Multi-Ethnic Norms for Volumes of Subcortical and Lobar Brain Structures Measured by Neuro I: Ethnicity May Improve the Diagnosis of Alzheimer's Disease1.

Background: We previously demonstrated the validity of a regression model that included ethnicity as a novel predictor for predicting normative brain volumes in old age. The model was optimized using brain volumes measured with a standard tool FreeSurfer. Objective: Here we further verified the prediction model using newly estimated brain volumes from Neuro I, a quantitative brain analysis system developed for Korean populations. Methods: Lobar and subcortical volumes were estimated from MRI images of 1,629 normal Korean and 786 Caucasian subjects (age range 59-89) and were predicted in linear regression from ethnicity, age, sex, intracranial volume, magnetic field strength, and scanner manufacturers. Results: In the regression model predicting the new volumes, ethnicity was again a substantial predictor in most regions. Additionally, the model-based z-scores of regions were calculated for 428 AD patients and the matched controls, and then employed for diagnostic classification. When the AD classifier adopted the z-scores adjusted for ethnicity, the diagnostic accuracy has noticeably improved (AUC = 0.85, ΔAUC = + 0.04, D = 4.10, p < 0.001). Conclusions: Our results suggest that the prediction model remains robust across different measurement tool, and ethnicity significantly contributes to the establishment of norms for brain volumes and the development of a diagnostic system for neurodegenerative diseases.

Modified RCTU Score: A Semi-Quantitative, Visual Tool for Predicting Alzheimer's Conversion from aMCI.

This research evaluated the modified RCTU score, derived from amyloid PET scans, for predicting the progression from amnestic Mild Cognitive Impairment (aMCI) to Alzheimer's Disease (AD). aMCI patients underwent baseline evaluations, including amyloid PET. AD conversion was identified through neuropsychological tests after observation. The RCTU was modified by segmenting frontal, parietal, and temporal lobes into left and right, resulting in seven areas. Scores from both modified and conventional RCTU were analyzed and compared. Among 45 patients, 12 progressed to AD (over 17.8 ± 6.8 months). AD converters showed higher scores in modified RCTU scores. Modified RCTU score had strong correlations with amyloid SUVR (r > 0.7). Modified RCTU sum score was the significant covariate of AD conversion. Modified RCTU could determine the asymmetry of amyloid deposits. We demonstrated that symmetric deposits of amyloid showed a higher risk for AD conversion when analyzed using modified RCTU. The modified RCTU score is a promising method for predicting AD conversion, correlating strongly with amyloid SUVR.

Asian Cohort for Alzheimer's Disease (ACAD) pilot study on genetic and non-genetic risk factors for Alzheimer's disease among Asian Americans and Canadians.

INTRODUCTION: Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non-genetic/lifestyle factors impact this multi-ethnic population. METHODS: The ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese. RESULTS: ACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception. DISCUSSION: ACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non-genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness. HIGHLIGHTS: The Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under-investment in clinical research for Asians. We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease. We describe culturally appropriate recruitment strategies and data collection protocol. ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities. We aim to implement a successful recruitment program that enrolls across three Asian subcommunities.

Efficacy of a Mobile-Based Multidomain Intervention to Improve Cognitive Function and Health-Related Outcomes Among Older Korean Adults with Subjective Cognitive Decline.

