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J Neuropathol Exp Neurol. 2018 Sep 1;77(9):793-802. doi: 10.1093/jnen/nly056.

Immunohistochemical Method and Histopathology Judging for the Systemic Synuclein Sampling Study (S4).

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Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, Arizona.
Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F Hoffman-La Roche, Ltd, Basel, Switzerland.
Roche Pharma Research and Early Development, Roche Innovation Center, Munich, Penzberg, Germany.
Department of Neurology, CHU Nantes, Inserm, U1235, Nantes University, Nantes F-44035, France.
CHU Angers, Neurobiology and Neuropathology Laboratory, Angers F-49033, France.
Laboratory Medicine and Keenan Research Centre for Biomedical Research of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.
Rush Alzheimer's Disease Center, Chicago, Illinois.
Department of Pathology, Fishberg Department of Neuroscience, Friedman Brain Institute, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, New York.
Department of Neurology, Mayo Clinic Arizona, Scottsdale, Arizona.
Indiana University School of Medicine, Indianapolis, Indiana.
Department of Biostatistics, University of Iowa, Iowa City, Iowa.
Targos Molecular Pathology GmbH, Kassel, Germany.
The Michael J. Fox Foundation for Parkinson's Research, New York, New York.
Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Avid Radiopharmaceuticals, Philadelphia, Pennsylvania.
Institute for Neurodegenerative Disorders, New Haven, Connecticut.
Paracelsus-Elena-Klinik, Kassel and University Medical Center Goettingen, Goettingen, Germany.
Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania.


Immunohistochemical (IHC) α-synuclein (Asyn) pathology in peripheral biopsies may be a biomarker of Parkinson disease (PD). The multi-center Systemic Synuclein Sampling Study (S4) is evaluating IHC Asyn pathology within skin, colon and submandibular gland biopsies from 60 PD and 20 control subjects. Asyn pathology is being evaluated by a blinded panel of specially trained neuropathologists. Preliminary work assessed 2 candidate immunoperoxidase methods using a set of PD and control autopsy-derived sections from formalin-fixed, paraffin-embedded blocks of the 3 tissues. Both methods had 100% specificity; one, utilizing the 5C12 monoclonal antibody, was more sensitive in skin (67% vs 33%), and was chosen for further use in S4. Four trainee neuropathologists were trained to perform S4 histopathology readings; in subsequent testing, their scoring was compared to that of the trainer neuropathologist on both glass slides and digital images. Specificity and sensitivity were both close to 100% with all readers in all tissue types on both glass slides and digital images except for skin, where sensitivity averaged 75% with digital images and 83.5% with glass slides. Semiquantitative (0-3) density score agreement between trainees and trainer averaged 67% for glass slides and 62% for digital images.

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