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Background: Plasma neurofilament light chain (NfL) is a blood biomarker of neurodegeneration, including Alzheimer's disease. However, its usefulness may be influenced by common conditions in older adults, including amyloid-β (Aβ) deposition and cardiometabolic risk factors like hypertension, diabetes mellitus (DM), impaired kidney function, and obesity. This longitudinal observational study using the Alzheimer's Disease Neuroimaging Initiative cohort investigated how these conditions influence the prognostic capacity of plasma NfL. Methods: Non-demented participants (cognitively unimpaired or mild cognitive impairment) underwent repeated assessments including the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores, hippocampal volumes, and white matter hyperintensity (WMH) volumes at 6- or 12-month intervals. Linear mixed-effect models were employed to examine the interaction between plasma NfL and various variables of interest, such as Aβ (evaluated using Florbetapir positron emission tomography), hypertension, DM, impaired kidney function, or obesity. Results: Over a mean follow-up period of 62.5 months, participants with a mean age of 72.1 years (n = 720, 48.8% female) at baseline were observed. Higher plasma NfL levels at baseline were associated with steeper increases in ADAS-Cog scores and WMH volumes, and steeper decreases in hippocampal volumes over time (all p-values < 0.001). Notably, Aβ at baseline significantly enhanced the association between plasma NfL and longitudinal changes in ADAS-Cog scores (p-value 0.005) and hippocampal volumes (p-value 0.004). Regarding ADAS-Cog score and WMH volume, the impact of Aβ was more prominent in cognitively unimpaired than in mild cognitive impairment. Hypertension significantly heightened the association between plasma NfL and longitudinal changes in ADAS-Cog scores, hippocampal volumes, and WMH volumes (all p-values < 0.001). DM influenced the association between plasma NfL and changes in ADAS-Cog scores (p-value < 0.001) without affecting hippocampal and WMH volumes. Impaired kidney function did not significantly alter the association between plasma NfL and longitudinal changes in any outcome variables. Obesity heightened the association between plasma NfL and changes in hippocampal volumes only (p-value 0.026). Conclusion: This study suggests that the prognostic capacity of plasma NfL may be amplified in individuals with Aβ or hypertension. This finding emphasizes the importance of considering these factors in the NfL-based prognostic model for neurodegeneration in non-demented older adults. [ABSTRACT FROM AUTHOR]

Background: Computerized cognitive training (CCT) has been proposed as a potential therapy for cognitive decline. One of the benefits of CCT is a transfer effect, but its mechanism on the memory domain is unclear. This study aimed to investigate the transfer effect of non‐memory multidomain CCT on the memory domain and its neural basis in patients with mild cognitive impairment (MCI) through a randomized controlled trial. Methods: Patients with MCI recruited from memory clinics were randomly assigned to either the CCT or the control group. The CCT group received multidomain CCT training excluding memory training, while the control group read educational books with learning‐based quizzes twice a week for 8 weeks. Participants underwent memory tests yielding a composite score, other cognitive domain tests, non‐cognitive scales, and resting‐state functional magnetic resonance imaging (rsfMRI), at baseline and after intervention. Within‐ and between‐group comparisons, group × time interactions, and seed‐to‐voxel analyses in memory‐involving brain networks were performed. Results: The CCT group showed improvement over the control group in memory domain (Group × time, F = 5.87, P = 0.03, η2 = 0.31), which was related with the increased connectivity in the hippocampal‐frontal and fusiform‐occipital network. No other cognitive and non‐cognitive symptoms differed between groups after adjusting for covariates. Conclusion: Eight weeks of multidomain CCT without memory training improved memory function and restored functional network in the hippocampal and medial temporal region in MCI patients. These results can provide evidence for the transferring ability of CCT on memory functioning with its neural basis. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms and delusions are highly prevalent among people with dementia. However, multiple roots of neurobiological bases and shared neural basis of delusion and cognitive function remain to be characterized. By utilizing a fine-grained multivariable approach, we investigated distinct neuroanatomical correlates of delusion symptoms across a large population of dementing illnesses. Methods: In this study, 750 older adults with mild cognitive impairment and Alzheimer's disease completed brain structural imaging and neuropsychological assessment. We utilized principal component analysis followed by varimax rotation to identify the distinct multivariate correlates of cortical thinning patterns. Five of the cognitive domains were assessed whether the general cognitive abilities mediate the association between cortical thickness and delusion. Results: The result showed that distributed thickness patterns of temporal and ventral insular cortex (component 2), inferior and lateral prefrontal cortex (component 1), and somatosensory-visual cortex (component 5) showed negative correlations with delusions. Subsequent mediation analysis showed that component 1 and 2, which comprises inferior frontal, anterior insula, and superior temporal regional thickness accounted for delusion largely through lower cognitive functions. Specifically, executive control function assessed with the Trail Making Test mediated the relationship between two cortical thickness patterns and delusions. Discussion: Our findings suggest that multiple distinct subsets of brain regions underlie the delusions among older adults with cognitive impairment. Moreover, a neural loss may affect the occurrence of delusion in dementia largely due to impaired general cognitive abilities. [ABSTRACT FROM AUTHOR]

