Resilience mechanisms in Parkinson's disease: a domain-specific conceptual framework

While nigrostriatal dopaminergic cell loss is the pathological hallmark of Parkinson's disease, it is well-known that dopamine deficiency cannot fully explain the clinical severity or disease progression. Emerging data suggest that resilience, i.e. the brain's capacity to maintain function despite pathology, plays a key role in shaping clinical variability of both motor and non-motor symptoms. However, different contributing terms have been proposed, including brain compensation and reserve, and it remains unclear how these terms can be delineated both conceptually and mechanistically. Therefore, here we provide a synthesis of recent neuroimaging evidence on resilience mechanisms in Parkinson's disease, with the following aims: (1) clarify the terminology, (2) define the mechanisms and (3) relate resilience mechanisms to treatments, including dopamine replacement therapy and deep brain stimulation. We distinguish between compensation and reserve. We define compensation as adaptive neural activity that stabilises task performance in the presence of pathology, particularly under increased demands, and is inversely related to clinical deficits. By contrast, reserve (cognitive or motor) refers to capacity of neural resources that is built up across the lifetime, shaped by factors of an individual's exposome. Compensation has been localised to the parieto-premotor network alongside the relatively preserved anterior striatum. Higher motor reserve has been linked to somatomotor network tolerance, preserved structural integrity and higher striatal functional network connectivity. Cognitive reserve relates to network robustness and structural integrity within the fronto-parietal network. Whether resilience mechanisms drive inter-individual variability in long-term treatment response remains unresolved. Lower motor reserve predicts accelerated levodopa dose escalation and increased risk of dyskinesias, while cognitive reserve modulates both cognitive and motor outcomes after deep brain stimulation, highlighting cross-domain interactions. Brain compensation and reserve are two key components of resilience that together shape clinical heterogeneity in Parkinson's disease, across motor and cognitive domains. Although they operate at different time scales and through distinct mechanisms, they remain intrinsically related. Our framework suggests that biomarkers of resilience could complement biological definitions of Parkinson's disease and shift therapeutic strategies from merely slowing degeneration toward strengthening adaptive capacity. Key priorities for future work are to define the longitudinal relationship between resilience failure and subcortical neurodegeneration using concurrent measures of nigrostriatal decline, multimodal datasets or controlled interventions, and to determine how symptom domain-specific resilience mechanisms shape treatment outcomes to enable targeted modulation and better capture disease heterogeneity.