The prevalence of mild cognitive impairment with type 2 diabetes mellitus among elderly people in China: A cross-sectional study.
Gao Yuxia,Xiao Yanyu,Miao Rujuan,Zhao Jiangang,Cui Mingfei,Huang Guowei,Fei Ma
Archives of gerontology and geriatrics
BACKGROUND:In absence of curative treatments for dementia with type 2 diabetes mellitus (T2DM), mild cognitive impairment (MCI) in T2DM, the preclinical transitional states of dementia with T2DM has attracted dramatic attention. Our study was to estimate the prevalence and distribution of MCI in T2DM subjects from China, and identify influencing factors of subjects in MCI with T2DM. METHODS:In the present study, we performed cluster random sampling of 8213 people aged 65 years and older in Tianjin, a metropolitan city, located in northern China. All participants were interviewed and screened for T2DM. 1109 subjects with T2DM were initially screened with American Diabetes Association criteria for diagnosis of diabetes mellitus and were diagnosed with MCI and dementia according to the criteria of DSM-IIIR. The prevalence of MCI and dementia in subjects with T2DM were compared with that in ordinary subjects. Logistic regression analyses were performed to evaluate risk of MCI with T2DM. RESULTS:Among all 8213 subjects, overall MCI and dementia with T2DM prevalence were 13.5% and 2.34%, respectively. Compared with ordinary subjects, the prevalence of MCI in the present study was more frequent than the prevalence of MCI for the general population in almost each age group. In the univariate analyses, among all diabetic subjects, compared with cognitive intactly subjects, MCI subjects had significantly higher levels of age, current smoking, mean waist circumference, duration from onset of diabetes, insulin intake, systolic BP, fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c) and immunoreactive insulin (IRI). In multivariate logistic regression analyses, variables including current smoking, duration from onset of diabetes, FPG, HbA1c and IRI were significantly associated with increased risk for MCI with T2DM, the ORs were 1.36,1.33,1.17,1.25 and 1.33, respectively (all P<0.05). CONCLUSIONS:The present study confirms the high prevalence of MCI with T2DM among the elderly population of China. T2DM is related to a higher risk of MCI in a population with a high prevalence of this disorder and may aggravate the clinical picture as a concomitant factor.
Sex-related differences in the prevalence of cognitive impairment among overweight and obese adults with type 2 diabetes.
Espeland Mark A,Carmichael Owen,Yasar Sevil,Hugenschmidt Christina,Hazzard William,Hayden Kathleen M,Rapp Stephen R,Neiberg Rebecca,Johnson Karen C,Hoscheidt Siobhan,Mielke Michelle M,
Alzheimer's & dementia : the journal of the Alzheimer's Association
INTRODUCTION:Type 2 diabetes mellitus and obesity may increase risks for cognitive decline as individuals age. It is unknown whether this results in different prevalences of cognitive impairment for women and men. METHODS:The Action for Health in Diabetes, a randomized controlled clinical trial of a 10-year intensive lifestyle intervention, adjudicated cases of cross-sectional cognitive impairment (mild cognitive impairment or dementia) 10-13 years after enrollment in 3802 individuals (61% women). RESULTS:The cross-sectional prevalences of cognitive impairment were 8.3% (women) and 14.8% (men): adjusted odds ratio 0.55, 95% confidence interval [0.43, 0.71], P < .001. Demographic, clinical, and lifestyle risk factors varied between women and men but did not account for this difference, which was limited to individuals without apolipoprotein E (APOE)-ε4 alleles (interaction P = .034). CONCLUSIONS:Among overweight and obese adults with type 2 diabetes mellitus, traditional risk factors did not account for the lower prevalence of cognitive impairment observed in women compared with men.
Antidiabetic Drugs in Alzheimer's Disease: Mechanisms of Action and Future Perspectives.
Femminella Grazia Daniela,Bencivenga Leonardo,Petraglia Laura,Visaggi Lucia,Gioia Lucia,Grieco Fabrizio Vincenzo,de Lucia Claudio,Komici Klara,Corbi Graziamaria,Edison Paul,Rengo Giuseppe,Ferrara Nicola
Journal of diabetes research
Diabetes mellitus (DM) and Alzheimer's disease (AD) are two highly prevalent conditions in the elderly population and major public health burden. In the past decades, a pathophysiological link between DM and AD has emerged and central nervous system insulin resistance might play a significant role as a common mechanism; however, other factors such as inflammation and oxidative stress seem to contribute to the shared pathophysiological link. Both preclinical and clinical studies have evaluated the possible neuroprotective mechanisms of different classes of antidiabetic medications in AD, with some promising results. Here, we review the evidence on the mechanisms of action of antidiabetic drugs and their potential use in AD.
Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study).
Femminella Grazia Daniela,Frangou Eleni,Love Sharon B,Busza Gail,Holmes Clive,Ritchie Craig,Lawrence Robert,McFarlane Brady,Tadros George,Ridha Basil H,Bannister Carol,Walker Zuzana,Archer Hilary,Coulthard Elizabeth,Underwood Ben R,Prasanna Aparna,Koranteng Paul,Karim Salman,Junaid Kehinde,McGuinness Bernadette,Nilforooshan Ramin,Macharouthu Ajay,Donaldson Andrew,Thacker Simon,Russell Gregor,Malik Naghma,Mate Vandana,Knight Lucy,Kshemendran Sajeev,Harrison John,Hölscher Christian,Brooks David J,Passmore Anthony Peter,Ballard Clive,Edison Paul
BACKGROUND:Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue currently approved for type 2 diabetes and obesity. Preclinical evidence in transgenic models of Alzheimer's disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferation of neuronal progenitor cells. The primary objective of the study is to evaluate the change in cerebral glucose metabolic rate after 12 months of treatment with liraglutide in participants with Alzheimer's disease compared to those who are receiving placebo. METHODS/DESIGN:ELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild Alzheimer's dementia. A total of 206 participants will be randomised to receive either liraglutide or placebo as a daily injection for a year. The primary outcome will be the change in cerebral glucose metabolic rate in the cortical regions (hippocampus, medial temporal lobe, and posterior cingulate) from baseline to follow-up in the treatment group compared with the placebo group. The key secondary outcomes are the change from baseline to 12 months in z scores for clinical and cognitive measures (Alzheimer's Disease Assessment Scale-Cognitive Subscale and Executive domain scores of the Neuropsychological Test Battery, Clinical Dementia Rating Sum of Boxes, and Alzheimer's Disease Cooperative Study-Activities of Daily Living) and the incidence and severity of treatment-emergent adverse events or clinically important changes in safety assessments. Other secondary outcomes are 12-month change in magnetic resonance imaging volume, diffusion tensor imaging parameters, reduction in microglial activation in a subgroup of participants, reduction in tau formation and change in amyloid levels in a subgroup of participants measured by tau and amyloid imaging, and changes in composite scores using support machine vector analysis in the treatment group compared with the placebo group. DISCUSSION:Alzheimer's disease is a leading cause of morbidity worldwide. As available treatments are only symptomatic, the search for disease-modifying therapies is a priority. If the ELAD trial is successful, liraglutide and GLP-1 analogues will represent an important class of compounds to be further evaluated in clinical trials for Alzheimer's treatment. TRIAL REGISTRATION:ClinicalTrials.gov, NCT01843075 . Registration 30 April 2013.
Comparative efficacy and acceptability of antidiabetic agents for Alzheimer's disease and mild cognitive impairment: A systematic review and network meta-analysis.
Cao Bing,Rosenblat Joshua D,Brietzke Elisa,Park Caroline,Lee Yena,Musial Natalie,Pan Zihang,Mansur Rodrigo B,McIntyre Roger S
Diabetes, obesity & metabolism
This study (registered with PROSPERO, CRD42018085967) compares the efficacy (i.e. pro-cognitive effects) and acceptability of antidiabetic agents for Alzheimer's disease (AD) and mild cognitive impairment (MCI). Cochrane Library (CENTRAL), PubMed/MEDLINE, EMBASE and PsycINFO were searched from inception to January 15, 2018 for randomized controlled trials comparing antidiabetic agents with placebo and/or another active antidiabetic agent for the treatment of AD or MCI. Nineteen eligible studies (n = 4855) evaluating the effects of 6 different antidiabetic drugs (i.e. intranasal insulin, pioglitazone, rosiglitazone, metformin, sitagliptin and liraglutide) were included. The results of 29 pairwise comparisons indicated that cognition was significantly improved in subjects treated with antidiabetic agents compared with placebo. Pioglitazone 15 to 30 mg demonstrated the greatest efficacy compared to placebo in network meta-analysis. No significant differences in acceptability were identified when comparing agents with each other and with placebo. The current findings indicate a pro-cognitive class effect of antidiabetic agents in AD/MCI. Other antidiabetic agents should also be investigated in future studies.
