Modeling the impact of COPD on the brain

Abstract

Previous studies have shown that COPD adversely affects distant organs and body systems, including the brain. This pilot study aims to model the relationships between respiratory insufficiency and domains related to brain function, including low mood, subtly impaired cognition, systemic inflammation, and brain structural and neurochemical abnormalities. Nine healthy controls were compared with 18 age- and education-matched medically stable-COPD patients, half of whom were oxygen-dependent. Measures included depression, anxiety, cognition, health status, spirometry, oximetry at rest and during 6-minute walk, and resting plasma cytokines and soluble receptors, brain MRI, and MR spectroscopy in regions relevant to mood and cognition. ANOVA was used to compare controls with patients and with COPD subgroups (oxygen users [n = 9] and nonusers [n = 9]), and only variables showing group differences at p < or = 0.05 were included in multiple regressions controlling for age, gender, and education to develop the final model. Controls and COPD patients differed significantly in global cognition and memory, mood, and soluble TNFR1 levels but not brain structural or neurochemical measures. Multiple regressions identified pathways linking disease severity with impaired performance on sensitive cognitive processing measures, mediated through oxygen dependence, and with systemic inflammation (TNFR1), related through poor 6-minute walk performance. Oxygen desaturation with activity was related to indicators of brain tissue damage (increased frontal choline, which in turn was associated with subcortical white matter attenuation). This empirically derived model provides a conceptual framework for future studies of clinical interventions to protect the brain in patients with COPD, such as earlier oxygen supplementation for patients with desaturation during everyday activities.

Figure 1

Modeling the impact of COPD on brain function (R² shown). Stepwise multiple regressions with “backbone” variables used as predictors of outcome variables already showing COPD group differences (see text). Numbers next to lines connecting domains indicate R² for the relevant relationship. All effects shown are independent of age, education, and gender. Variable definitions Independent variables – COPD backbone: Group: COPD vs control; Health status: total score, St. Georges Respiratory Questionnaire; FEV₁: forced expiratory volume % predicted; Oxygen use: use/nonuse of supple mental oxygen; Walk distance: distance (feet) walked in 6 minutes (or to maximum tolerated, if less than 6 minutes); Desaturation with activity: resting SpO₂ minus minimum SpO₂ during walk. Dependent variables: Global cognition: total score, Dementia Rating Scale; Mood: z score combination of 17-item Hamilton Depression Scale, Patient Rated Anxiety Scale, and Patient Health Questionnaire-9; Attention: digit symbol substitution (WAIS); Chronic inflammation: soluble tumor necrosis factor receptor 1 (TNFR1); Frontal choline measured in frontal white matter by ¹H MRS; White matter changes: subcortical white matter hyperintensities on MRI FLAIR images.