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Background: Despite the known associations between zinc levels and Alzheimer's disease (AD) dementia and related cognitive impairment, the underlying neuropathological links remain poorly understood. We tested the hypothesis that serum zinc level is associated with cerebral beta-amyloid protein (Aβ) deposition. Additionally, we explored associations between serum zinc levels and other AD pathologies [i.e., tau deposition and AD-signature cerebral glucose metabolism (AD-CM)] and white matter hyperintensities (WMHs), which are measures of cerebrovascular injury., Methods: A total of 241 cognitively normal older adults between 55 and 90 years of age were enrolled. All the participants underwent comprehensive clinical assessments, serum zinc level measurement, and multimodal brain imaging, including Pittsburgh compound B-positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and magnetic resonance imaging. Zinc levels were stratified into three categories: < 80 μg/dL (low), 80 to 90 μg/dL (medium), and > 90 μg/dL (high)., Results: A low serum zinc level was significantly associated with increased Aβ retention. In addition, apolipoprotein E ε4 allele (APOE4) status moderated the association: the relationship between low zinc level and Aβ retention was significant only in APOE4 carriers. Although a low zinc level appeared to reduce AD-CM, the relationship became insignificant on sensitivity analysis including only individuals with no nutritional deficiency. The serum zinc level was associated with neither tau deposition nor the WMH volume., Conclusions: Our findings suggest that decreased serum zinc levels are associated with elevation of brain amyloid deposition. In terms of AD prevention, more attention needs to be paid to the role of zinc., (© 2021. The Author(s).)

Background: Both elevated blood homocysteine and diabetes mellitus (DM) are related to cognitive impairments or dementia. A previous study also demonstrated that the association between homocysteine and cognitive decline was much stronger in individuals with DM than in those without DM., Objective: This study aimed to examine the interactive effect of blood homocysteine and DM on brain pathological changes including brain atrophy, amyloid-β and tau deposition, and small vessel disease (SVD) related to cognitive impairments., Methods: A total of 430 non-demented older adults underwent comprehensive clinical assessment, measurement of serum homocysteine level, [11C] Pittsburgh Compound B (PiB) PET, [18F] AV-1451 PET, and brain MRI., Results: The interactive effect of homocysteine with the presence of DM on brain atrophy, especially in aging-related brain regions, was significant. Higher homocysteine concentration was associated with more prominent brain atrophy in individuals with DM, but not in those without DM. In contrast, interaction effect of homocysteine and DM was found neither on Alzheimer's disease (AD) pathologies, including amyloid-β and tau deposition, nor white matter hyperintensity volume as a measure of SVD., Conclusion: The present findings suggest that high blood homocysteine level and DM synergistically aggravate brain damage independently of AD and cerebrovascular disease. With regard to preventing dementia or cognitive decline in older adults, these results support the importance of strictly controlling blood glucose in individuals with hyperhomocysteinemia and lowering blood homocysteine level in those with DM.

Objectives: To investigate the relationships of serum albumin with in vivo Alzheimer disease (AD) pathologies, including cerebral β-amyloid (Aβ) protein deposition, neurodegeneration of AD-signature regions, and cerebral white matter hyperintensities (WMH), in the human brain., Methods: A total of 396 older adults without dementia underwent comprehensive clinical assessments, measurement of serum albumin level, and multimodal brain imaging, including [ 11 C] Pittsburgh compound B-PET, 18 F-fluorodeoxyglucose-PET, and MRI. Serum albumin was categorized as follows: <4.4 g/dL (low albumin), 4.4 to 4.5 g/dL (middle albumin), and >4.5 g/dL (high albumin; used as a reference category). Aβ positivity, AD-signature region cerebral glucose metabolism (AD-CM), AD-signature region cortical thickness (AD-CT), and WMH volume were used as outcome measures., Results: Serum albumin level (as a continuous variable) was inversely associated with Aβ deposition and Aβ positivity. The low albumin group showed a significantly higher Aβ positivity rate compared to the high albumin group (odds ratio 3.40, 95% confidence interval 1.67-6.92, p = 0.001), while the middle albumin group showed no difference (odds ratio 1.74, 95% confidence interval 0.80-3.77, p = 0.162). Neither serum albumin level (as a continuous variable) nor albumin categories were related to AD-CM, AD-CT, or WMH volume., Conclusions: Low serum albumin may increase the risk of AD dementia by elevating amyloid accumulation. In terms of AD prevention, more attention needs to be paid to avoid a low serum albumin level, even within the clinical normal range, by clinicians., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: An emerging body of literature has indicated that moderate alcohol intake may be protective against Alzheimer disease (AD) dementia. However, little information is available regarding whether moderate alcohol intake is related to reductions in amyloid-beta (Aβ) deposition, or is protective via amyloid-independent mechanisms in the living human brain. Here we examined the associations of moderate alcohol intake with in vivo AD pathologies, including cerebral Aβ deposition, neurodegeneration of AD-signature regions, and cerebral white matter hyperintensities (WMHs) in the living human brain., Methods and Findings: The present study was part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE), an ongoing prospective cohort study that started in 2014. As of November 2016, 414 community-dwelling individuals with neither dementia nor alcohol-related disorders (280 cognitively normal [CN] individuals and 134 individuals with mild cognitive impairment [MCI]) between 56 and 90 years of age (mean age 70.9 years ± standard deviation 7.8; male, n [%] = 180 [43.5]) were recruited from 4 sites (i.e., 2 university hospitals and 2 public centers for dementia prevention and management) around Seoul, South Korea. All the participants underwent comprehensive clinical assessments comprising lifetime and current histories of alcohol intake and multimodal brain imaging, including [11C] Pittsburgh compound B positron emission tomography (PET), [18F] fluorodeoxyglucose (FDG) PET, and magnetic resonance imaging (MRI) scans. Lifetime and current alcohol intake were categorized as follows: no drinking, <1 standard drink (SD)/week, 1-13 SDs/week, and 14+ SDs/week. A moderate lifetime alcohol intake (1-13 SDs/week) was significantly associated with a lower Aβ positivity rate compared to the no drinking group, even after controlling for potential confounders (odds ratio 0.341, 95% confidence interval 0.163-0.714, p = 0.004). In contrast, current alcohol intake was not associated with amyloid deposition. Additionally, alcohol intake was not related to neurodegeneration of AD-signature regions or cerebral WMH volume. The present study had some limitations in that it had a cross-sectional design and depended on retrospective recall for alcohol drinking history., Conclusions: In this study, we observed in middle- and old-aged individuals with neither dementia nor alcohol-related disorders that moderate lifetime alcohol intake was associated with lower cerebral Aβ deposition compared to a lifetime history of not drinking. Moderate lifetime alcohol intake may have a beneficial influence on AD by reducing pathological amyloid deposition rather than amyloid-independent neurodegeneration or cerebrovascular injury., Competing Interests: The authors have declared that no competing interests exist.

