Interaction of systemic oxidative stress and mesial temporal network degeneration in Parkinson's disease with and without cognitive impairment

Abstract

Background: To identify the vulnerable areas associated with systemic oxidative stress and further disruption of these vulnerable areas by measuring the associated morphology and functional network alterations in Parkinson's disease (PD) patients with and without cognitive impairment.

Methods: This prospective study was approved by the institutional review board of KCGMH, and written informed consent was obtained. Between December 2010 and May 2015, 41 PD patients with different levels of cognitive functions and 29 healthy volunteers underwent peripheral blood sampling to quantify systemic oxidative stress, as well as T1W volumetric and resting state functional MRI (rs-fMRI) scans. Rs-fMRI was used to derive the healthy intrinsic connectivity patterns seeded by the vulnerable areas associated with any of the significant oxidative stress markers. The two groups were compared in terms of the functional connectivity correlation coefficient (fc-CC) and gray matter volume (GMV) of the network seeded by the vulnerable areas.

Results: The levels of oxidative stress markers, including leukocyte apoptosis and adhesion molecules, were significantly higher in the PD group. Using whole-brain VBM-based correlation analysis, the bilateral mesial temporal lobes (MTLs) were identified as the most vulnerable areas associated with lymphocyte apoptosis (P < 0.005). We found that the MTL network of healthy subjects resembled the PD-associated atrophy pattern. Furthermore, reduced fc-CC and GMV were further associated with the aggravated cognitive impairment.

Conclusion: The MTLs are the vulnerable areas associated with peripheral lymphocyte infiltration, and disruptions of the MTL functional network in both architecture and functional connectivity might result in cognitive impairments in Parkinson's disease.

Keywords: Cognitive impairment; Functional connectivity; Gray matter volume; Lymphocyte apoptosis; Mesial temporal network; Parkinson’s disease; Systemic oxidative stress.

Fig. 1

Neuronal vulnerable areas associated with lymphocyte. Bilateral mesial temporal lobes (MTLs, MNI space[x,y,z]: [− 32,− 6,− 29] and [18,− 2,− 35]) were identified as the vulnerable areas associated with lymphocyte apoptosis in PD patients (corrected P < 0.005, cluster > 288) (controlling for age, sex, and TIV)

Fig. 2

The MTL functional network. The MTL functional network seeded by the epicenters vulnerable to lymphocyte apoptosis in the NC (a), PDN (b), PDMCI (c), and PDD (d) groups. The intrinsic MTL functional network of healthy subjects (FEW corrected P < 0.01) is shown in a and reveals connectivity between the temporal and frontal lobes and other regions of the neocortex. Disrupted MTL functional networks, however, are shown for the PD patients, especially for the PDD subgroup

Fig. 3

The structural and functional alteration in the MTL network. (a) Comparison of GMVs under the intrinsic MTL functional network among the NC group and PD subgroups revealed significant atrophy in the PDD subgroup. (b) The functional connectivity between the MTL and middle occipital lobe (MOL) within the MTL functional network was significantly decreased in the PDD subgroup, (c) but the functional connectivity between the MTL and pons was significantly increased in the PDN and PDD subgroups

Fig. 4

a The correlation between disease severity and functional connectivity within the MTL functional network. The reduced fc-CC values of the MTL functional network were associated with worsening clinical symptoms, including UPDRS part I (mentation and mood) and part III (motor) and total scores (controlling for age and sex, Bonferroni corrected P < 0.05). b The correlation between cognition and functional connectivity within the MTL functional network. The reduced fc-CC values of the middle occipital lobe were associated with worsening cognitive impairment, including UPDRS part I (mentation and mood), MMSE, attention, and memory function scores (controlling for age and sex, Bonferroni corrected P < 0.05)