Rate of Change of Pons and Middle Cerebellar Peduncle Diameters is Diagnostic of Multiple System Atrophy of the Cerebellar Type (MSA-C)
Christopher Stephen1, Mark Vangel2, Anoopum Gupta1, Jason MacMore1, Jeremy Schmahmann1
1Department of Neurology, 2Department of Radiology, Massachusetts General Hospital and Harvard Medical School
Objective:

To develop an MRI biomarker for the diagnosis of Multiple System Atrophy of the cerebellar type (MSA-C).

Background:

MSA-C is a sporadic, adult-onset synucleinopathy with autonomic neuropathy and ataxia. Distinguishing MSA-C from other ataxias can be challenging. We hypothesized that rate of change of pons and middle cerebellar peduncle (MCP) diameters would facilitate accuracy and timeliness of diagnosis.

Design/Methods:

Exploratory cohort (88 MSA-C, 44 spinocerebellar ataxia, 13 Friedreich’s ataxia, 21 idiopathic/other ataxia) had baseline/longitudinal measurements (2002-2014) of anteroposterior (AP) mid-pons/transverse MCP diameters on conventional MRI. 73 Human Connectome Project subjects were sampled to derive normative data and pons diameter-volume correlations. Validation cohort (49 MSA-C, 13 MSA-P, 99 other ataxias, 79 Parkinson’s disease [PD], 200 other movement disorders) underwent similar baseline/longitudinal measurements (2015-2021).

Results:

Normative data: pons diameter 23.9±1.6 mm and MCP diameter 16.4±1.4 mm. Pons diameter-volume correlation r=0.94, p<0.0001.

Exploratory cohort:

Comparing MSA-C to other ataxias at first scan, pons diameter 19.3±2.6 mm vs. 20.7±2.6 mm, p=0.0006 and MCP 12.0±2.6 mm vs. 14.3±2.1 mm, p<0.0001.

Longitudinal rate of change (mean [SE]) using mixed-model regression in pons/MCP in MSA-C vs. other ataxias were markedly different: pons -0.85 [0.04] mm/year vs. -0.09 [0.02] mm/year; MCP -0.84 [0.05] mm/year vs. -0.08 [0.02] mm/year, both p<0.0001.

Pons/MCP measures were indistinguishable between Possible, Probable, and Definite MSA-C. 

AUC analysis in MSA-C with a threshold pons diameter decline -0.5 mm/year yielded sensitivity 0.92/specificity 0.87; while MCP diameter decline -0.4 mm/year, yielded sensitivity 0.85/specificity 0.79.

Validation cohort:

We replicated the findings. In non-ataxia movement disorders, pons diameter at first scan 22.5±1.5 and MCP diameter 17.1±1.2 mm were significantly different from MSA/other ataxias.

Conclusions:

A rate of change of mid-pons AP diameter and MCP diameters ~0.8 mm/year is sensitive and specific for the diagnosis of MSA-C, is necessary and sufficient, and represents a novel phenotypic imaging biomarker for use in clinical trials.

10.1212/WNL.0000000000201788