Young Min Choe

Whole-brain Functional Networks in Cognitively Normal, Mild Cognitive Impairment, and Alzheimer’s Disease

The conceptual significance of understanding functional brain alterations and cognitive deficits associated with Alzheimer’s disease (AD) process has been widely established. However, the whole-brain functional networks of AD and its prodromal stage, mild cognitive impairment (MCI), are not well clarified yet. In this study, we compared the characteristics of the whole-brain functional networks among cognitively normal (CN), MCI, and AD individuals by applying graph theoretical analyses to [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) data. Ninety-four CN elderly, 183 with MCI, and 216 with AD underwent clinical evaluation and FDG-PET scan. The overall small-world property as seen in the CN whole-brain network was preserved in MCI and AD. In contrast, individual parameters of the network were altered with the following patterns of changes: local clustering of networks was lower in both MCI and AD compared to CN, while path length was not different among the three groups. Then, MCI had a lower level of local clustering than AD. Subgroup analyses for AD also revealed that very mild AD had lower local clustering and shorter path length compared to mild AD. Regarding the local properties of the whole-brain networks, MCI and AD had significantly decreased normalized betweenness centrality in several hubs regionally associated with the default mode network compared to CN. Our results suggest that the functional integration in whole-brain network progressively declines due to the AD process. On the other hand, functional relatedness between neighboring brain regions may not gradually decrease, but be the most severely altered in MCI stage and gradually re-increase in clinical AD stages.

Association of homocysteine with hippocampal volume independent of cerebral amyloid and vascular burden

This study aimed to clarify whether homocysteine has independent association, not mediated by cerebral beta amyloid protein deposition and vascular burden, with whole brain or hippocampal volume in elderly individuals with normal cognition, mild cognitive impairment, and Alzheimers disease. Nineteen mild cognitive impairment and 24 Alzheimers disease patients were recruited from the Dementia Clinic of the Seoul National University Hospital. Fourteen cognitively normal elderly subjects were also selected from a pool of elderly volunteers. Multiple linear regression analyses showed that plasma total homocysteine level was significantly associated with hippocampal volume even after controlling the degree of global cerebral beta amyloid deposition and vascular burden as well as other potential confounders including age, gender, education, and apolipoprotein E ε4 genotype. On the contrary, plasma total homocysteine level did not show any significant association with whole brain volume. Our finding of the independent negative association between homocysteine and hippocampal volume suggests that homocysteine has a direct adverse effect, not mediated by cerebral beta amyloid deposition and vascular burden, on the hippocampus.

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

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

A Normative Study of the Digit Span in an Educationally Diverse Elderly Population

Objective The purpose of this study was to explore the effect of demographic variables on Digit Span test (DS) performance in an educationally diverse elderly population and to provide normative information. Methods The DS was administered to 784 community-dwelling volunteers aged 60-90 years with an educational history of from zero to 25 years of full-time education. People with serious neurological, medical and psychiatric disorders (including dementia) were excluded. Results Age, education and gender were found to be significantly associated with performance on the DS. Based on the results obtained, DS norms were stratified by age (2 strata), education (3 strata), and gender (2 strata). Conclusion Our results on DS performance suggest that both attention and working memory are influenced by age, education and gender. The present study provides reasonably comprehensive normative information on the DS for an educationally diverse elderly population.

Beta-Amyloid Associated Differential Effects of APOE ε4 on Brain Metabolism in Cognitively Normal Elderly

OBJECTIVE Although apolipoprotein (APOE) ε4 allele is a well-established risk factor for late-onset Alzheimer disease (AD), the mechanism of its effects on AD pathogenesis is not fully understood. We aimed to investigate the effects of APOE genotype on regional cerebral glucose metabolism in cognitively normal (CN) elderly. We further tried to elucidate whether or not such effects are associated with beta-amyloid protein (Aβ) deposition. METHODS 31 CN elderly participants underwent clinical examination, a range of neuropsychological tests, APOE genotyping, and Pittsburgh compound-B- and fluorodeoxyglucose-PET scans. RESULTS 17 APOE ε4 carriers and 15 non-carriers were included. Both hypometabolic and hypermetabolic regions were observed in ε4 carriers compared with noncarriers when age, education, and sex were controlled. When the degree of global cerebral Aβ deposition was adjusted, the hypometabolic regions in the temporo-parietal area (i.e., BA 22 and 39) largely disappeared, whereas the hypermetabolic regions persisted in medial frontal and anterior temporal areas (i.e., BA 38, 11, and 39). Behaviorally, verbal episodic memory scores of APOE ε4 carriers were slightly lower than those of noncarriers, though still within normal range. CONCLUSIONS Our findings indicate that decreased cerebral glucose metabolism in the temporoparietal junction associated with APOE ε4 in CN elderly appears to be mediated by Aβ deposition, and the effect of APOE ε4 on hypermetabolism in the frontal and anterior temporal regions is independent of Aβ and may be associated with presence of compensatory mechanism in CN elderly with the ε4 allele.

