Hyun Kook Lim

Regional Cortical Thickness and Subcortical Volume Changes Are Associated with Cognitive Impairments in the Drug-Naive Patients with Late-Onset Depression

Previous studies have shown an association between late-onset depression (LOD) and cognitive impairment in older adults. However, the neural correlates of this relationship are not yet clear. The aim of this study was to investigate the differences in both cortical thickness and subcortical volumes between drug-naive LOD patients and healthy controls and explore the relationship between LOD and cognitive impairments. A total of 48 elderly, drug-naive patients with LOD and 47 group-matched healthy control subjects underwent 3T MRI scanning, and the cortical thickness was compared between the groups in multiple locations, across the continuous cortical surface. The subcortical volumes were also compared on a structure-by-structure basis. Subjects with LOD exhibited significantly decreased cortical thickness in the rostral anterior cingulate cortex, the medial orbitofrontal cortex, dorsolateral prefrontal cortex, the superior and middle temporal cortex, and the posterior cingulate cortex when compared with healthy subjects (all p<0.05, false discovery rate corrected). Reduced volumes of the right hippocampus was also observed in LOD patients when compared with healthy controls (p<0.001). There were significant correlations between memory functions and cortical thickness of medial temporal, isthmus cingulate, and precuneus (p<0.001). This study was the first study to explore the relationships between the cortical thickness/subcortical volumes and cognitive impairments of drug-naive patients with LOD. These structural changes might explain the neurobiological mechanism of LOD as a risk factor of dementia.

Effect of the COMT val158met polymorphism on white matter connectivity in patients with major depressive disorder.

Cortico-limbic network dysfunction and genetic polymorphism are considered to be associated with major depressive disorder (MDD). Using diffusion tensor imaging (DTI), we investigated the relationship between catechol-O-methyltransferase (COMT) gene polymorphisms and white matter tract integrity in patients with MDD. Eighty-six patients with MDD and 62 healthy controls participated in this study. DTI and genotyping for the COMT val158met gene (rs4680) polymorphism were conducted to determine the impact of COMT polymorphisms on white matter changes in patients with MDD. Voxel-wise statistical analyses of fractional anisotropy (FA) were performed using tract-based spatial statistics (TBSS). FAs of the MDD patient group were significantly decreased in bilateral frontal forceps minor, bilateral anterior cingulum, genu of corpus callosum, left posterior cingulum, right superior longitudinal fasciculus, and right posterior thalamic radiation compared with those of healthy controls. In the MDD patient group, mean FA in subjects with the GG allele was significantly decreased in left inferior longitudinal fasciculus, bilateral middle temporal gyrus, right frontal gyrus, and right cingulum bundle area compared with subjects with the AA/AG allele. These findings suggest cortico-limbic network dysfunction in MDD. Specifically, further FA reduction was evident in MDD patients with the valine homozygote group of the COMT gene. MDD may be associated with dysfunctional white matter changes, and the valine homozygote of COMT gene may contribute to further abnormalities in these pathological changes.

Comparison of risperidone orodispersible tablet and intramuscular haloperidol in the treatment of acute psychotic agitation: a randomized open, prospective study.

Objectives: Psychotic agitation of psychiatric patients is a common manifestation that needs emergent management. Traditionally, parenteral or intramuscular injection of antipsychotics was conducted for treatment of psychotic agitation. Considering that the rapidly absorbed form of risperidone (risperidone orodispersible tablet) could be used for the agitated patient, comparison of oral risperidone and intramuscular haloperidol was performed in emergency treatment of psychotic agitation in this study. Methods: 124 patients with psychotic agitation were recruited at the emergency room or inpatient ward. They were randomly assigned to either the group of oral risperidone or intramuscular haloperidol. Efficacy of both treatments was measured and compared using the 5-item acute agitation cluster from the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) and the Clinical Global Impression-Severity of Illness Scale (CGI-S). Tolerability and safety were also compared between the two groups. Results: The PANSS-EC and CGI-S scores were significantly decreased over time in both treatment groups without any significant group difference and time by group interaction effect (F = 459.7, p < 0.0001). There were no serious adverse events in both groups. Conclusion: For the emergency treatment of psychotic agitation, risperidone orodispersible tablet was as effective and tolerable as intramuscular administration of haloperidol. Therefore, we might choose oral medication instead of intramuscular injection for treatment of patients with acute psychotic agitation.