Adiponectin is protective against oxidative stress induced cytotoxicity in amyloid-beta neurotoxicity.
Chan Koon-Ho,Lam Karen Siu-Ling,Cheng On-Yin,Kwan Jason Shing-Cheong,Ho Philip Wing-Lok,Cheng Kenneth King-Yip,Chung Sookja Kim,Ho Jessica Wing-Man,Guo Vivian Yawei,Xu Almin
Beta-amyloid (Aβ ) neurotoxicity is important in Alzheimer's disease (AD) pathogenesis. Aβ neurotoxicity causes oxidative stress, inflammation and mitochondrial damage resulting in neuronal degeneration and death. Oxidative stress, inflammation and mitochondrial failure are also pathophysiological mechanisms of type 2 diabetes (T(2)DM) which is characterized by insulin resistance. Interestingly, T(2)DM increases risk to develop AD which is associated with reduced neuronal insulin sensitivity (central insulin resistance). We studied the potential protective effect of adiponectin (an adipokine with insulin-sensitizing, anti-inflammatory and anti-oxidant properties) against Aβ neurotoxicity in human neuroblastoma cells (SH-SY5Y) transfected with the Swedish amyloid precursor protein (Sw-APP) mutant, which overproduced Aβ with abnormal intracellular Aβ accumulation. Cytotoxicity was measured by assay for lactate dehydrogenase (LDH) released upon cell death and lysis. Our results revealed that Sw-APP transfected SH-SY5Y cells expressed both adiponectin receptor 1 and 2, and had increased AMP-activated protein kinase (AMPK) activation and enhanced nuclear factor-kappa B (NF-κB) activation compared to control empty-vector transfected SH-SY5Y cells. Importantly, adiponectin at physiological concentration of 10 µg/ml protected Sw-APP transfected SH-SY5Y cells against cytotoxicity under oxidative stress induced by hydrogen peroxide. This neuroprotective action of adiponectin against Aβ neurotoxicity-induced cytotoxicity under oxidative stress involved 1) AMPK activation mediated via the endosomal adaptor protein APPL1 (adaptor protein with phosphotyrosine binding, pleckstrin homology domains and leucine zipper motif) and possibly 2) suppression of NF-κB activation. This raises the possibility of novel therapies for AD such as adiponectin receptor agonists.
Modulation of Glucose Metabolism in Hippocampal Neurons by Adiponectin and Resistin.
Cisternas Pedro,Martinez Milka,Ahima Rexford S,William Wong G,Inestrosa Nibaldo C
Obese individuals exhibit altered circulating levels of adipokines, the proteins secreted by adipose tissue to mediate tissue cross-talk and regulate appetite and energy expenditure. The effect of adipokines on neuronal glucose metabolism, however, remains largely unknown. Two adipokines produced in adipose tissue, adiponectin and resistin, can gain access to the central nervous system (CNS), and their levels in the cerebrospinal fluid (CSF) are altered in obesity. We hypothesized that dysregulated adipokines in the CNS may underlie the reported link between obesity and higher risk of neurological disorders like Alzheimer's disease (AD), by affecting glucose metabolism in hippocampal neurons. Using cultured primary rat hippocampal neurons and mouse hippocampus slices, we show that recombinant adiponectin and resistin, at a concentration found in the CSF, have opposing effects on glucose metabolism. Adiponectin enhanced glucose uptake, glycolytic rate, and ATP production through an AMP-activated protein kinase (AMPK)-dependent mechanism; inhibiting AMPK abrogated the effects of adiponectin on glucose uptake and utilization. In contrast, resistin reduced glucose uptake, glycolytic rate, and ATP production, in part, by inhibiting hexokinase (HK) activity in hippocampal neurons. These data suggest that altered CNS levels of adipokines in the context of obesity may impact glucose metabolism in hippocampal neurons, brain region involved in learning and memory functions.
Importance of adiponectin activity in the pathogenesis of Alzheimer's disease.
Waragai Masaaki,Ho Gilbert,Takamatsu Yoshiki,Sekiyama Kazunari,Sugama Shuei,Takenouchi Takato,Masliah Eliezer,Hashimoto Makoto
Annals of clinical and translational neurology
A recent study suggested that insulin resistance may play a central role in the pathogenesis of Alzheimer's disease (AD). In this regard, it is of note that upregulation of plasma adiponectin (APN), a benign adipokine that sensitizes the insulin receptor signaling pathway and suppresses inflammation, has recently been associated with the severities of amyloid deposits and cognitive deficits in the elderly, suggesting that APN may enhance the risk of AD. These results are unanticipated because AD has been linked to type II diabetes and other metabolic disorders in which hypoadiponectinemia has been firmly established, and because APN ameliorated neuropathological features in a mouse model of neurodegeneration. Therefore, the objective of this study is to discuss the possible mechanisms underlying the biological actions of APN in the context of AD. Given that insulin receptor signaling is required for normal function of the nervous system, we predict that APN may be upregulated to compensate for compromised activity of the insulin receptor signaling pathway. However, increased APN might be sequestered by tau in the brain, leading to neurotoxic protein aggregation in AD. Alternatively, misfolding of APN may result in downregulation of the insulin/APN signal transduction network, leading to decreased neuroprotective and neurotrophic activities. Thus, it is possible that both 'gain of function' and 'loss of function' of APN may underlie synaptic dysfunction and neuronal cell death in AD. Such a unique biological mechanism underlying APN function in AD may require a novel therapeutic strategy that is distinct from previous treatment for metabolic disorders.
Adiponectin Attenuates Streptozotocin-Induced Tau Hyperphosphorylation and Cognitive Deficits by Rescuing PI3K/Akt/GSK-3β Pathway.
Xu Zhi-Peng,Gan Guo-Sheng,Liu Yu-Min,Xiao Jin-Song,Liu Han-Xing,Mei Bin,Zhang Jun-Jian
Clinical studies have demonstrated that decreased adiponectin is associated with the development of Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). We focused on determining the neuroprotective effect offered by adiponectin against streptozotocin-induced brain damage in ICV-STZ rat model. We found that adiponectin supplements significantly restored the cognitive deficits in ICV-STZ rat model including shorter escape latency, more crossing times and increased time spent in the target quadrant. Adiponectin supplements also increased number of dendritic branches and mushroom percentage. In addition, adiponectin supplements attenuated tau hyperphosphorylation at multiple AD-related sites through activation of protein Ser9-phosphorylated glycogen synthase kinase-3β (Ser9-GSK-3β) with increased the Akt and PI3K activity. Our data suggest that adiponectin supplements have neuroprotective effects on the ICV-STZ rat model, which may be mediated by the activation of the PI3K/Akt/GSK-3β signaling pathway.
Adiponectin as a new paradigm for approaching Alzheimer's disease.
Song Juhyun,Lee Jong Eun
Anatomy & cell biology
Adiponectin is an adipocytokine released by the adipose tissue and has multiple roles in the immune system and in the metabolic syndromes such as cardiovascular disease, Type 2 diabetes, obesity and also in the neurodegenerative disorders including Alzheimer's disease. Adiponectin regulates the sensitivity of insulin, fatty acid catabolism, glucose homeostasis and anti-inflammatory system through various mechanisms. Previous studies demonstrated that adiponectin modulates memory and cognitive impairment and contributes to the deregulated glucose metabolism and mitochondrial dysfunction observed in Alzheimer's disease. Here, we aim to summarize recent studies that suggest the potential correlation between adiponectin and Alzheimer's disease.
Adiponectin in plasma and cerebrospinal fluid in MCI and Alzheimer's disease.
Une K,Takei Y A,Tomita N,Asamura T,Ohrui T,Furukawa K,Arai H
European journal of neurology
BACKGROUND AND PURPOSE:Life style-related disorders such as hypertension, diabetes, dyslipidemia, and obesity are reported to be a great risk of dementia. Adipocytokines released from adipose tissue are thought to modulate some brain functions including memory and cognition. We here analysed adiponectin, one of the most important adipocytokines, in plasma and cerebrospinal fluid (CSF) from cognitive normal controls (NC), mild cognitive impairment (MCI) subjects, and patients with Alzheimer's disease (AD) and discussed if/how adiponectin could relate to the pathogenesis of AD. METHODS:Normal controls (n = 28), MCI (n = 18), and AD (n = 27) subjects were recruited at Tohoku University Hospital. The diagnosis of AD was based on NINCDS-ADRDA criteria. All the blood and CSF samples were obtained from each fasted subject. Adiponectin was assayed using a sandwich ELISA system. RESULTS:The levels of adiponectin between in plasma and in CSF showed a positive correlation. Plasma adiponectin was significantly higher in MCI and AD compared to NC, whereas CSF adiponectin was significantly higher in MCI compared to NC. CONCLUSION:It is possible that the level of adiponectin in plasma reflects its level in CSF. The tendency to have higher adiponectin in plasma and CSF from MCI and AD suggests that this molecule plays a critical role in the onset of AD.
