A Biomarker for ALS?

Abdullah Hashmi, MD

April 21, 2022

The study covered in this summary was published in medRxiv.org as a preprint and has not yet been peer reviewed. 

Key Takeaways

  • Results from this study showed plasma phosphorylated tau (p-tau181), was higher in patients with amyotrophic lateral sclerosis than in patients without ALS.

  • In patients with ALS, plasma p-tau181 was associated with lower motor neuron (LMN) signs in cervical, thoracic, and lumbosacral regions, and was associated with neuron loss in the spinal cord but not the motor cortex. 

Why This Matters

  • The specificity of plasma p-tau181 has not been explored relative to other neurodegenerative conditions. 

  • The study found that plasma p-tau181 is elevated in ALS and may serve as a novel, inexpensive, less-invasive marker specifically for LMN dysfunction in neurodegenerative disease. 

Study Design

  • In this retrospective observational study, 130 patients clinically diagnosed with ALS and 82 patients with Alzheimer's disease (AD) were compared with 33 healthy, nonimpaired patients without ALS or AD. 

  • Patients with ALS were excluded if there was evidence of AD pathology as determined by autopsy or cerebrospinal fluid (CSF) amyloid-β 1-42 (Aβ42) ≤ 192. Patients with AD were excluded if there was no evidence of AD pathology or CSF Aβ42 > 192.  Healthy patients were excluded if evidence of AD pathology was present or there was evidence of cognitive impairment by mini-mental state exam < 27. 

  • Analysis involved investigations between plasma and CSF biomarkers in ALS.  Then, p-tau181 association with clinical or pathologic features of ALS (upper and/or lower motor neuron dysfunction as tested by a board-certified neurologist) was assessed.

  • The clinical significance of plasma p-tau181 was tested by association with ALS clinical outcomes like seated forced vital capacity and the ALS functional rating scale. 

  • Lastly, in patients with ALS with autopsy data, concentrations of p-tau181 and relative neuron loss in the motor and spinal cord were investigated.    

Key Results

  • Elevated p-tau181 levels were poorly discriminated in AD and ALS (area under the curve = 0.60).  Furthermore, CSF p-tau181 was lower in ALS than in controls (P < .01). 

  • Plasma p-tau181 was higher in ALS than in controls (P = .000002) despite the fact that ALS is associated with little tau accumulation.

  • Elevated p-tau181 level was associated with LMN signs in cervical (P = .007), thoracic (P = .00025), and lumbosacral regions (P = .000002), and was associated with neuron loss in the spinal cord (P = .017) but not the motor cortex (P = .41). 

  • Plasma neurofilament light chain (NfL) and low cerebrospinal fluid (CSF) p-tau181 supported findings of elevated plasma p-tau181 in patients with ALS. 


  • The number of patients with ALS with postmortem pathological data was small. As a result, the low number of patients with ALS limited the ability to investigate whether spinal cord pathology was specific to p-tau181.

  • Only a subset of patients had sample CSF data, and CSF NfL and plasma NfL could not be tested in relation to LMN disease and clinical outcomes.


  • The study received no commercial funding.

  • Among the authors, Laynie Dratch, ScM, receives consulting fees from Passage Bio. Thomas F. Tropea, DO, has received consulting fees from Sanofi Genzyme. 

This is a summary of a preprint research study, "Elevated plasma phosphorylated tau 181 in amyotrophic lateral sclerosis relates to lower motor neuron dysfunction," written by researchers at the University of Pennsylvania Perelman School of Medicine Department of Neurology on medRxiv, provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on medRxiv.org.

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