Objective: To investigate the diagnostic and prognostic value of fluid-based and PET imaging biomarkers related to neurodegeneration and neuroinflammation in Multiple System Atrophy (MSA).

Background: MSA is characterized by rapid neurodegeneration and concomitant neuroinflammation. Currently, there are no established in vivo biomarkers available for disease monitoring or early differential diagnosis against Parkinson’s Disease (PD), hindering accurate recruitment for interventional trials.

Method: Biomarkers associated with neurodegeneration (Neurofilament light chain (NfL), total Tau) and reactive astrocytosis (Glial fibrillar acidic protein (GFAP)) were cross-sectionally investigated in CSF and plasma of MSA, PD and healthy age-matched controls (HC) using the Quanterix Simoa® Platform. As a marker of microglial activation, sTREM2 in CSF was analyzed via a validated and published ELISA. In addition to comparative analyses between diagnostic groups, biomarker levels in MSA were correlated with clinical disease severity and progression rates using baseline and longitudinal UMSARS scores. Fluid-based biomarker levels were correlated with imaging values of [¹⁸F]D2-Deprenyl-PET (reactive astrocytosis) and [¹⁸F]GE-180-TSPO-PET (microglial activation) in a subset of MSA patients.

Results: In MSA, CSF and plasma levels of GFAP and CSF levels of sTREM2 showed strong positive correlation with baseline UMSARS values (p < 0.05), while NfL values significantly correlated with longitudinal increase in UMSARS scores (p < 0.05). CSF levels of NfL, Tau and sTREM2 were significantly elevated in MSA compared to PD (p < 0.05).
Spatial mapping of regional imaging signals of [¹⁸F]D2-Deprenyl-PET and [¹⁸F]GE-180-TSPO-PET imaging showed promising results with PET imaging signals matching the expected neuropathological distribution of neuroinflammatory processes in MSA patients.

Conclusion: These data indicate that both neuroinflammatory biomarkers, GFAP and sTREM2, are likely to reflect disease severity in MSA, while NfL shows promise as a prognostic biomarker. Aiming at early differential diagnosis, CSF-based NfL and Tau as biomarkers for neurodegeneration show higher promise than GFAP and sTREM2 for differentiation between MSA and PD. Combining global fluid-based biomarkers with regional PET imaging shows promise for comprehensive in-vivo characterization of MSA-related disease processes and the development of urgently-needed objective read-out parameters.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neurodegeneration-and-neuroinflammation-for-biomarker-development-in-msa/