Functional Neural Correlates of Semantic Fluency Task Performance in Mild Cognitive Impairment and Alzheimer's Disease: An FDG-PET Study.

BACKGROUND: Total score (TS) of semantic verbal fluency test (SVFT) is generally used to interpret results, but it is ambiguous as to specific neural functions it reflects. Different SVFT strategy scores reflecting qualitative aspects are proposed to identify specific cognitive functions to overcome limitations of using the TS. OBJECTIVE: Functional neural correlates of the TS as well as the other strategy scores in subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia using Fluorine-18-Fluorodeoxyglucose positron emission tomography (FDG-PET). METHODS: Correlations between various SVFT scores (i.e., TS, mean cluster size, switching (SW), hard switching, cluster switching (CSW)) and cerebral glucose metabolism were explored using voxelwise whole-brain approach. Subgroup analyses were also performed based on the diagnosis and investigated the effects of disease severity on the associations. RESULTS: Significant positive correlation between TS and cerebral glucose metabolism was found in prefrontal, parietal, cingulate, temporal cortex, and subcortical regions. Significantly increased glucose metabolism associated with the SW were found in similar but smaller regions, mainly in the fronto-parieto-temporal regions. CSW was only correlated with the caudate. In the subgroup analysis conducted to assess different contribution of clinical severity, differential associations between the strategy scores and regional glucose metabolism were found. CONCLUSION: SW and CSW may reflect specific language and executive functions better than the TS. The SVFT is influenced by brain dysfunction due to the progression of AD, as demonstrated by the SW with larger involvement of temporal lobe for the AD, and CSW with significant association only for the MCI.

Cognitive reserve proxies, Alzheimer pathologies, and cognition.

This study aimed to explore the moderating effects of the frequently used cognitive reserve (CR) proxies [i.e., education, premorbid intelligence quotient (pIQ), occupational complexity (OC), and lifetime cognitive activity (LCA)] on the relationships between various in vivo Alzheimer's disease (AD) pathologies and cognition. In total, 351 [268 cognitively unimpaired (CU), 83 cognitive impaired (CI)] older adults underwent multi-modal brain imaging to measure AD pathologies and cognitive assessments, and information on CR proxies was obtained. For overall participants, only education moderated the relationship between Aß deposition and cognition. Education, pIQ, and LCA, but not OC, showed moderating effect on the relationship between AD-signature cerebral hypometabolism and cognition. In contrast, only OC had a moderating effect on the relationship between cortical atrophy of the AD-signature regions and cognition. Such moderation effects of the CR proxies were similarly observed in CI individuals, but most of them were not in CU individuals. The findings suggest that the proposed CR proxies have different moderating effects on the relationships between specific AD pathologies and cognition.

Normative Study of the Block Design Test for Adults Aged 55 Years and Older in Korean Aging Population.

OBJECTIVE: The Block Design Test (BDT) is known to be an effective measure in diagnosing age-related cognitive decline of visuospatial function. The goal of this study is to investigate the effects of age, education years, and gender on the performance of the BDT and to provide normative data in Korean community-dwelling participants who are 55 to 90 years old. METHODS: The participants were 432 non-demented adults aging from 55 to 90 years old. The BDT was administered to participants according to its manual. Multiple linear regressions and analyses of variance were conducted, including age, gender, and educations were used as covariates. RESULTS: Age, educational years, and gender were found to be significantly associated with performance on the BDT. As age increased, BDT performance decreased. Educational years were associated with BDT performance. Men showed higher performance (29.9±10.3) compare to women (26.1±8.7). The BDT is influenced by age, educational years, and gender. CONCLUSION: Unlike the previous study, the current study shows that gender has a significant influence in visuospatial ability in the old population. Present normative data will be useful for clinicians in evaluating aging participants with cognitive impairment.

Validation of the Korean Version of the Anosognosia Questionnaire for Dementia.

