Network Structure of Depressive Symptomatology in Elderly with Cognitive Impairment.

Objective and objectives: Patients with cognitive disorders such as Alzheimer's disease (AD) and mild cognitive impairment (MCI) frequently exhibit depressive symptoms. Depressive symptoms can be evaluated with various measures and questionnaires. The geriatric depression scale (GDS) is a scale that can be used to measure symptoms in geriatric age. Many questionnaires sum up symptom scales. However, core symptoms of depression in these patients and connections between these symptoms have not been fully explored yet. Thus, the objectives of this study were (1) to determine core symptoms of two cognitive disorders, Alzheimer's disease and mild cognitive impairment, and (2) to investigate the network structure of depressive symptomatology in individuals with cognitive impairment in comparison with those with Alzheimer's disease. Materials and Methods: This study encompassed 5354 patients with cognitive impairments such as Alzheimer's disease (n 1889) and mild cognitive impairment (n = 3464). The geriatric depression scale, a self-administered questionnaire, was employed to assess depressive symptomatology. Using exploratory graph analysis (EGA), a network analysis was conducted, and the network structure was evaluated through regularized partial correlation models. To determine the centrality of depressive symptoms within each cohort, network parameters such as strength, betweenness, and closeness were examined. Additionally, to explore differences in the network structure between Alzheimer's disease and mild cognitive impairment groups, a network comparison test was performed. Results: In the analysis of centrality indices, "worthlessness" was identified as the most central symptom in the geriatric depression scale among patients with Alzheimer's disease, whereas "emptiness" was found to be the most central symptom in patients with mild cognitive impairment. Despite these differences in central symptoms, the comparative analysis showed no statistical difference in the overall network structure between Alzheimer's disease and mild cognitive impairment groups. Conclusions: Findings of this study could contribute to a better understanding of the manifestation of depressive symptoms in patients with cognitive impairment. These results are expected to aid in identifying and prioritizing core symptoms in these patients. Further research should be conducted to explore potential interventions tailored to these core symptoms in patients with Alzheimer's disease and mild cognitive impairment. Establishing core symptoms in those groups might have clinical importance in that appropriate treatment for neuropsychiatric symptoms in patients with cognitive impairment could help preclude progression to further impairment.

Genome-wide association study of occupational attainment as a proxy for cognitive reserve.

Occupational attainment, which represents middle-age cognitive activities, is a known proxy marker of cognitive reserve for Alzheimer's disease. Previous genome-wide association studies have identified numerous genetic variants and revealed the genetic architecture of educational attainment, another marker of cognitive reserve. However, the genetic architecture and heritability for occupational attainment remain elusive. We performed a large-scale genome-wide association study of occupational attainment with 248 847 European individuals from the UK Biobank using the proportional odds logistic mixed model method. In this analysis, we defined occupational attainment using the classified job levels formulated in the UK Standard Occupational Classification system considering the individual professional skill and academic level. We identified 30 significant loci (P < 5 × 10-8); 12 were novel variants, not associated with other traits. Among them, four lead variants were associated with genes expressed in brain tissues by expression quantitative trait loci mapping from 10 brain regions: rs13002946, rs3741368, rs11654986 and rs1627527. The single nucleotide polymorphism-based heritability was estimated to be 8.5% (standard error of the mean = 0.004) and partitioned heritability was enriched in the CNS and brain tissues. Genetic correlation analysis showed shared genetic backgrounds between occupational attainment and multiple traits, including education, intelligence, leisure activities, life satisfaction and neuropsychiatric disorders. In two-sample Mendelian randomization analysis, we demonstrated that high occupation levels were associated with reduced risk for Alzheimer's disease [odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.65-0.92 in inverse variance weighted method; OR = 0.73, 95% CI = 0.57-0.92 in the weighted median method]. This causal relationship between occupational attainment and Alzheimer's disease was robust in additional sensitivity analysis that excluded potentially pleiotropic single nucleotide polymorphisms (OR = 0.72, 95% CI = 0.57-0.91 in the inverse variance weighted method; OR = 0.72, 95% CI = 0.53-0.97 in the weighted median method). Multivariable Mendelian randomization confirmed that occupational attainment had an independent effect on the risk for Alzheimer's disease even after taking educational attainment into account (OR = 0.72, 95% CI = 0.54-0.95 in the inverse variance weighted method; OR = 0.68, 95% CI = 0.48-0.97 in the weighted median method). Overall, our analyses provide insights into the genetic architecture of occupational attainment and demonstrate that occupational attainment is a potential causal protective factor for Alzheimer's disease as a proxy marker of cognitive reserve.

