Introduction

In recent years, there has been growing evidence highlighting the detrimental impact of chronic stress on health¹. Stress is defined as a state in which the brain perceives an excessive quantity of stimulation or regards its quality as threatening, leading to a generalized physiological response². Moreover, stress has been shown to alter the immune system and oxidative stress defense mechanisms, ultimately leading to cellular apoptosis³-⁵. The hypothalamic-pituitary-adrenal (HPA) axis is a central component of the stress response within the central nervous system (CNS), influencing and sometimes disrupting various cerebral circuits. This intricate interplay involves the HPA axis, the autonomic nervous system (ANS), and the immune system, working together to coordinate hormonal and inflammatory stress responses⁶. Chronic stress, whether arising from major life events or persistent minor irritations and frustrations, induces prolonged activation of the HPA axis, paving the way for long-term pathological conditions⁷. The detrimental consequences on the CNS resulting from the complex interaction of inflammation and stress have been notably observed in the context of neurodegenerative disorders⁸,⁹. Therefore, stress is closely linked to neurodegenerative and mood disorders¹⁰ and plays a pivotal role in the onset of neuropsychiatric conditions¹¹. An expanding body of evidence underscores the central function of stress in priming midbrain microglia to enhance the inflammatory response, potentially serving as a contributing factor in the degenerative processes associated with Parkinson’s disease (PD)¹².

Post-traumatic stress disorder (PTSD) emerges as a significant risk factor within the context of PD. A nationwide longitudinal study revealed that individuals diagnosed with PTSD face a 3.5-fold elevated risk of developing PD, often at an earlier age than those without a PTSD diagnosis¹³. A population-based matched case-control study among veterans demonstrated that individuals with a diagnosis of PTSD are at a 2.71-fold increased risk of developing PD¹⁴. Another population-based cohort study reported that PTSD patients had a 1.48-fold excess risk for PD compared with non-PTSD patients¹⁵. Most recently, a case-control study examining traumatic brain injury (TBI) and PTSD related to early trauma in military veterans reported that TBI and PTSD increased the odds from 1.5 to 2.1 of subsequent PD¹⁶.

Given the information regarding the impact of stress on the HPA axis and its effect on the ANS and other circuits, we deem it crucial to investigate the relationship between stress-related disorders and the presence and severity of autonomic symptoms in PD. Leveraging the scientific background on stress-related disorders and their potential impact on PD, we aim to shed light on this connection to contribute valuable insights into the holistic understanding of PD pathology and offer potential avenues for therapeutic intervention.

Materials and methods

We conducted an observational, cross-sectional study previously approved by the Institutional Review Board: DEISC-19 01 22 030. The patient selection for this study was conducted using a non-probabilistic consecutive convenience sampling method, with participants recruited from a private practice clinic specializing in movement disorders in Monterrey, Mexico, during the period from July to December 2022. The inclusion criteria encompassed patients diagnosed with PD by a specialist in movement disorders based on established clinical diagnostic criteria published previously¹⁷. Exclusion criteria comprised individuals under the age of 18, those diagnosed with atypical Parkinsonism, dementia, or psychotic symptoms related to the disorder. Furthermore, patients without accessible medical records, those unable to engage in a structured interview, or those with a history of TBI were excluded from the study. Patients with concurrent diagnoses or the presence of another neurological disorder were also excluded from the study.

Sociodemographic data were documented, including age, gender, marital status, employment status, years of education, history of COVID-19, exposure to pesticides, and family history of PD. Clinical data, including age of disease onset, disease duration, and motor subtype of PD, were also documented¹⁸. Assessments to determine our main dependent variable, presence, and severity of autonomic symptoms in PD were conducted using the Scale for Outcomes in PD-Autonomic (SCOPA-AUT)¹⁹. The SCOPA-AUT is an assessment tool used to measure the presence and severity of autonomic symptoms in PD. It evaluates nine different autonomic domains, with each domain consisting of specific questions or items. Responses to these items are scored on a Likert scale, where "Never" equals 0, "Sometimes" equals 1, "Regularly" equals 2, and "Often" equals 3. The scores for all items are then summed to calculate the total SCOPA-AUT score. A higher score indicates a greater severity of autonomic symptoms, providing a quantitative measure for assessing autonomic dysfunction in PD.