Background: Although recent studies indicate that the relationship between body mass index (BMI) and Alzheimer's disease (AD) may differ by both sex and age of BMI measurement, little information is available on sex- or age-specific associations between BMI and AD neuropathologies., Objective: To examined whether sex-specific BMIs measured at different life-stages (in early adulthood, midlife, and late life) were associated with cerebral amyloid-β (Aβ) deposition and AD-signature region cortical thickness (AD-CT) in cognitively normal (CN) older adults., Methods: A total of 212 CN subjects aged 60-90 years (females 108, males 104), who participated in the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE), an ongoing prospective cohort study, were included. All participants underwent comprehensive clinical and neuropsychological assessments, [11C] Pittsburgh Compound B positron emission tomography, and brain magnetic resonance imaging. BMIs at different life stages were calculated. Multiple regression analyses were performed separately for either sex., Results: In males, lower early adulthood or midlife BMI was associated with greater cerebral Aβ deposition, but late life BMI was not. Lower midlife BMI was associated with reduced AD-CT, but the BMI in early adulthood and late life was not. In females, no significant association was observed between any lifetime BMI and Aβ deposition or AD-CT., Conclusion: Our results support a male-specific association between BMI prior to late life, and in vivo AD pathologies. Avoiding underweight status early in life may be important to prevent AD dementia in males, but not females.

Several epidemiological and preclinical studies supported the protective effect of coffee on Alzheimer's disease (AD). However, it is still unknown whether coffee is specifically related with reduced brain AD pathologies in human. Hence, this study aims to investigate relationships between coffee intake and in vivo AD pathologies, including cerebral beta-amyloid (Aβ) deposition, the neurodegeneration of AD-signature regions, and cerebral white matter hyperintensities (WMH). A total of 411 non-demented older adults were included. Participants underwent comprehensive clinical assessment and multimodal neuroimaging including [ 11 C] Pittsburgh compound B-positron emission tomography (PET), [ 18 F] fluorodeoxyglucose PET, and magnetic resonance imaging scans. Lifetime and current coffee intake were categorized as follows: no coffee or <2 cups/day (reference category) and ≥2 cups/day (higher coffee intake). Lifetime coffee intake of ≥2 cups/day was significantly associated with a lower Aβ positivity compared to coffee intake of <2 cups/day, even after controlling for potential confounders. In contrast, neither lifetime nor current coffee intake was not related to hypometabolism, atrophy of AD-signature region, and WMH volume. The findings suggest that higher lifetime coffee intake may contribute to lowering the risk of AD or related cognitive decline by reducing pathological cerebral amyloid deposition.

Background: Metamemory is the process of monitoring and controlling one's memory. Improving metamemory may reduce the memory problem in old age. We hypothesized that metamemory training (MMT) would improve cognition in older adults with subjective memory complaints and change the brain region related to metacognition., Method: We recruited and randomized older adults to the multi-strategic memory training of 10 weekly 90-min sessions, based on the metamemory concept or usual care. Cognitive tests including the Elderly Verbal Learning Test, Simple Rey Figure Test, Digit Span, Spatial Span, Categorical Fluency, and the Boston Naming Test were done in 201 participants, together with magnetic resonance imaging (MRI) in 49 participants before and after training., Results: A total of 112 in the training group and 89 in the control group participated. The training group had a significant increase in long-term delayed free recall, categorical fluency, and the Boston Naming test. In MRI, the mean diffusivity of the bundles of axon tracts passing from the frontal lobe to the posterior end of the lateral sulcus decreased in the training group., Conclusion: These results indicate that the MMT program has a positive impact on enhancing older people' cognitive performance. Improved white matter integrity in the anterior and posterior cerebrum and increased cortical thickness of prefrontal regions, which related to metacognition, possibly suggest that the effects of the MMT would be induced via the enhancement of cognitive control., (© 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

