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Aladdin N, Ghareib SA. Vitamin D3 Exerts a Neuroprotective Effect in Metabolic Syndrome Rats: Role of BDNF/TRKB/Akt/GS3Kβ Pathway. J Biochem Mol Toxicol 2024; 38:e70082. [PMID: 39651608 DOI: 10.1002/jbt.70082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 10/25/2024] [Accepted: 11/20/2024] [Indexed: 12/11/2024]
Abstract
Metabolic syndrome (MetS) is usually associated with cognitive impairment, neuropathic pain, and reduced brain-derived neurotrophic factor (BDNF) levels. BDNF via tropomyosin receptor kinase B (TrkB) exerts neuroprotection by activating protein kinase B (Akt) to inhibit glycogen synthase kinase-3β (GSK3β). Although Vitamin D3 (VitD3) has demonstrated favorable metabolic and neuronal outcomes in MetS, the precise molecular mechanisms underlying its neuroprotective effects remain poorly elucidated. We aimed to test the hypothesis that VitD3 mitigates MetS-induced cognition deficits and neuropathic pain via modulating the BDNF/TRKB/Akt/GS3Kβ signaling pathway. MetS was induced in male rats by 10% fructose-supplemented water and 3% salt-enriched diet. After 6 weeks, normal and MetS rats received either vehicle or VitD3 (10 µg/kg/day) for an additional 6 weeks. Glycemic status, lipid profile, and behavioral changes were assessed. The advanced glycation end products (AGEs), and markers of inflammation (TNF-α and NF-κB), oxidative stress (malondialdehyde), and apoptosis (caspase3), as well as BDNF, TrkB, PI3K, Akt, GSK3β, phosphorylated tau, and amyloid beta (Aβ) were assessed in the cerebral cortex. MetS rats had deteriorated glycemic and lipid profiles, higher AGEs, reduced levels of BDNF, TrkB, PI3K, and active Akt, along with increased GSK3β levels, inflammation, oxidative stress, and apoptosis. These changes were associated with higher levels of cognitive impairment markers phosphorylated tau and Aβ, as well as behavioral changes indicative of cognitive impairment and neuropathic pain. VitD3 improved the cognitive and behavioral alterations, while mitigating the associated molecular derangements. Our results indicate that VitD3 may exert neuroprotective effects by modulating the BDNF/TrkB/PI3K/Akt/GSK3β signaling pathway.
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Affiliation(s)
- Noha Aladdin
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Salah A Ghareib
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
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Davis TME, Bruce DG, Schimke K, Chubb SAP, Davis WA. The inter-relationship between Helicobacter pylori infection, dementia and mortality in type 2 diabetes: The Fremantle Diabetes Study Phase I. J Diabetes Complications 2024; 38:108854. [PMID: 39244938 DOI: 10.1016/j.jdiacomp.2024.108854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 08/24/2024] [Accepted: 09/04/2024] [Indexed: 09/10/2024]
Abstract
BACKGROUND Given sparse relevant data, the aim of this study was to determine whether Helicobacter pylori infection, including cytotoxin-associated gene-A (CagA) producing strains, is associated with dementia in type 2 diabetes (T2DM). METHODS Longitudinal data from 1115 participants in the community-based Fremantle Diabetes Study Phase I (mean age 64.0 years, 48.0 % males; 38.0 % H. pylori seronegative, 24.3 % H. pylori seropositive/CagA seronegative, and 37.7 % H. pylori/CagA seropositive at baseline) were analyzed. RESULTS During up to 19 years of follow-up, 50.3 % and 83.5 % of participants without and with incident dementia, respectively, died. In Cox proportional hazards models, H. pylori/CagA seropositivity (hazard ratio (95 % CI) 1.68 (1.15, 2.46), P = 0.008), but not H. pylori seropositivity/CagA seronegativity (P = 0.541) was an independent predictor of incident dementia, but neither H. pylori seropositivity/CagA seronegativity nor H. pylori/CagA seropositivity were significant predictors in competing risks models (P ≥ 0.280). CONCLUSIONS Although CagA seropositivity in T2DM may have a contributory etiologic role in the risk of dementia, this may be through its association with reduced cardiovascular/all-cause mortality.
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Affiliation(s)
- Timothy M E Davis
- University of Western Australia, Medical School, Fremantle Hospital, PO Box 480, Fremantle, Western Australia 6959, Australia; Department of Endocrinology and Diabetes, Fiona Stanley and Fremantle Hospitals Group, 11 Robin Warren Drive, Murdoch, Western Australia 6150, Australia.
