Objective: Evaluate nigrostriatal integrity using vesicular monoamine transporter 2 (VMAT2) PET in participants with early-stage PD enrolled in the LUMA study.

Background: LUMA is a Phase 2b study (NCT05348785) investigating the safety and efficacy of BIIB122/DNL151, a selective LRRK2 inhibitor in participants with early-stage PD.¹ VMAT2 plays a role in presynaptic dopaminergic signaling, transporting dopamine from the cytosol to synaptic vesicles for regulated release.^2,3 VMAT2 PET offers higher resolution than DAT-SPECT and is less susceptible to compensatory DAT regulation, potentially providing a more reliable index of nigrostriatal terminal integrity to capture disease progression and treatment effects. Limited PD cohorts demonstrated reduced binding relative to healthy controls and a moderate correlation with clinical severity.³ We report baseline outcomes from participants in an exploratory LUMA imaging substudy comparing with outcomes from Parkinson’s Progression Markers Initiative (PPMI) dataset.

Method: Eligible LUMA participants with PD (30-80yrs, mH&Y stages 1-2 [in OFF state], MDS-UPDRS parts II+III [in OFF state] combined score ≤50) were enrolled (N=650). A subset of participants in an imaging substudy underwent baseline and longitudinal VMAT2 assessment with ¹⁸F-AV133 (n=40; 61±10yrs; MDS-UPDRS Part III 19.3±7). Average standardized uptake value ratios (SUVRs) and SUVR asymmetry indices were calculated for basal ganglia regions of interest (ROIs). Associations between PET measures and clinical features were assessed. PPMI data for qualitative comparison were drawn from PD participants imaged with the same tracer (n=37; 63±10yrs; MDS-UPDRS III 27.9±12).⁴

Results: Baseline SUVRs were normally distributed with no outliers (>3 SDs) across all ROIs [Figure]. While regional SUVRs did not significantly correlate with MDS-UPDRS Part II or III scores, SUVR asymmetry significantly predicted the clinically defined first affected side. LUMA regional SUVR distributions were qualitatively similar in pattern to PPMI, but were consistently higher (e.g., striatal SUVR: LUMA 2.29±0.38; PPMI 1.74±0.24).

Conclusion: Baseline findings support the utility of VMAT2 PET as a biomarker of nigrostriatal integrity in early-stage PD. Ongoing longitudinal studies will assess relationship between VMAT2 changes, clinical progression, and potential treatment effects of BIIB122/DNL151.

Figure

References: 1. ClinicalTrials.gov. A Study to Assess the Safety of BIIB122 Tablets and if it Can Slow the Worsening of Early-Stage Parkinson’s Disease in Participants Between the Ages of 30 and 80 (LUMA). Updated 2026. Accessed March 3, 2026. https://clinicaltrials.gov/study/NCT05348785
2. Beauchamp LC, Dore V, Villemagne VL, et al. Using 18F-AV-133 VMAT2 PET imaging to monitor progressive nigrostriatal degeneration in Parkinson disease. Neurology. 2023;101(22):e2314-e2324.
3. Okamura N, Villemagne VL, Drago J, et al. In vivo measurement of vesicular monoamine transporter type 2 density in Parkinson disease with 18F-AV-133. J Nucl Med. 2010;51(2):223-228.
4. Marek K. Early Longitudinal Imaging in Parkinson’s Progression Markers Initiative Using [18F] AV-133 and DaTscanTM (PPMI Early Imaging). protocols.io. Published online. https://dx.doi.org/10.17504/protocols.io.5jyl825j6l2w/v1

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MDS Abstracts - https://www.mdsabstracts.org/abstract/baseline-assessment-of-nigrostriatal-integrity-via-vmat2-pet-in-participants-with-parkinsons-disease-from-the-biib122-dnl151-luma-phase-2b-study/