This study tested the efficacy of the phosphodiesterase type III inhibitor cilostazol in Alzheimer's disease patients with white matter lesions treated with donepezil in comparison with donepezil monotherapy using fluorodeoxyglucose ( 18 F) positron-emission tomography (FDG PET). A 24-week, randomized, double-blind, placebo-controlled, parallel-group study was conducted. Thirty-six Alzheimer's disease patients with white matter lesions who received donepezil (n = 18 each in the cilostazol and placebo groups) were enrolled. Participants underwent pre and post FDG PET imaging scans and three rounds of clinical and neuropsychological tests. The cilostazol group did not show a significant decrease of regional glucose metabolism; however, regional glucose metabolism was significantly decreased in the parietal and frontal lobes of the placebo group. The repeated measures ANOVA measuring differences in uptake change revealed that regional glucose metabolism in the left inferior frontal gyrus was significantly more preserved in the cilostazol group than that in the placebo group (p < 0.005). Mean changes from baseline on the Mini-Mental State Exam, Alzheimer's Disease Assessment Scale-cognitive subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory, and the Clinical Dementia Rating Sum of Boxes did not differ between the two groups. In the cilostazol group, the increase of glucose metabolism correlated with the improvment of the Alzheimer's Disease Assessment Scale-cognitive score. We conclude that cilostazol treatment added to donepezil may delay the decline in regional cerebral metabolism in Alzheimer's disease with white matter lesions compared with donepezil monotherapy. In additon, our results verified the efficacy of cilostazol in improving or protecting cognitive function in Alzheimer's disease through increased glucose metabolism. However, the long-term effect of cilostazol on cognitive function and Alzheimer's disease modification must be tested in further studies with larger sample size and longer study period. Trial registration: http://clinicaltrials.gov : NCT01409564.

Ojjective: The aim of this study was to find peripheral biomarkers and central metabolites affecting neuroinflammation in complex regional pain syndrome (CRPS) patients using [11C]-(R)-PK11195 positron emission tomography (PET) and magnetic resonance spectroscopy (MRS)., Methods: Using MRS and PET, we measured associations between neurometabolites and neuroinflammation in 12 CRPS patients and 11 healthy controls. Also, we investigated various peripheral parameters that may affect neuroinflammation in CRPS., Results: We found positive correlations of Lipid (Lip)13a/total creatine (tCr) and Lip09/tCr with neuroinflammation, the distribution volume ratio (DVR) of [11C]-(R)-PK11195 in the right and left insula in CRPS patients. However, these correlations were not found in controls. High hemoglobin levels correlated with decreased neuroinflammation (the DVR of [11C]-(R)-PK11195) in the right thalamus and left insula in healthy controls. We found that high levels of glucose and pH correlated with increased neuroinflammation, but high levels of CO2, basophil, and creatinine were associated with decreased neuroinflammation in the left thalamus and the right and left insula in CRPS patients., Conclusions: This is the first report indicating that elevated neuroinflammation levels are associated primarily with lipids in the brain and pH, glucose, CO2, basophil, and creatinine in the peripheral parameters in CRPS patients. Our results suggest that characterizing the peripheral biomarkers and central metabolites affecting neuroinflammation is essential to understanding the pathophysiology of CRPS., (© 2018 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The aim of this study was to investigate distinct neurometabolites in the right and left thalamus and insula of patients with complex regional pain syndrome (CRPS) compared with healthy controls using proton magnetic resonance spectroscopy. Levels of N-acetylaspartate (NAA), N-acetylaspartylglutamate (NAAG), myo-inositol (ml), glutamine (Gln), glycerophosphocholine (GPC), glutathione (GSH), and alanine (Ala) relative to total creatine (tCr) levels, including creatine and phosphocreatine, were determined in the right and left thalamus and insula in 12 patients with CRPS compared with 11 healthy controls using magnetic resonance spectroscopy. Levels of NAAG/tCr and Ala/tCr were higher in patients with CRPS than in controls in the left thalamus. NAAG/tCr, ml/tCr, and Gln/tCr levels were higher but NAA/tCr levels were lower in the right insula of patients with CRPS compared with controls. There were negative correlations between GSH/tCr and pain score (McGill Pain Questionnaire) in the left thalamus. These findings are paramount to understand and determine all aspects of the complex pathophysiological mechanisms that underlie CRPS, including involvement of the central and parasympathetic nervous systems as well as oxidative stress and antioxidants. Thus, the distinct metabolites presented herein may be essential to understand a strong diagnostic and prognostic potential for CRPS and to develop effective medical treatments.

The purpose of this study was to assess scores and processing speed distributions of the instrument, A Quick Test of Cognitive Speed (AQT), in Korean older adults through behavioral and brain imaging approaches. Participants were instructed to say the color names, stimuli's form, and both the color and form. Test scores and processing speeds were measured in these three subtests of color, form, and color-form. A total of 67 patients (22 healthy controls (HC), 22 with mild cognitive impairment (MCI), and 23 with Alzheimer's disease (AD)) participated. Only color-form score and processing speed of the three subtests could be used to differentiate AD from MCI and HC. Color-form score showed the largest effects size (partial η 2  = 0.268) for distinguishing AD, MCI from HC and ROC curve analysis confirmed a high level of sensitivity (0.857) and specificity (0.826) for discrimination between AD and HC. None of the subtests could differentiate HC from MCI. Voxel-based morphometry analysis of brain structure in 27 participants (9 in each group) revealed that gray matter volume of the middle occipital gyrus and inferior parietal cortex were associated with color-form score. This study suggests preliminary evidence in the clinical utility of the AQT for screening AD in older Korean adults. The color-form score could be implemented for clinical utilization in a very brief time. Furthermore, strong positive correlations between color-form scores and the brain areas responsible for visuospatial working memory corroborate the validity of AQT., (Copyright © 2018. Published by Elsevier B.V.)

