Plasma Leptin and Alzheimer Protein Pathologies Among Older Adults.

Importance: Many epidemiologic studies have suggested that low levels of plasma leptin, a major adipokine, are associated with increased risk of Alzheimer disease (AD) dementia and cognitive decline. Nevertheless, the mechanistic pathway linking plasma leptin and AD-related cognitive decline is not yet fully understood. Objective: To examine the association of plasma leptin levels with in vivo AD pathologies, including amyloid-beta (Aß) and tau deposition, through both cross-sectional and longitudinal approaches among cognitively unimpaired older adults. Design, Setting, and Participants: This was a longitudinal cohort study from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer Disease. Data were collected from January 1, 2014, to December 31, 2020, and data were analyzed from July 11 to September 6, 2022. The study included a total of 208 cognitively unimpaired participants who underwent baseline positron emission tomography (PET) scans for brain Aß deposition. For longitudinal analyses, 192 participants who completed both baseline and 2-year follow-up PET scans for brain Aß deposition were included. Exposure: Plasma leptin levels as assessed by enzyme-linked immunosorbent assay. Main Outcomes and Measures: Baseline levels and longitudinal changes of global Aß and AD-signature region tau deposition measured by PET scans. Results: Among the 208 participants, the mean (SD) age was 66.0 (11.3) years, 114 were women (54.8%), and 37 were apolipoprotein E ε4 carriers (17.8%). Lower plasma leptin levels had a significant cross-sectional association with greater brain Aß deposition (ß = -0.04; 95% CI, -0.09 to 0.00; P = .046), while there was no significant association between plasma leptin levels and tau deposition (ß = -0.02; 95% CI, -0.05 to 0.02; P = .41). In contrast, longitudinal analyses revealed that there was a significant association between lower baseline leptin levels and greater increase of tau deposition over 2 years (ß = -0.06; 95% CI, -0.11 to -0.01; P = .03), whereas plasma leptin levels did not have a significant association with longitudinal change of Aß deposition (ß = 0.006; 95% CI, 0.00-0.02; P = .27). Conclusions and Relevance: The present findings suggest that plasma leptin may be protective for the development or progression of AD pathology, including both Aß and tau deposition.

Graph Theoretical Analysis of Brain Structural Connectivity in Patients with Alcohol Dependence.

This study aimed to compare brain structural connectivity using graph theory between patients with alcohol dependence and social drinkers. The participants were divided into two groups; the alcohol group (N=23) consisting of patients who had been hospitalized and had abstained from alcohol for at least three months and the control group (N=22) recruited through advertisements and were social drinkers. All participants were evaluated using 3T magnetic resonance imaging. A total of 1000 repeated whole-brain tractographies with random parameters were performed using DSI Studio. Four hundred functionally defined cortical regions of interest (ROIs) were parcellated using FreeSurfer based on the Schaefer Atlas. The ROIs were overlaid on the tractography results to generate 1000 structural connectivity matrices per person, and 1000 matrices were averaged into a single matrix per subject. Graph analysis was performed through igraph R package. Graph measures were compared between the two groups using analysis of covariance, considering the effects of age and smoking pack years. The alcohol group showed lower local efficiency than the control group in the whole-brain (F=5.824, p=0.020), somato-motor (F=5.963, p=0.019), and default mode networks (F=4.422, p=0.042). The alcohol group showed a lower global efficiency (F=5.736, p=0.021) in the control network. The transitivity of the alcohol group in the dorsal attention network was higher than that of the control (F=4.257, p=0.046). Our results imply that structural stability of the whole-brain network is affected in patients with alcohol dependence, which can lead to ineffective information processing in cases of local node failure.

Development of a Cognitive Composite for Preclinical Alzheimer's Disease in Korean Older Adults.

