Sangha Kim

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 Alzheimers 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.

A genome-wide association study of antidepressant response in Koreans.

We conducted a three-stage genome-wide association study (GWAS) of response to antidepressant drugs in an ethnically homogeneous sample of Korean patients in untreated episodes of nonpsychotic unipolar depression, mostly of mature onset. Strict quality control was maintained in case selection, diagnosis, verification of adherence and outcome assessments. Analyzed cases completed 6 weeks of treatment with adequate plasma drug concentrations. The overall successful completion rate was 85.5%. Four candidate single-nucleotide polymorphisms (SNPs) on three chromosomes were identified by genome-wide search in the discovery sample of 481 patients who received one of four allowed selective serotonin reuptake inhibitor (SSRI) antidepressant drugs (Stage 1). In a focused replication study of 230 SSRI-treated patients, two of these four SNP candidates were confirmed (Stage 2). Analysis of the Stage 1 and Stage 2 samples combined (n=711) revealed GWAS significance (P=1.60 × 10-8) for these two SNP candidates, which were in perfect linkage disequilibrium. These two significant SNPs were confirmed also in a focused cross-replication study of 159 patients treated with the non-SSRI antidepressant drug mirtazapine (Stage 3). Analysis of the Stage 1, Stage 2 and Stage 3 samples combined (n=870) also revealed GWAS significance for these two SNPs, which was sustained after controlling for gender, age, number of previous episodes, age at onset and baseline severity (P=3.57 × 10-8). For each SNP, the response rate decreased (odds ratio=0.31, 95% confidence interval: 0.20–0.47) as a function of the number of minor alleles (non-response alleles). The two SNPs significantly associated with antidepressant response are rs7785360 and rs12698828 of the AUTS2 gene, located on chromosome 7 in 7q11.22. This gene has multiple known linkages to human psychological functions and neurobehavioral disorders. Rigorous replication efforts in other ethnic populations are recommended.

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 Alzheimers 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.

Overexpression of Cell Cycle Proteins of Peripheral Lymphocytes in Patients with Alzheimer's Disease.

Objective Biological markers for Alzheimers disease (AD) will help clinicians make objective diagnoses early during the course of dementia. Previous studies have suggested that cell cycle dysregulation begins earlier than the onset of clinical manifestations in AD. Methods We examined the lymphocyte expression of cell cycle proteins in AD patients, dementia controls (DC), and normal controls (NC). One-hundred seventeen subjects (36 AD, 31 DC, and 50 NC) were recruited. The cell cycle proteins CDK2, CDK4, CDK6, cyclin B, and cyclin D were measured in peripheral lymphocytes. Cell cycle protein expression in the three groups was compared after adjusting for age and sex. Results The levels of cell cycle proteins CDK2, CDK4, CDK6, cyclin B, and cyclin D were significantly higher in AD patients than in the NC subjects. The DC group manifested intermediate levels of cell cycle proteins compared with the AD patients and the NC subjects. The present study indicates that cell cycle proteins are upregulated in the peripheral lymphocytes of AD patients. Conclusion Cell cycle dysregulation in peripheral lymphocytes may present a promising starting point for identifying peripheral biomarkers of AD.

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

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).

Occupational Attainment as Risk Factor for Progression from Mild Cognitive Impairment to Alzheimer's Disease: A CREDOS Study.

High occupational attainment has been known as a marker of cognitive reserve. Previous studies in the general population have shown that high occupational attainment is associated with reduced risk of Alzheimers disease (AD). However, few studies have assessed the effect of occupational attainment on the clinical course of mild cognitive impairment (MCI). In this study, we evaluated whether individuals with high occupational attainment show more frequent progression from MCI to AD. Participants (n = 961) with MCI were recruited from a nationwide, hospital-based multi-center cohort, and were followed for up to 60 months (median: 17.64, interquartile range [12.36, 29.28]). We used Cox regression for competing risks to analyze the effect of occupational attainment on development of AD, treating dementia other than AD as a competing risk. Among the 961 individuals with MCI, a total of 280 (29.1%) converted to dementia during the follow-up period. The risk of progression to AD was higher in the individuals with high occupational attainment after controlling for potential confounders (hazard ratio = 1.83, 95% confidence interval = 1.25-2.69, p = 0.002). High occupational attainment in individuals with MCI is an independent risk factor for higher progression rate of MCI to AD. This result suggests that the protective effect of high occupational attainment against cognitive decline disappears in the MCI stage, and that careful assessment of occupational history can yield important clinical information for prognosis in individuals with MCI.

