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Background: Parkinson’s disease (PD) varies widely across individuals in terms of clinical manifestations and course of progression. We aimed to compare patterns of brain atrophy between PD clinical subtypes using longitudinally acquired brain MRIs. Methods: We used T1-weighted MRIs from Parkinson’s Progression Markers Initiative (PPMI) on 134 PD individuals and 60 healthy controls with at least two MRIs. Patients were classified into three clinical subtypes at de novostage using validated subtyping criteria based on major motor and non-motor classifiers (early cognitive impairment, RBD, dysautonomia): mild-motor predominant (n=74), intermediate (n=44), and diffuse-malignant (n=16). Deformation-based morphometry (DBM) maps were calculated and mixed effect models were used to examine the interaction between PD subtypes and rate of atrophy across brain regions over time, controlling for sex and age at baseline. Results: Individuals with ‘diffuse malignant’ PD showed a significantly higher rate of atrophy across multiple brain regions, including lateral nucleus of the forebrain, precuneus, paracentral lobule, inferior temporal gyrus, fusiform gyrus, and lateral hemisphere of the cerebellum (FDR corrected p<0.05). Conclusions: We demonstrated an accelerated atrophy pattern within several brain regions in ‘diffuse malignant’ PD subtype. These findings suggest the presence of a more diffuse multidomain neurodegenerative process in a subgroup of people with PD, favoring the existence of diverse underlying pathophysiologies.

Background:Parkinson’s disease (PD) varies in clinical manifestations and course of progression from person to person. Identification of distinct PD subtypes is of great priority to develop personalized care approaches. We aimed to compare long-term progression and prognosis between different PD subtypes. Methods:Data on 421 individuals with de novoearly-onset PD was retrieved from Parkinson’s Progression Markers Initiative (PPMI). Using a newly developed multi-domain subtyping method (based on motor phenotype, RBD, autonomic disturbance, early cognitive deficit), we divided PD population into three subtypes at baseline: “mild motor-predominant”, “Diffuse malignant” and “Intermediate”. Rate of global progression (mixed motor and non-motor features) and developing dementia were compared between the subtypes. Results:Patients with “diffuse malignant” PD experienced 0.5 z-score further worsening of global composite outcome (p=0.017) and 2.2 further decline in MOCA score (p=0.001) after 6-years of follow-up. Hazard for MCI/dementia was significantly higher in “diffuse malignant” (HR=3.2, p<0.001) and “intermediate” (HR=1.8, p<0.001) subtypes. Individuals with “diffuse malignant” PD had the lowest level of CSF amyloid-beta (p=0.006) and SPECT striatal binding ratio (p=0.001). Conclusions:This multi-domain subtyping is a valid method to predict subgroups of PD with distinct patterns of long-term progression at drug-naïve early-stage with potential application in real-life clinical practice.