Previous studies have utilized SCOPA-AUT cutoff scores between 9 and 13 based on their own criteria²⁰,²¹. We established a cut-off value of 10 based on our previous study²², wherein the mean (standard deviation [SD]) total SCOPA-AUT score among control subjects was 5.8 (3.7), while in Parkinson's patients, the lower 95% confidence interval (CI) limit for the mean was 8.9 and the upper limit was 10.2. This meticulous approach facilitated the stratification of the PD cohort into two distinct groups: Individuals with SCOPA-AUT scores < 10 and those with scores ≥ 10. By employing this criterion, our objective was to delineate autonomic symptoms specific to the disease rather than those influenced by age-related factors.

For the initial assessment of PTSD, we collected information about the patient's life experiences before the diagnosis of PD. This information was obtained through a question from the life events scale, which inquiries about potential stressful events²³ and traumatic experiences listed in the Traumatic Experiences Questionnaire (PQ)²⁴. A structured interview was then conducted to inquire about any event that the patient considered traumatic. If there was a positive response to any of the queried events, an evaluation for stress disorders was conducted using the following scales and clinical assessment. The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)²⁵ and the Checklist for DSM-5 PTSD (PCL-5)²⁶ were administered for the diagnosis of PTSD. The CAPS-5 scale will be used for the assessment of PTSD through interviews, and to facilitate data collection and analysis, we will use the validated PCL-5 scale. The CAPS-5 scale is administered through a structured 30-min clinician interview, consisting of 47 items scored on a four-point Likert scale to measure the frequency and intensity of PTSD symptoms. To diagnose PTSD using the CAPS-5, specific criteria must be met. On the other hand, the PCL-5 scale is a self-administered or patient-read questionnaire comprising 20 items rated on a 5-point Likert scale, and it aligns with the DSM-5 criteria for PTSD. Scores from the PCL-5 scale will be utilized to assess PTSD symptoms. In addition, the acute stress disorder scale was used to identify acute stress disorder²⁷, for the diagnosis of adaptive disorder, we utilized the diagnostic criteria based on the structured interview according to the DSM-5²⁸, and the Adverse Childhood Experiences (ACEs) Questionnaire was used to identify childhood trauma²⁹.

Results

Thirty-two PD patients were included in the analysis, with 16 of them having a SCOPA-AUT total score of ≥ 10, while the remaining 16 had a SCOPA-AUT total score of < 10. No significant differences were observed in sociodemographic and clinical variables related to the disease, except for individuals who were unemployed or retired, as they were 4.84 times more likely to score ≥ 10 on the SCOPA-AUT. Table 1 displays all the characteristics.

The analysis revealed significant differences in the PCL-5 scores between the SCOPA-AUT ≥ 10 group (23.1, SD = 6.1) and the SCOPA-AUT < 10 group (3.2, SD = 2.5), with a p = 0.013, as shown in Fig. 1. Furthermore, a positive and moderate correlation was observed between the PCL-5 score and the SCOPA-AUT total score for the entire cohort, with a correlation coefficient of ρ = 0.530 and a p = 0.002. The correlation remained significant even after controlling for age, employment status, years of education, and age of disease onset (ρ = 0.720, p < 0.0001). Our findings suggest that as post-traumatic stress symptoms increase, dysautonomic symptoms tend to become more pronounced in patients with PD.

Figure 1 PCL-5 scores between SCOPA-AUT groups. The analysis revealed significant differences in the PCL-5 scores between the SCOPA-AUT ≥ 10 group (23.1, SD 6.1) and the SCOPA-AUT < 10 group (3.2, SD 2.5), with a p = 0.013. SCOPA-AUT: scale for outcomes in Parkinson’s disease-autonomic; SD: standard deviation. 