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: Ankle-brachial index (ABI), an indicator of atherosclerosis or arterial stiffness, has been associated with Alzheimer's disease (AD) dementia and related cognitive impairment. Nevertheless, only limited information is available regarding its contribution to brain alterations leading to cognitive decline in late-life. Objective: We aimed to investigate the relationship of ABI with in vivo AD pathologies and cerebrovascular injury in cognitively impaired older adults. Methods: Total 127 cognitively impaired (70 mild cognitive impairment and 57 AD dementia) individuals, who participated in an ongoing prospective cohort study, were included. All participants underwent comprehensive clinical and neuropsychological assessment, ABI measurement, apolipoprotein E (APOE) ɛ4 genotyping, and multi-modal brain imaging including [11C] Pittsburgh Compound B (PiB)-positron emission tomography (PET) and [18F] fludeoxyglucose (FDG)-PET, and MRI. Results: General linear model analysis showed significant relationship between ABI strata (low ABI: <1.00, normal ABI: 1.00–1.29, and high ABI: ≥1.30) and AD-signature region cerebral glucose metabolism (AD-CM), even after controlling age, sex, clinical dementia rating–sum of box, and APOE ɛ4 positivity (p = 0.029). Post hoc comparison revealed that low ABI had significantly lower AD-CM than middle and high ABI, while no difference of AD-CM was found between middle and high ABI. There was no significant difference of global Aβ deposition, AD-signature region cortical thickness, and white matter hyperintensity volume between the three ABI strata. Conclusion: Our findings suggest that lower ABI, likely related to atherosclerosis, may contribute to the aggravation of AD-related regional neurodegeneration in cognitively impaired older adults. [ABSTRACT FROM AUTHOR]

Objective: Functional impairment in daily activity is a cornerstone in distinguishing the clinical progression of dementia. Multiple indicators based on neuroimaging and neuropsychological instruments are used to assess the levels of impairment and disease severity; however, it remains unclear how multivariate patterns of predictors uniquely predict the functional ability and how the relative importance of various predictors differs. Method: In this study, 881 older adults with subjective cognitive complaints, mild cognitive impairment (MCI), and dementia with Alzheimer's type completed brain structural magnetic resonance imaging (MRI), neuropsychological assessment, and a survey of instrumental activities of daily living (IADL). We utilized the partial least square (PLS) method to identify latent components that are predictive of IADL. Results: The result showed distinct brain components (gray matter density of cerebellar, medial temporal, subcortical, limbic, and default network regions) and cognitive–behavioral components (general cognitive abilities, processing speed, and executive function, episodic memory, and neuropsychiatric symptoms) were predictive of IADL. Subsequent path analysis showed that the effect of brain structural components on IADL was largely mediated by cognitive and behavioral components. When comparing hierarchical regression models, the brain structural measures minimally added the explanatory power of cognitive and behavioral measures on IADL. Conclusion: Our finding suggests that cerebellar structure and orbitofrontal cortex, alongside with medial temporal lobe, play an important role in the maintenance of functional status in older adults with or without dementia. Moreover, the significance of brain structural volume affects real-life functional activities via disruptions in multiple cognitive and behavioral functions. [ABSTRACT FROM AUTHOR]

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]

Objectives: The present study examined self-reports and informant reports of cognitive function and discrepancies between the two reporting methods in healthy controls (HC), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and very mild Alzheimer disease (AD) using three questionnaires.Methods: The study included a total of 300 individuals (mean age: 74.4 ± 5.7 y), including 130 HC, 70 SCD, 51 MCI, and 49 very mild AD patients. Self-ratings and informant ratings of cognitive function were assessed using the Korean Dementia Screening Questionnaire-Cognition (KDSQ-C), AD8, and Subjective Memory Complaints Questionnaire (SMCQ). Awareness of cognitive functioning was measured on the basis of the discrepancy scores between self-reports and informant reports.Results: Group comparisons on questionnaire scores adjusting for age, education, and depressive symptoms showed that self-reports were lowest in HC than other groups, with no differences between SCD and MCI groups. Informant reports were lower in SCD than in MCI, while discrepancy scores were higher in SCD than in MCI (P < .001 for KDSQ-C and SMCQ; P = .076 for AD8). There were no differences in self-reports, informant reports, and discrepancy scores between MCI and AD groups.Conclusions: These results support the usefulness of informant-reported cognitive functioning to classify MCI among elderly with subjective cognitive complaints. In addition, discrepancies between self-reports and informant reports demonstrate that overestimation and underestimation of cognitive function may serve as a clinical indicator of SCD and MCI across the cognitive continuum, respectively. [ABSTRACT FROM AUTHOR]

