Chronic Obstructive Pulmonary Disease And Cognitive Impairment
Ministry of health of the Republic of Moldova
Public Institution “Nicolae Testemitianu” State University of Medicine and Pharmacy of the Republic of Moldova
FACULTY OF MEDICINE
Department: Semeiology of Internal Medicine
DIPLOMA THESIS
CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND COGNITIVE IMPAIRMENT
Name and surname of student ASSADI ALI
year VI, group 1046
Name and surname of scientific advisor Phd. RODICA STRATU
University assistant
Chisinau, year 2016
CONTENT
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) affects up to 600 million people worldwide and it is currently one of the leading causes of morbidity and mortality in patients suffering from chronic diseases. The hallmark of COPD is chronic airflow obstruction that has a systemic impact and a progressive evolution.[ 1 ]. It is an important health problem that is estimated to become the fifth leading cause of disability and the third leading cause of death worldwide by 2020.[ 2 ] The prevalence of COPD in the global population is close to one percent and increases with age, and globally there is a growing number of people who are more than 65 years old,1 and major healthcare resources are spent on COPD, with 50% of costs accounted for by hospital stays. [3] Besides this, the demand for home care services has increased, and patients should be involved in monitoring and treatment of their disease in co-operation with the health professionals.[4]
COPD is characterized not only by progressive and largely irreversible limitation of air flow, shortness of breath, cough, and expectoration. The typical profile of patients with COPD includes multiple comorbidities,[ 4 , 5 ] such as heart disease,[ 6 ]osteoporosis,[ 7 ] type 2 diabetes mellitus,[ 8 ] lung cancer,[ 9 ] and cognitive impairment.[ 10 ] At recent, the clinical relevance of cognitive impairment has risen,[ 11 ] due to the increase in the prevalence of COPD and the growing interest in the aspects that determine functionality and treatment compliance [ 12 , 13 ] among patients with this disease.[ 14 ]. It is important to maintain a view of self-care that takes differences in cognitive ability into account. The literature indicate that cognitive dysfunction could be a limitation in patients with COPD.4 Thus, the level of cognitive functioning of these patients must be taken into consideration before self-care can be planned and tailored toward the patient’s individual capability and needs.5
Cognitive dysfunction reduces the level of functioning as assessed by activities of daily living,8,9 and it is associated with low compliance with both medication and oxygen therapy, and poor compliance increases the risk of acute exacerbation.10,11
Even though COPD and cognitive impairment have been studied separately (as individual diseases), there is increasing evidence of a relationship between the two.[ 11 ] Hugg et al.[ 15 ] analyzed cognitive impairment in patients with COPD and found that such patients had a greater risk of developing cognitive impairment than did patients without COPD. The hypoxemia found in some patients with COPD seems to be a essential factor for cognitive impairment, because it affects the oxygen-dependent enzymes that are important in the synthesis of neurotransmitters such as acetylcholine.[ 16 ] Different studies have shown that cognitive impairment has a prevalence of 77% in patients with COPD and hypoxemia.[ 17 ]
Increasing age and low level of education were also associated with cognitive deficiency.13. Moreover, a direct association between cerebral hypo-perfusion and cognitive dysfunction has been described.7,14 Magnetic resonance imaging (MRI) has shown altered cerebral perfusion in patients with COPD who have cognitive dysfunction as a clinical manifestation.7
The relationship between the many processes involved in an everyday cognitive task is complex, but cognitive ability is usually broken down into domains concerning memory, learning ability, attention/concentration, abstract thinking, and problem solving.4. There is a relationship between the different cognitive domains affected in COPD patients and the disease itself, and the prevalence of impairment varies among the different cognitive domains.
The objective of my thesis was to determine the incidence and severity of cognitive dysfunction in patients with COPD, based on a systematic review of the literature. Furthermore, I wanted to determine the association between the severity of COPD and the level of cognitive dysfunction, to examine mechanisms of injury and dysfunction to the brain and the methods used to evaluate cognition, and to characterize and clarify the relationship between the various cognitive domains affected in COPD patients and the disease itself.
In addition, I intended to examine the potential impact of treatment on cognitive function and subsequent patient outcomes.
CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND COGNITIVE FUNCTIONS
3.1. Chronic obstructive pulmonary disease: definition and characteristics
Chronic obstructive pulmonary disease is a progressive disease characterized by the presence of airflow obstruction secondary to emphysema or chronic bronchitis [9]. COPD does not cause a fully reversible airway limitation due to chronic inflammatory process in the pulmonary tissue that often results in breathlessness for the patients, cough [10, 11], and excessive mucus production [12, 13]. COPD is the fourth leading cause of death in the United States [13], after heart disease, cancer, and stroke [14], whereas its prevalence increases with aging [15, 16]. The incidence of COPD in general population is between 2.83% [15] and 6.9% [17], while in ages over 35 years old this percentage extent to 17.4% in developed countries [16]. More COPD patients are between their fifth and sixth decade of life [10] and there is a greater incidence of the disease among males than females [16, 18].