Influence of antidepressant treatment on SLC6A4 methylation in Korean patients with major depression.

Genetic variation of the serotonin transporter gene (SLC6A4) has been suggested as potential mediator for antidepressant response in patients with depression. This study aimed to determine whether DNA methylation in SLC6A4 changes after antidepressant treatment and whether it affects treatment response in patients with depression. Overall, 221 Korean patients with depression completed 6 weeks of selective serotonin reuptake inhibitor (SSRI) monotherapy. DNA was extracted from venous blood pre- and post-treatment, and DNA methylation was analyzed using polymerase chain reaction. We used Wilcoxon's signed-rank test to verify the difference in methylation after treatment. Treatment response was assessed using the 17-item Hamilton Depression Rating Scale, and mRNA levels were quantified. After adjusting for relevant covariates, DNA methylation was significantly altered in specific CpG sites in SLC6A4 (p < .001 in CpG3, CpG4, and CpG5) following 6 weeks of treatment. Methylation change's magnitude (ΔDNA methylation) after drug treatment was not associated with treatment response or mRNA level change. SSRI antidepressants can influence SLC6A4 methylation in patients with depression. However, ΔDNA methylation at CpG3, CpG4, and CpG5 in SLC6A4 was not associated with treatment response. Future studies should investigate the integrative effect of other genetic variants and CpG methylation on gene transcription and antidepressant treatment response.

Alteration of transthyretin and thyroxine-binding globulin in major depressive disorder: multiple reaction monitoring-based proteomic analysis.

BACKGROUND: Major depressive disorder (MDD), common mental disorder, lacks objective diagnostic and prognosis biomarkers. The objective of this study was to perform proteomic analysis to identify proteins with changed expression levels after antidepressant treatment and investigate differences in protein expression between MDD patients and healthy individuals. METHODS: A total of 111 proteins obtained from literature review were subjected to multiple reaction monitoring (MRM)-based protein quantitation. Finally, seven proteins were quantified for plasma specimens of 10 healthy controls and 78 MDD patients (those at baseline and at 6 weeks after antidepressant treatment of either selective serotonin reuptake inhibitors (SSRIs) or mirtazapine). RESULTS: Among 78 MDD patients, 35 patients were treated with SSRIs and 43 patients were treated with mirtazapine. Nineteen (54.3%) and 16 (37.2%) patients responded to SSRIs and mirtazapine, respectively. Comparing MDD patients with healthy individuals, alteration of transthyretin was observed in MDD (P = 0.026). A few differences were observed in protein levels related to SSRIs treatment, although they were not statistically significant. Plasma thyroxine-binding globulin (TBG) was different between before and after mirtazapine treatment only in responders (P = 0.007). CONCLUSIONS: In proteomic analysis of plasma specimens from MDD patients, transthyretin and TBG levels were altered in MDD and changed after antidepressant treatment.

5-HTTLPR-rs25531 and Antidepressant Treatment Outcomes in Korean Patients with Major Depression.