Deep subcortical white-matter hyperintensities independently predict depression in people with mild cognitive impairment

Background: Presence of cerebral microbleeds indicates underlying vascular brain disease and has been implicated in lobar hemorrhages and dementia. All these conditions relate to shorter survival, but it remains unknown to what extent microbleeds increase the risk of mortality. We investigated the association of microbleeds with all-cause and cause-specific mortality in the general population.Methods:We rated the brainMRI scans of 3979 Rotterdam Scan Study participants to determine presence, number, and location of microbleeds. Cox proportional hazard models, adjusted for age, sex, subcohort, vascular risk factors, and other MRI markers of cerebral vascular disease, were applied to quantify the association of microbleeds with mortality. Results: After a mean follow up of 5.2 (6 1.1) years, 172 (4.3%) persons had died. Presence of microbleeds, and particularly deep or infratentorial microbleeds, was significantly associated with an increased risk of all-cause mortality (sex-, age-, subcohort adjusted hazard ratio (HR) 2.27; CI 1.503.45), independent of vascular risk factors (HR 1.87; 95% CI 1.202.92). The presence of deep or infratentorial microbleeds strongly associated with the risk of cardiovascular related mortality (HR 4.08; CI 1.789.39). Mortality risk increased with increasing number of microbleeds. Conclusions: The presence of microbleeds, particularly those in deep or infratentorial regions and multiple microbleeds indicates an increased risk of mortality. Our data suggest that microbleeds may mark severe underlying vascular pathology associated with poorer survival.

Extrapyramidal Signs and Risk of Progression from Mild Cognitive Impairment to Dementia: A Clinical Research Center for Dementia of South Korea Study

Objective Extrapyramidal signs (EPS) are common in patients with mild cognitive impairment (MCI). However, few studies have assessed the effect of EPS on the clinical course of MCI. We aimed to evaluate whether patients with EPS show more frequent progression from MCI to Alzheimers disease (AD) and to other types of dementia. Methods Participants (n=882) with MCI were recruited, and were followed for up to 5 years. The EPS positive group was defined by the presence of at least one EPS based on a focused neurologic examination at baseline. Results A total of 234 converted to dementia during the follow-up period. The risk of progression to AD was lower in the patients with EPS after adjusting for potential confounders [hazard ratio (HR)=0.70, 95% confidence interval (CI)=0.53–0.93, p=0.01]. In contrast, the patients with EPS had a six-fold elevated risk of progression to dementia other than AD (HR=6.33, 95%CI=2.30–17.39, p<0.001). Conclusion EPS in patients with MCI is a strong risk factor for progression of MCI to non-Alzheimer dementia. The careful neurologic examination for EPS in patients with MCI can yield important clinical information for prognosis.

Comparison of neuropsychological profiles in patients with Alzheimer's disease and mixed dementia

OBJECTS We designed this study to extensively compare the neuropsychological profiles of Alzheimers disease (AD) and mixed dementia (MD) in a large multicenter cohort of patients. Specifically, we performed subgroup analyses to examine group differences associated with dementia severity. METHODS A total of 1021 AD patients and 577 MD patients were included from the Clinical Research Center for Dementia of South Korea (CREDOS) Study. All patients underwent comprehensive neuropsychological and functional ratings, as well as complete physical and neurological examinations. To avoid floor confounds, only patients with Clinical Dementia Rating (CDR) scores of 0.5-2.0 were included. RESULTS Overall, MD patients showed worse performance in frontal/executive function than those with AD. Stratification by dementia severity revealed a significant difference in global cognitive function scores between AD and MD patients only in the low severity groups (CDR 0.5). Also, MD patients showed worse performance in frontal/executive function domains in the CDR 0.5 groups whereas they had better performance in the memory domain in the CDR 1 groups than did AD patients. Additionally, AD patients showed better performance than MD patients with respect to activities of daily living at CDR levels 0.5 and 1. All differences had disappeared at the CDR 2 level of global dementia severity. CONCLUSION This study suggests that there are significant differences in neuropsychological profiles between AD and MD patients, with the pattern of this difference varying distinctively according to dementia severity.

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.