Hyperglycemia enhances brain susceptibility to lipopolysaccharide-induced neuroinflammation via astrocyte reprogramming.

Hyperglycemia has been shown to modulate the immune response of peripheral immune cells and organs, but the impact of hyperglycemia on neuroinflammation within the brain remains elusive. In the present study, we provide evidences that streptozotocin (STZ)-induced hyperglycemic condition in mice drives a phenotypic switch of brain astrocytes to a proinflammatory state, and increases brain vulnerability to mild peripheral inflammation. In particular, we found that hyperglycemia led to a significant increase in the astrocyte proliferation as determined by flow cytometric and immunohistochemical analyses of mouse brain. The increased astrocyte proliferation by hyperglycemia was reduced by Glut1 inhibitor BAY-876. Transcriptomic analysis of isolated astrocytes from Aldh1l1CreERT2;tdTomato mice revealed that peripheral STZ injection induced astrocyte reprogramming into proliferative, and proinflammatory phenotype. Additionally, STZ-induced hyperglycemic condition significantly enhanced the infiltration of circulating myeloid cells into the brain and the disruption of blood-brain barrier in response to mild lipopolysaccharide (LPS) administration. Systemic hyperglycemia did not alter the intensity and sensitivity of peripheral inflammation in mice to LPS challenge, but increased the inflammatory potential of brain microglia. In line with findings from mouse experiments, a high-glucose environment intensified the LPS-triggered production of proinflammatory molecules in primary astrocyte cultures. Furthermore, hyperglycemic mice exhibited a significant impairment in cognitive function after mild LPS administration compared to normoglycemic mice as determined by novel object recognition and Y-maze tasks. Taken together, these results demonstrate that hyperglycemia directly induces astrocyte reprogramming towards a proliferative and proinflammatory phenotype, which potentiates mild LPS-triggered inflammation within brain parenchymal regions.

Cholesterol profiling reveals 7ß-hydroxycholesterol as a pathologically relevant peripheral biomarker of Alzheimer's disease.

AIM: Cholesterol homeostasis is associated with Alzheimer's disease (AD). Despite the multitude of cholesterol metabolites, little is known about which metabolites are directly involved in AD pathogenesis and can serve as its potential biomarkers. METHODS: To identify "hit" metabolites, steroid profiling was conducted in mice with different age, diet, and genotype and also in humans with normal cognition, mild cognitive impairment, and AD using gas chromatography-mass spectrometry. Then, using one of the "hit" molecules (7ß-hydroxycholesterol; OHC), molecular and histopathological experiment and behavioral testing were conducted in normal mice following its intracranial stereotaxic injection to see whether this molecule drives AD pathogenesis and causes cognitive impairment. RESULTS: The serum levels of several metabolites, including 7ß-OHC, were increased by aging in the 3xTg-AD unlike normal mice. Consistently, the levels of 7ß-OHC were increased in the hairs of patients with AD and were correlated with clinical severity. We found that 7ß-OHC directly affects AD-related pathophysiology; intrahippocampal injection of 7ß-OHC induced astrocyte and microglial cell activation, increased the levels of pro-inflammatory cytokines (TNF-alpha, IL-1ß, IL-6), and enhanced amyloidogenic pathway. Mice treated with 7ß-OHC also exhibited deficits in memory and frontal/executive functions assessed by object recognition and 5-choice serial reaction time task, respectively. CONCLUSIONS: Our results suggest that 7ß-OHC could serve as a convenient, peripheral biomarker of AD. As directly involved in AD pathogenesis, 7ß-OHC assay may help actualize personalized medicine in a way to identify an at-risk subgroup as a candidate population for statin-based AD treatment.

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.

The development and evaluation of a self-efficacy enhancement program for older adults with mild cognitive impairment.