BACKGROUND: Subjective cognitive decline (SCD) is a self-reported experience of declining cognitive function showing normal performance in cognitive assessments, which is a known risk factor for dementia. Recent studies highlight the importance of nonpharmacological multidomain interventions that can target multiple risk factors of dementia in older adults. OBJECTIVE: This study investigated the efficacy of the Silvia program, a mobile-based multidomain intervention, to improve cognitive function and health-related outcomes of older adults with SCD. We compare its effects to a conventional paper-based multidomain program on various health indicators related to risk factors of dementia. METHODS: This prospective randomized controlled trial involved 77 older adults with SCD recruited from the Dementia Prevention and Management Center in Gwangju, South Korea during May to October 2022. Participants were randomly assigned to either the mobile- or paper-based group. Interventions were administered for 12 weeks, where pre- and post-assessments were conducted. RESULTS: The K-RBANS total score did not show significant differences between groups. The mobile group showed better improvement in K-PRMQ scores and PSS scores than the paper group. Differences within groups showed that mobile-based interventions significantly improved K-PRMQ, STAI-X-1, PSS, and EQ-5D-5 L scores, while paper-based interventions significantly improved PSS, and EQ-5D-5 L scores. Patient adherence rate was 76.6%. CONCLUSION: Overall, the Silvia program was effective for improving self-reported memory failures, stress, anxiety, and health-related quality of life in older adults with SCD. However, longer periods of administration for more than 12 weeks may be needed to achieve significant improvements in cognitive function by objective measures.

Heritability of cognitive abilities and regional brain structures in middle-aged to elderly East Asians.

This study examined the single-nucleotide polymorphism heritability and genetic correlations of cognitive abilities and brain structural measures (regional subcortical volume and cortical thickness) in middle-aged and elderly East Asians (Korean) from the Gwangju Alzheimer's and Related Dementias cohort study. Significant heritability was found in memory function, caudate volume, thickness of the entorhinal cortices, pars opercularis, superior frontal gyri, and transverse temporal gyri. There were 3 significant genetic correlations between (i) the caudate volume and the thickness of the entorhinal cortices, (ii) the thickness of the superior frontal gyri and pars opercularis, and (iii) the thickness of the superior frontal and transverse temporal gyri. This is the first study to describe the heritability and genetic correlations of cognitive and neuroanatomical traits in middle-aged to elderly East Asians. Our results support the previous findings showing that genetic factors play a substantial role in the cognitive and neuroanatomical traits in middle to advanced age. Moreover, by demonstrating shared genetic effects on different brain regions, it gives us a genetic insight into understanding cognitive and brain changes with age, such as aging-related cognitive decline, cortical atrophy, and neural compensation.

Can hippocampal subfield measures supply information that could be used to improve the diagnosis of Alzheimer's disease?

The diagnosis of Alzheimer's disease (AD) needs to be improved. We investigated if hippocampal subfield volume measured by structural imaging, could supply information, so that the diagnosis of AD could be improved. In this study, subjects were classified based on clinical, neuropsychological, and amyloid positivity or negativity using PET scans. Data from 478 elderly Korean subjects grouped as cognitively unimpaired ß-amyloid-negative (NC), cognitively unimpaired ß-amyloid-positive (aAD), mild cognitively impaired ß-amyloid-positive (pAD), mild cognitively impaired-specific variations not due to dementia ß-amyloid-negative (CIND), severe cognitive impairment ß-amyloid-positive (ADD+) and severe cognitive impairment ß-amyloid-negative (ADD-) were used. NC and aAD groups did not show significant volume differences in any subfields. The CIND did not show significant volume differences when compared with either the NC or the aAD (except L-HATA). However, pAD showed significant volume differences in Sub, PrS, ML, Tail, GCMLDG, CA1, CA4, HATA, and CA3 when compared with the NC and aAD. The pAD group also showed significant differences in the hippocampal tail, CA1, CA4, molecular layer, granule cells/molecular layer/dentate gyrus, and CA3 when compared with the CIND group. The ADD- group had significantly larger volumes than the ADD+ group in the bilateral tail, SUB, PrS, and left ML. The results suggest that early amyloid depositions in cognitive normal stages are not accompanied by significant bilateral subfield volume atrophy. There might be intense and accelerated subfield volume atrophy in the later stages associated with the cognitive impairment in the pAD stage, which subsequently could drive the progression to AD dementia. Early subfield volume atrophy associated with the ß-amyloid burden may be characterized by more symmetrical atrophy in CA regions than in other subfields. We conclude that the hippocampal subfield volumetric differences from structural imaging show promise for improving the diagnosis of Alzheimer's disease.

