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Neurol Neuroimmunol Neuroinflamm
Neurol Neuroimmunol Neuroinflamm
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Neurology® Neuroimmunology & Neuroinflammation
2332-7812
Lippincott Williams & Wilkins Hagerstown, MD

39270144
NXI-2024-100342DN
10.1212/NXI.0000000000200311
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Research Article
IGLON5 Frequency in Idiopathic REM Sleep Behavior Disorder
A Multicenter Study
https://orcid.org/0000-0002-6468-4734
Postuma Ronald MD, MSc
https://orcid.org/0000-0002-0751-8967
Vorasoot Nisa MD
https://orcid.org/0000-0002-2833-8826
St Louis Erik K. MD, MSc
https://orcid.org/0009-0001-5930-9796
Pelletier Amélie PhD
https://orcid.org/0000-0003-3876-3196
Lim Miranda M. MD, PhD
https://orcid.org/0000-0002-6992-6851
Elliott Jonathan PhD
https://orcid.org/0000-0003-1132-0563
Gagnon Jean-Francois PhD
Gan-Or Ziv MD, PhD
https://orcid.org/0000-0003-4086-9598
Forsberg Leah K. PhD
https://orcid.org/0000-0002-1282-9866
Fields Julie A. PhD
https://orcid.org/0000-0003-4813-756X
Ross Owen A. MD, PhD
https://orcid.org/0000-0003-1263-6850
Singer Wolfgang MD
https://orcid.org/0000-0003-0503-3736
Huddleston Daniel E. MD
https://orcid.org/0000-0002-5079-035X
Bliwise Donald L. MD
https://orcid.org/0000-0002-8817-6590
Avidan Alon Y. MD, MpH
https://orcid.org/0000-0001-7535-0724
Howell Michael MD
https://orcid.org/0000-0002-0095-2680
Schenck Carlos H. MD
https://orcid.org/0009-0004-2195-0264
McLeland Jennifer PhD
https://orcid.org/0000-0003-2042-8445
Davis Albert A. MD
https://orcid.org/0000-0001-8467-371X
Criswell Susan R. MD, MSCI
https://orcid.org/0000-0002-9237-1516
Videnovic Aleksandar MD, MSc
https://orcid.org/0000-0002-0539-5115
During Emmanuel H. MD, PhD
https://orcid.org/0000-0001-8488-0313
Miglis Mitchell G. MD
https://orcid.org/0000-0002-4153-8187
Boeve Bradley F. MD
https://orcid.org/0000-0001-9397-7475
Ju Yo-El S. MD
https://orcid.org/0000-0001-6856-8143
McKeon Andrew MD
as the North American Prodromal Synucleinopathy (NAPS) Consortium
From the Montreal Neurological Institute and Department of Neurology and Neurosurgery (R.P.), Montréal, McGill University; Center for Advanced Research in Sleep Medicine (R.P., A.P., J.-F.G.), Hôpital du Sacré-Coeur de Montréal; Research Institute of the McGill University Health Centre (R.P., A.P., Z.G.-O.), Montreal, Quebec, Canada; Neurology and Medicine (N.V., L.K.F., J.A.F., O.A.R., W.S., B.F.B., A.M.), Mayo Clinic, Rochester, MN; Division of Neurology (N.V., E.K.S.L.), Department of Medicine, Faculty of Medicine, Khon Kaen University, Thailand; Department of Neurology (M.M.L., J.E.), Oregon Health & Science University; Department of Behavioral Neuroscience (M.M.L.); Department of Pulmonary and Critical Care Medicine; Oregon Institute of Occupational Health Sciences; Mental Illness Research Education and Clinical Center (M.M.L.); Neurology; National Center for Rehabilitative Auditory Research; Research Service (M.M.L., J.E.), VA Portland Health Care System, OR; Département of Psychology (J.-F.G.), Université du Québec à Montréal; Department of Human Genetics (Z.G.-O.), McGill University, Montréal, Québec, Canada; Neurology (D.E.H., D.L.B.), Emory University, Atlanta, GA; Neurology (A.Y.A.), Sleep Disorders Center, University of California, Los Angeles; Minnesota Regional Sleep Disorders Center (M.H., C.H.S.), and Departments of Psychiatry, Hennepin County Medical Center, and University of Minnesota Medical School; Minnesota Regional Sleep Disorders Center (M.H.), Hennepin County Medical Center, Minneapolis, MN; Washington University School of Medicine (J.M., A.A.D., Y.-E.S.J.), Saint Louis, MO; Barrow Neurological Institute (S.R.C.), Phoenix, AZ; Movement Disorders Unit (A.V.), Division of Sleep Medicine, Massachusetts General Hospital; Neurological Clinical Research Institute (A.V.), Harvard Medical School, Boston, MA; Psychiatry and Behavioral Sciences (E.H.D., M.G.M.), Stanford University, Redwood City, CA; Neurology and Neurological Sciences (E.H.D., M.G.M.), Stanford University, Palo Alto, CA; and Neurology (E.H.D.), Mt. Sinai School of Medicine, New York.
Correspondence Dr. Postuma ron.postuma@mcgill.ca
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.

