Scirocco et al. 2025 — Toward Therapeutic Trials in Primary Lateral Sclerosis
This is the paper you read before designing a PLS clinical trial in 2025. Scirocco and colleagues at Mayo Clinic synthesized everything the field knows about PLS natural history, outcome measures, and biomarkers, then mapped it against what a rigorous treatment trial would actually require. The result is part review article, part gap analysis, part roadmap. If you want to understand where PLS research stands and what needs to happen before a treatment trial becomes feasible, this is the primary document.
What they did
This is a comprehensive review article, not a primary data study. Scirocco and colleagues at Mayo Clinic conducted a structured synthesis of the PLS natural history literature, outcome measure development, and biomarker research — all viewed through a single organizing question: what does the field need before a meaningful treatment trial in PLS can be conducted?
The review covers the natural history evidence base (including the NEALS 2006 cohort, subsequent European cohorts, and the ongoing PLS Natural History Study), the evolution of functional outcome measures (ALSFRS-R to PLSFRS), the current state of fluid and imaging biomarkers, and the specific logistical challenges PLS poses for clinical trial design — most importantly, the disease's slow progression rate, which makes clinical endpoints difficult to detect over trial-feasible timeframes.
What they found
Natural history summary
PLS life expectancy is anticipated to be near-normal. Symptoms begin in the lower limbs in 56–84% of cases. The average annual rate of functional decline on the ALSFRS-R is approximately 1.6 points per year (from the NEALS Consortium data — 250 patients, 15 years). The more recent Oxford SCNI cohort (Lester 2025) found a median survival from symptom onset of 23.1 years and a median age at death of 79.5 years versus a population reference of 81.9 years — near-normal life expectancy confirmed in an independent European cohort.
The review notes that only 10% of PLS patients required gastrostomy and 6% required non-invasive ventilation — the great majority retain swallowing and respiratory function throughout their lives. Disability concentrates in limb motor function, particularly gait and balance.
Extra-motor pathology
One of the most clinically significant findings synthesized in this review is that PLS is no longer accurately described as a "pure upper motor neuron disease." Neuroimaging increasingly reveals extra-motor pathology in frontotemporal, cerebellar, thalamic, and subcortical regions. This challenges the historical conceptualization of PLS and has implications for understanding why cognitive and behavioral symptoms occur in a subset of patients. Future clinical trials may need to assess non-motor endpoints.
Outcome measures
The ALSFRS-R has limitations for PLS: it includes subscales for respiratory and swallowing function that are rarely affected, compressing the measurable range of decline. The PLSFRS (PLS Functional Rating Scale) was developed to address this. The Scirocco review identifies the PLSFRS as the most promising primary outcome measure for future PLS trials, while acknowledging that its sensitivity and minimal clinically important difference still require further validation in a prospective cohort — which is one goal of the ongoing PNHS.
Biomarkers
The review identifies neurofilament light chain (NfL) as the most promising biomarker for PLS trials, supported by the PNHS finding that baseline NfL significantly predicts PLSFRS decline (p = 0.001). This positions NfL as a candidate stratification factor and potentially as a surrogate endpoint — critical for trial design when clinical endpoints are slow to accrue. MRI markers (corticospinal tract signal, motor cortex thickness) are described as supportive but not yet trial-ready.
Trial design challenges
The review is explicit about the core problem: PLS declines slowly, which means a trial powered to detect a treatment effect on functional decline requires either very large sample sizes, very long follow-up periods, or sensitive biomarker endpoints that can substitute for clinical endpoints. None of these are straightforwardly available — PLS is rare (1–4% of motor neuron disease), biomarkers are validated in ALS but less so in PLS specifically, and no drug candidate has yet reached Phase 2 in PLS.
The authors identify the absence of disease-modifying therapies as the most pressing unmet need in PLS care. No treatment has been shown to slow the progression of PLS. The drugs approved for ALS (riluzole, edaravone, AMX0035, tofersen) have not been tested in PLS clinical trials.
Why it matters
This review functions as the field's current consensus document. Any researcher designing a PLS trial in 2025 or 2026 would cite this paper to justify their choice of outcome measure, their approach to patient stratification, and their decision about what biomarkers to collect. It is the most complete synthesis of the PLS evidence base available.
For patients and families, the most important implication is that the field now has a clear map of what is missing and what needs to happen. The PLSFRS needs further validation. NfL needs prospective PLS-specific evidence (ongoing in the PNHS). Drug candidates need to be identified and tested. The Scirocco review does not promise that a trial is imminent, but it demonstrates that the groundwork for one is being deliberately laid.
How this connects
This review explicitly builds on Gordon 2006 as its natural history baseline. The prospective data it calls for is being generated by the PNHS Mayo Clinic study. The NfL biomarker evidence it highlights is covered in depth on the NfL biomarker studies page. The diagnostic criteria it assumes throughout are the 2020 consensus criteria. For what the trial readiness picture means for patients today, see Clinical Trials and the Prognosis page.
Citation
Scirocco C, et al. Toward therapeutic trials in primary lateral sclerosis. ALS and Frontotemporal Degeneration. 2025. Taylor & Francis (Tandfonline). doi:10.1080/21678421.2025.XXXXXX