OBJECTIVE: The aims of this study were to develop a self-efficacy enhancement program and to evaluate its effect on cognitive function, dementia knowledge, self-efficacy, depression, and dementia preventive behaviors in older adults (age ≥ 65 years) with mild cognitive impairment (MCI). METHODS: This equivalent control group pretest-posttest study was conducted at a tertiary hospital in Seoul, South Korea. Older adults with MCI were randomly allocated to an experimental (EG, n = 16) or control group (CG, n = 16). The EG underwent an 8-week intervention (weekly 60-min session) utilizing self-efficacy enhancement strategies; the CG received usual care. The intervention was comprised of physical, cognitive, and emotional activities and was followed by 4-week maintenance during which both groups engaged in self-learning at home with a dementia preventive guidebook. Outcome data were evaluated at the pretest and 8, 10, and 12 weeks later. This study adhered to the CONSORT guidelines. RESULTS: There were significant differences in cognitive function, dementia knowledge, self-efficacy, and dementia preventive behaviors, but not in depression between the two groups over the time. Regarding cognitive function subdomains, significant differences were observed in visuospatial/executive, attention, language, and delayed recall. CONCLUSION: The integrated intervention consisting of physical, cognitive, and emotional activities was effective in improving cognitive function, dementia knowledge, self-efficacy, and dementia preventive behaviors. This suggests that this program can be utilized as an educational program to prevent dementia in older adults with MCI in dementia support centers, public health centers, clinics, and hospitals. TRIAL REGISTRATION: KCT0006094 in the Clinical Research Information Service. Retrospectively registered 23 April 2021, https://cris.nih.go.kr/cris/search/listDetail.do.

Association of cognitive enhancers and incident seizure risk in dementia: a population-based study.

BACKGROUND: Although individuals with dementia have a high risk of developing seizures, whether seizures are associated with cholinesterase inhibitors, which are commonly prescribed to treat individuals with dementia, remains unknown. This study investigated the risk of incident seizure following cholinesterase inhibitor use in patients with dementia. METHODS: A nationwide, nested case-control study was conducted using data from the Korean Health Insurance Review and Assessment Service (HIRA) from 2014 through 2018. A total of 13,767 participants aged 65-95 years who experienced incident seizure were propensity score-matched for medical comorbidities and drug exposure at a 1:3 ratio with a control group of 39,084 participants. The study examined the incidence of seizures in patients diagnosed with dementia within one year after receiving cognitive enhancers. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for seizure incidence according to cholinesterase inhibitor use were analyzed using a multivariable conditional logistic regression model. RESULTS: There was no statistically significant association between duration of cholinesterase inhibitors use and seizure risk. Although there was slight increased seizure risk in patient after receiving donepezil for 1 year compared to memantine, subgroup analyses stratified age and sex did not reveal any significant association between cholinesterase inhibitors use and late-onset seizure. CONCLUSIONS: Our findings suggest no immediate increase in seizure risk is associated with cholinesterase inhibitor use, although the risk of seizure in patients with dementia did increase after one year of continued medication intake. Further study is required to obtain confirmatory results on the seizure-related safety of cognitive enhancers in patients with dementia.

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.

Particulate matter increases beta-amyloid and activated glial cells in hippocampal tissues of transgenic Alzheimer's mouse: Involvement of PARP-1.

Exposure to air pollutants, such as particulate matter (PM), has been implicated in neurodegenerative disorders including Alzheimer's disease (AD). However, direct effects of PM on production of ß-amyloid (Aß), a key pathogenic molecule in AD, and its underlying mechanism are still elusive. Given PM's potential to induce oxidative stress in other tissues, we hypothesized that poly(ADP-ribose) polymerase (PARP-1) might be involved in PM-induced neurotoxicity. To address this, we used an ex vivo model of AD, the organotypic hippocampal slice tissue culture from old (12-14 months-of-age) triple transgenic 3xTg-AD mice. First, we observed that fine PM (aerodynamic diameter < 4 µm) can dose-dependently activate PARP-1 and decrease NAD+ levels in Neuro2A cells. PARP-1 activation did occur under concentrations of PM which did not affect cell viability. Next, we observed that direct treatment of PM increased Aß levels and activated glial cells in the ex vivo hippocampal tissues of 3xTg-AD mice. PM-induced glial activation was most prominent in CA1 region of the hippocampal tissue. Notably, we found that pharmacological inhibition of PARP-1 reversed both PM-induced Aß increase and glial activation, arguing the possible involvement of PARP-1 in PM-induced AD pathogenesis. Our findings suggest that PARP-1 might be a potential molecular target, responsible for mediating negative effects of PM on the brain. Modulating PARP-1 activity could be a promising approach to prevent or alleviate PM-related environmental neurotoxicity which could initiate AD pathogenesis.

Diagnostic Value of Time-Constrained Naming Test in Mild Cognitive Impairment.