Tobacco smoking is the main cause of the disease, although only a minority of smokers develops clinically significant symptoms [10]. Other factors, such as indoor and outdoor air pollution, infection in childhood, asthma, genetic factors [1, 9] and occupational dust have been stated to contribute to the development of COPD [10]. COPD is associated with an increased mortality and morbidity implications such as lung cancer, pulmonary hypertension, obstructive sleep apnea, anemia [10], polycythaemia, peripheral oedema, cardiovascular complications, chronic infections, and musculoskeletal disorders (e.g., osteopenia and muscle atrophy) [1, 19] as well as nutritional depletion that is caused by increased metabolism during breathiness episodes [11, 13]. Patients with COPD are significantly more likely to have symptoms such as sleeplessness and difficulty in initiating and maintaining sleep [20]. Moreover, they have a higher rate of depression and anxiety related to general population [21]. Due to restriction of activities and limitation of social life COPD has also been associated with reduced patients’ quality of life [22].
The treatment of COPD patients is based on a combination of bronchodilatory, corticosteroid, antibiotic, and mucolytic drugs which have been found to improve lung functions, COPD symptoms and morbidity and mortality caused by extrapulmonary effects. Drug use has also been found to reduce exacerbation rates (major changes in patient’s symptoms or their requirement for drug therapy) and the duration of hospital stay [11, 12]. Moreover, it has been found that drugs improve patients’ quality of life [11] and mood [23]. However, the most effective treatment is smoking cessation which delays disease progression [11] or returns lung functioning to normal, if COPD is identified at early stages [12]. Some other kinds of treatment such as pulmonary rehabilitation, lung volume reduction surgery (LVRS) [10], long-term oxygen therapy (LTOT) [12], and continuous positive airway pressure (CPAP) [14] have been found to be effective in reducing patients’ morbidity and mortality.
COPD is diagnosed on the basis of chronic respiratory symptoms, including irreversible airflow limitation associated with dyspnea and particularly with exertion, cough with expectorations, and wheeze [11, 14]. The pathological processes in COPD include inflammatory injury of the large airways (trachea, bronchi) and small airways (bronchioles) and often alveolar dysfunction of small airways [12, 13]. The reduced number of cilia and the glandular hypertrophy that are observed in large airways cause increased cough [12]. However, the majority of symptoms in COPD patients are based on the reduced ability of lungs to empty appropriately. Inspiratory muscle weakness, lung hyperinflation, and increased ventilatory demand related to capacity contribute to the presence of dyspnea [12, 24]. On the other hand, alveolar dysfunction causes hypoventilation (impairment in gas exchange) and ventilation-perfusion mismatching, which result in hypoxemia and hypercapnia [12, 25].
The diagnosis of COPD is based on a characteristic history of persistent and progressive symptoms, on risk factors for COPD and on assessment of physiologic measurements of lung function [12]. The most commonly used test for the assessment of lung dysfunction is spirometry [10]. The severity of the disease is based on spirometric criteria measuring the forced expiratory volume in 1 sec (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) after administration of bronchodilator drugs [1, 11].
The stage of severity of COPD is determined according to 2010 Global initiative for Obstructive Lung Disease (GOLD) guidelines. Therefore, COPD is categorized as mild when FEV is ≥80%, moderate when FEV is among ≤50–<80%, severe when FEV is ≤30%–50%, and very severe when COPD patients are presented with an FEV <30%. Diagnosis also demands FEV1/FVC to be <0.70 [1, 26]. A useful feature for confirming the diagnosis of COPD is that patients’ lung functions do not return to normal after bronchodilator administration, as compared to patients with other breathing disorders (e.g., asthma) [12].
Severity of hypoxia in COPD is defined by blood oxygen levels. A mild stage of severity is considered the one with an oxygen partial pressure (PaO2) between 50 mmHg and 80 mmHg [27]. At this stage, there is complete compensation and general function is barely changed. Oxygen partial pressure between 35 mmHg and 50 mmHg is generally considered moderate hypoxia, a condition which leads to a negative impact on cognition. And finally, when PaO2 is below 35 mmHg the hypoxia is considered to be severe [6]. As regarding hypercapnia, it is considered as abnormal when carbon levels exceed the normal range of 35 mmHg to 45 mmHg [27].
. Cognition: definition and conceptual frameworks
Cognition is a collective term for high-order neural processes that underpin information handling. These have been sub-classified according to conceptual frameworks such as those shown (table 1).
Table 2.1
Cognitive domains and their relationship to cognitive functions tested in practice
In practice, cognitive aptitudes are mainly inferred from behaviour, which itself is determined by a wide range of neurological, psychological and emotional factors [7]. The relationships between the many processes intricate in an everyday cognitive task are complex, but cognitive ability is usually broken up into discrete domains, although it is rarely possible to study single domains in isolation.
