This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.
Abstract
Background and Objectives Multiple system atrophy (MSA) is a progressive neurodegenerative disorder caused by the abnormal accumulation of α-synuclein in the nervous system. Clinical features include autonomic and motor dysfunction, which overlap with those of Parkinson disease (PD), particularly at early disease stages. There is an unmet need for accurate diagnostic and prognostic biomarkers for MSA and, specifically, a critical need to distinguish MSA from other synucleinopathies, particularly PD. The purpose of the study was to develop a unique cutaneous pathologic signature of phosphorylated α-synuclein that could distinguish patients with MSA from patients with PD and healthy controls.
Methods We studied 31 patients with MSA and 54 patients with PD diagnosed according to current clinical consensus criteria. We also included 24 matched controls. All participants underwent neurologic examinations, autonomic testing, and skin biopsies at 3 locations. The density of intraepidermal, sudomotor, and pilomotor nerve fibers was measured. The deposition of phosphorylated α-synuclein was quantified. Results were compared with clinical rating assessments and autonomic function test results.
Results Patients with PD had reduced nerve fiber densities compared with patients with MSA (p < 0.05, all fiber types). All patients with MSA and 51/54 with PD had evidence of phosphorylated α-synuclein in at least one skin biopsy. No phosphorylated α-synuclein was detected in controls. Patients with MSA had greater phosphorylated α-synuclein deposition (p < 0.0001) and more widespread peripheral distribution (p < 0.0001) than patients with PD. These results provided >90% sensitivity and specificity in distinguishing between the 2 disorders.
Discussion α-synuclein is present in the peripheral autonomic nerves of patients with MSA and when combined with synuclein distribution accurately distinguishes MSA from PD.
Classification of Evidence This study provides Class II evidence that measurement of phosphorylated α-synuclein in skin biopsies can differentiate patients with MSA from those with PD.
Glossary
- AUC=
- area under the curve;
- BIDMC=
- Beth Israel Deaconess Medical Center;
- IENFD=
- intraepidermal nerve fiber density;
- MDS-UPDRS=
- Movement Disorders Society Unified Parkinson's Disease Rating Scale;
- MSA=
- multiple system atrophy;
- NYU=
- New York University;
- OHQ=
- Orthostatic Hypotension Questionnaire;
- P-SYN=
- phosphorylated α-synuclein;
- PD=
- Parkinson disease;
- RBD=
- REM sleep behavior disorder;
- ROC=
- receiver operating characteristic;
- UMSARS=
- Unified Multiple System Atrophy Rating Scale;
- UPSIT=
- University of Pennsylvania Smell Identification Test
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Submitted and externally peer reviewed. The handling editor was Associate Editor Peter Hedera, MD, PhD.
Editorial, page 691
Class of Evidence: NPub.org/coe
CME Course: NPub.org/cmelist
- Received March 9, 2022.
- Accepted in final form November 17, 2022.
- © 2023 American Academy of Neurology
AAN Members
We have changed the login procedure to improve access between AAN.com and the Neurology journals. If you are experiencing issues, please log out of AAN.com and clear history and cookies. (For instructions by browser, please click the instruction pages below). After clearing, choose preferred Journal and select login for AAN Members. You will be redirected to a login page where you can log in with your AAN ID number and password. When you are returned to the Journal, your name should appear at the top right of the page.
AAN Non-Member Subscribers
Purchase access
Letters: Rapid online correspondence
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
