The Role of Decreased Cortical Thickness and Volume of Medial Temporal Lobe Structures in Predicting Incident Psychosis in Patients With Alzheimer's Disease: A Prospective Longitudinal MRI Study.

OBJECTIVE: To investigate the effect of decreased cortical thickness or volume of medial temporal lobe structures on the risk of incident psychosis in patients with AD. DESIGN, SETTING, AND PARTICIPANTS: This hospital-based prospective longitudinal study enrolled 109 patients with AD. All patients with AD were evaluated at 3-month intervals to investigate the effect of decreased cortical thickness or volume of medial temporal lobe structures on the risk of incident psychosis in patients with AD. OUTCOME MEASURE: The main outcome measure was time-to-progression from AD to incident psychosis. The thickness or volume of medial temporal lobe structures (i.e., the hippocampus, entorhinal cortex, and parahippocampus) were measured using magnetic resonance imaging and the Freesurfer automated segmentation pipeline at baseline. RESULTS: Multivariate Cox proportional hazards regression analysis revealed that a decreased cortical thickness or volume of medial temporal region was associated with a higher risk of incident psychosis in patients with AD. The hazard ratios for decreased cortical thickness of the left entorhinal cortex and decreased cortical volume of the right hippocampus were 4.291 (95% confidence interval [CI], 1.196-15.384) and 2.680 [(CI, 1.003-1.196]), respectively. CONCLUSION: Our study revealed that decreased cortical thickness or volume of medial temporal sub-regions is a risk factor for incident psychosis in patients with AD. A careful assessment of the thickness or volume of the medial temporal lobe structures in AD may improve early detection and intervention of psychosis in AD.

Heritability and familiality of psychopathologic dimensions in Korean families with schizophrenia.

AIM: Categorical syndromes such as schizophrenia could be a combination of many continuous mental structure phenotypes including several personality development/degeneration dimensions. This study investigated the heritability and familiality of symptom check list (SCL) psychopathologic dimensions in Korean schizophrenia linkage disequilibrium families. METHOD: We recruited 204 probands (with schizophrenia) with their parents and siblings whenever possible. We used the SCL questionnaire to measure psychopathologic dimensions. The heritability of symptomatic dimensions in 543 family members was estimated using Sequential Oligogenic Linkage Analysis Routines (SOLAR). Psychopathologic dimensions in the 543 family members were compared with those in 307 healthy unrelated controls to measure familiality on using analysis of variance (ANOVA) analysis. RESULTS: Five of the nine SCL variables were significantly heritable and were included in the subsequent analyses. The three groups (control, unaffected first-degree relative, schizophrenia patient) were found to be significantly different with regard to the expected order of average group scores for all heritable dimensions. CONCLUSION: Aberrations in several symptomatic dimensions could contribute to the complexity of schizophrenia syndrome as a result of genetic-environment coaction or interaction in spite of some limitations (recruited family, phenotyping).

Right hippocampus atrophy is independently associated with Alzheimer's disease with psychosis.

AIM: The purpose of this study was to determine whether regionally distributed medial temporal cortex thickness (or hippocampal volume) and frontal lobe volume are independently associated with the onset of Alzheimer's disease (AD) with psychosis. METHODS: We identified 26 AD patients with psychosis (AD+P) and 48 AD patients without psychosis (AD-P) from the Memory Impairment Clinic at Pusan National University Hospital in South Korea. They were matched for age, gender, duration of AD, and Clinical Dementia Rating sum of box score. All participants met the National Institute of Neurological and Communication Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria for probable AD. Psychosis was diagnosed according to Jeste and Finkel's proposed diagnostic criteria for psychosis of AD. All participants underwent 3-T magnetic resonance imaging, and 3-D magnetization-prepared rapid gradient echo sequence was acquired for each. The FreeSurfer version 5.1 software package was used to analyze cortical thickness and volume on 3-D T1 -weighted images. anova was used to investigate the differences in cortical thickness and the volume of the total frontal cortex, total temporal cortex, and subregions of the medial temporal cortex between groups after age, gender, years of education, Clinical Dementia Rating sum of box score, duration of AD, and total intracranial volume were controlled for. Furthermore, we added the total frontal volume as an additional variable to investigate whether the association between the medial temporal cortex and AD+P is independent of the frontal cortex. RESULTS: We found that both left and right hippocampal volume were smaller in AD+P than in AD-P. In particular, there was a significant difference in right hippocampal volume between the AD+P and AD-P groups after total frontal volume was added as an additional variable. CONCLUSION: We found that more severe hippocampal atrophy is associated with AD+P than with AD-P. In addition, atrophy of the right hippocampus remained significant among AD+P after adjustment for frontal volume. These findings suggest that right hippocampal atrophy is independently associated with AD+P.