| | - David G Bruce
- University of Western Australia, Medical School, Fremantle Hospital, PO Box 480, Fremantle, Western Australia 6959, Australia
| | - Katrin Schimke
- University of Western Australia, Medical School, Fremantle Hospital, PO Box 480, Fremantle, Western Australia 6959, Australia; Center Practice, Neumarkt 1, St Leonhardstrasse 35, 9000 St Gallen, Switzerland
| | - S A Paul Chubb
- University of Western Australia, Medical School, Fremantle Hospital, PO Box 480, Fremantle, Western Australia 6959, Australia
| | - Wendy A Davis
- University of Western Australia, Medical School, Fremantle Hospital, PO Box 480, Fremantle, Western Australia 6959, Australia
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Kim HK, Biessels GJ, Yu MH, Hong N, Lee YH, Lee BW, Kang ES, Cha BS, Lee EJ, Lee M. SGLT2 Inhibitor Use and Risk of Dementia and Parkinson Disease Among Patients With Type 2 Diabetes. Neurology 2024; 103:e209805. [PMID: 39292986 DOI: 10.1212/wnl.0000000000209805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/20/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Despite the mechanistic potential of sodium-glucose cotransporter 2 inhibitor (SGLT2i) to improve neurologic outcomes, the efficacy of SGLT2i in neurodegenerative disorders among patients with type 2 diabetes is not well established. This population-based cohort study aimed to investigate the association of SGLT2i use with risks of incident dementia and Parkinson disease (PD) in patients with type 2 diabetes. METHODS This was a retrospective examination of data from a cohort of 1,348,362 participants with type 2 diabetes (≥40 years), who started antidiabetic drugs from 2014 to 2019, evaluated using the Korean National Health Insurance Service Database. Propensity score matching (1:1; SGLT2i to other oral antidiabetic drugs [OADs]) produced a cohort of 358,862 participants. Primary outcomes were the individual incidence of Alzheimer disease (AD), vascular dementia (VaD), and PD. Secondary outcomes were all-cause dementia (AD, VaD, and other dementia) and a composite of all-cause dementia and PD. Cox proportional hazards models were used to investigate the association between SGLT2i use and the risks of dementia and PD. RESULTS From the 358,862 participants analyzed (mean [SD] age, 57.8 [9.6] years; 58.0% male), 6,837 incident dementia or PD events occurred. Regarding the individual endpoints, SGLT2i use was associated with reduced risks of AD (adjusted hazard ratio [aHR] 0.81, 95% CI 0.76-0.87), VaD (aHR 0.69, 95% CI 0.60-0.78), and PD (aHR 0.80, 95% CI 0.69-0.91) with a 6-month drug use lag period. In addition, use of SGLT2i was associated with a 21% lower risk of all-cause dementia (aHR 0.79, 95% CI 0.69-0.90) and a 22% lower risk of all-cause dementia and PD than use of other OADs (aHR 0.78, 95% CI 0.73-0.83). The association between the use of SGLT2i and the lowered risk of these neurodegenerative disorders was not affected by sex, Charlson Comorbidity Index, diabetic complications, comorbidities, and medications. Sensitivity analysis further adjusting for bioclinical variables from health screening tests, including blood pressure, glucose, lipid profiles, and kidney function, yielded generally consistent results. DISCUSSION In this nationwide population-based study, SGLT2i use significantly reduced the risks of neurodegenerative disorders in patients with type 2 diabetes independent of various factors including comorbidities and bioclinical parameters. CLASSIFICATION OF EVIDENCE This study provides Class II evidence that SGLT2 antidiabetic drugs decrease the risk of dementia and PD in people with diabetes.
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Affiliation(s)
- Hae Kyung Kim
- From the Department of Internal Medicine (H.K.K., M.H.Y., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Institute of Endocrine Research (H.K.K., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Yonsei University College of Medicine, Seoul, South Korea; Department of Neurology (G.J.B.), University Medical Center (UMC) Utrecht Brain Center, UMC Utrecht, the Netherlands; and SENTINEL Team (M.H.Y.), Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Geert Jan Biessels
- From the Department of Internal Medicine (H.K.K., M.H.Y., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Institute of Endocrine Research (H.K.K., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Yonsei University College of Medicine, Seoul, South Korea; Department of Neurology (G.J.B.), University Medical Center (UMC) Utrecht Brain Center, UMC Utrecht, the Netherlands; and SENTINEL Team (M.H.Y.), Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Min Heui Yu
- From the Department of Internal Medicine (H.K.K., M.H.Y., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Institute of Endocrine Research (H.K.K., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Yonsei University College of Medicine, Seoul, South Korea; Department of Neurology (G.J.B.), University Medical Center (UMC) Utrecht Brain Center, UMC Utrecht, the Netherlands; and SENTINEL Team (M.H.Y.), Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Namki Hong
- From the Department of Internal Medicine (H.K.K., M.H.Y., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Institute of Endocrine Research (H.K.K., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Yonsei University College of Medicine, Seoul, South Korea; Department of Neurology (G.J.B.), University Medical Center (UMC) Utrecht Brain Center, UMC Utrecht, the Netherlands; and SENTINEL Team (M.H.Y.), Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Yong-Ho Lee