INTRODUCTION: Despite the ethnic differences in 5-HTTLPR (S allele relates to better antidepressant response in Korean and Japanese people, while L allele with better response in Caucasians), it is unclear whether 5-HTTLPR and its high expression locus rs25531 are interactively associated with antidepressant treatment outcome. We investigated the individual and interaction effects of these polymorphisms on antidepressant treatment outcomes in the Korean population. METHODS: A total of 464 Korean subjects with major depressive disorder completed 6 weeks of antidepressant monotherapy. Venous blood was extracted for genotyping 5-HTTLPR and rs25531 by polymerase chain reaction and DNA sequencing. We used logistic regression analyses to verify the main and interaction effects of 5-HTTLPR and rs25531 on response and remission after antidepressant treatment. RESULTS: After adjusting for covariates, the SS genotype of 5-HTTLPR was significantly associated with better treatment outcomes (p<0.001, odds ratio [OR] [95% confidence interval (CI)]=2.435 [1.551, 3.823] in response; p<0.001, OR [95% CI]=2.912 [1.730, 4.903] in remission), while G-containing genotype (AG+GG) of rs25531 was only associated with remission (p=0.034, OR [95% CI]=2.104 [1.058, 4.181]). The interaction effect of 5-HTTLPR and rs25531 on response and remission was insignificant (all p>0.05). DISCUSSION: Our findings suggest variations in allelic frequency and functionality of 5-HTTLPR and rs25531 among the different ethnicities. We found a minor advantage of rs25531 in achieving remission. However, there was no interaction effect with 5-HTTLPR.

Fast Feedback Inhibition of Adrenocorticotropic Hormone Secretion by Endogenous Cortisol in Humans.

BACKGROUND: Using high-frequency blood sampling, we demonstrate glucocorticoid fast feedback (FF) mediated by endogenous cortisol in 6 normal humans. METHODS: We stimulated adrenocorticotropic hormone (ACTH) secretion by ovine corticotropin-releasing hormone (oCRH) with the experimental paradigm in which a high-frequency blood sampling was designed for plasma ACTH and cortisol determinations. RESULTS: We saw previously unrecognized variability in the timing of key events such as onsets of ACTH and cortisol secretion, onset and offset of FF, and in FF duration. This variability mandated analyses referenced to case-wise event times rather than referenced simply to time since oCRH administration. The mean time of FF onset was 4.0 min (range 0-9; median 3) after cortisol secretion began, and the mean FF duration was 7.5 min (range 3-18; median 6.0). The FF effect was rate-sensitive and does not reflect level-sensitive cortisol feedback. In agreement with previous estimates using hydrocortisone infusions, the rate of rise of cortisol that triggered FF was approximately 44 nmol/L/min or 1.6 µg/dL/min. FF onset followed the trigger cortisol slope with an average lag of 1 min (range 0-3; median 0). Unexpectedly, this trigger cortisol slope quickly declined within the FF period. CONCLUSIONS: This experimental design may enable new physiological studies of human FF that is mediated by endogenous cortisol, including mechanisms, reproducibility, and generalizability to other activating stimuli.

Adverse Events With Sustained-Release Donepezil in Alzheimer Disease: Relation to Body Mass Index.

PURPOSE/BACKGROUND: Sustained-release, high-dose (23 mg/d) donepezil has been approved for treatment of moderate to severe Alzheimer disease (AD). Based on a previous clinical trial, body weight of less than 55 kg is a risk factor for adverse events with donepezil 23 mg/d treatment in global population. METHODS/PROCEDURES: To clarify whether this finding is consistent across ethnic groups that vary in absolute body mass, we recruited Korean patients aged 45 to 90 years with moderate to severe AD who had been receiving standard donepezil immediate release 10 mg/d for at least 3 months. After screening, we analyzed a final cohort of 166 patients who received donepezil 23 mg/d for 24 weeks to compare the occurrence of treatment-emergent adverse events (TEAEs) between patients with high versus low body mass index (BMI) based on the World Health Organization overweight criteria for Asian populations (23 kg/m). FINDINGS/RESULTS: Treatment-emergent adverse events were reported by 79.45% of patients in the lower BMI group and 58.06% of patients in the higher BMI group (odds ratio, 2.79; 95% confidence interval, 1.39-5.63; χ = 7.58, P = 0.006). In a multivariable survival analysis, the group with lower BMI showed a higher occurrence of TEAEs (hazard ratio, 1.83; 95% confidence interval, 1.25-2.68; P = 0.002). IMPLICATIONS/CONCLUSIONS: In Korean patients with moderate to severe AD receiving high-dose donepezil over 24 weeks, TEAEs were significantly more common in those with lower BMI (not clinically overweight), especially nausea. This finding may inform clinical practice for Asian patients.