Apolipoprotein E genotype modulates effects of vitamin B12 and homocysteine on grey matter volume in Alzheimer's disease.

AIMS: The aim of the present study was to investigate whether the effects of vitamin B12 and homocysteine on brain volume are influenced by apolipoprotein E (APOE) genotype. We examined the effects in each subgroup (APOE ε4 carriers and non-carriers) of Alzheimer's disease (AD) patients and healthy normal controls. METHODS: Forty participants with AD and 20 healthy normal controls were recruited from memory impairment clinics at Pusan National University Hospital in Korea. All participants were APOE genotyped and underwent magnetic resonance imaging, including 3-D volumetric images for grey matter (GM) volume. A multiple regression model integrated into statistical parametric mapping was used to see if there was any correlation between vitamin B12 or homocysteine and GM volume in each subgroup (APOE ε4 carriers and non-carriers) of AD patients and healthy normal controls. RESULTS: There was a significant positive correlation between serum concentrations of vitamin B12 and regional GM volume in APOE ε4 carriers with AD but not in non-carriers. We also found that there was a significant negative correlation between serum concentrations of homocysteine and regional GM volume in APOE ε4 non-carriers with AD but not in carriers (P < 0.001, uncorrected for multiple comparisons; extent threshold = 100 voxel). CONCLUSION: The present findings suggest that the effects of vitamin B12 and homocysteine on GM volume might be influenced by APOE genotype.

Amnestic multiple cognitive domains impairment and periventricular white matter hyperintensities are independently predictive factors progression to dementia in mild cognitive impairment.

OBJECTIVE: Mild cognitive impairment (MCI) usually represents a transitional phase between normal cognitive function and dementia, but not all people with MCI develop dementia because MCI is a clinically and etiologically heterogeneous grouping. The aim of this study was to determine whether clinical subtypes of MCI and severity of white matter hyperintensities (WMH) were associated with progression of MCI to dementia. METHOD: Our study cohort consisted of 840 patients aged 55 years or older who had a diagnosis of MCI at their baseline visit and had at least one follow-up contact after baseline. RESULTS: The results of the multivariable Cox proportional hazards model analysis revealed that both multiple domain amnestic MCI with WMH and multiple domain amnestic MCI without WMH were a significantly more likely to progress to dementia in comparison with patients with non-amnestic MCI. Logistic regression analyses showed that PWMH (periventricular white matter hyperintensities), not the deep white matter hyperintensities, was significantly associated with incident dementia. CONCLUSIONS: This study showed that mdMCI + a (-NL or -WMH) are more associated with progression to dementia. We also found that increasing severity of PWMH, not deep white matter hyperintensities, was significantly associated with incident dementia, independently of subtype of MCI. It suggests that both mdMCI + a and PWMH are good prognostic factors of progression to dementia in MCI.

Cortical atrophy, reduced integrity of white matter and cognitive impairment in subcortical vascular dementia of Binswanger type.

AIMS: An association between white matter hyperintensities (WMH) and cognitive dysfunction has long been recognized. However, subjects with identically appearing WMH on magnetic resonance imaging present with a wide variance in cognitive function ranging from normal cognition to dementia. The aim of this study was to compare cortical atrophy and integrity of white matter of patients with subcortical vascular dementia of Binswanger type (SVaD-BT) with those of the normal cognition group with WMH (ncWMH). METHODS: Eleven patients with SVaD-BT and 11 age-, sex-, education- and grade of WMH-matched ncWMH underwent magnetic resonance imaging, including 3-D volumetric images for cortical atrophy and diffusion tensor imaging for integrity of white matter. RESULTS: Compared to ncWMH, SVaD-BT patients showed cortical atrophies in frontal (i.e. frontal pole, precentral gyrus and frontal medial cortex) and occipital areas (i.e. lingual gyrus) followed by atrophies in temporal (i.e. fusiform cortex and middle temporal gyrus) areas. Along with cortical atrophies, reduced integrity with low fractional anisotropy and high mean diffusivity values in genu and splenium of the corpus callosum were detected in SVaD-BT patients. CONCLUSIONS: Our findings suggest that cognitive decline from ncWMH to SVaD-BT may be associated with cortical atrophy and reduced integrity of white matter.