Background: In assessing the levels of clinical impairment in dementia, a summary index of neuropsychological batteries has been widely used in describing the overall functional status.Objective: It remains unexamined how complex patterns of the test performances can be utilized to have specific predictive meaning when the machine learning approach is applied.Methods: In this study, the neuropsychological battery (CERAD-K) and assessment of functioning level (Clinical Dementia Rating scale and Instrumental Activities of Daily Living) were administered to 2,642 older adults with no impairment (n = 285), mild cognitive impairment (n = 1,057), and Alzheimer's disease (n = 1,300). Predictive accuracy on functional impairment level with the linear models of the single total score or multiple subtest scores (Model 1, 2) and support vector regression with low or high complexity (Model 3, 4) were compared across different sample sizes.Results: The linear models (Model 1, 2) showed superior performance with relatively smaller sample size, while nonlinear models with low and high complexity (Model 3, 4) showed an improved accuracy with a larger dataset. Unlike linear models, the nonlinear models showed a gradual increase in the predictive accuracy with a larger sample size (n > 500), especially when the model training is allowed to exploit complex patterns of the dataset.Conclusion: Our finding suggests that nonlinear models can predict levels of functional impairment with a sufficient dataset. The summary index of the neuropsychological battery can be augmented for specific purposes, especially in estimating the functional status of dementia. [ABSTRACT FROM AUTHOR]

Age-related white matter lesion (WML) is considered a manifestation of sporadic cerebral small vessel disease and an important pathological substrate for dementia. Asia is notable for its large population with a looming dementia epidemic. Yet, the burden of WML and its associated risk factors across different Asian societies are unknown. Subjects from 9 Asian cities (Bangkok, Bandung, Beijing, Bengaluru, Hong Kong, Kaohsiung, Manila, Seoul, and Singapore) were recruited (n = 5701) and classified into (i) stroke/transient ischemic attack (TIA), (ii) Alzheimer's disease (AD)/mild cognitive impairment (MCI), or (iii) control groups. Data on vascular risk factors and cognitive performance were collected. The severity of WML was visually rated on MRI or CT. The prevalence of moderate-to-severe WML was the highest in subjects with stroke/TIA (43.3%). Bandung Indonesia showed the highest prevalence of WML, adjusted for age, sex, education, disease groups, and imaging modality. Hypertension and hyperlipidemia were significant risk factors for WML, and WML was negatively associated with MMSE in all groups. WML is highly prevalent in Asia and is associated with increasing age, hypertension, hyperlipidemia, and worse cognitive performance. Concerted efforts to prevent WML will alleviate the huge dementia burden in the rapidly aging Asian societies. [ABSTRACT FROM AUTHOR]

Tinnitus is a conscious auditory perception in the absence of an external stimulus. Despite previous reports of a recognized association between tinnitus and cognitive deficits, the effects of tinnitus on functional and structural brain changes associated with cognitive deficits remain unknown. We aimed to investigate the changes in glucose metabolism and gray matter (GM) volume in subjects diagnosed with mild cognitive impairment (MCI) depending on tinnitus. Twenty-three subjects were subclassified into MCI with the chronic tinnitus (MCI_T) and MCI without tinnitus (MCI_NT) groups. Encouraged by the identification of neural substrates associated with tinnitus and cognitive deficits, we correlated the extent of tinnitus severity with the changes in glucose metabolism and GM volume and conducted a glucose metabolic connectivity study. Compared to the MCI_NT group, the MCI_T group showed significantly lower metabolism in the right superior temporal pole and left fusiform gyrus. Additionally, the GM volume in the right insula was markedly lower in the MCI_T group compared to the MCI_NT group. Moreover, correlation analyses in metabolism or GM volumes revealed specific brain regions associated with the cognitive decline with increasing tinnitus severity. Metabolic connectivity analysis revealed that MCI_NT had markedly strengthened intra-hemispheric connectivity in the frontal, parietal, and occipital regions than did MCI_T. Furthermore, MCI_NT showed a strong negative association between the parietal and temporal and parietal and limbic regions, but the association was not observed in MCI_T. These findings indicate that tinnitus may cause metabolic and structural changes in the brain and alters complex inter- or intra-hemispheric networks in MCI. Considering the impact of MCI on accelerating dementia, these results provide a valuable basis on which yet-to-be-identified neurodegenerative markers of tinnitus can be refined. [ABSTRACT FROM AUTHOR]

