MRI Biomarkers in PLS — Wine Glass Sign, Motor Cortex, Corticospinal Tract
When PLS damages the corticospinal tract — the pathway carrying signals from upper motor neurons in the primary motor cortex down through the brainstem and spinal cord — the damage leaves structural traces that MRI can detect. These traces are not pathognomonic: they occur in other conditions that affect the same pathway. But when a patient has progressive upper motor neuron signs and the MRI shows the wine glass pattern, reduced motor cortex thickness, or corpus callosum signal abnormalities, the imaging supports the clinical diagnosis and excludes some mimics. This page covers what those MRI findings are, what the evidence says about them, and where they stand as biomarkers for PLS monitoring.
The corticospinal tract in PLS
The corticospinal tract (CST) originates in the primary motor cortex — specifically from large Betz cells in layer V of the cortex — and descends through the corona radiata, the posterior limb of the internal capsule, the cerebral peduncles, the brainstem, and into the spinal cord. In PLS, these Betz cells and their axons degenerate selectively, while lower motor neurons (anterior horn cells in the spinal cord) are largely preserved.
As the corticospinal axons die, the myelin sheath surrounding them breaks down — a process called Wallerian degeneration. In the later stages, the tract itself is reduced in size. Both the myelin breakdown (visible as T2 signal abnormality) and the tract volume reduction (visible as atrophy) are detectable on MRI, typically on clinical 1.5T or 3T scanners.
The wine glass sign
The "wine glass sign" is a radiological pattern named for the visual appearance on axial MRI. As the corticospinal tract converges from the broad corona radiata through the narrowing of the posterior limb of the internal capsule, T2-hyperintense signal follows this course — creating a shape on coronal sequences that resembles an inverted wine glass. The signal reflects Wallerian degeneration of the corticospinal fibers as they pass through the internal capsule, a bottleneck where the tract is compact enough that the degeneration becomes radiologically visible.
A 2025 Radiopaedia case report documented the wine glass sign in a confirmed PLS case, contributing to the published case literature. Earlier case reports and series had described similar findings. The sign has also been documented in ALS patients with prominent UMN features, in rare hereditary spastic paraplegias, and in other conditions affecting the corticospinal tract — so its presence is supportive rather than diagnostic. In a patient with the appropriate clinical presentation (progressive pure UMN syndrome), the wine glass sign adds positive weight to the PLS diagnosis.
The wine glass sign is not consistently present in PLS — its presence depends on the severity and duration of corticospinal tract degeneration, the MRI field strength, and the specific sequences used. Absence of the sign does not exclude PLS.
Decreased primary motor cortex thickness (Butman 2007)
The primary motor cortex is where the Betz cells that give rise to the corticospinal tract reside. As these cells die in PLS, the cortex in this region loses volume, which manifests as reduced cortical thickness measurable by structural MRI analysis.
Butman et al. (AJNR, 2007) documented decreased cortical thickness of the primary motor cortex in PLS patients compared to healthy controls, using quantitative volumetric MRI analysis. This study was conducted at the NIH and represented one of the first systematic structural imaging characterizations of PLS motor cortex atrophy.
Motor cortex thinning in PLS is biologically specific — it reflects the loss of precisely the neurons that PLS selectively destroys. This specificity makes it a particularly meaningful imaging marker, though quantitative cortical thickness measurement requires specialized image processing software and is not routinely reported in clinical MRI reads. On a standard clinical report, the finding might be described as "subtle motor cortex atrophy" or may not be mentioned at all without specific cortical morphometry analysis.
Longitudinal cortical thickness measurement — tracking whether the motor cortex becomes thinner over time in a given patient — is a potential monitoring biomarker for PLS disease progression, but has not yet been validated in a prospective cohort as a trial outcome measure.
Corpus callosum T2 signal (Riad 2011)
The corpus callosum connects the two cerebral hemispheres. Its motor segment contains fibers connecting the two primary motor cortices and is involved in interhemispheric motor coordination. High T2 signal in the corpus callosum — reflecting fiber degeneration and myelin loss — is consistent with upper motor neuron degeneration in PLS.
