Prospective Validation of the New PLS Diagnostic Criteria From PLS Natural History Study: EMG and Neurofilament Analyses

doi:10.1002/mus.70192

Prospective Validation of the New PLS Diagnostic Criteria From PLS Natural History Study: EMG and Neurofilament Analyses

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Primary lateral sclerosis (PLS) is an ultrarare upper motor neuron syndrome with a prognosis unique from classical ALS. The study of PLS is complicated by its rarity and the difficulty distinguishing PLS from ALS. We present data from a 1-year prospective follow-up study on PLS and efforts to distinguish it from ALS. Methods: Seventy-six PLS participants enrolled in this prospective natural history study. EMG studies, blood neurofilament light chain levels (NfLs), and demographic characteristics were obtained at baseline. At 1-year follow-up, repeat EMG studies were conducted to determine which participants fulfilled criteria for ALS. Baseline characteristics were then compared to determine features that predict reclassification. Results: Seventy participants completed 1-year follow-up. Five of the 70 were reclassified to ALS (7.1%). Those reclassified had higher trends in baseline blood NfL levels (91.4 vs. 34.0 pg/mL, p = 0.13) and shorter symptom duration (39 vs. 69 months in the PLS group, p = 0.15). Reclassification was noted in both probable and definite PLS participants. All cases with a symptomatic duration of less than 2 years retained the PLS phenotype (5 of 5). NfL levels over 90 pg/mL predicted reclassification with 94% specificity and 60% sensitivity. No other features predicted reclassification to ALS. Conclusions: In our population, reclassification of PLS to ALS occurred at a low frequency at 1 year follow-up (7.1%). Baseline NfL was the strongest predictor in differentiating UMN dominant ALS from PLS at 1-year follow-up. Based on our data, we propose EMG and NfL criteria for enrollment in future PLS trials.

Original language	English
Pages (from-to)	976-983
Number of pages	8
Journal	Muscle and Nerve
Volume	73
Issue number	6
DOIs	https://doi.org/10.1002/mus.70192
State	Published - Jun 2026

Bibliographical note

Publisher Copyright:
© 2026 Wiley Periodicals LLC.

