Objective: To develop an MRI biomarker for the definitive diagnosis of Multiple System Atrophy of the Cerebellar Type (MSA-C).

Background: MSA is a sporadic, adult-onset synucleinopathy characterized by autonomic neuropathy with parkinsonism (MSA-P), ataxia (MSA-C), or both.  Diagnostic accuracy relies on clinical consensus criteria and is imperfect.  We proposed [1] that pons measurements may improve diagnostic accuracy, and we set out to study this.

Method: We performed baseline and longitudinal measurements including rate of change (2002-2015) of anteroposterior (AP) diameter of the mid-pons and transverse diameters of the middle cerebellar peduncles (MCPs) on conventional MRI in an exploratory cohort of 70 patients with MSA-C, 44 spinocerebellar ataxia, 15 Friedreich’s ataxia, 15 idiopathic ataxia, and 73 controls. We performed (2015-2021) baseline and longitudinal measurements in a validation cohort of 50 MSA-C, 13 MSA-P, 99 other ataxias, 79 Parkinson’s disease (PD) and 275 other movement disorder patients. 73 subjects in the Human Connectome Project (HCP) were sampled to derive normative data and pons diameter-volume correlations.

Results: HCP data:
The normal pons AP diameter was 23.9±1.6 mm and MCP diameter 16.7.9±1.5 mm. Pons diameter-volume correlation was r=0.94, p<0.0001.
Exploratory cohort:
In MSA-C vs. other ataxias at first scan, pons mean AP diameter was 18.9±2.9 mm vs. 20.7±2.7 mm, p=0.0003 and mean MCP diameters were 11.8±2.8 mm vs. 14.4±2.1 mm, p<0.0001. Rate of change of pons diameter was -0.98±0.59 mm/year in MSA-C vs -0.17±0.18 mm/year, p<0.0001 in other ataxias. MCP diameter loss was -1.15±1.5 mm/year in MSA-C vs. -0.22±2.1 mm/year, p=0.0013 in other ataxias.
Validation cohort:
The findings in MSA-C were replicated and essentially identical. In a large movement disorders cohort excluding MSA-C/P, other ataxias or atypical parkinsonism, mean AP pons diameter of 22.5±1.5 and MCPs 17.1±1.2 mm at first scan differed significantly from MSA and other ataxias. Pons/MCP measures were significantly different between MSA-C vs. MSA-P, and MSA-P vs. PD but were indistinguishable between Possible, Probable, and Definite MSA-C.

Conclusion: Pons and MCP diameters are key biomarkers in MSA-C and MSA-P. A rate of change of ~1 mm/year in each measure is sensitive and specific for the definitive diagnosis of MSA-C. These novel findings have relevance for clinical care and clinical trial design.

References: 1. Lin DJ, Hermann KL, Schmahmann JD. The Diagnosis and Natural History of Multiple System Atrophy, Cerebellar Type. Cerebellum. 2016 Dec;15(6):663-679. doi: 10.1007/s12311-015-0728-y. PMID: 26467153; PMCID: PMC4833693.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pons-and-middle-cerebellar-peduncle-diameters-are-diagnostic-of-multiple-system-atrophy-of-the-cerebellar-type-msa-c/