Differences in functional brain connectivity alterations associated with cerebral amyloid deposition in amnestic mild cognitive impairment

Despite potential implications for the early detection of impending Alzheimer’s disease (AD), very little is known about the differences of large-scale brain networks between amnestic mild cognitive impairment (aMCI) with high cerebral amyloid-beta protein (Aβ) deposition (i.e., aMCI+) and aMCI with no or very little Aβ deposition (i.e., aMCI−). We first aimed to extend the current literature on altering intrinsic functional connectivity (FC) of the default mode network (DMN) and salience network (SN) from cognitively normal (CN) to AD dementia. Second, we further examined the differences of the DMN and the SN between aMCI−, aMCI+, and CN. Forty-three older adult (12 CN, 10 aMCI+, 10 aMCI−, and 11 AD dementia) subjects were included. All participants received comprehensive clinical and neuropsychological assessment, resting-state functional magnetic resonance imaging, structural MRI, and Pittsburgh compound-B-PET scans. FC data were preprocessed using multivariate exploratory linear optimized decomposition into independent components of FMRIB’s Software Library. Group comparisons were carried out using the “dual-regression” approach. In addition, to verify presence of gray matter volume changes with intrinsic functional network alterations, voxel-based morphometry was performed on the acquired T1-weighted data. As expected, AD dementia participants exhibited decreased FC in the DMN compared to CN (particularly in the precuneus and cingulate gyrus). The degree of alteration in the DMN in aMCI+ compared to CN was intermediate to that of AD. In contrast, aMCI− exhibited increased FC in the DMN compared to CN (primarily in the precuneus) as well as aMCI+. In terms of the SN, aMCI− exhibited decreased FC compared to both CN and aMCI+ particularly in the inferior frontal gyrus. FC within the SN in aMCI+ and AD did not differ from CN. Compared to CN, aMCI− showed atrophy in bilateral superior temporal gyri whereas aMCI+ showed atrophy in right precuneus. The results indicate that despite the similarity in cross-sectional cognitive features, aMCI− has quite different functional brain connectivity compared to aMCI+.

Comparison of Regional Gray Matter Atrophy, White Matter Alteration, and Glucose Metabolism as a Predictor of the Conversion to Alzheimer's Disease in Mild Cognitive Impairment

We compared the predictive ability of the various neuroimaging tools and determined the most cost-effective, non-invasive Alzheimers disease (AD) prediction model in mild cognitive impairment (MCI) individuals. Thirty-two MCI subjects were evaluated at baseline with [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET), MRI, diffusion tensor imaging (DTI), and neuropsychological tests, and then followed up for 2 yr. After a follow up period, 12 MCI subjects converted to AD (MCIc) and 20 did not (MCInc). Of the voxel-based statistical comparisons of baseline neuroimaging data, the MCIc showed reduced cerebral glucose metabolism (CMgl) in the temporo-parietal, posterior cingulate, precuneus, and frontal regions, and gray matter (GM) density in multiple cortical areas including the frontal, temporal and parietal regions compared to the MCInc, whereas regional fractional anisotropy derived from DTI were not significantly different between the two groups. The MCIc also had lower Mini-Mental State Examination (MMSE) score than the MCInc. Through a series of model selection steps, the MMSE combined with CMgl model was selected as a final model (classification accuracy 93.8%). In conclusion, the combination of MMSE with regional CMgl measurement based on FDG-PET is probably the most efficient, non-invasive method to predict AD in MCI individuals after a two-year follow-up period. Graphical Abstract

Improvement of Screening Accuracy of Mini-Mental State Examination for Mild Cognitive Impairment and Non-Alzheimer's Disease Dementia by Supplementation of Verbal Fluency Performance

Objective This study aimed to investigate whether the supplementation of Verbal Fluency: Animal category test (VF) performance can improve the screening ability of Mini-Mental State Examination (MMSE) for mild cognitive impairment (MCI), dementia and their major subtypes. Methods Six hundred fifty-five cognitively normal (CN), 366 MCI [282 amnestic MCI (aMCI); 84 non-amnestic MCI (naMCI)] and 494 dementia [346 Alzheimers disease (AD); and 148 non-Alzheimers disease dementia (NAD)] individuals living in the community were included (all aged 50 years and older) in the study. Results The VF-supplemented MMSE (MMSE+VF) score had a significantly better screening ability for MCI, dementia and overall cognitive impairment (MCI plus dementia) than the MMSE raw score alone. MMSE+VF showed a significantly better ability than MMSE for both MCI subtypes, i.e., aMCI and naMCI. In the case of dementia subtypes, MMSE+VF was better than the MMSE alone for NAD screening, but not for AD screening. Conclusion The results support the usefulness of VF-supplementation to improve the screening performance of MMSE for MCI and NAD.

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.

Clinical Dementia Rating Orientation Score as an Excellent Predictor of the Progression to Alzheimer's Disease in Mild Cognitive Impairment

Objective This study aimed to examine the usefulness of each subscale score of the Clinical Dementia Rating (CDR) for predicting Alzheimers disease (AD) dementia progression in amnestic mild cognitive impairment (MCI) elderly subjects. Methods Fifty-nine elderly MCI individuals were recruited from a university dementia and memory disorder clinic. Standardized clinical and neuropsychological tests were performed both at baseline and at the time of 2 years follow-up. Logistic regression analyses were conducted to examine the ability of various clinical measures or their combinations to predict progression to AD dementia in MCI individuals. Results MCIp individuals showed significantly higher CDR Orientation subscale and CDR sum-of-boxes (SOB) score than MCInp ones, while there were no significant differences in other CDR subscale scores between the two. MCIp individuals also showed marginally higher MMSE scores than MCInp ones. A series of logistic regression analyses demonstrated that the model including CDR Orientation subscale had better AD dementia prediction accuracy than either the model with either MMSE or CDR-SOB. Conclusion Our findings suggest that CDR Orientation subscale score, a simple and easily available clinical measure, could provide very useful information to predict AD dementia progression in amnestic MCI individuals in real clinical settings.