The Article Processing Charge was funded by the NIH.

Submitted and externally peer reviewed. The handling editor was Editor Josep O. Dalmau, MD, PhD, FAAN.

11 2024
13 9 2024
13 9 2024
11 6 e20031106 6 2024
23 7 2024
Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.
2024
American Academy of Neurology
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Background and Objectives

Idiopathic/isolated REM sleep behavior disorder (iRBD) has been strongly linked to neurodegenerative synucleinopathies such as Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. However, there have been increasing reports of RBD as a presenting feature of serious and treatable autoimmune syndromes, particularly IGLON5. This study's objective was to investigate the frequency of autoantibodies in a large cohort of participants with iRBD.

Methods

Participants were enrolled in the North American Prodromal Synucleinopathy cohort with polysomnography-confirmed iRBD, free of parkinsonism and dementia. Plasma samples were systematically screened for the autoantibodies IGLON5, DPPX, LGI1, and CASPR2 using plasma IgG cell-based assay. Positive or equivocal results were confirmed by repeat testing, plus tissue-based indirect immunofluorescence assay for IGLON5.

Results

Of 339 samples analyzed, 3 participants (0.9%) had confirmed positive IGLON5 autoantibodies in the cell-based assay, which were confirmed by the tissue-based assay. An additional participant was positive for CASPR2 with low titer by cell-based assay only (of lower clinical certainty). These cases exhibited a variety of symptoms including dream enactment, cognitive decline, autonomic dysfunction, and motor symptoms. In 1 IGLON5 case and the CASPR2 case, evolution was suggestive of typical synucleinopathy, suggesting the possibility that findings were incidental. However, 2 participants with IGLON5 died before diagnosis was clinically suspected, with a final clinical picture highly suggestive of autoimmune disease.

Discussion

Our finding that nearly 1% of a large iRBD cohort may have a serious but potentially treatable autoantibody syndrome has important clinical implications. In particular, it raises the question of whether autoantibody testing for IGLON-5-IgG should be widely implemented for participants with iRBD, considering the difficulty in diagnosis of autoimmune diseases, their response to treatment, and the potential for rapid disease progression. However, any routine testing protocol will also have to consider costs and potential adverse effects of false-positive findings.

Trial Registration Information

NCT03623672

OPEN-ACCESSTRUE
==== Body
pmcIntroduction

REM sleep behavior disorder (RBD) is a parasomnia characterized by loss of the normal paralysis that accompanies REM sleep, such that patients ‘act out’ their dreams.1 RBD is generally considered to be a strong marker of neurodegenerative synucleinopathy; most of the patients with idiopathic/isolated RBD eventually develop either Parkinson disease (PD), dementia with Lewy bodies, or multiple system atrophy (MSA).2 The association with neurodegenerative synucleinopathy is highly specific; an autopsy study found that 98% of cases of polysomnography-confirmed RBD had pathologic synuclein deposition.3

Recently, there have been an increasing number of reports linking RBD with antibody-mediated syndromes, most notably those associated with IGLON5 and voltage-gated potassium channels (CASPR2, LGI1, and DPPX).4-8 In these cases, RBD symptoms often occur as part of a generalized sleep-wake disturbance, sometimes presenting subacutely in association with prominent sleep apnea and non-REM parasomnia. Polysomnograms generally detect severe disruption of sleep stages (termed variably as undifferentiated REM sleep, agrypnia excitata, etc). Response to treatment varies, but some show substantial improvement on immunosuppressive therapy.9

