Hyewon Baek

Heterogeneity of Regional Brain Atrophy Patterns Associated with Distinct Progression Rates in Alzheimer's Disease.

We aimed to identify and characterize subtypes of Alzheimer’s disease (AD) exhibiting different patterns of regional brain atrophy on MRI using age- and gender-specific norms of regional brain volumes. AD subjects included in the Alzheimers Disease Neuroimaging Initiative study were classified into subtypes based on standardized values (Z-scores) of hippocampal and regional cortical volumes on MRI with reference to age- and gender-specific norms obtained from 222 cognitively normal (CN) subjects. Baseline and longitudinal changes of clinical characteristics over 2 years were compared across subtypes. Whole-brain-level gray matter (GM) atrophy pattern using voxel-based morphometry (VBM) and cerebrospinal fluid (CSF) biomarkers of the subtypes were also investigated. Of 163 AD subjects, 58.9% were classified as the “both impaired” subtype with the typical hippocampal and cortical atrophy pattern, whereas 41.1% were classified as the subtypes with atypical atrophy patterns: “hippocampal atrophy only” (19.0%), “cortical atrophy only” (11.7%), and “both spared” (10.4%). Voxel-based morphometric analysis demonstrated whole-brain-level differences in overall GM atrophy across the subtypes. These subtypes showed different progression rates over 2 years; and all subtypes had significantly lower CSF amyloid-β1–42 levels compared to CN. In conclusion, we identified four AD subtypes exhibiting heterogeneous atrophy patterns on MRI with different progression rates after controlling the effects of aging and gender on atrophy with normative information. CSF biomarker analysis suggests the presence of Aβ neuropathology irrespective of subtypes. Such heterogeneity of MRI-based neuronal injury biomarker and related heterogeneous progression patterns should be considered in clinical trials and practice with AD patients.

Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease: Methodology and Baseline Sample Characteristics

Objective The Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimers disease (KBASE) aimed to recruit 650 individuals, aged from 20 to 90 years, to search for new biomarkers of Alzheimers disease (AD) and to investigate how multi-faceted lifetime experiences and bodily changes contribute to the brain changes or brain pathologies related to the AD process. Methods All participants received comprehensive clinical and neuropsychological evaluations, multi-modal brain imaging, including magnetic resonance imaging, magnetic resonance angiography, [11C]Pittsburgh compound B-positron emission tomography (PET), and [18F]fluorodeoxyglucose-PET, blood and genetic marker analyses at baseline, and a subset of participants underwent actigraph monitoring and completed a sleep diary. Participants are to be followed annually with clinical and neuropsychological assessments, and biannually with the full KBASE assessment, including neuroimaging and laboratory tests. Results As of March 2017, in total, 758 individuals had volunteered for this study. Among them, in total, 591 participants–291 cognitively normal (CN) old-aged individuals, 74 CN young- and middle-aged individuals, 139 individuals with mild cognitive impairment (MCI), and 87 individuals with AD dementia (ADD)–were enrolled at baseline, after excluding 162 individuals. A subset of participants (n=275) underwent actigraph monitoring. Conclusion The KBASE cohort is a prospective, longitudinal cohort study that recruited participants with a wide age range and a wide distribution of cognitive status (CN, MCI, and ADD) and it has several strengths in its design and methodologies. Details of the recruitment, study methodology, and baseline sample characteristics are described in this paper.

Functional Neuroanatomical Correlates of The Frontal Assessment Battery Performance in Alzheimer Disease A FDG-PET Study

Background/Objectives: We aimed to elucidate the functional neuroanatomical correlates of Frontal Assessment Battery (FAB) performances by applying [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) to a large population of patients with Alzheimer disease (AD). Methods: The FAB was administered to 177 patients with AD, and regional cerebral glucose metabolism (rCMglc) was measured by FDG-PET scan. Correlations between FAB scores and rCMglc were explored using both region-of-interest-based (ROI-based) and voxel-based approaches. Results: The ROI-based analysis showed that FAB scores correlated with the rCMglc of the dorsolateral prefrontal cortices. Voxel-based approach revealed significant positive correlations between FAB scores and rCMglc which were in various cortical regions including the temporal and parietal cortices as well as frontal regions, independent of age, gender, and education. After controlling the effect of global disease severity with Mini-Mental State Examination score, significant positive correlation was found only in the bilateral prefrontal regions. Conclusions: Although FAB scores are influenced by temporoparietal dysfunction due to the overall progression of AD, it likely reflects prefrontal dysfunction specifically regardless of global cognitive state or disease severity in patients with AD.

