Association of Early fMRI Connectivity Alterations With Different Cognitive Phenotypes in Patients With Newly Diagnosed Parkinson Disease

Abstract

Background and objectives: According to the dual syndrome hypothesis, patients with Parkinson disease (PD) with visuospatial deficits are more likely to progress to dementia, compared with patients with a prevalent dysexecutive syndrome. In this study, we aimed to investigate whether early connectivity changes in the dorsolateral prefrontal cortex (DLPFC) and the precuneus (PCun)-which are critical to fronto-executive and visuospatial functions, respectively-can identify distinct cognitive phenotypes in cognitively intact newly diagnosed patients with PD.

Methods: Newly diagnosed, drug-naïve patients with PD (≤2 years from clinical onset) with normal Montreal Cognitive Assessment (MoCA), were consecutively enrolled from our Movement Disorders Clinics in Italy. Sex-matched and age-matched healthy controls (HCs) were enrolled among nonconsanguineous patients' relatives. Participants underwent 3T-fMRI to investigate resting-state functional connectivity (rs-FC) of DLPFC and PCun with a seed-based approach at baseline (T0). K-means cluster analysis was performed on z scores of rs-FC values of patients with PD to identify clusters of patients sharing common patterns of connectivity. Differences in neurophysiologic, motor, and nonmotor scales among PD clusters were assessed at T0 and after a 3.5-year follow-up (T1).

Results: The study included 68 patients with PD (27% women; mean age: 60 ± 9 years; Hoehn & Yahr score: 1.4 ± 0.5; MoCA score: 27.9 ± 1.6) and 31 HCs (39% women; mean age 64.2 ± 9.3 years) at T0. Forty-two patients completed T1 evaluation. Patients displayed reduced rs-FC of both DLPFC and PCun with several cortical and subcortical areas compared with HCs. Cluster 1 was defined by lower values of rs-FC in all investigated regions of interest while clusters 2 and 3, respectively, by higher and intermediate values. Despite none meeting criteria for mild cognitive impairment (MCI) at T0, cluster 1 was older and lower performing in global cognition, fronto-executive, and memory domains, compared with clusters 2 and 3 (all p < 0.031). At T1, a more evident worsening in global cognition, fronto-executive, and visuospatial domains and nonmotor and motor symptoms was observed in clusters 1 and 3 vs cluster 2 (all p < 0.04), with MCI being more frequent in clusters 1 and 3.

Discussion: Early connectivity changes of the DLPFC and the PCun occur in newly diagnosed patients with PD without MCI and can distinguish cognitive phenotypes, as confirmed after a longitudinal clinical observation.