BACKGROUND: As tracking subtle cognitive declines in the preclinical stage of Alzheimer's disease (AD) is difficult with traditional individual outcome measures, need for cognitive composite for preclinical AD is widely recognized. OBJECTIVE: We aimed to develop culturally appropriate cognitive composite that sensitively identifies subtle cognitive decline of preclinical AD in Korean older adults. METHODS: A total 225 cognitively normal elderly individuals from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease, were included. Tests of episodic memory, orientation, and executive function were carefully selected through review of previously established composites. Three candidate composites including Consortium to Establish a Registry for Alzheimer's Disease Word list recall (WLR), Logical memory (LM) II, and Mini-Mental status examination (MMSE) in common, and Letter fluency test (LF), category fluency test, or Stroop color and word test, were selected. RESULTS: Student t-tests demonstrated that only the composite composed of WLR, LM II, MMSE, and LF (Composite 1) showed a significant difference in score decline over two-year follow-up period between Aß positive and negative group (p = 0.03). Linear mixed model analyses also showed that the Aß x time interaction effect was significant only for Composite 1 (p = 0.025). Based on the results, Composite 1 was chosen as the final cognitive composite for preclinical Alzheimer's disease (CPAD). CONCLUSIONS: CPAD can be used to assess subtle cognitive decline of preclinical AD in clinical research settings, especially in Korean older adults. It also may be used for monitoring progression or treatment benefits in clinical practices.

Body mass index and two-year change of in vivo Alzheimer's disease pathologies in cognitively normal older adults.

BACKGROUND: Low body mass index (BMI) or underweight status in late life is associated with an increased risk of dementia or Alzheimer's disease (AD). However, the relationship between late-life BMI and prospective longitudinal changes of in-vivo AD pathology has not been investigated. METHODS: This prospective longitudinal study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE). A total of 194 cognitive normal older adults were included in the analysis. BMI at baseline was measured, and two-year changes in brain Aß and tau deposition on PET imaging were used as the main outcomes. Linear mixed-effects (LME) models were used to examine the relationships between late-life BMI and longitudinal change in AD neuropathological biomarkers. RESULTS: A lower BMI at baseline was significantly associated with a greater increase in tau deposition in AD-signature region over 2 years (ß, -0.018; 95% CI, -0.028 to -0.004; p = .008), In contrast, BMI was not related to two-year changes in global Aß deposition (ß, 0.0002; 95% CI, -0.003 to 0.002, p = .671). An additional exploratory analysis for each sex showed lower baseline BMI was associated with greater increases in tau deposition in males (ß, -0.027; 95% CI, -0.046 to -0.009; p = 0.007), but not in females. DISCUSSION: The findings suggest that lower BMI in late-life may predict or contribute to the progression of tau pathology over the subsequent years in cognitively unimpaired older adults.

Serum Adiponectin and In Vivo Brain Amyloid Deposition in Cognitively Normal Older Adults: A Cohort Study.

High blood adiponectin has been associated with Alzheimer's disease (AD) dementia and related cognitive decline. We aimed to investigate the association between serum adiponectin level and in vivo AD pathologies. Cross-sectional and longitudinal study designs for the data of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease, an ongoing prospective cohort study that began in 2014. A total of 283 cognitively normal older adults between 55 and 90 years of age were included in community and memory clinic setting. Participants underwent comprehensive clinical assessments, measurement of serum adiponectin level, and multimodal brain imaging, including Pittsburgh compound-B positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and MRI at baseline and 2-year follow-up. Serum adiponectin level was positively associated with global beta-amyloid protein (Aß) retention and change therein over 2 years, but not with other AD neuroimaging markers including tau deposition, AD-related neurodegeneration, and white matter hyperintensities. Blood adiponectin level is associated with increased brain amyloid deposition, which suggests that adiponectin may be a potential target for therapeutic and preventive strategies against AD.

Low Ankle-Brachial Index Relates to Alzheimer-Signature Cerebral Glucose Metabolism in Cognitively Impaired Older Adults.

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 Aß 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.

Synergistic interaction of high blood pressure and cerebral beta-amyloid on tau pathology.

BACKGROUND: Hypertension has been associated with Alzheimer's disease (AD) dementia as well as vascular dementia. However, the underlying neuropathological changes that link hypertension to AD remain poorly understood. In our study, we examined the relationships of a history of hypertension and high current blood pressure (BP) with in vivo AD pathologies including ß-amyloid (Aß) and tau and also investigated whether a history of hypertension and current BP respectively affect the association between Aß and tau deposition. METHODS: This cross-sectional study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease, a prospective cohort study. Cognitively normal older adults who underwent both Aß and tau positron emission tomography (PET) (i.e., [11C]-Pittsburgh compound B and [18F] AV-1451 PET) were selected. History of hypertension and current BP were evaluated and cerebral Aß and tau deposition measured by PET were used as main outcomes. Generalized linear regression models were used to estimate associations. RESULTS: A total of 68 cognitively normal older adults (mean [SD] age, 71.5 [7.4] years; 40 women [59%]) were included in the study. Neither a history of hypertension nor the current BP exhibited a direct association with Aß or tau deposition. However, the synergistic interaction effects of high current systolic (ß, 0.359; SE, 0.141; p = 0.014) and diastolic (ß, 0.696; SE, 0.158; p < 0.001) BP state with Aß deposition on tau deposition were significant, whereas there was no such effect for a history of hypertension (ß, 0.186; SE, 0.152; p = 0.224). CONCLUSIONS: The findings suggest that high current BP, but not a history of hypertension, synergistically modulate the relationship between cerebral Aß and tau deposition in late-life. In terms of AD prevention, the results support the importance of strict BP control in cognitively normal older adults with hypertension.

