Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 793-802 |
| Number of pages | 10 |
| Journal | Journal of neuropathology and experimental neurology |
| Volume | 77 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2018 |
Keywords
- Biomarker
- Biopsy
- Colon
- Digital imaging
- Parkinson disease
- Skin
- Submandibular gland
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Neurology
- Clinical Neurology
- Cellular and Molecular Neuroscience
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Immunohistochemical method and histopathology judging for the systemic synuclein sampling study (S4). / Beach, Thomas G.; Serrano, Geidy E.; Kremer, Thomas et al.
In: Journal of neuropathology and experimental neurology, Vol. 77, No. 9, 01.09.2018, p. 793-802.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Immunohistochemical method and histopathology judging for the systemic synuclein sampling study (S4)
AU - Beach, Thomas G.
AU - Serrano, Geidy E.
AU - Kremer, Thomas
AU - Canamero, Marta
AU - Dziadek, Sebastian
AU - Sade, Hadassah
AU - Derkinderen, Pascal
AU - Corbillé, Anne Gaëlle
AU - Letournel, Franck
AU - Munoz, David G.
AU - White, Charles L.
AU - Schneider, Julie
AU - Crary, John F.
AU - Sue, Lucia I.
AU - Adler, Charles H.
AU - Glass, Michael J.
AU - Intorcia, Anthony J.
AU - Walker, Jessica E.
AU - Foroud, Tatiana
AU - Coffey, Christopher S.
AU - Ecklund, Dixie
AU - Riss, Holly
AU - Goßmann, Jennifer
AU - König, Fatima
AU - Kopil, Catherine M.
AU - Arnedo, Vanessa
AU - Riley, Lindsey
AU - Linder, Carly
AU - Dave, Kuldip D.
AU - Jennings, Danna
AU - Seibyl, John
AU - Mollenhauer, Brit
AU - Chahine, Lana
N1 - Funding Information: Send correspondence to: Thomas G. Beach, MD, PhD, Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85351; E-mail: thomas.beach@bannerhealth.com *See Supplementary Data Appendix for the list of S4 authors. This study was supported by the Michael J. Fox Foundation for Parkinson’s Research; National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders); the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center. Supplementary Data can be found at academic.oup.com/jnen. Funding Information: The Systemic Synuclein Sampling Study (S4) is funded by The Michael J. Fox Foundation for Parkinson’s Research, who is responsible for overseeing the design and conduct of the study. S4 was made possible with the support of site Principal Investigators, site Coordinators and study collaborators [https://www.michaeljfox.org/page.html? s4]. GE Healthcare donated the DaTscan doses used in the study. Prothena Biosciences donated the 5C12 antibody. Human autopsy tissue was obtained from the Banner Sun Health Research Institute’s Brain and Body Donation Program, supported by grants from the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research. Many thanks for helpful discussion from Roy Freeman (Harvard University, MA), Vincenzo Donadio (IRCCS Istituto delle Scienze Neurolo-giche di Bologna, Bologna, Italy), Drew Kern (University of Colorado, CO), Timo Siepmann (University Hospital Dresden, Dresden, Germany), Michael L. Hinni (Department of Otolaryngology, Mayo Clinic Arizona, Phoenix, AZ) and Wagner Zago (Prothena Biosciences, Inc., South San Francisco, CA). Finally, we would like to thank all of the study participants and generous MJFF donors that made this study possible. Funding Information: Mollenhauer has no conflict of interest related to this study. Brit Mol-lenhauer has in the past 12 months received independent research grants from the Michael J. Fox Foundation, GE Healthcare, the Deutsche For-schungsgemeinschaft (DFG), BMBF, EU (Horizon2020), Parkinson Fonds Deutschland and Deutsche Parkinson Vereinigung, and has scientific collaborations and received honoraria for consultancies from Roche, AbbVie, Biogen and UCB. Lana Chahine has no conflict of interest related to this study. Lana M. Chahine