Funding

Daragh Heitzman, has received clinical support from the ALS Association and the MDA. He has received research support from Abcuro, Clene Nanomedicine, Prilenia Therapeutics, Seelos Therapeutics, Abbvie/Calico, Denali Therapeutics, Cytokinetics, Amylyx Pharmaceuticals, Abbvie, Immunovant Sciences GmbH, and the NIH. Ikjae Lee has received research funding from the National Institute of Health, worked as a consultant for Argenx, and served on the Independent Data Monitoring Committee for Regeneron. Lauren Elman, has received grants from Biogen, Genentech, Voyager Therapeutics, Novartis, Edgewise, Passage Bio, and Lupin Pharmaceuticals. Ali Habib has research support: Alexion/Astra Zeneca, argenx, UCB, Immunovant, Regeneron, CabalettaBio, Horizon/Amgen, Genentech/Roche, Novartis, Arcellx, and Merck; Honoraria: UCB, argenx, Alexion, Immunovant, Regeneron, Genentech/Roche, Alpine Immune Sciences, Inhibrx, NMDpharma, Grifols, Horizon/Amgen, Arcellx, and Merck; DSMB: NIH/NINDS, Immunis Biomedical, and Genentech/Roche. Ghazala Hayat is MTPA Speaker and Alexion, Argenx speaker. Stephen Goutman provided scientific consulting for Evidera, is listed as an inventor on a patent, Issue number US10660895, held by the University of Michigan titled “Methods for Treating Amyotrophic Lateral Sclerosis” that targets immune pathways for use in ALS therapeutics, and received research funding from NIH grants R01NS120926, R01NS127188, R01ES030049, K23ES027221, and R01AG070883, CDC grants 1R01TS000289 and R01TS000327, and ALS Association. J. Americo M. Fernandes, MD has received research funding from MGH Foundation, Ra Pharma, Biohaven, Clene, Prilenia, Seelosm DenaliTherapeutics, Calico, PTC therapeutics and Columbia University. Senda Ajroud‐Driss, MD has received research support from Amylyx Pharmaceutical, Biogen, Alnylam, MT‐Pharma America, Helixmith, Novartis, Woolsey Pharmaceuticals, Sanofi, Edgewise Therapeutics and received speaking honorarium from Biogen. Edward Kasarskis has grants: NINDS, ALS Association, Cynthia Shaw Crispen and Heidrich/Team 7 Endowments. Support as a member of the ALS Healey Platform Trial group, AB Science, Woolsey. David Walk has received support from the FDA, the Minnesota Office of Higher Education, the ALS Association, and the Bob Allison Ataxia Research Center, and has served as a paid consultant for Mitsubishi Tanabe Pharma America, Biogen, and Amylyx Therapeutics. Participation in this study was supported in part by the Curt O'Hagan fund of the Minnesota Medical Foundation. Wendy S. Johnston has received grant funding from Brain Canada, University Hospital Foundation Kaye Research fund, research funding to the institution from Alexion, ALS Pharma, Annexon, Biogen, Cytokinetics, Calico, Orion, Medicinova, Mitsubishi‐Tanabe Canada, QURALS, Sanofi, and consulting fees from Amylyx, Biogen, Cytokinetics, and Mitsubishi‐Tanabe Canada. Nicholas J. Maragakis received research support from NIH/NINDS, Department of Defense ALSRP. Clinical Trial Support: Eledon; Apellis Pharma; Biogen Idec; Cytokinetics; Helixmith; Calico; Sanofi; Massachusetts General Hospital; Medicinova. He has been a paid consultant for Amylyx, Cytokinetics, Orion, and Orphazyme. He is on the Scientific Advisory Board of the NurBio, Akava Therapeutics, and Secretome Therapeutics, and the NEALS Consortium. Sabrina Paganoni has received research grants from Alector Therapeutics, Amylyx, Anelixis Pharmaceuticals, Biohaven, Calico, Clene, Cytokinetics, Denali Therapeutics, Department of Defense, Muscular Dystrophy Association, National Institutes of Health, Prilenia, Revalesio Corporation, Seelos Therapeutics, UCB and consulting fees from Amylyx, Arrowhead, Biogen, BMS, Clene, Cytokinetics, Eikonizo, Janssen, Merck, PharmAust, Prilenia, Revalesio Corporation, SOLA Pharmaceuticals. Jaimin Shah has received research support from MDA, NIH, CDC, Healey Center, Corbus Pharmaceuticals, Argenx, and Abcuro. Bjorn Oskarsson has received research funding to the institution from NINDS, Columbia University/Tsumura Inc., Biogen, MediciNova, Calico, UniQure, Ashwatta and TARGET ALS and consulting fees from Columbia University/Tsumura Inc. and MediciNova. Lorne Zinman has received research support from The Focused Ultrasound Foundation, NIH, ALS Canada, and has served as a paid consultant for Mitsubishi Tanabe Pharma, Amylyx, Biogen, and Cytokinetics. Kelly Gwathmey is a medical advisory board member for Alexion. Dr. Gwathmey has received consulting honoraria from argenx, UCB, and Amgen. Dr. Gwathmey has received speaking honoraria from Alexion. Terry Heiman‐Patterson has received Clinical Trial Funding: Amylyx, Novartis, Healy Platform Trial, Axcellis, Brainstorm Therapeutics; Independent Investigator Funding: Mitsubishi Tanabe Pharma America, and Amylyx; Medical Advisory Boards: Mitsubishi Tanabe America, Amylyx, Novartis; and DSMB: AB Biosciences. Christina N. Fournier has received consulting feeds from Novartis, Roon, and QurALIS. Dr. Fournier has received research funding to her institution from Amylyx, Biogen, Columbia University, Denali, MT Pharma. Michael T. Pulley is a medical advisory board member for Alexion. Dr. Pulley has participated in regional advisory board meetings for Argenx, Immunovant, UCB, CSL/Behring, Catalyst, Amylyx, and Amgen. Stephen N. Scelsa received grant support from Amylyx and Sanofi. Christen Shoesmith has received research funding to their institution from ALS‐Pharma, Calico, Cytokinetics, Mitsubishi Tanabe, Sanofi, and Neurosense. Zachary Simmons has received research support from MT Pharma and has served as a paid consultant for Amylyx, Biogen, Clene, Corcept, and Insmed. Alexander V. Sherman has received research grants from FDA, NIH/NIA, NIH/NINDS, The ALS Association, and ALS Finding a Cure, and research study support from Mitsubishi Tanabe Pharma America, Biogen, and Amylyx. Hiroshi Mitsumoto has received support for organizing the international PLS conference from SPF, ALS Association, MDA Wings, Mitsubishi‐Tanabe Pharma, and private donations. This work was supported by the Mr. David Marren and family, Spastic Paraplegia Foundation, ALS Association, Mitsubishi Tanabe Pharma Corporation, Muscular Dystrophy Association, Wings over wall street, and Sean M. Healey and AMG center for ALS research. We are deeply grateful for the participation by our patients with PLS and their families. We also are profoundly thankful for the generous support from Mr. David Marren and his family, and the following funding agencies: Spastic Paraplegia Foundation, ALS Association, Mitsubishi‐Tanabe Pharma, MDA, and Wings Over Wall Street. The grant from Sean M. Healey and AMG Center for ALS, under the direction of Dr. Merit Cudkowicz, funded the study's Data Coordinating Center at the Neurological Clinical Research Institue of Mass General Brigham, including the use of its NeuroBANK clinical research platform and all data management and curation activities. Regina Santella, PhD, Mailman School of Public Health Department of Environmental Health arranged for the biorepository of the biosamples of the PLS Natural History Study. We also appreciate the PLSNHS Publication Committee for reviewing and approving the manuscript.

