Publications by authors named "Jee Hoon Roh"

48 Publications

Clinical Evaluation of 18F-PI-2620 as a Potent PET Radiotracer Imaging Tau Protein in Alzheimer Disease and Other Neurodegenerative Diseases Compared With 18F-THK-5351.

Clin Nucl Med 2020 Nov;45(11):841-847

From the Departments of Nuclear Medicine.

Purpose: PET is a useful tool for detecting the presence and extent of brain tau accumulation. However, most first-generation tau PET tracers are limited for high off-target binding and detection of tau in non-Alzheimer disease (AD). This study evaluated potential clinical applications of F-PI-2620 as a novel PET tracer with a high binding affinity for tau deposition in AD and non-AD tauopathies.

Methods: Twenty-six participants diagnosed with either mild cognitive impairment, probable AD, frontotemporal dementia, or parkinsonism, as well as healthy controls underwent a 60- to 90-minute brain PET scan after 7 mci (259 MBq) injection of F-PI-2620. Some participants had previous PET scans using F-THK-5351 or F-FP-CIT for dopamine transporter imaging.

Results: All participants showed no increase in off-target binding in basal ganglia on F-PI-2620 PET images, as noted for first-generation tau tracers. Aβ+ mild cognitive impairment or AD patients showed diverse cortical F-PI-2620 uptake in frontotemporoparietal cortex that correlated with Mini-Mental Status Examination (ρ = -0.692, P = 0.013). Aβ+ Parkinson disease with dementia and (Aβ unknown) primary progressive aphasia patients also showed increased F-PI-2620 uptakes in the frontotemporoparietal cortex. Patients with parkinsonism showed increased uptakes in the pallidum compared with Aβ- healthy controls (left: 1.41 ± 0.14 vs 1.04 ± 0.13, P = 0.014; right: 1.18 ± 0.16 vs 0.95 ± 0.07, P = 0.014).

Conclusions: F-PI-2620 PET might be a sensitive tool to detect cortical tau deposits in patients with Aβ+ AD and Aβ+ non-AD tauopathies. Furthermore, this study showed that "off-target" binding in the basal ganglia does not affect F-PI-2620.
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http://dx.doi.org/10.1097/RLU.0000000000003261DOI Listing
November 2020

Executive Summary of the 2019 International Conference of Korean Dementia Association: Exploring the Novel Concept of Alzheimer's Disease and Other Dementia: a Report from the Academic Committee of the Korean Dementia Association.

Dement Neurocogn Disord 2020 Jun;19(2):39-53

Department of Bionano Technology, Gachon University, Seongnam, Korea.

Because of repeated failures of clinical trials, the concept of Alzheimer's disease (AD) has been changing rapidly in recent years. As suggested by the National Institute on Aging and the Alzheimer's Association Research Framework, the diagnosis and classification of AD is now based on biomarkers rather than on symptoms, allowing more accurate identification of proper candidates for clinical trials by pathogenesis and disease stage. Recent development in neuroimaging has provided a way to reveal the complex dynamics of amyloid and tau in the brain , and studies of blood biomarkers are taking another leap forward in diagnosis and treatment of AD. In the field of basic and translational research, the development of animal models and a deeper understanding of the role of neuroinflammation are taking a step closer to clarifying the pathogenesis of AD. Development of big data and the Internet of Things is also incorporating dementia care and research into other aspects. Large-scale genetic research has identified genetic abnormalities that can provide a foundation for precision medicine along with the aforementioned digital technologies. Through the first international conference of the Korean Dementia Association, experts from all over the world gathered to exchange opinions with association members on these topics. The Academic Committee of the Korean Dementia Association briefly summarizes the contents of the lectures to convey the depth of the conference and discussions. This will be an important milestone in understanding the latest trends in AD's pathogenesis, diagnostic and therapeutic research and in establishing a future direction.
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http://dx.doi.org/10.12779/dnd.2020.19.2.39DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326615PMC
June 2020

Pathological manifestation of the induced pluripotent stem cell-derived cortical neurons from an early-onset Alzheimer's disease patient carrying a presenilin-1 mutation (S170F).

Cell Prolif 2020 Apr 25;53(4):e12798. Epub 2020 Mar 25.

Department of Biomedical Science, CHA Stem Cell Institute, CHA University, Seongnam-si, Korea.

Objectives: Alzheimer's disease (AD) is the most common neurodegenerative disease which is characterized by the formation of amyloid beta (Aβ) plaques and neurofibrillary tangles. These abnormal proteins induce disturbance in mitochondrial dynamics and defect in autophagy system. Since presenilin-1 (PS1) is a core component in γ-secretase complex, the mutations of PS1 gene cause the interference of γ-secretase activity and lead to the increased Aβ secretion. We aimed to characterize the patient-specific induced pluripotent stem cell (iPSC) line carrying PS1-S170F mutation. Furthermore, we tested whether disease-modifying drug can reduce AD pathology in the AD iPSC-derived neurons.

Materials And Methods: Mononuclear cells (MNCs) were isolated freshly from the peripheral blood of an autosomal dominant AD (ADAD) patient carrying presenilin-1 (PS1) mutation (Ser170Phe; PS1-S170F) and a cognitively normal control. We generated induced pluripotent stem cell (iPSC) lines, which were differentiated into functional cortical neurons. Then, we measured the markers indicative of AD pathogenesis using immunocytochemistry and Western blot. We also investigated the mitochondrial dynamics in the AD iPSC-derived neurons using Mito-tracker.

Results: We observed that both extracellular and intracellular Aβ levels were dramatically increased in the PS1-S170F iPSC-derived neurons, compared with the control iPSC-derived neurons. Furthermore, PS1-S170F iPSC-derived neurons showed high expression levels of p-Tau, which were detected both in the soma and neurites. The mitochondrial velocity in the PS1-S170F iPSC-derived neurons was much reduced, compared with that of the control. We also found a significant decrease of fusion-related protein Mfn1 (membrane proteins mitofusin 1) and an increase of fission-related protein DRP1 (dynamin-related protein 1) in the PS1-S170F iPSC-derived neurons. We further observed the defects of autophagy-related clearance in the PS1-S170F iPSC-derived neurons. Finally, we demonstrated the levels of Aβ and p-Tau can be dramatically reduced by the treatment of LY-2886721, a BACE1 inhibitor.

