A multicenter comparison of [ 18 F]flortaucipir, [ 18 F]RO948, and [ 18 F]MK6240 tau PET tracers to detect a common target ROI for differential diagnosis

Purpose: This study aims to determine whether comparable target regions of interest (ROIs) and cut-offs can be used across [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau positron emission tomography (PET) tracers for differential diagnosis of Alzheimer's disease (AD) dementia vs either cognitively unimpaired (CU) individuals or non-AD neurodegenerative diseases. Methods: A total of 1755 participants underwent tau PET using either [18F]flortaucipir (n = 975), [18F]RO948 (n = 493), or [18F]MK6240 (n = 287). SUVR values were calculated across four theory-driven ROIs and several tracer-specific data-driven (hierarchical clustering) regions of interest (ROIs). Diagnostic performance and cut-offs for ROIs were determined using receiver operating characteristic analyses and the Youden index, respectively. Results: Comparable diagnostic performance (area under the receiver operating characteristic curve [AUC]) was observed between theory- and data-driven ROIs. The theory-defined temporal meta-ROI generally performed very well for all three tracers (AUCs: 0.926-0.996). An SUVR value of approximately 1.35 was a common threshold when using this ROI. Conclusion: The temporal meta-ROI can be used for differential diagnosis of dementia patients with [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau PET with high accuracy, and that using very similar cut-offs of around 1.35 SUVR. This ROI/SUVR cut-off can also be applied across tracers to define tau positivity.ope

Risks and Prognoses of Alzheimer's Disease and Vascular Dementia in Patients With Insomnia: A Nationwide Population-Based Study

This study aimed to investigate the risk and prognosis of Alzheimer's disease (AD) and vascular dementia (VaD) in patients with insomnia using the National Health Insurance Service database covering the entire population of the Republic of Korea from 2007 to 2014. In total, 2,796,871 patients aged 40 years or older with insomnia were enrolled, and 5,593,742 controls were matched using a Greedy digit match algorithm. Mortality and the rate of admission to a long-term care facility were estimated using multivariable Cox analysis. Of all patients with insomnia, 138,270 (4.94%) and 26,706 (0.96%) were newly diagnosed with AD and VaD, respectively. The incidence rate ratios for AD and VaD were 1.73 and 2.10, respectively, in patients with insomnia compared with those without. Higher mortality rates and long-term care facility admission rates were also observed in patients with dementia in the insomnia group. Known cardiovascular risk factors showed interactions with the effects of insomnia on the risk of AD and VaD. However, the effects of insomnia on the incidence of AD and VaD were consistent between the groups with and without cardiovascular risk factors. Insomnia is a medically modifiable and policy-accessible risk factor and prognostic marker of AD and VaD.ope

Study on Basic Characteristics of a Coplanar-type Transmission Line Employing Periodic Structure on Si RFIC

In this study, a short-wavelength coplanar-type transmission line employing periodic ground structure (PGS) was developed for application to miniaturized on-chip passive component on Si Radio Frequency Integrated Circuit (RFIC). The transmission line employing PGS showed shorter wavelength and lower characteristic impedance than conventional coplanar-type transmission line. The wavelength of the transmission line employing PGS structure was 57 % of the conventional coplanar-type transmission line on Si substrate. Using the theoretical analysis, basic characteristics of the transmission line employing PGS (e.g., bandwidth, loss, impedance, and resonance characteristics) were also investigated in order to evaluate its suitability for application to a development of miniaturized passive on-chip components on silicon RFIC. According to the results, the bandwidth of the transmission line employing PGS was more than 895 ㎓ as long as T is less than 20 ㎛, and the resonance characteristic was observed in 1239 ㎓, which indicates that the PPGM structure is a promising candidate for application to a development of miniaturized on-chip passive components on Si RFIC.Abstract = 1 제 1 장 연구 배경 및 목적 = 3 제 2 장 종래의 코프레너형 전송선로 구조 = 6 제 3 장 PGS 구조를 가지는 코프레너형 전송선로의 구조 = 8 제 4 장 PGS 구조의 등가회로 해석 및 이론적 특성 고찰 = 11 4.1 이론적 해석 및 대역폭 특성 = 11 4.2 등가회로 해석 및 공진주파수 특성 = 18 제 5 장 PGS 구조를 가지는 코프레너형 전송선로의 설계 및 제작 결과 = 21 5.1 PGS 구조를 가지는 코프레너형 전송선로의 설계 = 21 5.2 PGS 구조를 가지는 코프레너형 전송선로의 제작 = 22 5.3 선로파장 축소 특성 = 23 5.4 유효 유전율 특성 = 26 5.5 선로손실 특성 = 28 5.6 특성 임피던스 특성 = 30 제 6 장 결론 = 33 참고문헌 = 3