OBJECTIVE: Anosognosia is a common phenomenon in individuals with dementia. Anosognosia Questionnaire for dementia (AQ-D) is a well-known scale for evaluating anosognosia. This study aimed to establish a Korean version of the AQ-D (AQ-D-K) and to evaluate the reliability and validity of the AQ-D-K in patients with Alzheimer's disease (AD) dementia. METHODS: We translated the original English version of AQ-D into Korean (AQ-D-K). Eighty-four subjects with very mild or mild AD dementia and their caregivers participated. Reliability of AQ-D-K was assessed by internal consistency and one-month test-retest reliability. Construct validity and concurrent validity were also evaluated. RESULTS: Internal consistencies of the AQ-D-K patient form and caregiver form were high (Cronbach alpha 0.95 and 0.93, respectively). The test-retest reliability of AQ-D-K measured by intra-class correlation coefficient was 0.84. Three factors were identified: 1) anosognosia of instrumental activity of daily living; 2) anosognosia basic activity of daily living; and 3) anosognosia of depression and disinhibition. AQ-D-K score was significantly correlated with the clinician-rated anosognosia rating scale (ARS), center for epidemiological studies-depression scale (CES-D) and state-trait anxiety inventory (STAI). CONCLUSION: The findings suggest that the AQ-D-K is a reliable and valid scale for evaluating anosognosia for AD dementia patients using Korean language.

Functional Neural Correlates of the WAIS-IV Block Design Test in Older Adult with Mild Cognitive Impairment and Alzheimer's Disease.

The Wechsler Adult intelligence scale-Revised (WAIS-R) Block design test (BDT) is a neuropsychological test widely used to assess cognitive declines in aging population. Previous studies suggest parietal lobe is the key region to influence the performance on the BDT; yet, it has not been clearly identified. The aim of the current study, therefore, is to identify the functional neural correlates of the BDT in older adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia patients. The current study includes 213 cognitively impaired mid to old-aged community dwelling Korean. All participants underwent comprehensive clinical and neuropsychological assessments and 18F-fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) scans. Performance on the BDT was assessed using the WAIS-IV Korean version. Voxel-wise analyses were used to investigate the correlation between regional cerebral glucose metabolism and BDT performance. The same analyses were conducted on the subgroups categorized by clinical severity based on the Clinical Dementia Rating (CDR). Significant positive correlations between performance on the BDT and regional cerebral glucose metabolism were found bilaterally in the inferior parietal lobules, right thalamus and right middle frontal gyrus. Our results suggest that performance on the BDT in MCI and AD patients functionally relies on the brain regions known to be associated with motor and executive functions in addition to visuospatial function.

Association of Retinal Changes With Alzheimer Disease Neuroimaging Biomarkers in Cognitively Normal Individuals.