The Dropout Rates and Associated Factors in Patients with Mood Disorders in Long-term Naturalistic Treatment.

Objective: Although maintenance treatment for mood disorders is important, the treatment discontinuation rate is reported to be high. This study aimed to investigate the dropout rates and associated factors in mood disorders. Methods: The patients in a mood disorder clinic (n = 535) were examined. Demographic and clinical factors, scores of psychometric scales, time to dropout from initial treatment in patients with bipolar disorder (BP) (n = 288) and depressive disorder (DD) (n = 143) were evaluated based on database of the mood disorder clinic. Results: Among the studied patients with BP and DD, 50% showed dropout in 4.05 and 2.17 years, respectively. The mean survival times were 8.90 years in bipolar disorder I (BP-I), 5.19 years in bipolar II disorder, 3.22 years in bipolar disorder not otherwise specified, 4.24 years in major depressive disorder, and 4.03 years in other depressive disorders. In the multivariate Cox proportional hazards regression model in the BP group, diagnosis BP-I was found to be significantly related to the decrease in dropout rate (hazard ratio [HR] = 0.22, p = 0.001); however, increased past suicide attempt number was significantly related to the increase in dropout rate (HR = 1.13, p = 0.017). In the DD group, none of anxiety disorders as comorbidity, increased scores of openness, and extraversion personality were related to the increase in dropout rate. Conclusion: Patients with BP, especially BP-I, showed a lower dropout rate as compared to patients with other mood disorders.

Family-based genome-wide association analysis of novelty seeking in a Korean schizophrenic population: A pilot study.

Schizophrenia (SPR) is the most devastating mental illness that causes severe deterioration in social and occupational functioning, but, the etiology remains unknown. The objective of this study is to explore the genetic underpinnings of novelty seeking behavior in schizophrenic family within the Korean population. By conducting a family-based genome-wide association study, we aim to identify potential genetic markers and variations associated with novelty seeking traits in the context of SPR. We have recruited 27 probands (with SPR) with their parents and siblings whenever possible. DNA was extracted from blood sampling of 58 individuals in 27 families and analyzed in an Illumina core exome single nucleotide polymorphism (SNP) array. A family-based association test (qFAM) was used to derive SNP association values across all chromosomes. Although none of the final 800,000 SNPs reached the genome-wide significant threshold of 8.45 × 10-7, the most significant 4 SNPs were within the 10-5 to 10-7. This study identifies genetic associations between novelty seeking behavior and SPR within families. RAPGEF5 emerges as a significant gene, along with other neuropsychiatric-related genes. Noteworthy genes like DRD4 and COMT did not show associations, possibly due to the focus on schizophrenic family. While shedding light on this complex relationship, larger studies are needed for robust conclusions and deeper mechanistic insights.

A Validation Study of Mental Health Monitoring Through a Mobile Application.

OBJECTIVE: Face-to-face evaluation is the most important in psychiatric evaluation, but smart healthcare, including non-face-to-face evaluation, can be beneficial considering the situation in which face-to-face evaluation is limited or the preventive aspect of mental illness. In this paper, we aimed to check whether mental health screening tests have the same significance as paper-based tests even when collected through mobile applications. METHODS: A smart mental healthcare screening test was conducted on the 1,327 community subjects. We measured two indicators of depression (Patient Health Questionnaire 9-item scale, PHQ-9) and anxiety (Generalized Anxiety Disorder 7-item scale, GAD-7) to check mental health conditions. RESULTS: The average Cronbach's alpha value of the PHQ-9 questionnaire was good at 0.870. As a result of PHQ-9's principal component analysis, one component with an eigenvalue of 1 or more was identified, which is suitable to be described as a single factor. The average Cronbach's alpha value of the GAD-7 was 0.919. The structural validity of the GAD-7 was confirmed through principal component analysis. CONCLUSION: Our results show that PHQ-9 and GAD-7 scales performed through mobile applications can have the same meaning as paper-based tests. Surveys using a tablet PC, or smartphone application can monitor residents' mental health and accumulate data. Based on these data, smart mental health management can check the mental health of residents and treat mental illness in connection with medical services.