Background: Previous studies indicated an association between Alzheimer's disease (AD) dementia and air particulate matter (PM) with aerodynamic diameter <10μm (PM10), as well as smaller PM. Limited information, however, is available for the neuropathological links underlying such association.Objective: This study aimed to investigate the relationship between long-term PM10 exposure and in vivo pathologies of AD using multimodal neuroimaging.Methods: The study population consisted of 309 older adults without dementia (191 cognitively normal and 118 mild cognitive impairment individuals), who lived in Republic of Korea. Participants underwent comprehensive clinical assessments, 11C-Pittsburg compound B (PiB) positron emission tomography (PET), and magnetic resonance imaging scans. A subset of 78 participants also underwent 18F-AV-1451 tau PET evaluation. The mean concentration of PM with aerodynamic diameter <10μm over the past 5 years (PM10mean) collected from air pollution surveillance stations were matched to each participant's residence.Results: In this non-demented study population, of which 62% were cognitively normal and 38% were in mild cognitive impairment state, exposure to the highest tertile of PM10mean was associated with increased risk of amyloid-β (Aβ) positivity (odds ratio 2.19, 95% confidence interval 1.13 to 4.26) even after controlling all potential confounders. In contrast, there was no significant associations between PM10mean exposure and tau accumulation. AD signature cortical thickness and white matter hyperintensity volume were also not associated with PM10mean exposure.Conclusion: The findings suggest that long-term exposure to PM10 may contribute to pathological Aβ deposition. [ABSTRACT FROM AUTHOR]

Background: Although the existence of proteasomes in human blood, termed circulating proteasomes (c-proteasomes), has been reported previously, their origin and pathophysiological functions remain largely unknown.Objective: Given that c-proteasome activity was significantly reduced in Alzheimer's disease model mice and relatively high frequency of mild cognitive impairment (MCI) is accompanied by chronic tinnitus in aged patients, we examined whether c-proteasome activity in human plasma was associated with cognitive function in patients with chronic tinnitus.Methods: c-Proteasome activity in the plasma of tinnitus patients (N = 55) was measured with fluorogenic reporter substrate, suc-LLVY-AMC. To assess MCI, the Montreal Cognitive Assessment was conducted with a cut-off score of 22/23. All patients underwent audiological and psychoacoustic analyses. Levels of c-proteasomes, Aβ42, and Aβ40 were measured using ELISA, and their association with c-proteasome activity was evaluated.Results: The activity of circulating proteasomes was significantly lower in patients with chronic tinnitus and MCI (p = 0.042), whereas activities of other plasma enzymes showed little correlation. In addition, c-proteasome activity was negatively associated with the level of plasma Aβ and was directly dependent on its own concentration in the plasma of patients with chronic tinnitus.Conclusion: Our current work provides a new perspective for understanding the potential relationship between circulating proteasomes in the plasma and cognitive dysfunction, suggesting a novel, non-invasive biomarker in the context of MCI diagnosis. [ABSTRACT FROM AUTHOR]

In older adults with normal cognition, cognitive reserve (CR) is known to be associated with the neuropsychological profile. We investigated the association between comprehensive CR and detailed neuropsychological profile in the early stage of cognitive decline. Fifty-five participants with mild cognitive impairment or subjective cognitive decline completed the cognitive reserve index questionnaire (CRIq) that yielded total, education, working activity, and leisure time scores (CRI-Total, CRI-Education, CRI-Working activity, and CRI-Leisure time, respectively). Mini-mental state examination (MMSE) and detailed neuropsychological evaluation were performed. Psychiatric symptom scales were applied to measure depression, apathy, positive or negative affect, and quality of life. Correlation and linear regression analyses of the variables were performed. The effect of CR-Education, CRI-Working activity, and CRI-Leisure time on the composite cognitive score was determined using a multivariable regression model. We observed that for CRI-Total (B = 3.00, p = 0.005), CRI-Education (B = 3.39, p = 0.002), and CRI-Leisure time (B = 2.56, p = 0.015), CR correlated with MMSE scores, while only CRI-Leisure time associated with the naming ability (B = 2.20, p = 0.033) in the detailed neuropsychological test results of the participants. Multivariable regression model also indicated that among CRI subscores, CRI-Leisure time directly affects the composite cognitive score (β = 0.32, p = 0.011). We found that in the early stage of cognitive decline in older adults, comprehensive CR was associated with global cognition, and only leisure activity was identified to be associated with the detailed neuropsychological profile including naming ability. These results may imply the positive effect of leisure activity on cognitive function in the early stages of cognitive decline. [ABSTRACT FROM AUTHOR]