Extrapyramidal Signs and Cognitive Subdomains in Alzheimer Disease.

OBJECTIVE: Extrapyramidal signs (EPS), commonly observed in Alzheimer disease (AD), predict cognitive impairment and functional decline. This study investigated the association between EPS and five cognitive subdomains in a large number of participants with AD. DESIGN: Cross-sectional analyses of the nationwide Clinical Research of Dementia of South Korea (CREDOS) study, 2005-2012. SETTING: Multicenter clinical settings. PARTICIPANTS: 1,737 participants with AD drawn from the CREDOS study. MEASUREMENTS: The EPS group was defined by the presence of at least one EPS based on neurologic examination. We assessed five cognitive subdomains: attention, language, visuospatial function, memory, and frontal/executive function using the Seoul Neuropsychological Screening Battery-Dementia version. The associations of EPS with each cognitive subdomain were analyzed with a multiple linear regression model after controlling for confounding factors: sex, age, years of education, severity of dementia (Clinical Dementia Rating Sum of Boxes), and white matter hyperintensities. RESULTS: 164 AD participants (9.4%) had EPS. AD participants with EPS showed lower performance compared with those without EPS in two cognitive subdomains: attention and visuospatial function. The language, memory, and frontal/executive subdomains did not differ between the EPS-positive and the EPS-negative groups. In addition, we found a significant moderating relationship between EPS and deep white matter hyperintensities on visuospatial function score. CONCLUSIONS: EPS in AD are associated with severe cognitive impairment in attention and visuospatial function. Careful screening for EPS in patients with AD may assist in prediction of cognitive profile.

Factors related to prevalence, persistence, and incidence of depressive symptoms in mild cognitive impairment: vascular depression construct.

OBJECTIVE: Depression is prevalent among elders with cognitive impairment. Cerebral white matter hyperintensities (WMH) have consistently been implicated in late-life depression and in cognitive impairment. This study aims to clarify the factors related to prevalence, persistence, and new onset of depressive symptoms in subjects with mild cognitive impairment (MCI). METHODS: As part of a multicenter prospective study, the Clinical Research Center for Dementia of South Korea (CREDOS) Study, we enrolled 590 subjects diagnosed with MCI and with no prior history of depression. Depressive symptoms were assessed by the Korean version of the Geriatric Depression Scale short form (SGDS-K) at baseline and at follow-up visits. Brain magnetic resonance imaging was performed at baseline to quantify WMH using a visual rating scale. RESULTS: The baseline prevalence of clinically significant depressive symptoms (SGDS-K ≥5) was 51.4%, and this feature was associated with younger age, lower educational achievement, and higher Clinical Dementia Rating Sum of Boxes (CDR-SB) scores. Persistence of depressive symptoms across the study period was significantly associated with baseline CDR-SB and depression scores. New onset of depression (SGDS-K ≥8; incidence 15.7%) among subjects free of depressive symptoms (SGDS-K <5) at baseline was associated with severe deep subcortical, but not periventricular, WMH. CONCLUSIONS: In patients with MCI aged 50 years or older, depressive symptoms were highly prevalent. Cognitive status was closely related to both prevalence and persistence of depressive symptoms, while new onset of depression was associated with deep subcortical WMH severity in this MCI cohort. Our findings provide prospective evidence consistent with the vascular depression hypothesis. Copyright © 2015 John Wiley & Sons, Ltd.

Gender differences in risk factors for transition from mild cognitive impairment to Alzheimer's disease: A CREDOS study.

