Prospective Study of Lung Function with Prodromal, Clinical Parkinson’s Disease, and Mortality

INTRODUCTION

Parkinson’s disease (PD) is a progressive neurodegenerative disease, characterized by the presence of movement disorders, such as tremor, rigidity, and bradykinesia.^1,2 Interestingly, individuals with PD have been observed to have high prevalence of respiratory abnormalities.^3,4 A systematic review including 39 case-control studies summarized that strong evidence supported a restrictive pattern with inspiratory muscle weakness in PD compared with health controls.⁵ However, most previous studies mainly focused on the prevalence of respiratory abnormalities and the decline in lung function among individuals with PD. Whether poor lung function is associated with subsequent onset of prodromal and clinical PD remains needed to be studied in large– scale prospective studies. In addition, respiratory dysfunctions may be responsible for the mortality associated with PD.⁶ However, little is known regarding the long-term role of lung function in survival among individuals with PD.

Therefore, we prospectively examined the associations of lung function, as assessed by forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), peak expiratory flow (PEF), and FEV1/FVC ratio, with risk of prodromal and clinical PD among approximately 450,000 adults without PD at the baseline, and with risk of mortality among approximately 3,000 individuals with PD.

MATERIALS AND METHODS

Study population

The current analyses were based on a population– based prospective cohort study– the UK Biobank, which started from 2006 to 2010 with more than 500,000 participants aged 40– 69 years. Participants attended one of 22 assessment centers across England, Wales, and Scotland, where they completed a self-administered, touchscreen questionnaire, and face-to-face interview to collect information on their lifestyle, health characteristics, and socioeconomic characteristics, and trained research staff assessed their physical measurements and obtained blood samples. The UK Biobank obtained ethical approvals from the National Information Governance Board for Health and Social Care and National Health Service North West Multicenter Research Ethics Committee. All participants provided signed informed consent. Details of the UK Biobank were presented previously.^7,8

For this study, we first included 452,518 participants free of clinical PD and who received spirometry tests at baseline to assess the associations between lung function and risk of developing PD (Fig. 1). Moreover, we excluded 2,111 participants with ≥3 prodromal PD features at baseline to assess the association between lung function and risk of prodromal PD. Among participants who were newly diagnosed with clinical PD during the followed-up until October 31, 2022, in England, February 28, 2018, in Wales, and July 31, 2021, in Scotland, we further investigated the association between baseline lung function and mortality.

Fig. 1

Flow chart of the study population.

RESULTS

Among the 452,518 participants in the present analysis (mean age of 56.4±8.10 years), 45.2% were men, and most of them were White British (88.6%). At enrollment, compared with the lowest FEV1, FVC, and PEF groups, participants in the highest groups were more likely to be younger age, have higher education level, have higher socioeconomic status, never smoke, have regular physical activity, underweight/normal, and have healthier sleep pattern. Participants in the higher groups also tended to have a lower prevalence of preexisting hypertension, diabetes, or high cholesterol compared with those in lower group. Moreover, they were exposed to lower levels of PM_2.5 and NO₂.

During a median of 13.5 years of follow-up, 2,996 incident PD cases were documented. In the multivariable models adjusted for sociodemographic factors, lifestyle factors, health conditions, air pollution, and standard PRS, compared with the highest lung function group, participants in the lowest lung function group had a higher likelihood of incident PD. The HR comparing the lowest vs. the highest lung function quintile was 1.18 (95% CI, 1.02– 1.37) for FEV1 and 1.23 (95% CI, 1.08– 1.41) for PEF (Table 2). Per unit decrease in lung function was each associated with higher risk of PD (1.13 [95% CI, 1.04– 1.23] for FEV1, 1.09 [95% CI, 1.02–1.16] for FVC, and 1.08 [95% CI, 1.04–1.13] for PEF) (Table 2). In contrast, we did not find significant associations between FEV1/FVC ratio and risk of PD (HR, 0.92; 95% CI, 0.82– 1.04) (Table 2).

Similarly, lower lung function was associated with prodromal PD features. Comparing extreme quintiles of lung function, the HRs for having ≥3 versus 0 prodromal PD features was 1.17 (95% CI, 1.06– 1.29) for FEV1, 1.13 (95% CI, 1.03– 1.25) for FVC, and 1.24 (95% CI, 1.13– 1.36) for PEF (Table 3). Moreover, per unit decrease in lung function was each associated with having ≥3 prodromal PD features (1.10 [95% CI, 1.04–1.17] for FEV1, 1.05 [95% CI, 1.01–1.10] for FVC, 1.08 [95% CI, 1.05–1.11] for PEF, and 1.03 [95% CI, 1.00–1.06] for FEV1/FVC ratio) (Table 3).

In the analyses of lung function and mortality among individuals with PD, we found that lower lung function was associated with a higher risk of mortality. The adjusted HR comparing the lowest vs. the highest lung function quintile was 1.32 (95% CI, 1.07– 1.63) for FEV1, 1.38 (95% CI, 1.12– 1.70) for FVC, and 1.51 (95% CI, 1.16– 1.98) for PEF (Table 4). Moreover, per unit decrease in lung function was each associated with higher risk of mortality (1.15 [95% CI, 1.04–1.28] for FEV1, 1.12 [95% CI, 1.03–1.22] for FVC, and 1.16 [95% CI, 1.09–1.23] for PEF) (Table 4). In contrast, non-significant associations were found between FEV1/FVC ratio and risk of mortality (Table 4).