In our investigation of the presence of traumatic events among patients, 16 out of 32 individuals reported experiencing traumas of sufficient magnitude to induce significant distress before the onset of PD symptoms. Subsequent analysis unveiled differences in the occurrence of traumatic events between the study groups. The SCOPA-AUT ≥ 10 group exhibited a prevalence of 68.8%, whereas the SCOPA-AUT < 10 group had a lower frequency of 31.3% (p = 0.034, odds ratio [OR] = 4.84, 95% CI: 1.09-21.58). Similarly, when examining 13 out of 32 patients who presented with stress-related disorders, significant distinctions emerged between the study groups. The prevalence of these disorders was notably higher in the SCOPA-AUT ≥ 10 groups at 84.6%, as opposed to the SCOPA-AUT < 10 group, which had a prevalence of 15.4% (p = 0.003, OR = 15.4, 95% CI: 2.50-95.06). Furthermore, variations in the occurrence of adjustment disorders among 8 out of 32 patients were observed between the study groups. The SCOPA-AUT ≥ 10 group exhibited a prevalence of 87.5%, while the SCOPA-AUT < 10 group had a prevalence of 12.5% (p = 0.037, OR = 11.7, 95% CI: 1.23-110.96). Table 2 provides a detailed description of the association between stress-related disorders and the study groups. Regarding the ACEs questionnaire, 18 out of 32 (56.3%) PD patients reported having experienced at least one ACE. However, only 2 out of the 18 (11.1%) reported a score of 4 or more ACEs. No significant association was observed between the SCOPA-AUT study groups.

Discussion

Our observational cross-sectional study explored the complex relationship between stress-related disorders, particularly PTSD, and PD, with a particular focus on autonomic dysfunction. Our findings indicate that individuals with PD who also have higher post-traumatic stress symptoms tend to experience more pronounced autonomic dysfunction. We believe this observation is significant as autonomic dysfunction is a prevalent non-motor symptom in PD and can significantly impact patients' quality of life. While previous studies have established a link between PTSD and an increased risk of developing PD¹³-¹⁶, our study is the first to add to the literature by highlighting the potential impact of stress on non-motor symptoms, specifically autonomic dysfunction, in patients already diagnosed with PD.

Our study also examined the presence of traumatic events in PD patients before the onset of PD symptoms. We found that a significant proportion of patients reported experiencing traumatic events significant enough to induce distress. Importantly, these traumatic events were more prevalent in the group with higher SCOPA-AUT scores, indicating a potential link between trauma and autonomic dysfunction. In addition, stress-related disorders were more common in the group with higher SCOPA-AUT scores, further emphasizing the possible connection between stress-related conditions and autonomic symptoms in PD. Chronic stress has increasingly been recognized as a significant factor impacting health, with its detrimental effects on various physiological and immune responses well-documented³⁰. Stress, through its influence on the HPA axis, ANS, and the immune system, can contribute to the development of pathological conditions, including neurodegenerative disorders, such as PD³¹. The connection between stress and neurodegenerative conditions has garnered attention due to its potential impact on both motor and non-motor symptoms. Furthermore, individuals with PTSD exhibit irregular fluctuations in their autonomic states. This persistent defensive autonomic state can result in dysfunctional autonomic reactions. These phenomena might be influenced by right hemisphere systems, potentially playing a role in sympathetic activation and the adoption of defensive strategies in PTSD³². PTSD should be considered as a maladaptive disorder of the autonomic system that responds in an erroneous physiologic way to the environment's demands³³.

Our results should be interpreted with caution, as this is an observational, cross-sectional study with a limited sample size. Longitudinal studies with larger cohorts are needed to confirm these findings and establish causality. Several confounding variables linked to dysautonomia, such as diabetes and medication use, including beta-blockers, levodopa, and pramipexole, were not directly assessed or recorded in our study. Nevertheless, our study contributes to the growing body of evidence highlighting the importance of considering stress-related disorders in the management of PD, particularly in addressing non-motor symptoms, such as autonomic dysfunction.

Conclusion

Our study suggests that post-traumatic stress symptoms may exacerbate autonomic dysfunction in PD patients. Further research is needed to explore the underlying mechanisms and potential therapeutic implications of these findings. Understanding the relationship between stress-related disorders and non-motor symptoms in PD can have important implications for the holistic management of this complex neurological condition.