Motor System Neurodegeneration in Aging and Synucleinopathies: Circuit Vulnerability and Neuroimaging Biomarkers

Aging is the primary risk factor for synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), and independently contributes to motor dysfunction. This review summarizes motor system degeneration in aging and disease, focusing on the primary motor cortex (M1), its white matter tracts, and the nigrostriatal system. In healthy aging, M1 exhibits cortical thinning, myelin loss, reduced perfusion, and iron deposition. The motor cortex-derived corticospinal and corticostriatal pathways undergo microstructural decline, often linked to vascular factors. The substantia nigra (SN) demonstrates selective neuronal loss, oxidative stress, iron deposition, and synaptic reduction, contributing to motor impairment. In synucleinopathies, these age-related vulnerabilities are exacerbated by disease-specific pathology. In PD, progressive dopaminergic neuron loss in the SN is a core feature, detectable with advanced magnetic resonance imaging (MRI) markers of iron, neuromelanin, and microstructure. PD pathophysiology extends beyond the nigrostriatal system, involving M1 dysfunction and widespread white matter abnormalities linked to motor deficits and cognitive impairment. DLB is characterized by widespread involvement of cortex (especially posterior), limbic, basal ganglia, brainstem, and cholinergic system, accounting for its early cognitive impairment, neuropsychiatric, motor, and autonomic symptoms. In contrast, MSA is characterized by oligodendroglial α-synuclein inclusions, causing multi-system degeneration, with characteristic atrophy and microstructural disruption in the putamen, pons, and cerebellum that aid differential diagnosis. Multiparametric MRI offers in vivo insights into structural, microstructural, hemodynamic, metabolic, and pathological changes underlying motor dysfunction in aging and neurodegenerative disorders. Understanding the convergence of age-related motor neuron degeneration and disease-specific pathology is essential for elucidating disease mechanisms, identifying early biomarkers, and developing targeted therapies in synucleinopathies.