Objective: Plasma clusterin, a promising biomarker of Alzheimer disease (AD), has been associated with diabetes mellitus (DM). However, clusterin has not been investigated considering a relationship with both DM and AD. In this study, we aimed to investigate the individual and interactive relationships of plasma clusterin levels with both diseases.Design: Cross-sectional observation study.Methods: We classified participants by the severity of cognitive (normal cognition, mild cognitive impairment [MCI], and AD) and metabolic (healthy control, prediabetes, and DM) impairments. We evaluated the cognitive and metabolic functions of the participants with neuropsychological assessments, brain magnetic resonance imaging, and various blood tests, to explore potential relationships with clusterin.Results: Plasma clusterin levels were higher in participants with AD and metabolic impairment (prediabetes and DM). A two-way ANCOVA revealed no synergistic, but an additive effect of AD and DM on clusterin. Clusterin was negatively correlated with cognitive scores. It was also associated with metabolic status indicated by glycated hemoglobin A1c (HbA1c), the Homeostatic Model Assessment for Insulin Resistance index, and fasting C-peptide. It showed correlations between medial temporal atrophy and periventricular white matter lesions, indicating neurodegeneration and microvascular insufficiency, respectively. Further mediation analysis to understand the triadic relationship between clusterin, AD, and DM revealed that the association between DM and AD was significant when clusterin is considered as a mediator of their relationship.Conclusions: Clusterin is a promising biomarker of DM as well as of AD. Additionally, our data suggest that clusterin may have a role in linking DM with AD as a potential mediator. [ABSTRACT FROM AUTHOR]

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

Background: Fluorodeoxyglucose (FDG) positron emission tomography (PET) is useful to predict Alzheimer’s disease (AD) conversion in patients with mild cognitive impairment (MCI). However, few studies have examined the extent to which FDG PET alone can predict AD conversion and compared the efficacy between visual and computer-assisted analysis directly.Objective: The current study aimed to evaluate the value of FDG PET in predicting the conversion to AD in patients with MCI and to compare the predictive values of visual reading and computer-assisted analysis.Methods and materials: A total of 54 patients with MCI were evaluated with FDG PET and followed-up for 2 years with final diagnostic evaluation. FDG PET images were evaluated by (1) traditional visual rating, (2) composite score of visual rating of the brain cortices, and (3) composite score of computer-assisted analysis. Receiver operating characteristics (ROC) curves were compared to analyze predictive values.Results: Nineteen patients (35.2%) converted to AD from MCI. The area under the curve (AUC) of the ROC curve of the traditional visual rating, composite score of visual rating, and computer-assisted analysis were 0.67, 0.76, and 0.79, respectively. ROC curves of the composite scores of the visual rating and computer-assisted analysis were comparable (Z = 0.463, p = 0.643).Conclusions: Visual rating and computer-assisted analysis of FDG PET scans were analogously accurate in predicting AD conversion in patients with MCI. Therefore, FDG PET may be a useful tool for screening AD conversion in patients with MCI, when using composite score, regardless of the method of interpretation. [ABSTRACT FROM AUTHOR]