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, [ 11 C]Pittsburgh compound B (PiB)-positron emission tomography (PET), [ 18 F]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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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, 11 C-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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The present study investigated the relationships between thyroid hormone serum levels or thyroid-stimulating hormone (TSH) and two Alzheimer's disease (AD)-specific biomarkers, cerebral amyloid beta (Aβ) burden and glucose metabolism, in AD-signature brain regions in cognitively normal (CN) middle-aged and older individuals., Methods: This study assessed 148 CN individuals who received comprehensive clinical and neuropsychological assessments that included 11 C-Pittsburgh Compound B (PiB)-positron emission tomography (PET) scans, 18 F-deoxyglucose (FDG)-PET scans, and the quantification of serum triiodothyronine (T3), free T3, free thyroxine (fT4), and TSH levels., Results: All participants were clinically euthyroid. Independent negative associations were found between serum fT4 levels and global cerebral Aβ deposition after controlling for the effects of age, gender, and the apolipoprotein E ε4 (APOEε4) genotype. Although serum TSH levels were not associated with global cerebral Aβ deposition, they had a significant negative association with glucose metabolism in the precuneus/posterior cingulate cortex after controlling for age, gender, and the APOEε4 genotype. No other thyroid hormones exhibited relationships with either brain Aβ burden or glucose metabolism., Conclusions: Even in a clinical euthyroid state, low serum fT4 and high serum TSH levels appear to be differentially associated with AD-specific brain changes.

The present study compared neural connectivity and the level of phasic synchronization between neural populations in patients with Internet gaming disorder (IGD), patients with alcohol use disorder (AUD), and healthy controls (HCs) using resting-state electroencephalography (EEG) coherence analyses. For this study, 92 adult males were categorized into three groups: IGD (n = 30), AUD (n = 30), and HC (n = 32). The IGD group exhibited increased intrahemispheric gamma (30-40 Hz) coherence compared to the AUD and HC groups regardless of psychological features (e.g., depression, anxiety, and impulsivity) and right fronto-central gamma coherence positively predicted the scores of the Internet addiction test in all groups. In contrast, the AUD group showed marginal tendency of increased intrahemispheric theta (4-8 Hz) coherence relative to the HC group and this was dependent on the psychological features. The present findings indicate that patients with IGD and AUD exhibit different neurophysiological patterns of brain connectivity and that an increase in the fast phasic synchrony of gamma coherence might be a core neurophysiological feature of IGD.

As a new beta amyloid (Aβ) positron emission tomography (PET) tracer, F-FC119S has shown higher cortical uptake in patients with Alzheimer's disease (AD) than that in healthy control subjects without adverse effects in a previous preliminary study. The aim of this study was to compare F-FC119S PET and C-PiB PET in healthy control (HC) subjects, mild cognitive impairment (MCI) patients, and AD patients.A total of 48 subjects, including 28 HC subjects, 10 MCI patients, and 10 AD patients, underwent static F-FC119S PET (30 minutes after intravenous [i.v.] injection) and C-PiB PET (40 minutes after i.v. injection) on the same day. Both PET images were visually and quantitatively assessed. Standardized uptake value ratios (SUVRs) were calculated for each brain region using the cerebellar cortex as a reference region.None (0%) of the 28 HC subjects and 4 (40%) of 10 MCI patients had positive scans on both PET images. Of the 10 AD patients, 7 (70%) had positive scans on C-PiB PET while 6 (60%) had positive scans on F-FC119S PET. Overall, 47 (98%) of 48 participants showed identical results based on visual analysis. Cortical SUVR of F-FC119S was higher in AD patients (1.38 ± 0.16), followed by that in MCI patients (1.24 ± 0.10) and in HC subjects (1.14 ± 0.05). Compared with C-PiB PET, F-FC119S PET yielded a higher effect size (d = 2.02 vs. 1.67) in AD patients and a slightly lower effect size (d = 1.26 vs. 1.38) in MCI patients. In HC subjects, the nonspecific binding of F-FC119S to white matter (with the frontal cortex-to-white matter SUV ratio of 0.76) was slightly lower than that of C-PiB (ratio of 0.73). There was a significant linear correlation (slope = 0.41, r = 0.78, P < 0.001) between C-PiB and F-FC119S cortical SUVR.We could safely obtain images similar to C-PiB PET imaging Aβ in the brain using F-FC119S PET. Therefore, F-FC119S might be suitable for imaging Aβ deposition.

The identification of the predictive factors and biological markers associated with treatment-related changes in the symptoms of Internet gaming disorder (IGD) may provide a better understanding of the pathophysiology underlying this condition. Thus, the present study aimed to identify neurophysiological markers associated with symptom changes in IGD patients and to identify factors that may predict symptom improvements following outpatient treatment with pharmacotherapy. The present study included 20 IGD patients (mean age: 22.71 ± 5.47 years) and 29 healthy control subjects (mean age: 23.97 ± 4.36 years); all IGD patients completed a 6-month outpatient management program that included pharmacotherapy with selective serotonin reuptake inhibitors. Resting-state electroencephalography scans were acquired prior to and after treatment, and the primary treatment outcome was changes in scores on Young's Internet Addiction Test (IAT) from pre- to posttreatment. IGD patients showed increased resting-state electroencephalography activity in the delta and theta bands at baseline, but the increased delta band activity was normalized after 6 months of treatment and was significantly correlated with improvements in IGD symptoms. Additionally, higher absolute theta activity at baseline predicted a greater possibility of improvement in addiction symptoms following treatment, even after adjusting for the effects of depressive or anxiety symptoms. The present findings demonstrated that increased slow-wave activity represented a state neurophysiological marker in IGD patients and suggested that increased theta activity at baseline may be a favorable prognostic marker for this population.

