Decoupling of Global Brain Activity and Cerebrospinal Fluid Flow in Parkinson's Disease Cognitive Decline

Abstract

Background: Deposition and spreading of misfolded proteins (α-synuclein and tau) have been linked to Parkinson's disease cognitive dysfunction. The glymphatic system may play an important role in the clearance of these toxic proteins via cerebrospinal fluid (CSF) flow through perivascular and interstitial spaces. Recent studies discovered that sleep-dependent global brain activity is coupled to CSF flow, which may reflect glymphatic function.

Objective: The objective of this current study was to determine if the decoupling of brain activity-CSF flow is linked to Parkinson's disease cognitive dysfunction.

Methods: Functional and structural MRI data, clinical motor (Unified Parkinson's Disease Rating Scale), and cognitive (Montreal Cognitive Assessment [MoCA]) scores were collected from 60 Parkinson's disease and 58 control subjects. Parkinson's disease patients were subgrouped into those with mild cognitive impairment (MoCA < 26), n = 31, and those without mild cognitive impairment (MoCA ≥ 26), n = 29. The coupling strength between the resting-state global blood-oxygen-level-dependent signal and associated CSF flow was quantified, compared among groups, and associated with clinical and structural measurements.

Results: Global blood-oxygen-level-dependent signal-CSF coupling decreased significantly (P < 0.006) in Parkinson's disease patients showing mild cognitive impairment, compared with those without mild cognitive impairment and controls. Reduced global blood-oxygen-level-dependent signal-CSF coupling was associated with decreased MoCA scores present in Parkinson's disease patients (P = 0.005) but not in controls (P = 0.65). Weaker global blood-oxygen-level-dependent signal-CSF coupling in Parkinson's disease patients also was associated with a thinner right entorhinal cortex (Spearman's correlation, -0.36; P = 0.012), an early structural change often seen in Alzheimer's disease.

Conclusions: The decoupling between global brain activity and associated CSF flow is related to Parkinson's disease cognitive impairment. © 2021 International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; cerebrospinal fluid flow; cognitive impairment; global resting-state fMRI signal; glymphatic system.

Fig. 1.. Systematic coupling between the gBOLD and CSF signals measured by rsfMRI.

(A) The gBOLD and CSF fMRI signals were extracted from the whole-brain gray matter regions (the blue mask on a T1-weighted structural MRI in the left panel) and the CSF region at the bottom slice of the fMRI acquisition (the bright region in the right panel and the orange-shaded area in the middle panel), respectively. (B) The gBOLD and CSF signal from a representative subject (control) showed corresponding changes of large amplitude. Large CSF peaks (upwards black arrows) often are preceded by a large positive gBOLD peak (downwards black arrows) and followed by a large negative gBOLD peak (gray arrows). (C) The averaged cross-correlation function (N =118 subjects) between the gBOLD signal (reference) and the CSF signal (left), as well as between the first-order negative derivative of gBOLD signal (reference) and the CSF signal (right). The gray dashed line and the shaded region mark 95% confidence intervals for the mean correlation computed on shuffled signals (see Materials and methods for details). The cross-correlations between the gBOLD and CSF signal at the +4 seconds lag (mean r: −0.28; p < 0.0001, permutation test with N =10,000; red dashed line) was used to represent “the gBOLD-CSF coupling” for subsequent analyses.

Fig. 2.. The associations of gBOLD-CSF coupling to age, disease condition, and MoCA.

(A) Older subjects have a weaker (less negative) gBOLD-CSF coupling (Spearman’s ρ = 0.32, p = 0.0005). (B) Compared with controls and PD-non-MCI subjects, PD-MCI subjects have decreased gBOLD-CSF coupling strength (adjusted for age and gender; p ≤ 0.006, two-sample t-test). (C-D) The correlation between the gBOLD-CSF coupling (adjusted for age and gender) and MoCA scores is significant in the PD group (ρ = −0.36, p = 0.005, p_Bonferroni = 0.01; D) but not in the controls (ρ = −0.06, p = 0.65; C). (E) The significant correlation between gBOLD-CSF coupling and MoCA within PD subjects remained significant when removing the two subjects with extremely low MoCA scores (ρ = −0.31, p = 0.017, p_Bonferroni = 0.034). The dashed lines indicate where the gBOLD-CSF coupling equals zero.

Fig. 3.. Associations between gBOLD-CSF coupling and thickness of the entorhinal cortex in PD patients.

The PD patients with thinner right ERC tend to have weaker gBOLD-CSF coupling (Spearman’s ρ = −0.36, p = 0.012, p_Bonferroni = 0.024) (A). This association is similar but not significant (ρ = −0.19, p = 0.19, p_Bonferroni = 0.38) for the left ERC (B). The ERC thickness was normalized with the Sienax index.