BACKGROUND: Women are subject to a disproportionate burden from Alzheimer's disease (AD) and sex differences exist in treatment response and prognosis of the disease. Yet gender-specific risk factors have not been widely studied. We aimed to investigate gender-specific risk factors for AD in subjects with mild cognitive impairment (MCI). METHODS: Participants (n=294) with MCI were recruited from a nationwide, prospective cohort study of dementia and were followed for a median (range) of 13.8 (6.0-36.0) months. Sex-stratified associations of progression to AD with baseline characteristics were explored. RESULTS: Seventy-four individuals (25.2%) developed incident dementia (67 AD) during follow-up. Significant risk factors for probable AD differed by sex. In men, the significant risk factors were severe periventricular white matter hyperintensities, and poorer global cognitive function. In women, older age, clinically significant depressive symptoms at baseline, and positive APOE ε4 alleles were the significant risk factors. CONCLUSIONS: Risk factors for progression from MCI to probable AD differed in men and women. These results may translate to gender-specific preventative or therapeutic strategies for patients with MCI.

Periventricular white matter hyperintensities and the risk of dementia: a CREDOS study.

BACKGROUND: Cerebral white matter hyperintensities (WMH) are prevalent incident findings on brain MRI scans among elderly people and have been consistently implicated in cognitive dysfunction. However, differential roles of WMH by region in cognitive function are still unclear. The aim of this study was to ascertain the differential role of regional WMH in predicting progression from mild cognitive impairment (MCI) to different subtypes of dementia. METHODS: Participants were recruited from the Clinical Research Center for Dementia of South Korea (CREDOS) study. A total of 622 participants with MCI diagnoses at baseline and follow-up evaluations were included for the analysis. Initial MRI scans were rated for WMH on a visual rating scale developed for the CREDOS. Differential effects of regional WMH in predicting incident dementia were evaluated using the Cox proportional hazards model. RESULTS: Of the 622 participants with MCI at baseline, 139 patients (22.3%) converted to all-cause dementia over a median of 14.3 (range 6.0-36.5) months. Severe periventricular WMH (PWMH) predicted incident all-cause dementia (Hazard ratio (HR) 2.22; 95% confidence interval (CI) 1.43-3.43) and Alzheimer's disease (AD) (HR 1.86; 95% CI 1.12-3.07). Subcortical vascular dementia (SVD) was predicted by both PWMH (HR 16.14; 95% CI 1.97-132.06) and DWMH (HR 8.77; 95% CI 1.77-43.49) in more severe form (≥ 10 mm). CONCLUSIONS: WMH differentially predict dementia by region and severity. Our findings suggest that PWMH may play an independent role in the pathogenesis of dementia, especially in AD.

Cognitive subdomain responses to galantamine in Alzheimer's disease.

We investigated the effects of galantamine on cognitive subdomains in Alzheimer's disease (AD). Sixty-six patients with mild-to-moderate AD received open-label galantamine for 52 weeks. Cognitive function was measured using the Korean version of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog-K). Response to galantamine was defined as "improvement or no deterioration" on the total scores of the ADAS-cog-K at 26 weeks. In the overall intent-to-treat sample, we found less cognitive decline during 26 and 52 weeks than the expected untreated course as predicted by Stern's equation. The operationally defined response rate at 26 weeks was 66.7%. The responders differed significantly from the nonresponders only in the memory and language domains but not in the domains of praxis or frontal/executive function or in secondary outcome measures of neuropsychiatric symptoms and activities of daily living. The subdomain analysis revealed an effect of galantamine on preservation of memory that was not apparent in the overall analysis. Failure to achieve responder status by 26 weeks was associated with no further possibility of response.

T-lymphocyte CREB as a potential biomarker of response to antidepressant drugs.

