The associations of cerebrospinal fluid biomarkers with cognition, and rapid eye movement sleep behavior disorder in early Parkinson's disease

Abstract

Background: In Parkinson's disease (PD), levels of cerebrospinal fluid (CSF) biomarkers and progression of non-motor symptoms are associated, but the specifics are not yet clear.

Objective: The aim of this study was to investigate the associations of non-motor symptoms with CSF biomarkers in PD.

Materials and methods: We assessed 487 individuals from the Parkinson's Progression Markers Initiative (PPMI), consisting of 155 healthy controls (HCs) and 332 individuals with PD. Patients with PD were grouped according to non-motor symptoms and compared CSF α-synuclein (α-syn), amyloid-beta 1-42 (Aβ_1-42), and total tau (t-tau) levels. Multiple linear regressions were used in baseline analysis and linear mixed-effects models in longitudinal analysis. Analyses of mediating effects between cognition and CSF biomarkers were also performed.

Results: At baseline, PD patients with cognitive impairment (PDCI) exhibited significantly lower CSF α-syn (β = -0.1244; P = 0.0469), Aβ (β = -0.1302; P = 0.0447), and t-tau (β = -0.1260; P = 0.0131) levels than PD patients without cognitive impairment (PDCU). Moreover, a faster decline of α-syn (β = -0.2152; P = 0.0374) and Aβ (β = -0.3114; P = 0.0023) and a faster rise of t-tau (β = -0.1534; P = 0.0274) have been found in longitudinal analysis. The Aβ positive group showed an earlier decline in cognitive performance (β = -0.5341; P = 0.0180) compared with the negative Aβ group in both analyses. In addition, we found that PD patients with probable rapid eye movement sleep behavior disorder (pRBD) showed decreased CSF α-syn (β = -0.1343; P = 0.0033) levels. Finally, mediation analysis demonstrated that olfactory function partially mediated the relationship between cognition and CSF biomarkers levels.

Conclusion: Our study shows that CSF biomarkers are associated with cognition at baseline and longitudinally. Cognitive impairment is more severe in patients with a heavier Aβ burden. CSF α-syn decreased in PD patients with pRBD. This study suggests that early recognition of the increased risk of non-motor symptoms is important for disease surveillance and may be associated with the pathological progression of CSF markers.

Keywords: Parkinson’s disease; cerebrospinal fluid biomarker; cognition function; non-motor symptoms; rapid eye movement sleep behavior disorder (RBD).

FIGURE 1

Associations of non-motor symptoms with cerebrospinal fluid (CSF) biomarker levels in cross-sectional analyses.

FIGURE 2

Associations of cognitive impairments with lower cerebrospinal fluid (CSF) biomarker levels in cross-sectional analyses. Cognitive impairments were significantly associated with lower levels in (A) α-synuclein (B), Aβ_1–42, and (C) t-tau. Cross-sectional associations of sleep disorder with lower CSF (D) α-synuclein were shown. *P < 0.05.

FIGURE 3

Associations of cognitive impairments with lower cerebrospinal fluid (CSF) biomarker levels during the follow-up. Temporal trajectories of CSF (A) α-synuclein (B) and Aβ_1–42 show a decline in cognitive impairments. However, CSF (C) t-tau was elevated. Longitudinal associations of sleep disorders with CSF (D) α-synuclein were shown. *P < 0.05.

FIGURE 4

Olfactory dysfunctions mediate the effects of Montreal Cognitive Assessment (MoCA) on cerebrospinal fluid (CSF) biomarkers. Causal-step approach showed that (1) MoCA was significantly associated with olfaction and rates of CSF biomarkers change; (2) olfaction was associated with CSF biomarkers; (3) when controlling for olfaction, the associations between MoCA and rates of CSF biomarkers were still significant (P < 0.05). As such, all conditions for mediation were met. For Aβ_1–42 (A) and t-tau (B), the Sobel test for mediation estimated that the percentages of total effect mediated by olfaction were 35% (z = 2.1965; P = 0.024) and 37% (z = 0.7674; P = 0.026), respectively. *P < 0.05. MoCA, Montreal Cognitive Assessment; UPSIT, University of Pennsylvania Smell Identification Test; CSF, cerebrospinal fluid; Aβ_1–42, amyloid-β_1–42; t-tau, total tau.