Conclusions: Taken together, we have established and characterized the pathological features of an AD patient carrying PS1-S170F mutation using iPSC technology, which will be the first case on this mutation and this iPSC line will serve as a useful resource for studying AD pathogenesis and drug screening in the future.
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http://dx.doi.org/10.1111/cpr.12798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162796PMC
April 2020

Intra-individual correlations between quantitative THK-5351 PET and MRI-derived cortical volume in Alzheimer's disease differ according to disease severity and amyloid positivity.

PLoS One 2019 13;14(12):e0226265. Epub 2019 Dec 13.

Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

Purpose: To assess the in vivo whole-brain relationship between uptake of [18F]THK-5351 on PET and cortical atrophy on structural MRI according to the presence and severity of Alzheimer's disease (AD).

Materials And Methods: Sixty-five participants (21 normal controls, 32 mild cognitive impairment [MCI] subjects, and 12 AD patients) were enrolled from a prospective multicenter clinical trial (NCT02656498). Structural MRI and [18F]THK-5351 PET were performed within a 2-month interval. Cortical volume and standardized uptake value ratios (SUVR) were calculated from MRI and PET images, respectively, for 35 FreeSurfer-derived cortical regions. Pearson's correlation coefficients between SUVR and cortical volume were calculated for the same regions, and correlated regions were compared according to disease severity and β-amyloid PET positivity.

Results: No significantly correlated regions were found in the normal controls. Negative correlations between SUVR and cortical volume were found in the MCI and AD groups, mainly in limbic locations in MCI and isocortical locations in AD. The AD group exhibited stronger correlations (r = -0.576-0.781) than the MCI group (r = 0.368-0.571). Hippocampal atrophy did not show any correlation with SUVR in the β-amyloid PET-negative group, but negatively correlated with SUVR (r = -0.494, P = .012) in the β-amyloid PET-positive group.

Conclusions: Regional THK-5351 uptake correlated more strongly with cortical atrophy in AD compared with MCI, thereby demonstrating a close relationship between the neuro-pathologic process and cortical atrophy. Hippocampal atrophy was associated with both β-amyloid and THK-5351 uptake, possibly reflecting an interaction between β-amyloid and tau deposition in the neurodegeneration process.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226265PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910674PMC
April 2020

The clinical feasibility of deep learning-based classification of amyloid PET images in visually equivocal cases.

Eur J Nucl Med Mol Imaging 2020 02 6;47(2):332-341. Epub 2019 Dec 6.

Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.

Purpose: Although most deep learning (DL) studies have reported excellent classification accuracy, these studies usually target typical Alzheimer's disease (AD) and normal cognition (NC) for which conventional visual assessment performs well. A clinically relevant issue is the selection of high-risk subjects who need active surveillance among equivocal cases. We validated the clinical feasibility of DL compared with visual rating or quantitative measurement for assessing the diagnosis and prognosis of subjects with equivocal amyloid scans.

Methods: F-florbetaben scans of 430 cases (85 NC, 233 mild cognitive impairment, and 112 AD) were assessed through visual rating-based, quantification-based, and DL-based methods. DL was trained using 280 two-dimensional PET images (80%) and tested by randomly assigning the remaining (70 cases, 20%) cases and a clinical validation set of 54 equivocal cases. In the equivocal cases, we assessed the agreement among the visual rating, quantification, and DL and compared the clinical outcome according to each modality-based amyloid status.

Results: The visual reading was positive in 175 cases, equivocal in 54 cases, and negative in 201 cases. The composite SUVR cutoff value was 1.32 (AUC 0.99). The subject-level performance of DL using the test set was 100%. Among the 54 equivocal cases, 37 cases were classified as positive (Eq(deep+)) by DL, 40 cases were classified by a second-round visual assessment, and 40 cases were classified by quantification. The DL- and quantification-based classifications showed good agreement (83%, κ = 0.59). The composite SUVRs differed between Eq(deep+) (1.47 [0.13]) and Eq(deep-) (1.29 [0.10]; P < 0.001). DL, but not the visual rating, showed a significant difference in the Mini-Mental Status Examination score change during the follow-up between Eq(deep+) (- 4.21 [0.57]) and Eq(deep-) (- 1.74 [0.76]; P = 0.023) (mean duration, 1.76 years).

Conclusions: In visually equivocal scans, DL was more related to quantification than to visual assessment, and the negative cases selected by DL showed no decline in cognitive outcome. DL is useful for clinical diagnosis and prognosis assessment in subjects with visually equivocal amyloid scans.
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http://dx.doi.org/10.1007/s00259-019-04595-yDOI Listing
February 2020

The First Generation of iPSC Line from a Korean Alzheimer's Disease Patient Carrying APP-V715M Mutation Exhibits a Distinct Mitochondrial Dysfunction.

Exp Neurobiol 2019 Jun 14;28(3):329-336. Epub 2019 May 14.

CHA Stem Cell Institute, Department of Biomedical Science, CHA University, Seongnam 13488, Korea.

Alzheimer's Disease (AD) is a progressive neurodegenerative disease, which is pathologically defined by the accumulation of amyloid plaques and hyper-phosphorylated tau aggregates in the brain. Mitochondrial dysfunction is also a prominent feature in AD, and the extracellular Aβ and phosphorylated tau result in the impaired mitochondrial dynamics. In this study, we generated an induced pluripotent stem cell (iPSC) line from an AD patient with amyloid precursor protein (APP) mutation (Val715Met; APP-V715M) for the first time. We demonstrated that both extracellular and intracellular levels of Aβ were dramatically increased in the APP-V715M iPSC-derived neurons. Furthermore, the APP-V715M iPSC-derived neurons exhibited high expression levels of phosphorylated tau (AT8), which was also detected in the soma and neurites by immunocytochemistry. We next investigated mitochondrial dynamics in the iPSC-derived neurons using Mito-tracker, which showed a significant decrease of anterograde and retrograde velocity in the APP-V715M iPSC-derived neurons. We also found that as the Aβ and tau pathology accumulates, fusion-related protein Mfn1 was decreased, whereas fission-related protein DRP1 was increased in the APP-V715M iPSC-derived neurons, compared with the control group. Taken together, we established the first iPSC line derived from an AD patient carrying APP-V715M mutation and showed that this iPSC-derived neurons exhibited typical AD pathological features, including a distinct mitochondrial dysfunction.
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http://dx.doi.org/10.5607/en.2019.28.3.329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614069PMC
June 2019

Brain-State Extraction Algorithm Based on the State Transition (BEST): A Dynamic Functional Brain Network Analysis in fMRI Study.

