To investigate clinical and pathological features of primary lateral sclerosis (PLS).

Primary lateral sclerosis (PLS) is a neurodegenerative disorder characterized by slowly progressive upper motor neuron signs with minimal or no lower motor neuron signs. The pathology of most cases of PLS is associated with TDP-43 positive neuronal and glial inclusions; however, reports of clinicopathological features of PLS are sparse. We report a series of patients with pathologically-confirmed PLS who were clinically thought to have atypical parkinsonism, including corticobasal syndrome (CBS) or progressive supranuclear palsy (PSP).

A brain bank for neurodegenerative disease was queried for cases with upper motor neuron and corticospinal tract pathology with minimal or lower motor neuron pathology. All brains underwent systematic and standardized neuropathologic evaluation, including tau and TDP-43 immunohistochemistry. Clinicopathologic features were compiled and evaluated.

We found 30 patients with PLS with TDP-43 pathology. Age at death was 69 ± 8 years, and disease duration was 4.8 ± 4.7 years. Twenty-six patients had antemortem clinical diagnoses of atypical parkinsonian disorders (12 CBS, 11 PSP, 2 MSA). Only two patients were diagnosed with motor neuron disease, and two were diagnosed with frontotemporal dementia. Fourteen patients had asymmetric motor signs, and twelve of these were thought to have CBS. In retrospect, sixteen patients had parkinsonism with clinical features consistent with corticospinal tract degeneration. Pathologically, both upper and lower motor neurons were affected; however, neuronal loss, gliosis and TDP-43 pathology were more severe in the motor cortex than in the brainstem motor neurons or the anterior horns of the cervical spinal cord.

PLS with TDP-43 pathology can clinically mimic atypical parkinsonism, especially CBS and PSP, therefore, PLS should be considered in the differential diagnosis in these patients. These studies emphasize the need for further clinical and biomarker studies of patients with PLS.