Neuroanatomical and neurocognitive correlates of delusion in Alzheimer's disease and mild cognitive impairment.

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.

Risk of depression and anxiety disorders according to long-term glycemic variability.

BACKGROUND: Poor glycemic control has been linked to psychiatric symptoms. However, studies investigating the relationship between glycemic variability (GV) and depression and anxiety disorders are limited. We investigated the association of GV with depression and anxiety disorders. In addition, the relationship between trends in fasting plasma glucose (FPG) levels and these disorders were explored. METHODS: We analyzed the National Health Insurance Service-National Sample Cohort database (2002-2013) with 151,814 participants who had at least three health screenings between 2002 and 2010. Visit-to-visit FPG variability was measured as variability independent of the mean (VIM). Depression and anxiety disorders were diagnosed using ICD-10 codes (F41 for anxiety and F32 or F33 for depression) after index date. We analyzed the association between GV and incidences of these disorders using Kaplan-Meier and Cox proportional hazards methods. Trajectory analysis was conducted to explore the relationship between FPG trends and these disorders. RESULTS: During follow-up, 7166 and 14,149 patients were newly diagnosed with depression and anxiety disorders, respectively. The highest quartile group of FPG-VIM had a greater incidence of depression and anxiety than the lowest quartile group, with adjusted hazard ratios of 1.09 (95 % confidence interval [CI]: 1.02-1.17) and 1.08 (95 % CI: 1.03-1.14). Group with persistent hyperglycemia, identified through trajectory clustering of FPG levels, had a 1.43-fold increased risk of depression compared to those with consistently low FPG levels. LIMITATIONS: Potential selection bias by including participants with at least three health screenings. CONCLUSIONS: High GV and persistent hyperglycemia are associated with increased incidence of depression and anxiety disorders.

Evaluation of Efficacy and Safety Using Low Dose Radiation Therapy with Alzheimer's Disease: A Protocol for Multicenter Phase II Clinical Trial.

BACKGROUND: Alzheimer's disease (AD), the most common cause of dementia, is a neurodegenerative disease resulting from extracellular and intracellular deposits of amyloid-ß (Aß) and neurofibrillary tangles in the brain. Although many clinical studies evaluating pharmacological approaches have been conducted, most have shown disappointing results; thus, innovative strategies other than drugs have been actively attempted. OBJECTIVE: This study aims to explore low-dose radiation therapy (LDRT) for the treatment of patients with AD based on preclinical evidence, case reports, and a small pilot trial in humans. METHODS: This study is a phase II, multicenter, prospective, single-blinded, randomized controlled trial that will evaluate the efficacy and safety of LDRT to the whole brain using a linear accelerator in patients with mild AD. Sixty participants will be randomly assigned to three groups: experimental I (24 cGy/6 fractions), experimental II (300 cGy/6 fractions), or sham RT group (0 cGy/6 fractions). During LDRT and follow-up visits after LDRT, possible adverse events will be assessed by the physician's interview and neurological examinations. Furthermore, the effectiveness of LDRT will be measured using neurocognitive function tests and imaging tools at 6 and 12 months after LDRT. We will also monitor the alterations in cytokines, Aß42/Aß40 ratio, and tau levels in plasma. Our primary endpoint is the change in cognitive function test scores estimated by the Alzheimer's Disease Assessment Scale-Korea compared to baseline after 6 months of LDRT. CONCLUSIONS: This study is registered at ClinicalTrials.gov [NCT05635968] and is currently recruiting patients. This study will provide evidence that LDRT is a new treatment strategy for AD.

The efficacy of memory load on speech-based detection of Alzheimer's disease.

Introduction: The study aims to test whether an increase in memory load could improve the efficacy in detection of Alzheimer's disease and prediction of the Mini-Mental State Examination (MMSE) score. Methods: Speech from 45 mild-to-moderate Alzheimer's disease patients and 44 healthy older adults were collected using three speech tasks with varying memory loads. We investigated and compared speech characteristics of Alzheimer's disease across speech tasks to examine the effect of memory load on speech characteristics. Finally, we built Alzheimer's disease classification models and MMSE prediction models to assess the diagnostic value of speech tasks. Results: The speech characteristics of Alzheimer's disease in pitch, loudness, and speech rate were observed and the high-memory-load task intensified such characteristics. The high-memory-load task outperformed in AD classification with an accuracy of 81.4% and MMSE prediction with a mean absolute error of 4.62. Discussion: The high-memory-load recall task is an effective method for speech-based Alzheimer's disease detection.