The primary goals of the present study were to develop and validate the Rappel Indicé 24 (RI-24), a shorter version of the original Rappel Indicé, which includes 48 items (RI-48), and to identify the specific brain regions that were correlated with scores on the RI-24. Using these clinical scales, the present study evaluated 91 elderly Korean participants who were classified into 3 groups: normal control (NC; n = 34), patients with mild cognitive impairment (MCI; n = 29), and patients with Alzheimer disease (AD; n = 28). Of the 91 participants, 77 also underwent magnetic resonance imaging scans. The RI-24 delayed cued recall (DCR) scores significantly differed among the NC, MCI, and AD groups. A receiver-operating characteristic curve analysis revealed that the RI-24 was very sensitive (89%) and specific (91%) for the detection of AD. Furthermore, although the time needed to administer the RI-24 was half that needed for the RI-48, the 24-item version showed a high correlation (r= .85 for the DCR score) with the 48-item version. In terms of brain morphological characteristics, voxel-based morphometry analyses revealed a significant positive correlation between DCR score and gray matter volume in the parahippocampal gyrus (r= .468), which plays a role in cued recall. Taken together, the present findings indicate that the RI-24 is a sensitive and reliable test for the detection of memory impairments in patients with MCI and AD despite its brief administration time., (© The Author(s) 2016.)

A boronic acid-based fluorescent probe was developed for diagnosis of amyloid-β (Aβ) plaques from Alzheimer's disease (AD). Probe 4c, which included boronic acid as a functional group, exhibited a significant increase (64.37-fold, FAβ/F0) in fluorescence intensity as a response to Aβ aggregates, with a blue shift (105nm) in the maximum emission wavelength. We found that boronic acid as a functional group improved the binding affinity (KD value=0.79±0.05μM for 4c) for Aβ aggregates and confirmed that 4c selectively stained Aβ plaques in brain sections from APP/PS1 mice. Ex vivo fluorescence imaging using mice (normal and APP/PS1) also revealed that 4c was able to penetrate the blood-brain barrier (BBB) and to stain Aβ plaques in the brain. From these results, we believe that 4c will be useful as a fluorescent probe in preclinical research related to AD. Furthermore, we believe that our results with boronic acid also provide valuable information for the development of a probe for Aβ plaques., (Copyright © 2016. Published by Elsevier Ltd.)

Background: A standardized tool for evaluating semantic knowledge of the Korean population is needed., Objective: The purpose of this study was to develop a neuropsychological test for the evaluation of semantic knowledge in the Korean elderly population., Methods: The Korean version of the Size/Weight Attribute Test (SWAT-K) was developed in reference to the original version. The diagnostic validity of SWAT-K was evaluated with 95 elderly outpatients [67 normal controls; 18 with Alzheimer's disease (AD); 10 with semantic-variant progressive aphasia (SV-PPA)]. Voxel-based morphometry (VBM) was employed to examine associations between SWAT-K scores and morphological changes of the brain., Results: SWAT-K could discriminate the three subject groups (normal >AD, p <  0.001; AD >SV-PPA, p = 0.040), whereas Boston Naming Test could not distinguish SV-PPA from AD. ROC curve analysis confirmed high levels of sensitivity (0.90) and specificity (0.93) for SWAT-K. The test's inter-rater reliability (ICC = 0.827) and test-retest reliability (ICC = 0.666) were assessed as well. VBM found a significant positive correlation (uncorrected p <  0.005, k >  100) between SWAT-K scores and gray matter volume in right inferior frontal cortex (T = 4.08, k = 191) and bilateral temporal cortices (left, T = 4.42, k = 135; right, T = 3.55, k = 253), the areas the most affected in SV-PPA., Conclusions: SWAT-K is a sensitive and reliable test for evaluating semantic knowledge in the Korean elderly population. Strong positive correlations between SWAT-K scores and the brain areas responsible for semantic processing further corroborate the validity of SWAT-K.

Objective: Internet gaming disorder (IGD) shares core clinical features with other addictive disorders, such as gambling disorder and substance use disorder. Designation of IGD as a formal disorder requires elucidation of its neurobiological features and comparison of these with those of other addictive disorders. The aims of the present study were to identify the neurobiological features of the resting-state brain of patients with IGD, alcohol use disorder (AUD), and healthy controls, and to examine brain regions related to the clinical characteristics of IGD., Method: Functional magnetic resonance imaging was performed on 16 subjects with IGD, 14 subjects with AUD, and 15 healthy controls during the resting-state. We computed regional homogeneity (ReHo) measures to identify intrinsic local connectivity and to explore associations with clinical status and impulsivity., Results: We found significantly increased ReHo in the posterior cingulate cortex (PCC) of the IGD and AUD groups, and decreased ReHo in the right superior temporal gyrus (STG) of those with IGD, compared with the AUD and HC groups. We also found decreased ReHo in the anterior cingulate cortex of patients with AUD. Scores on Internet addiction severity were positively correlated with ReHo in the medial frontal cortex, precuneus/PCC, and left inferior temporal cortex (ITC) among those with IGD. Furthermore, impulsivity scores were negatively correlated with that in the left ITC in individuals with IGD., Conclusion: Our results provide evidence of distinctive functional changes in the resting-state of patients with IGD and demonstrate that increased ReHo in the PCC may be a common neurobiological feature of IGD and AUD and that reduced ReHo in the STG may be a candidate neurobiological marker for IGD, differentiating individuals with this disorder from those with AUD and healthy controls., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Many researchers have reported a relationship between Internet addiction and depression. In the present study, we compared the resting-state quantitative electroencephalography (QEEG) activity of treatment-seeking patients with comorbid Internet addiction and depression with those of treatment-seeking patients with Internet addiction without depression, and healthy controls to investigate the neurobiological markers that differentiate pure Internet addiction from Internet addiction with comorbid depression., Method: Thirty-five patients diagnosed with Internet addiction and 34 age-, sex-, and IQ-matched healthy controls were enrolled in this study. Patients with Internet addiction were divided into two groups according to the presence (N=18) or absence (N=17) of depression. Resting-state, eye-closed QEEG was recorded, and the absolute and relative power of the brain were analyzed., Results: The Internet addiction group without depression had decreased absolute delta and beta powers in all brain regions, whereas the Internet addiction group with depression had increased relative theta and decreased relative alpha power in all regions. These neurophysiological changes were not related to clinical variables., Conclusion: The current findings reflect differential resting-state QEEG patterns between both groups of participants with Internet addiction and healthy controls and also suggest that decreased absolute delta and beta powers are neurobiological markers of Internet addiction., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Pathological gambling (PG) and obsessive-compulsive disorder (OCD) are conceptualized as a behavioral addiction, with a dependency on repetitive gambling behavior and rewarding effects following compulsive behavior, respectively. However, no neuroimaging studies to date have examined reward circuitry during the anticipation phase of reward in PG compared with in OCD while considering repetitive gambling and compulsion as addictive behaviors., Methods/principal Findings: To elucidate the neural activities specific to the anticipation phase of reward, we performed event-related functional magnetic resonance imaging (fMRI) in young adults with PG and compared them with those in patients with OCD and healthy controls. Fifteen male patients with PG, 13 patients with OCD, and 15 healthy controls, group-matched for age, gender, and IQ, participated in a monetary incentive delay task during fMRI scanning. Neural activation in the ventromedial caudate nucleus during anticipation of both gain and loss decreased in patients with PG compared with that in patients with OCD and healthy controls. Additionally, reduced activation in the anterior insula during anticipation of loss was observed in patients with PG compared with that in patients with OCD which was intermediate between that in OCD and healthy controls (healthy controls < PG < OCD), and a significant positive correlation between activity in the anterior insula and South Oaks Gambling Screen score was found in patients with PG., Conclusions: Decreased neural activity in the ventromedial caudate nucleus during anticipation may be a specific neurobiological feature for the pathophysiology of PG, distinguishing it from OCD and healthy controls. Correlation of anterior insular activity during loss anticipation with PG symptoms suggests that patients with PG fit the features of OCD associated with harm avoidance as PG symptoms deteriorate. Our findings have identified functional disparities and similarities between patients with PG and OCD related to the neural responses associated with reward anticipation.

