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'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.

Fig. 1. The time course of the severity of the REM sleep behavior disorder phenotype assessed by means of an RBD-diary and expressed as the 3-week RBD-severity sum-score (RBD-SS-3) in patients 1 and 2.

The circles depict the sum of 21 subsequent daily (3 weeks) subjectively recorded severity scores of the RBD-phenotype of patients 1 (a) and 2 (b). The x-axis covers the first 18 weeks (left panel) and the last 18 weeks (right panel) of the 83-week therapy with ADLL. The red arrows in (b) indicate the consumption of alcohol restricted to a total of 5 days during weeks 7–9 and weeks 10–12 by patient 2 leading to an aggravation of the RBD severity. Following week 12, patient 2 stopped the consumption of alcohol (see Section C in Supplementary Information). Source data are provided as a Source Data file.

Fig. 2. Clinical evaluations and imaging procedures of the patients over time.

The temporal relationship between the time points of the clinical assessments (motor function test: UPDRS part III or MDS-UPDRS part III; cognitive function test: MOCA; olfactory function test: TDI sum-score) and the time points of the imaging procedures (DAT-SPECT, FDG-PET) is illustrated. The red-shaded area indicates therapy with Acetyl-DL-Leucine (5 g/day). Results of the clinical ratings are presented for patient 1 (a) and patient 2 (b). Note: during the study, the motor function assessment in patient 1 was switched from UPDRS III to MDS-UPDRS III. Motor scores are presented without the item action tremor, which does not belong to the cardinal motor signs of Parkinson’s disease. Time points of the imaging procedures are indicated as icons. Results of the imaging procedures are presented in Fig. 3 and Table 1. Source data are provided as a Source Data file.

Fig. 3. Serial Dopamine -Transporter Ligand-Binding (DAT) SPECT and FDG-PET imaging in both patients.

a, b DAT-SPECT results in patients 1 (a) and 2 (b). The upper part shows representative transversal images of DAT-SPECT at the level of the striatum. For patient 1, three pretreatment images (02/2013, 03/2014, 01/2019) and two images under ADLL therapy (02/2022, 09/2023) are shown. For patient 2, one pretreatment (08/2020) and one image under ADLL therapy (07/2023) are presented. The respective specific-to-non-specific striatal binding ratios of the right putamen are shown directly below the images. The graph shows the specific striatal DAT binding ratios in the striatum, the caudate nucleus and the putamen for the right and left sides. c The time course of the values of the z-score of the Parkinson Disease-related-Pattern (PDRP-z-score) in FDG-PET of patient 1 (blue triangle) is shown from 2014 to 2018 and from 2018 to 2022. ADLL treatment was started in November 2021. For patient 1, the PDRP z-score was 1.72 in 2014, rising to 3.28 in 2018. In 12/2022, 1 year after starting ADLL therapy, the FDG-PET PDRP-z-score was 3.18—similar to the z-score in 2018 (blue triangle). For comparison, the time course of the average PDRP-z-score (mean ± SD, gray shaded area) of 12 untreated iRBD patients from 2014 to 2018 and from 2018 to 2022 are illustrated. This untreated “disease control” iRBD group is divided into the group of converters (n = 5—dark gray circles) and non-converters (n = 7—light gray circles). The average z-scores of the converter group (n = 5; at baseline in 2014: 2.99 ± 1.68; first follow-up in 2018: 5.75 ± 2.28; second follow-up in 2022: 7.85 ± 2.12) were higher than the average z-scores of the non-converter group (n = 7; at baseline in 2014: 1.63 ± 0.69; first follow-up in 2018: 3.02 ± 1.32; second follow-up in 2022: 4.30 ± 2.04). d The time course of the PDRP-z-score in FDG-PET of patient 2 (pink triangle) is shown for 06/2021 (1.02). ADLL treatment was started in January 2022. When the second FDG-PET was performed in 01/2023, after 1 year of continuous ADLL treatment, the z-score was reduced to 0.30. Source data are provided as a Source Data file.