Aβ1-42 and Tau as Potential Biomarkers for Diagnosis and Prognosis of Amyotrophic Lateral Sclerosis.

Débora Lanznaster,Diane Dufour-Rainfray,Salah Eddine Bakkouche,Christian R Andres,Stephane Beltran,Hélène Blasco,Philippe Corcia,Rudolf C Hergesheimer,Patrick Vourc’H

doi:10.3390/ijms21082911

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, but its definitive diagnosis delays around 12 months. Although the research is highly active in the biomarker field, the absence of specific biomarkers for diagnosis contributes to this long delay. Another strategy of biomarker identification based on less specific but sensitive molecules may be of interest in clinical practice. For example, markers related to other neurodegenerative diseases such as Alzheimer’s disease (AD) could be fully explored. Here, we compared baseline levels of amyloidβ1-42 (Aβ1-42), total Tau, and phosphorylated-Tau (phospho-Tau) protein in the cerebrospinal fluid (CSF) of ALS patients to controls and correlated it with clinical parameters of ALS progression collected over 12 months. We observed increased levels of Aβ1-42 (controls: 992.9 ± 358.3 ng/L; ALS: 1277.0 ± 296.6 ng/L; p < 0.0001) and increased Aβ1-42/phospho-Tau ratio and Innotest Amyloid Tau Index (IATI) (both p < 0.0001). IATI and the phospho-Tau/total Tau ratio correlated positively with ALSFRS-R and weight at baseline. Multivariate analysis revealed that baseline ALSFRS-R was associated with Aβ1-42 and phospho-Tau/total Tau ratio (p = 0.0109 and p = 0.0013, respectively). Total Tau and phospho-Tau levels correlated negatively with ALSFRS-R variation at months 6 and 9, respectively (p = 0.02 and p = 0.04, respectively). Phospho-Tau/total Tau ratio correlated positively with ALSFRS-R variation at month 9 (p = 0.04). CSF levels of Aβ1-42 could be used as a complementary tool to ALS diagnosis, and total Tau and phospho-Tau levels may help establishing the prognosis of ALS. Further studies merit exploring the pathophysiological mechanisms associated with these markers. Despite their lack of specificity, phospho-Tau/total Tau and Aβ1-42 should be combined to other biological and clinical markers in order to improve ALS management.

Highlights

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons and consequent progressive muscular paralysis
We analyzed data collected from 90 controls subjects and 123 ALS patients enrolled in the CHU of Tours, France (Table 1)
We found increased levels of Aβ1-42 in the cerebrospinal fluid (CSF) of ALS patients compared to controls (ALS: 1277.07 ng/L, controls: 992.9 ng/L; p < 0.0001)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons and consequent progressive muscular paralysis. ALS patients usually die 3–5 years after the onset of symptoms by respiratory failure. Around 90% of ALS cases are sporadic, whereas the remaining cases are genetic forms [1]. ALS forms can be classified in bulbar and spinal, depending on the site of symptoms onset, with a higher severity in bulbar than in limb-onset patients. Only two drugs are approved for the treatment of ALS (riluzole and edaravone), with moderate effects on survival or disease progression. ALS is a very diverse pathology, and definite diagnosis can be prolonged for up to 12 months, with this delay being in part due to the lack of diagnosis biomarkers. Some biomarkers for ALS have been already proposed such as neurofilament and creatinine [2,3], none of them are validated in the clinical setting

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Discussion

Conclusion