We investigated the associations of periventricular white matter hyperintensities (PWMHs) and deep white matter hyperintensities (DWMHs) with cognition, activities of daily living (ADLs), and neuropsychiatric symptoms in dementia. This was a hospital-based MRI300 study. We recruited patients newly diagnosed with mild-to-moderate dementia caused either by Alzheimer's disease or subcortical ischemic vascular dementia from 13 dementia clinics at university or general hospitals in South Korea. We enrolled 289 patients aged over 50 from August 2007 to March 2008. We compared cognition, ADLs, and neuropsychiatric symptoms among 3 groups according to the severities of PWMHs and DWMHs, respectively, by adjusting for age, vascular risk factors, and level of other WMHs. A higher severity of PWMHs was related to lower cognitive function and severer neuropsychiatric symptoms, whereas basic ADLs were associated with DWMH. Both PWMHs and DWMHs exhibited different associations with cognition, neuropsychiatric symptoms, and daily activities.

Background: White matter hyperintensities (WMH) increase cognitive impairment in patients with dementia., Objective: We investigated the impact of WMH on the neuropsychological profiles in patients with mild to moderate dementia., Methods: We consecutively recruited newly diagnosed patients with mild to moderate dementia across South Korea for 1 year. The participants completed neuropsychological tests, magnetic resonance imaging, and structured neurological evaluations. The patients were divided into 3 categories, i.e. minimal, moderate, and severe WMH groups, according to the proportional degree of WMH., Results: 289 patients were recruited; 140 (48.3%) for the minimal WMH group, 99 (34.2%) for the moderate group, and 50 (17.5%) for the severe group. Both advanced age and low general cognitive level were significant contributors to WMH in patients with dementia. After adjusting for age, the neuropsychological correlates of the proportional impact of WMH were frontal executive, language, and attention profiles. However, the only significant neuropsychological correlate was the recognition memory profile after adjusting for both age and general cognitive level simultaneously., Conclusion: The results suggest that the most significant neuropsychological profile impacting the burden of WMH in patients with mild to moderate dementia was the recognition memory profile, regardless of age and general cognitive function., (Copyright © 2011 S. Karger AG, Basel.)

The association between white matter changes and activities of daily living (ADL) in a large, well-defined cohort of patients with mild-to-moderate dementia (either Alzheimer's disease or subcortical vascular dementia) were investigated. A total of 289 patients were divided into three groups (140 mild, 99 moderate, and 50 severe) depending on the degree of white matter changes as indicated on brain magnetic resonance image scans. Further, we analyzed the three groups' performances on basic and instrumental ADL. The degree of white matter changes was associated with greater age, hypertension, previous history of stroke, higher Hachinski Ischemic Score, worse global cognitive and functional status, and an increased impairment of basic ADL and instrumental ADL. The increased impairment with regard to the severe group's performance on both the basic and instrumental ADL remained significant after adjustment for age and hypertension. Tasks involving physical activities were most significant. This was the first study investigating the association between white matter changes and ADL in a large, well-defined dementia cohort. The present study suggests that severe white matter changes may be associated with higher impairment on both basic and instrumental ADL., (Copyright © 2010 S. Karger AG, Basel.)

