Elevated Cerebrospinal Fluid Proteins and Albumin Determine a Poor Prognosis for Spinal Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease, both in its onset phenotype and in its rate of progression. The aim of this study was to establish whether the dysfunction of the blood–brain barrier (BBB) and blood–spinal cord barrier (BSCB) measured through cerebrospinal fluid (CSF) proteins and the albumin-quotient (QAlb) are related to the speed of disease progression. An amount of 246 patients diagnosed with ALS were included. CSF and serum samples were determined biochemically for different parameters. Survival analysis based on phenotype shows higher probability of death for bulbar phenotype compared to spinal phenotype (p-value: 0.0006). For the effect of CSF proteins, data shows an increased risk of death for spinal ALS patients as the value of CSF proteins increases. The same model replicated for CSF albumin yielded similar results. Statistical models determined that the lowest cut-off value for CSF proteins able to differentiate patients with a good prognosis and worse prognosis corresponds to CSF proteins ≥ 0.5 g/L (p-value: 0.0189). For the CSF albumin, the QAlb ≥0.65 is associated with elevated probability of death (p-value: 0.0073). High levels of QAlb are a bad prognostic indicator for the spinal phenotype, in addition to high CSF proteins levels that also act as a marker of poor prognosis.

Implication of Central Nervous System Barrier Impairment in Amyotrophic Lateral Sclerosis: Gender-Related Difference in Patients

“…Despite its limitations, the albumin quotient (QAlb) is the most commonly used marker for reflecting BBB/BSCB permeability. Elevation in QAlb levels has been reported in 20–50% of ALS patients [ 17 , 18 , 19 ] and its association with the progression of the disease remains controversial [ 18 , 20 , 21 , 22 ]. Moreover, BBB/BSCB impairments have especially been studied in the context of SOD1 mutated models of the disease [ 9 ].…”

Risk of cognitive decline progression is associated to increased blood‐brain‐barrier permeability: A longitudinal study in a memory unit clinical cohort

“…The results of our study show that increased BBBp, which is associated with vascular risk factors and CVB, is independently associated with a worse prognosis in individuals with cognitive decline. QAlb has been associated with a poorer prognosis in other neurological diseases such as spinal amyotrophic lateral sclerosis or multiple sclerosis 60,61 . To the best of our knowledge, this is the first time that QAlb has been related to the progression of cognitive decline.…”

“…QAlb has been associated with a poorer prognosis in other neurological diseases such as spinal amyotrophic lateral sclerosis or multiple sclerosis. 60 , 61 To the best of our knowledge, this is the first time that QAlb has been related to the progression of cognitive decline. Moreover, the association between increased BBBp and clinical progression was observed independently of b‐AD.…”

Associations of cerebrospinal fluid profiles with severity and mortality risk of amyotrophic lateral sclerosis

“…The research of biomarkers in cerebrospinal fluid (CSF) is one of the most active areas of ALS. Most previous studies focused on comparing the differences between healthy controls (HCs) and ALS patients, and most found that CSF IgG levels, CSF protein levels, and the quotient of CSF albumin and blood albumin (Q ALB ) in ALS patients were higher than those in controls ( Gårde et al, 1971 ; Leonardi et al, 1984 ; Norris et al, 1993 ; Assialioui et al, 2022 ). However, the associations between CSF profiles and the disease phenotype of ALS are controversial.…”

“…Besides, the associations with the disease phenotypes such as the stage of the disease or the progression rate turned out to be unapparent in the majority of the studies ( Tarasiuk et al, 2012 ; Zhao et al, 2020 ). One recent study found CSF protein was significantly negatively associated with the ALS functional rating scale revised (ALSFRS-R) scores in female ALS, not in male ALS ( Assialioui et al, 2022 ). These inconsistent findings of the CSF profiles may result from inherent limitations, including small sample size, varied applied methods, characteristics of enrolled ALS patients, ethnic differences of participants, and so on.…”