IMPORTANCE: Retinal biomarkers reflecting in vivo brain Alzheimer disease (AD) pathologic abnormalities could be a useful tool for screening cognitively normal (CN) individuals at the preclinical stage of AD. OBJECTIVES: To investigate the association of both functional and structural alterations of the retina with in vivo AD pathologic abnormalities in CN older adults and model a screening tool for detection of preclinical AD. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study included a total of 49 CN individuals, and all assessment was done at the Seoul National University Hospital, Seoul, South Korea. All participants underwent complete ophthalmic examination, including swept-source optical coherence tomography (SS-OCT) and multifocal electroretinogram as well as amyloid-ß (Aß) positron emission tomography and magnetic resonance imaging. Data were collected from January 1, 2016, through October 31, 2017, and analyzed from February 1, 2018, through June 30, 2020. MAIN OUTCOMES AND MEASURES: For structural parameters of the retina, the thickness of the macula and layer-specific thicknesses, including peripapillary retinal nerve fiber layer and ganglion cell-inner plexiform layer measured by SS-OCT, were used for analysis. For functional parameters of the retina, implicit time and amplitude of rings 1 to 6 measured by multifocal electroretinogram were used. RESULTS: Of the 49 participants, 25 were women (51.0%); mean (SD) age was 70.6 (9.4) years. Compared with 33 CN individuals without Aß deposition (Aß-CN), the 16 participants with Aß (Aß+CN) showed reduced inner nasal macular thickness (mean [SD], 308.9 [18.4] vs 286.1 [22.5] µm; P = .007) and retinal nerve fiber layer thickness, particularly in the inferior quadrant (133.8 [17.9] vs 103.8 [43.5] µm; P = .003). In addition, the Aß+CN group showed prolonged implicit time compared with the Aß-CN group, particularly in ring 5 (41.3 [4.0] vs 38.2 [1.3] milliseconds; P = .002). AD-related neurodegeneration was correlated with the thickness of the ganglion cell-inner plexiform layer only (r = 0.41, P = .005). The model to differentiate the Aß+CN vs Aß-CN groups derived from the results showed 90% accuracy. CONCLUSIONS AND RELEVANCE: The findings of this study showing both functional as well as structural changes of retina measured by multifocal electroretinogram and SS-OCT in preclinical AD suggest the potential use of retinal biomarkers as a tool for early detection of in vivo AD pathologic abnormalities in CN older adults.

Blood Hemoglobin, in-vivo Alzheimer Pathologies, and Cognitive Impairment: A Cross-Sectional Study.

Background: Despite known associations between low blood hemoglobin level and Alzheimer's disease (AD) or cognitive impairment, the underlying neuropathological links are poorly understood. We aimed to examine the relationships of blood hemoglobin levels with in vivo AD pathologies (i.e., cerebral beta-amyloid [Aß] deposition, tau deposition, and AD-signature degeneration) and white matter hyperintensities (WMHs), which are a measure of cerebrovascular injury. We also investigated the association between hemoglobin level and cognitive performance, and then assessed whether such an association is mediated by brain pathologies. Methods: A total of 428 non-demented older adults underwent comprehensive clinical assessments, hemoglobin level measurement, and multimodal brain imaging, including Pittsburgh compound B-positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and magnetic resonance imaging. Episodic memory score and global cognition scores were also measured. Results: A lower hemoglobin level was significantly associated with reduced AD-signature cerebral glucose metabolism (AD-CM), but not Aß deposition, tau deposition, or WMH volume. A lower hemoglobin level was also significantly associated with poorer episodic memory and global cognition scores, but such associations disappeared when AD-CM was controlled as a covariate, indicating that AD-CM has a moderating effect. Conclusion: The present findings suggest that low blood hemoglobin in older adults is associated with cognitive decline via reduced brain metabolism, which seems to be independent of those aspects of AD-specific protein pathologies and cerebrovascular injury that are reflected in PET and MRI measures.

Long-Term Exposure to PM10 and in vivo Alzheimer's Disease Pathologies.

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-ß (Aß) 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 Aß deposition.

Multiparity, Brain Atrophy, and Cognitive Decline.

BACKGROUND: Multiparity - grand multiparity (i.e., five or more childbirths) in particular - has been reported to have an association with increased risk of Alzheimer's disease (AD) dementia or related cognitive decline in women. However, the pathological links underlying this relationship are still unknown. This study was conducted to examine the relationships of multiparity with cerebral amyloid-beta (Aß) deposition, brain atrophy, and white matter hyperintensities (WMHs). METHODS: In this study, total of 237 older women with 148 cognitively normal and 89 mild cognitive impairment from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) were included. Participants underwent clinical and neuropsychological assessments in addition to 11C-labeled Pittsburgh Compound B positron emission tomography, and magnetic resonance imaging. The associations of parity with Aß deposition, hippocampal volume, cortical volume, WMH volume and mini-mental status examination (MMSE) score were examined. RESULTS: Participants with grand multiparity showed significantly reduced adjusted hippocampal volume, spatial pattern of atrophy for recognition of AD volume and spatial pattern of atrophy for recognition of brain aging volume even after controlling for potential confounders. Furthermore, MMSE score was also significantly lower in this group. In contrast, grand multiparity did not show any association with global Aß retention, Aß positivity rate, or WMH volume, regardless of covariates. CONCLUSION: Our findings suggest that grand multiparity contributes to cognitive decline or increased dementia risk in older women by aggravating amyloid-independent hippocampal or cortical atrophy.