Given that these conditions may constitute a significant and potentially reversible cause of neurodegeneration, it is vital to assess how commonly they might occur in RBD, especially among those who are not identified as having a classic antibody-mediated syndrome. To this end, we undertook a systematic screening for autoantibodies in a large cohort of participants with iRBD enrolled in the North American Prodromal Synucleinopathy (NAPS) study.

Methods

All participants were enrolled in the NAPS cohort.10 This cohort follows participants with polysomnography-confirmed iRBD. All participants are free of parkinsonism and dementia and have no known alternate explanation for their RBD (i.e., any participant with a known antibody-mediated RBD would be excluded). Baseline characteristics of the cohort and details of clinical assessment procedures have been described in detail elsewhere.10 All participants provided informed consent to participate in the study, which received approval from the respective institutional research ethics boards.

Antibody Testing

Sampling was performed on 500-uL aliquots of plasma that had been collected between 2018 and 2022 and stored at −80°C. Plasma IgG testing was undertaken by the cell-based assay (CBA) that used slides consisting of a mosaic of biochips, each chip consisting of human embryonic kidney 293 cells transfected with complementary DNA for IGLON5, DPPX, LGI1, or CASPR2. The slides were fixed with 1% formalin and stored at 4°C (Euroimmun AG, Lubeck, Germany). CBA was performed using participant plasma (1:10 dilution), incubated with the transfected cells. The cells were then washed and exposed to fluorescein isothiocyanate–conjugated (FITC) goat anti-human IgG (Southern Biotech, Birmingham, AL). Samples positive or equivocal by CBA underwent repeat CBA testing to clarify results. Samples yielding a positive result for IGLON5-IgG by CBA were then tested by the murine tissue-based indirect immunofluorescence assay (IFA), which used a composite substrate of mouse hippocampus, cerebral cortex, cerebellum, basal ganglia, thalamus, kidney, and stomach. 4-micrometer frozen cryosections were fixed, blocked, and incubated with participant plasma for 40 minutes and then with FITC secondary antibody. Titrations to the end point by doubling dilutions were undertaken (normal, ≤1:240).

Data Availability

The principal author (RP) has full access to the data used in the analyses in the study. The full deidentified data set will be made accessible after standard written request according to NAPS guidelines.

Results

A total of 339 samples were analyzed, of which 329 were negative in all assays (Figure for flow diagram). 7 tested equivocally positive on preliminary assay for CASPR2; in 6 cases, these results were not confirmed on cell-based assay repeat testing, and 1 case was positive on low titer by cell-based assay. A total of 3 participants (0.9%) were positive for IGLON5. Details of these cases, as well as the low-titer CASPR2 case, are given further.

Figure Participant Flow and Testing Results

Case 1—IGLON5

Patient 1 was a 70-year-old man who reported a 3-year history of dream enactment behavior. He was known to have obstructive sleep apnea treated with CPAP. The diagnosis of obstructive sleep apnea was made by an outside sleep laboratory 3 years earlier (details of this trace are unavailable). CPAP had been provided with good compliance. Our baseline polysomnogram (performed on CPAP) showed overall good control of obstructive sleep apnea, with AHI of 5.9, and a total of 4 minutes with oxygen saturation less than 90%. Sleep efficiency was poor (47%), and he took 2 hours to fall asleep. No stridor was either reported on history or observed on our PSG. No elements of NREM parasomnia were evident at time of initial clinical visit, PSG, or baseline research visit. On video PSG, there were no pseudo-purposeful movements during NREM sleep, but during REM sleep, numerous twitches of hands and fingers and face were observed (there were no aggressive dream enactment behaviors observed). At baseline research visit, there was mild insomnia without somnolence (this reflected an improvement over the past 3 years, during which he had been troubled by severe sleep-onset insomnia). He had been previously prescribed venlafaxine, without clear changes in dream enactment when medications were stopped or started. Medical history was significant for type 2 diabetes. His father had dementia, although the specific diagnosis and clinical features were unknown.