A Single Baseline Amyloid Positron Emission Tomography Could Be Sufficient for Predicting Alzheimer's Disease Conversion in Mild Cognitive Impairment.

OBJECTIVE: Baseline amyloid burden in mild cognitive impairment (MCI) has been linked to conversion to Alzheimer's disease (AD), but the comparison of baseline and longitudinal changes in amyloid burden for predicting AD remains unresolved. The objectives of this study aimed to compare the prognostic ability of baseline and longitudinal changes in amyloid burden in MCI patients. METHODS: Seventy-five individuals with MCI were recruited and examined annually by clinical interviews for a mean follow-up of 24 months (range, 11.6-42.0). [18F]Florbetaben positron emission tomography (PET) scans were performed. T1-weighted 3D volumes were acquired for co-registration, and to define regions of interest. We examined whether baseline and longitudinal amyloid burden changes can improve AD conversion by Cox proportional hazard model analysis and receiver operating characteristic (ROC) curve analysis. RESULTS: Cox proportional hazards model analysis showed that baseline amyloid burden was significantly associated with increased risk of conversion to AD (hazard ratio [HR]=10.0; 95% confidence interval [CI], 1.15-85.39; p=0.04), but longitudinal amyloid burden changes was not (HR=0.2; 95% CI, 0.02-1.18; p=0.07). When predicting AD, longitudinal amyloid burden changes had better ROC accuracy of 65.2% (95% CI, 48.4-82.0) than baseline amyloid burden of 59.6% (95% CI, 40.3-79.0), without statistical significance in pairwise comparison. CONCLUSION: A single baseline amyloid PET could be sufficient in the prediction of AD conversion in MCI.

Plasma protein biomarker model for screening Alzheimer disease using multiple reaction monitoring-mass spectrometry.

Alzheimer disease (AD) is a leading cause of dementia that has gained prominence in our aging society. Yet, the complexity of diagnosing AD and measuring its invasiveness poses an obstacle. To this end, blood-based biomarkers could mitigate the inconveniences that impede an accurate diagnosis. We developed models to diagnose AD and measure the severity of neurocognitive impairment using blood protein biomarkers. Multiple reaction monitoring-mass spectrometry, a highly selective and sensitive approach for quantifying targeted proteins in samples, was used to analyze blood samples from 4 AD groups: cognitive normal control, asymptomatic AD, prodromal AD), and AD dementia. Multimarker models were developed using 10 protein biomarkers and apolipoprotein E genotypes for amyloid beta and 10 biomarkers with Korean Mini-Mental Status Examination (K-MMSE) score for predicting Alzheimer disease progression. The accuracies for the AD classification model and AD progression monitoring model were 84.9% (95% CI 82.8 to 87.0) and 79.1% (95% CI 77.8 to 80.5), respectively. The models were more accurate in diagnosing AD, compared with single APOE genotypes and the K-MMSE score. Our study demonstrates the possibility of predicting AD with high accuracy by blood biomarker analysis as an alternative method of screening for AD.

A missense variant in SHARPIN mediates Alzheimer's disease-specific brain damages.

Established genetic risk factors for Alzheimer's disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal cortical thickness in 2643 Koreans meeting the clinical criteria for AD (n = 209), mild cognitive impairment (n = 1449) or normal cognition (n = 985). A missense variant, rs77359862 (R274W), in the SHANK-associated RH Domain Interactor (SHARPIN) gene was associated with entorhinal cortical thickness (p = 5.0 × 10-9) and hippocampal volume (p = 5.1 × 10-12). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-ß accumulation (p = 0.03) and measures of memory (p = 1.0 × 10-4) and executive function (p = 0.04). We also found significant association of other SHARPIN variants with hippocampal volume in the Alzheimer's Disease Neuroimaging Initiative (rs3417062, p = 4.1 × 10-6) and AddNeuroMed (rs138412600, p = 5.9 × 10-5) cohorts. Further, molecular dynamics simulations and co-immunoprecipitation indicated that the variant significantly reduced the binding of linear ubiquitination assembly complex proteins, SHPARIN and HOIL-1 Interacting Protein (HOIP), altering the downstream NF-κB signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.