Association between hippocampal volume and serum adiponectin in patients with type 2 diabetes mellitus.
Masaki Takayuki,Anan Futoshi,Shimomura Tsuyoshi,Fujiki Minoru,Saikawa Tetsunori,Yoshimatsu Hironobu
Metabolism: clinical and experimental
Type 2 diabetes mellitus (DM) is associated with cognitive dysfunction and hippocampus volume. The aim of the present study was to test the hypothesis that the level of the adipocytokine adiponectin correlates with hippocampus volume and insulin resistance in patients with type 2 DM. A total of 45 patients with type 2 DM were divided into two groups: a low adiponectin group and a normal adiponectin group. Hippocampus volume was measured by computer-assisted analysis using a magnetic resonance imaging (MRI) voxel-based specific regional analysis system developed for the study of Alzheimer's disease as the end point for assessment of hippocampus volume. Mean hippocampus volume was lower in the low adiponectin group than in the normal adiponectin group (P<.0001). Fasting serum concentrations of glucose (P<.05) and insulin (P<.0001), and homeostasis model assessment index (P<.0001), were all higher in the low adiponectin group than in the normal adiponectin group. Multiple regression analysis showed that hippocampus volume independently predicted serum adiponectin level. These results suggest that circulating levels of adiponectin are related to hippocampus volume in patients with type 2 DM.
Alzheimer's like brain changes correlate with low adiponectin plasma levels in type 2 diabetic patients.
García-Casares Natalia,García-Arnés Juan A,Rioja Jose,Ariza María José,Gutiérrez Antonio,Alfaro Francisco,Nabrozidis Alejandro,González-Alegre Pedro,González-Santos Pedro
Journal of diabetes and its complications
AIM:To study the association between adiponectin plasma levels, and gray matter brain volume and cerebral glucose metabolism in a group of type 2 diabetes patients. METHODS:We studied 25 type 2 diabetes patients and 25 age- and gender-matched healthy control participants. Biochemical analysis and structural cerebral magnetic resonance imaging, including voxel-based morphometry and (18)-fluorodeoxyglucose positron emission tomography, were performed. The gray matter volumes and metabolism changes were analyzed using statistical parametric mapping (SPM8). RESULTS:Lower levels of adiponectin correlated with a lower gray matter volume in temporal regions and with reduced cerebral glucose metabolism in temporal regions (p<0.001), adjusted for age, gender, education, and the presence of at least one epsilon 4 allele for the apolipoprotein E (APOEε4 genotype). CONCLUSIONS:Positive correlations between adiponectin plasma levels and both gray matter volume and cerebral glucose metabolism were found, predominantly in temporal regions, as in Alzheimer's disease. Adiponectin might be a biomarker for the cognitive decline associated with type 2 diabetic patients.
Possible Involvement of Adiponectin, the Anti-Diabetes Molecule, in the Pathogenesis of Alzheimer's Disease.
Waragai Masaaki,Adame Anthony,Trinh Ivy,Sekiyama Kazunari,Takamatsu Yoshiki,Une Kaori,Masliah Eliezer,Hashimoto Makoto
Journal of Alzheimer's disease : JAD
Adiponectin (APN) is protective in animal models of neurodegenerative diseases, but the role of APN in human brain has not been established. Using an enzyme-linked immunosorbent assay, we found that APN was significantly decreased in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD), compared to those in patients with mild cognitive impairment (MCI) and in normal controls (NC), despite elevation of APN in serum of patients with MCI and AD compared to that in NC. The discrepancy of CSF APN from serum APN in AD may suggest some critical actions of APN in the pathogenesis of AD. Indeed, it was histologically observed that APN was co-localized with tau in neurofibrillary tangles and immunoblot analysis showed that the functional trimers of APN were significantly decreased in AD compared to those in NC. Collectively, a loss of function of APN may be involved in the pathogenesis of AD.
Chronic adiponectin deficiency leads to Alzheimer's disease-like cognitive impairments and pathologies through AMPK inactivation and cerebral insulin resistance in aged mice.
Ng Roy Chun-Laam,Cheng On-Yin,Jian Min,Kwan Jason Shing-Cheong,Ho Philip Wing-Lok,Cheng Kenneth King-Yip,Yeung Patrick Ka Kit,Zhou Lena Lei,Hoo Ruby Lai-Chong,Chung Sookja Kim,Xu Aimin,Lam Karen Siu-Ling,Chan Koon Ho
BACKGROUND:Insulin resistance is the major pathogenesis underlying type 2 diabetes mellitus (T2DM) and these patients have doubled risk of Alzheimer's disease (AD). Increasing evidence suggests that insulin resistance plays an important role in AD pathogenesis, possibly due to abnormal GSK3β activation, causing intra- and extracellular amyloid-beta (Aβ) accumulation. Adiponectin (APN) is an adipokine with insulin-sensitizing and anti-inflammatory effects. Reduced circulatory APN level is associated with insulin resistance and T2DM. The role of APN in AD has not been elucidated. In this study, we aim to examine if adiponectin deficiency would lead to cerebral insulin resistance, cognitive decline and Alzheimer's-like pathology in mice. METHODS:To study the role of adiponectin in cognitive functions, we employed adiponectin-knockout (APN-KO) mice and demonstrated chronic APN deficiency in their CNS. Behavioral tests were performed to study the cognitions of male APN-KO mice. Brains and tissue lysates were collected to study the pathophysiological and molecular changes in the brain of APN-KO mice. SH-SY5Y neuroblastoma cell line was used to study the molecular mechanism upon APN and insulin treatment. RESULTS:Aged APN-deficient mice displayed spatial memory and learning impairments, fear-conditioned memory deficit as well as anxiety. These mice also developed AD pathologies including increased cerebral Aβ level, Aβ deposition, hyperphosphorylated Tau proteins, microgliosis and astrogliosis with increased cerebral IL-1β and TNFα levels that associated with increased neuronal apoptosis and reduced synaptic proteins levels, suggesting APN deficiency may lead to neuronal and synaptic loss in the brain. AD pathologies-associated APN-KO mice displayed attenuated AMPK phosphorylation and impaired insulin signaling including decreased Akt induction and increased GSK3β activation in the hippocampus and frontal cortex. Aged APN-KO mice developed hippocampal insulin resistance with reduced pAkt induction upon intracerebral insulin injection. Consistently, APN treatment in SH-SY5Y cells with insulin resistance and overexpressing Aβ induce higher pAkt levels through AdipoR1 upon insulin treatment whereas the induction was blocked by compound C, indicating APN can enhance neuronal insulin sensitivity through AMPK activation. CONCLUSION:Our results indicated that chronic APN deficiency inactivated AMPK causing insulin desensitization and elicited AD-like pathogenesis in aged mice which also developed significant cognitive impairments and psychiatric symptoms.
Alpha lipoic acid and metformin alleviates experimentally induced insulin resistance and cognitive deficit by modulation of TLR2 signalling.
Ahuja Swati,Uniyal Ankit,Akhtar Ansab,Sah Sangeeta Pilkhwal
Pharmacological reports : PR
BACKGROUND:Obesity is commonly found to be co-morbid with type 2 Diabetes Mellitus. In obese diabetic patients, TLR-2 receptor induced inflammation leads to the development of insulin resistance (IR). Furthermore, the IR is considered to be the most important cause for promoting cognitive decline which is evident in brain of patients with Alzheimer's disease related dementia (ADRD). METHODS:In this study, the effect of α-lipoic acid (ALA) has been examined in rodent model of zymosan induced insulin resistance and cognitive deficits, targeting at TLR-2 signalling. TLR-2 agonist, Zymosan initiates inflammatory cascade, resulting in IR and cognitive dysfunction. Zymosan (50 mg/kg ip) was given to mice on 1st, 8th, 15th and 22nd day to induce IR which was confirmed by hyperglycaemia, hyperinsulinemia, hyperlipidimea, increased glycated haemoglobin and HOMA-IR. Further the cognitive performance was assessed in Morris water maze revealing cognitive deficit in zymosan treated mice. RESULTS:Daily treatment with ALA for 28 days (50, 100, 200 mg/kg, ip) significantly improved insulin sensitivity and cognitive performance in mice by decreasing insulin resistance, corticosterone, IL-6 levels, acetylcholinesterase enzyme activity and oxidative stress in liver, cortex and hippocampus. ALA also increased adiponectin level and reduced body weight. Combination of ALA (100 mg/kg, ip) with metformin (100 mg/kg, ip) exhibited a potentiating effect in improving cognitive performance and insulin signalling. CONCLUSION:The findings of the study supported the hypothesis that TLR-2 induced inflammation leads to insulin resistance and cognitive impairment and provides an evidence for the therapeutic effect of ALA in IR and ADRD patients.