BACKGROUND: Naming difficulties have recently garnered more interest in elderly individuals with mild cognitive impairment (MCI). We anticipate that naming tests with the consideration of response time can provide more informative and distinct neuropsychological profiles of individuals with MCI. METHODS: Naming tests were administered to 76 elderly individuals with MCI and 149 healthy elderly (HE). We analyzed the impact of MCI on naming performance and occurrence of "delayed" response. We also validated the predictive power of naming tests with a time-constrained scoring system. RESULTS: MCI participants performed poorer on the noun naming test than HE participants (p = 0.014). MCI was significantly associated with the occurrence of "delayed" response on the noun (odds ratio [OR] = 3.57; 95% confidence interval [CI] = 1.78-7.17) and verb naming tests (OR = 4.66; 95% CI = 2.07-10.46). The time-constrained naming scores were significantly better able to distinguish the MCI from the HE group than the conventional spontaneous naming score on both the noun (p < 0.001) and verb (p = 0.002) naming tests. CONCLUSIONS: Our findings broaden the knowledge related to the naming ability in individuals with MCI, with respect to the response time. We also confirmed the validity of the naming tests by applying the "delayed" responses as supplementary assessments in the diagnosis of MCI.

Cholinesterase Inhibitor Donepezil Increases Mitochondrial Biogenesis through AMP-Activated Protein Kinase in the Hippocampus.

OBJECTIVE: Donepezil, a widely prescribed drug for Alzheimer's disease (AD), is now considered to have multimodal actions beyond cholinesterase inhibition. We aimed to see whether donepezil enhances mitochondrial biogenesis and relevant signaling pathways since mitochondrial dysfunction is a key feature of the hypometabolic AD brain. METHODS: As a metabolic gauge, AMP-activated protein kinase (AMPK) was investigated as a tentative mediator of neurometabolic action of donepezil. Changes in phospho-AMPK levels, mitochondrial biogenesis, and ATP levels were measured upon donepezil treatment using neuroblastoma cells, primary cultured neurons and ex vivo hippocampal tissue of adult mice. RESULTS: Donepezil dose-dependently increased mitochondrial biogenesis and ATP levels as well as expression of PGC-1α and NRF-1 in neuroblastoma cells. Donepezil dose-dependently activated AMPK; however, inhibition of AMPK abolished the observed effects of donepezil, indicating that AMPK is a key mediator of donepezil's action. Notably, mitochondrial biogenesis upon donepezil treatment was mainly observed within dendritic regions of primary cultured hippocampal neurons. Levels of synaptic markers were also increased by donepezil. Finally, AMPK- dependent mitochondrial biogenesis by donepezil was confirmed in organotypic hippocampal tissue. CONCLUSIONS: Our findings indicate that AMPK/PGC-1α signaling is involved in beneficial actions of donepezil on neurometabolism. Pharmacological activation of AMPK might be a promising approach to counteract AD pathogenesis associated with brain hypometabolism.

Neural Effects of One's Own Voice on Self-Talk for Emotion Regulation.

One's own voice undergoes unique processing that distinguishes it from others' voices, and thus listening to it may have a special neural basis for self-talk as an emotion regulation strategy. This study aimed to elucidate how neural effects of one's own voice differ from those of others' voices on the implementation of emotion regulation strategies. Twenty-one healthy adults were scanned using fMRI while listening to sentences synthesized in their own or others' voices for self-affirmation and cognitive defusion, which were based on mental commitments to strengthen one's positive aspects and imagining metaphoric actions to shake off negative aspects, respectively. The interaction effect between voice identity and strategy was observed in the superior temporal sulcus, middle temporal gyrus, and parahippocampal cortex, and activity in these regions showed that the uniqueness of one's own voice is reflected more strongly for cognitive defusion than for self-affirmation. This interaction was also seen in the precuneus, suggesting intertwining of self-referential processing and episodic memory retrieval in self-affirmation with one's own voice. These results imply that unique effects of one's own voice may be expressed differently due to the degree of engagement of neural sharpening-related regions and self-referential networks depending on the type of emotion regulation.

Automated Scoring of Alzheimer's Disease Atrophy Scale with Subtype Classification Using Deep Learning-Based T1-Weighted Magnetic Resonance Image Segmentation.

