Oct 1, 2013 - The latest contribution of the Rotterdam Study Group, pub- .... Vestbo J, Hurd SS, Agustà AG, Jones PW, Vogelmeier C, Anzueto A, Barnes.
Editorials Changes in Your Breathing Can Change Your Brain Multimorbidity is the development of concomitant chronic diseases caused by common risk factors, such as aging, smoking, air pollution, physical inactivity, dyslipidemia, and hypertension (1–3). The number and severity of concomitant chronic diseases increase with age (2). The most frequent multimorbidities are cardiovascular (e.g., arterial hypertension, atherosclerosis, chronic heart failure, and ischemic heart disease), metabolic (diabetes, dyslipidemia, and obesity), respiratory (chronic obstructive pulmonary disease [COPD], asthma, and pulmonary fibrosis), endocrinological (osteoporosis), and neurologic (anxiety and depression) (2). Historically, multimorbidities have been considered either systemic manifestations of chronic disorders (e.g., cachexia as a manifestation of chronic heart failure or COPD) or comorbidities of an index disease such as COPD (3). However, these considerations may be inaccurate, because multiple chronic diseases most likely develop simultaneously in response to common risk factors. Although COPD is defined as a chronic respiratory disease (4), it is just the pulmonary component of multimorbidity, because almost every patient with COPD has more than one concomitant chronic disease (5). COPD and concomitant chronic diseases (3–5) are often associated with complications of the central nervous system. Hypertension and metabolic syndrome predispose to atherosclerosis and increase the risk of cerebrovascular disease in patients with COPD (3–5). Smoking, a common risk factor for all these conditions, damages microstructural integrity of cerebral white matter and induces small-vessel disease and cognitive dysfunction (6). Likewise, COPD predisposes to atherosclerotic diseases through chronic low-grade systemic inflammation and/or hypoxia, which can lead to arterial stiffness and impaired vascular reactivity (3, 7). These vascular abnormalities may be independent risk factors for atherosclerosis that are seen even before changes in structural plaque (8). Cerebral small-vessel disease comprises a group of pathological processes that affect small arteries, arterioles, and capillaries of the brain; they can be identified by neuroimaging as lacunar infarcts, leukoaraiosis, and microbleeds (9, 10). Cerebral microbleeds (CMBs) are markers of small-vessel brain disease and correspond to microscopic hemorrhagic foci (clusters of hemosiderin-laden macrophages) (9, 10) (Figure 1). The CMBs in basal ganglia, thalamus, brainstem, and cerebellum are associated with arterial hypertension and lacunar infarcts, suggesting an underlying hypertensive vasculopathy (9, 10). In contrast, CMBs observed exclusively in lobar regions seem to be more closely related to cerebral amyloid angiopathy (9, 10). The latest contribution of the Rotterdam Study Group, published in this issue of the Journal (pp. 783–788), shows that, in a large population of elderly patients with COPD, concomitant diseases were strongly associated with CMBs in deep or infratentorial brain locations, and their incidence increased in individuals without microbleed at baseline (11). Furthermore, the follow-up demonstrated that COPD is an independent risk factor for developing deep or infratentorial CMBs. The association between COPD and CMBs remained significant after adjusting for other vascular risk factors, such as age, smoking, obesity, and glucose. Am J Respir Crit Care Med Vol 188, Iss. 7, pp 763–769, Oct 1, 2013 Internet address: www.atsjournals.org
These observations are significant. First, they complement and extend findings from two previous studies. An update of the Rotterdam study showed that the prevalence of CMBs gradually increased with age and that their presence in deep or infratentorial brain regions was associated with cardiovascular risk factors (12). A more recent study, in a small subset of COPD patients with moderate-to-severe airflow limitation, revealed widespread abnormalities in white matter and a disturbance in the functional activation of gray matter, which may contribute to cognitive dysfunction (13). The most likely mechanism of these findings is cerebral small-vessel disease. The study of specific markers and risk factors, such as CMBs, can therefore provide further insight into COPD. The Rotterdam Study Group (11) also postulated that the association of CMBs and COPD suggests the concomitant presence of atherosclerosis secondary to hypertensive vasculopathy and lipohyalinosis. The investigators linked this association with their earlier findings of an increased prevalence of carotid artery wall thickening in patients with COPD (8). COPD was an independent