Inclusion Criteria:

• Adult participants (≥ 25 years of age).
• PLS diagnosis is based on the new PLS diagnostic criteria.
• Symptom onset was no more than 15 years prior to baseline.
• Ability to independently walk with or without an assistive device (e.g., walker) at the baseline evaluation.
• In cases where a molecular test has been done prior to enrollment in this study, HSP or HSP- related mutations are negative.
• Expected to have at least some bulbar symptoms (dysarthria, dysphagia, drooling or pseudobulbar affect); however, the absence of these symptoms will not exclude participants when molecular testing is negative for known HSP.
• UMN symptoms and signs in a region other than the legs.
• Normal brain and spinal cord neuroimaging except for changes expected for PLS.
• No active major neurological diseases other than PLS and no history of major neurological diseases.
• No major unstable medical diseases that require treatment (e.g., active cancer, dialysis) in the past 6 months.
• Participant is residing within a commutable distance to the study site and is willing to visit the study site as required.
• No history of ALS or PLS in immediate family and no family history of hereditary spastic paraplegia (HSP).
• gia (HSP) If disease duration is less than 5 years, no significant lower motor neuron (LMN) degeneration upon the EMG examination within 12 months before enrollment (evident entrapment neuropathy or radiculopathy are acceptable). If EMG tests were not done in this period, an EMG test should be obtained through regular patient care (through insurance) in order to make a diagnosis of PLS (this cost will not be covered by this research study). If disease duration is more than 5 years and at least one EMG was performed post-diagnosis, an EMG examination 12 months prior to enrollment is not required.
• Participant understands the study’s purpose, has capacity to consent, and is willing to sign the informed consent form.

Exclusion Criteria:

• Unwilling or unable to give informed consent.
• UMN symptoms and signs only in the legs.
• Unwilling or unable to visit the study site as required.
• Clinically obvious cognitive impairment that precludes obtaining informed consent, as determined by the site PI.
• Participating in clinical treatment trials.

Eligibility last updated 5/3/22. Questions regarding updates should be directed to the study team contact.