Hyuk Jin Yun

Association between phthalates and externalizing behaviors and cortical thickness in children with attention deficit hyperactivity disorder.

BACKGROUND Previous studies have implicated the relationship between environmental phthalate exposure and attention deficit hyperactivity disorder (ADHD) symptoms of childhood, but no studies have been conducted in children who have a confirmed diagnosis of ADHD obtained through meticulous diagnostic testing. We aimed to determine whether phthalate metabolites in urine would be higher in children with ADHD than in those without ADHD and would correlate with symptom severity and cortical thickness in ADHD children. METHOD A cross-sectional examination of urine phthalate metabolite concentrations was performed; scores for ADHD symptoms, externalizing problems, and continuous performance tests were obtained from 180 children with ADHD, and brain-imaging data were obtained from 115 participants. For the control group, children without ADHD (N = 438) were recruited. Correlations between phthalate metabolite concentrations and clinical measures and brain cortical thickness were investigated. RESULTS Concentrations of phthalate metabolites, particularly the di(2-ethylhexyl) phthalate (DEHP) metabolite, were significantly higher in boys with ADHD than in boys without ADHD. Concentrations of the di-n-butyl phthalate (DBP) metabolite were significantly higher in the combined or hyperactive-impulsive subtypes compared to the inattentive subtype, and the metabolite was positively correlated with the severity of externalizing symptoms. Concentrations of the DEHP metabolite were negatively correlated with cortical thickness in the right middle and superior temporal gyri. CONCLUSIONS The results of this study suggest an association between phthalate concentrations and both the diagnosis and symptom severity of ADHD. Imaging findings suggest a negative impact of phthalates on regional cortical maturation in children with ADHD.

Stereotactic brain injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer's disease dementia: A phase 1 clinical trial

We conducted a phase 1 clinical trial in nine patients with mild‐to‐moderate Alzheimers disease to evaluate the safety and dose‐limiting toxicity of stereotactic brain injection of human umbilical cord blood–derived mesenchymal stem cells (hUCB‐MSCs).

Automated Sulcal Depth Measurement on Cortical Surface Reflecting Geometrical Properties of Sulci

Sulcal depth that is one of the quantitative measures of cerebral cortex has been widely used as an important marker for brain morphological studies. Several studies have employed Euclidean (EUD) or geodesic (GED) algorithms to measure sulcal depth, which have limitations that ignore sulcal geometry in highly convoluted regions and result in under or overestimated depth. In this study, we proposed an automated measurement for sulcal depth on cortical surface reflecting geometrical properties of sulci, which named the adaptive distance transform (ADT). We first defined the volume region of cerebrospinal fluid between the 3D convex hull and the cortical surface, and constructed local coordinates for that restricted region. Dijkstra’s algorithm was then used to compute the shortest paths from the convex hull to the vertices of the cortical surface based on the local coordinates, which may be the most proper approach for defining sulcal depth. We applied our algorithm to both a clinical dataset including patients with mild Alzheimer’s disease (AD) and 25 normal controls and a simulated dataset whose shape was similar to a single sulcus. The mean sulcal depth in the mild AD group was significantly lower than controls (p = 0.007, normal [mean±SD]: 7.29±0.23 mm, AD: 7.11±0.29) and the area under the receiver operating characteristic curve was relatively high, showing the value of 0.818. Results from clinical dataset that were consistent with former studies using EUD or GED demonstrated that ADT was sensitive to cortical atrophy. The robustness against inter-individual variability of ADT was highlighted through simulation dataset. ADT showed a low and constant normalized difference between the depth of the simulated data and the calculated depth, whereas EUD and GED had high and variable differences. We suggest that ADT is more robust than EUD or GED and might be a useful alternative algorithm for measuring sulcal depth.

Mesenchymal stem cells can modulate longitudinal changes in cortical thickness and its related cognitive decline in patients with multiple system atrophy

Multiple system atrophy (MSA) is an adult-onset, sporadic neurodegenerative disease. Because the prognosis of MSA is fatal, neuroprotective or regenerative strategies may be invaluable in MSA treatment. Previously, we obtained clinical and imaging evidence that mesenchymal stem cell (MSC) treatment could have a neuroprotective role in MSA patients. In the present study, we evaluated the effects of MSC therapy on longitudinal changes in subcortical deep gray matter volumes and cortical thickness and their association with cognitive performance. Clinical and imaging data were obtained from our previous randomized trial of autologous MSC in MSA patients. During 1-year follow-up, we assessed longitudinal differences in automatic segmentation-based subcortical deep gray matter volumes and vertex-wise cortical thickness between placebo (n = 15) and MSC groups (n = 11). Next, we performed correlation analysis between the changes in cortical thickness and changes in the Korean version of the Montreal Cognitive Assessment (MoCA) scores and cognitive performance of each cognitive subdomain using a multiple, comparison correction. There were no significant differences in age at baseline, age at disease onset, gender ratio, disease duration, clinical severity, MoCA score, or education level between the groups. The automated subcortical volumetric analysis revealed that the changes in subcortical deep gray matter volumes of the caudate, putamen, and thalamus did not differ significantly between the groups. The areas of cortical thinning over time in the placebo group were more extensive, including the frontal, temporal, and parietal areas, whereas these areas in the MSC group were less extensive. Correlation analysis indicated that declines in MoCA scores and phonemic fluency during the follow-up period were significantly correlated with cortical thinning of the frontal and posterior temporal areas and anterior temporal areas in MSA patients, respectively. In contrast, no significant correlations were observed in the MSC group. These results suggest that MSC treatment in patients with MSA may modulate cortical thinning over time and related cognitive performance, inferring a future therapeutic candidate for cognitive disorders.

