Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterised by persistent respiratory symptoms and irreversible airflow limitation due to airway and/or alveolar abnormalities caused by smoking and air pollution [1]. COPD remains a serious global public health problem, accounting for a large proportion of the world's chronic disease morbidity and mortality, and has become the third leading cause of death and fifth leading cause of disability in humans [2]. Some data show that the prevalence of COPD has shown explosive growth since 2020, and COPD will cause more than 5.4 million deaths per year in the coming decades [3].
Although COPD has traditionally been recognised as a disease primarily affecting the lungs, it is often associated with many comorbidities outside the lungs, such as heart failure, osteoporosis, muscular dystrophy and cognitive impairment [4]. These comorbidities are not necessarily attributable to COPD, as they may occur alone or as a result of shared risk factors. Patients with COPD are typically characterised by the co-existence of comorbidities; evidence suggests that 98% of COPD patients have a single or multiple comorbidities [5]. It is worth noting that comorbidities increase the risk of death, and current evidence suggests that a higher proportion of COPD patients die from nonpulmonary causes compared with pulmonary causes [6]. With the development of research in recent years, cognitive impairment associated with COPD has attracted extensive attention from scholars. A large number of studies have confirmed [7, 8] that long-term smoking, hypoxia and hypercapnia, systemic inflammation, reduced physical activity, the number of exacerbations of the disease course, and respiratory complications such as sleep apnoea syndrome are all risk factors for cognitive impairment in COPD patients. Elderly COPD patients with cognitive impairment have almost three times the mortality rate of elderly patients with cognitive impairment or COPD[9]. The complication of cognitive impairment can exacerbate mortality and disability in patients with COPD and has implications for patient management, increasing the burden on the patient's family and society [10].
Cognition is a set of higher-level activities in the cerebral cortex that includes the perception, storage, retrieval, and use of information. Mild cognitive impairment (MCI) is a cognitive state intermediate between normal cognitive functioning and dementia, and is characterised by the impact it can have on the patient's level of health and ability to function in daily life. Between 50% and 70% of patients will develop dementia within 5 to 7 years of the diagnosis of MCI [11]. Cognitive dysfunction is common in COPD patients. A recent meta-analysis incorporating 14 studies reported that an average of 32% of COPD patients are affected by cognitive impairment, and a quarter of COPD patients suffer from MCI [12], which affects cognitive functions such as attention, memory, learning ability, psychomotor speed, visuospatial and motor structures, executive functioning, and language ability in COPD patients, with memory, attention, and executive functioning are the most common areas of impairment [13]. Assessing cognitive status requires taking into account the influence of subjective and objective factors of the subject, which is difficult to summarise simply and accurately. The Montreal Cognitive Assessment (MoCA) scale is a screening tool that can detect MCI in a timely manner with high sensitivity and specificity [14]. The content of the scale covers 8 cognitive domains with a total of 30 points, with higher scores indicating more intact cognitive functioning.The MoCA scale has been translated into 83 versions in 51 countries and is available in a variety of English language forms to support repeated assessment of patients. This outreach and diversity of delivery helps to ensure the accuracy and reliability of the assessment, which is essential for the prevention, treatment and intervention of MCI and helps to slow the progression of MCI to dementia.
In recent years, there has been an increasing number of studies on the relationship between cognitive impairment and the development of COPD, and many of them have shown that the inflammatory response plays an important role in the pathological process of cognitive dysfunction formation [15, 16]. A large number of scholars have become increasingly interested in CRP, WBC, serum amyloid A (SAA), and other biomarkers that are both simple and clinically significant, and it has now been found that these simple and easy-to-obtain indicators are valuable in reflecting the development and prognosis of cognitive impairment.
CRP is synthesised in the liver in response to activation of the interleukin-6 signalling pathway and is a systemic marker of inflammation, which has been linked to cognitive function [17]. COPD is a chronic lung disease due to persistent airflow limitation, and the hyperinflammatory response in vivo can result in extrapulmonary multiorgan involvement, and COPD participates in a wide range of inflammatory responses, such as neurally prominent metabolic, endocrine and other diverse activities. CRP as an acute inflammatory factor, CRP is considered an independent risk for future cardiovascular events, it has neurotoxic effects and induces vascular cognitive impairment by triggering, among other things, atherosclerosis [18]. Gorelick [19] found an inflammatory pathway of cognitive impairment confirmed by epidemiological studies and clinical trials. When inflammatory factors are consistently increased, inflammation can be involved in the development of neurodegenerative diseases through mechanisms such as activation of microglia, activation of the complement cascade, and disruption of the blood-brain barrier, which in turn impairs cognitive function [20, 21]. High levels of CRP in patients with COPD may be a useful biomarker for identifying individuals at increased risk of cognitive impairment and dementia. Secondly, monitoring CRP levels may have prognostic value once cognitive impairment is clinically evident in patients.
Hcy, a thiol-containing amino acid, is widely recognised as a risk factor for cognitive impairment and dementia [22]. Current studies suggest that Hcy toxicity is associated with neuronal and neurodegenerative diseases, and the possible pathways by which it induces cognitive impairment include increasing glutamate excitotoxicity, decreasing neuronal DNA repair capacity, accelerating oxidative stress and β-amyloid (Amyloid-β, Aβ) formation, and disrupting hippocampal neuron function [23]. On the other hand, Hcy can induce vascular endothelial cell dysfunction, which may lead to cerebrovascular cognitive impairment. Studies have shown that Hcy can ultimately lead to fibrosis, vasospasm, and reduced compliance by stimulating vascular smooth muscle growth, interfering with lipid metabolism, and increasing foam cell formation [24, 25]. In addition, Hcy inhibits the production of nitric oxide, which promotes the production of peroxides and oxygen free radicals. These compounds cause damage to vascular endothelial cells, interfering with the normally regulated diastolic and contractile functions of blood vessels. The free radicals produced by oxidative reactions and may also trigger hypoxia and ischaemia in the brain and inhibit nerve conduction function, which in turn impairs cognitive function and leads to the development of neurological problems such as cognitive impairment or dementia [26, 27].
Nomograms are used as predictive models in medicine and have been widely used in clinical practice for the prediction of disease, especially in the assessment of survival related to some tumour patients. There is still a lack of reliable predictive models for the risk of comorbid cognitive impairment in COPD patients. Therefore, in this study, we screened the independent risk factors associated with COPD combined with cognitive impairment through unifactorial and multifactorial analyses, and established a prediction model for the risk of COPD combined with cognitive impairment using the relevant factors. This will enable clinicians to identify COPD patients with potential cognitive impairment, intervene early to slow down the progression of the disease, and improve the quality of life and reduce the risk of death in COPD patients.