Associations between Brain Reserve Proxies and Clinical Progression in Alzheimer's Disease Dementia.

The purpose of this study was to investigate whether brain and cognitive reserves were associated with the clinical progression of AD dementia. We included participants with AD dementia from the Alzheimer's Disease Neuroimaging Initiative, provided they were followed up at least once, and candidate proxies for cognitive (education for early-life reserve and Adult Reading Test for late-life reserve) or brain reserve (intracranial volume [ICV] for early-life reserve and the composite value of [18F] fluorodeoxyglucose positron emission tomography regions of interest (FDG-ROIs) for late-life reserve) were available. The final analysis included 120 participants. Cox proportional hazards model revealed that FDG-ROIs were the only significant predictor of clinical progression. Subgroup analysis revealed a significant association between FDG-ROIs and clinical progression only in the larger ICV group (HR = 0.388, p = 0.028, 95% CI 0.167-0.902). Our preliminary findings suggest that relatively preserved cerebral glucose metabolism might delay further clinical progression in AD dementia, particularly in the greater ICV group. In addition to ICV, cerebral glucose metabolism could play an important role as a late-life brain reserve in the process of neurodegeneration. Distinguishing between early- and late-life reserves, and considering both proxies simultaneously, would provide a wider range of factors associated with the prognosis of AD dementia.

Depression Plays a Moderating Role in the Cognitive Decline Associated With Changes of Brain White Matter Hyperintensities.

OBJECTIVE: In the elderly, depression and white matter hyperintensities (WMH) are common and associated with cognitive impairment. This study investigated the possible interactions between depression and WMH in their influences on cognition of the elderly. METHODS: Using multiple neuropsychological tests, we evaluated the cognitive function of 122 community-dwelling elders with depression at baseline between November 2008 and February 2009. Major depressive disorder, dysthymic disorder, and minor depressive disorder were diagnosed according to DSM-IV criteria. Subsyndromal depressive disorder was operationally defined using a modification of DSM-IV criteria. We visually rated WMH severity according to the modified Fazekas scale and calculated WMH volume using an automated method. We defined WMH (+) as having a score of 2 or higher on the modified Fazekas scale. In the 3-year follow-up study, baseline participants were reassessed between November 2011 and February 2013 with the same methodology. RESULTS: Baseline depression was associated with a decline over 3 years in the Categorical Verbal Fluency Test (VFT) (P = .001), Word List Memory Test (WLMT) (P = .019), Trail Making Test A (TMT-A) (P = .018), and Mini-Mental State Examination (MMSE) (P = .017), while baseline WMH (+) was associated with a decline in WLMT (P = .039) only. An increase of WMH volume over 3 years was associated with a decline in the performances of VFT (P = .044), WLMT (P = .044), Word List Recall Test (P = .040), Word List Recognition Test (P = .036), and TMT-A (P = .001) over the same period only in the subjects with depression at baseline. CONCLUSIONS: Depressive disorder and WMH are interactively associated with the poor performance of multiple cognitive functions. Depressive disorder may moderate the cognitive decline associated with the changes of brain WMH.

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

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

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 Alzheimer's 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.

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

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

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

This study aimed to examine the sex-specific association between serum sex hormones and gonadotropins and the cerebral beta-amyloid (Aß) burden and hippocampal neurodegeneration in subjects with normal cognition and impaired cognition. Two hundred sixty-five older subjects received clinical assessments, serum measurements of sex hormones, gonadotropins, 11C-Pittsburgh compound B-positron emission tomography, and magnetic resonance imaging. In females, higher free testosterone and gonadotropin levels were associated with lower cerebral Aß 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 Aß burden or hippocampal neurodegeneration in either sex. These results suggest that testosterone might inhibit the early pathological accumulation of Aß in females and delay neurodegeneration in males.

Development of the Korean Adult Reading Test (KART) to estimate premorbid intelligence in dementia patients.