Brain Topogr 2019 09 3;32(5):897-913. Epub 2019 Jun 3.

Laboratory for Cognitive Neuroscience and NeuroImaging, Department of Bio and Brain Engineering, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, South Korea.

Spatial pattern of the brain network changes dynamically. This change is closely linked to the brain-state transition, which vary depending on a dynamic stream of thoughts. To date, many dynamic methods have been developed for decoding brain-states. However, most of them only consider changes over time, not the brain-state transition itself. Here, we propose a novel dynamic functional connectivity analysis method, brain-state extraction algorithm based on state transition (BEST), which constructs connectivity matrices from the duration of brain-states and decodes the proper number of brain-states in a data-driven way. To set the duration of each brain-state, we detected brain-state transition time-points using spatial standard deviation of the brain activity pattern that changes over time. Furthermore, we also used Bayesian information criterion to the clustering method to estimate and extract the number of brain-states. Through validations, it was proved that BEST could find brain-state transition time-points and could estimate the proper number of brain-states without any a priori knowledge. It has also shown that BEST can be applied to resting state fMRI data and provide stable and consistent results.
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http://dx.doi.org/10.1007/s10548-019-00719-7DOI Listing
September 2019

Comparative analyses of plasma amyloid-β levels in heterogeneous and monomerized states by interdigitated microelectrode sensor system.

Sci Adv 2019 04 17;5(4):eaav1388. Epub 2019 Apr 17.

Department of Clinical Pharmacology and Therapeutics, College of Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.

Detection of amyloid-β (Aβ) aggregates contributes to the diagnosis of Alzheimer disease (AD). Plasma Aβ is deemed a less invasive and more accessible hallmark of AD, as Aβ can penetrate blood-brain barriers. However, correlations between biofluidic Aβ concentrations and AD progression has been tenuous. Here, we introduce a diagnostic technique that compares the heterogeneous and the monomerized states of Aβ in plasma. We used a small molecule, EPPS [4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid], to dissociate aggregated Aβ into monomers to enhance quantification accuracy. Subsequently, Aβ levels of EPPS-treated plasma were compared to those of untreated samples to minimize inter- and intraindividual variations. The interdigitated microelectrode sensor system was used to measure plasma Aβ levels on a scale of 0.1 pg/ml. The implementation of this self-standard blood test resulted in substantial distinctions between patients with AD and individuals with normal cognition (NC), with selectivity and sensitivity over 90%.
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http://dx.doi.org/10.1126/sciadv.aav1388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469948PMC
April 2019

Comparison of Amyloid β and Tau Spread Models in Alzheimer's Disease.

Cereb Cortex 2019 09;29(10):4291-4302

Graduate School of Medical Science & Engineering, KAIST, Daejeon, Republic of Korea.

Tau and amyloid β (Aβ), 2 key pathogenic proteins in Alzheimer's disease (AD), reportedly spread throughout the brain as the disease progresses. Models of how these pathogenic proteins spread from affected to unaffected areas had been proposed based on the observation that these proteins could transmit to other regions either through neural fibers (transneuronal spread model) or through extracellular space (local spread model). In this study, we modeled the spread of tau and Aβ using a graph theoretical approach based on resting-state functional magnetic resonance imaging. We tested whether these models predict the distribution of tau and Aβ in the brains of AD spectrum patients. To assess the models' performance, we calculated spatial correlation between the model-predicted map and the actual map from tau and amyloid positron emission tomography. The transneuronal spread model predicted the distribution of tau and Aβ deposition with significantly higher accuracy than the local spread model. Compared with tau, the local spread model also predicted a comparable portion of Aβ deposition. These findings provide evidence of transneuronal spread of AD pathogenic proteins in a large-scale brain network and furthermore suggest different contributions of spread models for tau and Aβ in AD.
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http://dx.doi.org/10.1093/cercor/bhy311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963115PMC
September 2019

Neural substrates of cognitive reserve in Alzheimer's disease spectrum and normal aging.

Neuroimage 2019 02 29;186:690-702. Epub 2018 Nov 29.

Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea; KI for Health Science and Technology, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea; Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. Electronic address:

The concept of cognitive reserve (CR) originated from discrepancies between the degree of brain pathology and the severity of clinical manifestations. CR has been characterized through CR proxies, such as education and occupation complexity; however, such approaches have inherent limitations. Although several methods have been developed to overcome these limitations, they fail to reflect the entire Alzheimer's disease (AD) pathology. Meanwhile, graph theory analysis, one of most powerful and flexible approaches, have established remarkable network properties of the brain. The functional and structural brain networks are damaged in neurodegenerative diseases. Therefore, network analysis has been applied to clarify the characteristics of the disease or give insight. Here, using multimodal neuroimaging, we propose an intuitive model to estimate CR based on its original definition, and explore the neural substrates of CR from the perspective of networks and functional connectivity. A total of 87 subjects (21 AD, 32 mild cognitive impairment, and 34 normal aging) underwent tau and amyloid PET, 3D T1-weighted MR, and resting-state fMRI. We hypothesized CR as a residual of actual cognitive performance and expected performance to be related to quantitative factors, such as AD pathology, demographics, and a genetic factor. Then, we correlated this marker using education and occupation complexity as conventional CR proxies. We validated this marker by testing whether it would modulate the effect of brain pathology on memory function. To examine the neural substrates associated with CR, we performed graph analysis to investigate the association between the CR marker and network measures at different granularities in total subjects, AD spectrum and normal aging, respectively. The CR marker from our model was well associated with education and occupation complexity. More directly, the CR marker was revealed to modify the relationship between brain pathology and memory function among AD spectrum. The CR marker was correlated with the global efficiency of the entire network, nodal clustering coefficient, and local efficiency of the right middle-temporal pole. In connectivity analysis, one cluster of edges centered on right middle-temporal pole was significantly correlated with the CR marker. In subgroup analysis, the network measures of right middle-temporal pole still correlated with the CR marker among AD spectrum. However, right precentral gyrus was revealed to be associated with the CR marker in normal aging. This study demonstrates that our intuitive model using multimodal neuroimaging and network perspective adequately and comprehensively captures CR. From a network perspective, CR is associated with the capacity to process information efficiently in the brain. The right middle-temporal pole was revealed to be a pivotal neural substrate of CR in AD spectrum. These findings foster understanding of AD and will be useful to help identify individuals with vulnerability or resistance to AD pathology, and characterize patients for intervention or drug trials.
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http://dx.doi.org/10.1016/j.neuroimage.2018.11.053DOI Listing
February 2019

iPSC Modeling of Presenilin1 Mutation in Alzheimer's Disease with Cerebellar Ataxia.