- From the Department of Internal Medicine (H.K.K., M.H.Y., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Institute of Endocrine Research (H.K.K., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Yonsei University College of Medicine, Seoul, South Korea; Department of Neurology (G.J.B.), University Medical Center (UMC) Utrecht Brain Center, UMC Utrecht, the Netherlands; and SENTINEL Team (M.H.Y.), Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Byung-Wan Lee
- From the Department of Internal Medicine (H.K.K., M.H.Y., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Institute of Endocrine Research (H.K.K., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Yonsei University College of Medicine, Seoul, South Korea; Department of Neurology (G.J.B.), University Medical Center (UMC) Utrecht Brain Center, UMC Utrecht, the Netherlands; and SENTINEL Team (M.H.Y.), Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Eun Seok Kang
- From the Department of Internal Medicine (H.K.K., M.H.Y., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Institute of Endocrine Research (H.K.K., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Yonsei University College of Medicine, Seoul, South Korea; Department of Neurology (G.J.B.), University Medical Center (UMC) Utrecht Brain Center, UMC Utrecht, the Netherlands; and SENTINEL Team (M.H.Y.), Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Bong-Soo Cha
- From the Department of Internal Medicine (H.K.K., M.H.Y., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Institute of Endocrine Research (H.K.K., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Yonsei University College of Medicine, Seoul, South Korea; Department of Neurology (G.J.B.), University Medical Center (UMC) Utrecht Brain Center, UMC Utrecht, the Netherlands; and SENTINEL Team (M.H.Y.), Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Eun Jig Lee
- From the Department of Internal Medicine (H.K.K., M.H.Y., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Institute of Endocrine Research (H.K.K., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Yonsei University College of Medicine, Seoul, South Korea; Department of Neurology (G.J.B.), University Medical Center (UMC) Utrecht Brain Center, UMC Utrecht, the Netherlands; and SENTINEL Team (M.H.Y.), Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Minyoung Lee
- From the Department of Internal Medicine (H.K.K., M.H.Y., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Institute of Endocrine Research (H.K.K., N.H., Y.-h.L., B.-W.L., E.S.K., B.-S.C., E.J.L., M.L.), Yonsei University College of Medicine, Seoul, South Korea; Department of Neurology (G.J.B.), University Medical Center (UMC) Utrecht Brain Center, UMC Utrecht, the Netherlands; and SENTINEL Team (M.H.Y.), Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
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Yong S, Yuhan Z, Shanshan C, Xin W, Leilei S, Liu J. The effect and mechanism of palmar ginseng in type 2 diabetic cognitive impairment. Heliyon 2024; 10:e32525. [PMID: 38988538 PMCID: PMC11233887 DOI: 10.1016/j.heliyon.2024.e32525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 06/04/2024] [Accepted: 06/05/2024] [Indexed: 07/12/2024] Open
Abstract
Objective To investigate the therapeutic effect of palmar ginseng on cognitive impairment in rats with type 2 diabetes, evaluate its neuroprotective effects, and explore its underlying mechanism. Methods A rat model of diabetic cognitive impairment (DCI) was established by feeding with homemade high-fat, high-sugar chow combined with intraperitoneal injection of streptozotocin (STZ). Rats were continually fed high-fat, high-sugar chow for 60 days after successful induction of the model. Palmar ginseng was administered via gavage. The Morris test was performed after 30 days of treatment. At the end of the test, blood samples were collected, and the activities of IL-6, IL-10, TNF-α, and IL-1β in rat serum. Pathological changes in hippocampal tissues were observed by Haematoxylin-eosin (HE) staining of the brain, activation of microglia in hippocampal tissues was detected by immunofluorescence, and the expression of PI3K/Akt/mTOR and JAK2/STAT3 proteins in the hippocampal tissues by Western blot. Results During the administration of palmar Ginseng, the body weight and blood glucose levels of DCI rats were measured weekly, with results showing that Palmar Ginseng effectively reduced blood glucose levels and body weight of DCI rats. Behavioural tests in the water maze indicated that palmar ginseng effectively improved the learning and memory ability of DCI rats. HE and immunofluorescence staining showed that palmar ginseng improved DCI in rats, ameliorated hippocampal neuronal damage, and improved microglial activation. ELISA showed that palmar ginseng significantly reduced the expression of pro-inflammatory factors in the serum of DCI rats. Increased expression of anti-inflammatory factors was observed, and Western blot analysis showed that Palmar Ginseng regulated PI3K/Akt/mTOR and JAK2/STAT3 protein expression, promoted the phosphorylation of PI3K/Akt/mTOR, and inhibited JAK2/STAT3 protein phosphorylation in rat hippocampal tissues as well as in BV2 cells. Conclusions Palmar ginseng may improve the onset and development of DCI by upregulating the phosphorylation of proteins in the PI3K/Akt/mTOR pathway.
