Tau Levels in Spinal Fluid Possible Biomarker of ALS, Likely Progression

Levels of the protein tau found in the cerebrospinal fluid (CSF) — the transparent liquid surrounding the brain and spinal cord — can help in diagnosing amyotrophic lateral sclerosis (ALS), a study reported.

Tau levels in ALS patients also correlated with a faster progression rate and poorer survival, suggesting this protein could work as a prognosis biomarker.

The study, “Tau protein as a diagnostic and prognostic biomarker in Amyotrophic Lateral Sclerosis,” was published in the European Journal of Neurology.

As ALS shares many symptoms with other neurological diseases, no single test can diagnose the disorder. This often results in misdiagnoses, and in long waiting periods before a definite ALS diagnosis is in place.

Biomarkers that help to readily distinguish people with ALS from those without it could aid in a quicker diagnosis, enabling patients to start treatment in earlier disease stages.

In recent years, proteins of the cells’ cytoskeleton — which provide structural support and play important roles in molecular transport within cells — have emerged as promising CSF biomarkers.

Tau is a cytoskeletal protein that stabilizes a component of the cells’ skeleton called microtubules. These structures are essential to transport information along long nerve projections, and to ensure that nerve cells communicate effectively. Studies in Alzheimer’s disease have demonstrated that changes to the tau protein can damage this transport, and halt neuronal communication.

Yet, whether tau and its altered forms might also help in diagnosing and predicting the likely course of ALS in patients is still largely debated.

Researchers at the University of Palermo and colleagues elsewhere in Italy examined the levels of tau and those of phosphorylated tau (pTau) — a modification that adds a phosphate chemical group to the protein — in 196 ALS patients (median age, 65) and 91 other patients serving as controls. All underwent a lumbar puncture at the university hospital from 2000 to 2020.

Controls in this study included 35 people without a neurodegenerative disease, and 56 with a neurodegenerative disease whose symptoms mimic those of ALS.

Among ALS patients, the majority had relatively aggressive disease — meaning that from the time of first symptoms to a definite diagnosis, they experienced a one point or greater monthly reduction in their Revised ALS Functional Rating Scale (ALSFRS-R) scores, a measure of functional disability.

Analysis of tau levels showed that ALS patients had significantly greater levels of total tau than did controls, but no differences in the pTau levels. Consistently, a ratio between pTau and total tau was significantly lower in ALS patients.

To determine whether these levels could distinguish ALS patients from controls, researchers used a statistical measure called area under the curve (AUC), a measure of accuracy in which 0.5 means no differentiation between groups and 1 represents a perfect differentiation.

Overall, both tau and the ratio between pTau and total tau showed a good accuracy for diagnosing the condition, presenting AUC scores of 0.69 and 0.78, respectively. However, the ratio was best at discriminating ALS patients from those with and without other neurodegenerative diseases.

Elevated tau levels in ALS patients were also seen to associate with an older age at disease onset and a faster disease progression, suggesting its usefulness as a marker of likely disease prognosis or outcomes. Elevated CSF tau levels were also identified in patients with spinal onset ALS, or those that first present symptoms of muscle weakness in the arms or legs.

Results also found that tau levels may be used to predict likely overall survival, as people whose tau levels were below the median lived a median of 32 months, while those with higher tau levels lived a median of 24 months. In addition to tau levels, age at disease onset, diagnostic delay, and respiratory function at diagnosis were all independent predictors of survival.

Tau levels and the ratio between pTau and total tau “emerged as reliable diagnostic biomarkers of ALS, and [tau] as potential prognostic biomarker,” the investigators wrote, adding that the observational nature of the study may have limited their ability to validate the proteins as biomarkers of long-term prognosis.

“Further studies are needed to corroborate these findings in order to allow the [entry] of Tau biomarker in the clinical practice,” they added.