Exp Neurobiol 2018 Oct 31;27(5):350-364. Epub 2018 Oct 31.

CHA Stem Cell Institute, Department of Biomedical Science, CHA University, Seongnam 13488, Korea.

Disease modeling of Alzheimer's disease (AD) has been hampered by the lack of suitable cellular models while animal models are mainly based on the overexpression of AD-related genes which often results in an overemphasis of certain pathways and is also confounded by aging. In this study, we therefore developed and used induced pluripotent stem cell (iPSC) lines from a middle-aged AD patient with a known presenilin 1 (PSEN1) mutation (Glu120Lys; PS1-E120K) and as a control, an elderly normal subject. Using this approach, we demonstrated that the extracellular accumulation of Aβ was dramatically increased in PS1-E120K iPSC-derived neurons compared with the control iPSC line. PS1-E120K iPSC-derived neurons also exhibited high levels of phosphorylated tau, as well as mitochondrial abnormalities and defective autophagy. Given that the effect of aging is lost with iPSC generation, these abnormal cellular features are therefore indicative of PSEN1-associated AD pathogenesis rather than primary changes associated with aging. Taken together, this iPSC-based approach of AD modeling can now be used to better understand AD pathogenesis as well as a tool for drug discovery.
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http://dx.doi.org/10.5607/en.2018.27.5.350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221836PMC
October 2018

Qualitative Comparison of Semantic Memory Impairment in Patients with Amnestic Mild Cognitive Impairment Based on β-Amyloid Status.

J Clin Neurol 2019 Jan 26;15(1):27-37. Epub 2018 Oct 26.

Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.

Background And Purpose: Semantic memory remains more stable than episodic memory across the lifespan, which makes it potentially useful as a marker for distinguishing pathological aging from normal senescence. To obtain a better understanding of the transitional stage evolving into Alzheimer's dementia (AD), we focused on the amnestic mild cognitive impairment (aMCI) stage stratified based on β-amyloid (Aβ) pathology.

Methods: We analyzed the raw data from Korean version of the Boston Naming Test (K-BNT) and the Controlled Oral Word Association Test (COWAT). For K-BNT, the frequencies of six error types and accuracy rates were evaluated. For a qualitative assessment of the COWAT, we computed the number of switching, number of clusters, and mean cluster size.

Results: The data from 217 participants were analyzed (53 normal controls, 66 with Aβ- aMCI, 56 with Aβ+ aMCI, and 42 disease controls). There were fewer semantically related errors and more semantically unrelated errors on the K-BNT in Aβ+ aMCI than in Aβ- aMCI, without a gross difference in the z score. We also found that Aβ+ aMCI showed a more prominent deficit in the number of clusters in the semantic fluency task [especially for animal names (living items)] than Aβ- aMCI.

Conclusions: In spite of similar clinical manifestations, Aβ+ aMCI was more similar to AD than Aβ- aMCI in terms of semantic memory disruption. Semantic memory may serve as an early indicator of brain Aβ pathology. Therefore, semantic memory dysfunction deserves more consideration in clinical practice. Longitudinal research with the follow-up data is needed.
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http://dx.doi.org/10.3988/jcn.2019.15.1.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325377PMC
January 2019

Differences in gray and white matter F-THK5351 uptake between behavioral-variant frontotemporal dementia and other dementias.

Eur J Nucl Med Mol Imaging 2019 02 14;46(2):357-366. Epub 2018 Aug 14.

Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.

Purpose: We investigated the regional distribution of F-THK5351 uptake in gray (GM) and white matter (WM) in patients with behavioral-variant frontotemporal dementia (bvFTD) and compared it with that in patients with Alzheimer's disease (AD) or semantic dementia (SD).

Methods: F-THK-5351 positron emission tomography (PET), F-florbetaben PET, magnetic resonance imaging, and neuropsychological testing were performed in 103 subjects including 30, 24, 9, and 8 patients with mild cognitive impairment, AD, bvFTD, and SD, respectively, and 32 normal subjects. Standardized uptake value ratios (SUVRs) of F-THK-5351 PET images were measured from six GM and WM regions using cerebellar GM as reference. GM and WM SUVRs and WM/GM ratios, the relationship between GM SUVR and WM/GM ratio, and correlation between SUVR and cognitive function were compared.

Results: In AD, both parietal GM (p < 0.001) and WM (p < 0.001) SUVRs were higher than in bvFTD. In AD and SD, the WM/GM ratio decreased as the GM SUVR increased, regardless of lobar region. In AD, memory function correlated with parietal GM (ρ = -0.74, p < 0.001) and WM (ρ = -0.53, p < 0.001) SUVR. In SD, language function correlated with temporal GM SUVR (ρ = -0.69, p = 0.006). The frontal WM SUVR was higher in bvFTD than in AD (p = 0.003) or SD (p = 0.017). The frontal WM/GM ratio was higher in bvFTD than in AD (p < 0.001). In bvFTD, the WM/GM ratio increased more prominently than the GM SUVR only in the frontal lobe (R = 0.026). In bvFTD, executive function correlated with frontal WM SUVR (ρ = -0.64, p = 0.014).

Conclusions: Frontal WM F-THK5351 uptake was higher in bvFTD than in other dementias. The increase in frontal WM uptake was greater than the increase in GM uptake and correlated with executive function. This suggests that frontal lobe WM F-THK5351 uptake reflects neuropathological differences between bvFTD and other dementias.
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http://dx.doi.org/10.1007/s00259-018-4125-xDOI Listing
February 2019

Analysis of frontotemporal dementia, amyotrophic lateral sclerosis, and other dementia-related genes in 107 Korean patients with frontotemporal dementia.

Neurobiol Aging 2018 12 30;72:186.e1-186.e7. Epub 2018 Jun 30.

Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea. Electronic address:

To identify pathogenic variants in 107 Korean patients with sporadic frontotemporal dementia (FTD), 46 genes related to FTD, amyotrophic lateral sclerosis, and other dementias were screened by next-generation sequencing. Hexanucleotide repeats in C9orf72 gene were also tested by repeat-primed polymerase chain reaction. Next-generation sequencing revealed one known pathogenic variant (c.708+1G>A) in the GRN gene in a patient with behavioral variant FTD (bvFTD). In addition, a novel in-frame deletion (c.2675_2683del) in the CSF1R gene was identified in a patient with bvFTD who had severe bifrontal atrophy with frontal subcortical white matter changes. Novel compound heterozygous variants in the AARS2 gene, c.1040+1G>A and c.636G>A (p.Met212Ile), were found in a patient with bvFTD. Forty-six variants of uncertain significance were detected in other patients. None of the patients had expanded hexanucleotide repeats in C9orf72. These results show that pathogenic variants of known FTD genes are rare in Korean FTD patients but the CSF1R and AARS2 genes should be screened for a genetic diagnosis of FTD or other dementias.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.06.031DOI Listing
December 2018

Improved Diagnostic Accuracy of Alzheimer's Disease by Combining Regional Cortical Thickness and Default Mode Network Functional Connectivity: Validated in the Alzheimer's Disease Neuroimaging Initiative Set.

Korean J Radiol 2017 Nov-Dec;18(6):983-991. Epub 2017 Sep 21.

Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea.

Objective: To identify potential imaging biomarkers of Alzheimer's disease by combining brain cortical thickness (CThk) and functional connectivity and to validate this model's diagnostic accuracy in a validation set.

Materials And Methods: Data from 98 subjects was retrospectively reviewed, including a study set (n = 63) and a validation set from the Alzheimer's Disease Neuroimaging Initiative (n = 35). From each subject, data for CThk and functional connectivity of the default mode network was extracted from structural T1-weighted and resting-state functional magnetic resonance imaging. Cortical regions with significant differences between patients and healthy controls in the correlation of CThk and functional connectivity were identified in the study set. The diagnostic accuracy of functional connectivity measures combined with CThk in the identified regions was evaluated against that in the medial temporal lobes using the validation set and application of a support vector machine.

Results: Group-wise differences in the correlation of CThk and default mode network functional connectivity were identified in the superior temporal ( < 0.001) and supramarginal gyrus ( = 0.007) of the left cerebral hemisphere. Default mode network functional connectivity combined with the CThk of those two regions were more accurate than that combined with the CThk of both medial temporal lobes (91.7% vs. 75%).

Conclusion: Combining functional information with CThk of the superior temporal and supramarginal gyri in the left cerebral hemisphere improves diagnostic accuracy, making it a potential imaging biomarker for Alzheimer's disease.
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http://dx.doi.org/10.3348/kjr.2017.18.6.983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639164PMC
December 2017

Normalization of cortical thickness measurements across different T1 magnetic resonance imaging protocols by novel W-Score standardization.

Neuroimage 2017 10 28;159:224-235. Epub 2017 Jul 28.

Department of Bio and Brain Engineering, KI for Health Science and Technology, KAIST, Daejeon, Republic of Korea. Electronic address:

Background: The use of different 3D T1-weighted magnetic resonance (T1 MR) imaging protocols induces image incompatibility across multicenter studies, negating the many advantages of multicenter studies. A few methods have been developed to address this problem, but significant image incompatibility still remains. Thus, we developed a novel and convenient method to improve image compatibility.

Methods: W-score standardization creates quality reference values by using a healthy group to obtain normalized disease values. We developed a protocol-specific w-score standardization to control the protocol effect, which is applied to each protocol separately. We used three data sets. In dataset 1, brain T1 MR images of normal controls (NC) and patients with Alzheimer's disease (AD) from two centers, acquired with different T1 MR protocols, were used (Protocol 1 and 2, n = 45/group). In dataset 2, data from six subjects, who underwent MRI with two different protocols (Protocol 1 and 2), were used with different repetition times, echo times, and slice thicknesses. In dataset 3, T1 MR images from a large number of healthy normal controls (Protocol 1: n = 148, Protocol 2: n = 343) were collected for w-score standardization. The protocol effect and disease effect on subjects' cortical thickness were analyzed before and after the application of protocol-specific w-score standardization.

Results: As expected, different protocols resulted in differing cortical thickness measurements in both NC and AD subjects. Different measurements were obtained for the same subject when imaged with different protocols. Multivariate pattern difference between measurements was observed between the protocols. Classification accuracy between two protocols was nearly 90%. After applying protocol-specific w-score standardization, the differences between the protocols substantially decreased. Most importantly, protocol-specific w-score standardization reduced both univariate and multivariate differences in the images while maintaining the AD disease effect. Compared to conventional regression methods, our method showed the best performance for in terms of controlling the protocol effect while preserving disease information.

Conclusions: Protocol-specific w-score standardization effectively resolved the concerns of conventional regression methods. It showed the best performance for improving the compatibility of a T1 MR post-processed feature, cortical thickness.
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http://dx.doi.org/10.1016/j.neuroimage.2017.07.053DOI Listing
October 2017

Regional amyloid burden and lacune in pure subcortical vascular cognitive impairment.

Neurobiol Aging 2017 07 16;55:20-26. Epub 2017 Mar 16.

Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea. Electronic address:

We investigated the amyloid and vascular burden in Pittsburgh compound B (PiB)-negative subcortical vascular mild cognitive impairment (svMCI) and PiB-negative subcortical ischemic vascular dementia (SIVD) to elucidate the potential roles of amyloid deposition and small vessel disease (SVD). Thirty-eight svMCI patients and 42 SIVD patients were enrolled. The regional PiB uptake values and SVD markers were obtained and compared between groups. Additionally, correlations among amyloid burden, SVD, and cognition were made. Patients with PiB-negative SIVD showed more amyloid deposition than those with PiB-negative svMCI, particularly in the cuneus, lingual gyrus, supramarginal, and angular gyri. Despite subthreshold levels for amyloid deposition, our findings showed a marked regional difference in amyloid uptake between svMCI and SIVD, particularly in posteriorly located brain areas. However, lacune, a proxy for vascular burden, showed a broader association with cognition and had more impacts on developing dementia than amyloid burden. The topographical pattern of amyloid deposition and its impact on clinical status in pure subcortical vascular cognitive impairment were different from those in Alzheimer's disease.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.03.010DOI Listing
July 2017

Enhancing surface functionality of reduced graphene oxide biosensors by oxygen plasma treatment for Alzheimer's disease diagnosis.