predictor for the presence of a lipid core and vulnerable plaques. It was hypothesized that COPD is associated with abnormalities in both large and small blood vessels. In addition, by using the GOLD 2011 COPD severity assessment grade (4), the authors showed that the prevalence of CMBs was more prominent in COPD patients with more risks, that is, group D (high symptoms, high risk). Interestingly, they also showed that prevalence of CMBs in group B (high symptoms, low risk) was not inferior to that of group C (low symptoms, high risk), suggesting similar severity of these two groups. Systemic inflammation, one of the characteristic features of COPD, together with alveolar hypoxia due to progressive airflow limitation and underlying emphysema, might contribute to vessel wall abnormalities, resulting in stiffening of arteries and arterioles (7). Inflammation in the lungs of patients with COPD might act via a model of chronic inflammatory diseases, including diabetes and rheumatoid arthritis, and obesity. In this model, proinflammatory cytokines that activate T cells and monocytes are released, inducing chronic inflammation in the vascular wall; this contributes to both microvascular and macrovascular dysfunction, and microvascular dysfunction contributes to the observed CMBs (7, 9, 10). Alternatively, lung and vascular inflammation may develop simultaneously in response to common risk factors, particularly aging and smoking. Nonetheless, the Rotterdam study has a few shortcomings. For instance, the number of CMBs was not considered. Previous studies observed a correlation between the number of CMBs and the risk of occurrence of cerebrovascular events or the development of cognitive impairment. It would be interesting to explore this correlation in COPD (13). Studies combining several markers of small-vessel disease in COPD and the use of new magnetic resonance imaging techniques, such as susceptibility-weighted imaging with very high sensitivity for detecting hemosiderin deposits, could be promising. Another shortcoming was the low percentage of patients with severe-to-very-severe COPD, including those with chronic respiratory failure, which would cover the wide spectrum of COPD. Finally, despite the investigators finding an association between the severity of spirometric airflow limitation and the severity of microbleeds, they did not measure anatomic emphysema. Anatomic emphysema, assessed by high-resolution computed
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Figure 1. The topography of cerebral microbleeds and their magnetic resonance imaging (MRI) features. Microbleeds are small collections of blood-breakdown products (hemosiderinladen macrophages) that can be seen in vivo through blood-sensitive MRI sequences. Depending on their location, microbleeds are defined as “lobar” or “deep” and reflect different pathological processes affecting the brain’s small vessels. Lobar microbleeds (left side) affect small arteries, arterioles, and capillaries in the cerebral cortex, overlying leptomeninges and the gray–white matter junction; are caused by cerebral amyloid angiopathy; reflect the accumulation of amyloid b in the vessel walls (short blue lines in the upper left box); and appear as black spots in cortical or subcortical areas in the MRI images (yellow arrows in the left lower box). Deep and infratentorial microbleeds (right side) affect deep small arterioles; are caused by hypertensive arteriopathy, including lipohyalinosis and atherosclerosis; reflect damage to small perforating end arteries (short black lines in the upper right box); and appear as black spots in the basal ganglia in the MRI images (yellow arrows in the right lower box). The prevalence of deep and infratentorial microbleeds is associated with age and with cardiovascular risk factors. Also, they seem to have effects on cognition and increase the risk of stroke. Image courtesy of Amicus Visual Solutions.
tomography, is more closely related to impaired vascular function than is the degree of airflow limitation (14). COPD is increasingly viewed as a cardiopulmonary and vascular disease (3, 7, 15). The Rotterdam study shows that concomitant diseases involve cerebrovascular structures that need to be investigated and treated as a significant component of multimorbidity. Author disclosures are available with the text of this article at www.atsjournals.org.
Roberto Rodriguez-Roisin, M.D. Servei de Pneumologia (ICT) Universitat de Barcelona Villarroel Barcelona, Spain Sara Llufriu, M.D. Neuroscience Institute Hospital Clinic Institut d’Investigacions Biomediques August Pi i Sunyer Barcelona, Spain Leonardo M. Fabbri, M.D. Department of Oncology Haematology and Respiratory Diseases University of Modena and Reggio Emilia Modena, Italy
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