At the baseline visit, he reported numerous autonomic symptoms, including orthostatic intolerance (without objective blood pressure drop on examination), urinary frequency, severe erectile dysfunction, and constipation. He had longstanding symptoms of depression and anxiety. Motor symptoms included difficulty with swallowing, drooling, and speech/articulation, with subjective gait slowing and imbalance. Baseline motor examination revealed only subtle hypomimia with a quiet voice, equivocal slowing of leg movements, and subtle gait slowing (total MDS-UPDRS Part III score = 5). There was no rigidity, bradykinesia, or cerebellar dysfunction. Quantitative motor testing revealed slowed alternate tap test and reduced Purdue PegBoard performance. Olfactory testing was normal. Color vision was normal (Farnsworth-Munsell 100 = 56). Although his Montreal Cognitive Assessment (MoCA) score was low at 20, this was confounded by education and language barrier; cognition according to both the participant and his family was unchanged from his usual state.

One year later, sleep symptoms remained largely unchanged, with some improvement in depression, anxiety, and autonomic symptoms. His bed partner noted rare episodes of sleepwalking over the past year, suggesting possible NREM parasomnia. Motor examination was improved, with the MDS-UPDRS Part III score now only 1. Quantitative testing was also improved to within the low-normal range, and olfaction remained normal.

However, on the third visit (in 2020), symptoms had worsened. The frequency of dream enactment had increased to almost nightly, without change in the character of dream enactment. There was no worsening of insomnia or somnolence. All autonomic symptoms had recurred, and he now had a postural systolic blood pressure drop of 26 mm Hg (supine to standing at 3 minutes) with symptoms of urinary retention. He noted worsening of bulbar and gait symptoms. Examination revealed nonspecific generalized slowing/clumsiness, without decrementing bradykinesia or clear cerebellar signs. There was no rigidity or tremor. He had reduced postural stability. We observed no extraocular movement abnormalities. The MDS-UPDRS Part II score was 12. We raised concerns about possible early evolution to multiple system atrophy—cerebellar type—although he did not meet criteria for MSA at that time. Although we proposed closer research-based follow-up, he elected to return to his clinical neurologist and declined further research follow-up (he provided permission to contact him by telephone if needed).

IGLON5-IgG was positive by cell-based assay, and the distinctive staining pattern was also detected by tissue IFA (end-point dilution was 1:1920). On receipt of testing results, the participant and his treating team were promptly contacted. Unfortunately, since the last visit, he had continued to decline neurologically. His clinical neurology team gave a working diagnosis of MSA-C, based mainly on symptoms of orthostatic hypotension, bulbar symptoms, and gait instability. However, they noted numerous atypical features, most prominently atypical and nonlocalizable horizontal gaze abnormalities, very severe bulbar symptoms disproportionate to the remainder of the examination, and the later development of choreiform movements in the lower limbs. He developed aspiration pneumonia and was admitted twice to hospital. With the second admission, he contracted comorbid COVID-19 and died soon afterward, 6 months before antibody test results became available. No autopsy was performed.

Case 2—IGLON5

Patient 2 was a 75-year-old man who presented with a 15-year history of dream enactment behavior, along with occasional sleepwalking. A PSG in 2006 performed in an outside center had noted abnormal movements during REM sleep, but no diagnosis of RBD was made at that time. At the baseline visit in our center, he reported slight insomnia and slight daytime somnolence (although the Epworth Sleepiness Scale score was only 4). PSG in our center noted mild obstructive sleep apnea with AHI of 9 and a minimum oxygen saturation of 91%. CPAP was provided at this time, and the participant remained compliant on this. Medical history was otherwise significant for type 2 diabetes. There was no family history of RBD, dementia, or parkinsonism.

At baseline, he reported mild cognitive symptoms, particularly with memory and executive function. Autonomic symptoms included slight urinary frequency and occasional constipation without symptoms of orthostatic intolerance. There were no motor symptoms except for slight swallowing difficulty. He had a systolic blood pressure drop of 21 mm Hg from supine to standing at 3 minutes. The MoCA score was 25/30. Neurologic examination was normal. Motor examination was entirely normal with the MDS-UPDRS Part III score of 0. Quantitative motor testing revealed normal alternate tap test and equivocally reduced Purdue Pegboard performance. Olfaction was reduced, with a Brief Smell Identification Test score of 5/12. Color vision testing was abnormal (FM-100 = 284).