Chronic obstructive pulmonary disease has been found to cause a general cognitive deterioration [28, 29] especially in cognitive functions such as attention, psychomotor speed, memory and learning, visuospatial and constructional abilities, executive functions, and language skills [28, 30].
Attention
Attention in patients with COPD is one of the most widely studied cognitive functions. Deficiencies on vigilance and sustained visual attention have been documented by several studies [31–33]. More precisely, a study showed that severe-to-very severe COPD patients with mild hypoxia performed poorly on visual sustained and selective attention tasks [34]. Other studies have shown that severe COPD patients with mild-to-moderate hypoxia performed worse than healthy controls on alerting, orienting tasks, and sustained attention tasks [35–37]. Attention decay has also been observed in severe COPD patients with moderate hypoxia and hypercapnia [38].
Besides, a research on moderate and severe patients with COPD with mild severity oxygen pressure and moderate severity night time oxygen desaturation found deficiencies in selective and sustained attention [39]. Reduced performance in attention tasks has been demonstrated even in non-hypoxemic severe COPD patients [40, 41].
On the other hand, there are studies on COPD patients which showed a mild decay in attention abilities [42] and an undamaged visual immediate attention even in severe COPD patients [43]. A recent study on severe COPD patients who were mildly hypoxemic noted that the occurrence of visual and verbal attention decline was 14.9% and 2.2%, respectively [44]. Generally, the above-mentioned studies have demonstrated that COPD patients demonstrate poorer performance than healthy controls in several domains of attention.
Psychomotor Speed
Deterioration in psychomotor speed was evidenced by various research studies. It has been shown that 26% of patients in the group of very severe COPD with mild hypoxia were impaired in psychomotor speed [9]. A different study on severe COPD patients with mild-to-moderate hypoxia evidenced that they achieved statistically significant low scores in time reaction tests [35]. Moreover, it has been shown [45] that severe COPD patients who were oxygen and non-oxygen dependent demonstrated poor performance in psychomotor speed tests. This result was consistent with the findings of a study [46] in which non-hypoxemic patients with severe COPD had low performance in a psychomotor speed test. On the other hand, other investigators found [47] that moderate COPD patients, with mild hypoxia, performed within regular range in a test which assesses psychomotor speed. Lastly, there is a study [41] which failed to register differences between healthy controls and hypoxemic or non-hypoxemic patients in psychomotor speed tests. Up to now research has generated contradicting data on the association of COPD and psychomotor skills.
Consequently, more research is needed in order to shed light on the effect of COPD on psychomotor skills.
Memory and Learning
Memory dysfunctions are common in COPD patients. Most of the researchers have documented deficits in verbal short-term and long-term memory [32, 41], in visual memory [33], and in spatial memory [31].
Severe-to-very severe COPD patients usually have been presented with a significant short-term verbal memory decay. COPD patients’ performance in visual span tests was established to be impaired in compare to their performance in immediate visual memory tests which was found intact [48]. There is also a study [38] which has documented a decline in verbal memory in a patient with severe COPD and moderate hypoxia, which was in need for lung volume reduction surgery.
In patients with severe COPD and mild-to-moderate hypoxemia there were statistically significant differences in verbal and visual learning when compared to healthy controls [35]. A research in patients with severe COPD has documented deficiencies in delayed verbal memory [37]. Moreover, poor performance in verbal memory and delayed recall was detected in non-oxygen and oxygen dependent patients with severe COPD [41, 45], even though a decline in immediate visual memory was seldom found [41, 44].
Some other researchers have reported memory impairments in a considerable percentage of COPD patients of their samples. It was found [49] that 80% of patients with severe COPD and mild-to-moderate hypoxia performed inferior to healthy controls in verbal short-term and long-term memory tests, whilst 38.1% of them presented a specific verbal memory profile. Another research [9] found that 50% of very severe COPD patients with mild-to-moderate hypoxia had impaired immediate memory and 44% of them had difficulties in their long-term recovery ability. A specific pattern of cognitive decline was found in 48% of patients with COPD, which included a remarkable verbal memory decline [43].
A study on severe COPD patients with mild hypoxia established that 37.3% of them was impaired in terms of short-term memory and 26.1% obtained low scores in long-term memory tests [44]. Another study [50], noted that 30% of patients with COPD had impaired memory which was restricted to immediate verbal memory.
Lastly, there are some studies that failed to certificate any memory deficits in COPD patients. The performance of moderate COPD patients with mild hypoxia was found within usual normal range in memory tests [47], whereas another study [39] on moderate COPD patients with mild oxygen blood pressure did not reveal notably poor scores in verbal learning memory tests. Besides, short-term and long-term verbal memories have been found within normal range in non-hypoxemic patients with severe COPD [46, 48].