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Affiliation(s)
- Shi Yong
- Department of Pharmacology, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Century Avenue, Xianyang, 712046, People's Republic of China
| | - Zhang Yuhan
- Department of Pharmacology, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Century Avenue, Xianyang, 712046, People's Republic of China
| | - Cao Shanshan
- Department of Pharmacology, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Century Avenue, Xianyang, 712046, People's Republic of China
| | - Wang Xin
- Department of Pharmacology, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Century Avenue, Xianyang, 712046, People's Republic of China
| | - Shi Leilei
- Department of Pharmacology, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Century Avenue, Xianyang, 712046, People's Republic of China
| | - Jiping Liu
- Department of Pharmacology, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Century Avenue, Xianyang, 712046, People's Republic of China
- Key Laboratory of Pharmacodynamic Mechanism and Material Basis of Traditional Chinese Medicine, Shaanxi Administration of Traditional Chinese Medicine, Xianyang, 712046, People's Republic of China
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Sumbul‐Sekerci B, Velioglu HA, Sekerci A. Diabetes-related clinical and microstructural white matter changes in patients with Alzheimer's disease. Brain Behav 2024; 14:e3533. [PMID: 38715429 PMCID: PMC11077244 DOI: 10.1002/brb3.3533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 04/16/2024] [Accepted: 04/17/2024] [Indexed: 05/12/2024] Open
Abstract
AIM Although there exists substantial epidemiological evidence indicating an elevated risk of dementia in individuals with diabetes, our understanding of the neuropathological underpinnings of the association between Type-2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) remains unclear. This study aims to unveil the microstructural brain changes associated with T2DM in AD and identify the clinical variables contributing to these changes. METHODS In this retrospective study involving 64 patients with AD, 31 individuals had concurrent T2DM. The study involved a comparative analysis of diffusion tensor imaging (DTI) images and clinical features between patients with and without T2DM. The FSL FMRIB software library was used for comprehensive preprocessing and tractography analysis of DTI data. After eddy current correction, the "bedpost" model was utilized to model diffusion parameters. Linear regression analysis with a stepwise method was used to predict the clinical variables that could lead to microstructural white matter changes. RESULTS We observed a significant impairment in the left superior longitudinal fasciculus (SLF) among patients with AD who also had T2DM. This impairment in patients with AD and T2DM was associated with an elevation in creatine levels. CONCLUSION The white matter microstructure in the left SLF appears to be sensitive to the impairment of kidney function associated with T2DM in patients with AD. The emergence of AD in association with T2DM may be driven by mechanisms distinct from the typical AD pathology. Compromised renal function in AD could potentially contribute to impaired white matter integrity.
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Affiliation(s)
- Betul Sumbul‐Sekerci
- Department of Clinical Pharmacy, Faculty of PharmacyBezmialem Vakıf UniversityIstanbulTurkey
| | - Halil Aziz Velioglu
- Center for Psychiatric NeuroscienceFeinstein Institutes for Medical ResearchManhassetNew YorkUSA
- Department of Neuroscience, Faculty of MedicineIstanbul Medipol UniversityIstanbulTurkey
| | - Abdusselam Sekerci
- Department of Internal Medicine, Faculty of MedicineBezmialem Vakif UniversityIstanbulTurkey
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Li C, Guo J, Zhao Y, Sun K, Abdelrahman Z, Cao X, Zhang J, Zheng Z, Yuan C, Huang H, Chen Y, Liu Z, Chen Z. Visit-to-visit HbA1c variability, dementia, and hippocampal atrophy among adults without diabetes. Exp Gerontol 2023; 178:112225. [PMID: 37263368 DOI: 10.1016/j.exger.2023.112225] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/13/2023] [Accepted: 05/26/2023] [Indexed: 06/03/2023]
Abstract
OBJECTIVES Adults without diabetes are not completely healthy; they are probably heterogeneous with several potential health problems. The management of hemoglobin A1c (HbA1c) is crucial among patients with diabetes; but whether similar management strategy is needed for adults without diabetes is unclear. Thus, this study aimed to investigate the associations of visit-to-visit HbA1c variability with incident dementia and hippocampal volume among middle-aged and older adults without diabetes, providing potential insights into this question. METHODS We conducted a prospective analysis for incident dementia in 10,792 participants (mean age 58.9 years, 47.8 % men) from the UK Biobank. A subgroup of 3793 participants (mean age 57.8 years, 48.6 % men) was included in the analysis for hippocampal volume. We defined HbA1c variability as the difference in HbA1c divided by the mean HbA1c over the 2 sequential visits ([latter - former]/mean). Dementia was identified using hospital inpatient records with ICD-9 codes. T1-structural brain magnetic resonance imaging was conducted to derive hippocampal volume (normalized for head size). The nonlinear and linear associations were examined using restricted cubic spline (RCS) models, Cox regression models, and multiple linear regression models. RESULTS During a mean follow-up (since the second round) of 8.4 years, 90 (0.8 %) participants developed dementia. The RCS models suggested no significant nonlinear associations of HbA1c variability with incident dementia and hippocampal volume, respectively (All P > 0.05). Above an optimal cutoff of HbA1c variability at 0.08, high HbA1c variability (increment in HbA1c) was associated with an increased risk of dementia (Hazard Ratio, 1.88; 95 % Confidence Interval, 1.13 to 3.14, P = 0.015), and lower hippocampal volume (coefficient, -96.84 mm3, P = 0.037), respectively, in models with adjustment of covariates including age, sex, etc. Similar results were found for a different cut-off of 0. A series of sensitivity analyses verified the robustness of the findings. CONCLUSIONS Among middle-aged and older adults without diabetes, increasing visit-to-visit HbA1c variability was associated with an increased dementia risk and lower hippocampal volume. The findings highlight the importance of monitoring and controlling HbA1c fluctuation in apparently healthy adults without diabetes.