We aimed to develop a word-reading test for Korean-speaking adults using irregularly pronounced words that would be useful for estimation of premorbid intelligence. A linguist who specialized in Korean phonology selected 94 words that have irregular relationship between orthography and phonology. Sixty cognitively normal elderly (CN) and 31 patients with Alzheimer's disease (AD) were asked to read out loud the words and were administered the Wechsler Adult Intelligence Scale, 4th edition, Korean version (K-WAIS-IV). Among the 94 words, 50 words that did not show a significant difference between the CN and the AD group were selected and constituted the KART. Using the 30 CN calculation group (CNc), a linear regression equation was obtained in which the observed full-scale IQ (FSIQ) was regressed on the reading errors of the KART, where education was included as an additional variable. When the regressed equation computed from the CNc was applied to 30 CN individuals of the validation group (CNv), the predicted FSIQ adequately fit the observed FSIQ (R2 = 0.63). In addition, independent sample t-test showed that the KART-predicted IQs were not significantly different between the CNv and AD groups, whereas the performance of the AD group was significantly worse in the observed IQs. In addition, an extended validation of the KART was performed with a separate sample consisted of 84 CN, 56 elderly with mild cognitive impairment (MCI), and 43 AD patients who were administered comprehensive neuropsychological assessments in addition to the KART. When the equation obtained from the CNc was applied to the extended validation sample, the KART-predicted IQs of the AD, MCI and the CN groups did not significantly differ, whereas their current global cognition scores significantly differed between the groups. In conclusion, the results support the validity of KART-predicted IQ as an index of premorbid IQ in individuals with AD.

Prevalence Rates of Dementia and Mild Cognitive Impairment Are Affected by the Diagnostic Parameter Changes for Neurocognitive Disorders in the DSM-5 in a Korean Population.

AIM: To examine the impact of the revised diagnostic criteria for neurocognitive disorders (NCDs) in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) on the prevalence of dementia and mild cognitive impairment (MCI). METHODS: A total of 755 participants aged 65 years or older in the Nationwide Survey on Dementia Epidemiology in Korea 2012 were rediagnosed according to the DSM-5 criteria. RESULTS: The estimated age-, gender-, education-, and urbanicity-standardized prevalence rates of major and mild NCDs were 8.35 and 11.10%, respectively, and those of dementia and MCI were 8.74 and 31.85%, respectively. Cohen's κ for dementia and major NCD was 0.988, and that for MCI and mild NCD was 0.273. CONCLUSION: Diagnostic discrepancies between major/mild NCDs and dementia/MCI might depend on the operationalization of neuropsychological performance criteria.

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

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

Frequency of Depressive Syndromes in Elderly Individuals with No Cognitive Impairment, Mild Cognitive Impairment, and Alzheimer's Disease Dementia in a Memory Clinic Setting.

AIMS: The aims of this study were to investigate the frequency of various depressive syndromes in elderly individuals with no cognitive impairment (NC), mild cognitive impairment (MCI), and Alzheimer's disease dementia (AD) in a memory clinic setting, and then to test whether severe and milder forms of depressive syndromes are differentially associated with the cognitive groups. METHODS: For 216 NC, 478 MCI, and 316 AD subjects, we investigated the frequency of depressive syndromes, defined by three different categories: major and minor depressive disorder (MaDD and MiDD) according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, as well as depression according to the National Institute of Mental Health provisional diagnostic criteria for depression in Alzheimer's disease (NIMH-dAD). RESULTS: The frequency of MaDD did not show any significant difference among NC, MCI, and AD. In contrast, the frequencies of MiDD and NIMH-dAD were higher than those of MaDD and showed significant group differences with a gradual increase from NC to AD. CONCLUSION: The findings suggest that the degenerative process of Alzheimer's disease contributes to the occurrence of mild depressive conditions, but not to severe depression.

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 (Aß) could be classified as a prodromal state of Alzheimer's disease (AD) dementia, aMCI with the absence of or very little cerebral Aß 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 Aß 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 Aß (aMCI-, n=10) and high Aß (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.

Association Between Serum Triglycerides and Cerebral Amyloidosis in Cognitively Normal Elderly.

OBJECTIVES: Although many preclinical studies have suggested the possible linkage between dyslipidemia and cerebral amyloid deposition, the association between serum lipid measures and cerebral amyloid-beta (Aß) deposition in human brain is still poorly known. We aimed to investigate the association in cognitively normal (CN) elderly individuals. DESIGN: Cross-sectional study. SETTING: University hospital dementia clinic. PARTICIPANTS: 59 CN elderly. MEASUREMENTS: The study measures included comprehensive clinical and neuropsychological assessment based on the CERAD protocol, magnetic resonance imaging and (11)C-labelled Pittsburgh Compound B positron emission tomography scans, and quantification for serum lipid biomarkers. RESULTS: Multiple linear regression analyses showed that a higher serum triglycerides level was associated with heavier global cerebral Aß deposition even after controlling age, sex, and apolipoprotein E ε4 genotype. Serum apolipoprotein B also showed significant positive association with global cerebral Aß deposition, but the significance disappeared after controlling serum triglycerides level. No association was found between other lipid measures and global cerebral Aß deposition. CONCLUSIONS: The findings suggest that serum triglycerides are closely associated with cerebral amyloidosis, although population-based prospective studies are needed to provide further evidence of the causative effect of triglycerides on cerebral amyloidosis.