Response to drug treatment of major depression is variable and biomarkers of response are needed. Cyclic AMP response element binding protein (CREB) is considered a key mediator of antidepressant drug effect. We studied CREB in T-lymphocytes as a potential predictor of response to a selective serotonin reuptake inhibitor (SSRI) in 69 Korean depressed patients. We determined total CREB (tCREB), phosphorylated CREB (pCREB) and CRE-DNA binding using immunoblot and electrophoretic mobility shift assays, at baseline and after 6 wk treatment. Thirty-four healthy controls were also studied. The rate of response was 36 of 69 cases (52%). Baseline levels of tCREB and pCREB were lower in the total depressed group compared to controls (p = 0.044 and p<0.001, respectively). Baseline tCREB values in responders were significantly reduced in comparison to non-responders and to controls. After 6 wk treatment, median values of change of all CREB measures were greater in responders (36) than in non-responders (33; p<0.001 for tCREB, p = 0.003 for pCREB, and p=0.072 for CRE-DNA binding). Similar but less robust changes in CREB variables distinguished remitters from non-remitters. The optimum value of baseline tCREB predicted response with a positive predicted value of 0.778 [21/27; 95% confidence intervals (CI) 0.621-0.935], negative predictive value of 0.643 (27/42; 95% CI 0.498-0.788) and accuracy of 0.695 (48/69; 95% CI 0.586-0.804). Patients with low baseline tCREB had a significantly greater rate of response (78%) than patients with high baseline tCREB (36%), p < 0.001. Moreover, the greatest changes in tCREB with treatment were observed in subjects who did respond. This preliminary study suggests that T-lymphocytic CREB biomarkers are reduced in depressed patients and may assist in the prediction of response to SSRI drugs in depression.

Association between functional impairment, depression, and extrapyramidal signs in neuroleptic-free patients with Alzheimer disease.

BACKGROUND: Extrapyramidal signs (EPSs) are commonly observed in patients with Alzheimer disease (AD). We report here the base rate of EPS in a large cohort of patients with AD who were not receiving neuroleptic drugs, and the associations of EPS with functional outcomes and depressive symptoms. METHODS: In a consortium involving 56 clinics, we recruited 2614 patients with AD. We estimated basic activities of daily living (ADL) and instrumental ADL by the Barthel index and the Seoul-Instrumental Activities of Daily Living (S-IADL) scales, respectively. Depressive symptoms were assessed using the 15-item Geriatric Depression Scale (GDS-15). The EPS group was defined by the presence of at least 1 EPS based on a focused neurologic examination. RESULTS: The prevalence of EPS-positive patients was 12%. These had lower Korean version of the Mini-Mental State Examination (K-MMSE) scores than the EPS-negative cases (P < .001). After controlling for demographic, medical, radiological, genetic, and cognitive (K-MMSE) factors, the proportion of patients with impaired ADL was significantly higher in the EPS group than in the non-EPS group (P < .001, odds ratio = 1.90, 95% confidence interval, 1.45-2.48, and logistic regression). The S-IADL scores were significantly higher in the EPS group than this in the non-EPS group (P < .001, regression coefficient = 3.19, and median regression). The GDS-15 scores were higher in the EPS group (P = .04, regression coefficient = 0.89, and median regression). CONCLUSION: The presence of EPS in patients with AD who were not receiving neuroleptic drugs was associated with more impaired basic and instrumental ADL functioning and with greater depression symptoms.

Neurologic signs in relation to cognitive function in subcortical ischemic vascular dementia: a CREDOS (Clinical Research Center for Dementia of South Korea) study.

The objective of this study was to investigate the relationship between neurologic signs and cognitive dysfunction in subcortical ischemic vascular dementia (SIVD). 121 patients with SIVD were recruited from multiple nationwide hospitals. The patients' neurologic signs were evaluated using the Focal Neurologic Sign Score (FNSS). The FNSS scores did not correlate with the composite neuropsychology scores and Korean Mini-Mental State Examination scores. The FNSS scores correlated with the letter fluency and Rey-Osterrieth Complex Figure (ROCF) copy scores. Using a multivariate regression analysis controlled for age, sex, and educational level, the FNSS scores had a significant relationship with the letter fluency test scores (R (2) = 0.08, ß = -2.28, p = 0.02) and ROCF copy scores (R (2) = 0.08, ß = -0.42, p = 0.03). These findings suggest that the neurologic signs in patients with SIVD do not correlate with global cognitive functions; however, these signs do correlate with executive dysfunction in these patients.

Shared genetic architectures of subjective well-being in East Asian and European ancestry populations.