Memory impairment, in mild cognitive impairment without significant cerebrovascular disease, predicts progression to Alzheimer's disease.

AIMS: Mild cognitive impairment (MCI) usually represents a transitional phase between normal cognitive function and dementia, but not all people with MCI develop dementia because MCI is a clinically and etiologically heterogeneous grouping. The aim of this study was to compare progression rates to Alzheimer's disease (AD) among various MCI subtypes which show minimal white matter ischemia. METHODS: Our study cohort consisted of 504 patients aged 55 years or older who had a diagnosis of MCI at their baseline visit, and had at least 1 follow-up contact after baseline. RESULTS: Subjects with multiple-domain MCI with amnesia (mdMCI+a) were found to be significantly more likely to progress to AD in comparison to patients with nonamnesic MCI. There was no difference in the progression rate to AD between amnesic MCI and mdMCI+a during the follow-up period. The results of the multivariable Cox proportional hazards model analysis showed the same pattern of results as described above. CONCLUSION: Subjects with mdMCI+a had a statistically significant association with progression to AD. Especially, in cases of degenerative etiologies, impairment of the memory domain is more important than impairment of multiple domains in predicting the progression to dementia.

The Relationship of Plasma Transthyretin Level with Global or Regional Amyloid Beta Burden in Subjects with Amnestic Mild Cognitive Impairment: Cross-Sectional Amyloid PET Study.

Background: To investigate the relationships of plasma transthyretin levels with amyloid beta deposition and medial temporal atrophy in amnestic mild cognitive impairment. Methods: This is a cross-sectional study of association of subjects with amnestic mild cognitive impairment. Plasma transthyretin levels, brain magnetic resonance imaging, and 18F-florbetaben positron emission tomography were simultaneously measured in subjects with amnestic mild cognitive impairment. Results: Plasma transthyretin levels were positively associated with amyloid beta deposition in global (r = 0.394, P = .009), frontal cortex (r = 0.316, P = .039), parietal cortex (r = 0.346, P = .023), temporal cortex (r = 0.372, P = .014), occipital cortex (r = 0.310, P = .043), right posterior cingulate (r = 0.350, P = .021), left precuneus (r = 0.314, P = .040), and right precuneus (r = 0.398, P = .008). No association between plasma transthyretin level and medial temporal sub-regional atrophies was found. Conclusions: Our findings of positive association of plasma transthyretin levels with global and regional amyloid beta burden suggest upregulation of transthyretin level as a reactive response to amyloid beta deposition during the early stages of the Alzheimer's disease process.

Reduced Thickness of the Anterior Cingulate Cortex as a Predictor of Amnestic-Mild Cognitive Impairment Conversion to Alzheimer's Disease with Psychosis.

BACKGROUND: A long-term follow-up study in patients with amnestic mild cognitive impairment (aMCI) is needed to elucidate the association between regional brain volume and psychopathological mechanisms of Alzheimer's disease with psychosis (AD + P). OBJECTIVE: The purpose of this study was to investigate the effect of the thickness of the angular cingulate cortex (ACC) on the risk of AD + P conversion in patients with aMCI. METHODS: This was a hospital-based prospective longitudinal study including 174 patients with aMCI. The main outcome measure was time-to-progression from aMCI to AD + P. Subregions of the ACC (rostral ACC, rACC; caudal ACC, cACC) and hippocampus (HC) were measured as regions of interest with magnetic resonance imaging and the Freesurfer analysis at baseline. Survival analysis with time to incident AD + P as an event variable was calculated with Cox proportional hazards models using the subregions of the ACC and HC as a continuous variable. RESULTS: Cox proportional hazard analyses showed that the risk of AD + P was associated with sub-regional ACC thickness but not HC volume: reduced cortical thickness of the left cACC (HR [95%CI], 0.224 [0.087-0.575], p = 0.002), right cACC (HR [95%CI], 0.318 [0.132-0.768], p = 0.011). This association of the cACC with the risk of AD also remained significant when adjusted for HC volume. CONCLUSION: We found that reduced cortical thickness of the cACC is a predictor of aMCI conversion to AD + P, independent of HC, suggesting that the ACC plays a vital role in the underlying pathogenesis of AD + P.