IGLON5-IgG was positive by cell-based assay, and the distinctive staining pattern was also detected by tissue IFA (end-point dilution was 1:960). However, 4 months after baseline visit, he was diagnosed with esophageal cancer, and he underwent an esophagectomy. This was conducted successfully, with no noted intraoperative complications. However, postoperative course was complicated by severe delirium. After discharge home, there was significant deterioration in cognitive abilities. He developed severe circadian disruption. Frequency of RBD episodes increased. As the neurologic disorder progressed, he required intubation, subsequently became comatose, and eventually died. No autopsy was performed.

Case 3—IGLON5 Seropositivity With Alpha-Synucleinopathy

Clinical details of Case 3 have been withheld from publication at participant request. IGLON5-IgG was positive by cell-based assay, and the distinctive staining pattern was also detected by tissue IFA (end-point dilution was 1:4,800). This participant had numerous clinical and radiologic markers of synucleinopathy, including a positive synuclein seeding assay, and had no improvement with immunotherapy against IGLON5.

Other Antibody Findings

Results of DPPX and LGI-1 were negative in all cases. 1 case demonstrated equivocal CASPR2 seropositivity, with a result profile that suggested a possible incidental/false-positive finding. This participant had developed classic tremor-dominant parkinsonism responsive to levodopa with olfactory loss. Antibody testing performed on baseline samples (collected 3 years before PD diagnosis) found positivity of low-titer CASPR2 (1:10, considered nonspecific for neurologic autoimmunity) and low-titer anti-GAD65 (0.08) positivity. Of note, over the previous year, he had underwent an extensive systemic workup for a general medical condition, which involved repeated CT scans of the chest, abdomen, and pelvis. None showed evidence for malignancy (a previous colonoscopy was also negative). The possibility of offering immunotherapy was discussed, but the participant declined. As of the last visit, cognitive, motor, autonomic, and sleep/RBD symptoms had remained stable.

Discussion

The central finding of this study was that just under 1% of a large research cohort of people with idiopathic RBD may have had an underlying serious, potentially treatable IGLON5 autoimmunity syndrome. Two participants died before IGLON5 antibody positivity was known, without the diagnosis being previously suspected clinically.

These results raise an important question: should patients with iRBD undergo routine testing for autoantibodies, or would a more selective approach suffice? Regarding a selective approach, delving deeper into the clinical histories, there may have been some diagnostic clues, albeit with uncertain predictive value. For instance, 3 of 4 participants were diagnosed with obstructive sleep apnea, which is highly prevalent in these autoimmune syndromes (none had central apnea). However, 55% of the remaining NAPS cohort also had a sleep apnea diagnosis.10 Two cases had some NREM parasomnia features, which are classically seen in IGLON5-associated disease. However, 11% of the same cohort has reported sleepwalking or other NREM features alongside their RBD. Absence of hyposmia might have been a very useful clue because hyposmia is a strong marker of Lewy body disease; however, only case 1 had normal olfaction. While both fatal cases experienced a period of rapid decline, this was not apparent on initial visits because case 1 exhibited spontaneous improvement between baseline and 1 year and case 2's decline occurred after surgery for cancer, confounding the interpretation. In summary, both cases 1 and 2 had several atypical features at some point in their illness, which were arguably of high enough specificity to argue that a selective approach to testing could be warranted.

The second option would be to routinely test all patients, although this raises important concerns about cost, a low pretest probability (i.e., 0.9% positivity rate in our study), and potential harm related to incidental or false-positive findings. In particular, one of the IGLON5 cases and the single positive CASPR2 case have followed a clinical trajectory more akin to what is typically seen in synucleinopathy, including an evolution to classic PD in one. This may suggest that these positive antibody tests were only incidental findings.