Based on the inconsistency of the results of the abovementioned studies the matter of learning and memory abilities in COPD patients should be further studied in combination with the degree of hypoxia that these patients present because it seems that hypoxia negatively influence memory and learning.
Visuospatial and Motor Constructional Abilities
A decline in constructional abilities is very frequently found among COPD patients [32]. Patients with severe COPD and mild hypoxemia have been presented with impaired constructional abilities [37, 51]. Another research has revealed a decline in visuoconstructional abilities in 40.3% of severe COPD patients with mild hypoxia [44]. On the other hand, there are studies in which hypoxemic and nonhypoxemic COPD patients had a normal performance [41] as well as severe-to-very severe COPD patients with mild hypoxia [48]. Although there is a slight discrepancy among the findings of studies on the influence of COPD on visuospatial and motor constructional abilities, most of them present confirmation for impaired visuoconstructional abilities in COPD patients.
Executive Functions
The existence of executive impairments among COPD patients is still equivocal. There are studies that found dysfunctions in problem solving ability, abstraction abilities, and deductive thinking [40]. In particular, studies on severe-to-very severe COPD patients with mild hypoxia have established mild dysfunctions in executive functions [37]. A study on severe COPD patients with mild-to-moderate hypoxia found impairments in logical thinking but not in general executive functioning [35].
A research [52] on severe COPD patients with mild hypoxemia also revealed a mild decline in letter fluency; but this was not at a clinically impaired degree. Regarding non-hypoxemic severe COPD patients, their scores in tests that assess mental flexibility was found poor [46]. A different study [47] established that performance of moderate COPD patients with mild hypoxia in tests that involve mental shift ability was below normal average.
Furthermore, it was found [9] that 31% of very severe COPD patients with mild-to-moderate hypoxia presented deficient performance in tests measuring executive functioning. Finally, in a group of patients with severe COPD and mild hypoxemia, it was noted that 40.3% of them performed poorly in copying complex drawings and 11.2% in Raven progressive matrices, the latter examining nonverbal reasoning.
Nevertheless, there were researches, even if limited number, that either failed to find any considerable poor performance in executive functioning in severe COPD patients with mild hypoxia [48] or found that COPD patients’ performance was comparable to controls in executive functioning tests [41]. It must be paid attention to that fact, however, that most studies support the notion that COPD is typically associated with executive dysfunctions.
Language Abilities
There have been an important number of studies that have recognized severe language impairments assessed with verbal fluency tests in COPD patients [33, 36]. A recent study established a language decline in non-hypoxemic and hypoxemic COPD patients in selected tests of verbal accomplishment [40]. One more research found that 48% of severe COPD patients presented a definite pattern of cognitive worsening which included a serious decline in verbal fluency [43]. On the other hand, there is a study which has shown that merely 10.4% of severe COPD patients with mild hypoxia showed sentence construction deterioration and 7.5% – a verbal fluency impairment [44].
However, the existence of language dysfunctions in COPD patients is still controversial. There is a study which found that severe COPD patients with mild hypoxia had low scores in verbal fluency tests, although this was not at a clinically impaired degree [52]. Likewise, it was proved [47] that patients with moderate COPD and mild hypoxia performed within average range in the aphasia screening test, although in a verbal fluency test their performance was just near the low end of the average range.
Moreover, a research [9] on very severe COPD patients with mild-to-moderate hypoxia revealed normal scores in vocabulary tests. In addition, it has been shown that the performance of severe COPD patients in crystallized intelligence (knowledge and vocabulary) [35] and in language (verbal fluency, sentence construction) was within normal range [48].
After all, there is a study [41] which noted that the performance of hypoxemic and non-hypoxemic COPD patients was comparable to controls in verbal production and verbal competence tests. From the abovementioned studies it is evident that the uncertain association of COPD and language abilities can be partly ascribed to differences in the severity of disease, mode of patients’ selection and control groups selection, and on different criteria that are used to appreciate the severity of syndromes.
Mechanisms of cognitive impairment in COPD patients
It has been supposed that cognitive dysfunctions in COPD patients are determined by autonomous factors, such as COPD severity parameters (FEV1, FEV1/FVC) [95], oxygen desaturation (SaO2) [96], oxygen partial pressure (PaO2), and hypercapnia (PaCO2) [97].
COPD severity parameters and cognitive function
Lung volume dysfunctions defined by FEV1/FVC (%), FEV1 (%), and FVC (%) have been shown to correlate with performance in cognitive tests, like the Mini-Mental State Test, which assesses memory, along with orientation, and language skills [27]. It has also been found that low performance during middle age was a major predictor of cognitive disabilities in later life [98]. Besides, research has revealed that more severe COPD patients presented lower scores in cognitive tests than moderate or healthy adults [29].
Consequently, the degree of pulmonary decline has a critical role on the degree of cognitive impairment [99]. However, most of researches failed to demonstrate a strong relationship between lung parameters (FEV1, FVC) and cognitive impairments [39, 46, 96].