Psychometric Properties of Behavioral Checklist for Coping with Stress in Patients with Mood Disorders.

OBJECTIVE: Even though the importance of stress-coping, there is no reliable and valid scale to measure the stress-coping behavior yet. The purpose of this study is to explore the psychometric properties of Behavioral Checklist for Coping with Stress (BCCS). METHODS: A total of 458 subjects including healthy subjects and patients with bipolar or depressive disorders were analyzed. The reliability and validity of BCCS were examined by Chronbach's alpha and exploratory factor analysis using Principal Component Analysis. In order to evaluate criterion-related validity, the Pearson's correlation analyses between factors of BCCS and relevant scales were performed. RESULTS: BCCS showed good Chronobach's alpha (0.695-0.833) and had acceptable validity. Factor 1 and factor 4 of BCCS were negatively correlated with depression, anxiety and positivity correlated with task and problem-solving, avoidance, tension-releasing copings in common. Factor 2 and 3 were positively correlated with impulsivity, emotionality, avoidance, behavioral and verbal aggression and tension-releasing copings in common. Different from factor 2, factor 3 was positively correlated with depression, anxiety and anger-suppression. CONCLUSION: The results of this study suggest that this BCCS might be a reliable and valid scale for measuring stress-coping behaviors. This scale could facilitate research to investigate clinical implications related to behavioral stress-coping.

Smaller hippocampal volume in APOE ε4 carriers independent of amyloid-ß (Aß) burden.

OBJECTIVE: To investigate the association of the APOE ε4 genotype with hippocampal volume, independent of Aß burden. METHOD: This cross-sectional study included 71 participants with mild cognitive impairment or mild AD. All participants were divided into carriers or non-carriers of the ε4 allele. The main outcome was hippocampal volume measured using structural magnetic resonance imaging; 18F-florbetaben positron emission tomography was additionally performed to investigate the association of APOE ε4 genotype with hippocampal volumes, independently of Aß burden. Analysis of covariance was conducted to compare the differences in hippocampal volumes between carriers and non-carriers of the ε4 allele after controlling for global Aß burden or local hippocampal Aß burden. RESULTS: The APOE ε4 genotype was associated with a smaller right and total hippocampal volume (right: 3160.16 ± 365.71 vs. 3365.24 ± 434.88, p < 0.05; total: 6257.48 ± 790.60 vs. 6599.52 ± 840.58, p < 0.05), independent of Aß burden. CONCLUSION: Our findings on the association of APOEε4 genotype with hippocampal volume independent of Aß burden suggest that the APOEε4 genotype may contribute to hippocampal neurodegeneration through an Aß-independent mechanism.

Various Psychiatric Manifestation in DiGeorge Syndrome (22q11.2 Deletion Syndrome): A Case Report.

This case report aimed to describe various psychiatric manifestation and treatment course in a patient with DiGeorge syndrome. Psychiatric symptoms and treatment course in a female patient with DiGeorge syndrome were described. This patient showed psychotic symptoms, mood symptoms, and intellectual disability. As well as various psychiatric symptoms, treatment response and sensitivity of side effect by antipsychotics were different from typical characteristics in psychiatric disorders. This case suggests that the genetic defect in DiGeorge syndrome might have a great association with psychiatric problems and response of antipsychotics.

Similarities and Differences of Strategies between Bipolar and Depressive Disorders on Stress Coping.