Study Objectives: To investigate differences in brain gray matter concentrations or volumes in patients with obstructive sleep apnea syndrome (OSA) and healthy volunteers., Designs: Optimized voxel-based morphometry, an automated processing technique for MRI, was used to characterize structural differences in gray matter in newly diagnosed male patients., Setting: University hospital., Patients and Participants: The study consisted of 36 male OSA and 31 non-apneic male healthy volunteers matched for age (mean age, 44.8 years)., Interventions: Using the t-test, gray matter differences were identified. The statistical significance level was set to a false discovery rate P < 0.05 with an extent threshold of k(E) > 200 voxels., Measurements and Results: The mean apnea-hypopnea index (AHI) of patients was 52.5/h. On visual inspection of MRI, no structural abnormalities were observed. Compared to healthy volunteers, the gray matter concentrations of OSA patients were significantly decreased in the left gyrus rectus, bilateral superior frontal gyri, left precentral gyrus, bilateral frontomarginal gyri, bilateral anterior cingulate gyri, right insular gyrus, bilateral caudate nuclei, bilateral thalami, bilateral amygdalo-hippocampi, bilateral inferior temporal gyri, and bilateral quadrangular and biventer lobules in the cerebellum (false discovery rate P < 0.05). Gray matter volume was not different between OSA patients and healthy volunteers., Conclusions: The brain gray matter deficits may suggest that memory impairment, affective and cardiovascular disturbances, executive dysfunctions, and dysregulation of autonomic and respiratory control frequently found in OSA patients might be related to morphological differences in the brain gray matter areas.

Ictal Single Proton Emission Computed Tomography (SPECT) has demonstrated high levels of sensitivity in localizing seizures among patients with epilepsy of the mesial temporal lobe (mTLE). However, incorrect information on the lateralization of mTLE has also been reported. In order to investigate the causes of these incorrect localizations, the authors assessed clinical symptoms, as well as the electroencephalography (EEG) and brain SPECT scan data of five patients with mTLE experiencing ictal hyperperfusion of the contralateral temporal lobe. All patients underwent presurgical evaluations, including an interictal and ictal brain SPECT scan. A subtraction ictal SPECT co-registered with Magnetic Resonance Imaging (MRI) procedure or SISCOM was performed. Hyperperfusion (ictal perfusion greater than interictal perfusion) and hypoperfusion (ictal perfusion lower than interictal perfusion), results of SISCOM were analyzed and compared with seizure and ictal EEG pattern patterns. All the five patients had unilateral hippocampal sclerosis, and the radiotracer for the ictal SPECT was injected after the ictal EEG pattern had propagated to the contralateral side. The average delay between the ictal EEG onset and the radiotracer injection was 29.7+/-9.6s. All hyperperfusion SISCOM results revealed hyperperfusion in the contralateral temporal region with a more intense ictal EEG build-up. However, hypoperfusion SISCOM results demonstrated significant hypoperfusion in the epileptogenic temporal lobe of three of the five patients, but no hypoperfusion finding in the other two patients. This study demonstrates that early ictal EEG pattern propagation to the contralateral side in mTLE may be associated with contralateral ictal hyperperfusion with or without ipsilateral temporal hypoperfusion. The authors recommend simultaneous interpretations of ictal SPECT and ictal EEG propagation patterns at the time of the injection of radiotracers.

ObjectiveTo assess the effect of subsyndromal symptoms of depression (SSD) on ratings of disability for individuals with mild cognitive impairment (MCI).MethodsData from 405 MCI participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were analyzed. Participants were evaluated at baseline and at 6-month intervals over 2 years. Severity of depressive symptoms was rated utilizing the Geriatric Depression Scale. Disability was assessed utilizing the Functional Assessment Questionnaire (FAQ). Other clinical variables included white matter lesion (WML) and intracranial brain (ICV) volumes derived from magnetic resonance imaging, ratings of overall cognitive function (Alzheimer's Disease Assessment Scale, ADAS), and apolipoprotein E (ApoE) status. Demographic variables included age, education, and gender.ResultsSSD individuals had a lower volume of WML and higher frequency of ApoE ε4 alleles than nondepressed participants but the two groups did not differ with respect to other clinical or demographic variables. At baseline, SSD individuals were 1.77 times more likely to have poorer FAQ scores than individuals with no symptoms of depression after controlling for the effect of cognitive functioning, ICV, WML, and ApoE status. The presence of SSD at baseline was not associated with a poorer course of disability outcomes, cognitive functioning, or conversion to dementia over 24 months.ConclusionsSSD demonstrated a significant impact on disability for MCI individuals, who are also at high risk for functional limitations related to neurodegenerative disease. Therefore, the treatment of SSD may represent a significant avenue to reduce the burden of disability in this vulnerable patient population.

Background: Physical activities (PA) have been suggested to reduce the risk of Alzheimer's disease (AD) dementia. However, information on the neuropathological links underlying the relationship is limited.Objective: We investigated the role of midlife and late-life PA with in vivo AD neuropathologies in old adults without dementia.Methods: This study included participants from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's disease (KBASE). The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B positron emission tomography (PET), [18F] fluorodeoxyglucose PET, and magnetic resonance imaging. Using the multi-modal brain imaging data, in vivo AD pathologies including global amyloid deposition, AD-signature region cerebral glucose metabolism (AD-CM), and AD-signature region cortical thickness (AD-CT) were quantified. Both midlife and late-life PA of participants were measured using the Lifetime Total Physical Activity Questionnaire.Results: This study was performed on 260 participants without dementia (195 with normal cognitive function and 65 with mild cognitive impairment). PA of neither midlife nor late-life showed direct correspondence with any neuroimaging biomarker. However, late-life PA moderated the relationship of brain amyloid-β (Aβ) deposition with AD-CM and AD-CT. Aβ positivity had a significant negative effect on both AD-CM and AD-CT in individuals with lower late-life PA, but those with higher late-life PA did not show such results. Midlife PA did not have such a moderation effect.Conclusion: The findings suggest that physically active lifestyle in late-life, rather than that in midlife, may delay AD-associated cognitive decline by decreasing Aβ-induced neurodegenerative changes in old adults. [ABSTRACT FROM AUTHOR]