Clinical Applications of Adiponectin Measurements in Type 2 Diabetes Mellitus: Screening, Diagnosis, and Marker of Diabetes Control.
Abdella Nabila A,Mojiminiyi Olusegun A
Background:Adipose tissue-derived adiponectin has pleiotropic protective effects with suppression of inflammatory and metabolic derangements that may result in insulin resistance, metabolic syndrome, type 2 diabetes mellitus (T2DM), and cardiovascular disease. The aim of this study was to evaluate adiponectin as a diagnostic marker of T2DM and diabetes control. Methods:Fasting adiponectin, insulin, glucose, and HbA1c were determined in 376 patients with known T2DM and 575 subjects with undiagnosed diabetes but with family history of T2DM. Clinical and anthropometric data were recorded. Subjects were classified on the basis of degree of adiposity, insulin resistance (IR), and achievement of target HbA1c levels. Receiver operating characteristic (ROC) curve analysis was used to examine the diagnostic performance for undiagnosed DM. Results:In undiagnosed subjects, adiponectin was significantly lower in subjects with IR and diabetic subjects compared with those without. The area under the adiponectin ROC curve for diagnosis of DM was 0.740. In known T2DM subjects, those with good control had significantly higher adiponectin (8.6 versus 7.4 g/mL) compared to subjects with poor control. Conclusions:Adiponectin levels are associated with better glycemic control and could be a useful adjunct for screening for IR and T2DM. Therapeutic measures that increase adiponectin levels might be valuable targets for improving diabetes control and decreasing complications.
Analysis of correlation between the mild cognitive impairment (MCI) and level of adiponectin in elderly patients with type 2 diabetes mellitus (T2DM).
Liu Z-Q,Zhang M-X,Wang J,Ding N
European review for medical and pharmacological sciences
OBJECTIVE:To investigate the correlation between the mild cognitive impairment (MCI) and serum level of adiponectin in elderly patients with Type II diabetes mellitus (T2DM), so as to provide evidence for early diagnosis of MCI and effective evaluation of the impairment of cognitive functions, thereby preventing the impairment of cognitive function as early as possible. PATIENTS AND METHODS:Clinical data were collected from 260 T2DM patients (≥ 60 years old) in Endocrine Department and 120 healthy subjects (≥ 60 years old) who underwent physical examination in our hospital between June 2015 and June 2017. According to the evaluation results of MCI, these T2DM patients were further divided into the T2DM + MCI group (n = 138) and the T2DM + NMCI group (n = 122). General data, including gender, age, disease history and body mass index (BMI), and the laboratory indexes, including serum adiponectin, fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c) and blood fat, were collected for statistical analysis in T2DM + MCI group, T2DM + NMCI group and healthy control group. RESULTS:Comparisons among T2DM + MCI group, T2DM + NMCI group and healthy control group, showed that the serum level of adiponectin in T2DM + MCI group was significantly lower than those in remaining two groups (p < 0.01). Spearman correlation analysis revealed that score of Montreal Cognitive Assessment (MoCA) was positively correlated with the serum level of adiponectin (r = 0.446, p < 0.01). Multivariate linear regression analysis indicated that education (standard β = 0.325, p = 0.003), age (standard β = -0.236, p = 0.016), disease course of hypertension (standard β = -0.242, p = 0.006), disease course of diabetes mellitus (standard β = -0.377, p < 0.001) and the level of adiponectin were correlated with the cognitive impairment. The results of itemized assessment in MoCA scale showed that in T2DM + MCI group, the scores in visuospatial and executive abilities, attention, language and orientation were significantly lower than those in other two groups (p < 0.01). As for the delayed recall, the score in T2DM + MCI group was significantly lower than those in other two groups (p < 0.01), while the score in T2DM + NMCI group was lower than that in the healthy control group (p < 0.01); in terms of the naming ability and abstraction, no statistically significant differences were identified among three groups (p > 0.05). CONCLUSIONS:Age, poor education, disease course of hypertension, disease course of diabetes mellitus and a low level of adiponectin in serum are the risk factors in MCI of T2DM patients. Besides, the level of adiponectin in serum of T2DM patients is correlated with the development of MCI; elderly T2DM patients are afflicted by cognitive impairment, mainly in visuospatial and executive abilities, attention, language, delayed recall and orientation.
Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes: A Systematic Review and Meta-Analysis.
Campbell Jared M,Stephenson Matthew D,de Courten Barbora,Chapman Ian,Bellman Susan M,Aromataris Edoardo
Journal of Alzheimer's disease : JAD
BACKGROUND:Metformin, a first line antihyperglycemic medication, is an AMPK activator and has been hypothesized to act as a geroprotective agent. Studies on its association with various classifications of age-related cognitive decline have shown mixed results with positive and negative findings. OBJECTIVE:To synthesize the best available evidence on the association of metformin-use with risk, progression, and severity of dementia. METHOD:Eligible research investigated the effect of metformin on dementia, Alzheimer's disease, or any measure of cognitive impairment compared to any control group who were not receiving metformin. The initial search resulted in 862 citations from which 14 studies (seven cohort, four cross-sectional, two RCTs, and one case control) were included. RESULTS:Meta-analysis of three studies showed that cognitive impairment was significantly less prevalent in diabetic metformin (Odds ratio = 0.55, 95% CI 0.38 to 0.78), while six studies showed that dementia incidence was also significantly reduced (Hazard ratio = 0.76, 95% CI 0.39 to 0.88). Mini-Mental State Examination scores were not significantly affected by metformin-use, although both RCTs showed that metformin had a neuroprotective effect compared to placebo. Some studies found negative or neutral effects for metformin use by people with diabetes; the potential mechanism of metformin-induced vitamin B12 deficiency is discussed. CONCLUSIONS:Metformin should continue to be used as a first line therapy for diabetes in patients at risk of developing dementia or Alzheimer's disease. The use of metformin by individuals without diabetes for the prevention of dementia is not supported by the available evidence.
Association of metformin, sulfonylurea and insulin use with brain structure and function and risk of dementia and Alzheimer's disease: Pooled analysis from 5 cohorts.
Weinstein Galit,Davis-Plourde Kendra L,Conner Sarah,Himali Jayandra J,Beiser Alexa S,Lee Anne,Rawlings Andreea M,Sedaghat Sanaz,Ding Jie,Moshier Erin,van Duijn Cornelia M,Beeri Michal S,Selvin Elizabeth,Ikram M Arfan,Launer Lenore J,Haan Mary N,Seshadri Sudha
OBJECTIVE:To determine whether classes of diabetes medications are associated with cognitive health and dementia risk, above and beyond their glycemic control properties. RESEARCH DESIGN AND METHODS:Findings were pooled from 5 population-based cohorts: the Framingham Heart Study, the Rotterdam Study, the Atherosclerosis Risk in Communities (ARIC) Study, the Aging Gene-Environment Susceptibility-Reykjavik Study (AGES) and the Sacramento Area Latino Study on Aging (SALSA). Differences between users and non-users of insulin, metformin and sulfonylurea were assessed in each cohort for cognitive and brain MRI measures using linear regression models, and cognitive decline and dementia/AD risk using mixed effect models and Cox regression analyses, respectively. Findings were then pooled using meta-analytic techniques, including 3,590 individuals with diabetes for the prospective analysis. RESULTS:After adjusting for potential confounders including indices of glycemic control, insulin use was associated with increased risk of new-onset dementia (pooled HR (95% CI) = 1.58 (1.18, 2.12);p = 0.002) and with a greater decline in global cognitive function (β = -0.014±0.007;p = 0.045). The associations with incident dementia remained similar after further adjustment for renal function and excluding persons with diabetes whose treatment was life-style change only. Insulin use was not related to cognitive function nor to brain MRI measures. No significant associations were found between metformin or sulfonylurea use and outcomes of brain function and structure. There was no evidence of significant between-study heterogeneity. CONCLUSIONS:Despite its advantages in controlling glycemic dysregulation and preventing complications, insulin treatment may be associated with increased adverse cognitive outcomes possibly due to a greater risk of hypoglycemia.
[Diabetes mellitus and dementia].
