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Clinical Trial
. 2023 Apr;10(4):520-535.
doi: 10.1002/acn3.51738. Epub 2023 Feb 8.

Baseline characteristics of the North American prodromal Synucleinopathy cohort

Jonathan E Elliott #  1   2 , Miranda M Lim #  2   3   4   5   6   7   8 , Allison T Keil  1 , Ronald B Postuma  9   10 , Amelie Pelletier  11 , Jean-François Gagnon  10   11 , Erik K St Louis  12 , Leah K Forsberg  12 , Julie A Fields  12 , Daniel E Huddleston  13 , Donald L Bliwise  13 , Alon Y Avidan  14 , Michael J Howell  15   16 , Carlos H Schenck  15 , Jennifer McLeland  17 , Susan R Criswell  17 , Aleksandar Videnovic  18   19 , Emmanuel H During  20   21 , Mitchell G Miglis  20   21 , David R Shprecher  22 , Joyce K Lee-Iannotti  22 , Bradley F Boeve  12 , Yo-El S Ju  17 ; North American Prodromal Synucleinopathy (NAPS) Consortium
Collaborators, Affiliations
Clinical Trial

Baseline characteristics of the North American prodromal Synucleinopathy cohort

Jonathan E Elliott et al. Ann Clin Transl Neurol. 2023 Apr.

Abstract

Objective: Rapid eye movement (REM) sleep behavior disorder (RBD) is widely considered a prodromal synucleinopathy, as most with RBD develop overt synucleinopathy within ~10 years. Accordingly, RBD offers an opportunity to test potential treatments at the earliest stages of synucleinopathy. The North American Prodromal Synucleinopathy (NAPS) Consortium has created a multisite RBD participant, primarily clinic-based cohort to better understand characteristics at diagnosis, and in future work, identify predictors of phenoconversion, develop synucleinopathy biomarkers, and enable early stage clinical trial enrollment.

Methods: Participants ≥18 years of age with overnight polysomnogram-confirmed RBD without Parkinson's disease, dementia, multiple system atrophy, or narcolepsy were enrolled from nine sites across North America (8/2018 to 4/2021). Data collection included family/personal history of RBD and standardized assessments of cognitive, motor, sensory, and autonomic function.

Results: Outcomes are primarily reported based on sex (361 total: n = 295 male, n = 66 female), and secondarily based on history of antidepressant use (n = 200 with, n = 154 without; with correction for sex differences) and based on extent of synucleinopathy burden (n = 56 defined as isolated RBD, n = 305 defined as RBD+ [i.e., exhibiting ≥1 abnormality]). Overall, these participants commonly demonstrated abnormalities in global cognition (MoCA; 38%), motor function (alternate tap test; 48%), sensory (BSIT; 57%), autonomic function (orthostatic hypotension, 38.8%), and anxiety/depression (BAI and PHQ-9; 39.3% and 31%, respectively).

Interpretation: These RBD participants, assessed with extensive history, demographic, cognitive, motor, sensory, and autonomic function demonstrated a lack of sex differences and high frequency of concomitant neurological abnormalities. These participants will be valuable for future longitudinal study and neuroprotective clinical trials.

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Conflict of interest statement

  1. Dr. 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.

  2. Dr. Lim has received support from 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.

  3. Allison Keil, Dr. Pelletier, Dr. Forsberg, Jennifer McLeland has no disclosures.

  4. Dr. 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, the Webster Foundation; and personal fees from Takeda, Roche/Prothena, Teva Neurosciences, Novartis Canada, Biogen, Boehringer Ingelheim, Ther‐ anexus, GE HealthCare, Jazz Pharmaceuticals, Abbvie, Jannsen, Otsuko, Phytopharmics, Inception Sciences, and Curasen.

  5. Dr. Gagnon has received support from the NIH, the Canadian Institutes of Health Research and the Fonds de Recherche du Québec – Santé.

  6. Dr. St. Louis has received support from NIH (NIA, NINDS, and NHLBI), the Michael J. Fox Foundation, Harmony, Inc., and Sunovion, Inc.

