Acetyl-DL-leucine in two individuals with REM sleep behavior disorder improves symptoms, reverses loss of striatal dopamine-transporter binding and stabilizes pathological metabolic brain pattern—case reports

Wolfgang H. Oertel; Annette Janzen; Martin T. Henrich; Fanni F. Geibl; Elisabeth Sittig; Sanne K. Meles; Giulia Carli; Klaus Leenders; Jan Booij; D. James Surmeier; Lars Timmermann; Michael Strupp

doi:10.1038/s41467-024-51502-7

Acetyl-DL-leucine in two individuals with REM sleep behavior disorder improves symptoms, reverses loss of striatal dopamine-transporter binding and stabilizes pathological metabolic brain pattern—case reports

Wolfgang H. Oertel^*, Annette Janzen, Martin T. Henrich, Fanni F. Geibl, Elisabeth Sittig, Sanne K. Meles, Giulia Carli, Klaus Leenders, Jan Booij, D. James Surmeier, Lars Timmermann, Michael Strupp^*

^*Corresponding author for this work

Neuroscience

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

3 Scopus citations

Abstract

Isolated REM Sleep Behavior Disorder (iRBD) is considered a prodrome of Parkinson’s disease (PD). We investigate whether the potentially disease-modifying compound acetyl-DL-leucine (ADLL; 5 g/d) has an effect on prodromal PD progression in 2 iRBD-patients. Outcome parameters are RBD-severity sum-score (RBD-SS-3), dopamine-transporter single-photon emission computerized tomography (DAT-SPECT) and metabolic “Parkinson-Disease-related-Pattern (PDRP)”-z-score in ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET). After 3 weeks ADLL-treatment, the RBD-SS-3 drops markedly in both patients and remains reduced for >18 months of ADLL-treatment. In patient 1 (female), the DAT-SPECT putaminal binding ratio (PBR) decreases in the 5 years pretreatment from normal (1.88) to pathological (1.22) and the patient’s FDG-PET-PDRP-z-score rises from 1.72 to 3.28 (pathological). After 22 months of ADLL-treatment, the DAT-SPECT-PBR increases to 1.67 and the FDG-PET-PDRP-z-score stabilizes at 3.18. Similar results are seen in patient 2 (male): his DAT-SPECT-PBR rises from a pretreatment value of 1.42 to 1.72 (close to normal) and the FDG-PET-PDRP-z-score decreases from 1.02 to 0.30 after 18 months of ADLL-treatment. These results support exploration of whether ADLL may have disease-modifying properties in prodromal PD.

Original language	English (US)
Article number	7619
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-51502-7
State	Published - Dec 2024