Diabetes mellitus, particularly type 2 diabetes, is a risk factor for dementia and this holds true for incident vascular dementia and Alzheimer's disease. Cerebrovascular complications of diabetes and chronic mild inflammation in insulin resistant states partly account for this increased risk. In addition, cellular resistance to the trophic effects of insulin on neurons and glial cells favor the accumulation of toxic metabolic products, such as amyloid and hyperphosphorylated tau protein (pTau). Weight loss frequently precedes overt cognitive symptoms of Alzheimer's disease. This results in an increased risk of hypoglycemic episodes in stable diabetic patients who are on suitably adjusted doses of oral insulin or insulinotropic antidiabetic drugs. In turn, hypoglycemic episodes may induce further damage in the vulnerable brains of type 2 diabetes patients. Patients with unexplained weight loss, hypoglycemic episodes and subjective memory complaints must be screened for dementia. Once dementia has been diagnosed the goals of diabetes management must be reevaluated as prevention of hypoglycemia becomes more important than tight metabolic control. As weight loss accelerates the rate of cognitive decline, nutritional goals must aim at stabilizing body weight. There is no available evidence on whether drug treatment of diabetes in middle-aged persons can help to prevent dementia; however, physical exercise, mental activity and higher education have preventive effects on the risk of dementia in later life. In addition, nutritional recommendations that are effective in preventing cardiovascular events have also been shown to reduce the risk of dementia.
Thiamine diphosphate reduction strongly correlates with brain glucose hypometabolism in Alzheimer's disease, whereas amyloid deposition does not.
Sang Shaoming,Pan Xiaoli,Chen Zhichun,Zeng Fan,Pan Shumei,Liu Huimin,Jin Lirong,Fei Guoqiang,Wang Changpeng,Ren Shuhua,Jiao Fangyang,Bao Weiqi,Zhou Weiyan,Guan Yihui,Zhang Yiqiu,Shi Hongcheng,Wang Yanjiang,Yu Xiang,Wang Yun,Zhong Chunjiu
Alzheimer's research & therapy
BACKGROUND:The underlying mechanism of brain glucose hypometabolism, an invariant neurodegenerative feature that tightly correlates with cognitive impairment and disease progression of Alzheimer's disease (AD), remains elusive. METHODS:Positron emission tomography with 2-[F]fluoro-2-deoxy-D-glucose (FDG-PET) was used to evaluate brain glucose metabolism, presented as the rate of 2-[F]fluoro-2-deoxy-D-glucose standardized uptake value ratio (FDG SUVR) in patients with AD or control subjects and in mice with or without thiamine deficiency induced by a thiamine-deprived diet. Brain amyloid-β (Aβ) deposition in patients with clinically diagnosed AD was quantified by performing assays using C-Pittsburgh compound B PET. The levels of thiamine metabolites in blood samples of patients with AD and control subjects, as well as in blood and brain samples of mice, were detected by high-performance liquid chromatography with fluorescence detection. RESULTS:FDG SUVRs in frontal, temporal, and parietal cortices of patients with AD were closely correlated with the levels of blood thiamine diphosphate (TDP) and cognitive abilities, but not with brain Aβ deposition. Mice on a thiamine-deprived diet manifested a significant decline of FDG SUVRs in multiple brain regions as compared with those in control mice, with magnitudes highly correlating with both brain and blood TDP levels. There were no significant differences in the changes of FDG SUVRs in observed brain regions between amyloid precursor protein/presenilin-1 and wild-type mice following thiamine deficiency. CONCLUSIONS:We demonstrate, for the first time to our knowledge, in vivo that TDP reduction strongly correlates with brain glucose hypometabolism, whereas amyloid deposition does not. Our study provides new insight into the pathogenesis and therapeutic strategy for AD.
Assessment of change in glucose metabolism in white matter of amyloid-positive patients with Alzheimer disease using F-18 FDG PET.
Jeong Young Jin,Yoon Hyun Jin,Kang Do-Young
In Alzheimer disease (AD), neuroinflammation is an important process related to the deposition of beta-amyloid plaques and the activation of microglia. The inflammatory process can occur in both the gray matter and the white matter. We evaluated glucose metabolism of the white matter in AD patients and compared the value with cognitive parameters of the patients.Eighteen AD patients and 18 healthy subjects underwent F-18 fluorodeoxyglucose (FDG) and F-18 florbetaben positron emission tomography (PET). After segmentation of the white matter in both PET images, the specific binding ratio (SBR) of the global and regional cerebral white matter was checked. We evaluated the differences in SBR of the global and regional white matter between AD patients and healthy subjects. Then, we assessed the correlation between SBR and cognitive parameters in AD patients.In F-18 FDG PET images, the global white matter SBR was significantly higher in AD patients than in healthy subjects. In the regional analysis, the white matter SBR was significantly higher for the frontal, temporal, and parietal areas in AD patients. In the correlation analysis with F-18 FDG PET, SBR was significantly correlated with the Global Deterioration Scale, Mini-Mental State Examination scores, and amyloid deposition.Glucose metabolism of the white matter was significantly higher in AD patients than in healthy subjects and it was related to the scores of cognitive parameters. We suggest that F-18 FDG PET, like 18-kDa translocator protein PET, could be used as an indicator of neuroinflammation; however, further research is needed for a direct comparison between the 2 tests.
Cerebral PET glucose hypometabolism in subjects with mild cognitive impairment and higher EEG high-alpha/low-alpha frequency power ratio.
Moretti Davide Vito,Pievani Michela,Pini Lorenzo,Guerra Ugo Paolo,Paghera Barbara,Frisoni Giovanni Battista
Neurobiology of aging
In Alzheimer's disease (AD) research, both 2-deoxy-2-(F)fluoro-D-glucose (FDG) positron emission tomography (PET) and electroencephalography (EEG) are reliable investigational modalities. The aim of this study was to investigate the associations between EEG High-alpha/Low-alpha (H-alpha/L-alpha) power ratio and cortical glucose metabolism. A total of 23 subjects with mild cognitive impairment (MCI) underwent FDG-PET and EEG examinations. H-alpha/L-alpha power ratio was computed for each subject and 2 groups were obtained based on the increase of the power ratio. The subjects with higher H-alpha/L-alpha power ratio showed a decrease in glucose metabolism in the hub brain areas previously identified as typically affected by AD pathology. In subjects with higher H-alpha/L-alpha ratio and lower metabolism, a "double alpha peak" was identified in the EEG spectrum and a U-shaped correlation between glucose metabolism and increase of H-alpha/L-alpha power ratio has been found. Moreover, in this group, a conversion rate of 62.5% at 24 months was detected, significantly different from the chance percentage expected. The neurophysiological meaning of the interplay between alpha oscillations and glucose metabolism and the possible interest of the H-alpha/L-alpha power ratio as a clinical biomarker in AD have been discussed.
Cerebrospinal fluid lactate levels and brain [18F]FDG PET hypometabolism within the default mode network in Alzheimer's disease.
Liguori Claudio,Chiaravalloti Agostino,Sancesario Giuseppe,Stefani Alessandro,Sancesario Giulia Maria,Mercuri Nicola Biagio,Schillaci Orazio,Pierantozzi Mariangela
European journal of nuclear medicine and molecular imaging
PURPOSE:It has been suggested that neuronal energy metabolism may be involved in Alzheimer's disease (AD). In this view, the finding of increased cerebrospinal fluid (CSF) lactate levels in AD patients has been considered the result of energetic metabolism dysfunction. Here, we investigated the relationship between neuronal energy metabolism, as measured via CSF lactate levels, and cerebral glucose metabolism, as stated at the 2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography ([18F]FDG PET) in AD patients. METHODS:AD patients underwent lumbar puncture to measure CSF lactate levels and [18F]FDG PET to assess brain glucose metabolism. CSF and PET data were compared to controls. Since patients were studied at rest, we specifically investigated brain areas active in rest-condition owing to the Default Mode Network (DMN). We correlated the CSF lactate concentrations with the [18F]FDG PET data in brain areas owing to the DMN, using sex, age, disease duration, Mini Mental State Examination, and CSF levels of tau proteins and beta-amyloid as covariates. RESULTS:AD patients (n = 32) showed a significant increase of CSF lactate levels compared to Control 1 group (n = 28). They also showed brain glucose hypometabolism in the DMN areas compared to Control 2 group (n = 30). Within the AD group we found the significant correlation between increased CSF lactate levels and glucose hypometabolism in Broadman areas (BA) owing to left medial prefrontal cortex (BA10, mPFC), left orbitofrontal cortex (BA11, OFC), and left parahippocampal gyrus (BA 35, PHG). CONCLUSION:We found high CSF levels of lactate and glucose hypometabolism within the DMN in AD patients. Moreover, we found a relationship linking the increased CSF lactate and the reduced glucose consumption in the left mPFC, OFC and PHG, owing to the anterior hub of DMN. These findings could suggest that neural glucose hypometabolism may affect the DMN efficiency in AD, also proposing the possible role of damaged brain energetic machine in impairing DMN.