Sex-specific association of sex hormones and gonadotropins, with brain amyloid and hippocampal neurodegeneration

This study aimed to examine the sex-specific association between serum sex hormones and gonadotropins and the cerebral beta-amyloid (Aβ) burden and hippocampal neurodegeneration in subjects with normal cognition and impaired cognition. Two hundred sixty-five older subjects received clinical assessments, serum measurements of sex hormones, gonadotropins, 11C-Pittsburgh compound B-positron emission tomography, and magnetic resonance imaging. In females, higher free testosterone and gonadotropin levels were associated with lower cerebral Aβ positivity. In males, free testosterone was positively related to hippocampal volume with significant interaction with cognitive status. Further subgroup analyses showed that the association was significant only in impaired cognition but not in normal cognition. Free estradiol was not associated with Aβ burden or hippocampal neurodegeneration in either sex. These results suggest that testosterone might inhibit the early pathological accumulation of Aβ in females and delay neurodegeneration in males.

Differential patterns of regional cerebral hypometabolism according to the level of cerebral amyloid deposition in patients with amnestic mild cognitive impairment

Although amnestic mild cognitive impairment (aMCI) with high cerebral deposition of amyloid-beta proteins (Aβ) could be classified as a prodromal state of Alzheimers disease (AD) dementia, aMCI with the absence of or very little cerebral Aβ deposition is likely related to other pathophysiological processes. Thus, the present study aimed to investigate the differential patterns of regional cerebral glucose metabolism (rCMglu) according to the level of Aβ burden in the brains of patients with aMCI. This study included 25 patients with aMCI and 33 cognitively normal (CN) elderly individuals who underwent a comprehensive clinical examination, (11)C-labelled Pittsburgh Compound B (PiB) positron emission tomography (PET) scans, and (18)F-fluorodeoxyglucose (FDG) PET scans. Based on cerebral PiB retention, the aMCI subjects were divided into low Aβ (aMCI-, n=10) and high Aβ (aMCI+, n=15) subgroups, and differences in rCMglu among the CN group and aMCI subgroups were estimated on a voxel-by-voxel basis. Compared with the CN group, rCMglu was decreased in the bilateral medial temporal regions of the aMCI- subgroup and in the medial temporal cortices as well as the right precuneus of the aMCI+ subgroup. Additionally, rCMglu was lower in the right precuneus of the aMCI+ subgroup compared with the aMCI- subgroup. The present findings indicate that, even though both aMCI subgroups were phenomenologically very similar, the patients with aMCI- exhibited a markedly different regional pattern of functional neurodegeneration compared with the aMCI+ patients.

Differential effects of blood insulin and HbA1c on cerebral amyloid burden and neurodegeneration in nondiabetic cognitively normal older adults

We tested the hypothesis that lower insulin or higher glycated hemoglobin (HbA1c) levels in blood are associated with increased cerebral beta amyloid (Aβ) deposition and neurodegeneration in nondiabetic cognitively normal (CN) older adults. A total of 205 nondiabetic CN older adults underwent comprehensive clinical assessment, [11C]Pittsburgh compound B (PiB)-positron emission tomography (PET), [18F]fluorodeoxyglucose-PET, magnetic resonance imaging, and blood sampling for fasting insulin and HbA1c measurement. Lower blood insulin was significantly associated with increased Aβ positivity rates and decreased cerebral glucose metabolism in the AD-signature region. In contrast, higher HbA1c levels were not associated with Aβ positivity rates but were significantly associated with higher rates of having neurodegeneration in the AD-signature regions. Our results suggest different roles of insulin and HbA1c in AD pathogenesis, in that decreased blood insulin below optimal levels may contribute to increasing cerebral Aβ deposition and neurodegeneration whereas impaired glycemic control may aggravate neurodegeneration through a nonamyloid mechanism in nondiabetic CN older adults.

