Individual disease trajectory modifiers in Parkinson’s Disease: how motor compensation and biological phenotypes shape disease evolution

Parkinson’s disease (PD) is not a uniform disorder but a dynamic spectrum of biological processes interacting with the brain’s intrinsic capacity for adaptation. Disease manifestation and progression vary widely across individuals. Understanding the individual trajectory modifiers, the biological and neurophysiological factors that determine how pathology translates into symptoms, is essential for explaining clinical heterogeneity and developing stage-specific interventions. This thesis explores PD evolution in individual trajectories through two complementary perspectives: (I) how neurophysiological adaptations delay the clinical manifestation of PD despite ongoing dopaminergic loss, and (II) dissects why patients with apparently similar motor diagnoses follow vastly different clinical trajectories by identifying and validating pathophysiology-grounded phenotypes that diverge in their pathological origin and spread, molecular signatures, and clinical outcomes. In the first part, we established an empirical framework to quantify motor compensation in early PD by integrating dopaminergic imaging, clinical data, and transcranial magnetic stimulation. We identified a subgroup of patients with bilateral nigrostriatal degeneration but unilateral symptoms, revealing that enhanced plasticity in the presymptomatic hemisphere sustains motor function despite substantial dopamine loss. These results provide direct in vivo evidence that cortical adaptability can mask neurodegeneration, effectively decoupling biological and clinical disease stages. In the second part, we tested the Synuclein Origin and Connectome model in over 2,000 prodromal and clinical PD cases from the Parkinson’s Progression Marker Initiative. This model proposes two biologically distinct subtypes defined by the presumed site of α-synuclein pathology onset, peripheral autonomic structures in the body-first form and central brain regions in the brain-first form. We demonstrated that body-first and brain-first forms of PD represent distinct biological entities with specific clinical trajectories, imaging signatures, and genetic determinants. Body-first PD presenting with early autonomic and REM sleep dysfunction showed symmetrical dopaminergic and glymphatic alterations, and faster motor and cognitive decline, whereas brain-first PD exhibited asymmetric top-down propagation, slower progression. The phenotypes were linked with unique genetic associations. Together, these studies propose an integrated model of PD evolution in which disease expression emerges from the balance between neurodegeneration and compensation, modulated by individual biological architecture. By linking molecular, imaging, and physiological dimensions, this work moves toward a biologically grounded stratification of PD, proposing updates to the actual PD staging system frameworks, redefining how we conceptualise, monitor, and treat the disease across its continuum.