Weight loss and risk of dementia in individuals with versus without obesity.

INTRODUCTION: Using nationwide cohort data, we aimed to elucidate whether baseline obesity altered the relationship between loss in body mass index (BMI) or waist circumference (WC) and risk of dementia. METHODS: Among 9689 participants whose BMIs and WCs were repeatedly measured over 1 year, 1:1 propensity score matching was conducted between participants with and without obesity (n = 2976 per group, mean age 70.9). For each group, we explored the association between loss in BMI, or WC, and incidence of dementia during an approximately 4-year follow-up period. RESULTS: BMI loss was associated with an increased risk of all-cause dementia and Alzheimer's disease in participants without obesity; however, this association was absent in participants with obesity. WC loss was associated with decreased Alzheimer's disease risk only in participants with obesity. DISCUSSION: Only unfavorable loss (loss from non-obese state) in BMI, not WC, can be a metabolic biomarker of prodromal dementia.

Restless leg syndrome and risk of all-cause dementia: a nationwide retrospective cohort study.

BACKGROUND: Restless leg syndrome (RLS) is associated with poor sleep quality, depression or anxiety, poor dietary patterns, microvasculopathy, and hypoxia, all of which are known risk factors for dementia. However, the relationship between RLS and incident dementia remains unclear. This retrospective cohort study aimed to explore the possibility that RLS could be deemed as a non-cognitive prodromal feature of dementia. METHODS: This was a retrospective cohort study using the Korean National Health Insurance Service-Elderly Cohort (aged ≥ 60). The subjects were observed for 12 years, from 2002 to 2013. Identifying patients with RLS and dementia was based on the 10th revised code of the International Classification of Diseases (ICD-10). We compared the risk of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD) in 2501 subjects with newly diagnosed RLS and 9977 matched controls based on age, sex, and index date. The association between RLS and the risk of dementia was assessed using Cox regression hazard regression models. The effect of dopamine agonists on the risk of dementia among RLS patients was also explored. RESULTS: The baseline mean age was 73.4, and the subjects were predominantly females (63.4%). The incidence of all-cause dementia was higher in the RLS group than that in the control group (10.4% vs 6.2%). A baseline diagnosis of RLS was associated with an increased risk of incident all-cause dementia (adjusted hazard ratio [aHR] 1.46, 95% confidence interval [CI] 1.24-1.72). The risk of developing VaD (aHR 1.81, 95% CI 1.30-2.53) was higher than that of AD (aHR 1.38, 95% CI 1.11-1.72). The use of dopamine agonists was not associated with the risk of subsequent dementia among patients with RLS (aHR 1.00, 95% CI 0.76-1.32). CONCLUSIONS: This retrospective cohort study suggests that RLS is associated with an increased risk of incident all-cause dementia in older adults, providing some evidence that requires confirmation through prospective studies in the future. Awareness of cognitive decline in patients with RLS may have clinical implications for the early detection of dementia.

Pioglitazone Use and Reduced Risk of Dementia in Patients With Diabetes Mellitus With a History of Ischemic Stroke.

BACKGROUND AND OBJECTIVES: Previous studies have reported the protective effect of pioglitazone on dementia in patients with type 2 diabetes mellitus (DM). Recent studies have shown that pioglitazone also lowers the risk of primary and recurrent stroke. Understanding the characteristics of patients particularly associated with the benefits of pioglitazone would facilitate its personalized use by specifying subpopulations during routine clinical care. The aim of this study was to examine the effects of pioglitazone use on dementia in consideration of stroke occurrence. METHODS: Using nationwide longitudinal data of patients with DM from the Korean National Health Insurance Service DM cohort (2002-2017), we investigated the association of pioglitazone use with incident dementia in patients with new-onset type 2 DM. The heterogeneity of the treatment effect was examined using exploratory analyses. Using a multistate model, we assessed the extent to which incident stroke affects the association between pioglitazone use and dementia. RESULTS: Pioglitazone use was associated with a reduced risk of dementia, compared with nonuse (adjusted hazard ratio [aHR] = 0.84, 95% CI 0.75-0.95); the risk reduction in dementia was greater among patients with a history of ischemic heart disease or stroke before DM onset (aHR = 0.46, 95% CI 0.24-0.90; aHR = 0.57, 95% CI 0.38-0.86, respectively). The incidence of stroke was also reduced by pioglitazone use (aHR = 0.81, 95% CI 0.66-1.00). However, when the stroke developed during the observation period of pioglitazone use, such lowered risk of dementia was not observed (aHR = 1.27, 95% CI 0.80-2.04). DISCUSSION: Pioglitazone use is associated with a lower risk of dementia in patients with DM, particularly in those with a history of stroke or ischemic heart disease, suggesting the possibility of applying a personalized approach when choosing pioglitazone to suppress dementia in patients with DM.

