The present study demonstrated impaired cognitive performance as well as elevated inflammatory cytokines (IL-6, HMGB1, Netrin-1) in patients with asthma and depression comorbidity. Moreover, we found a significant elevation in white matter lesion related indexes (MBP, MOG), one of which negatively correlated with cognitive performance. These findings provided important evidence on potential mechanism of cognitive deficit in asthmatic patients with depression.
Existing studies have recognized cognitive burden in patients with asthma.25 Specifically, asthma has a strong effect, not only on broader capacities involving academic achievement and global intellect, but also on particular cognitive domain including processing speed, executive function, attention, visuospatial functioning, language, learning, and memory.26 However, there is few research on cognition in patients with asthma and depression comorbidity. Our preliminary investigation showed that the A + D patients presented higher incidence of cognition deficit compared to patients with single asthma or depression and healthy controls. The particular vulnerable cognition domains included attention, language, abstract, orientation, visuospatial and executive function. The vulnerability of specific cognitive domains remains to be verified with more delicate neuropsychological assessments and its underlying mechanism remains to be explored.
Alterations in the immune systems are very likely to contribute to the increased risk of co-occurrence of asthma and depression.27 One study reported that the CRP level was elevated in children and adolescents with both diseases.28 Another study on gene expression of blood CD4 + T cells from comorbid patients showed that the main active pathways in depressive asthma are IL-6 and CRP signalling.29 In our study, the acute inflammatory mediator IL-6 was elevated significantly in A + D group. This finding is partly in accordance with a previous Meta-analysis illustrating that concentrations of cytokines such as IL-1, IL-4, IL-6, TNF-α were higher in depressive patients than non-depressive controls.2 Furthermore, we discovered a significant increase in HMGB1 and Netrin-1 of A + D patients. HMGB1 has been shown to involve in the diseases characterized by chronic inflammation, especially in pulmonary pathology,30 and elevate in the depressive animal models established with chronic stress.31 Considering asthma comorbid with depression could be a chronic inflammatory reaction, it would be reasonable to find increased HMGB1 in patients with both diseases. As a new anti-inflammatory factor, Netrin-1 express in both acute and chronic inflammatory response. Considerable studies have demonstrated that Netrin-1 was consumed in acute inflammation such as acute lung injury or pancreatitis, thus playing protective role by restraining inflammatory damage.32–33 Interestingly, we also found elevated Netrin-1 in asthma patients with depression. A possible explanation is that the chronic inflammatory respond in A + D group may induce a simultaneous process of compensatory protective reaction. Therefore, IL-6, HMGB1 and Netrin-1 may be sensitive indexes to reflect the activation of multiple inflammatory pathway in comorbid asthma and depression.
As cerebral white matter related index maintaining the structure and function of myelin in central nervous system, MBP and MOG have been reported to increase significantly in the peripheral blood of depressive individuals.34–35 To our knowledge, it is still lack of data on the alterations in white matter related markers in asthma patients. Our study showed that both MBP and MOG increased significantly in patients with asthma and depression comorbidity, similarly to the findings in patients with depression. The relationship between inflammation and white matter has been largely explored. Our previous work36 as well as other researches37 have demonstrated that systemic inflammation could alter the development of the white matter by blocking the maturation process of oligodendrocytes through changing the coordinated expression of several transcription factors. Given the above empirical evidence, our results on elevated MBP and MOG may suggest an important pathophysiological alteration in asthma and depression comorbidity, that is, the white matter damage.
Furthermore, our study showed that cognitive deficit was negatively correlated with MOG, indicating that white matter lesion may result in cognitive alteration in asthmatic patients with depression. This result was consistent with previous imaging study showing a negative correlation between cognition, depressive syndrome and white matter hyperintensities.38 A recent DTI study further showed that MOG correlated positively with white matter damage in depression.35 Despite a minor component of myelin sheath (0.01–0.05% of the membrane protein) compared to MBP (30% of the membrane protein),39 MOG has been exclusively expressed in oligodendrocytes in central nervous system (CNS),40 while MBP was found to additionally express in peripheral nervous system and cells of the immune system.41 We assume that MOG may be a more specific index than MBP to reflect CNS myelin injury in brain, therefore could be a more sensitive biomarker of cognitive deficit in asthma patients with comorbid depression.
The present study has some limitations. Firstly, this is a cross-sectional study therefore is unable to determine a causal relationship between cognitive deficits and inflammation or white matter injury. It would be of greater value to elucidate whether cognitive performance changes over time. Nevertheless, we observed a phenomena which could give a clue on this relationship and further research would be encouraged to conduct its potential mechanism. Secondly, we performed only MoCA as assessment tool of cognition, which is routinely a screen test for mild cognitive deficit. Complete and detailed neuropsychological assessments are encouraged such as Wechsler Intelligence Scale and other cognition battery tests which evaluate multiple cognitive domains. Thirdly, we provided evidence on white matter injuries by means of serum markers but lack of structural or functional image findings. More researches using advanced neuroimaging technic are needed to explore the unique characteristics of white matter injury in asthma and depression comorbid condition.
In conclusion, the present study identified high incidence of cognitive deficit and inflammatory cytokine levels in patients with asthma and depression comorbidity. Cerebral white matter injuries characterized by increased levels of MOG could be a potential biomarker of this process.