Parkinsonism Across Age-Related Neurodegenerative Diseases: Vulnerable Circuits, Proteinopathies, and Multimodal Biomarkers

Parkinsonism is a common motor phenotype across age-related neurodegenerative diseases and frequently coexists with cognitive and behavioral syndromes. Although Parkinson’s disease is the prototypical parkinsonian syndrome, parkinsonism also occurs in dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, and in dementia due to Alzheimer’s disease. These conditions frequently coexist with mixed neuropathologies, including α-synuclein, tau, TDP 43, and Aβ-amyloid pathology. These overlapping phenotypes interacting pathologies challenge traditional diagnostic boundaries and complicate clinical trial design, particularly in older adults where co-pathologies are common. This Special Topic treats parkinsonism as a transdiagnostic feature emerging from dysfunction of distributed motor networks. We focus on how distinct proteinopathies (including α-synuclein, tau, TDP 43, and Aβ-related disease biology) and their interactions target selectively vulnerable neuronal populations and circuit nodes—producing convergent but often distinct motor phenotypes. We invite studies that bridge molecular pathology to systems-level dysfunction, including in cortico–basal ganglia–thalamocortical loops, cortical motor networks, brainstem locomotor systems, and cerebello-thalamo-cortical circuits.This Research Topic aims to:1. Identify mechanisms of selective vulnerability that determine why specific cell types and circuit nodes fail across distinct proteinopathies and mixed-pathology states.2. Define circuit-level pathophysiology underlying parkinsonism across neurodegenerative diseases, including oscillatory and network biomarkers.3. Elucidate the role of co-pathologies in shaping parkinsonian phenotypes, examining how combinations of α-synuclein, tau, TDP 43, and Aβ-amyloid pathology interact to influence motor symptoms, cognitive and behavioral syndromes, disease progression and therapeutic response. 4. Advance multimodal biomarker strategies for etiologic diagnosis, prognosis, and trial stratification—integrating fluid biomarkers, imaging, electrophysiology, and computational models.5. Strengthen genotype–phenotype–circuit frameworks linking genetic variation to vulnerable cell types, network degeneration, and clinical heterogeneity.6. Translate mechanistic insights into precision therapeutic strategies, including biomarker-enriched trials and circuit-informed neuromodulation.Submissions are welcomed across the spectrum of age-related neurodegenerative diseases and their resulting clinical syndromes that include parkinsonism, including: Parkinson’s disease (PD) and Parkinson’s disease dementia (PDD); dementia with Lewy bodies (DLB); multiple system atrophy (MSA); progressive supranuclear palsy (PSP); corticobasal degeneration (CBD) and corticobasal syndrome (CBS); frontotemporal lobar degeneration (FTLD) subtypes (FTLD tau, FTLD TDP, FTLD FUS); Alzheimer’s disease with parkinsonism; and mixed-pathology states in aging.We explicitly encourage multimodal and integrative methods, including: genetics and GWAS; single-cell and spatial transcriptomics; iPSC and organoid models; animal models; α-synuclein seed amplification assays; tau PET (general); CSF and blood biomarkers (including AT(N)-aligned biomarkers for Alzheimer biology); neuropathology and brain bank-based studies; structural and functional MRI; connectomics; electrophysiology/oscillations; computational modeling; and neuromodulation (including adaptive approaches).We welcome submissions addressing, but not limited to: mechanisms of selective vulnerability; proteinopathy interactions and co-pathology effects; circuit dysfunction in cortico–basal ganglia–thalamocortical, cortical motor, brainstem locomotor, and cerebellar networks; genotype–phenotype–circuit relationships; multimodal biomarker validation and harmonization; clinicopathologic dissociations and diagnostic boundary overlap; and translational implications for diagnosis, prognosis, trial enrichment, and precision therapeutics.Accepted papers will be organized into thematic lanes such as: (1) Proteinopathies and selective vulnerability; (2) Dysfunctional motor circuits and network biomarkers; (3) Genotype–phenotype–circuit integration; (4) Multimodal biomarker validation and etiologic stratification; (5) Translation to trials and precision therapeutics (including neuromodulation). Topic editors: D. Luke Fischer, Tamara Stiep, Mary De May Source: https://www.frontiersin.org/research-topics/78023/parkinsonism-across-age-related-neurodegenerative-diseases-vulnerable-circuits-proteinopathies-and-multimodal-biomarkers