Sex-Related Reserve Hypothesis in Alzheimer's Disease: Changes in Cortical Thickness with a Five-Year Longitudinal Follow-Up

Background: Sex effects on the progression of Alzheimer's disease (AD) have received less attention than other demographic factors, including onset age and education. Objective: The aim of this study was to investigate whether sex affected cortical thinning in the disease progression of AD. Methods: We prospectively recruited 36 patients with early-stage AD and 14 people with normal cognition. All subjects were assessed with magnetic resonance imaging at baseline, Year 1, Year 3, and Year 5. We performed cortical thickness analyses using surface-based morphometry on magnetic resonance imaging. Results: Women with AD showed more rapid cortical thinning in the left dorsolateral frontal cortex, left superior temporal gyrus, bilateral temporo-parietal association cortices, bilateral anterior cingulate gyri, bilateral medial frontal cortices, and bilateral occipital cortices over 5 years than men with AD, even though there was no difference in cortical thickness at baseline. In contrast, there were no regions of significantly more rapid atrophy in men with AD. Conclusions: Our findings suggest that women deteriorate faster than men in the progression of AD.ope

국가 데이터를 이용한 선천 소화기 기형 환자의 신경학적 발달에 대한 분석 연구

학위논문(박사) -- 서울대학교대학원 : 의과대학 의학과, 2024. 2. 김한석.Analysis of neurodevelopmental outcomes among children with congenital gastrointestinal anomalies using Korean national claims data Background: This retrospective cohort study aimed to investigate the neurodevelopmental outcomes and risk factors in children surgically treated for congenital gastrointestinal anomalies (CGIA). Methods: Data of children born between 2008 and 2015 who underwent surgical treatment for CGIA were retrieved from the Korean National Health Insurance Database. CGIA include esophageal atresia (EA), duodenal atresia (DA), jejunoileal atresia (JIA), anorectal malformation (ARM), and congenital megacolon (CMC). Children with a birth weight of 4.0 kg, or those diagnosed with chromosomal or brain anomalies were excluded. These data were compared to those of a control group, matched at a 1:4 ratio based on birth year, sex, and income level using propensity score matching. Neurodevelopmental impairment (NDI) was defined as Korean Ages and Stages Questionnaire scores below the determined cutoff or Korean Developmental Screening Test scores of less than -2 standard deviations. The neurodevelopmental outcomes and the effects of risk factors at 1 and 3 years of age (YA) were analyzed. Results: Children with CGIA had a significantly increased risk of NDI compared to healthy controls. Children with ARM had a significant association with NDI at 1YA (p<0.001, adjusted odds ratio (aOR): 2.796, 95% confidence interval (CI): 1.602-4.879). At 3YA, children with EA, JIA, ARM, and CMC were significantly associated with NDI. Among the risk factors, birth weight and growth failure (GF) of three parameters were associated with NDI at 1YA. GF in height and weight were associated with NDI at 3YA. Congenital