PLS Natural History Study (PNHS) — Mayo Clinic / Johns Hopkins
The PLS Natural History Study is the most methodologically rigorous PLS cohort ever conducted. Unlike the NEALS registry that generated the 2006 Gordon data — a retrospective analysis of prospectively collected clinical records — the PNHS was designed from the ground up as a prospective natural history study with biospecimen collection, standardized outcome measures, and an explicit goal of generating data suitable for future clinical trial design. It is a living study: enrollment continues, and its findings will compound over time.
What they did
The PNHS recruited participants with confirmed or probable PLS according to the 2020 consensus criteria at Mayo Clinic sites in Rochester, Minnesota and Jacksonville, Florida, and at Johns Hopkins. The study enrolled 76 participants — a relatively small number, but one that reflects the rarity of PLS and the difficulty of recruiting a population where diagnosis itself takes years to establish.
At enrollment and at regular follow-up visits, participants underwent clinical assessment using the PLSFRS (PLS Functional Rating Scale), a scale designed specifically for PLS that improves on the ALSFRS-R by excluding subscales rarely relevant in PLS (respiratory and swallowing items dominate ALSFRS-R but are often unaffected in PLS). Blood was drawn for biospecimen banking and for measurement of serum neurofilament light chain (NfL) using the Simoa platform.
The planning and design phase was published first by the Johns Hopkins group. The primary results — functional decline rates, NfL correlations, and subgroup analyses — were published in Annals of Neurology in September 2025. The study is ongoing: participants continue to be followed, and additional analyses will be published as the dataset matures.
What they found
Functional decline rate
The PLSFRS total score declined by an average of 0.33 points per month across the cohort, or approximately 4 points per year. This is measured on the PLSFRS, not the ALSFRS-R, so direct numerical comparison with the Gordon 2006 figure (1.6 ALSFRS-R points per year) requires caution — the scales have different ranges and subscale structures. The 0.33 points per month figure is the reference rate for PLSFRS-based trial power calculations.
Early disease is faster
Rate of decline was steepest in the early PLS subgroup — defined as disease duration less than two years at enrollment. This finding has clinical and trial design implications. It suggests that PLS is not uniformly slow throughout its course: patients early in the disease may be declining faster than the population average, which means earlier enrollment in treatment trials could capture more detectable change. It also means that patients in the "probable PLS" diagnostic window (2–4 years from onset) may be biologically in the most active phase of the disease.
NfL predicts progression — the key biomarker finding
Baseline serum NfL level was significantly associated with rate of PLSFRS decline over the following year (p = 0.001). This is the most important finding from the PNHS for trial design. It means that a blood test taken at the time of diagnosis predicts how fast a patient will decline over the next year — before any functional decline is observed. This has two direct applications:
- Stratification: Future treatment trials can use baseline NfL to stratify patients into faster and slower progressors, reducing variance and increasing the ability to detect a treatment effect with smaller sample sizes.
- Surrogate endpoint: If a treatment reduces NfL, that reduction would be expected to correlate with slower functional decline. This could allow trials to use NfL as an earlier, more sensitive endpoint rather than waiting years for clinical differences to emerge.
Why it matters
The PNHS is the infrastructure that PLS treatment trials will be built on. The Gordon 2006 data was important but came from a retrospective registry analysis using a scale not designed for PLS. The PNHS is prospective, uses a PLS-specific scale, collects biospecimens, and was designed explicitly to generate data suitable for future trials.
The NfL finding (p = 0.001) is a landmark result for PLS biomarker research. Before this, NfL had been validated as a prognostic biomarker in ALS, but there was no direct prospective evidence that it predicted PLS progression specifically. The PNHS provides that evidence. It moves NfL from "plausibly useful" to "demonstrated prognostic value" in PLS.
For patients, the significance is indirect but real: the PNHS is making the first PLS treatment trial statistically and logistically feasible. Without rigorous natural history data and validated biomarkers, a PLS trial would require enormous sample sizes and many years of follow-up to detect any effect. The PNHS data reduces both requirements.
Participation
The PNHS is a living study. Patients with confirmed or probable PLS who are interested in participating can inquire at Mayo Clinic (Rochester or Jacksonville) or Johns Hopkins. The study is CDC-funded and enrollment is ongoing. Earlier enrollment means longer follow-up and more contribution to the biorepository. For information on how to connect with the PNHS and other active PLS research, see Clinical Trials.
How this connects
The PNHS is the methodological successor to Gordon 2006. Its NfL findings are the primary PLS-specific evidence cited in the NfL biomarker studies page. The Scirocco 2025 review identifies PNHS as the central infrastructure for trial readiness. The PLSFRS decline rate it established (0.33 points/month) is the number used when calculating sample size for any future PLS trial. For what the progression rate means practically, see Prognosis.
Citation
PLS Natural History Study Group (Sorenson E, Shah J, et al.). Primary lateral sclerosis natural history study: PLSFRS outcomes and neurofilament light chain as a prognostic biomarker. Annals of Neurology. September 2025. CDC-funded study, CLS-20515794.