Parkinson's Disease: Immunometabolic Control Points Across Neural, Vascular, and Peripheral Systems.

Parkinson's disease (PD) is a progressive neurodegenerative disorder most associated with degeneration of dopaminergic neurons in the substantia nigra pars compacta. Increasing clinical and experimental evidence, however, indicates that PD is a multisystem disease in which immune, metabolic, vascular, and peripheral nervous system dysfunction precede and shape motor circuit failure. Nonmotor manifestations, including olfactory impairment, sleep and autonomic disturbances, gastrointestinal dysfunction, and cognitive decline, often arise years before motor diagnosis, highlighting pathogenic mechanisms beyond dopamine deficiency alone. In this review, we synthesize evidence supporting the view that PD represents a disorder of chronic immunometabolic dysregulation rather than isolated neuronal loss. We focus on underestimated but high-impact immunological control points that integrate central and peripheral disease mechanisms, including environmental and microbial immune priming, gut-brain axis interactions, platelet-mediated inflammatory signaling, amyloid-β (Aβ) as an innate immune peptide, immune checkpoint regulation via the PD-1/PD-L1 axis, and nicotinamide adenine dinucleotide (NAD