Resting State Glucose Utilization and Adult Reading Test Performance.

Adult reading tests (ART) have been widely used in both research and clinical settings as a measure of premorbid cognitive abilities or cognitive reserve. However, the neural substrates underlying ART performance are largely unknown. Furthermore, it has not yet been examined whether the neural substrates of ART performance reflect the cortical regions associated with premorbid intelligence or cognitive reserve. The aim of the study is to identify the functional neural correlates of ART performance using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging in the cognitively normal (CN) middle- and old-aged adults. Voxel-wise analyses revealed positive correlations between glucose metabolism and ART performance in the frontal and primary somatosensory regions, more specifically the lateral frontal cortex, anterior cingulate cortex and postcentral gyrus (PCG). When conducted again only for amyloid-ß (Aß)-negative individuals, the voxel-wise analysis showed significant correlations in broader areas of the frontal and primary somatosensory regions. This is the first neuroimaging study to directly demonstrate the cerebral resting-state glucose utilization associated with ART performance. Our findings provide important evidence at the neural level that ART predicts premorbid general intelligence and cognitive reserve, as brain areas that showed significant correlations with ART performance correspond to regions that have been associated with general intelligence and cognitive reserve.

Normative Data for the Logical Memory Subtest of the Wechsler Memory Scale-IV in Middle-Aged and Elderly Korean People.

OBJECTIVE: The purpose of this study is to identify the demographic variables that are affecting performances on the Logical Memory (LM) subtest included in the Korean version of the Wechsler Memory Scale (WMS)-IV and to provide normative data on the LM subtest for the middle-age and elderly Korean people. METHODS: The participants were 435 non-demented adults aging from 50 to 90 and with the educational level ranging from 0 to 21 years. RESULTS: Age and education were found to be significantly associated with performance on the LM subtest, while gender effect was not statistically significant. Therefore, we stratified the norm blocks by age and education. Age was divided into three groups: 50-59, 60-74, and 75-90 years. Education was stratified into three groups: 0-8 years, 9-12 years, and 13 years or more. CONCLUSION: The normative data provided in the current study are expected to be useful in clinical and research settings to detect or define subtle changes in episodic memory in Korean adults and elderly, and can also be used for cross-cultural comparison of verbal episodic memory performance among elderly populations using different languages.

An apolipoprotein B100 mimotope prevents obesity in mice.

Although apolipoprotein B100 (ApoB100) plays a key role in peripheral fat deposition, it is not considered a suitable therapeutic target in obesity. In the present study we describe a novel ApoB100 mimotope, peptide pB1, and the use of pB1-based vaccine-like formulations (BVFs) against high-fat diet (HFD)-induced obesity. In HFD- compared with chow-fed adolescent mice, BVFs reduced the 3-month body-weight gains attributable to increased dietary fat by 44-65%, and prevented mesenteric fat accumulation and liver steatosis. The body-weight reductions paralleled the titres of pB1-reactive immunoglobulin G (IgG) antibodies, and pB1-reactive antibodies specifically recognized native ApoB100 and a synthetic peptide from the C-terminal half of ApoB100. In cultured 3T3L1 adipocytes, anti-pB1 antibodies increased lipolysis and inhibited low-density lipoprotein (LDL) uptake. In cultured RAW 264.7 macrophages, the same antibodies enhanced LDL uptake (without causing foam cell formation). These findings make ApoB100 a promising target for an immunization strategy against HFD-induced obesity.