Hypoxemia and cognitive function
Another factor that has been found to be connected to cognitive dysfunctions is low oxygen desaturation (SaO2) [22, 100]. It has been demonstrated that there is a strong association between low baseline oxygen saturation (≤80%) and cognitive impairment [96]. Moreover, it has been found that the risk of cognitive disturbances rises with decreasing oxygen desaturation [96]. It has been supposed that low night-time desaturation or night-time blood gas may elucidate better the cognitive deficits in a similar way in OSA patients [46], as hypoxemic COPD patients become more hypoxemic during sleep [25].
Most of researches documented an association between cognitive functions and the level of hypoxemia defined by arterial oxygen pressure (PaO2). In particular, it was established that partial pressure of arterial oxygen (PaO2) is associated with complex attention, psychomotor speed, executive functioning, constructional abilities [44, 47], and visual and verbal short-term memory [47].
The essential impact of blood oxygen level on cognitive functions can also be confirmed by the fact that non-hypoxemic patients show less cognitive decline [41]. Otherwise saying, oxygen-dependent patients have been found to accomplish lower scores than controls or non-oxygen dependent COPD patients in cognitive tests [29, 45] assessing verbal memory, delayed recall, and attention [41]. As for simple attention and delayed logical memory tests, it has been documented [47] that severely hypoxic patients obtained lower scores than mildly hypoxic patients.
The role of hypoxia and hypercapnia on cognitive decline can be proved also by the fact that therapy, specifically, long-term oxygen therapy (LTOT) or lung volume reduction Surgery (LVRS), appears to improve several cognitive functions [101, 102] such as attention and verbal memory [31, 38] or at least partly reverses these functions [97]. Furthermore, it has been suggested that the regular inhalation of oxygen has a neuroprotective effect in COPD [96].
Nevertheless, there are researches that have failed to demonstrate any relationship between gas blood and damaged cognitive functions such as attention [34, 39], mental speed, fluid intelligence [46, 103], language abilities, and executive functions [47].
The precise pathophysiological and biological mechanisms that could elucidate the effects of impaired lungs’ functions on the development of cognitive dysfunctions are still uncertain. It has been suggested that low lung functioning may lead to cognitive disorders by neuronal damage mediated through hypoxia, but also that oxygen-dependant enzymes, such as acetylcholine, which are important in the synthesis of neurotransmitters may be affected [9].
A magnetic resonance spectroscopy study in patients with non-hypoxic severe COPD demonstrated that cerebral metabolism was considerably changed and that the pattern of alterations differed from the one seen in diabetes and heart failure [10].
Inflammation may have a role, given that there is evidence that C-reactive protein may be associated with cognitive decline, either through a direct neurotoxic action [11] or an effect on cerebral atherosclerosis. Other mediators of inflammation, including interleukin (IL)-6, IL-1b, tumour necrosis factor-a and a1-antichymotrypsin [12, 13], have also been related to cognitive dysfunction. Nevertheless, these studies suggest an association rather than a causal connection [14].
Persistent inflammation causes chronic airflow limitation and is maximally effective in the most severe conditions. As cognitive decline has been proved to be related to hypoxemia and to degree of airway obstruction [22], the active role of chronic inflammation in sustaining cognitive impairment can also be suggested in COPD.
Low arterial oxygen blood pressure and hypercapnia may develop in these patients as a consequence of their disease and as a result of it, both contribute extensively to the development of pathophysiology in COPD [97]. It has been considered that impaired lung functioning leads to changes in the central nervous system due to such processes as cerebral diseases consequential to impaired fibrinolytic activity, oxidate stress, [99] vascular diseases, and increased proinflammatory cytokines (TNFR1) that act as a possible systemic mediator by means of cardiovascular disease between lung functions and brain [45]. High levels of circulating thrombotic factors may possibly increase the risk for cardiovascular disease [104]. Thus, cognitive deficiencies are mediated by the presence of changes in systemic hemodynamic and cerebral diseases. Besides, it has been suggested that COPD may speed up processes of aging which result in decreased cerebral blood flow and oxygen consumption [49]. The possible mechanism by which cognitive functions in COPD are affected is summarized in Figure 3.1.
Fig. 3.1 Potential COPD mechanism by which cognitive functions are affected
Concerning hypoxemia, it has been established that decreased oxygen transportation to brain cells transform ion channels (potassium, sodium, calcium) and increases glomus cell excitability. Besides, it causes changes in neurotransmitters (dopamine, acetylcholine, and ATP) and reduces breathing followed by enhancement of sympathetic and respiratory activities which leads to changes involving alteration in signalling pathways, in neuromodulators (endothelin-1) and their receptors and genome effects [6, 115]. For that reason, brain oxygenation is vital for neural biosynthetic processes situation [6]. It has been found that repeated oxygen desaturation during everyday activity increases choline level in frontal brain areas that damage myelin and membrane precursors [45]. It is notable that even blood oxygen levels at low normal range may cause cognitive decline [6].