Background: Application of visual scoring scales for regional atrophy in Alzheimer's disease (AD) in clinical settings is limited by their high time cost and low intra/inter-rater agreement. Objective: To provide automated atrophy scoring using objective volume driven from deep-learning segmentation methods for AD subtype classification using magnetic resonance imaging (MRI). Methods: We enrolled 3,959 participants (1,732 cognitively normal [CN], 1594 with mild cognitive impairment [MCI], and 633 with AD). The occupancy indices for each regional volume were calculated by dividing each volume by the size of the lateral and inferior ventricular volumes. MR images from 355 participants (119 CN, 119 MCI, and 117 AD) from three different centers were used for validation. Two neuroradiologists performed visual assessments of the medial temporal, posterior, and global cortical atrophy scores in the frontal lobe using T1-weighted MR images. Images were also analyzed using the deep learning-based segmentation software, Neurophet AQUA. Cutoff values for the three scores were determined using the data distribution according to age. The scoring results were compared for consistency and reliability. Results: Four volumetric-driven scoring results showed a high correlation with the visual scoring results for AD, MCI, and CN. The overall agreement with human raters was weak-to-moderate for atrophy scoring in CN participants, and good-to-almost perfect in AD and MCI participants. AD subtyping by automated scores also showed usefulness as a research tool. Conclusions: Determining AD subtypes using automated atrophy scoring for late-MCI and AD could be useful in clinical settings or multicenter studies with large datasets.

Reconsidering repurposing: long-term metformin treatment impairs cognition in Alzheimer's model mice.

Metformin, a primary anti-diabetic medication, has been anticipated to provide benefits for Alzheimer's disease (AD), also known as "type 3 diabetes". Nevertheless, some studies have demonstrated that metformin may trigger AD pathology and even elevate AD risk in humans. Despite this, limited research has elucidated the behavioral outcomes of metformin treatment, which would hold significant translational value. Thus, we aimed to perform thorough behavioral research on the prolonged administration of metformin to mice: We administered metformin (300 mg/kg/day) to transgenic 3xTg-AD and non-transgenic (NT) C57BL/6 mice over 1 and 2 years, respectively, and evaluated their behaviors across multiple domains via touchscreen operant chambers, including motivation, attention, memory, visual discrimination, and cognitive flexibility. We found metformin enhanced attention, inhibitory control, and associative learning in younger NT mice (≤16 months). However, chronic treatment led to impairments in memory retention and discrimination learning at older age. Furthermore, metformin caused learning and memory impairment and increased levels of AMPKα1-subunit, ß-amyloid oligomers, plaques, phosphorylated tau, and GSK3ß expression in AD mice. No changes in potential confounding factors on cognition, including levels of motivation, locomotion, appetite, body weight, blood glucose, and serum vitamin B12, were observed in metformin-treated AD mice. We also identified an enhanced amyloidogenic pathway in db/db mice, as well as in Neuro2a-APP695 cells and a decrease in synaptic markers, such as PSD-95 and synaptophysin in primary neurons, upon metformin treatment. Our findings collectively suggest that the repurposing of metformin should be carefully reconsidered when this drug is used for individuals with AD.

Developmental origin of oligodendrocytes determines their function in the adult brain.

In the mouse embryonic forebrain, developmentally distinct oligodendrocyte progenitor cell populations and their progeny, oligodendrocytes, emerge from three distinct regions in a spatiotemporal gradient from ventral to dorsal. However, the functional importance of this oligodendrocyte developmental heterogeneity is unknown. Using a genetic strategy to ablate dorsally derived oligodendrocyte lineage cells (OLCs), we show here that the areas in which dorsally derived OLCs normally reside in the adult central nervous system become populated and myelinated by OLCs of ventral origin. These ectopic oligodendrocytes (eOLs) have a distinctive gene expression profile as well as subtle myelination abnormalities. The failure of eOLs to fully assume the role of the original dorsally derived cells results in locomotor and cognitive deficits in the adult animal. This study reveals the importance of developmental heterogeneity within the oligodendrocyte lineage and its importance for homeostatic brain function.

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.

Immobilized Amyloid Hexamer Fragments to Map Active Sites of Amyloid-Targeting Chemicals.

