Opportunities and challenges of alpha-synuclein as a potential biomarker for Parkinson's disease and other synucleinopathies

Parkinson's disease (PD), the second most common progressive neurodegenerative disease, develops and progresses for 10-15 years before the clinical diagnostic symptoms of the disease are manifested. Furthermore, several aspects of PD pathology overlap with other neurodegenerative diseases (NDDs) linked to alpha-synuclein (aSyn) aggregation, also called synucleinopathies. Therefore, there is an urgent need to discover and validate early diagnostic and prognostic markers that reflect disease pathophysiology, progression, severity, and potential differences in disease mechanisms between PD and other NDDs. The close association between aSyn and the development of pathology in synucleinopathies, along with the identification of aSyn species in biological fluids, has led to increasing interest in aSyn species as potential biomarkers for early diagnosis of PD and differentiate it from other synucleinopathies. In this review, we (1) provide an overview of the progress toward mapping the distribution of aSyn species in the brain, peripheral tissues, and biological fluids; (2) present comparative and critical analysis of previous studies that measured total aSyn as well as other species such as modified and aggregated forms of aSyn in different biological fluids; and (3) highlight conceptual and technical gaps and challenges that could hinder the development and validation of reliable aSyn biomarkers; and (4) outline a series of recommendations to address these challenges. Finally, we propose a combined biomarker approach based on integrating biochemical, aggregation and structure features of aSyn, in addition to other biomarkers of neurodegeneration. We believe that capturing the diversity of aSyn species is essential to develop robust assays and diagnostics for early detection, patient stratification, monitoring of disease progression, and differentiation between synucleinopathies. This could transform clinical trial design and implementation, accelerate the development of new therapies, and improve clinical decisions and treatment strategies.

Proton and phosphorus magnetic resonance spectroscopy of a mouse model of Alzheimer's disease

Patrick Aebischer, Cristina Ramona Cudalbu, Rolf Gruetter, Sharon Janssens, Hongxia Lei, Bernard Schneider, Lili Sun-Reimer

The development of new diagnostic criteria for Alzheimer's disease (AD) requires new in vivo markers reflecting early pathological changes in the brain of patients. Magnetic resonance (MR) spectroscopy has been shown to provide useful information about the biochemical changes occurring in AD brain in vivo. The development of numerous transgenic mouse models of AD has facilitated the evaluation of early biomarkers, allowing researchers to perform longitudinal studies starting before the onset of the pathology. In addition, the recent development of high-field animal scanners enables the measurement of brain metabolites that cannot be reliably quantified at lower magnetic fields. In this report, we studied a new transgenic mouse model of AD, the 5xFAD model, by in vivo proton and phosphorus MR spectroscopy. This model, which is characterized by an early-onset and a robust amyloid pathology, developed changes in the neurochemical profile, which are typical in the human disease, i.e., an increase in myo-inositol and a decrease in N-acetylaspartate concentrations, as early as in the 40th week of age. In addition, a significant decrease in the γ-aminobutyrate concentration was observed in transgenic mice at this age compared to controls. The pseudo-first-order rate constant of the creatine kinase reaction as well as relative concentrations of phosphorus-containing metabolites were not changed significantly in the 36 and 72-week old transgenic mice. Overall, these results suggest that mitochondrial activity in the 5 × FAD mice is not substantially affected but that the model is relevant for studying early biomarkers of AD.

Ios Press2012

Plasma neurofilament light and phosphorylated tau 181 as biomarkers of Alzheimer's disease pathology and clinical disease progression

