Circuit imaging biomarkers in preclinical and prodromal Parkinson's disease

Abstract

Parkinson’s disease (PD) commences several years before the onset of motor features. Pathophysiological understanding of the pre-clinical or early prodromal stages of PD are essential for the development of new therapeutic strategies. Two categories of patients are ideal to study the early disease stages. Idiopathic rapid eye movement sleep behavior disorder (iRBD) represents a well-known prodromal stage of PD in which pathology is presumed to have reached the lower brainstem. The majority of patients with iRBD will develop manifest PD within years to decades. Another category encompasses non-manifest mutation carriers, i.e. subjects without symptoms, but with a known mutation or genetic variant which gives an increased risk of developing PD. The speed of progression from preclinical or prodromal to full clinical stages varies among patients and cannot be reliably predicted on the individual level. Clinical trials will require inclusion of patients with a predictable conversion within a limited time window. Biomarkers are necessary that can confirm pre-motor PD status and can provide information regarding lead time and speed of progression. Neuroimaging changes occur early in the disease process and may provide such a biomarker. Studies have focused on radiotracer imaging of the dopaminergic nigrostriatal system, which can be assessed with dopamine transporter (DAT) single photon emission computed tomography (SPECT). Loss of DAT binding represents an effect of irreversible structural damage to the nigrostriatal system. This marker can be used to monitor disease progression and identify individuals at specific risk for phenoconversion. However, it is known that changes in neuronal activity precede structural changes. Functional neuro-imaging techniques, such as 18F-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography (18F-FDG PET) and functional magnetic resonance imaging (fMRI), can be used to model the effects of disease on brain networks when combined with advanced analytical methods. Because these changes occur early in the disease process, functional imaging studies are of particular interest in prodromal PD diagnosis. In addition, fMRI and 18F-FDG PET may be able to predict a specific future phenotype in prodromal cohorts, which is not possible with DAT SPECT. The goal of the current review is to discuss the network-level brain changes in pre-motor PD.

Searching for Biomarkers in the Blood of Patients at Risk of Developing Parkinson’s Disease at the Prodromal Stage

“…The decrease in the concentration of L-DOPA in plasma found in this study in patients at risk of developing PD can be due to the death of nigrostriatal dopaminergic neurons, which leads to a decrease in the synthesis of DA and L-DOPA. This is confirmed by a decrease in the concentration of L-DOPA and DA in the CFS [58], as well as by a decrease in the level of 18F-DOPA incorporation (positron emission tomography) into dopamine synthesis [51] and DAT binding (DAT scan) in nigrostriatal dopaminergic neurons in patients at risk of PD development [59].…”

“…One of them is the search for biomarkers in body fluids in patients at risk of developing PD at the prodromal stage. These patients are selected for the presence of premotor symptoms, in the absence of motor symptoms [51]. Changes in body fluids found in patients at risk of developing PD, in contrast to those detected in untreated patients at an early clinical stage of PD, can be considered with certainty as candidates for diagnostic biomarkers of PD at the preclinical stage.…”

Functional Covariance Connectivity of Gray and White Matter in Olfactory-Related Brain Regions in Parkinson’s Disease

“…The clinical diagnosis of PD is based on motor symptoms such as bradykinesia, resting tremor, stiffness, and postural instability. The transition from prodromal PD to PD is characterized by the change from non-motor symptoms to clinically diagnosable motor symptoms (Meles et al, 2021). Olfactory dysfunction is one of the earliest non-motor features of PD, appearing several years before the onset of motor symptoms, and can predict the transition from prodromal PD to PD, independent of medication and age of onset (Tissingh et al, 2001;Dan et al, 2021).…”

Alpha-Synuclein Strain Variability in Body-First and Brain-First Synucleinopathies

“…Pre-motor or isolated RBD (iRBD) is therefore considered a marker of (prodromal) body-first PD as ascending pathology affects pontine structures prior to involvement of the SN. Importantly, 80% of iRBD cases pheno-convert to PD or DLB within a decade (Meles et al, 2021 ). By contrast, in later stage brain-first PD, RBD develops after motor symptoms as ultimately pathology will descend from the SN to lower Braak stage structures in these patients, causing RBD (Borghammer and Van Den Berge, 2019 ; Andersen et al, 2020 ; Horsager et al, 2020 ).…”