Visuospatial memory impairment as a potential neurocognitive marker to predict tau pathology in Alzheimer's continuum.

BACKGROUND: Given that tau accumulation, not amyloid-ß (Aß) burden, is more closely connected with cognitive impairment in Alzheimer's disease (AD), a detailed understanding of the tau-related characteristics of cognitive function is critical in both clinical and research settings. We investigated the association between phosphorylated tau (p-Tau) level and cognitive impairment across the AD continuum and the mediating role of medial temporal lobe (MTL) atrophy. We also developed a prediction model for abnormal tau accumulation. METHODS: We included participants from the Gwangju Alzheimer's Disease and Related Dementia Cohort in Korea, who completed cerebrospinal fluid analysis and clinical evaluation, and corresponded to one of three groups according to the biomarkers of A and T profiles based on the National Institute on Aging and Alzheimer's Association research framework. Multiple linear and logistic regression analyses were performed to examine the association between p-Tau and cognition and to develop prediction models. Receiver operating characteristic curve analysis was performed to examine the discrimination ability of the models. RESULTS: Among 185 participants, 93 were classified as A-T-, 23 as A+T-, and 69 as A+T+. There was an association between decreased visuospatial delayed memory performance and p-Tau level (B = - 0.754, ß = - 0.363, p < 0.001), independent of other relevant variables (e.g., Aß). MTL neurodegeneration was found to mediate the association between the two. Prediction models with visuospatial delayed memory alone (area under the curve [AUC] = 0.872) and visuospatial delayed memory and entorhinal thickness (AUC = 0.921) for abnormal tau accumulation were suggested and they were validated in an independent sample (AUC = 0.879 and 0.891, respectively). CONCLUSION: It is crucial to identify sensitive cognitive measures that capture subtle cognitive impairment associated with underlying pathological changes. Preliminary findings from the current study might suggest that abnormal tau accumulation underlies episodic memory impairment, particularly visuospatial modality, in the AD continuum. Suggested models are potentially useful in predicting tau pathology, and might be utilized practically in the field.

Multi-Racial Normative Data for Lobar and Subcortical Brain Volumes in Old Age: Korean and Caucasian Norms May Be Incompatible With Each Other†.

Brain aging is becoming an increasingly important topic, and the norms of brain structures are essential for diagnosing neurodegenerative diseases. However, previous studies of the aging brain have mostly focused on Caucasians, not East Asians. The aim of this paper was to examine ethnic differences in the aging process of brain structures or to determine to what extent ethnicity affects the normative values of lobar and subcortical volumes in clinically normal elderly and the diagnosis in multi-racial patients with Alzheimer's disease (AD). Lobar and subcortical volumes were measured using FreeSurfer from MRI data of 1,686 normal Koreans (age range 59-89) and 851 Caucasian, non-Hispanic subjects in the ADNI and OASIS datasets. The regression models were designed to predict brain volumes, including ethnicity, age, sex, intracranial volume (ICV), magnetic field strength (MFS), and MRI scanner manufacturers as independent variables. Ethnicity had a significant effect for all lobar (|ß| > 0.20, p < 0.001) and subcortical regions (|ß| > 0.08, p < 0.001) except left pallidus and bilateral ventricles. To demonstrate the validity of the z-score for AD diagnosis, 420 patients and 420 normal controls were selected evenly from the Korean and Caucasian datasets. The four validation groups divided by race and diagnosis were matched on age and sex using a propensity score matching. We analyzed whether and to what extent the ethnicity adjustment improved the diagnostic power of the logistic regression model that was built using the only z-scores of six regions: bilateral temporal cortices, hippocampi, and amygdalae. The performance of the classifier after ethnicity adjustment was significantly improved compared with the classifier before ethnicity adjustment (ΔAUC = 0.10, D = 7.80, p < 0.001; AUC comparison test using bootstrap). Korean AD dementia patients may not be classified by Caucasian norms of brain volumes because the brain regions vulnerable to AD dementia are bigger in normal Korean elderly peoples. Therefore, ethnicity is an essential factor in establishing normative data for regional volumes in brain aging and applying it to the diagnosis of neurodegenerative diseases.