  7. Dr. Fields has received support from the NIH.

  8. Dr. Bliwise has received support from the NIH and has been a Consultant to CliniLabs, Eisai, Ferring, Huxley, Idorsia, and Merck.

  9. Dr. 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).

  10. Dr. Avidan has received consultant fees from Avadel, Merck, Takeda, Eisai, Idorsia, and Harmony, and speaker honoraria from Merck, Eisai, Harmony, and Idorsia.

  11. Dr. Howell has received research support from the NIH.

  12. Dr. Schenck has received a one‐time speaker honorarium from Eisai, Inc.

  13. Dr. Criswell has received support from the NIH and consulting fees from Abbvie and Sio Gene Therapies.

  14. Dr. Videnovic has received research support from the NIH and the Michael J Fox Foundation; consultancy fees from Alexion Pharmaceuticals, Biogen, XW Pharma, Jazz.

  15. Dr. During has received support from Jazz Pharmaceuticals, Sanofi, Takeda, Rythm Inc., and the Feldman Foundation CA.

  16. Dr. 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; Royalties from Elsevier Inc.

  17. Dr. Shprecher has received support from the Arizona Alzheimer's Consortium, Abbvie, Acadia, Aptinyx, Axovant, Biogen, Eisai, Eli Lilly, Enterin, Neurocrine, Michael J Fox Foundation, NIH, Nuvelution, Theravance, and Teva; consultant fees from Amneal, Forensis, and Neurocrine; speaker honoraria from Acorda, Amneal, Neurocrine, Sunovion, Teva, and US World Meds/Supernus.

  18. Dr. Lee‐Iannotti has received support from NIH, Liva Nova, Respicardia, and the Arizona Alzheimer's Consortium. She serves on the Scientific Advisory Board for Jazz Pharmaceuticals, INSPIRE, and Avadel. She is a consultant and speaker for Jazz Pharmaceuticals.

  19. Dr. Boeve has served as an investigator for clinical trials sponsored by Alector and Biogen. He serves on the Scientific Advisory Board of the Tau Consortium. 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.

  20. Dr. 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.

Figures

Figure 1
Figure 1
Distribution of scores in primary domains of function. The distribution of individual scores (open circles) with the mean value indicated via the shaded bar and the threshold for abnormality (dotted line) with the percentage of the total cohort falling above/below this threshold and meeting criteria for abnormal function for (A) the Montreal Cognitive Assessment (% abnormal based on Z‐score of 1.5 SD or below after normalization), (B) the MDS‐UPDRS part III (% abnormal based on total score > 4), (C) the Brief Smell Identification Test (% abnormal based on total score ≤ 8), (D) the SCOPA‐AUT (% abnormal based on total score > 13), (E) Farnsworth‐Munsell 100 color vision test (% abnormal based on total score > 100), (F) the Alternate Tap Test for participants dominant hand (% abnormal based on total score < 165).
Figure 2
Figure 2
Genealogy of known RBD and related neurologic and sleep disorders. Participant (shaded center box) with offspring, sibling, and maternal (m.) and paternal (p.) family members. Non‐shaded circles indicate female sex and non‐shaded squares indicate male sex (shaded squares for participant, cousins and non‐immediate family imply male or female). Rates for RBD, Dementia (including: Alzheimer's Disease (AD), Dementia with Lewy Bodies (DLB), and Dementia NOS [no other symptoms]), Parkinson's Disease (PD), Multiple Systems Atrophy (MSA), other neurological diseases (dz), and other sleep disorders (ds) are listed within each family member. Within the Dementia category, the rate of DLB is indented and indicated. Rates above 1% are bolded for clearer visualization. Note: Raw frequency counts are not embedded due to (1) space constraints, and (2) limitations inherent to these data. All percentages reflect a total sample size of n = 361. However, this is only strictly applicable to participants mother/father, and m./p. grandparents, with the greater confidence in these categories denoted by thicker borders. Not all participants have siblings, offspring, m./p. aunts/uncles, cousins, or other non‐immediate family members. Further, participant “unknown” responses were not recorded.
See this image and copyright information in PMC

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