received research support from the Michael J. Fox Foundation (MJFF), has received travel payment from MJFF, is a paid consultant to MJFF, and received royalties from Wolters Kluwer for book authorship. Funding Information: Thomas Beach has been paid as a consultant by Roche Diagnostics, whose immunohistochemical method is used in this study. Thomas Beach has received grant support and has been paid travel expenses from the Michael J. Fox Foundation, is paid as a consultant and/or has had travel paid, by Prothena Biosciences and Roche Diagnostics, and is doing con-tract research for Avid Radiopharmaceuticals, Navidea Biopharmaceut-icals and Aprinoia Therapeutics. Geidy E. Serrano has no conflict of interest to declare. Thomas Kremer, Marta Canamero, Sebastian Dzia-dek, and Hadassah Sade are employees of F. Hoffmann-La Roche Ltd. Marta Canamero and Sebastian Dziadek own Roche stocks. Pascal Der-kinderen, Anne-Ga€elle Corbillé, Franck Letournel, David Munoz, Charles White, and Julie Schneider have no conflicts of interest or no financial disclosures related to this study. John F. Crary and Lucia I. Sue have no conflict of interest related to this study. John F. Crary has received research support from Genentech/Roche. Lucia I. Sue has no financial disclosure. Charles Adler has no conflict of interest related to this study. Consulting in the past year: Extera Partners, Jazz, Lundbeck, Minerva, Neurocrine, Revance, Scion, Sunovion. Michael Glass, An-thony J. Intorcia, and Jessica E. Walker have no conflict of interest re-lated to this study. Tatiana Foroud has no conflict of interest related to this study. Tatiana Foroud received funding from the National Institutes of Health (NIH), The Michael J. Fox Foundation, the US Department of Defense, San Diego State University, The University of Texas at Aus-tin, and Waggoner Center for Alcohol/Addiction Research. Christopher S. Coffey has no conflict of interest related to this study. Christopher S. Coffey received research support from the Michael J. Fox Foundation. Dixie Ecklund has no conflict of interest related to this study. Dixie Ecklund received research support from the National Institute of Health and the Michael J. Fox Foundation. Holly Riss has no conflict of inter-est related to this study. Holly Riss received research support from the National Institute of Health and the Michael J. Fox Foundation. Jennifer Goßmann is an employee of Targos Molecular Pathology, Gmbh. Fatima König is an employee of Targos Molecular Pathology, Gmbh. Catherine M. Kopil is an employee of the Michael J. Fox Foundation. Vanessa Arnedo is an employee of the Michael J. Fox Foundation. Lindsey Riley is an employee of the Michael J. Fox Foundation. Carly Linder has no conflict of interest or no financial disclosures related to this study. Kuldip D. Dave is an employee of the Michael J. Fox Foun-dation. Danna Jennings is an employee of Denali Therapeutics. Danna Jennings is a minor share holder Eli Lilly and Co. John Seibyl has no conflict of interest to declare. John Seibyl has equity interest in Invicro and is a consultant to GE Healthcare, Piramal, Roche, and Biogen. Brit Publisher Copyright: © 2018 American Association of Neuropathologists, Inc.
PY - 2018/9/1
Y1 - 2018/9/1
N2 - 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.
AB - 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.
KW - Biomarker
KW - Biopsy
KW - Colon
KW - Digital imaging
KW - Parkinson disease
KW - Skin
KW - Submandibular gland
UR - http://www.scopus.com/inward/record.url?scp=85052753155&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052753155&partnerID=8YFLogxK
U2 - 10.1093/jnen/nly056
DO - 10.1093/jnen/nly056
M3 - Article
C2 - 30107604
AN - SCOPUS:85052753155
SN - 0022-3069
VL - 77
SP - 793
EP - 802
JO - Journal of Neuropathology and Experimental Neurology
JF - Journal of Neuropathology and Experimental Neurology
IS - 9
ER -