Regarding treatment decisions in the case of a positive test, detecting IGLON5-IgG by both cell-based and tissue-based assays provides a high level of confidence in the serologic diagnosis, even in the absence of CSF antibody testing.9 IGLON5 autoimmunity seems to occur in the borderlands of neurodegeneration and autoimmunity. Pathologic studies have revealed 3R/4R tauopathy, which could support a primary degenerative etiology.11 However, systemic screens of patients with clinical 4R tauopathy have not found positive tests, and functional effects of IGLON5-IgGs in neuronal cell cultures and responses to immunotherapy in some patients are consistent with a primary autoimmune etiology.12,13 This might suggest that IGLON-5 results are relatively unlikely to be incidental and so warranted consideration of a trial of treatment in that case. By contrast, the CASPR2 antibody was of very low titer and is, therefore, unlikely to be of clinical significance, given evolution to classic PD with levodopa responsivity and absence of other syndromic autoimmune features; CASPR2 antibody positivity at 1:10 titer may have lower predictive value for an autoimmune diagnosis than titers of 1:100.

In conclusion, we have found potentially treatable positive IGLON5 syndromes in 1% of patients with iRBD in whom the diagnosis was not clinically suspected. These findings raise considerations of implementing screening protocols for patients with iRBD, particularly those who do not present with features indicative of underlying synucleinopathies.

Acknowledgment

Data collection and dissemination of the data presented in this study were supported by the NAPS Consortium (R34 AG056639 and U19 AG071754 funded by the National Institutes of Health), the National Centralized Repository for Alzheimer's Disease and Related Dementias (U24 AG021886), the National Alzheimer's Coordinating Center (U24 AG072122), the National Institutes of Health (P50 AG016574, P30 AG62677), Veterans Affairs RRD 1K2 RX002947, and Canadian support via Research Chair in Cognitive Decline in Pathological Aging. The authors acknowledge the invaluable contributions of the participants in NAPS Consortium and the assistance of the support staff at each of the participating sites. The interpretations and conclusions expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs, the National Institute of Health, or the United States government.

Study Funding

NAPS Consortium (R34 AG056639 and U19 AG071754 funded by the NIH), the National Centralized Repository for Alzheimer's Disease and Related Dementias (U24 AG021886), the National Alzheimer's Coordinating Center (U24 AG072122), the National Institutes of Health (P50 AG016574, P30 AG62677), Veterans Affairs RRD 1K2 RX002947, and Canadian support via Research Chair in Cognitive Decline in Pathologic Aging.

