The path to biomarker-based diagnostic criteria for the spectrum of neurodegenerative diseases

ABSTRACT

Introduction: The postmortem examination still represents the reference standard for detecting the pathological nature of chronic neurodegenerative diseases (NDD). This approach displays intrinsic conceptual limitations since NDD represent a dynamic spectrum of partially overlapping phenotypes, shared pathomechanistic alterations that often give rise to mixed pathologies.

Areas covered: We scrutinized the international clinical diagnostic criteria of NDD and the literature to provide a roadmap toward a biomarker-based classification of the NDD spectrum. A few pathophysiological biomarkers have been established for NDD. These are time-consuming, invasive, and not suitable for preclinical detection. Candidate screening biomarkers are gaining momentum. Blood neurofilament light-chain represents a robust first-line tool to detect neurodegeneration tout court and serum progranulin helps detect genetic frontotemporal dementia. Ultrasensitive assays and retinal scans may identify Aβ pathology early, in blood and the eye, respectively. Ultrasound also represents a minimally invasive option to investigate the substantia nigra. Protein misfolding amplification assays may accurately detect α-synuclein in biofluids.

Expert opinion: Data-driven strategies using quantitative rather than categorical variables may be more reliable for quantification of contributions from pathophysiological mechanisms and their spatial-temporal evolution. A systems biology approach is suitable to untangle the dynamics triggering loss of proteostasis, driving neurodegeneration and clinical evolution.

KEYWORDS:

• Alzheimer’s disease
• biomarkers
• cerebral amyloid angiopathy
• Parkinson disease
• amyotrophic lateral sclerosis

Article highlights

• The clinical diagnostic guidelines of neurodegenerative diseases (NDD) based on post-mortem evaluations as reference standard do not reflect the dynamic continuum of overlapping pathophysiological abnormalities, mixed pathologies, and the shared anatomic, phenotypic constituents.

• Few pathophysiological biomarkers are reported in the NDD diagnostic criteria

• CSF Aβ42, t-tau, p-tau concentrations or, alternatively, cerebral amyloid-PET and tau-PET retention, essentially confirm or exclude an Alzheimer’s disease pathology

• SPECT with datscan detects specific dopaminergic denervation; electrophysiological tests identify lower motor neuron degeneration

• Altered patterns of cerebral atrophy or hypometabolism on conventional MRI and FDG-PET, respectively, reflect phenotypes but not pathophysiologies

• Protein misfolding amplification assays may accurately detect α-synuclein prion-like seeds in synucleinopathies and serum progranulin some genetic forms of frontotemporal dementia.

• Ultrasensitive techniques measuring blood Aβ42 and NFL concentrations might represent screening tools in select populations

• Other potential screening tools are retina scanning and ultrasound to non-invasively investigate β-amyloid and substantia nigra

• Strategies combining clinical and biomarker information to gather individuals from large heterogeneous cohorts into consistent clusters might improve classifications of NDD across the wide spectrum of presentations, and aid the uncovering of pathophysiological causes and identification of impactful therapies

Declaration of interest

AV is an employee of Eisai Inc. and serves as Associate Editor for the Journal of Alzheimer’s disease; he received lecture honoraria from Roche, MagQu LLC, and Servier. HH is an employee of Eisai Inc. and serves as Senior Associate Editor for the Journal Alzheimer’s & Dementia; he received lecture fees from Biogen, Roche, and Servier, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from 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.

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

SL serves as Associate Editor for the Journal of Alzheimer’s disease; he received lecture honoraria from Roche and Servier.

KHM is a co-founding member and consultant for NeuroVision Imaging (NVI), also a co-inventor on the following patent as a scientist and has received no royalties: Optical method for the detection of Alzheimer’s disease. Patent Number: 9839699.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewers Disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

NIH/NIA R01 AG055865 and R01 AG056478 awards (M.K.H.).HH is an employee of Eisai Inc. During his previous work (until April 2019) he was supported by the AXA Research Fund, the ‘Fondation partenariale Sorbonne Université’ and the ‘Fondation pour la Recherche sur Alzheimer,’ Paris, France.AV is an employee of Eisai Inc.