Objective: Report a patient with Multiple System Atrophy (MSA) misdiagnosed as Parkinson’s disease (PD) and enrolled in a clinical trial for PD treatment with Mesenchymal Stem Cell (MSC) therapy

Background: Clinical trials in adult neurodegenerative diseases face challenges due to the limited accuracy of premortem clinical diagnoses [1]. MSA is a neurodegenerative disorder often misdiagnosed as PD [2]. Recently, alpha-synuclein aggregation assays (α-SAA) from cerebrospinal fluid (CSF) have been shown to reliably distinguish between these two disorders [3]. In this case report, we present a patient initially diagnosed with PD who participated in an MSC clinical trial, where α-SAA played a crucial role in determining a final diagnosis of MSA.

Method: Case report

Results: We present a 63-year-old left-handed male with normosmia and a medical history of coronary artery disease and erectile dysfunction (ED). At 56, he began acting out his dreams, and by 59, he developed progressive tremors, stiffness, and slowness on his right side, along with speech disturbance. He was diagnosed with PD by a Movement Neurologist and reportedly benefited from dopaminergic therapies over the next two years. He described multiple events of syncope, worsening ED, urinary incontinence, and constipation over this time.  

At 61, he was enrolled in our phase II trial of allogeneic MSC infusions compared to placebo to slow the progression of PD[4]. α-SAA was not part of the inclusion criteria, but it was collected before the first infusion and 3 months after the final infusion. The subject’s CSF α-SAA profile was consistent with MSA, not PD [figure1]. Changes in maximum fluorescence (F_max), time to reach 50% of the F_max (T₅₀) and other biomarkers are summarized in [table1]. Over the 2-year course of the study, his motor symptoms progressed, but his urinary incontinence, constipation, and insomnia all improved by the final visit [figure2][table2]

Conclusion: Accurate diagnosis is crucial for homogeneous enrollment in clinical trials. MSA is frequently misdiagnosed as PD. In this case, initially diagnosed with PD, α-SAA exhibited a typical MSA pattern of faster aggregation with a lower fluorescence plateau. α-SAA could potentially serve as a tool for diagnostic confirmation before enrolling patients in clinical trials.

Figure 1

Table 1

Figure 2

Table 2

References: 1. Coysh T, Mead S. The Future of Seed Amplification Assays and Clinical Trials. Front Aging Neurosci. 2022;14:872629. Epub 20220622. doi: 10.3389/fnagi.2022.872629. PubMed PMID: 35813946; PMCID: PMC9257179.
2. Koga S, Aoki N, Uitti RJ, van Gerpen JA, Cheshire WP, Josephs KA, Wszolek ZK, Langston JW, Dickson DW. When DLB, PD, and PSP masquerade as MSA: an autopsy study of 134 patients. Neurology. 2015;85(5):404-12. Epub 20150702. doi: 10.1212/WNL.0000000000001807. PubMed PMID: 26138942; PMCID: PMC4534078.
3. Grossauer A, Hemicker G, Krismer F, Peball M, Djamshidian A, Poewe W, Seppi K, Heim B. alpha-Synuclein Seed Amplification Assays in the Diagnosis of Synucleinopathies Using Cerebrospinal Fluid-A Systematic Review and Meta-Analysis. Mov Disord Clin Pract. 2023;10(5):737-47. Epub 20230315. doi: 10.1002/mdc3.13710. PubMed PMID: 37205253; PMCID: PMC10187020.
4. ClinicalTrials.gov. Phase IIa Randomized Placebo Controlled Trial: Mesenchymal Stem Cells as a Disease-modifying Therapy for iPD. Available from: https://clinicaltrials.gov/study/NCT04506073.

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