Serum levels of glial fibrillary acidic protein in patients with amyotrophic lateral sclerosis

Abstract

Objective To compare serum levels of the astrocyte biomarker glial fibrillary acidic protein (GFAP) in patients with amyotrophic lateral sclerosis (ALS) and neurologically healthy controls and to analyze the relations between serum GFAP (sGFAP) and phenotype in ALS. Methods We studied 114 ALS patients and 38 controls. sGFAP was quantified with single molecule array (Simoa) technology. Results In both ALS patients and controls, sGFAP moderately correlated with age. ALS patients had higher sGFAP levels compared to controls, but this yielded a weak discriminative performance (AUC = 0.6198). In ALS, sGFAP was not associated with most of the motor phenotypic features, including site of onset, functional status, disease progression rate, disease stage, and indices of upper (UMN) and lower motor neuron (LMN) impairment. However, sGFAP negatively correlated with cognitive scores regarding ALS‐nonspecific functions, particularly memory ( r = −0.2082) and tended to be higher in ALS patients with eye movement abnormalities ( p = 0.0628). sGFAP also correlated with polysomnographic indices of oxygen desaturation (ODI; r = 0.2639) and apnea‐hypopnea (AHI; r = 0.2858). In a multivariate analysis, sGFAP was negatively associated with survival (HR = 1.005). Relevantly, we found a negative correlation between sGFAP and estimated glomerular filtration rate (eGFR; r = −0.3500). Interpretation Our work provides neurochemical evidence of astrocyte involvement in ALS pathophysiology and particularly in the development of extra‐motor manifestations (namely, cognitive – memory – impairment) and respiratory dysfunction. The negative correlation between sGFAP and eGFR has practical relevance and should not be disregarded in future investigations.

Phenotypic correlates of serum neurofilament light chain levels in amyotrophic lateral sclerosis

“…One of the clearest findings of our study is the lack of association of sNFL levels with cognitive deficits in ALS. The apparent independence of sNFL from extra-motor pathology contrasts with the recent report of higher serum GFAP levels in ALS patients with neuropsychological abnormalities ( Falzone et al, 2022 ; Verde et al, 2023 ). The motor specificity of NFL might be a consequence of the unique amount of NFL which the axon of a degenerating MN, given its length, can release.…”

Amyloid-Beta Co-Pathology Is a Major Determinant of the Elevated Plasma GFAP Values in Amyotrophic Lateral Sclerosis

“…Similarly, we found no differences in plasma levels across onset types and clinical phenotypes. Taken together, these data, in agreement with previous reports in smaller ALS cohorts [ 18 , 19 ], suggest that plasma GFAP elevation in ALS also reflects the astrocytic activation secondary to neurodegeneration at sites unrelated to motor neurons. The moderate association between plasma GFAP and parameters of cognitive impairment, including ALS-specific ECAS scores, the BMDB total score, and the scores in tests exploring semantic fluency and constructional praxis, suggest a link with extra-motor cortical areas.…”

“…Regarding the possible influence of gender on plasma GFAP values, we found that in our ALS population females showed higher biomarker levels than males, with the difference almost reaching statistical significance. Higher plasma GFAP values in females were previously reported in ALS patients, albeit potentially related to the older age [ 19 ], and in subjects with other neurodegenerative disorders as well [ 12 , 13 ]. However, such a difference was not highlighted in other patient groups [ 22 ].…”

“…As for ALS, data on CSF and blood GFAP levels are fewer and less concordant, with a preliminary study showing elevated CSF GFAP values in ALS patients compared to controls [ 16 ] and others reporting no difference in blood or CSF between ALS and healthy subjects [ 17 , 18 ]. Recently, a single study showed higher blood GFAP values in ALS than in controls and reported a positive correlation between biomarker levels and parameters of cognitive and behavioral impairment [ 19 ].…”

Proteomic profiling of the brain from the <i>wobbler</i> mouse model of amyotrophic lateral sclerosis reveals elevated levels of the astrogliosis marker glial fibrillary acidic protein

“…complications due to frontotemporal dementia or cognitive impairmen. 53 , 54 In addition, neurofilament light chain (NfL), one of the polypeptide chains of the neurofilament triplet that structurally supports the neuronal cytoskeleton of axons, was shown to be a suitable diagnostic marker and strongest predictor of patient survival. 51 , 52 , 54 Ubiquitin C-terminal hydrolase UCHL1 was established as a robust prognostic indicator for stratifying slow disease progression and survival rates in patients with low levels of neurofilament light chain.…”