heart disease (CHD) increased the risk of NDI in children with CMC only. Among the clinical factors, the duration of oxygen support (p=0.037, aOR: 1.194, 95% CI: 1.011–1.410), duration of mechanical ventilation (p=0.023, aOR: 1.295, 95% CI: 1.036-1.619), and the duration of PN (p=0.046, aOR: 1.022, 95% CI: 1.000–1.045) were significantly associated with NDI at 3YA in children with JIA. NDI was related to the duration of oxygen support at 1YA (p≤0.001, aOR: 1.212, 95% CI: 1.085-1.353) and 3YA (p=0.012, aOR: 1.071, 95% CI: 1.016–1.130) in children with ARM. Additionally, NDI was significantly affected by the number of surgeries (p=0.020, aOR: 2.278, 95% CI: 1.136-4.567) at 1YA in children with CMC. Conclusion: Children diagnosed with CGIA face an increased risk of NDI. These findings underscore the critical importance of monitoring neurodevelopmental outcomes, enabling the provision of tailored interventions, and implementing comprehensive perioperative management and nutritional support strategies for children affected by CGIA. Due to limitations in the research methodology, further research should be conducted using well-defined prospective cohort studies. Keywords: congenital gastrointestinal anomalies, neurodevelopmental outcomes, risk factors Student Number: 2019-30632연구 목적: 본 연구에서는 국민건강보험에서 추출한 자료를 기반으로 선천성 소화기 기형(CGIA)을 동반하여 수술이 필요하였던 아동의 신경학적 발달과 위험요인에 대해서 알아보고자 하였다. 연구 방법: 2008년부터 2015년 사이에 태어난 CGIA로 수술 치료를 받은 어린이에 대한 데이터는 국민건강보험공단자료를 활용하였다. CGIA에는 식도 폐쇄증(EA), 십이지장 폐쇄증(DA), 공회장 폐쇄증(JIA), 항문직장 기형(ARM) 및 선천성 거대결장(CMC)이 포함되었다. 출생 시 체중이 2.5kg 미만, 4.0kg 이상이거나 염색체 이상 또는 선천적 뇌 이상으로 진단받은 아동은 제외되었다. 질병군에는 4명의 건강한 대조군 참가자를 출생 연도, 성별, 소득에 대해 무작위로 연결하였으며 1세와 3세 경 아동의 신경발달 결과를 비교하였다. 신경발달 장애(NDI)는 영유아 건강검진에서 한국형 Ages and Stages Questionnaire (K-ASQ) 혹은 한국영유아발달선별검사(K-DST)의 비정상적인 결과로 정의하였다. 연구 결과: CGIA 아동은 신경발달장애의 위험이 높다. 1세 경 시행한 신경학적 발달 결과 ARM 아동만 NDI와 관련이 있었다 (p<0.001, aOR: 2.796, 95% CI: 1.602-4.879). 반면 3세 경 시행한 신경학적 발달 결과 EA, JIA, ARM 및 CMC 아동이 NDI와 유의미한 관련이 있었다. 위 험인자에서는 출생 체중과 키, 몸무게, 머리둘레의 성장지연이 1세 경 NDI와 관련이 있었다. 3세 경에는 키와 몸무게의 성장지연이 NDI와 관련이 있었다. 선천 심기형의 경우 CMC 아동에서 1세경 NDI와 관련이 있었다. 임상적 요인은 JIA 아동에서는 산소 공급 기간 (p= 0.037, aOR: 1.194, 95% CI: 1.011–1.410), 기계환기 기간 (p=0.023, aOR: 1.295, 95% CI: 1.036-1.619), 정맥영양 기간(p=0.046, aOR: 1.022, 95% CI: 1.000–1.045)이 3세 NDI에 유의미한 영향을 미쳤다. ARM이 있는 아동의 경우 산소 공급이 1세 (p=<0.001, aOR: 1.212, 95% CI: 1.085-1.353) 와 3세 (p=0.012, aOR: 1.071, 95% CI: 1.016–1.130)에 NDI와 관련이 있었다. CMC 아동의 경우 수술 횟수가 1세 NDI와 관련이 있었다(p=0.020, aOR: 2.278, 95% CI: 1.136-4.567). 결론: CGIA 진단을 받은 아동은 NDI의 위험이 높다. 이러한 발견은 신경발달 결과를 모니터링하여 적절한 치료적 중재를 제공하며 포괄적인 수술 전후 관리 및 영양지원을 하는 것의 중요성을 강조한다. 연구 방법론의 한계로 인해 전향적 코호트 연구를 활용한 추가 연구가 필요하다.Introduction 1 Methods 2 Results . 5 Discussion 22 Conclusion 30 References 31 Abstract in Korean . 36 List of Figures and Tables Figure 1 5 Figure 2 6 Figure 3 12 Table 1 . 7 Table 2 . 8 Table 3 . 9 Table 4 11 Table 5 13 Table 6 15 Table 7 16 Table 8 17 Table 9 18 Table 10 20 Table 11 21박

Transferability of Alzheimer Disease Polygenic Risk Score Across Populations and Its Association With Alzheimer Disease-Related Phenotypes