Multicenter, randomized, placebo-controlled, double-blind clinical trial of escitalopram on the progression-delaying effects in Alzheimer's disease.

OBJECTIVES: A series of preclinical studies have suggested that selective serotonin reuptake inhibitor antidepressants not only stimulate neurogenesis but also have neuroprotective effects. The present study primarily aimed to investigate whether escitalopram would decelerate the brain atrophy of patients with mild-to-moderate Alzheimer's disease (AD). We also assessed the effects of escitalopram on the cognitive function and neuropsychiatric symptoms of these participants. METHODS: Seventy-four probable AD patients without major depression were recruited from four dementia clinics of university hospitals and randomly assigned in a 1:1 ratio. Each group received 20 mg/day of escitalopram or placebo for 52 weeks. The primary outcome measures were the change rates of hippocampal and whole brain volume on magnetic resonance imaging for 52 weeks. The Alzheimer's Disease Assessment Scale-cognitive subscale, Mini-Mental State Examination, Neuropsychiatric Inventory, and Cornell Scale for Depression in Dementia (CSDD) were also applied. RESULTS: We did not find any significant differences in the changes of hippocampal or whole brain volume between the groups. Escitalopram showed significant beneficial effects on the CSDD score at 28 weeks compared with placebo (t = -2.17, df = 50.42, p = 0.035), but this finding did not persist throughout the study. CONCLUSION: The findings of the present study do not support the role of escitalopram as a progression-delaying treatment for AD. However, the negative results of the present trial should be interpreted cautiously because of the relatively small sample size. Further large-scale escitalopram trials targeting the earlier stages of AD, even prodromal AD, are still needed. Copyright © 2015 John Wiley & Sons, Ltd.

Amyloid-Independent Amnestic Mild Cognitive Impairment and Serum Apolipoprotein A1 Levels.

OBJECTIVES: The present study investigated the characteristics of amnestic mild cognitive impairment (aMCI) in subjects with low brain amyloid-beta (Aß) burden. Furthermore, the relationships between amyloid-independent cognitive decline and serum lipid profiles, particularly apolipoprotein A1 (APOA1), were evaluated. DESIGN: Cross-sectional and longitudinal follow-up study. SETTING: University hospital dementia clinic. PARTICIPANTS: 28 aMCI and 35 cognitive normal (CN) elderly. MEASUREMENTS: The study measures included baseline assessments of the subjects' clinical characteristics, lipid profiles, and magnetic resonance imaging and (11)C-labelled Pittsburgh Compound B (PiB) positron emission tomography scans. Based on PiB retention at baseline, the aMCI subjects were divided into low Aß (aMCI-) and high Aß (aMCI+) subgroups. All aMCI subjects were followed up over a 1-year period. RESULTS: The aMCI- group had a longer duration of illness than did the aMCI+ group. None of the aMCI- subjects were diagnosed with Alzheimer disease (AD) dementia during the 1-year follow-up period, whereas 26.7% of aMCI+ subjects developed AD dementia. The aMCI- group also exhibited lower serum APOA1 levels compared with both the aMCI+ and CN groups. Additionally, lower serum APOA1 levels were associated with cognitive decline and brain atrophy independent of Aß deposition and vascular burden. CONCLUSIONS: Patients with aMCI- likely exhibit different clinical and pathophysiological characteristics than patients with aMCI+. Additionally, APOA1 may be an important contributor underlying amyloid-independent neurodegeneration.

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 Alzheimer's 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-ß 1-42 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 Aß 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.

Functional neural correlates of figure copy and recall task performances in cognitively impaired individuals: an 18F-FDG-PET study.

