Rates of change of pons and middle cerebellar peduncle diameters are diagnostic of multiple system atrophy of the cerebellar type

Abstract

Definitive diagnosis of multiple system atrophy of the cerebellar type (MSA-C) is challenging. We hypothesized that rates of change of pons and middle cerebellar peduncle (MCP) diameters on MRI would be unique to MSA-C and serve as diagnostic biomarkers. We defined the normative data for anterior-posterior (AP) pons and transverse MCP diameters on brain MRI in healthy controls, performed diameter-volume correlations, and measured intra-and inter-rater reliability. We studied an Exploratory cohort (2002-2014) of 88 MSA-C and 78 other cerebellar ataxia patients, and a Validation cohort (2015-2021) of 49 MSA-C, 13 MSA-P, 99 other cerebellar ataxia patients, and 314 non-ataxia patients. We measured AP Pons and MCP diameters on baseline and subsequent MRIs, and correlated results with Brief Ataxia Rating Scale scores. We assessed midbrain:pons and MCP:pons ratios over time. The normative AP Pons diameter was 23.6±1.6 mm, and MCP diameter 16.4±1.4 mm. Pons diameter correlated with volume, r=0.94, p<0.0001. The AP Pons and MCP measures were smaller at first scan in MSA-C compared to all other ataxias. AP Pons diameter: Exploratory, 19.3±2.6 mm vs. 20.7±2.6 mm, Validation, 19.9±2.1 mm vs 21.1±2.1 mm. MCP transverse diameter, Exploratory, 12.0±2.6 mm vs. 14.3±2.1 mm, Validation, 13.6±2.1 mm vs 15.1±1.8 mm, all p<0.001. The AP Pons and MCP rates of change were faster in MSA-C than in all other ataxias. AP Pons diameter rates of change: Exploratory, -0.87±0.04 mm/year vs. -0.09±0.02 mm/year, Validation, -0.89±0.48 mm/year vs. -0.10±0.21 mm/year. MCP transverse diameter rates of change: Exploratory, -0.84±0.05 mm/year vs. -0.08±0.02 mm/year, Validation, -0.94±0.64 mm/year vs -0.11±0.27 mm/year, all values p<0.0001. AP Pons and MCP diameters were indistinguishable between Possible, Probable, and Definite MSA-C. The rate of AP Pons atrophy was linear, correlating with ataxia severity. Using a lower threshold AP Pons diameter decrease of -0.4 mm/year to balance sensitivity and specificity, area under the curve analysis (AUC) discriminating MSA-C from other ataxias was 0.94, yielding sensitivity 0.92 and specificity 0.87. For the MCP, with threshold decline -0.5 mm/year, AUC was 0.90 yielding sensitivity 0.85 and specificity 0.79. The Midbrain:pons ratio increased progressively in MSA-C, whereas the MCP:pons ratio was almost unchanged. AP Pons and MCP diameters were smaller in MSA-C than in MSA-P, p<0.001. We conclude from this 20-year longitudinal clinical and imaging study that AP Pons and MCP diameters are phenotypic imaging biomarkers of MSA-C. In the correct clinical context, an AP Pons and transverse MCP diameter decline of ∼0.8 mm/year is sufficient for and diagnostic of MSA-C.