A Pilot Study On Correlation Between Anti-inflammatory Cytokines And Cognition In The Patients With Insomnia Comorbid With Depression

BackgroundDepression is a chronic mental disorder that frequently co-occurs with other medical conditions or psychiatric illnesses.Although depression typically manifests as low mood and cognitive impairment,chronic insomnia disorder（CID）is a frequent complaint.Insomnia is not only a risk factor for depression but is also a residual symptom following its treatment,highlighting a bidirectional relationship between insomnia and depression.Additionally,cognitive deficits are present in both disorders and exacerbate cognitive impairment in patients with depression.Inflammation has been proposed as a mechanism underlying multiple chronic diseases,especially in pro-inflammatory cytokines.While the roles of other inflammatory factors such as TGF,GM-CSF,IFN,and RANTES remain unclear.ObjectTo distinguish insomnia comorbid with depression（ICD）from chronic insomnia disorder（CID）by exploring the relationship between serum levels of frequently overlooked anti-inflammatory cytokines and cognitive function.MethodsA total of 42 ICD patients,63 CID patients and 42 control subjects（CON）were recruited continuously at the Clinic of Sleep and Memory Disorder.General information was collected on each participant including sex,age,education level,body mass index（BMI）,individual history,daily life history,medical history,and family medical history.The Pittsburgh Sleep Quality Index（PSQI）and Hamilton Depression Rating Scale（HAMD）were used to assess sleep quality and depression severity,respectively.The Chinese-Beijing version of Montreal Cognitive Assessment scale（Mo CA-C）were used to assess cognitive function.The Nine-Box Maze Test（NBMT）was modified to evaluate subjects’multi-aspect memory functions,including spatial/object working memories（SWM/OWM）,spatial/object reference memories（SRM/ORM）,and object recognition memory（ORc M）.After the intervention and all other assessments had been completed,a 3-ml sample of blood was obtained from each subject the next morning between 7:30 a.m.and 8:00 a.m.,with fasting and avoidance of strenuous activity and mental stimulation.Serum levels of anti-inflammatory interleukins（IL-1RA,IL-4,IL-5,IL-10,IL-13,and IL-28A）,transforming growth factor（TGF）-β1,granulocyte-macrophage colony-stimulating factor,interferon-γ,and the chemokine regulated upon activation,normal T cell expressed and secreted（RANTES）were measured by enzyme-linked immunosorbent assay.Results1.General characteristics of the study subjects:There were no significant differences in sex ratio（c~2=2.7,P=0.3）,age（F=0.3,P=0.7）,education level（H=3.1,P=0.2）,or BMI（t=0.02,P=0.98）among the 3 groups.2.Depression severity:HAMD scores of the 3 groups differed significantly（H=108.55,P<0.001）.Pairwise comparison revealed that the ICD and CID groups had significantly higher scores than control subjects（P_s<0.001）.Additionally,the score for the ICD group was nearly 2 times higher than that of the CID group（P<0.001）.3.Sleep quality:PSQI scores differed significantly across groups（H=95.34,P<0.001）.Both the ICD and CID groups had significantly higher scores than control subjects（P_s<0.001）,although there was no significant difference between them.4.Cognitive functions:There were no significant differences in Mo CA scores among the 3 groups（H=1.85,P=0.40）.For performance in the NBMT,significant differences were observed in SRM（H=9.36,P=0.01）,SWM（H=37.60,P<0.001）,and ORc M（H=8.79,P=0.01）.The ICD group had more errors related to SRM than the CID and control groups（P=0.01;P=0.03）,with no difference between the latter 2 groups（P=1.00）.The ICD and CID groups had more errors related to SWM than controls（P_s<0.001）but there were no differences between them（P=0.56）.Only the CID group had significantly more errors related to ORc M than controls（P=0.01）.5.Serum cytokine levels:There were significant intergroup differences in serum levels of IL-1RA（H=9.85,P=0.007）,IL-4（H=15.85,P<0.001）,IL-5（H=14.77,P=0.001）,IL-10（H=31.58,P<0.001）,IL-13（H=14.37,P=0.001）,IL-28A（H=17.55,P<0.001）,and GM-CSF（H=18.37,P<0.001）.The results of multiple comparisons indicated that the ICD group had significantly lower levels of IL-1RA（P=0.01）,IL-4（P=0.03）,IL-5（P=0.02）,IL-10（P<0.001）,and IL-28A（P=0.02）than control subjects,and lower levels of IL-1RA（P=0.02）,IL-5（P=0.002）,IL-10（P<0.001）,IL-13（P=0.001）,and GM-CSF（P=0.02）than the CID group.Moreover,the CID group had elevated IL-13 and GM-CSF（P=0.03;P<0.001）and reduced IL-4 and IL-28A（P=0.001;P<0.001）levels relative to controls.6.Correlations among serum cytokine levels,depression severity,sleep quality,and cognitive function:In the ICD group,partial correlation analysis between serum cytokine levels and cognitive performance showed that IL-4 level was positively correlated with the number of errors in OWM（r=0.39,P=0.04）while IL-5 level was correlated with the number of errors in OWM（r=0.39,P=0.04）and ORc M（r=0.58,P<0.01）,IL-10 level was also positively correlated with the number of errors in 3tasks—ie,ORM（r=0.40,P=0.03）,SRM（r=0.57,P<0.01）,and ORc M（r=0.47,P=0.01）,and IL-13（r=0.51,P<0.01）and TGF-β₁（r=0.51,P<0.01）after controlling for sex,age,education,BMI,and PSQI and HAMD-17 scores.In the CID group,the identical partial correlation analysis showed that serum concentration of IL-1RA was positively correlated with ORM errors（r=0.34,P=0.01）,whereas IL-5（r=0.37,P<0.001）,IL-10（r=0.28,P=0.03）,and IL-13（r=0.40,P<0.001）levels were positively correlated with OWM errors.ConclusionICD is a distinct condition that can be distinguished from CID based on immune dysfunction and specific types of cognitive dysfunction.