Additionally, oxygen desaturation may increase hematocrit levels and lead to angiogenesis through enhancement of production of vascular growth factors [6]. Ultimately, it has been assert that hypoxemia, inflammation, and oxidate stress trigger the processes of endothelial dysfunction that plays a significantly role in vascular tone and cellular growth [116].
Regarding the negative effect of hypoxemia on brain regions, it has been found that there is an importantly decreased cerebral perfusion in left middle and superior frontal, right superior frontal and left parietal lobes [41], and in subcortical regions [43] that are correlated to attention, verbal memory, executive functions, and psychomotor speed [117]. Several regions of the brain, such as the hippocampus, basal ganglia, cerebellum, occipital cortex, and several frontal regions are predominantly susceptible to oxygen deficiency than others [118]. Studies on hypobaric hypoxemia also registered a neuronal loss in hippocampus [119]. Also, magnetic resonance image studies shown a significant gray matter loss and atrophy in some brain regions such as cortex, hippocampus, and striatum proving that chronic hypoxemia results in neuronal damage and consequently in impaired cognitive functions [120, 121].
Patients’ cognition was demonstrated to improve proportionally to the amelioration of their neurological parameters, cerebral blood flow velocity, and autonomic function following LTOT, thus underlining the reversibility (at least partial) of the COPD-induced cognitive damage and the therapeutic effect of long-term oxygen from this point of view.
An ample vision of the role of hypoxemia and of oxygen supplementation in modulating the pathways of cognitive dysfunction is demonstrated in Figure 3.2.
In clinical terms, the strong data, proving that cognition may be considerably deteriorated in hypoxemic COPD patients allow to explain why these subjects often demonstrate an insufficient self management and their compliance to therapeutic strategies frequently results inadequate.
Fig. 3.2 Deterioration of cognition in COPD: an ample vision of the oxygen role in modulating the pathways of cognitive dysfunction
(from: Dal Negro et al. Multidisciplinary Respiratory Medicine (2015) 10:17)
Hypercapnia and cognitive function
One more essential factor that enhances cognitive decline is hypercapnia or hypercapnia-induced hypoventilation [43]. It has been demonstrated [27] that hypercarbia had a high correspondence with information-memory-concentration tests. There are studies that have reported a significant correlation between high levels of PaCO2 and deficits in reaction time or logical thinking [35], in immediate and delayed memory, complex attention, information speed processing, animal-naming of verbal fluency test [47] and in concentration and orientation [27]. Unexpectedly, it has been observed [47] that neuropsychological test performance was generally more highly related to PaCO2 than to PaO2.
Other studies have found an inconsistent correlation between arterial carbon dioxide pressure (PaCO2) and cognitive function. In patients with hypercapnic respiratory insufficiency, there is a correlation between PaCO2 and memory, complex attention and information processing speed, but not between PaCO2 and language, motor function and simple attention [19]. INCALZI et al. [18] suggested that PaCO2 was related to verbal memory and attainment and, in a study of patients awaiting lung transplantation, lower PaCO2 was considerably correlated to better performance of executive function, attention and verbal memory [47]. On the other hand, there was no correlation between cognitive function and hypercapnia in the NOTT and IPPB studies or in studies by GRANT et al. [31] and FIX et al. [25]. In general the relationship between PaCO2 and cognitive impairment is even less understandable than that for PaO2.
Other factors that influence cognitive function in COPD
COPD exacerbations
Only a small number of researches have directly studied the influence of exacerbations on cognitive function. In old-aged patients admitted with a non-acidotic exacerbation of COPD, MMSE scores were low but not related to 6-month mortality [48]. In another study which performed MMSE test in patients who needed mechanical ventilation during the exacerbation, there was considerably impaired cognitive function at the time of discharge, but this function had improved significantly by 6 months [49]. The P300 is an electrophysiological test used as a surrogate marker of information processing, attention and intellect memory [50]. During an exacerbation, patients with COPD were noticed to have impaired information processing and an inclination to poorer attention and memory [51]. It seems, therefore, that during exacerbation cognitive function is impaired, but may recover.
Physical activity
Some studies have revealed that physical activity is connected with both the preservation and improvement in cognitive function in COPD [52–58]. A case –control research of lung rehabilitation demonstrated that if visual attention, verbal memory and visuospatial functions were disturbed at baseline, they improved after 3 weeks of treatment. Verbal fluency enhanced considerably with exercise in a randomised control trial of non-hypoxaemic patients with COPD that evaluated exercise training plus education compared with education only [53]. Another trial evidenced improvement in verbal fluency even after as little as 20 min of physical exercise [54]. In one group of robust patients with mild COPD, 6-min walk distance and aerobics foreseen 83% of the enhancement in reasoning and problem solving (‘‘fluid intelligence’’) amongst COPD patients enrolled in short- and long-term exercise programmes [56].