Funding

Wolfgang H. Oertel has received speaker\u2019s honoria on educational symposia sponsored by Abbvie, the International Movement Disorders Society and Stada Pharma. He acts as a consultant for Lario Therapeutics and is a member of advisory boards with Intrabio and MODAG. He holds stock options with Intrabio related to this manuscript and stock options with MODAG unrelated to this work. The institution of W.H.O., not W.H.O personally received/s scientific grants from the German Research Foundation, the Michael J Fox Foundation and Rittal Foundation unrelated to the manuscript. Jan Booij is a consultant of GE Healthcare. The institution of J.B., not J.B. personally received research funding from GE Healthcare. Lars Timmermann has received speaker\u2019s honoria on educational symposia sponsored by Abbvie, Boston Scientific, DIAPLAN, Neuraxpharm, Novartis, the International Movement Disorders Society und Teva. He has been a consultant for Boston Scientific. The institution of L.T., not L.T. personally received/s funding by Boston Scientific, the German Research Foundation, the German Ministry of Education and Research, the Otto-Loewi-Foundation and the Deutsche Parkinson Vereinigung. Neither L.T. nor any member of his family holds stocks, stock options, patents or financial interests in any of the above-mentioned companies or their competitors. Michael Strupp is Joint Chief Editor of the Journal of Neurology, Editor in Chief of Frontiers of Neuro-otology and Section Editor of F1000. He has received speaker\u2019s honoraria on educational symposia sponsored by Abbott, Auris Medical, Biogen, Eisai, Gr\u00FCnenthal, GSK, Henning Pharma, Interacoustics, J&J, MSD, NeuroUpdate, Otometrics, Pierre-Fabre, TEVA, UCB, and Viatris. He acts as a consultant for Abbott, AurisMedical, Bulbitec, Heel, IntraBio, Sensorion and Vertify. He is an investor and share-holder of IntraBio. The institution of M.S., not M.S. personally received/s support for clinical studies from Decibel, USA, Cure within Reach, USA and Heel, Germany. He distributes \u201CM-glasses\u201D and \u201CPositional vertigo App\u201D. The remaining authors declare no competing interests. Funding for this study was in part provided by the Andre-Leysen-Ulran-Foundation, Belgium (W.H.O.), the ParkinsonFonds, Deutschland (W.H.O. and A.J.) and Stichting ParkinsonFonds, The Netherlands (K.L. and S.K.M.) and the JPB Foundation (D.J.S.). W.H.O. is Hertie Senior Research Professor supported by the Charitable Hertie-Foundation, Frankfurt/Main, Germany. The authors are very grateful to the two individuals suffering from iRBD who agreed to participate in this study under \u201Cindividual case of off-label use rules\u201D. The expert support in olfactory function testing by Christine H\u00F6ft, Marburg, and the expert support in analyzing the FDG-PET data by Anna Dortmond, Groningen, are highly appreciated. The authors thank Mrs. Taylor Fields, IntraBio Ltd., London, United Kingdom for a critical review of the manuscript.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Oertel, W. H., Janzen, A., Henrich, M. T., Geibl, F. F., Sittig, E., Meles, S. K., Carli, G., Leenders, K., Booij, J., Surmeier, D. J., Timmermann, L., & Strupp, M. (2024). Acetyl-DL-leucine in two individuals with REM sleep behavior disorder improves symptoms, reverses loss of striatal dopamine-transporter binding and stabilizes pathological metabolic brain pattern—case reports. Nature communications, 15(1), Article 7619. https://doi.org/10.1038/s41467-024-51502-7

@article{8decddbfee3c43a58169e09585a7fb5f,

title = "Acetyl-DL-leucine in two individuals with REM sleep behavior disorder improves symptoms, reverses loss of striatal dopamine-transporter binding and stabilizes pathological metabolic brain pattern—case reports",

abstract = "Isolated REM Sleep Behavior Disorder (iRBD) is considered a prodrome of Parkinson{\textquoteright}s disease (PD). We investigate whether the potentially disease-modifying compound acetyl-DL-leucine (ADLL; 5 g/d) has an effect on prodromal PD progression in 2 iRBD-patients. Outcome parameters are RBD-severity sum-score (RBD-SS-3), dopamine-transporter single-photon emission computerized tomography (DAT-SPECT) and metabolic “Parkinson-Disease-related-Pattern (PDRP)”-z-score in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). After 3 weeks ADLL-treatment, the RBD-SS-3 drops markedly in both patients and remains reduced for >18 months of ADLL-treatment. In patient 1 (female), the DAT-SPECT putaminal binding ratio (PBR) decreases in the 5 years pretreatment from normal (1.88) to pathological (1.22) and the patient{\textquoteright}s FDG-PET-PDRP-z-score rises from 1.72 to 3.28 (pathological). After 22 months of ADLL-treatment, the DAT-SPECT-PBR increases to 1.67 and the FDG-PET-PDRP-z-score stabilizes at 3.18. Similar results are seen in patient 2 (male): his DAT-SPECT-PBR rises from a pretreatment value of 1.42 to 1.72 (close to normal) and the FDG-PET-PDRP-z-score decreases from 1.02 to 0.30 after 18 months of ADLL-treatment. These results support exploration of whether ADLL may have disease-modifying properties in prodromal PD.",

author = "Oertel, {Wolfgang H.} and Annette Janzen and Henrich, {Martin T.} and Geibl, {Fanni F.} and Elisabeth Sittig and Meles, {Sanne K.} and Giulia Carli and Klaus Leenders and Jan Booij and Surmeier, {D. James} and Lars Timmermann and Michael Strupp",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41467-024-51502-7",

language = "English (US)",

volume = "15",

journal = "Nature communications",

issn = "2041-1723",

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Oertel, WH, Janzen, A, Henrich, MT, Geibl, FF, Sittig, E, Meles, SK, Carli, G, Leenders, K, Booij, J, Surmeier, DJ, Timmermann, L & Strupp, M 2024, 'Acetyl-DL-leucine in two individuals with REM sleep behavior disorder improves symptoms, reverses loss of striatal dopamine-transporter binding and stabilizes pathological metabolic brain pattern—case reports', Nature communications, vol. 15, no. 1, 7619. https://doi.org/10.1038/s41467-024-51502-7

Acetyl-DL-leucine in two individuals with REM sleep behavior disorder improves symptoms, reverses loss of striatal dopamine-transporter binding and stabilizes pathological metabolic brain pattern—case reports. / Oertel, Wolfgang H.; Janzen, Annette; Henrich, Martin T. et al.
In: Nature communications, Vol. 15, No. 1, 7619, 12.2024.