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Affiliation(s)
- Chenxi Li
- School of Public Health, The Second Affiliated Hospital, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China
| | - Junyan Guo
- School of Public Health, The Second Affiliated Hospital, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China
| | - Yining Zhao
- School of Public Health, The Second Affiliated Hospital, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China
| | - Kaili Sun
- School of Public Health, The Second Affiliated Hospital, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China
| | - Zeinab Abdelrahman
- Department of Neurobiology, Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, Zhejiang, China; Department of Rehabilitation Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China
| | - Xingqi Cao
- School of Public Health, The Second Affiliated Hospital, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China
| | - Jingyun Zhang
- School of Public Health, The Second Affiliated Hospital, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China
| | - Zhoutao Zheng
- School of Public Health, The Second Affiliated Hospital, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China
| | - Changzheng Yuan
- Department of Big Data in Health Science School of Public Health, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China
| | - Huiqian Huang
- Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China
| | - Yaojing Chen
- State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875, China
| | - Zuyun Liu
- School of Public Health, The Second Affiliated Hospital, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China.
| | - Zuobing Chen
- Department of Rehabilitation Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China.
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Roy B, Choi SE, Freeby MJ, Kumar R. Microstructural brain tissue changes contribute to cognitive and mood deficits in adults with type 2 diabetes mellitus. Sci Rep 2023; 13:9636. [PMID: 37316507 PMCID: PMC10267112 DOI: 10.1038/s41598-023-35522-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 05/19/2023] [Indexed: 06/16/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) patients show brain tissue changes in mood and cognitive regulatory sites, but the nature and extent of tissue injury and their associations with symptoms are unclear. Our aim was to examine brain tissue damage in T2DM over controls using mean diffusivity (MD) computed from diffusion tensor imaging (DTI), and assess correlations with mood and cognitive symptoms in T2DM. We collected DTI series (MRI), mood, and cognitive data, from 169 subjects (68 T2DM and 101 controls). Whole-brain MD-maps were calculated, normalized, smoothed, and compared between groups, as well as correlated with mood and cognition scores in T2DM subjects. Type 2 diabetes patients showed altered cognitive and mood functions over control subjects. Multiple brain sites in T2DM patients showed elevated MD values, indicating chronic tissue changes, including the cerebellum, insula, and frontal and prefrontal cortices, cingulate, and lingual gyrus. Associations between MD values and mood and cognition scores appeared in brain sites mediating these functions. Type 2 diabetes patients show predominantly chronic brain tissue changes in areas mediating mood and cognition functions, and tissue changes from those regions correlate with mood and cognitive symptoms suggesting that the microstructural brain changes may account for the observed functional deficits.
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Affiliation(s)
- Bhaswati Roy
- Department of Anesthesiology, David Geffen School of Medicine at UCLA, University of California Los Angeles, 56-141 CHS, 10833 Le Conte Ave, Los Angeles, CA, 90095-1763, USA
| | - Sarah E Choi
- UCLA School of Nursing, University of California Los Angeles, Los Angeles, CA, USA
| | - Matthew J Freeby
- Department of Medicine, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, USA
| | - Rajesh Kumar
- Department of Anesthesiology, David Geffen School of Medicine at UCLA, University of California Los Angeles, 56-141 CHS, 10833 Le Conte Ave, Los Angeles, CA, 90095-1763, USA.
- Department of Radiological Sciences, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, USA.
- Department of Bioengineering, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, USA.
- Brain Research Institute, University of California Los Angeles, Los Angeles, CA, USA.
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8
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Molecular and neural roles of sodium-glucose cotransporter 2 inhibitors in alleviating neurocognitive impairment in diabetic mice. Psychopharmacology (Berl) 2023; 240:983-1000. [PMID: 36869919 PMCID: PMC10006050 DOI: 10.1007/s00213-023-06341-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 02/10/2023] [Indexed: 03/05/2023]
Abstract
Diabetes causes a variety of molecular changes in the brain, making it a real risk factor for the development of cognitive dysfunction. Complex pathogenesis and clinical heterogeneity of cognitive impairment makes the efficacy of current drugs limited. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) gained our attention as drugs with potential beneficial effects on the CNS. In the present study, these drugs ameliorated the cognitive impairment associated with diabetes. Moreover, we verified whether SGLT2i can mediate the degradation of amyloid precursor protein (APP) and modulation of gene expression (Bdnf, Snca, App) involved in the control of neuronal proliferation and memory. The results of our research proved the participation of SGLT2i in the multifactorial process of neuroprotection. SGLT2i attenuate the neurocognitive impairment through the restoration of neurotrophin levels, modulation of neuroinflammatory signaling, and gene expression of Snca, Bdnf, and App in the brain of diabetic mice. The targeting of the above-mentioned genes is currently seen as one of the most promising and developed therapeutic strategies for diseases associated with cognitive dysfunction. The results of this work could form the basis of a future administration of SGLT2i in diabetics with neurocognitive impairment.