PREDICTION OF BETA-AMYLOID POSITIVITY IN MILD COGNITIVE IMPAIRMENT WITH DATA OBTAINED FROM ROUTINE MEMORY CLINIC PRACTICE

Abbreviations: ROC, receiver operating characteristic; AUC, area under the curve; SD, standard deviation; CI, confidence interval. Jun Ho Lee, Min Soo Byun, Dahyun Yi, Young Min Choe, Hyo Jung Choi, Hyewon Baek, Bo Kyung Sohn, Hyun Jung Kim, Jee Wook Kim, Younghwa Lee, Seon Jin Yim, Shin Gyeom Kim, Dong Young Lee, Seoul National University Hospital, Seoul, Republic of South Korea; Medical Research Center Seoul National University, Seoul, Republic of South Korea; Ulsan University Hospital, Ulsan, Republic of South Korea; Kyunggi Provincial Hospital for the Elderly, Yongin, Republic of South Korea; Seoul National University College of Medicine, Seoul, Republic of South Korea; SMG-SNU Boramae Medical Center, Seoul, Republic of South Korea; Changsan Convalescent Hospital, Changwon, Republic of South Korea; Hallym University Dongtan Sacred Hospital, Seoul, Republic of South Korea; Seoul National Hospital, Seoul, Republic of South Korea; Soon ChunHyang University Bucheon Hospital, Bucheon, Republic of South Korea. Contact e-mail: kukulolv@naver.com

Association of Cerebral Amyloidosis, Blood Pressure, and Neuronal Injury with Late-Life Onset Depression

Previous literature suggests that Alzheimers disease (AD) process may contribute to late-life onset depression (LLOD). Therefore, we investigated the association of LLOD with cerebral amyloidosis and neuronal injury, the two key brain changes in AD, along with vascular risks. Twenty nine non-demented individuals who first experienced major depressive disorder (MDD) after age of 60 years were included as LLOD subjects, and 27 non-demented elderly individuals without lifetime experience of MDD were included as normal controls (NC). Comorbid mild cognitive impairment (MCI) was diagnosed in 48% of LLOD subjects and in 0% of NC. LLOD, irrespective of comorbid MCI diagnosis, was associated with prominent prefrontal cortical atrophy. Compared to NC, LLOD subjects with comorbid MCI (LLODMCI) showed increased cerebral 11C-Pittsburg compound B (PiB) retention and plasma beta-amyloid 1–40 and 1–42 peptides, as measures of cerebral amyloidosis; and, such relationship was not observed in overall LLOD or LLOD without MCI (LLODwoMCI). LLOD subjects, particularly the LLODwoMCI, had higher systolic blood pressure (SBP) than NC. When analyzed in the same multiple logistic regression model that included prefrontal gray matter (GM) density, cerebral amyloidosis, and SBP as independent variables, only prefrontal GM density showed a significant independent association with LLOD regardless of MCI comorbidity status. Our findings suggest AD process might be related to LLOD via prefrontal neuronal injury in the MCI stage, whereas vascular processes—SBP elevation, in particular—are associated with LLOD via prefrontal neuronal injury even in cognitively intact or less impaired individuals.

SLEEP QUALITY IN YOUNG AND MIDDLE AGE-PERIOD IS ASSOCIATED WITH CEREBRAL AMYLOID BURDEN IN COGNITIVELY NORMAL ELDERLY PEOPLE

trate the regions of significance. Results:The association between baseline levels of cognition and inflammation was greater in the Tg than Wt rats in the right nucleus accumbens, whereas in the opposite was seen in the right inferior colliculus. The association between baseline levels of inflammation and change in cognition at follow-up, several regions including the left retrosplenial cortex, right hippocampus, and the right posterior commissure showed higher decrease in cognition of the Tg animals compared to the Wt (Figure 1). Conclusions:At baseline, there is no association between neuroinflammation and cognitive performance; however in more aged rats, baseline levels of PBR is able to predict cognitive decline. The results provide a framework that could potentially be applied in human studies focusing on the detrimental roles of neuroinflammation in AD.

ASSOCIATION OF SERUM THYROID HORMONE WITH CEREBRAL AMYLOID DEPOSITION AND REGIONAL CEREBRAL GLUCOSE METABOLISM IN COGNITIVELY NORMAL, CLINICALLY EUTHYROID ELDERLY INDIVIDUALS

Hyo Jung Choi, Min Soo Byun, Dahyun Yi, Hyewon Baek, Jun Ho Lee, Hyun Jung Kim, Young Min Choe, Bo Kyung Sohn, Jee Wook Kim, Younghwa Lee, Hyunwoong Ko, Na Young Han, Seung Hoon Lee, Kang Ko, Jong Inn Woo, Dong Young Lee, Seoul National University Hospital, Seoul, The Republic of Korea; 2 Medical Research Center Seoul National University, Seoul, The Republic of Korea; Ulsan University Hospital, Ulsan, The Republic of Korea; SMG-SNU Boramae Medical Center, Seoul, South Korea; 5 Hallym University Dongtan Sacred Hospital, Seoul, The Republic of Korea. Contact e-mail: jung830313@hanmail.net