Generally, there becomes evident that there is a link between cognitive function and exercise and it is essential to determine whether improved exercise gets better the cognitive function.
Vascular disease and other comorbidities
In the general population, hypertension has been connected with a more rapid decline in logical reasoning and problem solving, and diabetes has been connected with a faster decline in executive function tasks [59]. Moreover, combined risk factors for vascular disease explicated a significant percentage of the discrepancy in information processing capacity and speed, along with general cognitive status [40]. Due to the fact that over 50% of hospitalised patients with COPD have in parallel a vascular disease [60], it is expected that this will influence cognitive function. Nevertheless, the pattern of cognitive dysfunction in COPD has been demonstrated to be different to the one found in multiinfarct dementia [18], and memory has been demonstrated to be worse in patients with chronic cerebrovascular disease than in patients with COPD [61]. For that reason, it is improbable that cognitive dysfunction in COPD patients is owing to vascular comorbidity by itself.
Smoking
It is thought that besides to the higher risk of cerebral atherosclerosis, certain particles in cigarette smoke have a direct neurotoxic effect, and heavy metal components of smoke are supposed to be linked to an increased risk of Alzheimer’s disease [62, 63]. By exacerbating cerebral hypoxia due to chronically elevated carbon monoxide causing a left shift of the oxyhaemglobin dissociation curve smoking may damage cognitive function as well [3].
Smoking is a risk factor for pre-clinical changes identified on computed tomography of the brain. Longitudinal researches have found relationships with middle-age smoking and impairment of cognitive function in males over a 20-year period. Cognitive deficits connected to smoking embrace reduced processing speed, verbal memory and MMSE. However, although smoking seems to be an independent factor in cognitive dysfunction, studies have revealed associations between impaired pulmonary function and cognition that are independent of present and lifetime smoking status [41, 65].
Sleep and obstructive sleep apnoea
Sleep is considered to be important for memory, learning, attention and tracking [31, 66]. Patients with COPD experience excessive sleepiness during daytime and more than 50% of them report long sleep latency [67].
OSA could be found in 20% of subjects with COPD [68], both these conditions share a analogous profile of comorbidities [69, 70]. Moderate-to-severe OSA may be coupled with impaired cognitive performance, mainly vigilance and executive function and there is less decay in intellectual and verbal abilities [71]. Nevertheless, the increase in cognitive impairmet appears lesser than the increase in sleepiness [72].
Although the level of cognitive impairment has been reported to be comparable in OSA and COPD with deficits in complex reasoning, learning and memory, cognitive domains considered to be dependent on sleep, such as attention, were more damaged in OSA, while those considered to be affected by hypoxaemia, such as motor skills, were more damaged in COPD [73].
Age and educational level
Age and educational level are demographic variables considered to have a strong relationship with neuropsychological presentation in all populations [7].
Figure 3.3 reviews the factors considered to be important in acting on the development of cognitive dysfunction in both COPD patients and healthy subjects. It shows that, even if many factors are the same in both groups, many gather together more frequently within COPD.
Fig. 3.3 Potential factors thought to effect cognitive function in COPD.
OSA: obstructive sleep apnoea; BMI: body mass index;
TSH: thyroid stimulating hormone
ASSESSMENT OF COGNITIVE IMPAIRMENT IN COPD PATIENTS, TREATMENT AND PATIENT OUTCOMES
Complete neuropsychological assessment requires time and specialist training to conduct and interpret. An uncomplicated and concise clinical assessment would be useful to screen persons who may require further more complete neuropsychological testing. A recent study advises that the combination of an MMSE score < 24 and dependence in at least one IADL may accomplish this task [24]. Additional research is required to determine whether all COPD patients need screening or whether it could be limited to those patients who report cognitive difficulties or who have risk factors for cognitive dysfunction (hypoxemia, airflow obstruction, vascular comorbidities). Figure 4.1 (from: J.W. Dodd et al. Cognitive function in COPD European respiratory journal volume 35 number 4 919) illustrates the potential impact of treatment on cognitive function and consequent patient outcomes.
Figure 4.1 Potential impact of treatment on cognitive function
and subsequent patient outcomes
LVRS: lung volume reduction surgery; ADL: activities of daily living.
4.1. Lung volume reduction surgery
Lung volume reduction surgery has been demonstrated to improve neuropsychological function along with measures of depression, anxiety and quality of life over a period of 6 months follow-up [23], but there was no relationship between cognitive enhancement and alteration in other variables. Even after modification for differences in exercise ability and hypercapnia between the patients with LVRS and control subjects, improvement in psychomotor speed and verbal memory stayed considerable. On the other hand, the number of patients enrolled in this study was small with a test group of just 19 subjects.