Apolipoprotein E Mimetic Peptide Increases Cerebral Glucose Uptake by Reducing Blood-Brain Barrier Disruption after Controlled Cortical Impact in Mice: An F-Fluorodeoxyglucose PET/CT Study.
Qin Xinghu,You Hong,Cao Fang,Wu Yue,Peng Jianhua,Pang Jinwei,Xu Hong,Chen Yue,Chen Ligang,Vitek Michael P,Li Fengqiao,Sun Xiaochuan,Jiang Yong
Journal of neurotrauma
Traumatic brain injury (TBI) disrupts the blood-brain barrier (BBB) and reduces cerebral glucose uptake. Vascular endothelial growth factor (VEGF) is believed to play a key role in TBI, and COG1410 has demonstrated neuroprotective activity in several models of TBI. However, the effects of COG1410 on VEGF and glucose metabolism following TBI are unknown. The current study aimed to investigate the expression of VEGF and glucose metabolism effects in C57BL/6J male mice subjected to experimental TBI. The results showed that controlled cortical impact (CCI)-induced vestibulomotor deficits were accompanied by increases in brain edema and the expression of VEGF, with a decrease in cerebral glucose uptake. COG1410 treatment significantly improved vestibulomotor deficits and glucose uptake and produced decreases in VEGF in the pericontusion and ipsilateral hemisphere of injury, as well as in brain edema and neuronal degeneration compared with the control group. These data support that COG1410 may have potential as an effective drug therapy for TBI.
Effects of plasma glucose levels on regional cerebral 18F-fluorodeoxyglucose uptake: Implications for dementia evaluation with brain PET imaging.
Viglianti Benjamin L,Wale Daniel J,Ma Tianwen,Johnson Timothy D,Bohnen Nicolaas I,Wong Ka Kit,Ky Christy,Frey Kirk A,Townsend Danyelle M,Rubello Domenico,Gross Milton D
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
PURPOSE:Hyperglycemia affects FDG uptake in the brain, potentially emulating Alzheimer's disease in normal individuals. This study investigates global and regional cerebral FDG uptake as a function of plasma glucose in a cohort of patients. METHODS:120 consecutive male patients with FDG PET/CT for initial oncologic staging (July-Dec 2015) were reviewed. Patients with dementia, cerebrovascular accident, structural brain lesion, prior oncology treatment or high metabolic tumor burden (recently shown affecting brain FDG uptake) were excluded. 53 (24 nondiabetic) eligible patients (age 65.7 ± 2.8 mean ± SE) were analyzed with parametric computer software, MIMneuro™. Regional Z-scores were evaluated as a function of plasma glucose and age using multi variable linear mixed effects models with false discovery analysis adjusting for multiple comparisons. If the regression slope was significantly (p < 0.05) different than zero, hyperglycemia effect was present. RESULTS:There was a negative inverse relationship (p < 0.001) between global brain FDG uptake and hyperglycemia. No regional hyperglycemia effect on uptake were present when subjects were normalized using pons or cerebellum. However, regional hyperglycemia effects were seen (p < 0.047-0.001) when normalizing by the whole brain. No obvious pattern was seen in the regions affected. Age had a significant effect using whole brain normalization (p < 0.04-0.01). CONCLUSIONS:Cortical variation in FDG uptake were identified when subjects were hyperglycemic. However, these variations didn't fit a particular pattern of dementia and the severity of the affect is not likely to alter clinical interpretation.
Age- and Brain Region-Specific Changes of Glucose Metabolic Disorder, Learning, and Memory Dysfunction in Early Alzheimer's Disease Assessed in APP/PS1 Transgenic Mice Using F-FDG-PET.
Li Xue-Yuan,Men Wei-Wei,Zhu Hua,Lei Jian-Feng,Zuo Fu-Xing,Wang Zhan-Jing,Zhu Zhao-Hui,Bao Xin-Jie,Wang Ren-Zhi
International journal of molecular sciences
Alzheimer's disease (AD) is a leading cause of dementia worldwide, associated with cognitive deficits and brain glucose metabolic alteration. However, the associations of glucose metabolic changes with cognitive dysfunction are less detailed. Here, we examined the brains of APP/presenilin 1 (PS1) transgenic (Tg) mice aged 2, 3.5, 5 and 8 months using F-labed fluorodeoxyglucose (F-FDG) microPET to assess age- and brain region-specific changes of glucose metabolism. FDG uptake was calculated as a relative standardized uptake value (SUVr). Morris water maze (MWM) was used to evaluate learning and memory dysfunction. We showed a glucose utilization increase in multiple brain regions of Tg mice at 2 and 3.5 months but not at 5 and 8 months. Comparisons of SUVrs within brains showed higher glucose utilization than controls in the entorhinal cortex, hippocampus, and frontal cortex of Tg mice at 2 and 3.5 months but in the thalamus and striatum at 3.5, 5 and 8 months. By comparing SUVrs in the entorhinal cortex and hippocampus, Tg mice were distinguished from controls at 2 and 3.5 months. In MWM, Tg mice aged 2 months shared a similar performance to the controls (prodromal-AD). By contrast, Tg mice failed training tests at 3.5 months but failed all MWM tests at 5 and 8 months, suggestive of partial or complete cognitive deficits (symptomatic-AD). Correlation analyses showed that hippocampal SUVrs were significantly correlated with MWM parameters in the symptomatic-AD stage. These data suggest that glucose metabolic disorder occurs before onset of AD signs in APP/PS1 mice with the entorhinal cortex and hippocampus affected first, and that regional FDG uptake increase can be an early biomarker for AD. Furthermore, hippocampal FDG uptake is a possible indicator for progression of Alzheimer's cognition after cognitive decline, at least in animals.
Cognitive dysfunctions in middle-aged type 2 diabetic patients and neuroimaging correlations: a cross-sectional study.
García-Casares Natalia,Jorge Ricardo E,García-Arnés Juan A,Acion Laura,Berthier Marcelo L,Gonzalez-Alegre Pedro,Nabrozidis Alejandro,Gutiérrez Antonio,Ariza María José,Rioja Jose,González-Santos Pedro
Journal of Alzheimer's disease : JAD
BACKGROUND/OBJECTIVE:The aim was to assess the neuropsychological performance of a group of middle-aged patients with well-controlled type 2 diabetes mellitus (T2DM) and to examine whether the neuropsychological deficits correlate with structural and functional brain alterations. METHODS:We compared 25 subjects with T2DM aged 45-65 years with 25 control participants matched for age, gender, and educational level. The neuropsychological battery was designed to examine executive functions, attention, information processing speed, and verbal memory. Severity of depression was assessed using the Hamilton Depression Rating Scale and cardiovascular risk factors were assessed using the Framingham Cardiovascular Risk Profile Score. The presence of at least one APOEε4 allele was determined. Reduced gray matter density was analyzed using voxel-based morphometry and brain glucose metabolic changes were assessed by 18FDG-PET. RESULTS:T2DM subjects had significantly lower scores than subjects without T2DM in the Trail-making Test B (p < 0.004), Color-Word Stroop test (p < 0.005), Semantic Fluency (p < 0.006), Digit-Symbol modalities test (p < 0.02), Text Recall from the Wechsler Memory Scale (p < 0.0001), Rey-Osterrieth Complex Figure-copy (p < 0.004), and delayed reproduction (p < 0.03). Worse executive functions and memory functioning correlated predominantly with less gray matter density and reduced glucose metabolism in the orbital and prefrontal cortex, temporal (middle gyrus, parahippocampus and uncus), and cerebellum regions (p < 0.001). CONCLUSIONS:T2DM subjects presented cognitive dysfunctions compared with controls. Clinical-neuroimaging correlations corresponded to brain changes (reduced gray matter density and glucose metabolism) mainly in fronto-temporal areas.
Neuronal human BACE1 knockin induces systemic diabetes in mice.