In the stratified analyses, no significant effect modifications were detected in sex, gender, smoking status, and BMI (Table 5). Additional sensitivity analyses were overall consistent with the primary analysis when we only included 269,770 participants with both FEV1 and FVC were reproducible (Supplementary Table 2), or restricted our analyses to participants without cancer at baseline (Supplementary Table 3), or performed two-year lagged analyses (Supplementary Table 4). Furthermore, our results remained robust when PD diagnosis was restricted to ICD codes only (Supplementary Table 5).

DISCUSSION

In this population-based cohort of 452,518 participants, we observed that lower FEV1, PEF levels were associated with higher risk of prodromal and clinical PD. Consistently, individuals with PD who had poor lung function were likely to have a higher risk of mortality, relative to those with better lung function.

To the best of our knowledge, the current investigation is the first prospective study for the association between lung function and risk of PD. Consistently, a systematic review and meta-analysis pooling 39 retrospective case-control studies with 1,070 PD participants and 928 healthy controls summarized that high-to-moderate certainty evidence of impairment in PD was identified for vital capacity (standardized mean difference [SMD] 0.75; 95% CI, 0.45– 1.05), total chest wall volume (SMD 0.38; 95% CI, 0.09– 0.68), maximum inspiratory pressure (SMD 0.91; 95% CI, 0.64– 1.19), and sniff nasal inspiratory pressure (SMD 0.58; 95% CI, 0.30– 0.87).⁵ Our findings added valuable evidence to the current literature that poor lung function could be a predictor of PD, which was independent of the sociodemographic factors, socioeconomic status, lifestyle factors, health conditions, air pollution, and PRS for PD.

It is well known that a prodromal phase exists prior to the time when PD can be formally diagnosed. Actually, most prodromal PD features are oriented outside of central nervous system, such as autonomic system, urogenital system and gastrointestinal system.^24,25 Our results provide evidence that poor lung function may also be a marker for the prodromal phase of the PD.¹⁵ Our finding may provide a potential temporal window for PD prevention. Once such prevention becomes available, it could be administered to screen for high-risk patient groups, such as those with anosmia, autonomic disorders, RBD, and individuals who are genetically at risk of developing PD.

Over the past generation, the number of individuals with PD globally has more than doubled and the death rates increased for all global burdens of disease regions except for southern Latin America, Eastern Europe, and Oceania.² Previous physiological evidence indicated that respiratory disorders were recognized predictors of mortality and morbidity in PD.^5,26 A meta-analysis pooling nine studies (including 7,162 individuals with PD) summarized that one of the leading cause of hospitalization was pneumonia, with a prevalence of 22%.²⁷ In Sweden, a 9– year follow-up case control study including 170 PD patients and 510 sex- and age-matched controls found that other respiratory disease (mostly pneumonia) was the second largest category of cause of death (24.0%), compared to 8.3% among the controls.²⁸ Actually, most patients do not report respiratory symptoms until the final stages of PD.^26,29 Probably this disturbance remains unnoticed because physical disability in patients often makes a patient lead a sedentary life and limits activities where respiratory problems can become manifest.³⁰ Overall, most studies did not estimate the long-term association between lung function and risk of all-cause mortality among individuals with newly diagnosed PD. We herein elucidated firsthand evidence among individuals with newly diagnosed PD, if confirmed, may contribute to delay the progression of PD and reduce the risk of all-cause mortality.

Although the exact mechanism underlying the association between poor lung function and the risk of PD remains to be further elucidated, we speculated several potential mechanisms to explain the observed association. Mechanisms of respiratory disorders in PD, both central and peripheral, have been proposed in recent narrative reviews.^31–33 Central mechanisms focus on brain and brain stem respiratory control center changes. Previous studies suggested that early central mechanisms affect respiratory control structures functioning to co-ordinate ventilation and detect peripheral oxygen and carbon dioxide levels.⁵ Peripheral mechanisms include restrictive dysfunction and obstructive dysfunction. Restrictive dysfunction may result from motor impairments of bradykinesia and rigidity, muscle weakness.^33,34 Obstructive disorders may affect the upper or lower airways, especially the upper airways.³⁵ However, no significant association was found between the FEV1/FVC ratio and PD, indicating that other mechanisms, rather than obstructive disorders, might be involved. Further investigations on obstructive disorders are warranted.

The strengths of the current study included the population-based cohort, the long-term follow-up, the high-quality assessment of lung function, and the extensive measurement of covariates. Nevertheless, several limitations need to be considered. First, dynamic data of lung function during follow-up was not largely recorded in the UK Biobank, which prevent us from illustrating the precise impacts of the PD. Given the long preclinical stage of PD, low lung function could be the outcome rather than the prodromal PD feature in disease progression and severity. To minimize the possibility of reverse causation, we conducted a sensitivity analysis that left a lag time of two years between the assessment of lung function and the PD diagnosis. Second, misclassification in PD might still occur because some early stages of PD cases may not be captured because the incident PD cases were only ascertained through electronic health records. Third, given that non-motor symptoms including hyposmia, constipation, and urinary incontinence could not be routinely screened for in primary care settings, there may be an underestimation of participants with these non-motor symptoms. However, the combined criterion of ICD– 9 codes, ICD– 10 codes, primary care data collection, and self-reported medical conditions were used to categorize the prodromal PD features. Further, this misclassification of non-motor symptoms, if non-differential, would like to result in attenuation of the effect size. Moreover, the UK Biobank participants were relatively healthy and affluent, predominantly of White ethnicity, and thus the generalization of our findings was thus of concern. Finally, even though we adjusted for major confounders, residual and unmeasured confounding cannot be fully controlled.

In this prospective cohort study, we found that individuals with lower lung function were more likely to have a higher risk of prodromal and clinical PD, relative to those with higher lung function. Consistently, lower lung function was associated with a higher risk of all-cause mortality among individuals with PD. Future studies are needed to confirm the study findings and to explore the underlying biological mechanisms.