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9
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Loughman A, Adler CJ, Macpherson H. Unlocking Modifiable Risk Factors for Alzheimer's Disease: Does the Oral Microbiome Hold Some of the Keys? J Alzheimers Dis 2023; 92:1111-1129. [PMID: 36872775 DOI: 10.3233/jad-220760] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
Abstract
Advancing age is recognized as the primary risk factor for Alzheimer's disease (AD); however approximately one third of dementia cases are attributable to modifiable risk factors such as hypertension, diabetes, smoking, and obesity. Recent research also implicates oral health and the oral microbiome in AD risk and pathophysiology. The oral microbiome contributes to the cerebrovascular and neurodegenerative pathology of AD via the inflammatory, vascular, neurotoxic, and oxidative stress pathways of known modifiable risk factors. This review proposes a conceptual framework that integrates the emerging evidence regarding the oral microbiome with established modifiable risk factors. There are numerous mechanisms by which the oral microbiome may interact with AD pathophysiology. Microbiota have immunomodulatory functions, including the activation of systemic pro-inflammatory cytokines. This inflammation can affect the integrity of the blood-brain barrier, which in turn modulates translocation of bacteria and their metabolites to brain parenchyma. Amyloid-β is an antimicrobial peptide, a feature which may in part explain its accumulation. There are microbial interactions with cardiovascular health, glucose tolerance, physical activity, and sleep, suggesting that these modifiable lifestyle risk factors of dementia may have microbial contributors. There is mounting evidence to suggest the relevance of oral health practices and the microbiome to AD. The conceptual framework presented here additionally demonstrates the potential for the oral microbiome to comprise a mechanistic intermediary between some lifestyle risk factors and AD pathophysiology. Future clinical studies may identify specific oral microbial targets and the optimum oral health practices to reduce dementia risk.
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Affiliation(s)
- Amy Loughman
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, Food & Mood Centre, Barwon Health, Geelong, Victoria, Australia
| | - Christina J Adler
- Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Helen Macpherson
- Deakin University, IPAN - the Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Geelong, Victoria, Australia
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10
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Tang X, Wang Y, Simó R, Stehouwer CDA, Zhou JB. The Association Between Diabetes Duration and Domain-Specific Cognitive Impairment: A Population-Based Study. J Alzheimers Dis 2023; 91:1435-1446. [PMID: 36641674 DOI: 10.3233/jad-220972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND Diabetes is a risk factor for cognitive impairment, and disease duration is associated with geriatric decline and functional disabilities. OBJECTIVE This study aimed to examine the association of diabetes duration with domain-specific cognitive impairment in elderly. METHODS A total of 3,142 participants from the National Health and Nutrition Examination Survey (NHANES) from the period between 2011 and 2014 were included. We assessed cognitive function using the Digit Symbol Substitution Test (DSST), the CERAD Word Learning (CERAD-WL) test, the CERAD Delayed Recall (CERAD-DR) test and animal fluency (AF) test. RESULTS After adjusting for age, sex, race/ethnicity, education level, and annual household income, we found that diabetes with a duration longer than 20 years were at 3.32-fold increased risk of DSST impairment (OR = 3.32, 95% CI: 1.95 to 5.67), 1.72-fold increased risk of CERAD-WL impairment (OR = 1.72, 95% CI: 1.13 to 2.62), and 1.76-fold increased risk of AF impairment (OR = 1.76, 95% CI: 1.23 to 2.53), compared with those with no diabetes. Associations were generally stronger in women than in men. Participants with diabetes, who were diagnosed at 50-59 years old were at increased risk of DSST impairment, CERAD-WL impairment, CERAD-DR impairment, and AF impairment per 5 years longer duration of diabetes. CONCLUSION Longer diabetes duration was associated with the increased risk of cognitive impairment, especially in processing speed and attention. The presence of chronic kidney disease was associated with the increased risk of DSST impairment.
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Affiliation(s)
- Xingyao Tang
- Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Ying Wang
- Endocrinology and Metabolism Department, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Rafael Simó
- Endocrinology and Nutrition Department, Hospital Universitari Vall d'Hebron, Diabetes and Metabolism Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Passeig de la Vall d'Hebron, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Coen D A Stehouwer
- Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Jian-Bo Zhou
- Endocrinology and Metabolism Department, Beijing Tongren Hospital, Capital Medical University, Beijing, China
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11
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Palarino JV, Boardman JD, Rogers RG. Cognition and Diabetes: Examining Sex Differences Using a Longitudinal Sample of Older Adults. Res Aging 2023; 45:161-172. [PMID: 35418264 DOI: 10.1177/01640275221084282] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Objectives: This study aims to investigate sex-based differences in the diabetes status and cognition relationship using a representative sample of older Americans. Methods: Using a sample of 19,190 females and 15,580 males from the Health and Retirement Study, we conduct mixed-effects linear regression analyses to examine sex differences in the association between diabetes and cognition over a 20-year follow-up period among older adults in the United States. Main Findings: Females experience slightly steeper declines in cognition that are further exacerbated by diabetes. At age 65, females without diabetes have significantly higher cognition than males; this gap is eliminated by age 85. Among diabetics, there is no initial sex disparity, but females' cognition becomes significantly lower than males' over the following 20 years. Principal Conclusions: Relative to males, females are particularly susceptible to diabetes-related declines in cognition with increasing age.
