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

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.

Keywords: Parkinson’s Disease; cardiovascular autonomic control; dysautonomia; glucocerebrosidase gene mutations; heart rate variability (HRV).

FIGURE 1

Distribution of GBA mutations in our cohort.

FIGURE 2

Differences between groups in cardiovascular autonomic control at rest. HR values are presented as mean ± standard error. HRV parameters are presented as median and interquartile range. CTR, control group; iPD, idiopathic Parkinson’s Disease patients; GBA-PD, Parkinson’s Disease patients with GBA mutation; HR, heart rate; HF, high frequency; nu, normalized unity; LF, low frequency power; 2LV%, patterns with 2 like variations. *Significant p-values < 0.05, comparison versus controls.

FIGURE 3

Differences between groups in cardiovascular autonomic response to orthostatic challenge. HR and HRV parameters are presented as estimated marginal means adjusted by Age. CTR, control group; iPD, idiopathic Parkinson’s Disease patients; GBA-PD, Parkinson’s Disease patients with GBA mutation; HR, heart rate; 2UV%, patterns with 2 unlike variations. # Significant p-values < 0.05, comparison versus iPD.

FIGURE 4

Association between cardiovascular parameters at rest and clinical data. HR and HRV parameters are presented as estimated marginal means adjusted by Age and presence of GBA mutation. 0, absence of symptom; 1, presence of symptom; HR, heart rate; LDOPA, levodopa; TP, total power; RBD, REM sleep behavior disorder; 0 V%, patterns with no variations; 2UV%, patterns with 2 unlike variations; OH, orthostatic hypotension. * Significant p-values < 0.05 in partial correlation analysis.