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

TY - JOUR

T1 - Acetyl-DL-leucine in two individuals with REM sleep behavior disorder improves symptoms, reverses loss of striatal dopamine-transporter binding and stabilizes pathological metabolic brain pattern—case reports

AU - Oertel, Wolfgang H.

AU - Janzen, Annette

AU - Henrich, Martin T.

AU - Geibl, Fanni F.

AU - Sittig, Elisabeth

AU - Meles, Sanne K.

AU - Carli, Giulia

AU - Leenders, Klaus

AU - Booij, Jan

AU - Surmeier, D. James

AU - Timmermann, Lars

AU - Strupp, Michael

PY - 2024/12

Y1 - 2024/12

N2 - Isolated REM Sleep Behavior Disorder (iRBD) is considered a prodrome of Parkinson’s disease (PD). We investigate whether the potentially disease-modifying compound acetyl-DL-leucine (ADLL; 5 g/d) has an effect on prodromal PD progression in 2 iRBD-patients. Outcome parameters are RBD-severity sum-score (RBD-SS-3), dopamine-transporter single-photon emission computerized tomography (DAT-SPECT) and metabolic “Parkinson-Disease-related-Pattern (PDRP)”-z-score in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). After 3 weeks ADLL-treatment, the RBD-SS-3 drops markedly in both patients and remains reduced for >18 months of ADLL-treatment. In patient 1 (female), the DAT-SPECT putaminal binding ratio (PBR) decreases in the 5 years pretreatment from normal (1.88) to pathological (1.22) and the patient’s FDG-PET-PDRP-z-score rises from 1.72 to 3.28 (pathological). After 22 months of ADLL-treatment, the DAT-SPECT-PBR increases to 1.67 and the FDG-PET-PDRP-z-score stabilizes at 3.18. Similar results are seen in patient 2 (male): his DAT-SPECT-PBR rises from a pretreatment value of 1.42 to 1.72 (close to normal) and the FDG-PET-PDRP-z-score decreases from 1.02 to 0.30 after 18 months of ADLL-treatment. These results support exploration of whether ADLL may have disease-modifying properties in prodromal PD.

AB - Isolated REM Sleep Behavior Disorder (iRBD) is considered a prodrome of Parkinson’s disease (PD). We investigate whether the potentially disease-modifying compound acetyl-DL-leucine (ADLL; 5 g/d) has an effect on prodromal PD progression in 2 iRBD-patients. Outcome parameters are RBD-severity sum-score (RBD-SS-3), dopamine-transporter single-photon emission computerized tomography (DAT-SPECT) and metabolic “Parkinson-Disease-related-Pattern (PDRP)”-z-score in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). After 3 weeks ADLL-treatment, the RBD-SS-3 drops markedly in both patients and remains reduced for >18 months of ADLL-treatment. In patient 1 (female), the DAT-SPECT putaminal binding ratio (PBR) decreases in the 5 years pretreatment from normal (1.88) to pathological (1.22) and the patient’s FDG-PET-PDRP-z-score rises from 1.72 to 3.28 (pathological). After 22 months of ADLL-treatment, the DAT-SPECT-PBR increases to 1.67 and the FDG-PET-PDRP-z-score stabilizes at 3.18. Similar results are seen in patient 2 (male): his DAT-SPECT-PBR rises from a pretreatment value of 1.42 to 1.72 (close to normal) and the FDG-PET-PDRP-z-score decreases from 1.02 to 0.30 after 18 months of ADLL-treatment. These results support exploration of whether ADLL may have disease-modifying properties in prodromal PD.

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Acetyl-DL-leucine in two individuals with REM sleep behavior disorder improves symptoms, reverses loss of striatal dopamine-transporter binding and stabilizes pathological metabolic brain pattern—case reports

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