Figure copy and recall tasks from the Benton Visual Retention Test (BVRT) and the Consortium to Establish a Registry of Alzheimer's Disease (CERAD) neuropsychological battery are used widely to assess visuospatial function in cognitively impaired (CI) individuals. We aimed to identify functional neural correlates of figure copy and recall task performances as measured by the BVRT and the CERAD constructional praxis (CP) and CP recall (CR) in CI individuals. Both tasks were administered to 64 CI individuals with early or prodromal stage Alzheimer's disease and 36 cognitively normal individuals. Voxel-wise correlations between test scores and regional cerebral glucose metabolism (rCMglc) measured by fluorine-18 fluorodeoxyglucose PET in CI participants were analyzed. BVRT figure copy task performance was associated with rCMglc of the bilateral posterior brain regions including the parieto-temporo-occipital regions, whereas the BVRT figure recall task performance was predominantly correlated with rCMglc of the left parietal and temporo-occipital regions. Meanwhile, CERAD CP performance was associated mainly with rCMglc of the left prefrontal and temporo-occipital areas as well as in the bilateral parietal regions, whereas CERAD CR performance was correlated with rCMglc of the right prefrontal, parietal, and temporal regions. In conclusion, the functional neural correlates of the two tasks were markedly different, suggesting that these tasks might measure different visuospatial functions. Our findings contribute toward understanding the functional neuroanatomical aspects of these tasks, which is useful for both interpreting the task results as well as for more sophisticated utilization of these tasks for probing specific neuroanatomical functions.

The Effect of Choline Acetyltransferase Genotype on Donepezil Treatment Response in Patients with Alzheimer's Disease.

OBJECTIVE: We examined the difference in responses to donepezil between carriers and non-carriers of the A allele at the +4 position of the choline acetyltransferase (ChAT) gene in Koreans. METHODS: Patients who met the criteria for probable Alzheimer's disease (AD) (n=199) were recruited. Among these, 145 completed the 12-week follow-up evaluation and 135 completed the 26-week scheduled course. Differences and changes in the Korean version of the mini-mental state examination (MMSE-KC) score, Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery (CERAD-K[N]) wordlist subtest score (WSS), CERAD-K(N) total score (TS), and the Korean version of geriatric depression scale (GDS-K) score between baseline and 12 weeks or 26 weeks were assessed by the Student's t-test. RESULTS: At 12 weeks, the changes in the MMSE-KC score, CERAD-K(N) WSS, and CERAD-K(N) TS from baseline were not significant between ChAT A allele carriers and non-carriers; however, at 26 weeks, these changes were significantly larger in ChAT A allele carriers than in non-carriers (p=0.02 for MMSE-KC and p=0.03 for CERAD-K(N) WSS respectively). CONCLUSION: Our findings in this study suggested that presence of the A allele at the +4 position of ChAT might positively influence the treatment effect of donepezil in the early stages of AD in Koreans.

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 Alzheimer's disease (AD) prediction model in mild cognitive impairment (MCI) individuals. Thirty-two MCI subjects were evaluated at baseline with [(18)F]-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.

Epidemiology of MRI-defined vascular depression: A longitudinal, community-based study in Korean elders.

BACKGROUND: There are no cross-sectional or longitudinal epidemiological studies present on MRI-defined vascular depression in community populations. The purpose of this study was to estimate the prevalence rates of both vascular and non-vascular late life depression (LLD) at baseline, to examine the natural course of LLD, and to investigate the influence of White matter hyperintensities (WMHs) on depression after three years. METHOD: The baseline study employed a two-stage design, Phase I population survey (n=783) and Phase II diagnostic evaluation (n=122). In the 3-year follow-up study, baseline participants completing the second phase were reassessed with the same methodology. WMHs severity was rated visually by the modified Fazekas scale and WMHs volume was calculated using an automated method. RESULTS: The prevalence rates of vascular major depressive disorder (MDD) and vascular non-major depressive disorder (nMDD) were 2.39% (56.2% of MDD) and 4.24% (34.0% of nMDD). Subjects with a score of 2 or more on the modified Fazekas scale in either deep white matter hyperintensities or subcortical gray matter ratings had an 8.1 times greater risk of developing a depressive disorder in the 3-year follow-up study. Greater Log WMHs volume (odds ratio=5.78, 95% CI, 1.04-31.72) at baseline was an independent predictor for depressive disorder in the 3-year assessment. LIMITATIONS: Response rate and follow-up rate were relatively low. CONCLUSIONS: Vascular depression is common and makes up about a half of MDD in elders. Greater WMHs severity is a crucial factor predicting future depression risk, which supports the previous vascular depression hypothesis.

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 (Aß) deposition (i.e., aMCI+) and aMCI with no or very little Aß 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+.