Floeter and Mills 2009 — Progression in PLS: A Prospective Analysis
One challenge running through all PLS natural history research is the question of how to measure a disease that progresses slowly. Clinical rating scales designed for ALS miss much of what happens in PLS. Floeter and Mills, working at the NIH, took a different approach: they combined clinical measurement with neurophysiological techniques — specifically transcranial magnetic stimulation (TMS) — to track PLS progression from multiple angles simultaneously. Their findings established that multimodal measurement is more sensitive than clinical scores alone, and contributed directly to the design of subsequent studies.
What they did
Working at the National Institutes of Health (NIH), Floeter and Mills recruited a cohort of PLS patients for prospective follow-up. This was an NIH-based study — smaller than a multicenter registry but more intensively measured, with access to advanced neurophysiology equipment and specialized expertise.
At each assessment, participants underwent standard clinical evaluation including the ALSFRS-R and clinical UMN examination. They also underwent transcranial magnetic stimulation (TMS), a non-invasive technique that measures the excitability and conductivity of the motor cortex and corticospinal tract. TMS can quantify upper motor neuron function in ways that standard clinical examination cannot — measuring cortical silent period, central motor conduction time, and threshold for motor cortex activation.
The study also examined pseudobulbar affect (PBA) — the involuntary laughing or crying that occurs in a significant minority of PLS patients due to disruption of corticobulbar pathways. PBA is clinically significant and undertreated in PLS, and Floeter's work contributed to the evidence base on its prevalence and neurophysiological correlates.
What they found
Clinical decline
Functional decline in PLS was slow and measurable. The ALSFRS-R captured decline, consistent with the Gordon 2006 cohort data. The NIH cohort was smaller and followed over a different timeframe, but the core finding — that PLS progresses at a fraction of the rate of ALS — was confirmed prospectively.
TMS correlates with clinical progression
Measures of cortical excitability on TMS correlated with clinical progression, and TMS abnormalities were detectable in patients at stages where clinical rating scales showed only minimal decline. This is an important finding: it demonstrates that the corticospinal tract degeneration underlying PLS can be detected neurophysiologically before it fully manifests in measurable functional change. TMS could, in principle, serve as a more sensitive measure of disease activity — detecting change earlier, when sample sizes needed to demonstrate it are smaller.
Central motor conduction time (CMCT) — the time it takes for a TMS pulse to travel from motor cortex to the muscle — was prolonged in PLS patients and correlated with the degree of UMN involvement clinically. Cortical silent period duration was also altered, consistent with inhibitory circuit dysfunction in the motor cortex.
Pseudobulbar affect
Floeter's work documented pseudobulbar affect in a meaningful proportion of PLS patients and characterized it as reflecting corticobulbar rather than corticospinal tract involvement. PBA can be one of the most distressing symptoms in PLS — involuntary emotional expression is socially disruptive and is frequently misunderstood — and it responds to treatment (dextromethorphan/quinidine or low-dose tricyclics). Having systematic clinical data on its prevalence and correlates in PLS was a contribution to practical patient care.
Why it matters
Floeter 2009 made two lasting contributions to PLS research. First, it provided neurophysiological validation that TMS measures track PLS progression and are detectable before clinical scores change substantially. This established TMS as a candidate biomarker or outcome measure in future trials — a role that imaging-based approaches later took up more fully with the development of advanced MRI protocols. Second, it provided systematic clinical data on PBA prevalence and correlates in PLS, contributing to the evidence base for a symptom that is clinically important but rarely gets dedicated research attention.
The study also established the NIH as a site of PLS-specific research and demonstrated that intensive, multimodal prospective measurement of a small PLS cohort could yield information that large registry analyses could not. This methodological approach — small, deep, and multimodal — has influenced subsequent PLS research design.
For patients, the direct relevance is twofold. Floeter's work on PBA contributed to the clinical recognition that PLS is not just a motor disease: it affects emotional and behavioral regulation through corticobulbar pathways, and this needs to be assessed and treated. And the TMS findings reinforced the understanding that PLS affects the motor cortex and corticospinal tract directly — not merely as incidental collateral damage, but as the primary site of pathology.
Limitations
The NIH cohort was small and conducted at a single highly specialized center, limiting generalizability. TMS is technically demanding and not available at all clinical sites, which limits its adoption as a routine outcome measure. The study predates modern quantitative MRI techniques that can now provide comparable or superior sensitivity to TMS for tracking corticospinal tract degeneration.
How this connects
The multimodal approach Floeter pioneered influenced the design of the PNHS, which combined clinical (PLSFRS) and biological (NfL) measurement. The MRI techniques that have since supplemented TMS for tracking corticospinal degeneration are covered on the Corticospinal Tract MRI page. The PBA findings relate to symptom management covered across the site. For the broader natural history context, see Natural History Research and the Biomarkers hub.
Citation
Floeter MK, Mills R. Progression in primary lateral sclerosis: a prospective analysis. Amyotrophic Lateral Sclerosis. 2009;10(5-6):339–346. PMID: 19922126. PMC2783549.