A structure‐based fluid biomarker for the differential diagnosis of early‐stage neurodegenerative diseases measured by the immuno‐infrared‐sensor (iRS)

Abstract

AbstractBackgroundNeurodegenerative diseases like Alzheimer’s (AD) and Parkinson’s disease (PD) are accompanied by misfolding of the key proteins into beta‐sheet enriched structures resulting in high neurotoxicity in early phases. We have developed a diagnostic immuno‐infrared‐sensor (iRS) that monitors the secondary structure distribution of these key proteins (Abeta for AD, alpha‐synuclein for PD) as an early detectable biomarker before the clinical manifestation, which is shown exemplarily for AD.1 MethodThe iRS combines the secondary‐structure‐specific infrared spectroscopy in a flow system based attenuated total reflection (ATR) set‐up with methods of immuno‐detection by surface‐immobilized antibodies. The antibodies specifically capture disease‐related target proteins (e.g., Abeta) from complex media (cerebrospinal fluid or blood plasma) for measurements. The readout is the amide‐I band, which directly reflects the secondary structure distribution of the captured proteins in body fluids and thus, indicates the protein misfolding: The lower the amide‐I frequency, the higher the content of misfolded Abeta species in the sample present.2 ResultThe structure biomarker for Abeta has been validated in multiple independent clinical studies with strong correlation to CSF biomarkers and PET scans.1,3‐5 Especially, very early preclinical AD could be identified in symptom‐free individuals before plaque formation, up to 17 years before the diagnosis.6 ConclusionThe results demonstrate a highly specific and sensitive immune‐assay capable of tracking structural changes of Abeta before clinical manifestation of AD. In addition, alpha‐synuclein and TDP‐43 misfolding indicate PD and ALS in current discovery studies, providing a tool for differential diagnosis at early stages.