Biosens Bioelectron 2017 Jun 21;92:610-617. Epub 2016 Oct 21.

Center for BioMicrosystems, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea. Electronic address:

We performed oxygen plasma treatment on reduced graphene oxide (rGO) to improve its surface reactivity with respect to biomolecular interactions. Oxygen-plasma-treated rGO surfaces were employed as reactive interfaces for the detection of amyloid-beta (Aβ) peptides, the pathological hallmarks of Alzheimer's disease (AD), as the target analytes. By measuring the changes in electrical characteristics and confirmation through topographic analysis, the oxygen-plasma-treated rGO sensors had enhanced surface functionality for better antibody immobilization and sensing performance, with a 3.33-fold steeper slope for the electrical responses versus analyte concentration curve (logarithmic scale) compared to the untreated. The elicited biomolecular reactivity of the rGO surfaces with the oxygen plasma treatment remained at 46-51% of the initial value even after aging for 6h in ambient conditions. This phenomenon was also confirmed by pretreating the rGO surfaces with a blocking agent and subsequently subjecting them to antibody immobilization. Finally, the feasibility of the oxygen-plasma-treated rGO sensors as a diagnostic tool was evaluated with clinical samples of neural-derived exosomal Aβ peptides extracted from apparent AD patients and normal controls (NC). In contrast to the untreated sensors (p=0.0460), the oxygen-plasma-treated rGO sensors showed a significant p-value in the identification of clinical samples of AD and NC subjects (p<0.001). These results suggest that oxygen plasma treatment improves sensor performance without complicated fabrication procedures and should aid in the development of novel diagnostic tools based on carbon nanomaterials.
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http://dx.doi.org/10.1016/j.bios.2016.10.049DOI Listing
June 2017

White Matter Changes May Precede Gray Matter Loss in Elderly with Subjective Memory Impairment.

Dement Geriatr Cogn Disord 2016 5;42(3-4):227-235. Epub 2016 Oct 5.

Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background/aims: A limited number of studies addressed MRI-based neurodegenerative changes in subjective memory impairment (SMI). We investigated changes in white matter (WM) microstructures as well as gray matter (GM) macrostructures in subjects with SMI of high and low risk for progression.

Methods: A modeling scale (score range, 0-6) developed for prediction of SMI progression was used to divide SMI subjects (n = 46) into two groups: a high risk of progression (score ≥3; n = 19) and a low risk of progression (score ≤2; n = 27). Cross-sectional comparisons were performed using a region-of-interest-based diffusion tensor imaging (DTI) analysis, cortical thickness analysis, and hippocampal volumetry.

Results: The high-risk group had more microstructural disruption shown by lower fractional anisotropy in the hippocampus, parahippocampal gyrus, supramarginal gyrus, and parts of frontotemporal lobes. On the other hand, GM macrostructural changes did not differ between the groups and were not associated with modeling scale scores.

Conclusion: SMI subjects with a high risk of progression had more WM microstructural disruption than those with a low risk, and the changes were not explained by GM atrophy. Our findings suggest that the degree of microstructural alterations in SMI may be distinctive according to the risk factors and may precede GM atrophy.
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http://dx.doi.org/10.1159/000450749DOI Listing
January 2018

Human Herpes Virus 6 Encephalitis Following Bone Marrow Transplantation with Uncommon Magnetic Resonance Imaging Findings.

Dement Neurocogn Disord 2016 Sep 30;15(3):88-91. Epub 2016 Sep 30.

Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background: Human Herpes Virus 6 (HHV6) is commonly associated with encephalitis following bone marrow transplantation. However, hippocampal atrophy and global hypometabolism are rare findings in HHV6 encephalitis.

Case Report: A 41-year-old right-handed woman with acute lymphoblastic leukemia presented with fever and mental changes 2 weeks after receiving a sibling bone marrow transplant. The patient's cerebrospinal fluid (CSF) was positive for HHV-6 deoxyribonucleic acid (DNA), but was negative for other viral DNA. Brain magnetic resonance imaging revealed atrophic changes in bilateral medial temporal lobes. Following 4 weeks of ganciclovir therapy, a CSF exam was negative for HHV-6 DNA and the patient's neurological symptoms partially improved. However, she was disoriented and had severe retrograde and anterograde amnesia. 18F-fluorodeoxyglucose-positron emission tomography indicated global hypometabolism in the medial temporal lobes and the fronto-parietal cortices.

Conclusions: This is a rare and unusual case of hippocampal atrophy in the acute stage of HHV6 encephalitis. Our imaging findings may reflect the chronic indolent course of HHV6 encephalitis.
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http://dx.doi.org/10.12779/dnd.2016.15.3.88DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427967PMC
September 2016

Prediction of Alzheimer's disease pathophysiology based on cortical thickness patterns.

Alzheimers Dement (Amst) 2016 28;2:58-67. Epub 2015 Dec 28.

Department of Neurology, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Korea; Neuroscience Center, Samsung Medical Center, Seoul, Korea; Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.

Introduction: Recent studies have shown that pathologically defined subtypes of Alzheimer's disease (AD) represent distinctive atrophy patterns and clinical characteristics. We investigated whether a cortical thickness-based clustering method can reflect such findings.

Methods: A total of 77 AD subjects from the Alzheimer's Disease Neuroimaging Initiative 2 data set who underwent 3-T magnetic resonance imaging, [(18)F]-fluorodeoxyglucose-positron emission tomography (PET), [(18)F]-Florbetapir PET, and cerebrospinal fluid (CSF) tests were enrolled. After clustering based on cortical thickness, diverse imaging and biofluid biomarkers were compared between these groups.

Results: Three cortical thinning patterns were noted: medial temporal (MT; 19.5%), diffuse (55.8%), and parietal dominant (P; 24.7%) atrophy subtypes. The P subtype was the youngest and represented more glucose hypometabolism in the parietal and occipital cortices and marked amyloid-beta accumulation in most brain regions. The MT subtype revealed more glucose hypometabolism in the left hippocampus and bilateral frontal cortices and less performance in memory tests. CSF test results did not differ between the groups.

Discussion: Cortical thickness patterns can reflect pathophysiological and clinical changes in AD.
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http://dx.doi.org/10.1016/j.dadm.2015.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879518PMC
May 2016

The neural correlates of motor intentional disorders in patients with subcortical vascular cognitive impairment.

