Dysautonomia in Parkinson's Disease: Impact of Glucocerebrosidase Gene Mutations on Cardiovascular Autonomic Control.

Angelica Carandina,Emanuele Frattini,Pedro Paulo Da Silva Soares,Giulia Lazzeri,Gabriel Dias Rodrigues,Eleonora Tobaldini,Alessio Di Fonzo,Edoardo Monfrini,Federica Arienti,Ilaria Trezzi,Nicola Montano,Chiara Bellocchi,Giulia Franco,Ludovico Furlan

doi:10.3389/fnins.2022.842498

Abstract

Evidence from clinical practice suggests that PD patients with the Glucocerebrosidase gene mutations (GBA-PD) are characterized by more severe dysautonomic symptoms than patients with idiopathic PD (iPD). Therefore, an accurate assessment of cardiovascular autonomic control (CAC) is necessary to clarify the role of GBA mutations in the pathophysiology of PD. We evaluated the CAC at rest and during orthostatic challenge of 15 iPD, 15 GBA-PD and 15 healthy controls (CTR). ECG and respiration were recorded in supine position and during active standing. The analysis of Heart Rate Variability (HRV) was performed on ECG recordings using two different approaches, linear spectral analysis and non-linear symbolic analysis. GBA-PD patients presented more frequently an akinetic-rigid phenotype and cognitive dysfunction than iPD patients. Both iPD and GBA-PD group were characterized by a lower spectral HRV than CTR group. At rest, the GBA-PD group was characterized by a lower parasympathetic modulation and a shift of the sympathovagal balance toward a sympathetic predominance compared to the CTR group. Moreover, the GBA-PD patients presented a lower HR increment and a lower or absent reduction of the vagal modulation in response to the active standing than iPD patients. Lastly, the cardiovascular autonomic dysfunction in PD patients was associated with longer disease duration, and with the occurrence of REM sleep behavior disorder and constipation. Our findings suggest a more severe impairment of the CAC in PD patients with GBA mutations. These results and further studies on the role of GBA mutations could allow a stratification based on cardiovascular risk in PD patients and the implementation of specific prevention programs.

Highlights

Parkinson’s Disease (PD) is the second most frequent neurodegenerative disorder after Alzheimer’s Disease; it affects an estimated 1.2 million people in Europe and the number is expected to double by 2030 as a result of the population ageing (Dorsey and Bloem, 2018)
The observations from our study are of clinical significance with particular regard to the identification of a specific cardiovascular autonomic pattern: (i) both idiopathic Parkinson’s Disease (iPD) and GBA-PD group were characterized by a lower spectral Heart Rate Variability (HRV); FIGURE 3 | Differences between groups in cardiovascular autonomic response to orthostatic challenge
(ii) at rest, the GBA-PD group was characterized by higher heart rate (HR) values compared to the CTR group, resulting from a lower parasympathetic modulation and a shift of the sympathovagal balance toward a sympathetic predominance, as shown by both spectral and symbolic analysis; whereas the iPD group presented intermediate values between CTR and GBA-PD groups; (iii) the dynamic response of the cardiovascular autonomic control (CAC) to the orthostatic challenge was significantly different in the two PD groups, as GBA-PD patients presented a lower HR increment and a lower or absent reduction of the vagal modulation; (iv) lastly, higher HR values were associated with longer disease duration and cardiovascular autonomic dysfunction was associated with the occurrence of REM sleep behavior disorder (RBD) and constipation

Summary

Introduction

Parkinson’s Disease (PD) is the second most frequent neurodegenerative disorder after Alzheimer’s Disease; it affects an estimated 1.2 million people in Europe and the number is expected to double by 2030 as a result of the population ageing (Dorsey and Bloem, 2018). 10–15% of PD cases are associated with pathogenetic variants of the β-glucocerebrosidase gene (GBA), conferring a cumulative risk of developing PD of 5% at age 60, rising to 15–30% at age 80 (Avenali et al, 2020). It has been suggested that both a chronic loss of the lysosomal enzyme β-glucocerebrosidase (GCase) activity as well as a possible toxic gain-of-function of the mutated protein result in lysosomal dysfunction and endoplasmic reticulum stress, which could contribute to disease pathogenesis (O’Regan et al, 2017). Evidence from clinical practice suggests that PD patients carrying mutations of the GBA gene (GBA-PD) may present more frequently dysautonomic manifestations and REM sleep behavior disorder (RBD) than patients with idiopathic Parkinson’s Disease (iPD; Brockmann et al, 2011; Gan-Or et al, 2016; Petrucci et al, 2020)

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