Relationship Between Adipokines, Cognition, and Brain Structures in Old Age Depending on Obesity.

BACKGROUND: Adipokines such as leptin and adiponectin are associated with cognitive function. Although adiposity crucially affects adipokine levels, it remains unclear whether the relationship between adipokines and cognition is influenced by obesity. METHODS: We enrolled 171 participants and divided them into participants with obesity and without obesity to explore the effect of obesity on the relationship between adipokines and cognition. In addition to plasma levels of leptin and adiponectin, multidomain cognitive functions and brain structures were assessed using neuropsychological testing and magnetic resonance imaging. Association between levels of these adipokines and Alzheimer's disease (AD) was then assessed by logistic regression. RESULTS: We found that cognitive function was negatively associated with leptin levels and leptin-to-adiponectin ratio (LAR). Such correlations between leptin and cognitive domains were prominent in participants with obesity but were not observed in those without obesity. Leptin levels were associated with lower hippocampal volumes in participants with obesity. A significant interaction of leptin and obesity was found mostly in the medial temporal lobe. Both leptin and LAR were positively associated with insulin resistance and inflammation markers in all participants. Of note, LAR was associated with a higher risk of AD after adjusting for demographic variables, Apolipoprotein E genotype, and body mass index. CONCLUSIONS: Obesity might be a factor that determines how adipokines affect brain structure and cognition. Leptin resistance might influence the relationship between adipokines and cognition. In addition, LAR rather than each adipokine levels alone may be a better indicator of AD risk in older adults with metabolic stress.

Plasma amyloid-beta oligomer is related to subjective cognitive decline and brain amyloid status.

BACKGROUND: Subjective cognitive decline (SCD) is a target for Alzheimer's disease prediction. Plasma amyloid-beta oligomer (AßO), the pathogenic form of Aß in blood, has recently been proposed as a novel blood-based biomarker of AD prediction by representing brain Aß deposition. The relationship between plasma AßO, brain Aß deposition, and SCD in individuals with normal objective cognition has not been investigated. METHODS: In this cross-sectional study, we analyzed 126 participants with normal objective cognition. More SCD symptoms were expressed as higher scores of the Subjective Cognitive Decline Questionnaire (SCDQ) and Memory Age-associated Complaint Questionnaire (MACQ). The plasma AßO level of each participant was measured twice for validation and expressed as a concentration (ng/mL) and a ratio relative to the mean value of two internal standards. Brain Aß deposition was assessed by [18F] flutemetamol positron emission tomography (PET) and expressed as standard uptake value ratio (SUVR). Associations of SCDQ and MACQ with plasma AßO levels or SUVR were analyzed in multiple linear regression models. The association between plasma AßO level and flutemetamol PET positivity was assessed in logistic regression and receiver operative characteristic analyses. RESULTS: Overall, participants were 73.3 years old with female predominance (69.0%). After adjustment for confounders, high SCDQ and MACQ scores were associated with the high plasma AßO levels as both concentrations and ratios (ratios: standardized coefficient = 0.246 and p = 0.023 for SCDQ, standardized coefficient = 0.209 and p = 0.029 for MACQ; concentrations: standardized coefficient = 0.257 and p = 0.015 for SCDQ, standardized coefficient = 0.217 and p = 0.021 for MACQ). In contrast, SCDQ and MACQ were not significantly associated with SUVRs (p = 0.134 for SCDQ, p = 0.079 for MACQ). High plasma AßO levels were associated with flutemetamol PET (+) with an area under the curve of 0.694 (ratio) or 0.662 (concentration). Combined with APOE e4, plasma AßO presented area under the curves of 0.789 (ratio) and 0.783 (concentration). CONCLUSIONS: Our findings indicate that the high plasma AßO level could serve as a potential surrogate biomarker of severe SCD and the presence of brain Aß deposition in individuals with normal objective cognition.

Plasma adiponectin levels predict cognitive decline and cortical thinning in mild cognitive impairment with beta-amyloid pathology.