Plucińska Kaja,Dekeryte Ruta,Koss David,Shearer Kirsty,Mody Nimesh,Whitfield Phillip D,Doherty Mary K,Mingarelli Marco,Welch Andy,Riedel Gernot,Delibegovic Mirela,Platt Bettina
AIMS:β-Secretase 1 (BACE1) is a key enzyme in Alzheimer's disease pathogenesis that catalyses the amyloidogenic cleavage of amyloid precursor protein (APP). Recently, global Bace1 deletion was shown to protect against diet-induced obesity and diabetes, suggesting that BACE1 is a potential regulator of glucose homeostasis. Here, we investigated whether increased neuronal BACE1 is sufficient to alter systemic glucose metabolism, using a neuron-specific human BACE1 knockin mouse model (PLB4). METHODS:Glucose homeostasis and adiposity were determined by glucose tolerance tests and EchoMRI, lipid species were measured by quantitative lipidomics, and biochemical and molecular alterations were assessed by western blotting, quantitative PCR and ELISAs. Glucose uptake in the brain and upper body was measured via (18)FDG-PET imaging. RESULTS:Physiological and molecular analyses demonstrated that centrally expressed human BACE1 induced systemic glucose intolerance in mice from 4 months of age onward, alongside a fatty liver phenotype and impaired hepatic glycogen storage. This diabetic phenotype was associated with hypothalamic pathology, i.e. deregulation of the melanocortin system, and advanced endoplasmic reticulum (ER) stress indicated by elevated central C/EBP homologous protein (CHOP) signalling and hyperphosphorylation of its regulator eukaryotic translation initiation factor 2α (eIF2α). In vivo (18)FDG-PET imaging further confirmed brain glucose hypometabolism in these mice; this corresponded with altered neuronal insulin-related signalling, enhanced protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4) levels, along with upregulation of the ribosomal protein and lipid translation machinery. Increased forebrain and plasma lipid accumulation (i.e. ceramides, triacylglycerols, phospholipids) was identified via lipidomics analysis. CONCLUSIONS/INTERPRETATION:Our data reveal that neuronal BACE1 is a key regulator of metabolic homeostasis and provide a potential mechanism for the high prevalence of metabolic disturbance in Alzheimer's disease.
Brain accumulation of amyloid β protein visualized by positron emission tomography and BF-227 in Alzheimer's disease patients with or without diabetes mellitus.
Tomita Naoki,Furukawa Katsutoshi,Okamura Nobuyuki,Tashiro Manabu,Une Kaori,Furumoto Shozo,Iwata Ren,Yanai Kazuhiko,Kudo Yukitsuka,Arai Hiroyuki
Geriatrics & gerontology international
AIM:Although diabetes mellitus (DM) is considered to be one of the most consistent risks for developing dementia, it is not known if the pathology in dementia patients with DM is similar to or distinct from typical pathological features of Alzheimer's disease (AD). To discover the mechanism of developing dementia in AD patients with DM in a living state, we studied the distribution of amyloid β (Αβ) protein of diabetic AD patients. METHODS:To evaluate the accumulation of Aβ, we examined 14 normal controls, four diabetic patients with AD and 11 non-diabetic patients with AD by positron emission tomography (PET) using BF-227, a currently developed Aβ tracer. RESULTS:The analysis of PET images among the three groups showed an abundant aggregated Aβ accumulation in the cerebral cortex of both AD patients with and without DM. The extent and distributions of BF-227 accumulation in diabetic AD patients were not significantly different from these of non-diabetic AD patients. CONCLUSION:These results suggest that the degree and extent of Aβ deposition is not significantly different between AD with DM and AD alone.
Diabetes and elevated hemoglobin A1c levels are associated with brain hypometabolism but not amyloid accumulation.
Roberts Rosebud O,Knopman David S,Cha Ruth H,Mielke Michelle M,Pankratz V Shane,Boeve Bradley F,Kantarci Kejal,Geda Yonas E,Jack Clifford R,Petersen Ronald C,Lowe Val J
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
UNLABELLED:Dysfunctional insulin signaling may affect brain metabolism or amyloid deposition. We investigated the associations of type 2 diabetes with amyloid accumulation measured using (11)C-Pittsburgh compound B ((11)C-PiB) and brain hypometabolism measured using (18)F-FDG PET. METHODS:We studied a sample of nondemented participants from the population-based Mayo Clinic Study of Aging. All subjects underwent MR imaging, amyloid PET, and (18)F-FDG PET. Alzheimer disease (AD) signature and region-of-interest (ROI) measures for (11)C-PiB retention ratio and (18)F-FDG ratio were measured. Diabetes was assessed from the Rochester Epidemiology Project medical records linkage system. RESULTS:Among 749 participants (median age, 79.0 y; 56.5% men, 81.0% cognitively normal; 20.6% diabetic individuals), (18)F-FDG hypometabolism ((18)F-FDG ratio < 1.31) in the AD signature meta-ROI was more common in diabetic individuals (48.1%) than in nondiabetic individuals (28.9%; P < 0.001). The median (18)F-FDG ratio was lower in diabetic individuals than in nondiabetic individuals in the AD signature meta-ROI (1.32 vs. 1.40, P < 0.001) and in the angular (1.40 vs. 1.48, P < 0.001) and posterior cingulate gyri ROIs (1.63 vs. 1.72, P < 0.001). The odds ratio (OR) for abnormal AD signature (18)F-FDG hypometabolism was elevated (2.28; 95% confidence interval [CI], 1.56-3.33) in diabetic individuals versus nondiabetic individuals after adjustment for age, sex, and education and after additional adjustment for apolipoprotein ε4 allele, glycemic level, and cognitive status (OR, 1.69; 95% CI, 1.10-2.60). However, the AD signature (11)C-PiB retention ratio was similar in diabetic individuals versus nondiabetic individuals (OR, 1.03; 95% CI, 0.71-1.51; P = 0.87). In post hoc analyses in nondiabetic individuals, a 1% increase in hemoglobin A1c was associated with greater AD signature hypometabolism in cognitively normal subjects (OR, 1.93; 95% CI, 1.03-3.62; P = 0.04) and in the total cohort (OR 1.59; 95% CI, 0.92-2.75; P = 0.10). CONCLUSION:Diabetes and poor glycemic control in nondiabetic individuals may enhance glucose hypometabolism in AD signature regions. These factors should be investigated in longitudinal studies for their role in detecting onset of symptoms in AD.
Effects of amyloid precursor protein 17 peptide on the protection of diabetic encephalopathy and improvement of glycol metabolism in the diabetic rat.
Meng Heng,Zhang Duo,Yang Haishan
Journal of diabetes research
Researchers have proposed that amyloid precursor protein 17 peptide (APP17 peptide), an active fragment of amyloid precursor protein (APP) in the nervous system, has therapeutic effects on neurodegeneration. Diabetic encephalopathy (DE) is a neurological disease caused by diabetes. Here we use multiple experimental approaches to investigate the effect of APP17 peptide on changes in learning behavior and glycol metabolism in rats. It was found that rats with DE treated by APP17 peptide showed reversed behavioral alternation. The [(18)F]-FDG-PET images and other results all showed that the APP17 peptide could promote glucose metabolism in the brain of the DE rat model. Meanwhile, the insulin signaling was markedly increased as shown by increased phosphorylation of Akt and enhanced GLUT4 activation. Compared with the DE group, the activities of SOD, GSH-Px, and CAT in the rat hippocampal gyrus were increased, while MDA decreased markedly in the DE + APP17 peptide group. No amyloid plaques in the cortex and the hippocampus were detected in either group, indicating that the experimental animals in the current study were not suffering from Alzheimer's disease. These results indicate that APP17 peptide could be used to treat DE effectively.
Intensive glycaemic control and cognitive decline in patients with type 2 diabetes: a meta-analysis.
Tuligenga Richard H
The aim of this meta-analysis was to compare the effect of intensive vs standard glycaemic control on cognitive decline in type 2 diabetic patients. A systematic search of PubMed and ALOIS was conducted from inception up to October 30, 2014. Randomised controlled trials (RCTs) of type 2 diabetic patients comparing the rate of change in cognitive function among participants assigned to intensive vs standard glycaemic control were included. An inverse-variance-weighted random effects model was used to calculate standardised mean differences (SMDs) and 95% CIs. A total of 24 297 patients from five RCTs were included in the meta-analysis. Follow-up ranged from 3.3 to 6.2 years. The result from the pooled analysis showed that intensive glycaemic control was not associated with a slower rate of cognitive decline in patients with type 2 diabetes, compared with standard glycaemic control (SMD=0.02; 95% CI=-0.03 to 0.08) although there was some heterogeneity across individual studies (I(2)=68%, P for heterogeneity=0.01). There are few diabetes control trials including cognitive endpoints and a small number of trials comparing intensive and standard treatment strategies. Currently, intensive glycaemic control should not be recommended for prevention of cognitive decline in patients with type 2 diabetes because there is no evidence of its effectiveness. Moreover, the use of intensive diabetes treatment results in an increase of risk of hypoglycaemia, which is linked to a greater risk of poor cognition.