Aberrant topographical organization in gray matter structural network in late life depression: a graph theoretical analysis.

BACKGROUND Although previous studies on late life depression (LLD) have shown morphological abnormalities in frontal-striatal-temporal areas, alterations in coordinated patterns of structural brain networks in LLD are still poorly understood. The aim of this study was to investigate differences in gray matter structural brain network between LLD and healthy controls. METHODS We used gray matter volume measurement from magnetic resonance imaging to investigate large-scale structural brain networks in 37 LLD patients and 40 normal controls. Brain networks were constructed by thresholding gray matter volume correlation matrices of 90 regions and analyzed using graph theoretical approaches. RESULTS Although both LLD and control groups showed a small-world organization of group networks, there were no differences in the clustering coefficient, the path length, and the small-world index across a wide range of network density. Compared with controls, LLD patients showed decreased nodal betweenness in the medial orbitofrontal and angular gyrus regions. In addition, LLD patients showed hub regions in superior temporal gyrus and middle cingulate gyrus, and putamen. On the other hand, the control group showed hub regions in the medial orbitofrontal gyrus, middle cingulate gyrus, and cuneus. CONCLUSION Our findings suggest that the gray matter structural networks are not globally but regionally altered in LLD patients. This multivariate structural analysis using graph theory might provide a more appropriate paradigm for understanding complicated neurobiological mechanism of LLD.

Automated hippocampal subfields segmentation in late life depression

Although a few automated hippocampal subfields segmentation methods have been developed, there has been no in vivo Magnetic Resonance Imaging (MRI) study on the hippocampal subfields volumes of Late Life Depression (LLD). The aim of this study was to investigate the hippocampal subfields volume differences between LLD subjects and healthy elderly controls using an automated hippocampal subfields segmentation technique. Thirty subjects with LLD and 30 group-matched healthy control subjects underwent 3T MRI scanning, and hippocampal subfields volumes were measured and compared between the groups. Subjects with LLD exhibited significant hippocampal volume reductions in the total hippocampus, subiculum, and Cornu Ammonis (CA) 2-3 areas compared with healthy subjects (uncorrected, p<0.001). This study is the first to elaborate the subfields volume differences of both hippocampi between controls and LLD patients. These structural changes in the hippocampal presubiculum, subiculum, and CA2-3 areas might be at the core of the underlying neurobiological mechanisms of hippocampal dysfunction in LLD.

Relationships between hippocampal shape and cognitive performances in drug-naïve patients with Alzheimer's disease

Previous studies provided hippocampal shape analysis of Alzheimers disease (AD) patients using automated segmentation techniques. However, the relationships between the hippocampal deformations and various cognitive impairments were not clear. The aim of this study was to investigate hippocampal shape changes and their relationship to cognitive impairments. Fifty-one drug-naïve patients with AD and 50 group-matched healthy control subjects underwent 3T MRI scanning, and the hippocampal volumes and deformations were compared between the groups. Additionally, we explored the correlation pattern between the hippocampal deformations and the cognitive dysfunctions in AD using the Korean version of the Consortium to Establish a Registry for Alzheimers Disease (CERAD-K). AD subjects exhibited significant hippocampal deformations in the cornu ammnonis (CA1) and subiculum areas compared to those in healthy subjects (p<0.05, false discovery rate (FDR) corrected). Significant correlations were observed between hippocampal deformations in CA1 and subiculum areas and verbal immediate recall, verbal delayed recall, verbal recognition memory, and constructional recall scores (p<0.05, FDR corrected). This study was the first to explore the relationships between hippocampal deformations and various cognitive impairments of drug-naïve patients with AD. These structural changes in hippocampal CA1 and subiculum areas might be the core of the underlying neurobiological mechanisms of hippocampal dysfunction and their relevance to the various cognitive dysfunctions in AD.

Brainstem morphological changes in Alzheimer's disease.

