Ultrasensitive techniques and protein misfolding amplification assays for biomarker-guided reconceptualization of Alzheimer’s and other neurodegenerative diseases

ABSTRACT

Introduction

The clinical validation and qualification of biomarkers reflecting the complex pathophysiology of neurodegenerative diseases (NDDs) is a fundamental challenge for current drug discovery and development and next-generation clinical practice. Novel ultrasensitive detection techniques and protein misfolding amplification assays hold the potential to optimize and accelerate this process.

Areas covered

Here we perform a PubMed-based state of the art review and perspective report on blood-based ultrasensitive detection techniques and protein misfolding amplification assays for biomarkers discovery and development in NDDs.

Expert opinion

Ultrasensitive assays represent innovative solutions for blood-based assessments during the entire Alzheimer’s disease (AD) biological and clinical continuum, for contexts of use (COU) such as prediction, detection, early diagnosis, and prognosis of AD. Moreover, cerebrospinal fluid (CSF)-based misfolding amplification assays show encouraging performance in detecting α-synucleinopathies in prodromal or at-high-risk individuals and may serve as tools for patients’ stratification by the presence of α-synuclein pathology. Further clinical research will help overcome current methodological limitations, also through exploring multiple accessible bodily matrices. Eventually, integrative longitudinal studies will support precise definitions for appropriate COU across NDDs.

KEYWORDS:

• Alzheimer’s disease
• fluid biomarkers
• neurodegenerative diseases
• Parkinson’s disease
• PMCA
• RT-QuIC
• ultrasensitive techniques

Article highlights

• Distinct fluid biomarkers tracking key in vivo pathophysiological mechanisms represent an unmet need across the spectrum of NDDs;

• With the exception of AD, currently defined as a clinical-biological construct, the detection and diagnosis of most of the NDDs are based on clinical-symptomatic features, and pathophysiological fluid biomarkers are usually not integrated in the diagnostic/prognostic pathway;

• Ultrasensitive detection techniques have been recently applied for the quantification of amyloid-β (Aβ) peptides, tau proteins, and neurofilament light chain (NfL), in easily accessible bodily matrices such as blood, demonstrating good accuracy in identifying AD;

• Protein misfolding amplification assays like Protein Misfolding Cyclic Amplification (PMCA) and Real-Time Quaking-Induced Conversion (RT-QuIC) showed a potential utility in identifying α-synucleinopathies in both late-stage clinical and prodromal stages; preliminary results support a role of these techniques in the isolation of tau seeds and of transactive response DNA-binding protein of 43 kDa (TDP-43);

• A more extensive validation and cross-comparisons are required for defining the most appropriate COU of these techniques for the development of fluid biomarkers in NDDs.

Declaration of interest

This study was not funded, academic study without external financial support. N.C. nothing to disclose M.F.B nothing to disclose C.D.G. nothing to discloseE.B. nothing to disclose L.G. nothing to disclose E.D.P. nothing to disclose A.G. nothing to disclose A. V declares no competing financial interests related to the present article and his contribution to this article reflects entirely and only his own academic expertise on the matter. This work was initiated during his previous position at Sorbonne University, Paris, France. AV was an employee of Eisai Inc. AV does not receive any fees or honoraria since November 2019. Before November 2019 he had he received lecture honoraria from Roche, MagQu LLC, and Servier. G.S. nothing to disclose R.C. nothing to disclose H. H is an employee of Eisai Inc. The present article has been initiated and prepared during HH’s previous academic position at Sorbonne University, Paris, France and it reflects entirely and only his own opinion on the subject matter. He serves as Senior Associate Editor for the Journal Alzheimer’s & Dementia and does not receive any fees or honoraria since May 2019; before May 2019 he had received lecture fees from Servier, Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Eisai, Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare and Oryzon Genomics, consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon Genomics, and Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics and Roche Diagnostics.He is co-inventor in the following patents as a scientific expert and has received no royalties: • In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Patent Number: 8916388 • In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Patent Number: 8298784 • Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20120196300 • In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100062463 • In Vitro Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100035286 • In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Publication Number: 20090263822 • In Vitro Method for The Diagnosis of Neurodegenerative Diseases Patent Number: 7547553 • CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases Publication Number: 20080206797 • In Vitro Method for The Diagnosis of Neurodegenerative Diseases Publication Number: 20080199966 • Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20080131921• Method for diagnosis of dementias and neuroinflammatory diseases based on an increased level of procalcitonin in cerebrospinal fluid: Publication number: United States Patent 10921330 F.B. has received funding from Allergan, Biogen, Eisai, Novartis and travel grants from Allergan, Eli Lilly, Novartis, Teva.

Reviewer disclosures

A reviewer on this manuscript is an inventor on certain RT-QuIC-related patents. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.