Funders	Funder number
University Hospital Foundation Kaye Research fund
Cytokinetics, Inc.
Voyager Therapeutics
Calico Consulting
Amylyx Therapeutics
NINDS FIRST
MDA
QURALS
Sanofi
Bob Allison Ataxia Research Center
MGH Foundation
Amylyx Pharmaceuticals Inc.
National Institutes of Health (NIH)
Amylyx and Sanofi
Muscular Dystrophy Association
Alector Therapeutics
Brain Canada Research
Abcuro Inc.
Mitsubishi‐Tanabe Canada
Spastic Paraplegia Foundation
FDA‐OPD
ALS Association
NIA
Prilenia Therapeutics
Genentech Incorporated
Minnesota Medical Foundation
Denali Therapeutics
NIH
US Department of Defense/Department of Army
AbbVie
Seelos Therapeutics
ALS Society of Canada
Biogen IDEC
Univ. of Northern British Columbia
Minnesota Office of Higher Education
Clene Nanomedicine
Mitsubishi Tanabe Pharma Corporation
Focused Ultrasound Surgery Foundation Borah
Novartis	US10660895
Michigan Diabetes Research Center, University of Michigan	R01NS120926, K23ES027221, R01ES030049, R01NS127188, R01AG070883
CDC	R01TS000327, 1R01TS000289

Keywords

EMG
motor neuron disease
natural history
neurofilament
primary lateral sclerosis

ASJC Scopus subject areas

Physiology
Clinical Neurology
Cellular and Molecular Neuroscience
Physiology (medical)

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10.1002/mus.70192

Cite this

@article{eb557918fe69455e9704fb3e1f77c52b,

title = "Prospective Validation of the New PLS Diagnostic Criteria From PLS Natural History Study: EMG and Neurofilament Analyses",

abstract = "Background: Primary lateral sclerosis (PLS) is an ultrarare upper motor neuron syndrome with a prognosis unique from classical ALS. The study of PLS is complicated by its rarity and the difficulty distinguishing PLS from ALS. We present data from a 1-year prospective follow-up study on PLS and efforts to distinguish it from ALS. Methods: Seventy-six PLS participants enrolled in this prospective natural history study. EMG studies, blood neurofilament light chain levels (NfLs), and demographic characteristics were obtained at baseline. At 1-year follow-up, repeat EMG studies were conducted to determine which participants fulfilled criteria for ALS. Baseline characteristics were then compared to determine features that predict reclassification. Results: Seventy participants completed 1-year follow-up. Five of the 70 were reclassified to ALS (7.1\%). Those reclassified had higher trends in baseline blood NfL levels (91.4 vs. 34.0 pg/mL, p = 0.13) and shorter symptom duration (39 vs. 69 months in the PLS group, p = 0.15). Reclassification was noted in both probable and definite PLS participants. All cases with a symptomatic duration of less than 2 years retained the PLS phenotype (5 of 5). NfL levels over 90 pg/mL predicted reclassification with 94\% specificity and 60\% sensitivity. No other features predicted reclassification to ALS. Conclusions: In our population, reclassification of PLS to ALS occurred at a low frequency at 1 year follow-up (7.1\%). Baseline NfL was the strongest predictor in differentiating UMN dominant ALS from PLS at 1-year follow-up. Based on our data, we propose EMG and NfL criteria for enrollment in future PLS trials.",