Bi-directional interaction between hypoglycaemia and cognitive impairment in elderly patients treated with glucose-lowering agents: a systematic review and meta-analysis.
Mattishent K,Loke Y K
Diabetes, obesity & metabolism
AIMS:To examine the bi-directional relationship, whereby hypoglycaemia is a risk factor for dementia, and where dementia increases risk of hypoglycaemia in older patients with diabetes mellitus treated with glucose-lowering agents. METHODS:We searched MEDLINE and EMBASE over a 10-year span from 2005 to 2015 (with automated PubMed updates to August 2015) for observational studies of the association between hypoglycaemia and cognitive impairment or dementia in participants aged >55 years. Assessment of study validity was based on ascertainment of hypoglycaemia, dementia and risk of confounding. We conducted random effects inverse variance meta-analyses, and assessed heterogeneity using the I(2) statistic. RESULTS:We screened 1177 citations, and selected 12 studies, of which nine were suitable for meta-analysis. There were a total of 1,439,818 participants, with a mean age of 75 years. Meta-analysis of five studies showed a significantly increased risk of dementia in patients who had hypoglycaemic episodes: pooled odds ratio 1.68 [95% confidence interval (CI) 1.45, 1.95]. We also found a significantly increased risk of hypoglycaemia in patients with dementia: pooled odds ratio from five studies 1.61 (95% CI 1.25, 2.06). Limitations of the study were heterogeneity in the meta-analysis, and uncertain ascertainment of dementia and hypoglycaemic outcomes and temporal relationships. Publication bias may have favoured the reporting of more significant findings. CONCLUSIONS:Our meta-analysis shows a bi-directional relationship between cognitive impairment and hypoglycaemia in older patients. Glucose-lowering therapy should be carefully tailored and monitored in older patients who are susceptible to cognitive decline.
An updated meta-analysis of cohort studies: Diabetes and risk of Alzheimer's disease.
Zhang Jieyu,Chen Chunxiang,Hua Shuizhen,Liao Hairong,Wang Meixiang,Xiong Yan,Cao Fei
Diabetes research and clinical practice
BACKGROUND:In recently, several large longitudinal population-based studies have shown that the rate of cognitive decline is accelerated in elderly people with diabetes mellitus. But the relation between diabetes and AD is still an area of controversy. The objective of this review was to update the evidence for or against diabetes as a risk factor of AD. METHODS:We searched the literature from their inception to May 2016 without restriction of language. We included all longitudinal population-based studies examining the association between diabetes and risk of AD. The meta-analysis was conducted using Stata software. RESULTS:A total of 17 studies involving 1,746,777 individuals were included. After pooling these 17 studies, subjects with diabetes had significant higher incidence of AD than those without diabetes (RR: 1.53, 95% CI: 1.42-1.63). When stratified by ethnicity, five cohorts were identified as Eastern populations, twelve were identified as Western populations. The Relative risk of AD in Western populations and Eastern populations were 1.36(1.18-1.53) and 1.62(1.49-1.75). CONCLUSION:The risk of AD is higher among people with diabetes than in the general population, especially in Eastern populations. So the necessary treatment measures should be taken in order to decrease the risk of AD.
Type 1 Diabetes Mellitus and Cognitive Impairments: A Systematic Review.
Li Wei,Huang Edgar,Gao Sujuan
Journal of Alzheimer's disease : JAD
Type 1 diabetes mellitus (T1DM) is a major subtype of diabetes and is usually diagnosed at a young age with insulin deficiency. The life expectancy of T1DM patients has increased substantially in comparison with that three decades ago due to the availability of exogenous insulin, though it is still shorter than that of healthy people. However, the relation remains unclear between T1DM and dementia as an aging-related disease. We conducted a systematic review of existing literature on T1DM and cognition impairments by carrying out searches in electronic databases Medline, EMBASE, and Google Scholar. We restricted our review to studies involving only human subjects and excluded studies on type 2 diabetes mellitus or non-classified diabetes. A meta-analysis was first performed on the relationship between T1DM and cognitive changes in youths and adults respectively. Then the review focused on the cognitive complications of T1DM and their relation with the characteristics of T1DM, glycemic control, diabetic complications, comorbidities, and others. First, age at onset, disease duration, and glycemic dysregulation were delineated for their association with cognitive changes. Then diabetic ketoacidosis, angiopathy, and neuropathy were examined as diabetic complications for their involvement in cognitive impairments. Lastly, body mass index and blood pressure were discussed for their relations with the cognitive changes. Future studies are needed to elucidate the pathogenesis of T1DM-related cognitive impairments or dementia.
Diabetes mellitus and risks of cognitive impairment and dementia: A systematic review and meta-analysis of 144 prospective studies.
Xue Mei,Xu Wei,Ou Ya-Nan,Cao Xi-Peng,Tan Meng-Shan,Tan Lan,Yu Jin-Tai
Ageing research reviews
BACKGROUND:Uncertainties persist about the associations of diabetes with risk of cognitive impairment and dementia. We aimed to illuminate these associations from various aspects. METHODS:We identified relevant prospective studies by searching PubMed up to Jun 2019. Summary relative risks (RR) were estimated using random-effects models. Credibility of each meta-analysis was assessed. Meta-regression and subgroup analyses were conducted. RESULTS:Of 28,082 identified literatures, 144 were eligible for inclusion in the systematic review, among which 122 were included in the meta-analysis. Diabetes conferred a 1.25- to 1.91-fold excess risk for cognitive disorders (cognitive impairment and dementia). Subjects with prediabetes also had higher risk for dementia. As for diabetes-related biochemical indicators, fasting plasma glucose (FPG) was non-linearly related to cognitive disorders; the elevated levels of 2 -h postload glucose (2h-PG), glycosylated hemoglobin (HbA1c), low and high levels of fasting plasma insulin (FPI) were associated with an increased risk of dementia. Encouragingly, the use of pioglitazone exhibited a 47% reduced risk of dementia in diabetic population. CONCLUSIONS:Diabetes, even prediabetes and changes of diabetes-related biochemical indicators, predicted increased incidence of cognitive impairment and dementia. The protective effects of pioglitazone warrant further investigation in randomized trials.
Type 2 diabetes mellitus, brain atrophy and cognitive decline in older people: a longitudinal study.
Callisaya Michele L,Beare Richard,Moran Chris,Phan Thanh,Wang Wei,Srikanth Velandai K
AIMS/HYPOTHESIS:The aims of the study were to examine whether type 2 diabetes mellitus is associated with greater brain atrophy and cognitive decline, and whether brain atrophy mediates associations between type 2 diabetes and cognitive decline. METHODS:Participants without dementia aged 55-90 years from the Cognition and Diabetes in Older Tasmanians (CDOT) study underwent brain MRI (ventricular and total brain volume) and neuropsychological measures (global function and seven cognitive domains) at three time points over 4.6 years. Mixed models were used to examine longitudinal associations of type 2 diabetes with cognitive and MRI measures, adjusting for covariates. A test of mediation was used to determine whether brain atrophy explained associations between type 2 diabetes and cognitive decline. RESULTS:A total of 705 participants (diabetes: n = 348, mean age 68.2 years [SD 7.0]; no diabetes: n = 357, mean age 72.5 years [SD 7.1]) were available at baseline. Adjusting for age, sex, education and vascular risk factors, there were significant diabetes × time interactions for verbal memory (β -0.06; 95% CI -0.09, -0.02) and verbal fluency (β -0.03; 95% CI -0.06, -0.00). Although people with diabetes had lower brain (β -14.273; 95% CI -21.197, -6.580) and greater ventricular (β 2.672; 95% CI 0.152, 5.193) volumes at baseline, there were no significant diabetes × time interactions (p > 0.05) or evidence of mediation of the diabetes-cognition relationship by brain atrophy. CONCLUSIONS/INTERPRETATION:In older community-dwelling people, type 2 diabetes is associated with decline in verbal memory and fluency over ~5 years. The effect of diabetes on brain atrophy may begin earlier (midlife).
[Diabetes mellitus and cognitive disorders from the diabetologists perspective].
Diabetes mellitus is associated with cognitive impairment which may convert to vascular or neurodegenerative dementia. Impairment of cognitive functions affects patients with type 1 and especially type 2 diabetes, with a number of vascular, metabolic and psychosocial factors involved in its development. As hyperglycemia and hypoglycemia also play an important role, important is the correct strategy of diabetes therapy which utilizes a combination of metformin with modern safe antidiabetics (incretin drugs, gliflozins, insulin analogues). It seems that some antidiabetic drugs (metformin, incretin drugs) and nasal form of application of insulin could improve cognition in diabetics.Key words: antidiabetic drugs - diabetes mellitus - hyperglycemia - hypoglycemia - cognition.