J Neurol 2016 Jan 29;263(1):89-99. Epub 2015 Oct 29.

Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Subcortical vascular cognitive impairment (SVCI) refers to cognitive impairment associated with small vessel disease. Motor intentional disorders (MID) have been reported in patients with SVCI. However, there are no studies exploring the neuroanatomical regions related to MID in SVCI patients. The aim of this study, therefore, was to investigate the neural correlates of MID in SVCI patients. Thirty-one patients with SVCI as well as 10 healthy match control participants were included. A "Pinch-Grip" apparatus was used to quantify the force control capabilities of the index finger in four different movement phases including initiation, development, maintenance, and termination. All participants underwent magnetic resonance imaging (MRI). Topographical cortical areas and white matter tracts correlated with the performances of the four different movement phases were assessed by the surface-based morphometry and tract-based spatial statistics analyses. Poorer performance in the maintenance task was related to cortical thinning in bilateral dorsolateral prefrontal, orbitofrontal and parietal cortices, while poorer performance in the termination task was associated with the disruption of fronto-parietal cortical areas as well as the white matter tracts including splenium and association fibers such as superior longitudinal fasciculus. Our study demonstrates that cortical areas and underlying white matter tracts associated with fronto-parietal attentional system play an important role in motor impersistence and perseveration in SVCI patients.
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http://dx.doi.org/10.1007/s00415-015-7946-6DOI Listing
January 2016

The Efficacy of Cognitive Intervention Programs for Mild Cognitive Impairment: A Systematic Review.

Curr Alzheimer Res 2015 ;12(6):527-42

Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic- ro 43-gil, Songpa-gu, Seoul 138-736, Korea.

Mild cognitive impairment (MCI) describes a transitional state in progression from normal aging to dementia, especially Alzheimer's disease (AD). Currently, there is no effective pharmacological treatment that offers a long-term beneficial effect to delay the progression to dementia. There is growing evidence that supports an important role of non-pharmacological cognitive interventions. Therefore, it is warranted to clarify the distinct forms of cognitive interventions and their effects based on previous clinical trials. We aimed to provide a review of clinical trials of non-pharmacological cognitive interventions for MCI and to address the characteristics of the study patients, cognitive intervention programs and short-term / long-term benefits of the interventions. A total of 32 articles were identified according to the inclusion criteria. The results showed positive effects for both objective and subjective outcome variables, and these effects persisted from 1 month up to 5 years. Although many of the positive effects were related to improvement in trained tasks, alterations in neuroimaging and the transfer effects shown by some studies are encouraging. Future research in this area requires a larger sample size with a wider spectrum of MCI, more instructive outcome measures and a longer follow up duration.
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http://dx.doi.org/10.2174/1567205012666150530201636DOI Listing
May 2016

Amyloid Beta-Weighted Cortical Thickness: A New Imaging Biomarker in Alzheimer's Disease.

Curr Alzheimer Res 2015 ;12(6):563-71

Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic- ro 43-gil, Songpa-gu, Seoul 138-736, Korea.

Alzheimer's disease (AD) is the most common neurodegenerative disorder pathologically characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The aggregation of Aβ precedes tau pathologies in AD; however, the causal relation between the two pathologies and the mechanisms by which aggregated forms of Aβ contribute to cortical thinning are not fully understood. We proposed quantitative Aβ-weighted cortical thickness analysis to investigate the regional relationship between cortical thinning and amyloid plaque deposition using magnetic resonance (MR) and Pittsburg Compound B (PiB) positron emission tomography (PET) images in patients with AD, mild cognitive impairment (MCI), and subjects with normal cognition. We hypothesized that there are cortical areas that have prominent changes associated with Aβ deposition and there are areas that are relatively independent from Aβ deposition where pathologies other than Aβ (such as tau) are predominant. The study was performed using MRI and PiB PET data from the Alzheimer's Disease Neuroimaging Initiative. We measured accuracy of classification models in three different pairs of groups comparing AD, MCI, and normal cognition. Classification models that used Aβ-weighted cortical thickness were not inferior to classification models that used only cortical thickness or amyloid deposition. In addition, based on timing of changes in cortical thinning and Aβ deposition such as Aβ deposition after cortical thinning; cortical thinning after Aβ deposition, or concurrent Aβ deposition and cortical thinning, we identified three types of relationships between cortical thinning and Aβ deposition: (1) Aβ-associated cortical thinning; (2) Aβ-independent cortical thinning; and (3) Aβ deposition only without cortical thinning. Taken together, these findings suggest that Aβ-weighted cortical thickness values can be used as an objective biomarker of structural changes caused by amyloid pathology in the brain.
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http://dx.doi.org/10.2174/1567205012666150530202124DOI Listing
May 2016

A consensus in Korea regarding a protocol to reduce preanalytical sources of variability in the measurement of the cerebrospinal fluid biomarkers of Alzheimer's disease.

J Clin Neurol 2015 Apr;11(2):132-41

Department of Neurology, Seoul National University Bundang Hospital, Seongnam, Korea.

Cerebrospinal fluid (CSF) can provide vital informative about pathological processes occurring in the brain. In particular, the CSF concentrations of Aβ42, tTau, and pTau181 are useful for the early diagnosis of Alzheimer's disease (AD). However, many studies have demonstrated that confounding factors related to the preanalytical processing of CSF can seriously influence measurements of these AD biomarkers. It is therefore important to develop a standardized protocol for the acquisition and handling of CSF, particularly with regard to the types of tube used for collection and storage, the proper aliquot volume, blood contamination, and the number of tube transfers and freeze-thaw cycles, because these aspects of the procedure have been shown to affect AD biomarker measurements. A survey of the impact of several individual preanalytical procedures on the measurement of AD biomarkers in CSF was conducted for this review article, and the implications of the differences among them are discussed. Furthermore, following a review of the procedures used in Korean and international biomarker laboratories, a consensus was reached among a cooperative Korean multicenter research group regarding a standardized protocol for the analysis of AD biomarkers in CSF. All efforts were made to be stringent regarding the controversial issues associated with this protocol, thus minimizing the confounding influence of various factors on current investigations using established AD biomarkers and on future studies using novel biomarkers of AD and other neurodegenerative disorders.
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http://dx.doi.org/10.3988/jcn.2015.11.2.132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387478PMC
April 2015

Effect of midazolam on memory during fiberoptic gastroscopy under conscious sedation.

