PLS Biomarker Research
One of the deepest practical problems in PLS research is that the disease moves slowly and quietly. Patients decline, but on timescales that make clinical rating scales a blunt instrument for measuring change over the 12 to 24 months a drug trial can afford to run. Biomarkers — proteins in the blood, structural changes on MRI, neurophysiological signals — offer a different kind of window: one that might detect biological changes before they manifest as observable functional loss. In ALS, biomarker science has matured into a critical tool for drug development. In PLS, that science is earlier-stage, more fragmentary, and often borrowed from adjacent diseases. But one finding from 2025 changed what is possible: a single p-value from the PLS Natural History Study that may eventually define how the first successful PLS trial is designed.
The central problem biomarkers are meant to solve
PLS presents two distinct challenges where biomarkers could matter. The first is diagnosis. PLS is currently recognized through clinical observation over years — you watch for the absence of lower motor neuron signs through the 2- and 4-year windows defined by the 2020 consensus criteria, and you hope the picture does not shift. A biomarker that could reliably distinguish PLS from early ALS would compress that diagnostic delay and spare patients years of uncertainty.
The second challenge is trial design. If PLS declines at an average of 1.6 to 2 ALSFRS-R points per year, and you want a trial to detect a 30% slowing of that decline with adequate statistical power, you are looking at either very large cohorts or very long follow-up — or both. A biological endpoint that tracks disease activity more sensitively than clinical scales, and that responds to effective treatment before functional changes become measurable, could make shorter, smaller, and therefore feasible trials possible. That is exactly what happened with tofersen in ALS: the FDA accepted blood NfL reduction as the basis for accelerated approval, setting a regulatory precedent that the PLS community is watching closely.
Where the evidence comes from
Neurofilament light chain is the biomarker that has attracted the most serious attention in PLS. NfL is a structural protein in the neuronal cytoskeleton; when axons are damaged or dying, it leaks into cerebrospinal fluid and from there into blood, where ultra-sensitive assays can detect it at picogram concentrations. Across dozens of neurological diseases, NfL has proven to be a reliable index of how much neuronal damage is actively occurring.
In ALS, the picture for NfL is clear. The NfL biomarker studies in MND show serum NfL in ALS patients averaging around 81 pg/mL versus roughly 9 pg/mL in healthy controls, with levels correlating with progression rate. Fast progressors have higher NfL. When the FDA approved tofersen for SOD1-ALS in 2023, it did so partly because tofersen reduced plasma NfL — establishing NfL as a pharmacodynamic biomarker that regulators would accept as evidence of biological effect, even before clinical endpoints were fully resolved. That regulatory moment was noticed in every corner of the MND field.
The PLS-specific evidence came from the PLS Natural History Study at Mayo Clinic and Johns Hopkins, with results published in Annals of Neurology in September 2025. In 76 prospectively enrolled PLS participants, the study found that baseline NfL level was significantly associated with rate of PLSFRS decline over the following year, at p = 0.001. That single finding — the most direct PLS-specific biomarker result in the literature — positions NfL as a candidate stratification factor and endpoint for future PLS trials. It means a blood draw at diagnosis may predict whether a given patient is a fast or slow progressor, which has implications both for how clinicians counsel patients and for how trial sponsors select and stratify participants.
A related neurofilament marker, phosphorylated neurofilament heavy chain (pNfH), has its own evidence story — one that unfolded in ALS rather than PLS, but with direct implications for PLS trial design. The pNfH biomarker evidence includes a striking finding from the MIROCALS trial: when the IL-2 immunotherapy trial used CSF pNfH as a stratification factor, patients in the lower pNfH group — roughly 80% of participants — showed a greater than 40% reduction in risk of death with active treatment. That result did not earn the drug an approval, but it demonstrated that pNfH could identify trial subgroups in which a treatment effect was detectable. If pNfH performs similarly as a stratifier in PLS, it could allow more precise trial design — enriching enrollment with patients who have biologically active disease even when their clinical scores are moving slowly.
Glial fibrillary acidic protein (GFAP) rounds out the fluid biomarker picture, though with less direct PLS evidence than either NfL or pNfH. As the GFAP biomarker studies describe, GFAP reflects astrogliosis — the activation and damage of the glial cells that support neurons — rather than axonal injury directly. In ALS, serum GFAP is elevated roughly twofold compared to healthy controls and correlates with disease duration. In PLS, no dedicated GFAP studies have been published, but the logic is straightforward: PLS involves astrogliosis in the motor cortex, so GFAP elevation would be expected, likely at lower levels than in ALS given the slower rate of degeneration.
The broader shift in ALS biomarker science is toward panels rather than single markers, and PLS will likely follow that trajectory. The multi-biomarker panel work developing in the ALS field combines NfL, pNfH, GFAP, and other markers to build a more complete picture of disease activity than any single protein can provide. Each marker reflects a different biological process — axonal damage, glial activation, inflammatory signaling — and together they may eventually enable the kind of molecular staging that would allow trials to enroll more precisely and detect effects earlier.
Away from blood and CSF, MRI offers a structural window into PLS pathology. The corticospinal tract MRI studies document the radiological signs of upper motor neuron degeneration in PLS: T2 signal change along the corticospinal tract producing what is sometimes called the "wine glass sign," decreased cortical thickness in the primary motor cortex, and high T2 signal in the motor segment of the corpus callosum. These structural markers confirm the pathology and can support diagnosis, but they have a limitation that fluid biomarkers may not: they appear to reflect cumulative, irreversible structural loss rather than ongoing biological activity, which makes them less useful as sensitive endpoints for detecting whether a treatment is slowing the active disease process.
What we know — and what we don't
The honest summary of where PLS biomarker science stands: NfL is the real breakthrough. Its p = 0.001 association with PLSFRS decline in the PNHS is the single most important PLS-specific biomarker finding to date, and it will almost certainly shape how the first serious PLS treatment trial is designed. pNfH has strong ALS evidence for stratification but limited primary PLS data. GFAP is part of the emerging multi-marker picture but has no PLS-specific validation. MRI markers support diagnosis and provide structural correlates, but are not yet standardized as outcome measures for trials.
The missing piece remains a validated fluid biomarker panel specific to PLS — not extrapolated from ALS, but tested against clinical outcomes in a PLS-only prospective cohort. The PNHS is building that evidence. Until it is complete and replicated, PLS biomarker interpretation borrows heavily from the ALS literature, with the caveat that PLS disease biology is not identical to ALS: the upper motor neuron degeneration in PLS is slower, more selective, and possibly driven by different cellular mechanisms. Whether NfL, pNfH, and GFAP behave quantitatively the same way in PLS as in ALS, or whether PLS-specific reference ranges and thresholds are needed, remains an open question.
Why it matters for you
If you are living with PLS, the biomarker research has two practical implications, now and in the future. Now: if your neurologist orders a serum NfL as part of monitoring, a high value relative to age-adjusted reference ranges is associated with faster functional decline — not a certainty, but a signal worth tracking. In the future: the validation of NfL as a trial endpoint is the regulatory key that could make a PLS drug trial feasible within the next several years. You can read more about how this fits into the broader treatment pipeline in the drug trials section, and about how biomarkers connect to your diagnosis at the diagnosis guide.
Individual studies in this section
Full details on each study, including methods, findings, and context: