Novel PET Biomarkers to Disentangle Molecular Pathways across Age-Related Neurodegenerative Diseases

Abstract

There is a need to disentangle the etiological puzzle of age-related neurodegenerative diseases, whose clinical phenotypes arise from known, and as yet unknown, pathways that can act distinctly or in concert. Enhanced sub-phenotyping and the identification of in vivo biomarker-driven signature profiles could improve the stratification of patients into clinical trials and, potentially, help to drive the treatment landscape towards the precision medicine paradigm. The rapidly growing field of neuroimaging offers valuable tools to investigate disease pathophysiology and molecular pathways in humans, with the potential to capture the whole disease course starting from preclinical stages. Positron emission tomography (PET) combines the advantages of a versatile imaging technique with the ability to quantify, to nanomolar sensitivity, molecular targets in vivo. This review will discuss current research and available imaging biomarkers evaluating dysregulation of the main molecular pathways across age-related neurodegenerative diseases. The molecular pathways focused on in this review involve mitochondrial dysfunction and energy dysregulation; neuroinflammation; protein misfolding; aggregation and the concepts of pathobiology, synaptic dysfunction, neurotransmitter dysregulation and dysfunction of the glymphatic system. The use of PET imaging to dissect these molecular pathways and the potential to aid sub-phenotyping will be discussed, with a focus on novel PET biomarkers.

Keywords: biomarkers; neurodegeneration; positron emission tomography; precision medicine.

Figure 1

Schematic illustration of interlinked genotypes, molecular pathways and clinical phenotypes across age-related neurodegenerative diseases showing the overlap between various components and pathways at different levels, from genetics and molecular pathways to clinical phenotypes. Disentangling this etiological puzzle of known and yet unknown pathways acting distinctly or in concert could improve the stratification of patients into clinical trials and, potentially, help to drive the treatment landscape towards the precision medicine paradigm. The relationship between clinical diagnosis and clinical phenotypes was adapted from Ahmed et al., 2016 [3]. Abbreviations: AD: Alzheimer’s disease, ALS: Amyotrophic Lateral Sclerosis, FTD: Fronto-Temporal Dementia and PD: Parkinson’s disease.

Figure 2

Overview of molecular pathways targeted with PET radioligands. (A) Mitochondrial dysfunction and energy dysregulation can be investigated using (¹⁸F)BCPP-EF, for mitochondrial complex 1 and (¹¹C)SA4503 for sigma 1 receptor. (B) Neuroinflammation can be investigated by targeting translator protein expressed on activated microglia using PET radioligands such as (¹¹C)PK11195 and astroglia activation using novel PET radioligands such as (¹¹C)BU99008 for imidazoline 2-binding sites. (C) Abnormal protein aggregation of tau and amyloid-β can be quantified using specific radioligands such as (¹⁸F)AV1451 and (¹⁸F)Florbetaben, respectively. (D) Synaptic pathology can be investigated using (¹¹C)UCB-J targeting synaptic vesicle glycoprotein 2A. (E) Dysregulation of neurotransmitter systems can be investigated by employing various PET radioligands, including serotonergic markers such as (¹¹C)DASB for the serotonin transporter and dopaminergic markers such as presynaptic markers (¹⁸F)DOPA for dopamine storage, (¹¹C)PE2I for dopamine transporter and (¹¹C)Raclopride for postsynaptic dopaminergic receptors, as well as PET radioligands for noradrenergic, glutamatergic and GABAergic systems. Abbreviations: D2R/D3R: Dopamine type-2/type-3 receptor, DAT: Dopamine transporter, DDC: Dopa Decarboxylase, I2BS: Imidazoline 2-binding sites, MC1: Mitochondrial Complex 1, SERT: Serotonin transporter, Sigma 1R: Sigma 1 receptor, SV2A: Synaptic vesicle glycoprotein 2A and TSPO: Translocator protein.