Objective Lack of knowledge about a disease could impede early diagnosis and may lead to delays in seeking appropriate medical care. The aim of this study was to explore knowledge of dementia (KOD) and to find the determinants of KOD among three groups: older adults with normal cognition, mild cognitive impairment (MCI), and dementia. Methods A representative nationwide sample of 6141 Korean elders aged 65 years or older participated in face-to-face interviews and answered 14 questions pertaining to general information, etiology, symptoms, and treatment of dementia. Stepwise multiple regressions and path analyses probed the relationships between various sociodemographic variables and KOD. Results The percentage of correct responses was only 62%. The item ‘A person who remembers things that happened in the past does not have dementia’ was answered correctly (false) by only 24.8–27% of the respondents in all groups. Older adults with normal cognition had higher KOD scores than those with MCI or dementia. In the normal-cognition group, KOD scores were higher among highly educated, younger, and literate women with no depression and a family history of dementia. In contrast with the determinants in the normal-cognition group, only the ability to read and write predicted KOD scores in the dementia group. Conclusions Efforts to enhance KOD in elder adults are needed. Public education regarding the differences between dementia and healthy aging may increase KOD among normal elders and those with MCI. Among elders with dementia, educational materials that do not require literacy may be more helpful in increasing KOD with the aim of preventing treatment delay. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background:We assessed eight-year mortality rates and predictors in a rural cohort of elderly individuals with cognitive impairment.Methods:A total of 1,035 individuals, including 155 (15.0%) individuals with cognitive impairment, no dementia (CIND), and 69 (6.7%) individuals with clinically diagnosed dementia were followed for eight years from 1997. The initial assessment involved a two-step diagnostic procedure performed during a door-to-door survey, and mortality data were obtained from the Korean National Statistical Office (KNSO). The relationship between clinical diagnosis and risk of death was examined using the Cox proportional hazards model after adjusting for age, sex, and education.Results:During follow-up, 392 individuals died (37.9%). Compared to persons without cognitive impairment, mortality risk was nearly double among those with CIND (hazard ratio [95% confidence interval], 1.92 [1.46–2.54]), and this increased more than three-fold among those with dementia (3.20 [2.30–4.44]). Old age and high scores on the behavioral changes scale at diagnosis were two common predictors of mortality among those with CIND and dementia. Among the items on the behavioral changes scale, low sociability, less spontaneity, and poor hygiene were associated with increased mortality in individuals with CIND. Conversely, low sociability, excessive emotionality, and irritability were associated with increased mortality in patients with dementia.Conclusions:Both dementia and CIND increased mortality risk compared with normal cognition in this community cohort. It is important to identify and manage early behavioral changes to reduce mortality in individuals with CIND and dementia. [ABSTRACT FROM AUTHOR]

The purpose of this preliminary study was to test the hypothesis that subsyndromal depression is associated with the volume of medial prefrontal regional gray matter and that of white matter lesions (WMLs) in the brains of cognitively normal older people. We also explored the relationships between subsyndromal depression and medial prefrontal regional gray matter volume, limbic regional gray matter volume, and lobar WMLs in the brains of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). We performed a cross-sectional study comparing patients with subsyndromal depression and nondepressed controls with normal cognition (n = 59), MCI (n = 27), and AD (n = 27), adjusting for sex, age, years of education, and results of the Mini-Mental State Examination. Frontal WML volume was greater, and right medial orbitofrontal cortical volume was smaller in cognitively normal participants with subsyndromal depression than in those without subsyndromal depression. No volume differences were observed in medial prefrontal, limbic, or WML volumes according to the presence of subsyndromal depression in cognitively impaired patients. The absence of these changes in patients with MCI and AD suggests that brain changes associated with AD pathology may override the changes associated with subsyndromal depression. [ABSTRACT FROM AUTHOR]

Background: Cognitive training can potentially prevent cognitive decline. However, the results of recent studies using semi-immersive virtual reality (VR)-assisted cognitive training are inconsistent.Objective: We aimed to examine the hypothesis that cognitive training using fully immersive VR, which may facilitate visuospatial processes, could improve visuospatial functioning, comprehensive neuropsychological functioning, psychiatric symptoms, and functional connectivity in the visual brain network in predementia.Methods: Participants over 60 years old with subjective cognitive decline or mild cognitive impairment from a memory clinic were randomly allocated to the VR (n=23) or the control (n=18) group. The VR group participants received multidomain and neuropsychologist-assisted cognitive training in a fully immersive VR environment twice a week for 1 month. The control group participants did not undergo any additional intervention except for their usual therapy such as pharmacotherapy. Participants of both groups were evaluated for cognitive function using face-to-face comprehensive neuropsychological tests, including the Rey-Osterrieth Complex Figure Test (RCFT) copy task; for psychiatric symptoms such as depression, apathy, affect, and quality of life; as well as resting-state functional magnetic resonance imaging (rsfMRI) at baseline and after training. Repeated-measures analysis of variance was used to compare the effect of cognitive training between groups. Seed-to-voxel-based analyses were used to identify the cognitive improvement-related functional connectivity in the visual network of the brain.Results: After VR cognitive training, significant improvement was found in the total score (F1,39=14.69, P=.001) and basic components score of the RCFT copy task (F1,39=9.27, P=.005) compared with those of the control group. The VR group also showed improvements, albeit not significant, in naming ability (F1,39=3.55, P=.07), verbal memory delayed recall (F1,39=3.03, P=.09), and phonemic fluency (F1,39=3.08, P=.09). Improvements in psychiatric symptoms such as apathy (F1,39=7.02, P=.01), affect (F1,39=14.40, P=.001 for positive affect; F1,39=4.23, P=.047 for negative affect), and quality of life (F1,39=4.49, P=.04) were found in the VR group compared to the control group. Improvement in the RCFT copy task was associated with a frontal-occipital functional connectivity increase revealed by rsfMRI in the VR group compared to the control group.Conclusions: Fully immersive VR cognitive training had positive effects on the visuospatial function, apathy, affect, quality of life, and increased frontal-occipital functional connectivity in older people in a predementia state. Future trials using VR cognitive training with larger sample sizes and more sophisticated designs over a longer duration may reveal greater improvements in cognition, psychiatric symptoms, and brain functional connectivity.Trial Registration: Clinical Research Information Service KCT0005243; https://tinyurl.com/2a4kfasa. [ABSTRACT FROM AUTHOR]