Pathobiolgy and Management of Alzheimer's Disease.

Amyloid and tau protein abnormalities have been identified as the main causes of Alzheimer's disease but exact mechanisms remain to be revealed. Especially, amyloid beta and tau protein coupling and neuroinflammatory and neurovascular contributions to Alzheimer disease are quite mysterious. Many animal models and basic biological research are trying to solve these puzzles. Known as aging processes, autophagy, mitochondrial degeneration with generation of reactive oxygen species, and age-related epigenetic modifications are also known to be associated with development of Alzheimer's disease. Environmental factors such as bacterial and viral infections, heavy metal ions, diet, sleep, stress, and gut microbiota are also risk factors of Alzheimer's disease. Future development of preventive and therapeutic modalities may be dependent on the pathobiology of Alzheimer's disease.

Potential Novel Genes for Late-Onset Alzheimer's Disease in East-Asian Descent Identified by APOE-Stratified Genome-Wide Association Study.

The present study reports two novel genome-wide significant loci for late-onset Alzheimer's disease (LOAD) identified from APOE ε4 non-carrier subjects of East Asian origin. A genome-wide association study of Alzheimer's disease was performed in 2,291 Korean seniors in the discovery phase, from the Gwangju Alzheimer' and Related Dementias (GARD) cohort study. The study was replicated in a Japanese cohort of 1,956 subjects that suggested two novel susceptible SNPs in two genes: LRIG1 and CACNA1A. This study demonstrates that the discovery of AD-associated variants is feasible in non-European ethnic groups using samples comprising fewer subjects from the more homogeneous genetic background.

Corrigendum: The Aging Slopes of Brain Structures Vary by Ethnicity and Sex: Evidence From a Large Magnetic Resonance Imaging Dataset From a Single Scanner of Cognitively Healthy Elderly People in Korea.

[This corrects the article DOI: 10.3389/fnagi.2020.00233.].

The Aging Slopes of Brain Structures Vary by Ethnicity and Sex: Evidence From a Large Magnetic Resonance Imaging Dataset From a Single Scanner of Cognitively Healthy Elderly People in Korea.

The aging of the brain is a well-investigated topic, but existing analyses have mainly focused on Caucasian samples. To investigate brain aging in East Asians, we measured cortical and subcortical volumes from magnetic resonance imaging (MRI) scans of 1,008 cognitively normal elderly Koreans from the Gwangju Alzheimer's and Related Dementia cohort and 342 Caucasians from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. To determine whether the aging effect varies with ethnicity and sex, beta coefficients of age and confidence intervals (CIs) were estimated in each ethnicity-sex group using a bootstrap method and a regression analysis using the relative volume to intracranial volume as predicted. The betas or aging slopes largely were not significantly different between ethnicity and sex groups in most types of brain structures. However, ethnic differences between the two female groups were found in the brain, most cortical regions, and a few subcortical regions. Ethnic differences in brain aging are likely due in large part to genetic factors; thus, we compared carriers and non-carriers of a gene relevant to longevity and neurodegenerative diseases, such as apolipoprotein E (APOE) ε4. The regions with ethnic differences in women also showed significant differences between Korean APOE ε4 non-carriers and Caucasian APOE ε4 carriers. Furthermore, Caucasian women showed significant APOE ε4 effects in the largest number of regions. These results illustrate that much of the ethnic differences in females may be explained by synergistic effects of ethnic background and APOE ε4 carrier status. Our results suggest that sex-dependent differences of aging between ethnic backgrounds may be due to ethnicity-dependent effects of genetic risk factors, such as APOE ε4. We also presented the normative information on volume estimates of the brain structures of the elderly Korean people in the subdivided age groups. This normative information of the aging brain stratified by ethnicity provides the age-related reference ranges quantified to replace visual judgment and facilitate precise clinical decision-making.