Disclosure

R. Postuma has received support from the Fonds de Recherche du Quebec - Santé, the Canadian Institutes of Health Research, the Parkinson Society of Canada, the Weston-Garfield Foundation, the Michael J. Fox Foundation, and the Webster Foundation and personal fees from Takeda, Roche/Prothena, Teva Neurosciences, Novartis Canada, Biogen, Boehringer Ingelheim, Theranexus, GE HealthCare, Jazz Pharmaceuticals, Abbvie, Jannsen, Otsuko, Phytopharmics, Inception Sciences, and Curasen. N. Vorasoot has no disclosures. E.K. St. Louis has received support from NIH (NIA, NINDS, and NHLBI), the Michael J. Fox Foundation, Harmony, Inc., and Sunovion, Inc.; A.Y. Avidan has received consultant fees from Avadel, Merck, Takeda, Eisai, Idorsia and Harmony and speaker honoraria from Merck, Eisai, Harmony and Idorsia, A. Pelletier has no disclosures. M.M. Lim has received support from federal, state, and non-profit organizations including Department of Veteran Affairs, Department of Defense, NIH (NIMH, NHLBI, NIA, NCCIH, NINDS, NIGMS, NCATS), NSF, Center for Neuroscience & Regenerative Medicine (Henry Jackson Foundation), Oregon Medical Research Foundation, Collins Medical Trust, Brain & Behavior Foundation (NARSAD), American Sleep Medicine Foundation, Hartford Center of Gerontological Excellence, Pacific Northwest National Laboratory, and Portland VA Research Foundation. M.M. Lim receives compensation as a member of the Scientific Advisory Board for Applied Cognition. J. Elliott has received support from the Department of Veteran Affairs, NIH (NHLBI, NIA, NCCIH), Oregon Medical Research Foundation, Portland VA Research Foundation, Eugene & Clarissa Evonuk Foundation in Environmental Physiology, and American Heart Association. J.-F. Gagnon has received support from the NIH, the Canadian Institutes of Health Research and the Fonds de Recherche du Québec - Santé. Z. Gan-Or has received support from Bial, Bial Biotech, Capsida Biotherapeutics, Handl Therapeutics, Idorsia, Neuron23, Ono Pharmaceutical, Prevail Therapeutics, UCB, and Vanqua Bio. L.K. Forsberg has no disclosures. J.A. Fields has received support from the NIH and is a consultant for Medtronic, Inc. O.A. Ross has no disclosures. W. Singer has no disclosures. D.E. Huddleston has received support from NIH (NIA, NINDS, Department of Veteran Affairs, the American Parkinson's Disease Association Center for Advanced Research, the Emory Udall Parkinson's Disease Research Center, the Emory Lewy Body Dementia Association Research Center of Excellence, the Emory Alzheimer's Disease Research Center, the Michael J. Fox Foundation, the Georgia Research Alliance, the Bumpus Family Foundation, and the McMahon Family. D.L. Bliwise has received support from the NIH and has been a Consultant to CliniLabs, Eisai, Ferring, Huxley, Idorsia and Merck. M. Howell has received research support from the NIH. Dr. Schenck has received a one-time speaker honorarium from Eisai, Inc. J. McLeland has no disclosures. A.A. Davis has received research support from the Department of Defense, NIH (NINDS), and the Michael J. Fox Foundation. S.R. Criswell has received support from the NIH and consulting fees from Abbvie and Sio Gene Therapies. A. Videnovic has received research support from the NIH and the Michael J. Fox Foundation; consultancy fees from Alexion Pharmaceuticals, Biogen, XW Pharma, and Jazz. E.H. During has received support from Jazz Pharmaceuticals, Sanofi, Takeda, Rythm Inc., and the Feldman Foundation CA. M.G. Miglis has received support from Jazz Pharmaceuticals, Embr Wave, and Biohaven Pharmaceuticals; consulting fees from 2nd MD, Infinite MD and Guidepoint LLC; payments for CME lectures from MED-IQ; and royalties from Elsevier Inc. B.F. Boeve has served as an investigator for clinical trials sponsored by Alector, Biogen and Transposon. He serves on the Scientific Advisory Board of the Tau Consortium, which is funded by the Rainwater Charitable Foundation. He receives support from NIH, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, the Little Family Foundation, and the Ted Turner and Family Foundation. Y.-E.S. Ju has received support from the NIH and the Centene Corporation contract (P19-00559) for the Washington University-Centene ARCH Personalized Medicine Initiative and compensation for consultant activities for Applied Cognition. A. McKeon reports research funding from the National Institutes of Health: RO1NS126227, U01NS120901; has patents issued for GFAP and MAP1B-IgGs and patents pending for PDE10A, Septins-5 and -7, and KLCHL11-IgGs; and has consulted for Janssen and Roche pharmaceuticals, without personal compensation. Go to Neurology.org/NN for full disclosures.