Clin Neuropharmacol 2015 Mar-Apr;38(2):47-51

*Department of Neurology, and †Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.

Objective: As the fiberoptic gastroscopy using midazolam is being in widespread use, the exact nature of midazolam on memory should be clarified. We intended to examine whether midazolam causes selective anterograde amnesia and what impact it has on other aspects of memory and general cognitive function.

Methods: We recruited healthy subjects undergoing fiberoptic gastroscopy under conscious sedation. At baseline, history taking for retrograde amnesia and the Korean version of the Montreal Cognitive Assessment were performed. A man's name and address were given immediately after intravenous midazolam administration. After gastroscopy, the subjects were asked to recall those items. By the time they had fully recovered consciousness, the same test was repeated along with the Korean version of the Montreal Cognitive Assessment and a test for retrograde amnesia.

Results: A total of 30 subjects were enrolled in this study. Subjects with high-dose midazolam showed lower scores in the immediate and delayed recall of "a man's name and address" compared with those with low-dose midazolam. The midazolam dose was inversely correlated with the delayed recall scores of "a man's name and address." On full recovery of consciousness, the subjects did not exhibit any of anterograde or retrograde amnesia.

Conclusions: These findings suggest that midazolam causes transient selective anterograde amnesia in a dose-dependent manner.
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http://dx.doi.org/10.1097/WNF.0000000000000067DOI Listing
November 2015

Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer's disease.

J Exp Med 2014 Dec 24;211(13):2487-96. Epub 2014 Nov 24.

Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 Department of Neurology, Hope Center for Neurological Disorders, and Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110

Age-related aggregation of amyloid-β (Aβ) is an upstream pathological event in Alzheimer's disease (AD) pathogenesis, and it disrupts the sleep-wake cycle. The amount of sleep declines with aging and to a greater extent in AD. Poor sleep quality and insufficient amounts of sleep have been noted in humans with preclinical evidence of AD. However, how the amount and quality of sleep affects Aβ aggregation is not yet well understood. Orexins (hypocretins) initiate and maintain wakefulness, and loss of orexin-producing neurons causes narcolepsy. We tried to determine whether orexin release or secondary changes in sleep via orexin modulation affect Aβ pathology. Amyloid precursor protein (APP)/Presenilin 1 (PS1) transgenic mice, in which the orexin gene is knocked out, showed a marked decrease in the amount of Aβ pathology in the brain with an increase in sleep time. Focal overexpression of orexin in the hippocampus in APP/PS1 mice did not alter the total amount of sleep/wakefulness and the amount of Aβ pathology. In contrast, sleep deprivation or increasing wakefulness by rescue of orexinergic neurons in APP/PS1 mice lacking orexin increased the amount of Aβ pathology in the brain. Collectively, modulation of orexin and its effects on sleep appear to modulate Aβ pathology in the brain.
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http://dx.doi.org/10.1084/jem.20141788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267230PMC
December 2014

Recent updates on subcortical ischemic vascular dementia.

J Stroke 2014 Jan 31;16(1):18-26. Epub 2014 Jan 31.

Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Vascular dementia (VaD) is a history-laden disease entity that dates back to the 19th century when arteriosclerotic brain atrophy due to hardening of the arteries was perceived as the major cause of senile dementia. Its existence had been overshadowed by the emergence of Alzheimer's disease (AD) in the past century and research on AD dominated the field of dementia. Interest in VaD has been revived in recent years as vascular lesions have been shown to make great contributions to the development of dementia, particularly in the elderly. VaD has now evolved into the concept of vascular cognitive impairment (VCI), which encompasses not only VaD but also AD with cerebrovascular disorder and VCI with no dementia. The concept of VCI is intended to maximize the therapeutic potential in dementia management because the vascular component may be amenable to therapeutic intervention particularly in the early stages of cognitive impairment. Subcortical ischemic vascular dementia (SIVD) is pathologically driven by severe stenosis and the occlusion of small vessels that culminate into white matter ischemia and multiple lacunar infarctions in the subcortical structures. The relatively slow progression of symptoms and clinical manifestations associated with cholinergic deficits often make the differentiation of SIVD from AD difficult. The recent development of in vivo amyloid imaging enabled further pathological breakdown of SIVD into pure SIVD and mixed dementia with subcortical ischemia based on the absence or existence of amyloid pathology in the brain. In this article, the authors reviewed the emerging concepts of VaD/VCI and the clinical manifestations, biomarkers, treatments, and preclinical models of SIVD based on the pathophysiologic mechanisms of the disease.
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http://dx.doi.org/10.5853/jos.2014.16.1.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961819PMC
January 2014

Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration.

J Clin Invest 2013 Dec 25;123(12):5389-400. Epub 2013 Nov 25.

Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration.
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http://dx.doi.org/10.1172/JCI70317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859381PMC
December 2013

Translational profiling of hypocretin neurons identifies candidate molecules for sleep regulation.

Genes Dev 2013 Mar 21;27(5):565-78. Epub 2013 Feb 21.

Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.

Hypocretin (orexin; Hcrt)-containing neurons of the hypothalamus are essential for the normal regulation of sleep and wake behaviors and have been implicated in feeding, anxiety, depression, and reward. The absence of these neurons causes narcolepsy in humans and model organisms. However, little is known about the molecular phenotype of these cells; previous attempts at comprehensive profiling had only limited sensitivity or were inaccurate. We generated a Hcrt translating ribosome affinity purification (bacTRAP) line for comprehensive translational profiling of all ribosome-bound transcripts in these neurons in vivo. From this profile, we identified >6000 transcripts detectably expressed above background and 188 transcripts that are highly enriched in these neurons, including all known markers of the cells. Blinded analysis of in situ hybridization databases suggests that ~60% of these are expressed in a Hcrt marker-like pattern. Fifteen of these were confirmed with double labeling and microscopy, including the transcription factor Lhx9. Ablation of this gene results in a >30% loss specifically of Hcrt neurons, without a general disruption of hypothalamic development. Polysomnography and activity monitoring revealed a profound hypersomnolence in these mice. These data provide an in-depth and accurate profile of Hcrt neuron gene expression and suggest that Lhx9 may be important for specification or survival of a subset of these cells.
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http://dx.doi.org/10.1101/gad.207654.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605469PMC
March 2013