Increased Levels of Proteins in CSF Linked to Poor Prognosis in ALS

More CSF proteins tied to higher risk of death in limb-onset ALS

Teresa Carvalho, MS avatar

by Teresa Carvalho, MS |

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High total protein levels in the cerebrospinal fluid (CSF) — the liquid that surrounds the brain and spinal cord — are linked to shorter survival among amyotrophic lateral sclerosis (ALS) patients with limb-onset disease, a study showed.

The researchers noted a similar association was found for high CSF levels of albumin, the most abundant circulating protein in blood.

According to the team, higher-than-normal levels of proteins in the CSF indicate a disruption in the protective membranes that prevent certain circulating molecules from entering the brain and spinal cord.

These findings suggest that both total protein and albumin levels in the CSF may be strong biomarkers for ALS prognosis among patients with the limb-onset disease type.

“High levels of [albumin] are a bad prognostic indicator for [limb-onset ALS], in addition to high CSF proteins levels that also act as a marker of poor prognosis,” the researchers wrote.

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Investigating protein levels in the CSF

The study, “Elevated Cerebrospinal Fluid Proteins and Albumin Determine a Poor Prognosis for Spinal Amyotrophic Lateral Sclerosis,” was published in the International Journal of Molecular Sciences.

ALS is characterized by the progressive loss of voluntary muscle movements. It has different forms, depending on the rate of progression and the site of disease onset.

The muscles controlling the arms and legs are often the first affected in ALS — a form called limb-onset or spinal-onset ALS. However, some patients have bulbar-onset disease, in which the bulbar muscles, or those involved in swallowing, speaking, and breathing, are the first to be affected.

Identifying prognostic factors is crucial to inform patients about the predictive course of their disease, help them in family planning, and in the design of clinical trials.

Increasing evidence has linked ALS with the disruption of the blood brain barrier (BBB) and the blood spinal cord barrier (BSCB) — two highly selective membranes that tightly regulate what substances from the bloodstream can enter the brain and spinal cord.

When these barriers are disrupted, they allow the entry of circulating immune cells and other potentially harmful substances, which may speed ALS-associated neurodegeneration, and thereby disease progression.

Now, a team of researchers in Barcelona, Spain, examined whether the disruption of these barriers is linked to a faster disease progression.

Their study included 246 people — 138 men and 108 women — diagnosed with ALS from 2012 to 2019. These patients were followed up to 2022.

The mean age at symptom onset was 60.8 years, and patients were diagnosed with the disease after a median of 9.87 months. Most (70%) had limb-onset ALS, while nearly 29% had bulbar-onset disease. In three patients — just over 1% — respiratory symptoms were the first to develop.

Barrier disruption was assessed through the CSF levels of total proteins and albumin — whose higher-than-normal CSF levels are known markers of BBB dysfunction. The albumin quotient, a ratio between albumin levels in the blood and in the CSF, also was measured as a potentially more specific marker of BBB disruption.

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ALS prognosis differs by type

Results showed that limb-onset patients with higher-than-normal CSF protein levels had a shorter diagnostic delay time compared with those with normal levels — a mean of 9.5 months vs. 12.6 months. This difference nearly reached statistical significance.

That suggests that the rate of disease progression is different between these two groups of patients from disease start, the team noted. Patients with higher CSF protein levels experience more rapid disease progression.

Also, bulbar-onset ALS patients had a 65% significantly higher risk of death than those with limb-onset disease, which is consistent with the poor prognosis reported for bulbar-onset ALS.

However, neither total protein levels nor albumin levels in the CSF were strong predictors of disease progression rate, or survival, in patients with the bulbar-onset form.

In turn, in limb-onset ALS patients, higher CSF levels of proteins and albumin were associated with a significantly higher risk of death. Further analyses revealed that 0.5 g/L or higher total protein levels and an albumin quotient of 0.65 or higher were significantly associated with a poorer prognosis in this group of ALS patients.

“Unlike other prognostic biomarkers, CSF proteins and albumin are easy parameters to obtain, well within the reach of practically all clinical analysis laboratories,” the researchers wrote.

The team noted that “the best prognostic indicator of the spinal [form]” is likely the albumin quotient. When this cannot be determined, they said, 0.5 g/L or higher CSF total protein levels are “a clear marker of poor prognosis in the spinal [form].”

Given the difficulties of predicting the prognosis of limb-onset ALS patients, these potential biomarkers “can be of great help in this regard,” the team wrote.

“Our data suggest that blood-brain barrier dysfunction accelerates disease progression from the onset of symptoms and decreases [limb-onset ALS] patient survival,” the researchers wrote.

The findings also highlight that bulbar-onset ALS patients “worsen rapidly, but they do not manifest the same effects on the BBB and BSCB dysfunction parameters measured in our study and altered in the spinal onset ALS [group],” they added.

However, “blood-brain barrier dysfunction does not increase as the disease progresses, because patients with normal proteins had the longest diagnostic delay,” the team wrote — meaning that CSF analysis in these patients was performed at a later stage of the disease.