OBJECTIVE: As coping strategies can influence the illness course of mood disorder, they could be potential targets for psychological intervention. The current study investigated the similarities and differences in stress coping styles between bipolar disorder (BD) and depressive disorder (DD). METHODS: Subjects with BD (n=135) and DD (n=100) who met the DSM-IV diagnostic criteria were included in this analysis. Coping strategies were assessed using the coping inventory for stressful situations and depressive symptoms were assessed by Beck depression inventory. RESULTS: The BD group showed significantly more avoidant and task-oriented coping than the DD group (t=2.714, p=0.007; t=2.193, p=0.039). After excluding the effect of the depressive symptoms themselves (by comparing two groups in non-depressive state), the BD group still showed significantly more avoidant and task-oriented coping than the DD group (t=2.040, p=0.045; t=2.556, p=0.013), but when the symptoms of depression get greater, the difference between BD and DD coping strategies were reduced. CONCLUSION: Subjects with BD tend to use more task and avoidant coping than DD subjects. But when the symptoms of depression get greater, the difference in coping strategies between BD and DD were reduced.

Anger-Related Characteristics According to Chronotypes in Bipolar or Depressive Disorders.

OBJECTIVE: Though anger was highly associated with eveningness in general population, there is no study on the relationship between chronotype and anger-related characteristics in bipolar or depressive disorders. This study aimed to investigate the difference of anger-related characteristics according to chronotypes in bipolar or depressive disorders. METHODS: Patients with bipolar or depressive disorders (n=238) were included in this study. Their chronotypes and anger-related characteristics were assessed with a self-evaluation of the Composite Scale of Morningness (CSM), the State Trait Anger Expression Inventory (STAXI) and the Anger Coping Scale (ACS). RESULTS: The eveningness group in patients with mood disorders showed the highest scores of anger-trait (p<0.001), anger-expression (p=0.002) and anger-in (p<0.001) in STAXI subscales, verbal aggression (p=0.010) in ACS subscales among three groups, but the morningess group showed the lowest scores of these subscales among three groups. However, there were no significant differences in all subscales of the STAXI and ACS according to diagnostic subtypes in the Friedman test. CONCLUSION: The results of this study suggested that eveningness in patients with mood disorders might be related to anger proneness and maladaptive anger coping. To manage anger emotion in the patients with mood disorders, therapeutic interventions to modulate eveningness might be helpful.

Investigation of Maternal Effects, Maternal-Fetal Interactions, and Parent-of-Origin Effects (Imprinting) for Candidate Genes Positioned on Chromosome 18q21, in Probands with Schizophrenia and their First-Degree Relatives.

OBJECTIVE: A popular design for the investigation of such effects, including effects of parent-of-origin (imprinting), maternal genotype, and maternal-fetal genotype interactions, is to collect deoxyribonucleic acid (DNA) from affected offspring and their mothers and to compare with an appropriate control sample. We investigate the effects of estimation of maternal, imprinting and interaction effects using multimodal modeling using parents and their offspring with schizophrenia in Korean population. METHODS: We have recruited 27 probands (with schizophrenia) with their parents and siblings whenever possible. We analyzed 20 SNPs of 7 neuronal genes in chromosome 18. We used EMIM analysis program for the estimation of maternal, imprinting and interaction effects using multimodal modeling. RESULTS: Of analyzed 20 single nucleotide polymorphisms (SNPs), significant SNP (rs 2276186) was suggested in EMIM analysis for child genetics effects (p=0.0225438044) and child genetic effects allowing for maternal genetic effects (p=0.0209453210) with very stringent multiple comparison Bonferroni correction. CONCLUSION: Our results are the pilot study for epigenetic study in mental disorder and help to understanding and use of EMIM statistical genetics analysis program with many limitations including small pedigree numbers.

A whole exome sequencing study of a Korean proband with idiopathic basal ganglia calcification and its daughter.

Idiopathic basal ganglia calcification (IBGC) is characterized by brain calcification and a wide variety of neurological and psychiatric symptoms. In families displaying an autosomal dominant inheritance pattern, three causative genes have been identified: SLC20A2, PDGFRB, and very recently, PDGFB. While in clinical practice sporadic presentation of IBGC is frequent, well-documented reports of true sporadic occurrences are rare. We report a case of a 61-year-old woman who presented with depressive and dystonic symptoms revealing IBGC. Her 41-year-old daughter was healthy. In the proband, we identified 4 mutations in PDGFB, and 1 exonic mutation in SLC20A2, all of which were absent in the daughter. These mutations may result in a loss-of-function of PDGF-B or SLC20A2, which has been shown to cause IBGC in humans and disrupts the blood-brain barrier in mice resulting in brain calcification. Herein, we present the occurrence of a sporadic patient of IBGC and its causative mutations.