Follow-Up of Brain Single-Photon Emission Computed Tomography (SPECT) and Magnetic Resonance Imaging (MRI) in a Case of Seizure Caused by Osmotic Demyelination Syndrome.

BACKGROUND Osmotic demyelination syndrome (ODS) is an uncommon neurological disorder. Until the mid-1980s, the mortality rate was 90-100%, but more than half of patients now have a good prognosis. Early suspicion of ODS is important. However, radiologic findings of ODS are variable and scintigraphy findings have not been reported. CASE REPORT A 38-year-old man with alcohol abuse history was admitted due to electrolyte imbalance. On the 10th day of his hospital stay, he had a generalized tonic-clonic seizure. Brain perfusion SPECT showed asymmetrically hyperperfused and hypoperfused lesions. Brain MRI revealed diffuse T2 hyperintensity with mild diffusion restriction in the pons and hyperperfused lesions on brain SPECT. He was treated based on the diagnosis of hyponatremia and osmotic demyelination. After treatment, the asymmetric hyperperfusion was decreased. MRI showed that the cortical hyperintensity had resolved, with encephalomalacic change shown in the pons. CONCLUSIONS To the best of our knowledge, this is the first report showing changes in brain perfusion SPECT and MRI in an ODS patient with a seizure. This case report may be helpful to neurologists, radiologists, and nuclear physicians.

Comparison of Two Analytical Platforms in Cerebrospinal Fluid Biomarkers for the Classification of Alzheimer's Disease Spectrum with Amyloid PET Imaging.

BACKGROUND: Cerebrospinal fluid (CSF) amyloid-ß1-42 (Aß1-42), total tau protein (t-Tau), and phosphorylated Tau (p-Tau) are ATN biomarkers for Alzheimer's disease (AD) and reflect pathogenic changes in the brain. CSF biomarkers of AD are considered for inclusion in the diagnostic criteria for research and clinical purposes to reduce the uncertainty of clinical diagnosis and to distinguish among AD stages. OBJECTIVE: This study aims to compare two commercially available analytical platforms with respect to accuracy and the potential for early diagnosis of AD. METHODS: A total of 211 CSF samples from healthy control (HC) and AD subjects were analyzed using two analytical platforms, INNOTEST ELISA and INNOBIA AlzBio3 xMAP kits. The accuracy of diagnosis and AUC values distinguishing study groups were compared between the two analytical platforms. RESULTS: The absolute values for Aß1-42, t-Tau, and p-Tau181 levels differed between the two platforms. The Aß1-42 levels decreased, while t-Tau and p-Tau levels increased according to the AD stages. The AUC of Aß1-42 and t-Tau, which distinguish the early stages of AD (preclinical and prodromal AD), were similar between the two platforms, whereas there were significant differences in p-Tau AUC values. CSF p-Tau using the INNOBIA was highly accurate for distinguishing both preclinical AD (AUC = 0.826, cut-off score≥38.89) and prodromal AD (AUC = 0.862, cut-off score≥41.88) from HC. CONCLUSION: The accuracy of CSF p-Tau levels in the preclinical and prodromal AD is higher for the INNOBIA than the INNOTEST, and the early stage AD can be accurately distinguished from HC.

Association of Subjective Memory Complaints with the Left Parahippocampal Amyloid Burden in Mild Cognitive Impairment.