keywords = "EMG, motor neuron disease, natural history, neurofilament, primary lateral sclerosis",

author = "Eric Sorenson and Daragh Heitzman and Ikjae Lee and Grace Jang and Lauren Elman and Habib, \{Ali A.\} and James Wymer and Ghazala Hayat and Goutman, \{Stephen A.\} and Fernandes, \{J. Americo M.\} and Floeter, \{Mary Kay\} and Senda Ajroud-Driss and Kelly Gwathmey and Edward Kasarskis and Kisanuki, \{Yasushi Y.\} and Catherine Lomen-Hoerth and David Walk and Johnston, \{Wendy S.\} and Frank Diaz and Maragakis, \{Nicholas J.\} and Sabrina Paganoni and Jaimin Shah and Bjorn Oskarsson and Lorne Zinman and Terry Heiman-Patterson and Omar Jawdat and Fournier, \{Christina N.\} and Pulley, \{Michael T.\} and Scelsa, \{Stephen N.\} and Christen Shoesmith and Zachary Simmons and Sherman, \{Alexander V.\} and Hoover, \{Benjamin N.\} and Yun, \{Rebecca Y.\} and Ken Cheung and Hiroshi Mitsumoto and Hiroshi Mitsumoto and Lee Ikjae and Ken Cheung and Grace Jang and Hoover, \{Benjamin N.\} and Yun, \{Rebecca Y.\} and Santella, \{Regina M.\} and Frank Diaz and Richard Lewis and Susan Joh and Youstina Makary and Melendez, \{Noemi Hernandes\} and Sophia Mostowy and Fournier, \{Christina N.\}",

note = "Publisher Copyright: {\textcopyright} 2026 Wiley Periodicals LLC.",

year = "2026",

month = jun,

doi = "10.1002/mus.70192",

language = "English",

volume = "73",

pages = "976--983",

number = "6",

}

TY - JOUR

T1 - Prospective Validation of the New PLS Diagnostic Criteria From PLS Natural History Study

T2 - EMG and Neurofilament Analyses

AU - Sorenson, Eric

AU - Heitzman, Daragh

AU - Lee, Ikjae

AU - Jang, Grace

AU - Elman, Lauren

AU - Habib, Ali A.

AU - Wymer, James

AU - Hayat, Ghazala

AU - Goutman, Stephen A.

AU - Fernandes, J. Americo M.

AU - Floeter, Mary Kay

AU - Ajroud-Driss, Senda

AU - Gwathmey, Kelly

AU - Kasarskis, Edward

AU - Kisanuki, Yasushi Y.

AU - Lomen-Hoerth, Catherine

AU - Walk, David

AU - Johnston, Wendy S.

AU - Diaz, Frank

AU - Maragakis, Nicholas J.

AU - Paganoni, Sabrina

AU - Shah, Jaimin

AU - Oskarsson, Bjorn

AU - Zinman, Lorne

AU - Heiman-Patterson, Terry

AU - Jawdat, Omar

AU - Fournier, Christina N.

AU - Pulley, Michael T.

AU - Scelsa, Stephen N.

AU - Shoesmith, Christen

AU - Simmons, Zachary

AU - Sherman, Alexander V.

AU - Hoover, Benjamin N.

AU - Yun, Rebecca Y.

AU - Cheung, Ken

AU - Mitsumoto, Hiroshi

AU - Ikjae, Lee

AU - Cheung, Ken

AU - Jang, Grace

AU - Hoover, Benjamin N.