Riad et al. (AJNR, 2011) documented high T2 signal in the corpus callosum in PLS patients, consistent with the topographic distribution of motor fibers. This finding is particularly visible in the motor segment (middle third, anterior to the splenium) of the corpus callosum and represents another structural consequence of corticospinal pathway degeneration.
Corpus callosum atrophy and signal abnormality are also seen in ALS, in hereditary spastic paraplegia, and in other corticospinal tract disorders — again, supportive rather than pathognomonic. The value is in the pattern: corpus callosum + internal capsule + motor cortex abnormalities together, in a patient with a pure UMN clinical syndrome and no lower motor neuron findings, constitute a coherent imaging profile that supports PLS.
Advanced MRI: diffusion tensor imaging and beyond
Beyond structural T1 and T2 sequences, diffusion tensor imaging (DTI) can measure the microstructural integrity of white matter tracts — specifically, the coherence and directionality of water diffusion along axon bundles. Reduced fractional anisotropy (FA) and increased mean diffusivity (MD) in the corticospinal tract on DTI reflect tract degeneration at a microstructural level, often detectable before frank T2 signal abnormality appears on conventional sequences.
DTI tractography of the corticospinal tract in PLS shows reduced FA consistent with bilateral CST degeneration. This approach has been used in research settings at the NIH (Floeter's group) and in European centers, and has been proposed as a more sensitive outcome measure for tracking PLS progression than clinical scales alone. DTI is available at most academic centers but requires specialized post-processing and is not routinely reported in clinical radiology.
Where MRI biomarkers stand as trial endpoints
MRI markers are not yet standardized as primary endpoints in PLS clinical trials. The practical challenges are significant: MRI protocols vary across sites; quantitative analysis (cortical thickness measurement, DTI tractography) requires specialized software and expertise; and normative reference ranges for PLS patients are not established. No study has yet demonstrated that an MRI change in PLS predicts clinical outcome in a way that would support regulatory acceptance as a surrogate endpoint.
This does not mean MRI biomarkers are without value. As exploratory endpoints in future trials — measuring whether a treatment affects corticospinal tract integrity alongside functional scales and NfL — imaging markers could provide converging evidence of biological effect. And for diagnosis, the supportive role of MRI findings is already embedded in the 2020 consensus criteria as one of the recommended investigations.
Practical implications for patients
If your MRI report mentions "T2 signal in the corticospinal tract" or "subtle motor cortex atrophy," these findings are consistent with PLS but do not confirm it. Their significance depends on the full clinical picture. Many patients with early or mild PLS have normal-appearing conventional MRI — the absence of these findings does not mean the diagnosis is wrong.
If your neurologist orders an MRI specifically for PLS evaluation, ask whether the report will include comment on the corticospinal tract and motor cortex. Standard clinical MRI reads vary in how much attention they pay to these areas without a specific clinical question prompting them.
How this connects
These MRI findings are listed as supportive features in the 2020 consensus criteria. The NIH neurophysiology studies by Floeter (see Floeter 2009) used TMS alongside MRI to track PLS progression. Fluid biomarkers — particularly NfL — are the primary biological outcome measure in current PLS research, with MRI as a structural complement. The full biomarker landscape is covered on the Biomarker Research hub. For how imaging is used in the diagnostic workup today, see Diagnosis.
Key studies referenced
Butman JA, et al. Decreased thickness of the primary motor cortex in primary lateral
sclerosis. AJNR American Journal of Neuroradiology. 2007.
Riad A, et al. High T2 signal in primary lateral sclerosis: corpus callosum topography.
AJNR American Journal of Neuroradiology. 2011.
Wine glass appearance: a unique MRI observation in a case of primary lateral sclerosis.
Radiopaedia. 2025.
Floeter MK, Mills R. Progression in primary lateral sclerosis: a prospective analysis.
Amyotrophic Lateral Sclerosis. 2009. [DTI and TMS methods referenced]