Subjective well-being (SWB) has been explored in European ancestral populations; however, whether the SWB genetic architecture is shared across populations remains unclear. We conducted a cross-population genome-wide association study for SWB using samples from Korean (n = 110,919) and European (n = 563,176) ancestries. Five ancestry-specific loci and twelve cross-ancestry significant genomic loci were identified. One novel locus (rs12298541 near HMGA2) associated with SWB was also identified through the European meta-analysis. Significant cross-ancestry genetic correlation for SWB between samples was observed. Polygenic risk analysis in an independent Korean cohort (n = 22,455) demonstrated transferability between populations. Significant correlations between SWB and major depressive disorder, and significant enrichment of central nervous system-related polymorphisms heritability in both ancestry populations were found. Hence, large-scale cross-ancestry genome-wide association studies can advance our understanding of SWB genetic architecture and mental health.

Additive interaction of mid- to late-life depression and cerebrovascular disease on the risk of dementia: a nationwide population-based cohort study.

BACKGROUND: Dementia is a progressive neurocognitive disease with a substantial social burden. No apparent breakthroughs in treatment options have emerged so far; thus, disease prevention is essential for at-risk populations. Depression and cerebrovascular disease (CVD) are independent risk factors for dementia, but no studies have examined their interaction effect on dementia risk. This study aimed to identify the association of depression and CVD with the risk of dementia and evaluate whether dementia risk among patients with comorbid depression and CVD is higher than the sum of the individual risk due to each condition. METHODS: A population-based cohort study was conducted to analyze the Korean National Health Insurance Service-National Sample Cohort data of all individuals over 50 years of age. Individuals who had not been diagnosed with dementia at baseline were included and followed up from January 1, 2005, to December 31, 2013. A time-varying Cox proportional hazard regression model adjusted for potential confounding factors was used for the analysis. The interaction between depression and CVD was estimated based on the attributable proportion (AP), relative excess risk due to interaction (RERI), synergy index (SI), and multiplicative-scale interaction. RESULTS: A total of 242,237 participants were included in the analytical sample, of which 12,735 (5.3%) developed dementia. Compared to that for participants without depression or CVD, the adjusted hazard ratio for the incidence of dementia for those with depression alone was 2.35 (95% confidence interval [CI] 2.21-2.49), CVD alone was 3.25 (95% CI 3.11-3.39), and comorbid depression and CVD was 5.02 (95% CI 4.66-5.42). The additive interaction between depression and CVD was statistically significant (AP-0.08, 95% CI 0.01-0.16; RERI-0.42, 95% CI 0.03-0.82; SI-1.12, 95% CI 1.01-1.24). The multiplicative interaction was significant too, but the effect was negative (0.66, 95% CI 0.60-0.73). CONCLUSIONS: In this population-based nationwide cohort with long-term follow-up, depression and CVD were associated with an increased risk of dementia, and their coexistence additively increased dementia risk more than the sum of the individual risks.

Shared Genetic Background between Parkinson's Disease and Schizophrenia: A Two-Sample Mendelian Randomization Study.

Background and objectives: Parkinson's disease (PD) and schizophrenia often share symptomatology. Psychotic symptoms are prevalent in patients with PD, and similar motor symptoms with extrapyramidal signs are frequently observed in antipsychotic-naïve patients with schizophrenia as well as premorbid families. However, few studies have examined the relationship between PD and schizophrenia. We performed this study to evaluate whether genetic variants which increase PD risk influence the risk of developing schizophrenia, and vice versa. Materials and Methods: Two-sample Mendelian randomization (TSMR) with summary statistics from large-scale genome-wide association studies (GWAS) was applied. Summary statistics were extracted for these instruments from GWAS of PD and schizophrenia; Results: We found an increase in the risk of schizophrenia per one-standard deviation (SD) increase in the genetically-predicted PD risk (inverse-variance weighted method, odds ratio = 1.10; 95% confidence interval, 1.05-1.15; p = 3.49 × 10-5). The association was consistent in sensitivity analyses, including multiple TSMR methods, analysis after removing outlier variants with potential pleiotropic effects, and analysis after applying multiple GWAS subthresholds. No relationships were evident between PD and smoking or other psychiatric disorders, including attention deficit hyperactivity disorder, autism spectrum disorder, bipolar affective disorder, major depressive disorder, Alzheimer's disease, or alcohol dependence. However, we did not find a reverse relationship; genetic variants increasing schizophrenia risk did not alter the risk of PD; Conclusions: Overall, our findings suggest that increased genetic risk of PD can be associated with increased risk of schizophrenia. This association supports the intrinsic nature of the psychotic symptom in PD rather than medication or environmental effects. Future studies for possible comorbidities and shared genetic structure between the two diseases are warranted.

