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The neuropathology of genetic Parkinson's disease

Authors

  • Markos Poulopoulos MD,

    1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
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    • *

      These authors contributed equally to this work.

  • Oren A. Levy MD, PhD,

    1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
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    • *

      These authors contributed equally to this work.

  • Roy N. Alcalay MD, MSc

    Corresponding author
    1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
    2. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York, USA
    • Department of Neurology, College of Physicians and Surgeons, Columbia University, 710 West 168th Street, New York, NY 10032, USA
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  • Relevant conflicts of interest/financial disclosures: M.P. is a Parkinson's Disease Foundation fellow. O.A.L. is supported by the National Institutes of Health (K08NS070608) and the Smart Foundation. R.N.A. is funded by the Brookdale Foundation, the Smart Foundation, the Michael J. Fox Foundation, and the Parkinson's Disease Foundation.

  • Full financial disclosures and author roles may be found in the online version of this article.

Abstract

Pathological data from autopsies genotyped for Parkinson's disease (PD)-related mutations in alpha-synuclein, Parkin, PINK1, DJ1, LRRK2, and glucocerebrosidase have accumulated in recent years. The aim of this review is to systematically review all pathological reports of mutation carriers and to identify pathological patterns and gaps in the currently available data. A systematic review of the English literature was done using the terms “Parkinson's disease,” “brain pathology,” “autopsy,” the specific gene nomenclature, and any combination of the above. Most studies included reports of convenience samples: either cases that were preidentified as mutation carriers before autopsy or screens of Lewy body brain banks. Nineteen autopsies of alpha-synuclein mutation carriers, 49 of LRRK2 mutation carriers, nine of Parkin mutation carriers, one of a PINK1 mutation carrier, and 86 of glucocerebrosidase mutation carriers were identified. Most autopsies of alpha-synuclein, LRRK2 G2019S, and glucocerebrosidase mutation carriers demonstrated Lewy body pathology, as opposed to Parkin and LRRK2 non-G2019S mutation carriers. However, there was a marked variability in pathological findings, even among carriers of identical mutations. Pathological data from DJ1 mutation carriers, nonmanifesting mutation carriers (e.g., of LRRK2 mutations), and carriers of a single Parkin mutation were lacking. In gathering together all studies of PD autopsies with an identified genetic risk, this review highlights the wealth of information generated as well as shortcomings in the available data. In particular, there is a need for larger, unbiased pathological studies. Differential association of Lewy pathology with specific mutations may reflect heterogeneity in pathogenic mechanisms among the different PD-related genes. © 2012 Movement Disorder Society

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