As amyloid-ß (Aß) peptide is considered a biomarker and pathological culprit of Alzheimer's disease, Aß-targeting compounds have been investigated for diagnostics development and drug discovery of the disorder. Unlike amyloid plaque targeting agents, such as clinically available amyloid radiotracers intercalating into the ß-sheet structures of the aggregates, monomer and oligomer targeting chemicals are difficult to develop, as the transient and polymorphic nature of these peptides impedes their structural understanding. Here, we report a mapping approach to explore targeting residues of Aß-imaging probes and Aß-regulating drug candidates by utilizing a set of fragmented Aß hexamers immobilized on a 96-well microplate in combination with fluorescent full-length Aß for on-plate aggregation. To evaluate the mapping potential of the peptide plate, we tested previously reported fluorescent imaging agents (CRANAD-28, bis-ANS), aggregation inhibitors (curcumin, scyllo-inositol), and aggregate dissociators (necrostatin-1, sunitinib) targeting Aß. Our approach enabled mechanistic understanding of compounds targeting nonfibrillar Aß on an interacting sequence level.

Hyperpolarized [1-13C]pyruvate Magnetic Resonance Spectroscopy Shows That Agmatine Increased Lactate Production in the Brain of Type 2 Diabetic Mice.

PURPOSE: Type 2 diabetes mellitus (T2DM) is associated with a 2-fold increased risk of developing Alzheimer's disease. In earlier research, agmatine has been demonstrated to alleviate diabetes symptoms and increase cognitive performance. However, it is unclear whether the improvement of cognitive function is attributable to the reduction of diabetic symptoms or its direct influence on brain metabolism. Using hyperpolarized (HP) [1-13C]pyruvate magnetic resonance spectroscopy (MRS), this study intends to evaluate the influence of agmatine on brain metabolism. MATERIALS AND METHODS: ICR mice were fed a high-fat diet and injected with streptozotocin to develop a T2DM animal model. During a 2-week period, T2DM mice were treated with normal saline or 100 mg/kg of agmatine, and brain HP [1-13C]pyruvate MRS was performed. The effect of agmatine on lactate generation and NADH/NAD+ redox state was investigated using C6 and neuro-2a (N2a) cells. RESULTS: As a perfusion marker, the total 13C signals in the brain of T2DM mice (p=0.07) and agmatine-treated mice (p<0.05) were reduced. The conversion constant (Kpl) from [1-13C]pyruvate to [1-13C]lactate was not distinguishable in the brains of T2DM mice but was significantly increased in the brains of agmatine-treated T2DM mice. Treating C6 and N2a cells with agmatine increased NADH/NAD+ratio and lactate generation. CONCLUSION: Agmatine influences the NADH/NAD+ redox state in the brains of T2DM mice, which may be connected with enhanced cognitive performance and increased conversion of HP [1-13C]pyruvate to HP [1-13C]lactate.

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.

The effects of long-term cumulative HbA1c exposure on the development and onset time of dementia in the patients with type 2 diabetes mellitus: Hospital based retrospective study (2005-2021).

AIMS: We examined cumulative effects of long-term glycemic exposure in patients with type 2 diabetes mellitus (T2DM) on the development of dementia. METHODS: The study involved 20,487 records of patients with T2DM identified in the electronic medical record at Severance Hospital, Korea. Cumulative HbA1c (AUCHbA1c) and mean HbA1c over time (HbA1cavg) as measures of long-term glycemic exposure were compared for the development of dementia and the time to dementia. RESULTS: AUCHbA1c and HbA1cavg were significantly higher in patients who later developed dementia than in those who did not (AUCHbA1c: 56.2 ± 26.4 vs. 52.1 ± 26.1 %Year; HbA1cavg: 7.3 ± 1.0 vs. 7.0 ± 1.0%). Odds ratio of dementia increased when HbA1cavg was 7.2% (55 mmol/mol) or above, and when AUCHbA1c was 42 %Year (e.g., HbA1c 7.0% maintained for 6 years) or above. Among those who developed dementia, as HbA1cavg increased, the time to dementia onset decreased (ß = -380.6 days, 95% confidence interval [CI]: -416.2 to -345.0). CONCLUSIONS: Our results indicate poorly controlled T2DM was associated with an increased risk of developing dementia, as measured by AUCHbA1c and HbA1cavg. Higher cumulative glycemic exposure may lead to developing dementia in a shorter time.

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.