Background: To clarify whether atherosclerosis of the carotid and intracranial arteries is related to Alzheimer's disease (AD) pathology in vivo, we investigated the associations of carotid and intracranial artery stenosis with cerebral beta-amyloid (Aβ) deposition and neurodegeneration in middle- and old-aged individuals. Given different variations of the pathologies between cognitive groups, we focused separately on cognitively normal (CN) and cognitively impaired (CI) groups. Methods: A total of 281 CN and 199 CI (mild cognitive impairment and AD dementia) subjects underwent comprehensive clinical assessment, [11C] Pittsburgh compound B-positron emission tomography, and magnetic resonance (MR) imaging including MR angiography. We evaluated extracranial carotid and intracranial arteries for the overall presence, severity (i.e., number and degree of narrowing), and location of stenosis. Results: We found no associations between carotid and intracranial artery stenosis and cerebral Aβ burden in either the CN or the CI group. In terms of neurodegeneration, exploratory univariable analyses showed associations between the presence and severity of stenosis and regional neurodegeneration biomarkers (i.e., reduced hippocampal volume [HV] and cortical thickness in the AD-signature regions) in both the CN and CI groups. In confirmatory multivariable analyses controlling for demographic covariates and diagnosis, the association between number of stenotic intracranial arteries ≥ 2 and reduced HV in the CI group remained significant. Conclusions: Neither carotid nor intracranial artery stenosis appears to be associated with brain Aβ burden, while intracranial artery stenosis is related to amyloid-independent neurodegeneration, particularly hippocampal atrophy. [ABSTRACT FROM AUTHOR]

Intervention programs to relieve memory impairment and memory-related complaints in older adults with mild cognitive impairment are needed. Objective: The purpose of the current study was to assess the efficacy of a novel cognitive training approach—named multi-strategic metamemory training—in older adults with amnestic mild cognitive impairment. Among a total of 113 older adults with mild cognitive impairment, 66 participated in the memory training program (training group) and 47 did not (control group). Repeated measures of analysis of variance revealed that compared with the control group, the training group experienced: (i) a significantly greater increase in cognitive test scores of long-term delayed free recall (Finteraction = 6.04, p = 0.016) and fluency (Finteraction = 4.11, p = 0.045) and (ii) significantly greater decrease in their subjective memory complaints for everyday memory (Finteraction = 7.35, p = 0.009). These results suggest that the training program can improve verbal memory (i.e., delayed free recall), language processing (i.e., categorical fluency) and limit complaints in everyday instrumental memory activities of mildly impaired older adults. [ABSTRACT FROM AUTHOR]

Background: Subjective memory complaint (SMCs) is a common trait amongst older population. The subjective cognition about their memory could depend on objective cognition. The aim of the current study was to examine the interaction between subjective memory cognition (i.e., SMC) and objective cognition on cognitive functions in participants from older generation.Methods: A total of 219 patients, 181 normal control (NC) patients and 38 patients with mild cognitive impairment (MCI), were examined through standardized and comprehensive clinical evaluation and neuropsychological assessment. The Subjective Memory Complaints Questionnaire was used to assess SMCs along with five cognitive tasks were used to evaluate cognitive decline over following areas: verbal memory, visuospatial memory, attention, fluency, and language.Results: The results of 2 × 2 two-way analysis of variance (ANOVA) showed that there were significant interactions between SMCs and cognitive status (NC, MCI) on memory performances. NC with SMCs showed significantly lower performance in verbal memory and visuospatial memory compared to NCs without SMCs. Conversely, no effect was observed in the MCI group.Conclusion: There are interactions between subjective cognition (i.e., SMC) and objective cognition (i.e., cognitive status) on memory performances in older adults. The roles of SMCs on memory performances should be interpreted with older adults' objective cognitive status. [ABSTRACT FROM AUTHOR]

