. Evidence for this theory from the perspective of olfactory and autonomic dysfunction is reviewed, and the possible routes of pathogenic invasion are considered. It is concluded that the most parsimonious explanation for the initial events of sporadic Parkinson's disease is pathogenic access to the brain through the stomach and nose – hence the term ‘dual‐hit’.

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          Stages in the development of Parkinson's disease-related pathology.

          The synucleinopathy, idiopathic Parkinson's disease, is a multisystem disorder that involves only a few predisposed nerve cell types in specific regions of the human nervous system. The intracerebral formation of abnormal proteinaceous Lewy bodies and Lewy neurites begins at defined induction sites and advances in a topographically predictable sequence. As the disease progresses, components of the autonomic, limbic, and somatomotor systems become particularly badly damaged. During presymptomatic stages 1-2, inclusion body pathology is confined to the medulla oblongata/pontine tegmentum and olfactory bulb/anterior olfactory nucleus. In stages 3-4, the substantia nigra and other nuclear grays of the midbrain and forebrain become the focus of initially slight and, then, severe pathological changes. At this point, most individuals probably cross the threshold to the symptomatic phase of the illness. In the end-stages 5-6, the process enters the mature neocortex, and the disease manifests itself in all of its clinical dimensions.
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            Diagnostic criteria for Parkinson disease.

            The clinical diagnosis of Parkinson disease (PD) is based on the identification of some combination of the cardinal motor signs of bradykinesia, rigidity, tremor, and postural instability, but few attempts have been made to develop explicit diagnostic criteria. We propose a clinical diagnostic classification based on a comprehensive review of the literature regarding the sensitivity and specificity of the characteristic clinical features of PD. Three levels of diagnostic confidence are differentiated: Definite, Probable, and Possible. The diagnoses of Possible and Probable PD are based on clinical criteria alone. Neuropathologic confirmation is required for the diagnosis of Definite PD in patients with the clinical diagnosis of Possible or Probable PD. Criteria for histopathologic confirmation of PD are also presented.
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              Movement Disorders Society Scientific Issues Committee report: SIC Task Force appraisal of clinical diagnostic criteria for Parkinsonian disorders.

              As there are no biological markers for the antemortem diagnosis of degenerative parkinsonian disorders, diagnosis currently relies upon the presence and progression of clinical features and confirmation depends on neuropathology. Clinicopathologic studies have shown significant false-positive and false-negative rates for diagnosing these disorders, and misdiagnosis is especially common during the early stages of these diseases. It is important to establish a set of widely accepted diagnostic criteria for these disorders that may be applied and reproduced in a blinded fashion. This review summarizes the findings of the SIC Task Force for the study of diagnostic criteria for parkinsonian disorders in the areas of Parkinson's disease, dementia with Lewy bodies, progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration. In each of these areas, diagnosis continues to rest on clinical findings and the judicious use of ancillary studies. Copyright 2003 Movement Disorder Society
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                Author and article information

                Journal
                Neuropathol Appl Neurobiol
                Neuropathol. Appl. Neurobiol
                10.1111/(ISSN)1365-2990
                NAN
                Neuropathology and Applied Neurobiology
                Blackwell Publishing Ltd (Oxford, UK )
                0305-1846
                1365-2990
                24 October 2007
                December 2007
                : 33
                : 6 ( doiID: 10.1111/nan.2007.33.issue-6 )
                : 599-614
                Affiliations
                [ 1 ]Essex Neuroscience Centre, Queen's Hospital, Romford, Essex UK, and
                [ 2 ]Institute for Clinical Neuroanatomy, Johann Wolfgang Goethe University, Frankfurt am Main, Germany
                Author notes
                [*] [* ]Dr Christopher H. Hawkes, Essex Neuroscience Centre, Queen's Hospital, Romford, Essex RM7 0AG, UK. Tel. +44 1708 435000; E‐mail: chrishawkes@ 123456msn.com
                Article
                NAN874
                10.1111/j.1365-2990.2007.00874.x
                7194308
                17961138
                43afc490-db6a-4009-8f21-61e3c1232b13

                This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

                History
                : 27 May 2007
                : 15 June 2007
                Page count
                links-crossref: 0, links-pubmed: 0, Figures: 4, Tables: 0, Equations: 0, References: 157, Pages: 16, Words: 17845
                Categories
                Original Articles
                Custom metadata
                2.0
                December 2007
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.0 mode:remove_FC converted:15.04.2020

                Neurosciences
                aetiology,autonomic regulation,olfaction,parkinson's disease
                Neurosciences
                aetiology, autonomic regulation, olfaction, parkinson's disease

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