Importance: Polygenic risk scores (PRSs), which aggregate the genetic effects of single-nucleotide variants identified in genome-wide association studies (GWASs), can help distinguish individuals at a high genetic risk for Alzheimer disease (AD). However, genetic studies have predominantly focused on populations of European ancestry. Objective: To evaluate the transferability of a PRS for AD in the Korean population using summary statistics from a prior GWAS of European populations. Design, setting, and participants: This cohort study developed a PRS based on the summary statistics of a large-scale GWAS of a European population (the International Genomics of Alzheimer Project; 21 982 AD cases and 41 944 controls). This PRS was tested for an association with AD dementia and its related phenotypes in 1634 Korean individuals, who were recruited from 2013 to 2019. The association of a PRS based on a GWAS of a Japanese population (the National Center for Geriatrics and Gerontology; 3962 AD cases and 4074 controls) and a transancestry meta-analysis of European and Japanese GWASs was also evaluated. Data were analyzed from December 2020 to June 2021. Main outcomes and measures: Risk of AD dementia, amnestic mild cognitive impairment (aMCI), earlier symptom onset, and amyloid β deposition (Aβ). Results: A total of 1634 Korean patients (969 women [59.3%]), including 716 individuals (43.6%) with AD dementia, 222 (13.6%) with aMCI, and 699 (42.8%) cognitively unimpaired controls, were analyzed in this study. The mean (SD) age of the participants was 71.6 (9.0) years. Higher PRS was associated with a higher risk of AD dementia independent of APOE ɛ4 status in the Korean population (OR, 1.95; 95% CI, 1.40-2.72; P < .001). Furthermore, PRS was associated with aMCI, earlier symptom onset, and Aβ deposition independent of APOE ɛ4 status. The PRS based on a transancestry meta-analysis of data sets comprising 2 distinct ancestries showed a slightly improved accuracy. Conclusions and relevance: In this cohort study, a PRS derived from a European GWAS identified individuals at a high risk for AD dementia in the Korean population. These findings emphasize the transancestry transferability and clinical value of PRSs and suggest the importance of enriching diversity in genetic studies of AD.ope

PSEN1 variants in Korean patients with clinically suspicious early-onset familial Alzheimer's disease

Pathogenic variants in the PSEN1 gene are known to be the most common cause of early-onset Alzheimer's disease but there are few data on the frequency and spectrum of PSEN1 variants in Korea. In this study, we investigated PSEN1 variants in a consecutive series of clinically suspicious early-onset familial AD (EOFAD) Korean patients and their clinical characteristics and imaging findings. From January 2007 to December 2013, EOFAD patients with very early onset AD (<50 yr), early onset AD (<60 yr) with two or more relatives with AD, and early onset AD (<60 yr) with one or more first-degree relatives with very early onset AD (<50 yr) were enrolled in this study. Sequence analysis of the PSEN1 gene was performed by Sanger sequencing. Neuroimaging data and conventional brain MRIs and FDG-PET and/or [11C] PiB-PET scans were analyzed in patients with PSEN1 variants. Among the 28 patients with EOFAD, six (21.4%, 6/28) patients had pathogenic or likely pathogenic variants in the PSEN1 gene. Two pathogenic variants were p.Glu120Lys and p.Ser170Phe and four likely pathogenic variants were p.Thr119Ile, p.Tyr159Cys, p.Leu282Pro, and p.Ala285Ser. Two patients had variants of unknown significance, p.Tyr389His and p.Tyr389Ser. EOFAD patients with PSEN1 variants showed early AD onset, frequent visuospatial dysfunction, movement disorders, and rapid disease progression. Brain MRIs revealed diffuse cortical atrophy, including parietal lobe atrophy, and/or hippocampal atrophy. FDG-PET scans also revealed significant hypometabolism in the bilateral temporo-parietal regions. Our findings provide insight to better understand the genetic background of Korean EOFAD patients.ope

Glomerular hyperfiltration is associated with dementia: A nationwide population-based study

Background Glomerular hyperfiltration may be a clinical phenotype of endothelial dysfunction. Endothelial dysfunction may cause vascular dementia through the deterioration of cerebral blood flow. We aimed to identify the risk of dementia in people with glomerular hyperfiltration. Methods Using the Korean National Health Information Database, we included subjects aged >= 45 years who underwent national health screening examinations between 2012 and 2015 and who had no previous history of end-stage renal disease or dementia (n = 2,244,582). The primary exposure was glomerular hyperfiltration. We divided the subjects into groups by sex and five-year age intervals and categorized each group into 8 intervals according to estimated glomerular filtration (eGFR). The subjects with an eGFR >= 95th percentile in each group were defined as the hyperfiltration group. The outcomes were development of all types of dementia, Alzheimer's dementia and vascular dementia. Multivariable Cox proportional hazards models were used to analyze the hazard ratios (HRs) for outcomes. Results The Hyperfiltration group showed a higher risk for the development of all types of dementia [adjusted HR 1.09 (95% CI, 1.03-1.15)] and vascular dementia [adjusted HR 1.33 (95% CI, 1.14-1.55)] than the reference group. However, the association between hyperfiltration and Alzheimer's dementia was not statistically significant. Conclusions Glomerular hyperfiltration may be associated with dementia. In this respect, subjects with glomerular hyperfiltration should be monitored more closely for signs and symptoms of dementia.ope