Associations between serotonin transporter gene (SLC6A4) methylation and clinical characteristics and cortical thickness in children with ADHD.

BACKGROUND Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Additionally, environmental factors such as perinatal stress and early adversities contribute to the occurrence and severity of ADHD. Recently, DNA methylation has emerged as a mechanism that potentially mediates gene-environmental interaction effects in the aetiology and phenomenology of psychiatric disorders. Here, we investigated whether serotonin transporter gene (SLC6A4) methylation patterns were associated with clinical characteristics and regional cortical thickness in children with ADHD. METHOD In 102 children with ADHD (age 6-15 years), the methylation status of the SLC6A4 promoter was measured. Brain magnetic resonance imaging was obtained and ADHD symptoms were evaluated. RESULTS A higher methylation status of the SLC6A4 promoter was significantly associated with worse clinical presentations (more hyperactive-impulsive symptoms and more commission errors). Additionally, a negative correlation was observed between SLC6A4 methylation levels and cortical thickness values in the right occipito-temporal regions. CONCLUSIONS Our results suggest that the SLC6A4 methylation status may be associated with certain symptoms of ADHD, such as behavioural disinhibition, and related brain changes. Future studies that use a larger sample size and a control group are required to corroborate these results.

Cognitive and cortical thinning patterns of subjective cognitive decline in patients with and without Parkinson's disease

BACKGROUND Subjective cognitive decline (SCD) has gained attention as a predictor of future cognitive decline in neurodegenerative diseases. Based on the hypothesis that different pathologies may distinctly contribute to SCD, we investigated the cognitive profiles and cortical thickness of patients with SCD, with and without Parkinsons disease (PD). METHODS In total, 96 patients experiencing SCD were classified as having PD (SCD-PD(+), n = 49) or no neurological disease (SCD-PD(-), n = 47); cognitively normal subjects without SCD (n = 23) were included as controls. Neurocognitive profiles and cortical thickness were examined using standardized neuropsychological tests and magnetic resonance imaging-based analysis. RESULTS No significant differences in demographic characteristics were found among the three groups. Neuropsychological tests demonstrated that the SCD-PD(+) patients had lower semantic fluency than SCD-PD(-) patients and controls, and showed poorer performance in visual memory and confrontational naming than controls, whereas no significant difference in cognitive performance was observed between the SCD-PD(-) patients and controls. Cortical thickness analysis revealed that the SCD-PD(+) patients had focal cortical thinning in the dorsolateral prefrontal, orbitofrontal, parietal, and parahippocampal areas compared with controls. Compared with SCD-PD(-) patients, SCD-PD(+) patients had cortical thinning in the frontal, parahippocampal, and posterior cortical areas. CONCLUSION Our data show that cortical thinning and cognitive performance in patients with SCD may differ based on the presence of PD, suggesting that SCD in patients with PD reflects disease-related cortical thinning and cognitive dysfunctions more closely than SCD without PD.

Comparison of regional brain atrophy and cognitive impairment between pure akinesia with gait freezing and Richardson's syndrome

Pure akinesia with gait freezing (PAGF) is considered a clinical phenotype of progressive supranuclear palsy. The brain atrophy and cognitive deficits in PAGF are expected to be less prominent than in classical Richardsons syndrome (RS), but this hypothesis has not been explored yet. We reviewed the medical records of 28 patients with probable RS, 19 with PAGF, and 29 healthy controls, and compared cortical thickness, subcortical gray matter volume, and neuropsychological performance among the three groups. Patients with PAGF had thinner cortices in frontal, inferior parietal, and temporal areas compared with controls; however, areas of cortical thinning in PAGF patients were less extensive than those in RS patients. In PAGF patients, hippocampal, and thalamic volumes were also smaller than controls, whereas subcortical gray matter volumes in PAGF and RS patients were comparable. In a comparison of neuropsychological tests, PAGF patients had better cognitive performance in executive function, visual memory, and visuospatial function than RS patients had. These results demonstrate that cognitive impairment, cortical thinning, and subcortical gray matter atrophy in PAGF patients resemble to those in RS patients, though the severity of cortical thinning and cognitive dysfunction is milder. Our results suggest that, PAGF and RS may share same pathology but that it appears to affect a smaller proportion of the cortex in PAGF.