Association of low meal frequency with decreased in vivo Alzheimer's pathology.

Little is known about the association between meal frequency and Alzheimer's disease (AD) in humans. We tested the hypothesis that low meal frequency (LMF) is associated with reduced in vivo AD pathology in human brain, and additionally investigated the mediation of serum ghrelin, a hunger-related hormone, for the association. A total of 411 non-demented older adults were systematically interviewed to identify their dietary patterns including meal frequency and underwent multi-modal neuroimaging for cerebral beta-amyloid (Aß) and tau deposition, glucose metabolism, and cerebrovascular injury. LMF (less than three meals a day) was significantly associated with lower Aß deposition compared to high meal frequency (HMF). In addition, both LMF and reduced Aß deposition were significantly related to elevated serum ghrelin. Our findings suggest that LMF may be related to the lower risk of AD through reduced brain amyloid deposition. Additionally, ghrelin appears mediate the association between LMF and lower amyloid deposition.

Gut microbiome alterations in preclinical Alzheimer's disease.

BACKGROUND: Although some human studies have reported gut microbiome changes in individuals with Alzheimer's disease (AD) dementia or mild cognitive impairment (MCI), gut microbiome alterations in preclinical AD, i.e., cerebral amyloidosis without cognitive impairment, is largely unknown. OBJECTIVE: We aimed to identify gut microbial alterations associated with preclinical AD by comparing cognitively normal (CN) older adults with cerebral Aß deposition (Aß+ CN) and those without cerebral Aß deposition (Aß- CN). METHODS: Seventy-eight CN older participants (18 Aß+ CN and 60 Aß- CN) were included, and all participants underwent clinical assessment and Pittsburg compound B-positron emission tomography. The V3-V4 region of the 16S rRNA gene of genomic DNA extracted from feces was amplified and sequenced to establish the microbial community. RESULTS: Generalized linear model analysis revealed that the genera Megamonas (B = 3.399, q<0.001), Serratia (B = 3.044, q = 0.005), Leptotrichia (B = 5.862, q = 0.024) and Clostridium (family Clostridiaceae) (B = 0.788, q = 0.034) were more abundant in the Aß+ CN group than the Aß- CN group. In contrast, genera CF231 (B = -3.237, q< 0.001), Victivallis (B = -3.447, q = 0.004) Enterococcus (B = -2.044, q = 0.042), Mitsuokella (B = -2.119, q = 0.042) and Clostridium (family Erysipelotrichaceae) (B = -2.222, q = 0.043) were decreased in Aß+ CN compared to Aß- CN. Notably, the classification model including the differently abundant genera could effectively distinguish Aß+ CN from Aß- CN (AUC = 0.823). CONCLUSION: Our findings suggest that specific alterations of gut bacterial taxa are related to preclinical AD, which means these changes may precede cognitive decline. Therefore, examining changes in the microbiome may be helpful in preclinical AD screening.

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.

Reproducibility of calcium scoring of the coronary arteries: comparison between different vendors and iterative reconstructions.

BACKGROUND: The coronary artery calcium scoring (CCS) has been widely used for cardiac risk stratification for asymptomatic patients. PURPOSE: To assess the reproducibility of CCS performed on four different computed tomography (CT) scanners, and compare the variability between two reconstruction algorithms, filtered back projection (FBP), and iterative reconstruction (IR). MATERIAL AND METHODS: A CCS phantom was made from agar and contained 23 pieces of chicken bones. The phantom was repeatedly scanned using four different CT scanners: Toshiba; GE; Philips; and Siemens. Images were reconstructed using FBP and IR. Agatston and volume scores of total bone fragments were calculated and the overall differences between the instruments were evaluated using the Friedman test. Comparison of the Agatston and volume scores between the two reconstruction algorithms, for each instrument, was evaluated using the Wilcoxon signed rank test. RESULTS: The difference in the Agatston scores was significantly different between the four machines (P = 0.001). The Toshiba scanner yielded the highest score followed by Philips, GE, and Siemens scanners. There was no difference in the CCS evaluated using the two reconstruction algorithms, except in case of the Siemens scanner (P = 0.032). CONCLUSION: CCS performed on different scanners varied significantly. In the Toshiba, Philips, and GE scanners, there was no significant difference in the CCS determined using either an IR or the FBP algorithm. In the Siemens scanner, applying the IR algorithm resulted in a slightly different scores, which might not be clinically significant.

