From disease to syndrome: the evolution of Parkinson's as a heterogeneous entity

Abstract

Parkinson’s disease (PD) is increasingly recognised as a multifactorial and heterogeneous condition rather than a single uniform disorder, supported by advances in molecular biology, genetics and pathology. This review provides a perspective on the shifting concept of PD from an idiopathic, strictly defined pathological entity to a highly heterogeneous clinical and etiopathological condition. We outline the diverse aetiologic pathways and clinical expressions of PD, with particular emphasis on genetic contributors and the role of neuroinflammation. Genetic studies have identified monogenic causes — including SNCA, LRRK2, VPS35, RAB32, PRKN and PINK1 — as well as increased risk linked to heterozygous GBA1variants and more than 90 susceptibility loci from genome-wide association studies (GWAS), highlighting converging pathogenic mechanisms. Recent work underscores significant involvement of innate and adaptive immune responses from the earliest disease stages, suggesting a central shared role in PD onset and progression. This contemporary framework opens new avenues for biology-based, disease-modifying therapeutic strategies.