Topography of cortical thinning associated with white matter hyperintensities in Parkinson's disease

BACKGROUND Although white matter hyperintensities (WMHs) are associated with cognitive impairments in Parkinsons disease (PD), the relationships between WMHs and cortical atrophy in regard to cognitive impairments are unknown. Here, we investigated the topography of cortical thinning related to deep (DWMHs) and periventricular WMHs (PWMHs) and their differential impacts on cognitive performance in PD. METHODS We enrolled 87 patients with non-demented PD and evaluated WMH scores using a semi-quantitative visual rating system. The patients were divided into low-, moderate-, and high-grade groups based on WMH severity for total WMHs (TWMHs), DWMHs, and PWMHs, and cortical thickness was measured using a surface-based method according to the WMHs severity. Additionally, the correlations between WMH-associated cortical thinning and neuropsychological performance were analyzed. RESULTS The detailed neuropsychological test demonstrated that PD patients with high-grade WMHs showed poorer performance on frontal lobe-based cognitive tasks compared with those with low-grade DWMHs. The areas of cortical thinning were more extensive in patients with DWMHs, involving the entire frontal areas and restricted temporoparietal areas, whereas in patients with PWMHs, cortical thinning was localized in the small frontal areas. A multiple regression analysis of the relationships between WMH-associated cortical thickness and cognition revealed that DWMH-associated frontal thickness had an independent effect on frontal lobe-based cognition, while frontal thickness related to PWMHs did not have a significant correlation with cognitive tasks. CONCLUSIONS These data suggest that in patients with PD, DWMHs are closely coupled with decreased cortical thickness in the frontal areas and may lead to declines in executive function.

Patterns of Neuropsychological Profile and Cortical Thinning in Parkinson’s Disease with Punding

Background Punding, one of dopamine replacement treatment related complications, refers to aimless and stereotyped behaviors. To identify possible neural correlates of punding behavior in patients with Parkinson’s disease (PD), we investigated the patterns of cognitive profiles and cortical thinning. Methods Of the 186 subjects with PD screened during the study period, we prospectively enrolled 10 PD patients with punding and 43 without punding on the basis of a structured interview. We performed comprehensive neuropsychological tests and voxel-based and regions-of-interest (ROIs)-based cortical thickness analysis between PD patients with and without punding. Results The prevalence of punding in patients with PD was 5.4%. Punding behaviors were closely related to previous occupations or hobbies and showed a temporal relationship to changes of levodopa-equivalent dose (LED). Significant predisposing factors were a long duration of PD and intake of medications of PD, high total daily LED, dyskinesia, and impulse control disorder. Punding severity was correlated with LED (p = 0.029). The neurocognitive assessment revealed that PD patients with punding showed more severe cognitive deficits in the color Stroop task than did those without punding (p = 0.022). Voxel-based analysis showed that PD-punders had significant cortical thinning in the dorsolateral prefrontal area relative to controls. Additionally, ROI-based analysis revealed that cortical thinning in PD-punders relative to PD-nonpunders was localized in the prefrontal cortices, extending into orbitofrontal area. Conclusions We demonstrated that PD patients with punding performed poorly on cognitive tasks in frontal executive functions and showed severe cortical thinning in the dorsolateral prefrontal and orbitofrontal areas. These findings suggest that prefrontal modulation may be an essential component in the development of punding behavior in patients with PD.

Prediction for human intelligence using morphometric characteristics of cortical surface: partial least square analysis.

A number of imaging studies have reported neuroanatomical correlates of human intelligence with various morphological characteristics of the cerebral cortex. However, it is not yet clear whether these morphological properties of the cerebral cortex account for human intelligence. We assumed that the complex structure of the cerebral cortex could be explained effectively considering cortical thickness, surface area, sulcal depth and absolute mean curvature together. In 78 young healthy adults (age range: 17-27, male/female: 39/39), we used the full-scale intelligence quotient (FSIQ) and the cortical measurements calculated in native space from each subject to determine how much combining various cortical measures explained human intelligence. Since each cortical measure is thought to be not independent but highly inter-related, we applied partial least square (PLS) regression, which is one of the most promising multivariate analysis approaches, to overcome multicollinearity among cortical measures. Our results showed that 30% of FSIQ was explained by the first latent variable extracted from PLS regression analysis. Although it is difficult to relate the first derived latent variable with specific anatomy, we found that cortical thickness measures had a substantial impact on the PLS model supporting the most significant factor accounting for FSIQ. Our results presented here strongly suggest that the new predictor combining different morphometric properties of complex cortical structure is well suited for predicting human intelligence.