Background: A standardized tool for evaluating semantic knowledge of the Korean population is needed.Objective: The purpose of this study was to develop a neuropsychological test for the evaluation of semantic knowledge in the Korean elderly population.Methods: The Korean version of the Size/Weight Attribute Test (SWAT-K) was developed in reference to the original version. The diagnostic validity of SWAT-K was evaluated with 95 elderly outpatients [67 normal controls; 18 with Alzheimer's disease (AD); 10 with semantic-variant progressive aphasia (SV-PPA)]. Voxel-based morphometry (VBM) was employed to examine associations between SWAT-K scores and morphological changes of the brain.Results: SWAT-K could discriminate the three subject groups (normal >AD, p <  0.001; AD >SV-PPA, p = 0.040), whereas Boston Naming Test could not distinguish SV-PPA from AD. ROC curve analysis confirmed high levels of sensitivity (0.90) and specificity (0.93) for SWAT-K. The test's inter-rater reliability (ICC = 0.827) and test-retest reliability (ICC = 0.666) were assessed as well. VBM found a significant positive correlation (uncorrected p <  0.005, k >  100) between SWAT-K scores and gray matter volume in right inferior frontal cortex (T = 4.08, k = 191) and bilateral temporal cortices (left, T = 4.42, k = 135; right, T = 3.55, k = 253), the areas the most affected in SV-PPA.Conclusions: SWAT-K is a sensitive and reliable test for evaluating semantic knowledge in the Korean elderly population. Strong positive correlations between SWAT-K scores and the brain areas responsible for semantic processing further corroborate the validity of SWAT-K. [ABSTRACT FROM AUTHOR]

Objective: This study was conducted to explore differences in cortical thickness between subjects with bipolar disorder and healthy comparison subjects using cortical surface-based analysis. Methods: Brain magnetic resonance images were acquired from 25 subjects with bipolar disorder and 21 healthy comparison subjects. Cortical surface-based analysis was conducted using the Freesurfer application. Group differences in cortical thickness, defined by the distance from gray/white boundary to the pial surface, were assessed using statistical difference maps. Results: Subjects with bipolar disorder exhibited significantly decreased cortical thickness in left cingulate cortex, left middle frontal cortex, left middle occipital cortex, right medial frontal cortex, right angular cortex, right fusiform cortex and bilateral postcentral cortices, relative to healthy comparison subjects (all p < 0.001). Duration of illness in bipolar subjects was inversely correlated with the cortical thickness of the left middle frontal cortex. Conclusions: Cortical thinning was present in multiple prefrontal cortices in bipolar disorder. There was also cortical thinning in sensory and sensory association cortices, which has not been reported in previous studies using region-of-interest or voxel-based morphometry methods. Cortical thinning observed in the current study may be related to impairment of emotional, cognitive, and sensory processing in bipolar disorder but longitudinal studies will be necessary to test this hypothesis. [ABSTRACT FROM AUTHOR]

Background: Late-life depression (LDD) results from multiple psychosocial and neurobiological changes occurring in later life. The current study investigated how patterns of clinical symptoms and brain structural features are classified into LDD subtypes.Method: Self-report scale of depression, behavioral rating of affective symptoms, and brain structural imaging of white matter change and cortical thickness were assessed in 541 older adults with no cognitive impairment or mild cognitive impairment. Latent profile analysis was used to identify distinct subtypes of depression.Results: The latent profile analysis identified four classes with mild to severe depressive symptoms and two classes with minimal symptoms. While the classes primarily differed in the overall severity, the combinatory patterns of clinical symptoms and neuropathological signature distinguished the classes with similar severity. The classes were distinguished in terms of whether or not neurodegenerative risk accompanied the corresponding depressive symptoms. The presence of the negative self-scheme and cortical thinning pattern notably characterized the subtypes of LDD.Limitations: The underlying etiologies of the biological subtypes are still speculative, and the current study lacks clinical history that differentiates late- and early-onset depression.Conclusions: Our finding provides insight in identifying heterogeneities of depressive disorder in later life and suggests that self-report and behavioral symptom profile in combination with white matter lesion and cortical thickness effectively characterizes distinct subtypes of LDD. [ABSTRACT FROM AUTHOR]

Objectives: To investigate neural substrates of symptomatic rapid eye movement sleep behavior disorder (RBD) in Parkinson's disease (PD) by analyzing brain changes based on both hypothesis-free and hypothesis-driven neuroimaging analyses.Methods: A total of 63 subjects (14 PDRBD-, 24 PDRBD+, and 25 age-matched healthy controls = HC) were enrolled in this study. RBD was defined by RBD screening questionnaire with video-polysomnographic confirmation. All subjects underwent volumetric and diffusion tensor imaging. The whole brain gray- and white-matter changes were analyzed and the central ascending cholinergic pathway involving the pedunculopontine nucleus and thalamus was compared with a region-of-interest analysis and probabilistic tractography.Results: The PDRBD+ group showed decreased gray matter volume of the left posterior cingulate and hippocampus compared to the PDRBD- and additional gray matter decrease in the left precuneus, cuneus, medial frontal gyrus, postcentral gyrus and both inferior parietal lobule compared to the HC group (uncorrected p < 0.001, k = 50). There were no significant differences in white matter changes between the PDRBD- and PDRBD+ groups both by fractional anisotropy and mean diffusivities. However, both PD groups showed widespread changes by fractional anisotropy reductions and mean diffusivity increments compared to HC (p < 0.05 corrected). There were no significant differences in tract-based spatial statistics and the normalized tract volumes as well as the diffusion indices of both the thalamus and pedunculopontine nuclei among the study groups.Conclusions: The appearance of RBD in PD may be related to regional gray matter changes in the left posterior cingulate and hippocampus but not localized to the brainstem. [ABSTRACT FROM AUTHOR]