Atypical Antipsychotics Augmentation in Patients with Depressive Disorder and Risk of Subsequent Dementia: A Nationwide Population-Based Cohort Study.

BACKGROUND: While atypical antipsychotic medications are widely used for treating depressive disorders, their long-term effects on the risk of subsequent dementia have not been studied adequately. OBJECTIVE: To investigate whether the risk of dementia differs according to the use of atypical antipsychotic drugs, and compare the effects of antipsychotic agents on dementia risk in individuals with late-life depressive disorders. METHODS: A nationwide population-based retrospective cohort study was conducted using data from the National Health Insurance Service-Senior Cohort of South Korea. Atypical antipsychotic dosages were standardized using a defined daily dose, and the cumulative dosage was calculated. Participants were observed from January 2008 to December 2015. Cox proportional hazard regression analysis was used to estimate the hazard ratios. RESULTS: The cohort included 43,788 elderly adults with depressive disorders: 9,901 participants (22.6%) were diagnosed with dementia. Findings showed that atypical antipsychotics were prescribed to 1,967 participants (4.5%). Compared with non-users, users of atypical antipsychotics experienced a significantly higher risk for dementia with an adjusted hazard ratio (aHR) of 1.541 (95% confidence interval [CI], 1.415-1.678). A cumulative dose-response relationship was observed (test for trend, p < 0.0001). Among atypical antipsychotics, risperidone displayed the highest risk for dementia (aHR 1.767, [95% CI, 1.555-2.009]). CONCLUSION: In this study of elderly individuals with depressive disorders, atypical antipsychotic use was associated with a significantly higher risk of subsequent dementia. Healthcare professionals should be aware of this potential long-term risk. A limitation that should be mentioned is that we could not exclude patients with bipolar depression.

Whole-genome sequencing reveals KRTAP1-1 as a novel genetic variant associated with antidepressant treatment outcomes.

Achieving remission following initial antidepressant therapy in patients with major depressive disorder (MDD) is an important clinical result. Making predictions based on genetic markers holds promise for improving the remission rate. However, genetic variants found in previous genetic studies do not provide robust evidence to aid pharmacogenetic decision-making in clinical settings. Thus, the objective of this study was to perform whole-genome sequencing (WGS) using genomic DNA to identify genetic variants associated with the treatment outcomes of selective serotonin reuptake inhibitors (SSRIs). We performed WGS on 100 patients with MDD who were treated with escitalopram (discovery set: 36 remitted and 64 non-remitted). The findings were applied to an additional 553 patients with MDD who were treated with SSRIs (replication set: 185 remitted and 368 non-remitted). A novel loss-of-function variant (rs3213755) in keratin-associated protein 1-1 (KRTAP1-1) was identified in this study. This rs3213755 variant was significantly associated with remission following antidepressant treatment (p = 0.0184, OR 3.09, 95% confidence interval [CI] 1.22-7.80 in the discovery set; p = 0.00269, OR 1.75, 95% CI 1.22-2.53 in the replication set). Moreover, the expression level of KRTAP1-1 in surgically resected human temporal lobe samples was significantly associated with the rs3213755 genotype. WGS studies on a larger sample size in various ethnic groups are needed to investigate genetic markers useful in the pharmacogenetic prediction of remission following antidepressant treatment.