BACKGROUND: Subjective memory complaints (SMC) are a risk factor for Alzheimer's disease. OBJECTIVE: We aimed to explore the association between SMC and regional amyloid-ß (Aß) deposition in mild cognitive impairment (MCI). METHODS: Sixty-eight individuals with MCI were recruited. [18F]Florbetaben PET scans were performed. T1-weighted 3D volumes were also acquired for co-registration with PET and for defining the regions of interest (ROI). Two step exploratory partial correlation analyses between SMC and Aß deposition were performed with covariates of age, sex, education, and depression. Furthermore, for the priori ROI that had the most significant partial correlation, we investigated the correlation between the SMC and regional Aß burden using a multiple linear regression model controlling for depression, age, sex, and education. RESULTS: Significant positive correlations between the SMC and Aß burden was found in the medial temporal ROI (first step) and in the left parahippocampus ROI (second step). In the priori left parahippocampus, we found significant correlation between the SMC and Aß burden (R2 = 0.473, p = 0.014). CONCLUSIONS: Our study suggested that the SMC was associated with amyloid accumulation, especially in the left parahippocampus, in individuals with MCI.

Reversion From Mild Cognitive Impairment To Normal Cognition: False-Positive Error Or True Restoration Thanks To Cognitive Control Ability?

PURPOSE: Relatively little attention has been paid to the meaning of reversion from mild cognitive impairment (MCI) to cognitively normal (CN), compared to MCI progression studies. The purpose of the study was to investigate the characteristics contributing to reversion from MCI to CN and to identify the associated factors with such reversion. PATIENTS AND METHODS: We retrospectively identified 200 individuals who initially diagnosed as MCI and completed the second visit from the National Research Center for Dementia (NRCD) registry in Korea. Participants underwent comprehensive clinical and neuropsychological assessments. Factors associated with reversion were examined by a independent-samples t-test, χ2 test, and logistic regression. Longitudinal change was examined by a repeated measures analysis of variance (rANOVA). RESULTS: Based on the second assessment, 78 (39%) individuals were found to have reverted to CN (rMCI) and 118 (59%) remained with MCI (sMCI). Four (2%) progressed to Alzheimer's disease dementia and they were excluded from further analysis. Over a wide range of socio-demographic, clinical, and neuropsychological variables, group difference was significant only in neuropsychological tests of cognitive control. Both groups showed improvement in several neuropsychological tests, implying a practice effect, but the rMCI group showed greater improvement. CONCLUSION: Reversion from MCI to CN might not be a false-positive error but a true recovery from cognitive impairment. Our results suggest that cognitive control ability may be a characteristic favorable for the restoration of cognitive function. Therefore, assessment of cognitive control might facilitate the development of appropriate interventions for MCI as well as prognosis evaluation.

APOE Promoter Polymorphism-219T/G is an Effect Modifier of the Influence of APOE ε4 on Alzheimer's Disease Risk in a Multiracial Sample.

Variants in the APOE gene region may explain ethnic differences in the association of Alzheimer's disease (AD) with ε4. Ethnic differences in allele frequencies for three APOE region SNPs (single nucleotide polymorphisms) were identified and tested for association in 19,398 East Asians (EastA), including Koreans and Japanese, 15,836 European ancestry (EuroA) individuals, and 4985 African Americans, and with brain imaging measures of cortical atrophy in sub-samples of Koreans and EuroAs. Among ε4/ε4 individuals, AD risk increased substantially in a dose-dependent manner with the number of APOE promoter SNP rs405509 T alleles in EastAs (TT: OR (odds ratio) = 27.02, p = 8.80 × 10-94; GT: OR = 15.87, p = 2.62 × 10-9) and EuroAs (TT: OR = 18.13, p = 2.69 × 10-108; GT: OR = 12.63, p = 3.44 × 10-64), and rs405509-T homozygotes had a younger onset and more severe cortical atrophy than those with G-allele. Functional experiments using APOE promoter fragments demonstrated that TT lowered APOE expression in human brain and serum. The modifying effect of rs405509 genotype explained much of the ethnic variability in the AD/ε4 association, and increasing APOE expression might lower AD risk among ε4 homozygotes.