Background: Cognitive frailty and impairment are phenotypically and pathophysiologically correlated with physical frailty. We examined associations between accumulation of amyloid-β in the brain as a brain imaging biomarker and phenotypes of physical frailty (weight loss, weakness, exhaustion, slowness, low physical activity) in older adults with mild cognitive impairment (MCI) and cognitive frailty. Methods: Cross-sectional associations between brain amyloid-β accumulation measured with 11C-Pittsburgh compound B (PiB)-positron emission tomography (PET) and physical frailty were examined in 48 elderly participants (mean age: 75.1 ± 6.6 years; 73% female). Cortical and regional standard uptake value ratios (SUVRs) were obtained. Main outcome measures included frailty phenotypes and physical functions (gait speed, short physical performance battery, and Timed Up and Go tests). Results: Mean cortical region of interest and regional SUVRs (frontal cortex, temporal cortex, parietal cortex, precuneus/posterior cingulate cortex (PC/PCC), hippocampus, basal ganglia, and global SUVR) were associated with gait speed, Timed Up and Go, and short physical performance battery (PC/PCC, basal ganglia). In addition, SUVRs of all brain regions were significantly linked to weakness. Conclusion: SUVRs of all brain regions revealed an association between brain amyloid-β accumulation and weakness. Furthermore, global SUVRs (frontal cortex, temporal cortex, parietal cortex, PC/PCC, hippocampus, basal ganglia) were associated with gait parameters. [ABSTRACT FROM AUTHOR]

Objectives: Assessment of depressive symptoms in older adults is challenging especially in the presence of risks in cognitive impairment. We aimed to examine whether the convergence between two measures of depressive symptoms (self‐report and observer ratings) is affected by varying levels of cognitive function in older adults. Methods: Self‐reported scale of depression, informant‐based rating of affective symptoms, and global cognitive function were assessed in 2533 older adults with no impairment, mild cognitive impairment, and Alzheimer's disease. The strength of rank‐order correlation between the Geriatric Depression Scale (GDS) and behavioral ratings of the Neuropsychiatric Inventory (NPI) was examined as the metric of convergent validity. Results: The results showed that the strength of convergence between the two measurements gradually decreased as a function of lowered cognitive function. Overall tendency showed that diagnoses of cognitive impairment and lower levels of cognitive function were associated with lower correspondence between the two depression measurements. The loss of convergent validity is especially evident in the behavioral symptom of apathy. Conclusions: Utilizing self‐report scales of depression in older adults requires a cautious approach even with minimal or mild levels of cognitive impairment. [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]

Highlights • Color-form score of A Quick Test of Cognitive Speed (AQT) can discriminate between healthy control and Alzheimer's disease in the participants of the present study. • Processing speed of the three subtests (i.e., color, form, color-form) of AQT can differentiate Alzheimer's disease from mild cognitive impairment and healthy control, but not mild cognitive impairment from healthy control in the participants of the present study. • Voxel-based morphometry has found a positive correlation between the color-form score and the gray matter volumes of the areas responsible for visuospatial working memory. Abstract 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 η2 = 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. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder with the clinical symptom of the progressive loss of cognitive function and mild cognitive impairment (MCI) is a translational state between cognitive changes of normal aging and AD. Lipid metabolism and pathogenesis of Alzheimer’s disease (AD) are closely linked. Despite obviously discrete lipidome constitutions across lipoproteins, lipidomic approaches of AD has been mostly conducted without considering lipoprotein-dependent alterations. This study introduces a combination of asymmetrical flow field-flow fractionation (AF4) and nanoflow ultrahigh performance liquid chromatography-tandem mass spectrometry (nUHPLC-ESI-MS/MS) for a comprehensive lipid profiling in different lipoprotein level of patients plasma with AD and amnestic MCI in comparison to age-matched healthy controls. Lipoproteins in plasma samples were size-sorted by a semi-preparative scale AF4, followed by non-targeted lipid identification and high speed targeted quantitation with nUHPLC-ESI-MS/MS. It shows 14 significantly altered high abundance lipids in AD, exhibiting >2-fold increases ( p  < 0.01) in LDL/VLDL including triacylglycerol, ceramide, phosphatidylethanolamine, and diacylglycerol. Three lipid species (triacylglycerol 50:1, diacylglycerol 18:1_18:1, and phosphatidylethanolamine 36:2) showing a strong correlation with the degree of brain atrophy were found as candidate species which can be utilized to differentiate the early stage of MCI when simple Mini-Mental State Examination results were statistically incorporated. The present study elucidated lipoprotein-dependent alterations of lipids in progression of MCI and further to AD which can be utilized for the future development of lipid biomarkers to enhance the predictability of disease progress. [ABSTRACT FROM AUTHOR]