| BACKGROUNDDepression is one of the most common mental disorders in clinics. It is characterized by pervasive, and persistent low mood that is accompanied by somatic and cognitive changes which impact individual’s capacity of functioning significantly. Meanwhile, depression is a serious mental disorder with high relapse rate, and could lead to social dysfunction, reduced quality of life and increased mortality. Currently, depression is considered to be the second leading illness that causes disability worldwide. It is expected in 2030, depression would be the second leading cause of disease burden following AIDS. The depression diagnosis is made through clinic interviews and observations based on the assessment of patient’s behavioral symptoms. No effective physiological or biochemical markers are available to help clinician make diagnosis. It is noteworthy that the current first-line antidepressant treatment (Selective Serotonin Reuptake Inhibitor, SSRI) only works in around 50% of the depressive patients and it is difficult to predict or monitor drug response and efficacy. Although many hypotheses are established trying to explain the etiology of depression, none of these theories could explain the pathophysiology of depression sufficiently. Thus, there is an increasing need for the pathophysiological and eiological research on depression.Cognitive dysfunction is an important feature of depression and cognitive symptoms are part of the DSM-IV definition of depression. Studies have shown that neurocognitive deficits in patients with depression in several cognitive domains, including executive function, attention and concentration conversion, memory, visual-spatial processing, and psychomotor function. Moreover, cognitive dysfunction has also been proposed to precede depression and to persist after complete recovery. Furthermore, the cognitive function in patients with recurrent depression declines gradually after each episode of depression. Given the important role of cognitive dysfunction plays in a persistent dysfunction in depression, cognitive dysfunction drew increasing research attention in depression. Recently, cognitive dysfunction has been suggested as the new target for developing depression therapy. The KIBRA protein, encoded by KIBRA, is implicated in synaptic plasticity and memory maintenance. The relationship between KIBRA polymorphism rs17070145 and episodic memory has been focused on healthy individuals and has been replicated in several studies.The high disease burden caused by depression is partly attributed to the comorbidity of depression with other physical diseases, especially aging-related diseases, such as cardiovascular disease, diabetes and dementia. Compared to single disease, the comorbidity with depression lead to increased mortality and economic cost and more serious functional disability. In recent years, telomere biology has been studied in a number of psychiatric disorders, including depression. Telomeres are protective protein-DNA complex located at the end of each chromosome. Telomeres are shortened during each cell division, and it is considered as a biomarker for cellular aging. Increasing studies have related elevated morbidity and mortality of aging-related somatic diseases to telomere shortening. Based on that, studies have tested the hypothesis that accelarated telomere attrition is a molecular signature of depression although with mixed results. In most studies, the environmental stressors were rarely considered for the relationship between depression and telomere length (TL). It is well documented that accumulated chronic stress can accelerate leukocyte telomere shortening. On the other hand, since chronic stress are always overrepresented in depression, the association between depression and TL attrition might be overestimated. Therefore, adjusting for the stressors might improve the assessment of the relationship between depressive status and TL,OBJECTIVESIn study I, the relationship between KIBRA polymorphism rs17070145 and cognitive function was explored, for the first time to our knowledge, in individuals with major depression. In study II, we used path analysis to investigate the statistical relationships between a stressful experience in childhood and recent adulthood, depressive status and telomere length, and explored if social interaction and coping strategies acted as mediators.METHODSThe study subjects derived from a longitudinal population-based cohort study-Psykiskhalsa, Arbete, RelaTioner (PART), aimed at identifying risk and protective factors for mental health in Stockholm County, Sweden. Epidemiological data have been collected three times:wave I (1998-2000), wave Ⅱ (2001-2003) and wave Ⅲ (2010-2011). A subsample was selected for semi-structured psychiatric interview according to Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and a neurocognitive test battery was administered. DNA samples used in present studies were extracted from saliva samples which were collected four years after wave Ⅱ. The depressive status of participants were assessed using the Major Depression Inventory (MDI). MDI has been validated in clinical and outpatient settings, and the total score of the MDI is a validated statistic to measure severity of depression states.In study I,338 individuals with major depression and 1776 healthy controls were genotyped for rs 17070145. Cognitive function was assessed by (ⅰ) a self-rated questionnaire on concentration difficulties and (ⅱ) a cognitive test battery covering four cognitive domains: episodic memory, phonemic fluency, psychomotor speed and executive function. The latter was administered to a subsample (n=105 with major depression).In study Ⅱ, only participants who are 60 years old or younger at the saliva sampling were included. In the controls, a subsample was initially randomly picked and thereafter slightly modified to obtain a Mean and Standard deviation (SD) for age, as well as an equal proportion of females, as in the depression group. Relative TL was determined using quantitative PCR. Finally, the telomere length was tested in 337 depressive individuals and 574 controls. The mean values of wave 1 and 2 were used for all the psychosocial variables involved in present study. The sociodemographic variables and possible confounders that were suggested to influence telomere length in previous studies were derived from wave Ⅱ, which was much closer to saliva collection. Theoretical model was established based on previous studies and fitted in males and females respectively.RESULTSIn study I, we first associated concentration difficulties and the two core symptoms of depression, specifically sadness and loss of interest, to the KIBRA rs 17070145 genotype. The C-carriers tended to report less concentration difficulties than those with TT even after adjusting for age, gender and education level (F(1,338)=3.91,η2=0.012,η=0.049). No association was found between rs 17070145 and the core depression symptoms (p>0.15). Compared with TT homozygotes, depressive individuals carrying at least one C allele showed better performance, especially in cued recall and phonemic fluency tasks (F (1,105)=5.10, η2=0.048,p=0.026; F(1,105)=7.37,η2=0.069,p=0.008).In study II, we found that both stressors, i.e. childhood adversity (CA) and negative life events (NLE), associated significantly with depression and TL, and also with social interaction and the coping strategies in the expected direction. We tested the statistic relationship between stressors, depressive status and telomere length using path analysis in model Ⅰ. In both sexes, 29% of the variance of depressive status could be explained by CA and NLE (p=0.001). In females,2% of the variance in TL was explained by the model variables (p=0.022), in which depressive status and age indicated direct negative effects and both CA and NLE had indirect negative effects on TL. For males however, no direct and indirect effects were found. In model Ⅱ, we introduced social interaction and coping strategy as mediators. In females, as in Model 1, only depressive status and age showed direct effects on TL, but a presence of mediation effects of social interaction or coping strategy was not supported. While in males, the mediation effects of social interaction and worry coping were significant. Thus, the CA, NLE and depressive status showed significant indirect effect on TL (indirect effectCA:β=-0.061,SE=0.014,p=0.006; indirect effectNLE:β=-0.044, SE=0.027,p=0.066; indirect effectdep: β=-0.12, SE=0.043,β=0.002).CONLUSIONSThe results from study Ⅰ suggested that KIBRA polymorphism rs 17070145 associated with cognitive function in adults with major depression, with a direction of the association similar to that reported from patients with subjective memory complaints. To be specific, compared to C carriers of depression, TT homozygotes reported more difficulties in concentration and performed worse in cognitive tasks. The results suggested us to pay more attention on improving the cognitive function of TT carriers with depression. To confirm these results, replication in larger samples set is needed.Our findings clarified the relationship between stress, depressive status and telomere length in study Ⅱ. The result suggested that chronic stress contributed to depressive state and in turn accelerated telomere erosion. Social interaction and coping strategy played a mediating role in males. Our study adds evidence supporting previous studies that depression was associated with accelerated telomere shortening and this effect was independent of stress. Present findings suggest possible pathways of intervention improving the prognosis of depression, especially in males. |
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