Christopher Clark, Bénédicte Marie Maréchal, Jonas Richiardi

BackgroundTo assess the performance of plasma neurofilament light (NfL) and phosphorylated tau 181 (p-tau181) to inform about cerebral Alzheimer's disease (AD) pathology and predict clinical progression in a memory clinic setting.MethodsPlasma NfL and p-tau181, along with established cerebrospinal fluid (CSF) biomarkers of AD pathology, were measured in participants with normal cognition (CN) and memory clinic patients with cognitive impairment (mild cognitive impairment and dementia, CI). Clinical and neuropsychological assessments were performed at inclusion and follow-up visits at 18 and 36months. Multivariate analysis assessed associations of plasma NfL and p-tau181 levels with AD, single CSF biomarkers, hippocampal volume, and clinical measures of disease progression.ResultsPlasma NfL levels were higher in CN participants with an AD CSF profile (defined by a CSF p-tau181/A beta (1-42)>0.0779) as compared with CN non-AD, while p-tau181 plasma levels were higher in CI patients with AD. Plasma NfL levels correlated with CSF tau and p-tau181 in CN, and with CSF tau in CI patients. Plasma p-tau181 correlated with CSF p-tau181 in CN and with CSF tau, p-tau181, A beta (1-42), and A beta (1-42)/A beta (1-40) in CI participants. Compared with a reference model, adding plasma p-tau181 improved the prediction of AD in CI patients while adding NfL did not. Adding p-tau181, but not NfL levels, to a reference model improved prediction of cognitive decline in CI participants.ConclusionPlasma NfL indicates neurodegeneration while plasma p-tau181 levels can serve as a biomarker of cerebral AD pathology and cognitive decline. Their predictive performance depends on the presence of cognitive impairment.

BMC2021

Capturing the heterogeneity of alpha-synuclein pathology in synucleinopathies

Melek Firat Altay

Synucleinopathies such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy (MSA) are detrimental neurodegenerative diseases. Alpha-synuclein (aSyn), the main aggregating protein found in the pathological inclusions of these ailments, exists in numerous modified forms and conformations, leading to neuropathological heterogeneity in synucleinopathies. The functional, pathological and clinical implications of this heterogeneity remain unclear. Responding this knowledge gap requires the development of novel toolsets capable of capturing the biochemical and structural diversity of aSyn pathology in the brain and peripheral tissues.To address this challenge, we describe in Chapter 2 the development and characterisation of antibodies that cover all three regions and post-translational modifications (PTMs) of aSyn. We assess these antibodies through a comprehensive validation pipeline, and select the best performing antibody subset to capture the neuropathological diversity of aSyn across Lewy body diseases (LBDs). We demonstrate that these antibodies could be used to achieve an in-depth characterization of the biochemical and morphological diversity of aSyn aggregates in the neuronal and in vivo models of aSyn seeding. Our results suggest that aSyn pathology is rich in Serine 129 phosphorylation (pS129) and in previously under-described PTMs, including nitration and phosphorylation at Tyrosine 39 (nY39, pY39) and C-terminal tyrosine phosphorylations (pY133, pY136) across neuronal and glial populations in LBDs. We also report that aSyn is hyperphosphorylated in the cellular and in vivo seeding models. In Chapter 3, we demonstrate the power of our antibodies to achieve an unprecedented analysis of astrocytic aSyn pathology in LBDs. We characterise the biochemical properties, post-translational modifications and the aggregation state of astrocytic aSyn accumulations in the limbic regions across sporadic and familial LBDs. The astrocytic aSyn is revealed distinctively by antibodies against the late amino-terminus (N-terminus) and non-amyloid-beta component (NAC) region of aSyn, but not by the extreme N-terminal or carboxy-terminal (C-terminal) antibodies, suggesting that these aSyn species are truncated at both ends. The astrocytic aSyn accumulations are negative for the key markers of Lewy bodies (aSyn pS129, Amytracker, p62- and ubiquitin-positivity and proteinase K resistance), and positive for aSyn nY39 and pY39. These findings suggest that the astrocytic accumulations may be composed of non-fibrillar, possibly oligomeric conformers of aSyn. Chapter 4 focuses on deciphering the biochemical and morphological signatures of aSyn pathology in MSA. The antibodies described in Chapter 2 are applied to high and low pathology regions of MSA brains by immunohistochemistry (IHC). We also biochemically profile the aSyn species, and report an abundance of aSyn pS129-positive glial and neuronal inclusions that correspond to insoluble high molecular weight species by Western blot. We detect an enrichment of insoluble and truncated aSyn in the MSA cerebellum. By IHC, there is an enhancement of aSyn nY39, pY136 and of other aSyn PTMs.Collectively, the new tools and findings described here may pave the way for future studies elucidating the role of these neuronal and glial aSyn proteoforms in disease pathogenesis and propagation in synucleinopathies.

EPFL2022

Capturing the heterogeneity of alpha-synuclein pathology in synucleinopathies

Melek Firat Altay

EPFL2022