Younghwa Lee

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.

CHANGES IN PERSPECTIVE TAKING ABILITY IN AGING PROCESS ARE DEPENDENT ON GENDER AND ALZHEIMER-RELATED COGNITIVE DECLINE

Algorithms were developed to estimate rest-activity patterns during the night, which were then extrapolated to variables such as total time asleep, sleep latency, and time awake after sleep onset. Results: Activity data was collected from the sensors for more than five hundred days. Sleep patterns were found to vary seasonally for the cognitively intact group with longer sleep periods during the winter months. This seasonal variation was not observed for those with non-amnestic mild cognitive impairment. Total time asleep was associated with the seasonal length of the night for the cognitively intact group and more weakly for the group with amnestic MCI. The cognitively intact group was found to sleep an average of 18 minutes longer in winter, while the MCI group slept 9 minutes less in winter. Conclusions:MCI is associated with an attenuation of seasonal variation in sleep patterns during the night, particularly within the subjects with non-amnestic MCI. Detection of changes in infradian sleep patterns may be an early marker of cognitive decline. Which key determinants are driving these disturbed rhythms, home environmental factors or external environmental cues, remains an important question for ongoing and future studies. P1-303 CHANGES IN PERSPECTIVE TAKING ABILITY IN AGING PROCESS ARE DEPENDENT ON GENDER AND ALZHEIMER-RELATED COGNITIVE DECLINE Dahyun Yi, Kyungjin Chu, Hyunwoong Ko, Younghwa Lee, Min Soo Byun, Jun Ho Lee, Dong Young Lee, Medical Research Center Seoul National University, Seoul, Republic of South Korea; Seoul National University Hospital, Seoul, Republic of South Korea. Contact e-mail: dahyunyi@gmail.com

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

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

Prediction of Cerebral Amyloid with Common Information Obtained from Memory Clinic Practice

Background: Given the barriers prohibiting the broader utilization of amyloid imaging and high screening failure rate in clinical trials, an easily available and valid screening method for identifying cognitively impaired patients with cerebral amyloid deposition is needed. Therefore, we developed a prediction model for cerebral amyloid positivity in cognitively impaired patients using variables that are routinely obtained in memory clinics. Methods: Six hundred and fifty two cognitively impaired subjects from the Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer disease (KBASE) and the Alzheimer’s Disease Neuroimaging Initiative-2 (ADNI-2) cohorts were included in this study (107 amnestic mild cognitive impairment (MCI) and 69 Alzheimer’s disease (AD) dementia patients for KBASE cohort, and 332 MCI and 144 AD dementia patients for ADNI-2 cohort). Using the cross-sectional dataset from the KBASE cohort, a multivariate stepwise logistic regression analysis was conducted to develop a cerebral amyloid prediction model using variables commonly obtained in memory clinics. For each participant, the logit value derived from the final model was calculated, and the probability for being amyloid positive, which was calculated from the logit value, was named the amyloid prediction index. The final model was validated using an independent dataset from the ADNI-2 cohort. Results: The final model included age, sex, years of education, history of hypertension, apolipoprotein ε4 positivity, and score from a word list recall test. The model predicted that younger age, female sex, higher educational level, absence of hypertension history, presence of apolipoprotein ε4 allele, and lower score of word list recall test are associated with higher probability for being amyloid positive. The amyloid prediction index derived from the model was proven to be valid across the two cohorts. The area under the curve was 0.873 (95% confidence interval 0.815 to 0.918) for the KBASE cohort, and 0.808 (95% confidence interval = 0.769 to 0.842) for ADNI-2 cohort. Conclusion: The amyloid prediction index, which was based on commonly available clinical information, can be useful for screening cognitively impaired individuals with a high probability of amyloid deposition in therapeutic trials for early Alzheimer’s disease as well as in clinical practice.

MODERATING EFFECT OF COGNITIVE RESERVE PROXIES ON THE ASSOCIATION BETWEEN IN VIVO AD PATHOLOGIES AND COGNITION

n 174 22 128 71 Beta-amyloid Global Pib (SUVR) 1.627 60.530 1.609 60.412 0.857 1.648 60.539 1.573 60.472 0.304 Neurodegeneration ADT (mm) 2.600 60.284 2.518 60.260 0.205 2.596 60.311 2.562 60.234 0.376 HVa (mm) -206461225 -2396 6947 0.146 -2004 61262 -2362 6 1109 0.047 50 % intracranial stenosis Number of intracranial stenosis 2 StenosisStenosis+ P-value StenosisStenosis+ P-value n 178 21 161 38 Beta-amyloid Global Pib (SUVR) 1.646 60.522 1.415 60.411 0.052 1.640 60.536 1.544 60.414 0.234 Neurodegeneration ADT (mm) 2.584 60.290 2.579 60.254 0.940 2.598 60.292 2.521 60.252 0.136 HVa (mm) -2087 6 1202 -2515 61327 0.128 -2021 61227 -2602 6 1080 0.008

Synergistic interaction between APOE and family history of Alzheimer’s disease on cerebral amyloid deposition and glucose metabolism

BackgroundRecently, the field of gene-gene or gene-environment interaction research appears to have gained growing interest, although it is seldom investigated in Alzheimer’s disease (AD). Hence, the current study aims to investigate interaction effects of the key genetic and environmental risks—the apolipoprotein ε4 allele (APOE4) and family history of late-onset AD (FH)—on AD-related brain changes in cognitively normal (CN) middle-aged and older adults.Methods[11C] Pittsburg compound-B (PiB) positron emission tomography (PET) imaging as well as [18F] fluoro-2-deoxyglucose (FDG) PET that were simultaneously taken with T1-weighted magnetic resonance imaging (MRI) were obtained from 268 CNs from the Korean Brain Aging Study for Early Diagnosis and Prediction of AD (KBASE). Composite standardized uptake value ratios were obtained from PiB-PET and FDG-PET images in the AD signature regions of interests (ROIs) and analyzed. Voxel-wise analyses were also performed to examine detailed regional changes not captured by the ROI analyses.ResultsA significant synergistic interaction effect was found between the APOE4 and FH on amyloid-beta (Aβ) deposition in the AD signature ROIs as well as other regions. Synergistic interaction effects on cerebral glucose metabolism were observed in the regions not captured by the AD signature ROIs, particularly in the medial temporal regions.ConclusionsStrong synergistic effects of APOE4 and FH on Aβ deposition and cerebral glucose metabolism in CN adults indicate possible gene-to-gene or gene-to-environment interactions that are crucial for pathogenesis of AD involving Aβ. Other unspecified risk factors—genes and/or environmental—that are captured by the positive FH status might either coexpress or interact with APOE4 to alter AD-related brain changes in CN. Healthy people with both FH and APOE4 need more attention for AD prevention.