The STRAT-PARK initiative aims to provide a platform for stratifying Parkinson's disease (PD) into biological subtypes, using a bottom-up, multidisciplinary biomarker-based and data-driven approach. PD is a heterogeneous entity, exhibiting high interindividual clinicopathological variability. This diversity suggests that PD may encompass multiple distinct biological entities, each driven by different molecular mechanisms. Molecular stratification and identification of disease subtypes is therefore a key priority for understanding and treating PD. STRAT-PARK is a multi-center longitudinal cohort aiming to recruit a total of 2000 individuals with PD and neurologically healthy controls from Norway and Canada, for the purpose of identifying molecular disease subtypes. Clinical assessment is performed annually, whereas biosampling, imaging, and digital and neurophysiological phenotyping occur every second year. The unique feature of STRAT-PARK is the diversity of collected biological material, including muscle biopsies and platelets, tissues particularly useful for mitochondrial biomarker research. Recruitment rate is ~150 participants per year. By March 2023, 252 participants were included, comprising 204 cases and 48 controls. STRAT-PARK is a powerful stratification initiative anticipated to become a global research resource, contributing to personalized care in PD.

Background: Sex differences in cognitive impairment in Parkinson’s disease (PD) have been reported, with several studies suggesting greater cognitive decline in males. However, evidence on long-term trajectories across specific cognitive domains is limited, as most prior work is cross-sectional. Aim: To investigate sex-specific longitudinal changes across multiple cognitive domains over 9 years in idiopathic PD, compared to age- and sex-matched controls. Methods: We analyzed data from the prospective ParkWest study, including n = 190 persons with PD (PwPs) and n = 202 controls. Regularly assessed cognitive domains included semantic fluency, processing speed, cognitive control, memory, and visuospatial ability. Linear mixed-effect models including a three-way interaction between time, disease status, and sex, to test whether sex-specific cognitive change in PD differed from that observed in controls, were estimated. Models were adjusted for age, years of education, baseline depression, and UPDRS part II. Results: Male PwPs showed faster decline than female PwPs in most cognitive measures, resulting in gradually increasing sex differences over 9 years. However, compared with controls, the differential sex-specific decline was statistically significant only for semantic fluency (p = 0.013) and processing speed (p = 0.027 and p = 0.035). These findings remained significant after covariate adjustment. Conclusions: PD was associated with increasing sex differences in semantic fluency and processing speed, likely driven by faster decline in males. Other domains did not show sex-specific divergence over time, suggesting that sex-specific vulnerabilities in cognitive trajectories are domain-specific rather than generalized among PwPs.

Widespread neuronal complex I (CI) deficiency was recently reported to be a characteristic in a subgroup of individuals with idiopathic Parkinson’s disease (PD). Here, we sought to determine whether a CI deficient subgroup could be discerned using clinically accessible muscle biopsy. Vastus lateralis needle biopsies were collected from 83 individuals with PD and 29 neurologically healthy controls and analyzed by immunohistochemistry for complexes I and IV, cytochrome c oxidase/succinate dehydrogenase (COX/SDH) histochemistry, and spectrophotometric activity assays of complexes I-IV. Mitochondrial DNA (mtDNA) copy number, deletions, and point variation were analyzed in single muscle fibers and bulk biopsy samples. PD muscle exhibited reduced CI activity at the group level, with 9% of cases falling below two standard deviations of the control group. This deficiency was not associated with mtDNA abnormalities. Our findings support the existence of a PD subpopulation characterized by CI pathology and suggest that stratification by extra-neural mitochondrial dysfunction may be informative for selecting individuals for clinical trials.