Age and sex differentially shape brain networks in Parkinson's disease

Abstract

Aims: Age and sex are important individual factors modifying the clinical symptoms of patients with Parkinson's disease (PD). Our goal is to evaluate the effects of age and sex on brain networks and clinical manifestations of PD patients.

Methods: Parkinson's disease participants (n = 198) receiving functional magnetic resonance imaging from Parkinson's Progression Markers Initiative database were investigated. Participants were classified into lower quartile group (age rank: 0%~25%), interquartile group (age rank: 26%~75%), and upper quartile group (age rank: 76%~100%) according to their age quartiles to examine how age shapes brain network topology. The differences of brain network topological properties between male and female participants were also investigated.

Results: Parkinson's disease patients in the upper quartile age group exhibited disrupted network topology of white matter networks and impaired integrity of white matter fibers compared to lower quartile age group. In contrast, sex preferentially shaped the small-world topology of gray matter covariance network. Differential network metrics mediated the effects of age and sex on cognitive function of PD patients.

Conclusion: Age and sex have diverse effects on brain structural networks and cognitive function of PD patients, highlighting their roles in the clinical management of PD.

Keywords: Parkinson's disease; age; clinical phenotype; network; sex.

FIGURE 1

Group differences of clinical assessments among different age quartiles of control and PD participants. Compared to PD patients in Q1 group (n = 49), PD patients in Q4 group (n = 50) showed higher Hoehn & Yahr stages (A), tremor scores (B), UPDRS‐III scores (C), SCOPA‐AUT scores (D) and lower SDMT scores (E), MoCA scores (F), BJLOT scores (G), LNS scores (H), and SFT scores (I). Compared to PD patients in Q1 group (n = 49), PD patients in Q2–3 group (n = 99) also had higher Hoehn & Yahr stages (A), UPDRS‐III scores (C), SCOPA‐AUT scores (D) and lower SDMT scores (E), MoCA scores (F), and LNS scores (H). Two‐way ANOVA test followed by Tukey's post‐hoc test was used for the comparisons of clinical assessments among different age quartiles of PD patients. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Abbreviations: BJLOT, Benton Judgment of Line Orientation; LNS, Letter Number Sequencing; MoCA, Montreal Cognitive Assessment; SCOPA‐AUT, Scale for Outcomes in Parkinson's Disease‐Autonomic; SDMT, Symbol Digit Modalities Test; SFT, Semantic Fluency Test Score; UPDRS‐III, Unified Parkinson’ s Disease Rating Scale Part III.

FIGURE 2

Group differences in the AUCs of white matter network metrics among different age quartiles of PD patients. Group differences in the AUC of hierarchy (A), AUC of global efficiency (B), AUC of local efficiency (C), AUC of Cp (D), AUC of Lp (E), AUC of γ (F), AUC of λ (G), and AUC of σ (H). ANOVA test followed by FDR correction was used for the comparisons of AUCs of graphical metrics among three age quartile groups. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Abbreviations: AUC, area under curve; Cp, clustering coefficient; Lp, characteristic path length.

FIGURE 3

Group differences of DTI metrics among different age quartiles of PD patients. Group differences of FA (A) and MD (B). Two‐way ANOVA test followed by FDR correction was used for the comparisons of FA and MD among three age quartile groups. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Abbreviations: DTI, Diffusion tensor imaging; FA, Fractional anisotropy; MD, Mean diffusivity.

FIGURE 4

The white matter network topology mediated the relationship between age and cognitive assessments of PD patients. Mediation analysis of global efficiency and SFT (A), local efficiency and SFT (B), small‐worldness Lp and SFT(C), global efficiency and SDMT (D), local efficiency and SDMT (E), and small‐worldness Lp and SDMT (F). During the mediation analysis, sex, years of education, and disease duration were included as covariates. p < 0.05 was considered statistically significant. Abbreviations: Lp, characteristic path length; SDMT, Symbol Digit Modalities Test; SFT, Semantic Fluency Test Score.

FIGURE 5

The integrity of white matter tracts mediated the relationship between age and cognitive assessments of PD patients. Mediation analysis of right cerebral peduncle and BJLOT (A), retrolenticular part of right internal capsule and BJLOT (B), retrolenticular part of left internal capsule and BJLOT (C), right inferior frontal‐occipital fasciculus and BJLOT (D), right inferior cerebellar peduncle and SDMT (E), and left inferior cerebellar peduncle and SDMT (F). During the mediation analysis, sex, years of education, and disease duration were included as covariates. p < 0.05 was considered statistically significant. Abbreviations: BJLOT, Benton Judgment of Line Orientation; SDMT, Symbol Digit Modalities Test.