Anatomical heterogeneity of Alzheimer disease: based on cortical thickness on MRIs.

OBJECTIVE: Because the signs associated with dementia due to Alzheimer disease (AD) can be heterogeneous, the goal of this study was to use 3-dimensional MRI to examine the various patterns of cortical atrophy that can be associated with dementia of AD type, and to investigate whether AD dementia can be categorized into anatomical subtypes. METHODS: High-resolution T1-weighted volumetric MRIs were taken of 152 patients in their earlier stages of AD dementia. The images were processed to measure cortical thickness, and hierarchical agglomerative cluster analysis was performed using Ward's clustering linkage. The identified clusters of patients were compared with an age- and sex-matched control group using a general linear model. RESULTS: There were several distinct patterns of cortical atrophy and the number of patterns varied according to the level of cluster analyses. At the 3-cluster level, patients were divided into (1) bilateral medial temporal-dominant atrophy subtype (n = 52, ∼ 34.2%), (2) parietal-dominant subtype (n = 28, ∼ 18.4%) in which the bilateral parietal lobes, the precuneus, along with bilateral dorsolateral frontal lobes, were atrophic, and (3) diffuse atrophy subtype (n = 72, ∼ 47.4%) in which nearly all association cortices revealed atrophy. These 3 subtypes also differed in their demographic and clinical features. CONCLUSIONS: This cluster analysis of cortical thickness of the entire brain showed that AD dementia in the earlier stages can be categorized into various anatomical subtypes, with distinct clinical features.ope

Distribution and clinical impact of apolipoprotein E4 in subjective memory impairment and early mild cognitive impairment

The apolipoprotein E (APOE) e4 allele is the most common genetic variant associated with Alzheimer's disease (AD). We sought to investigate the distribution of APOE genotypes across the full clinical AD spectrum including AD, late-stage amnestic mild cognitive impairment (L-aMCI), early-stage aMCI (E-aMCI), subjective memory impairment (SMI), and controls. We prospectively recruited 713 AD patients, 735 aMCI patients, 575 SMI patients, and 8,260 individuals as controls. The frequency of the APOE e4 allele revealed an ordered fashion in the AD (30.8%), L-aMCI (24.0%), E-aMCI (15.1%), SMI (11.7%), and control (9.1%) groups. APOE e3/e4 and e4/e4 genotype frequencies also appeared in an ordered fashion in the AD group (39.1% of e3/e4 and 10.9% of e4/e4), as well as the L-aMCI (28.3% and 9.4%), E-aMCI (22.3% and 3.7%), SMI (18.3% and 1.9%), and control (15.1% and 0.8%) groups. In the comparisons of APOE e3/e3 vs. e3/e4 genotypes, all patient groups had a higher frequency of APOE e3/e4 relative to the control group. Relative to the SMI and E-aMCI groups, the AD and L-aMCI groups had higher frequency of the APOE e3/e4 genotype, and the AD group had a higher frequency relative to the L-aMCI group. However, there was no significant difference between the E-aMCI and SMI groups. In our longitudinal data, APOE e4 carrier showed a steeper incline slope in a clinical dementia rating sum of boxes (CDR-SB) score than APOE e4 non-carrier in SMI (B = 0.0066, p = 0.0104), E-aMCI (B = 0.0313, p < 0.0001), and L-aMCI (B = 0.0178, p = 0.0007). APOE e4 carrier showed a steeper decline slope in the CDR-SB than APOE e4 non-carrier in AD (B = - 0.0309, p = 0.0003). These findings suggest that E-aMCI and SMI are associated with a similarly increased frequency of the APOE e4 allele compared to controls, suggesting a greater genetic risk for AD and the importance of monitoring the allele more closely.ope