Predicting Clinical Trajectories in Prodromal and Early Parkinson’s Disease and Atypical Parkinsonism Using Genetic, Fluid and Tissue-Based Biomarkers of Neurodegeneration, Co-Pathology and Neuroinflammation

Parkinson’s disease (PD) and atypical parkinsonism (including multiple system atrophy, MSA; progressive supranuclear palsy, PSP; and corticobasal degeneration, CBD) show remarkable heterogeneity in age at onset, clinical presentation and rate of progression. Prodromal cohorts – including individuals with idiopathic REM sleep behavior disorder (iRBD), hyposmia, “at-risk” tremor or genetic susceptibility – provide a unique window to study the earliest stages of the parkinsonian continuum, but robust tools to predict individual clinical trajectories are still lacking.Converging neuropathological and biomarker data indicate that parkinsonian disorders are rarely “single protein” diseases. In PD and related synucleinopathies, co-occurring Alzheimer-type pathology (amyloid-β and tau) and widespread axonal injury and astroglial activation are increasingly recognized as key modifiers of disease course, especially cognitive trajectories and global functional decline.Cerebrospinal fluid (CSF) and blood biomarkers such as Aβ42/40, phosphorylated tau, total tau, neurofilament light (NfL), TAR DNA-binding protein 43 (TDP-43), glial fibrillary acidic protein (GFAP), YKL-40, sTREM2 and other inflammatory markers, together with alpha-synuclein seed amplification assays (SAA), now allow in vivo assessment of key molecular and cellular pathological processes, including neurodegeneration, co-pathology and neuroinflammation, along the PD and atypical parkinsonism spectrum. Beyond qualitative positivity, quantitative features—particularly kinetic parameters of the alpha-synuclein SAA curve in CSF—provide an opportunity to investigate whether specific aspects of alpha-synuclein–related protein aggregation pathology are associated with clinical heterogeneity and cognitive trajectories, potentially contributing to patient stratification in longitudinal studies. Studies that explore the combined use of multiple biomarkers—alpha-synuclein SAA features, markers of amyloid/tau pathology, axonal damage and glial activation—are warranted to improve prediction of clinical and prognostic trajectories and to better elucidate cross-pathway interactions among protein aggregation, neurodegeneration and neuroinflammatory mechanisms in PD pathophysiology.This Research Topic brings together clinical and translational studies in prodromal and early Parkinson’s disease and early-stage atypical parkinsonism (MSA, PSP, CBD) that explore genetic, neuroimaging, fluid and tissue-based biomarkers to characterize underlying pathological processes and predict motor and non-motor disease trajectories. An integrative approach, by combining these biomarkers with clinical and neuropathological data, may help to develop dynamic prognostic models, risk scores and biological staging frameworks to stratify individuals at risk and newly diagnosed patients. These frameworks could predict phenoconversion and clinically meaningful outcomes—including cognitive decline, motor complications, institutionalization and survival—since early-stage phases, and guide patient selection and outcome definition for disease-modifying therapy–oriented clinical trials.The Research Topic welcomes contribution to the following themes (but not limited to):• Genetic, CSF, plasma and tissue-based biomarkers (including alpha-synuclein SAA, Aβ42/40, p-tau/t-tau, NfL, GFAP, TDP-43 and related markers) use in predicting phenoconversion and early progression in prodromal and de novo PD, and in early atypical parkinsonism (MSA, PSP, CBD).• Integration of multiple biomarkers in the early differential diagnostic work-up between PD and atypical parkinsonism.• Longitudinal studies of associations between neurodegeneration, glial/inflammatory biomarkers and key outcomes (cognitive decline, dementia, motor complications, axial symptoms, survival) across PD and atypical parkinsonian syndromes.• Multimodal and data-driven prognostic models combining fluid biomarkers (including quantitative and kinetic features of alpha-synuclein SAA) with clinical, imaging or genetic data for individualized risk stratification and differential prognosis in PD and atypical parkinsonism.• Standardisation, cut-off harmonisation and practical implementation of biomarker-based prognosis—including alpha-synuclein SAA—in clinical care and trial enrichment for prodromal and early PD, and for early atypical parkinsonian syndromes. Topic editors: Alessandro Mechelli, Jolanda Buonocore, Jacopo Bissacco, Alessandro Bombaci Source: https://www.frontiersin.org/research-topics/77267/predicting-clinical-trajectories-in-prodromal-and-early-parkinsons-disease-and-atypical-parkinsonism-using-genetic-fluid-and-tissue-based-biomarkers-of-neurodegeneration-co-pathology-and-neuroinflammation