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Affiliation(s)
- Justin V Palarino
- Department of Sociology, 1877University of Colorado Boulder, Boulder, CO, USA.,Institute of Behavioral Science, 1877University of Colorado Boulder, Boulder, CO, USA
| | - Jason D Boardman
- Department of Sociology, 1877University of Colorado Boulder, Boulder, CO, USA.,Institute of Behavioral Science, 1877University of Colorado Boulder, Boulder, CO, USA
| | - Richard G Rogers
- Department of Sociology, 1877University of Colorado Boulder, Boulder, CO, USA.,Institute of Behavioral Science, 1877University of Colorado Boulder, Boulder, CO, USA
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12
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Palm Oil Derived Tocotrienol-Rich Fraction Attenuates Vascular Dementia in Type 2 Diabetic Rats. Int J Mol Sci 2022; 23:ijms232113531. [PMID: 36362316 PMCID: PMC9653761 DOI: 10.3390/ijms232113531] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 10/24/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
Vascular dementia (VaD) is a serious global health issue and type 2 diabetes mellitus (T2DM) patients are at higher risk. Palm oil tocotrienol-rich fraction (TRF) exhibits neuroprotective properties; however, its effect on VaD is not reported. Hence, we evaluated TRF effectiveness in T2DM-induced VaD rats. Rats were given a single dose of streptozotocin (STZ) and nicotinamide (NA) to develop T2DM. Seven days later, diabetic rats were given TRF doses of 30, 60, and 120 mg/kg orally for 21 days. The Morris water maze (MWM) test was performed for memory assessment. Biochemical parameters such as blood glucose, plasma homocysteine (HCY) level, acetylcholinesterase (AChE) activity, reduced glutathione (GSH), superoxide dismutase (SOD) level, and histopathological changes in brain hippocampus and immunohistochemistry for platelet-derived growth factor-C (PDGF-C) expression were evaluated. VaD rats had significantly reduced memory, higher plasma HCY, increased AChE activity, and decreased GSH and SOD levels. However, treatment with TRF significantly attenuated the biochemical parameters and prevented memory loss. Moreover, histopathological changes were attenuated and there was increased PDGF-C expression in the hippocampus of VaD rats treated with TRF, indicating neuroprotective action. In conclusion, this research paves the way for future studies and benefits in understanding the potential effects of TRF in VaD rats.
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13
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Kang P, Wang Z, Qiao D, Zhang B, Mu C, Cui H, Li S. Dissecting genetic links between Alzheimer’s disease and type 2 diabetes mellitus in a systems biology way. Front Genet 2022; 13:1019860. [PMID: 36186446 PMCID: PMC9523408 DOI: 10.3389/fgene.2022.1019860] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Alzheimer’s disease (AD) and Type 2 Diabetes Mellitus (T2DM) are two of the most common diseases for older adults. Accumulating epidemiological studies suggest that T2DM is a risk factor for cognitive dysfunction in the elderly. In this study, we aimed to dissect the genetic links between the two diseases and identify potential genes contributing the most to the mechanistic link.Methods: Two AD (GSE159699 and GSE28146) and two T2DM (GSE38642 and GSE164416) datasets were used to identify the differentially expressed genes (DEGs). The datasets for each disease were detected using two platforms, microarray and RNA-seq. Functional similarity was calculated and evaluated between AD and T2DM DEGs considering semantic similarity, protein-protein interaction, and biological pathways.Results: We observed that the overlapped DEGs between the two diseases are not in a high proportion, but the functional similarity between them is significantly high when considering Gene Ontology (GO) semantic similarity and protein-protein interactions (PPIs), indicating that T2DM shares some common pathways with AD development. Moreover, we constructed a PPI network consisting of AD and T2DM DEGs, and found that the hub gene SLC2A2 (coding transmembrane carrier protein GLUT2), which connects the most DEGs in both AD and T2DM, plays as a key regulator in linking T2DM and AD via glucose metabolism related pathways.Conclusion: Through functional evaluation at the systems biology level, we demonstrated that AD and T2DM are similar diseases sharing common pathways and pathogenic genes. SLC2A2 may serve as a potential marker for early warning and monitoring of AD for the T2DM patients.
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Affiliation(s)
- Peiyuan Kang
- Clinical Medicine, Hebei Medical University, Shijiazhuang, China
| | - Zhao Wang
- Department of Anatomy, Hebei Medical University, Shijiazhuang, China
- Neuroscience Research Center, Hebei Medical University, Shijiazhuang, China
| | - Dan Qiao
- Department of Anatomy, Hebei Medical University, Shijiazhuang, China
- Neuroscience Research Center, Hebei Medical University, Shijiazhuang, China
| | - Bohan Zhang
- Department of Anatomy, Hebei Medical University, Shijiazhuang, China
- Neuroscience Research Center, Hebei Medical University, Shijiazhuang, China
| | - Chenyu Mu
- Department of Anatomy, Hebei Medical University, Shijiazhuang, China
- Neuroscience Research Center, Hebei Medical University, Shijiazhuang, China
| | - Huixian Cui
- Department of Anatomy, Hebei Medical University, Shijiazhuang, China
- Neuroscience Research Center, Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Neurodegenerative Disease Mechanism, Shijiazhuang, China
- *Correspondence: Sha Li, ; Huixian Cui,
| | - Sha Li
- Department of Anatomy, Hebei Medical University, Shijiazhuang, China
- Neuroscience Research Center, Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Neurodegenerative Disease Mechanism, Shijiazhuang, China
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China
- *Correspondence: Sha Li, ; Huixian Cui,
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14
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Agrawal M, Agrawal AK. Pathophysiological Association Between Diabetes Mellitus and Alzheimer's Disease. Cureus 2022; 14:e29120. [PMID: 36258952 PMCID: PMC9559718 DOI: 10.7759/cureus.29120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/13/2022] [Indexed: 12/05/2022] Open
Abstract
Worldwide elderly people are being affected by diabetes mellitus (DM) and dementia. The risk for the development of dementia is higher in people with DM. DM causes a marked cognitive reduction and increases the risk of dementia, most commonly vascular dementia and Alzheimer's disease. People affected by DM and dementia seem to be at higher risk for intense hypoglycemia. Hypoglycemia, the complication of DM treatment, is believed as an independent risk factor for dementia in people with DM. Both Alzheimer's disease and DM are linked with decreased insulin secretion, reduced uptake of glucose, raised oxidative stress, angiopathy, activation of the apoptotic pathway, aging, abnormal peroxidation of lipids, increased production of advanced glycation end products and tau phosphorylation, brain atrophy, and decreased fat metabolism. In this paper, we will review the association between Alzheimer's disease and DM. In addition, we will discuss the agents that enhance the risk for dementia in elderly people with DM and how to prevent the development of cognitive dysfunction in DM.