Pulmonary rehabilitation/exercise
A recent meta-analysis of randomised controlled trials of physical activity in the old-aged general population revealed that a 14% expansion in aerobic activity leads to an improvement in cognitive ability, predominantly in auditory attention and motor function, as well as in processing speed and visual attention [92]. In COPD patients, evidence is incomplete, but advocate improvements in verbal fluency after 3 months [56]. It seems that suitable exercise programmes may have positive effects on cognitive functions but it is uncertain if these benefits are long term.
Oxygenation and ventilation
Acute oxygen therapy has not been demonstrated to get better neuropsychological performance [27, 90]. Longer term oxygen therapy had shown either no benefit [18, 21] or reserved cognitive improvement after administration during 6 months to hypoxaemic subjects, although a large amount of the improvement was described by practice effects [9, 15, 91]. Although oxygen therapy appears to reduce cognitive injury, it may not avoid it completely. There are some longitudinal studies performed [6, 9, 47], but as to be concludent longer follow-up periods are required with larger, more various cohorts of COPD patients.
Cognitive training
In COPD patients, cognitive training was not shown to be effective [94].
Treating comorbidities
A number of reviews tried to elucidate the impact of interventions to control diabetes, hypertension, dyslipidemia, and vitamin B12 and folate deficiencies on cognitive function. No benefit has been testified as assessed in terms of incidence of dementia or decline in cognitive function. Cognitive dysfunction was associated with low response to antidepressant therapy [80].
Patient outcomes
In general population researches, cognitive impairment has been associated with prolonged stay, mortality, discharge destination [81], instrumental activities of daily living (IADL) [82] and the management of medications [83].
Only few studies have directly examined the impact of cognitive impairment in COPD. One study suggested a relationship between poor verbal memory and mortality [6] and, in severe COPD patients, decline in verbal memory was associated with poor compliance to medications [19].
Inaccurate use of inhaler has been associated with executive dysfunction, which affects planning and sequencing [84].
A large prospective study in COPD declared no relationship between mortality and MMSE [48]; on the other hand, in another study, social isolation, number of drugs and comorbidities were the single independent factors associated with length of hospital stay following admission for exacerbation of COPD, not measures of cognitive function [85].
Cognitive dysfunctions have been linked with impairment in IADL in COPD [4], though in patients with mild cognitive deficiency prevalence of disturbed activities of daily living is low [86].
In subjects limited in activity, using oxygen supplementation, the rate of decay in cognitive function may be correlated to impairment of IADL [32]. On the other hand, an earlier study did not confirm the same relationship [87].
In summary, cognitive impairment in COPD may be related to mortality and other essential patient outcomes including functional impairment; but these relations were not constant between studies. Also, there seems to be an uncertain relationship between health status and cognitive impairment [9, 29, 49, 88, 89].
CONCLUSIONS
Cognitive function is impaired in patients with COPD as compared to healthy controls.
Patients’ cognitive impairments are significantly associated with the severity of COPD.
There is a strong association between severity of COPD as measured in relation to lung function (FEV1, FEV1/FVC) and/or blood gases (PaO2, PaCO2, SaO2) in patients with severe to very severe COPD, but no significant association in patients with moderate COPD.
Because of the presence of significant correlation between cognitive deficits and low blood oxygen levels, it seems that low blood oxygen pressure is the dominant factor that contributes to cognitive impairments in COPD, although there is evidence for multiple factors working together in causing impaired cognition in COPD.
The relationship between increased inflammatory markers in patients with COPD and decrease of the cognitive functions is caused by a series of mechanisms that need further research to be completely understood.
COPD is associated with neuronal damage or dysfunction that is separate from other comorbidities, such as vascular disease. But clear theoretical definition of “cognitive impairment” that is appropriate for patients with COPD have not been generally accepted.
Regarding cognitive domains, memory 7,8,11,16,24,27,29,31 and attention 7,8,11,15,24,27,30 are shown to be the most influenced domains in most of the studies. Also speed, coordination and learning abilities are affected,7,15,27
Cognitive dysfunction may be associated with increased mortality and disability, but despite its potential importance, it remains a poorly understood comorbidity of COPD.
A structured assessment of cognitive function should be a routine component of the evaluation of all COPD patients, independently of their severity.
As cognitive impairment might have important clinical and healthcare implications in patients with COPD more work is required to validate methods of its assessment, screening and treatment.
A better understanding of the complex nature of what causes cognitive impairments in patients with COPD could greatly benefit treatments and rehabilitation programs.
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ATTACHMENTS
Attachment 1: Abbreviations of the word combinations
Attachment 2:
Classification of airflow limitation severity according to GOLD guidelines (based on post-bronhodilatator FEV1)
Attachment 3: Some neuropsychological tests used for cognitive dysfunction
Attachment 4: Studies examining the effects of COPD on cognitive functions
Attachment 5: Montreal cognitive assessment (MoCA) test
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