Objective: To select the most effective number of repeat doses of mesenchymal stem cells (MSC) delivered intravenously to slow the progression of Parkinson’s disease (PD). Secondary outcome for substantia nigra pars compacta (SNpc) neuromelanin (NM) change was assessed by neuromelanin-sensitive MRI (NM-MRI) sequences in each active treatment arm versus placebo at 40 weeks follow-up.

Background: In PD, the NM-containing structures (SN and LC) undergo significant atrophy, which manifests as a longitudinal decrease in the NM-MRI signal ¹. NM-MR can provide a valuable measurement for midbrain dopamine neuronal function². Findings from our Phase I trial determine that MSCs infusions are safe³; however, changes in NM remain to be explored.

Method: Forty-five subjects with mild/moderate iPD were randomized to 1 of the three treatment arms (Arm 0=14, Arm 1=15, Arm 2=16). The 3 treatment arms include: a) 2 infusions of 10 X 10⁶ MSC/kg & 1 placebo; b) 3 infusions of 10 X 10⁶ MSC/kg or c) 3 infusions of placebo. 43 subjects received 3 infusions at 4-month intervals. Two-time points (baseline and one month after the last infusion) partial volume neuromelanin-sensitized 3T MRI images⁴ were acquired for 41 subjects. SNc ROIs were individually normalized with respect to an adjacent ROI encompassing crus cerebri². Repeated measurement ANOVAs for left and right SN factoring time and arm were performed using JASP 0.15.0.

Results: *Baseline characteristics appeared similar across groups.

*There was a non-statistically significant increase from T1 to T2 in normalized neuromelanin signal in the left substantia nigra pars compacta (mean diference= 4.47, SE= 2.99, p=0.139). Mean & SE increase change per treatment arm from baseline was 4.32 (5.31) for arm Zero, 4.02 (5.12) for arm One, and 5.08 (5.12) for arm Two.

*No discernable trends were identified from T1 to T2 in normalized neuromelanin signal in the right substantia nigra pars compacta (p= 0.877). Mean & SE change per treatment arm from baseline was 3.39 (5.48) for arm Zero, -5.56 (5.28) for arm One, and 0.74 (5.24) for arm Two.

Conclusion: Preliminary data from this study showed a non-statistically significant increase over 9 months in normalized NM signal in the left SNpc, contrary to our current understanding of NM loss with disease progression.

References: 1Xing Y, Sapuan AH, Martín-Bastida A, Naidu S, Tench C, Evans J, Sare G, Schwarz ST, Al-Bachari S, Parkes LM, Kanavou S, Raw J, Silverdale M, Bajaj N, Pavese N, Burn D, Piccini P, Grosset DG, Auer DP. Neuromelanin-MRI to Quantify and Track Nigral Depigmentation in Parkinson’s Disease: A Multicenter Longitudinal Study Using Template-Based Standardized Analysis. Mov Disord. 2022 May;37(5):1028-1039

2Cassidy CM, Zucca FA, Girgis RR, Baker SC, Weinstein JJ, Sharp ME, Bellei C, Valmadre A, Vanegas N, Kegeles LS, Brucato G, Kang UJ, Sulzer D, Zecca L, Abi-Dargham A, Horga G. Neuromelanin-sensitive MRI as a noninvasive proxy measure of dopamine function in the human brain. Proc Natl Acad Sci U S A. 2019 Mar 12;116(11):5108-5117
3Schiess, M., Suescun, J., Doursout, M.-F., Adams, C., Green, C., Saltarrelli, J.G., Savitz, S. and Ellmore, T.M. (2021), Allogeneic BoneMarrow–Derived Mesenchymal Stem Cell Safety in Idiopathic Parkinson’s Disease. Mov Disord, 36: 1825-1834.
4Chen X, Huddleston DE, Langley J, et al. Simultaneous imaging of locus coeruleus and substantia nigra with a quantitative neuromelanin MRI approach. Magnetic resonance imaging. 2014;32(10):1301-1306.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/preliminary-report-on-neuromelanin-sensitive-mri-signal-change-after-allogeneic-bone-marrow-derived-mesenchymal-stem-cells-therapy-phase-iia-double-blind-randomized-controlled-trial/