AU - Yun, Rebecca Y.

AU - Santella, Regina M.

AU - Diaz, Frank

AU - Lewis, Richard

AU - Joh, Susan

AU - Makary, Youstina

AU - Melendez, Noemi Hernandes

AU - Mostowy, Sophia

AU - Fournier, Christina N.

PY - 2026/6

Y1 - 2026/6

N2 - Background: Primary lateral sclerosis (PLS) is an ultrarare upper motor neuron syndrome with a prognosis unique from classical ALS. The study of PLS is complicated by its rarity and the difficulty distinguishing PLS from ALS. We present data from a 1-year prospective follow-up study on PLS and efforts to distinguish it from ALS. Methods: Seventy-six PLS participants enrolled in this prospective natural history study. EMG studies, blood neurofilament light chain levels (NfLs), and demographic characteristics were obtained at baseline. At 1-year follow-up, repeat EMG studies were conducted to determine which participants fulfilled criteria for ALS. Baseline characteristics were then compared to determine features that predict reclassification. Results: Seventy participants completed 1-year follow-up. Five of the 70 were reclassified to ALS (7.1%). Those reclassified had higher trends in baseline blood NfL levels (91.4 vs. 34.0 pg/mL, p = 0.13) and shorter symptom duration (39 vs. 69 months in the PLS group, p = 0.15). Reclassification was noted in both probable and definite PLS participants. All cases with a symptomatic duration of less than 2 years retained the PLS phenotype (5 of 5). NfL levels over 90 pg/mL predicted reclassification with 94% specificity and 60% sensitivity. No other features predicted reclassification to ALS. Conclusions: In our population, reclassification of PLS to ALS occurred at a low frequency at 1 year follow-up (7.1%). Baseline NfL was the strongest predictor in differentiating UMN dominant ALS from PLS at 1-year follow-up. Based on our data, we propose EMG and NfL criteria for enrollment in future PLS trials.

AB - Background: Primary lateral sclerosis (PLS) is an ultrarare upper motor neuron syndrome with a prognosis unique from classical ALS. The study of PLS is complicated by its rarity and the difficulty distinguishing PLS from ALS. We present data from a 1-year prospective follow-up study on PLS and efforts to distinguish it from ALS. Methods: Seventy-six PLS participants enrolled in this prospective natural history study. EMG studies, blood neurofilament light chain levels (NfLs), and demographic characteristics were obtained at baseline. At 1-year follow-up, repeat EMG studies were conducted to determine which participants fulfilled criteria for ALS. Baseline characteristics were then compared to determine features that predict reclassification. Results: Seventy participants completed 1-year follow-up. Five of the 70 were reclassified to ALS (7.1%). Those reclassified had higher trends in baseline blood NfL levels (91.4 vs. 34.0 pg/mL, p = 0.13) and shorter symptom duration (39 vs. 69 months in the PLS group, p = 0.15). Reclassification was noted in both probable and definite PLS participants. All cases with a symptomatic duration of less than 2 years retained the PLS phenotype (5 of 5). NfL levels over 90 pg/mL predicted reclassification with 94% specificity and 60% sensitivity. No other features predicted reclassification to ALS. Conclusions: In our population, reclassification of PLS to ALS occurred at a low frequency at 1 year follow-up (7.1%). Baseline NfL was the strongest predictor in differentiating UMN dominant ALS from PLS at 1-year follow-up. Based on our data, we propose EMG and NfL criteria for enrollment in future PLS trials.

KW - EMG

KW - motor neuron disease

KW - natural history

KW - neurofilament

KW - primary lateral sclerosis

UR - https://www.scopus.com/pages/publications/105032393873

UR - https://www.scopus.com/pages/publications/105032393873#tab=citedBy

U2 - 10.1002/mus.70192

DO - 10.1002/mus.70192

M3 - Article

C2 - 41772409

AN - SCOPUS:105032393873

SN - 0148-639X

VL - 73

SP - 976

EP - 983

JO - Muscle and Nerve

JF - Muscle and Nerve

IS - 6

ER -

Prospective Validation of the New PLS Diagnostic Criteria From PLS Natural History Study: EMG and Neurofilament Analyses

Abstract

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