As brainstem nuclei are interconnected with several cortical structures and regulate several autonomic, cognitive, and behavioral functions, it might be important to place the brainstem within an important pathologic core in the progression of Alzheimer’s disease (AD). Although there have been several postmortem studies reporting neuropathological alterations of the brainstem in AD, there has been no in-vivo structural neuroimaging study of the brainstem in the patients with AD. The aim of this study was to investigate differences in the brainstem volume and shape between patients with AD and elderly normal controls. Fifty AD patients (the Clinical Dementia Rating Scale≥1) and 50 normal controls were recruited, and the brainstem volumes and deformations were compared between the AD and the controls. Patients with AD showed significant total volume [(mean±SD) 21007±1640 mm3] reduction in the brainstem compared with the controls [(mean±SD) 22530±1750 mm3] (P<0.001). In addition, AD patients showed significant brainstem deformations in the upper posterior brainstem corresponding to the midbrain compared with the healthy individuals (false discovery rate corrected P<0.05). This study is the first to explore brainstem volume change and deformations in AD. These structural changes in the midbrain areas might be at the core of the underlying neurobiological mechanisms of brainstem dysfunction with relevance to their various cognitive and behavioral symptoms such as memory impairment, sleep, and emotional disturbance in AD. However, further longitudinal studies might be needed to confirm these findings.

Three Large-Scale Functional Brain Networks from Resting-State Functional MRI in Subjects with Different Levels of Cognitive Impairment

Normal aging and to a greater degree degenerative brain diseases such as Alzheimers disease (AD), cause changes in the brains structure and function. Degenerative changes in brain structure and decline in its function are associated with declines in cognitive ability. Early detection of AD is a key priority in dementia services and research. However, depending on the disease progression, neurodegenerative manifestations, such as cerebral atrophy, are detected late in course of AD. Functional changes in the brain may be an indirect indicator of trans-synaptic activity and they usually appear prior to structural changes in AD. Resting-state functional magnetic resonance imaging (RS-fMRI) has recently been highlighted as a new technique for interrogating intrinsic functional connectivity networks. Among the majority of RS-fMRI studies, the default mode network (DMN), salience network (SN), and central executive network (CEN) gained particular focus because alterations to their functional connectivity were observed in subjects who had AD, who had mild cognitive impairment (MCI), or who were at high risk for AD. Herein, we present a review of the current research on changes in functional connectivity, as measured by RS-fMRI. We focus on the DMN, SN, and CEN to describe RS-fMRI results from three groups: normal healthy aging, MCI and AD.

Automated hippocampal subfield segmentation in amnestic mild cognitive impairments.

Although a few automated hippocampal subfield segmentation methods have been developed, the effects of amnestic mild cognitive impairment (aMCI) on the hippocampal subfield volumes on magnetic resonance imaging (MRI) are not clear. The aim of this study was to investigate the hippocampal subfield volume changes and their relationships with various neuropsychological tests in aMCI using an automated hippocampal subfield segmentation technique. Forty-five subjects with aMCI and 49 group-matched healthy control subjects underwent 3-tesla MRI scanning, and hippocampal subfield volumes were measured and compared. Additionally, we explored the correlation pattern between hippocampal subfield volumes and the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD-K) neuropsychological test scores in aMCI subjects. Subjects with aMCI exhibited significant hippocampal volume reductions in the presubiculum, subiculum and cornu ammonis 2–3 areas compared with healthy subjects. In addition, we also found significant positive correlations between presubiculum and subicular area volumes and the CERAD-K verbal and visuospatial delayed recall scores in aMCI. This study was the first to explore the relationships between hip-pocampal subfield volumes and various types of cognitive performances in aMCI. These structural changes might be at the core of the underlying neurobiological mechanisms of hippocampal dysfunction in aMCI.

Stem Cell Therapy: A Prospective Treatment for Alzheimer's Disease.

Alzheimers disease (AD) without cure remains as a serious health issue in the modern society. The major neuropathological alterations in AD are characterized by chronic neuroinflammation and neuronal loss due to neurofibrillary tangles (NFTs) of abnormally hyperphosphorylated tau, plaques of β-amyloid (Aβ) and various metabolic dysfunctions. Due to the multifaceted nature of AD pathology and our limited understanding on its etiology, AD is difficult to be treated with currently available pharmaceuticals. This unmet need, however, could be met with stem cell technology that can be engineered to replace neuronal loss in AD patients. Although stem cell therapy for AD is only in its development stages, it has vast potential uses ranging from replacement therapy to disease modelling and drug development. Current progress with stem cells in animal model studies offers promising results for the new prospective treatment for AD. This review will discuss the characteristics of AD, current progress in stem cell therapy and remaining challenges and promises in its development.