Neuroticism, conscientiousness, and in vivo Alzheimer pathologies measured by amyloid PET and MRI.

AIM: It has been suggested that personality traits, particularly neuroticism and conscientiousness, are risk factors for Alzheimer's disease (AD) and related cognitive decline. However, the underlying pathological links between personality traits and AD-related cognitive impairments remain unclear. Thus, the present study investigated associations of neuroticism and conscientiousness with in vivo cerebral amyloid-beta (Aß) burden, AD-signature regional neurodegeneration, and white matter hyperintensities (WMH) in non-demented middle- and old-aged adults. METHODS: A total of 397 non-demented participants underwent comprehensive clinical and neuropsychological assessments, 11 C-labeled Pittsburgh Compound B positron emission tomography, and magnetic resonance imaging. Additionally, the NEO Five-Factor Inventory was administered to both the participants and their informants to measure neuroticism and conscientiousness. RESULTS: Neither neuroticism nor conscientiousness was associated with cerebral Aß deposition or WMH. In contrast, higher neuroticism and lower conscientiousness, reported by informants in particular, were significantly associated with reduced AD-signature region cortical thickness. In regards to the direct and indirect effect of each personality on AD-signature region cortical thickness, only the direct effects were found, whereas indirect effects via Aß deposition or WMH were not. CONCLUSION: The present findings suggest that amyloid-independent regional neurodegeneration might underlie relations of neuroticism and conscientiousness with AD.

The Effects of Continuation-Maintenance Electroconvulsive Therapy on Reducing Hospital Re-Admissions in Patients with Treatment-Resistant Schizophrenia.

OBJECTIVE: Continuation-maintenance electroconvulsive therapy (C/M-ECT) is used to prevent relapse or recurrence in patients with severe mental illnesses. We aimed to investigate the effect of C/M-ECT on reducing hospital re-admissions in patients with treatment-resistant schizophrenia. METHODS: We applied a mirror-image design by retrospectively examining re-hospitalization rates of 18 patients with schizophrenia spectrum disorders. We compared the numbers of psychiatric admissions during the actual period over which C/M-ECT was administered with the same period prior to the beginning of C/M-ECT. RESULTS: The number of psychiatric admissions was reduced significantly during C/M-ECT (0.33±0.77) compared with that of the same period prior to C/M-ECT (2.67±1.33) (Wilcoxon signed rank Z=-3.663; p＜0.001). CONCLUSION: This finding shows that C/M-ECT augmentation could successfully reduce the re-hospitalization rates in patients with treatment-resistant schizophrenia.

Do Patients Want to Listen to a Diagnosis of Dementia in Korea? Preferences on Disclosing a Diagnosis of Dementia and Discussing Advance Care Planning in Elderly Patients with Memory Concerns and Their Families.

OBJECTIVE: In this study, we aimed to investigate preferences regarding the disclosure of a dementia diagnosis and advance care planning (ACP) in patients with memory complaints and their families. METHODS: A total of 98 patients who visited the department of psychiatry at a tertiary hospital with memory complaints and 62 family members completed a structured questionnaire. The questionnaire included preferences on disclosure of dementia and cancer diagnosis, awareness and preferences on ACP. RESULTS: In total, 96.9% of patients were willing to know their dementia diagnosis. There were no significant differences in preferences between the diagnosis of cancer and dementia. Only 24.7% of patients and 45.8% of family members have heard of ACP. However, 82.8% of patients agreed on the necessity of ACP under the current condition. Multivariate analysis revealed that younger patients were more likely to agree with necessity for ACP under the current condition. CONCLUSION: In Korea, patients with memory complaints and their family members strongly favored a disclosure of dementia diagnosis. The majority of participants also agreed on the necessity of ACP. More active involvement of patients is needed in treatment decisions and care planning in cases of dementia as well as other life-threatening illnesses.