BACKGROUND: Blood adiponectin and leptin are adipokines that emerged as potential biomarkers for predicting Alzheimer's disease (AD) owing to their strong connection with obesity. Although obesity affects the relation between beta-amyloid (Aß) aggregation and cognitive decline, the longitudinal interactive effect of adipokines and Aß on cognition and brain structures in humans remains unexplored. Hence, we investigated whether plasma levels of adiponectin and leptin are associated with future cognitive decline and cortical thinning across Aß conditions (Aß [+] and Aß [-]) in individuals with mild cognitive impairment (MCI). METHODS: Of 156 participants with MCI from the longitudinal cohort study of Alzheimer's Disease Neuroimaging Initiative (ADNI), 31 were Aß (-) and 125 were Aß (+) as determined by CSF analysis. The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores and the thickness of the parahippocampal and entorhinal cortices were used to evaluate cognition and brain structure, respectively. After stratifying groups by Aß conditions, the association of cognitive and brain structural changes with baseline plasma levels of adiponectin and leptin was examined. RESULTS: Of the total 156 participants, 51 were women (32.7%). The mean age of participants was 74.5 (standard deviation 7.57), and the mean follow-up period was 54.3 months, without a difference between the Aß (+) and (-) groups. After adjustment for confounders, higher plasma adiponectin levels were associated with a faster increase in ADAS-Cog scores, indicating faster cognitive decline under the Aß (+) condition (beta = 0.224, p = 0.018). Likewise, participants with higher plasma adiponectin presented faster cortical thinning in the bilateral parahippocampal cortices under the Aß (+) condition (beta = - 0.004, p = 0.012 for the right side; beta = - 0.004, p = 0.025 for the left side). Interestingly, plasma adiponectin levels were not associated with longitudinal ADAS-Cog scores or cortical thickness in the Aß (-) condition. Plasma leptin levels were not predictive of cognition or cortical thickness regardless of Aß status. CONCLUSION: Plasma adiponectin can be a potential biomarker for predicting the speed of AD progression in individuals with Aß (+) MCI.

Loss of association between plasma irisin levels and cognition in Alzheimer's disease.

BACKGROUND: Irisin, an exercise-induced myokine, has been shown to have beneficial effects on cognitive and metabolic functions. However, previous studies assessing the levels of circulating irisin in patients with Alzheimer's disease (AD) or diabetes mellitus (DM) have provided inconsistent results. This suggests that the normal physiological action of irisin may be altered by disease-associated pathological conditions in target organs. OBJECTIVE: To investigate the association of plasma levels of irisin with cognition and brain structures according to the presence or absence of AD and DM. METHODS: Plasma levels of irisin, multi-domain cognition, and volumes of relevant brain regions were assessed using enzyme-linked immunoassay, neuropsychological test, and magnetic resonance imaging, respectively. We classified 107 participants by cognitive (cognitively normal [CN, n = 23], mild cognitive impairment [MCI, n = 49], and AD [n = 35]) and metabolic (non-DM [n = 75] and DM [n = 32]) states. RESULTS: Disease state-stratified multiple regression analyses showed that plasma levels of irisin were positively associated with cognition only in participants without AD (CN plus MCI). By contrast, in participants with AD, these associations lost significance, and furthermore, higher levels of irisin indicated smaller hippocampal, superior temporal, and inferior frontal volumes. The association between plasma irisin levels and cognition was not affected by the presence of DM. Consistently, moderation analysis revealed that the relationship between plasma irisin levels and cognition or brain structures was significantly modified by the presence of AD, not that of DM. CONCLUSION: Our findings suggest that the beneficial actions of circulating irisin on cognition may be attenuated by AD-induced pathological conditions in the brain.

Virtual reality-based monitoring test for MCI: A multicenter feasibility study.