Appendix Authors

Name	Location	Contribution	
Ronald Postuma, MD, MSc	Montreal Neurological Institute and Department of Neurology and Neurosurgery, Montréal, McGill University; Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Coeur de Montréal; Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Nisa Vorasoot, MD	Neurology and Medicine, Mayo Clinic, Rochester, MN; Division of Neurology, Department of Medicine, Faculty of Medicine, Khon Kaen University, Thailand	Drafting/revision of the manuscript for content, including medical writing for content	
Erik K. St. Louis, MD, MSc,	Division of Neurology, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Amélie Pelletier, PhD	Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Coeur de Montréal; Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Miranda M. Lim, MD, PhD	Department of Neurology, Oregon Health & Science University; Department of Behavioral Neuroscience; Department of Pulmonary and Critical Care Medicine; Oregon Institute of Occupational Health Sciences; 8. Mental Illness Research Education and Clinical Center; Neurology; National Center for Rehabilitative Auditory Research; 9. Research Service, VA Portland Health Care System, OR	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Jonathan Elliott, PhD	Department of Neurology, Oregon Health & Science University; Research Service, VA Portland Health Care System, Portland, OR	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Jean-Francois Gagnon, PhD	Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Coeur de Montréal; Département of Psychology, Université du Québec à Montréal, Montréal, Québec, Canada	Drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data	
Ziv Gan-Or, MD, PhD	Research Institute of the McGill University Health Centre; Department of Human Genetics, McGill University, Montréal, Québec, Canada	Drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data	
Leah K. Forsberg, PhD	Neurology and Medicine, Mayo Clinic, Rochester, MN	Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data	
Julie A. Fields, PhD	Neurology and Medicine, Mayo Clinic, Rochester, MN	Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data	
Owen A. Ross, MD, PhD	Neurology and Medicine, Mayo Clinic, Rochester, MN	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Wolfgang Singer, MD	Neurology and Medicine, Mayo Clinic, Rochester, MN	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Daniel E. Huddleston, MD	Neurology, Emory University, Atlanta, GA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data	
Donald L. Bliwise, MD	Neurology, Emory University, Atlanta, GA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Alon Y. Avidan, MD, MpH	Neurology, Sleep Disorders Center, University of California, Los Angeles	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Michael Howell, MD	Minnesota Regional Sleep Disorders Center, and Departments of Psychiatry, Hennepin County Medical Center, and University of Minnesota Medical School; Minnesota Regional Sleep Disorders Center, Hennepin County Medical Center, Minneapolis, MN	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Carlos H. Schenck, MD	Minnesota Regional Sleep Disorders Center, and Departments of Psychiatry, Hennepin County Medical Center, and University of Minnesota Medical School, Minneapolis, MN	Drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data	
Jennifer McLeland, PhD	Washington University School of Medicine, Saint Louis, MO	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Albert A. Davis, MD	Washington University School of Medicine, Saint Louis, MO	Drafting/revision of the manuscript for content, including medical writing for content	
Susan R. Criswell, MD, MSCI	Barrow Neurological Institute, Phoenix, AZ	Drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data	
Aleksandar Videnovic, MD, MSc	Movement Disorders Unit, Division of Sleep Medicine, Massachusetts General Hospital; Neurological Clinical Research Institute, Harvard Medical School, Boston, MA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Emmanuel H. During, MD, PhD	Psychiatry and Behavioral Sciences, Stanford University, Redwood City; Neurology and Neurological Sciences, Stanford University, Palo Alto, CA; Neurology, Mt. Sinai School of Medicine, New York	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Mitchell G. Miglis, MD	Psychiatry and Behavioral Sciences, Stanford University, Redwood City, CA; Neurology and Neurological Sciences, Stanford University, Palo Alto, CA	Drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data	
Bradley F. Boeve, MD	Neurology and Medicine, Mayo Clinic, Rochester, MN	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Yo-El S. Ju, MD	Washington University School of Medicine, Saint Louis, MO	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Andrew McKeon, MD	Neurology and Medicine, Mayo Clinic, Rochester, MN	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	

Glossary

CBA cell-based assay

FITC fluorescein isothiocyanate–conjugated

IFA immunofluorescence assay

iRBD idiopathic/isolated REM sleep behavior disorder

MoCA Montreal Cognitive Assessment

MSA multiple system atrophy

NAPS North American Prodromal Synucleinopathy

PD Parkinson disease

RBD REM sleep behavior disorder
==== Refs
References

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8. Gadoth A, Devine MF, Pittock SJ, et al. Sleep disturbances associated with DPPX autoantibodies: a case series. J Neurol. 2023;270 (7 ):3543-3552. doi:10.1007/s00415-023-11698-y 37024733
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10. Elliott JE, Lim MM, Keil AT, et al. Baseline characteristics of the North American prodromal Synucleinopathy cohort. Ann Clin Transl Neurol. 2023;10 (4 ):520-535. doi:10.1002/acn3.51738 36751940
11. Gelpi E, Hoftberger R, Graus F, et al. Neuropathological criteria of anti-IgLON5-related tauopathy. Acta Neuropathol. 2016;132 (4 ):531-543. doi:10.1007/s00401-016-1591-8 27358064
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