Objectives: As the significance of the early diagnosis of mild cognitive impairment (MCI) has emerged, it is necessary to develop corresponding screening tools with high ecological validity and feasible biomarkers. Virtual reality (VR)-based cognitive assessment program, which is close to the daily life of the older adults, can be suitable screening tools for MCI with ecological validity and accessibility. Meanwhile, dehydroepiandrosterone (DHEA) has been observed at a low concentration in the older adults with dementia or cognitive decline, indicating its potential as a biomarker of MCI. This study aimed to determine the efficacy and usability of a VR cognitive assessment program and salivary DHEA for screening MCI. Methods: The VR cognitive assessment program and the traditional Montreal Cognitive Assessment (MOCA) test were performed on 12 patients with MCI and 108 healthy older adults. The VR program operates in a situation of caring for a grandchild, and evaluates the memory, attention, visuospatial, and executive functions. An analysis of covariance (ANCOVA), a partial correlation analysis, and receiving operating characteristic (ROC) curve analysis were conducted for statistical analysis. Results: According to the ANCOVA, no significant difference in MOCA scores was found between the normal and MCI groups (F = 2.36, p = 0.127). However, the VR total score of the MCI group was significantly lower than that of the normal group (F = 8.674, p = 0.004). There was a significant correlation between the MOCA and VR scores in the total and matched subdomain scores. The ROC curve analysis also showed a larger area under the curve (AUC) for the VR test (0.765) than for the MOCA test (0.598), and the sensitivity and specificity of the VR program were 0.833 and 0.722, respectively. Salivary DHEA was correlated with VR total (R 2 = 0.082, p = 0.01) and attention scores (R 2 = 0.086, p = 0.009). Conclusion: The VR cognitive test was as effective as the traditional MOCA test in the MCI classification and safe enough for older adults to perform, indicating its potential as a diagnostic tool. It has also been shown that salivary DHEA can be used as a biomarker for MCI.

Association of metformin use with Alzheimer's disease in patients with newly diagnosed type 2 diabetes: a population-based nested case-control study.

Metformin reduces insulin resistance, which constitutes a pathophysiological connection of diabetes with Alzheimer's disease (AD), but the evidence of metformin on AD development was still insufficient and conflicting. We investigated AD risk in patients with newly diagnosed type 2 DM treated with metformin. This retrospective, observational, nested case-control study included patients with newly diagnosed type 2 DM obtained from the Korean National Health Insurance Service DM cohort (2002-2017). Among 70,499 dementia-free DM patients, 1675 AD cases were matched to 8375 controls for age, sex, and DM onset and duration. The association between AD and metformin was analyzed by multivariable regression analyses, adjusted for comorbidities and cardiometabolic risk profile. Metformin use was associated with an increased odds of AD (adjusted odds ratio [AOR] 1.50; 95% CI 1.23-1.83). The risk of AD was higher in patients with a longer DM duration. Furthermore, AD risk was significantly high in DM patients with depression (AOR 2.05; 95% CI 1.02-4.12). Given the large number of patients with DM who are taking metformin worldwide, a double-blinded, prospective study is required to determine the long-term cognitive safety of metformin.

Pioglitazone use associated with reduced risk of the first attack of ischemic stroke in patients with newly onset type 2 diabetes: a nationwide nested case-control study.

BACKGROUND: Pioglitazone use is known to be associated with a reduced risk of recurrent stroke in patients with diabetes mellitus (DM) who have a history of stroke. However, it is unclear whether this benefit extends to patients without a history of stroke. We aimed to evaluate the association between pioglitazone use and development of first attack of ischemic stroke in patients with newly diagnosed type 2 DM. METHODS: Using longitudinal nationwide data from the 2002-2017 Korean National Health Insurance Service DM cohort, we analyzed the association between pioglitazone use and incidence of primary ischemic stroke using a nested case-control study. Among 128,171 patients with newly onset type 2 DM who were stroke-free at the time of DM diagnosis, 4796 cases of ischemic stroke were identified and matched to 23,980 controls based on age, sex, and the onset and duration of DM. The mean (standard deviation) follow-up time was 6.08 (3.34) years for the cases and controls. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between ischemic stroke and pioglitazone use were analyzed by multivariable conditional logistic regression analyses adjusted for comorbidities, cardiometabolic risk profile, and other oral antidiabetic medications. RESULTS: Pioglitazone use was associated with a reduced risk of first attack of ischemic stroke (adjusted OR [AOR] 0.69, 95% CI 0.60-0.80) when compared with non-use. Notably, pioglitazone use was found to have a dose-dependent association with reduced rate of ischemic stroke emergence (first cumulative defined daily dose [cDDD] quartile AOR 0.99, 95% CI 0.74-1.32; second quartile, AOR 0.77, 95% CI 0.56-1.06; third quartile, AOR 0.51, 95% Cl 0.36-0.71; highest quartile, AOR 0.48, 95% CI 0.33-0.69). More pronounced risk reduction was found in patients who used pioglitazone for more than 2 years. A further stratified analysis revealed that pioglitazone use had greater protective effects in patients with risk factors for stroke, such as high blood pressure, obesity, and current smoking. CONCLUSIONS: Pioglitazone use may have a preventive effect on primary ischemic stroke in patients with type 2 DM, particularly in those at high risk of stroke.