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15
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ER stress and UPR in Alzheimer's disease: mechanisms, pathogenesis, treatments. Cell Death Dis 2022; 13:706. [PMID: 35970828 PMCID: PMC9378716 DOI: 10.1038/s41419-022-05153-5] [Citation(s) in RCA: 89] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 07/26/2022] [Accepted: 07/29/2022] [Indexed: 01/21/2023]
Abstract
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by gradual loss of memory and cognitive function, which constitutes a heavy burden on the healthcare system globally. Current therapeutics to interfere with the underlying disease process in AD is still under development. Although many efforts have centered on the toxic forms of Aβ to effectively tackle AD, considering the unsatisfactory results so far it is vital to examine other targets and therapeutic approaches as well. The endoplasmic reticulum (ER) stress refers to the build-up of unfolded or misfolded proteins within the ER, thus, perturbing the ER and cellular homeostasis. Emerging evidence indicates that ER stress contributes to the onset and development of AD. A thorough elucidation of ER stress machinery in AD pathology may help to open up new therapeutic avenues in the management of this devastating condition to relieve the cognitive dementia symptoms. Herein, we aim at deciphering the unique role of ER stress in AD pathogenesis, reviewing key findings, and existing controversy in an attempt to summarize plausible therapeutic interventions in the management of AD pathophysiology.
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16
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Muhammad T, Drishti D, Srivastava S. Prevalence and correlates of vision impairment and its association with cognitive impairment among older adults in India: a cross-sectional study. BMJ Open 2022; 12:e054230. [PMID: 35523503 PMCID: PMC9083423 DOI: 10.1136/bmjopen-2021-054230] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVE This study aimed to investigate the predictors of vision impairment in old age and how impaired vision is associated with cognitive impairment among the ageing population. DESIGN A cross-sectional study was conducted using a large country-representative survey data. SETTING AND PARTICIPANTS This study used data from the 'Building a Knowledge Base on Population Ageing in India' survey, conducted in 2011. Participants included 9541 older adults aged 60 years and above. PRIMARY AND SECONDARY OUTCOME MEASURES The outcome variables were vision impairment and cognitive impairment. Descriptive statistics along with bivariate analysis were presented. Additionally, multivariable binary logistic regression analysis was performed to fulfil the objectives. RESULTS A proportion of 59.1% of the respondents had vision impairment. Nearly 60% of the participants had cognitive impairment. Those who had vision impairment were 11% more likely to have cognitive impairment compared to their counterparts (OR: 1.11, 95% CI: 1.01 to 1.23). low psychological health (OR: 1.55; 95% CI: 1.36 to 1.77), low activities of daily living (OR: 1.80; 95% CI: 1.43 to 2.27), low instrumental activities of daily living (OR: 1.26; 95% CI: 1.14 to 1.40), poor self-rated health (OR: 1.28; 95% CI: 1.15 to 1.41) and chronic morbidity (OR: 1.27; 95% CI: 1.14 to 1.41) were found to be risk factors for cognitive impairment among older adults. CONCLUSIONS Additional efforts in terms of advocacy, availability, affordability and accessibility especially in a country with big illiteracy issue are mandatory to increase the reach of eye-care services and reduce the prevalence of avoidable visual impairment and vision losses that lead to cognitive deficits among the older population.
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Affiliation(s)
- T Muhammad
- Department of Family & Generations, International Institute for Population Sciences, Mumbai, Maharashtra, India
| | - Drishti Drishti
- Department of Public Health & Mortality Studies, International Institute for Population Sciences, Mumbai, Maharashtra, India
| | - Shobhit Srivastava
- Department of Survey Research & Data Analytics, International Institute for Population Sciences, Mumbai, Maharashtra, India
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17
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Yoo JE, Han K, Kim B, Park SH, Kim SM, Park HS, Nam GE. Changes in Physical Activity and the Risk of Dementia in Patients With New-Onset Type 2 Diabetes: A Nationwide Cohort Study. Diabetes Care 2022; 45:1091-1098. [PMID: 35192690 DOI: 10.2337/dc21-1597] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 01/28/2022] [Indexed: 02/03/2023]
Abstract
OBJECTIVE We investigated the association between interval changes in physical activity (PA) and dementia risk among patients with new-onset type 2 diabetes. RESEARCH DESIGN AND METHODS We identified 133,751 participants newly diagnosed with type 2 diabetes in a health screening (2009-2012), with a follow-up health screening within 2 years (2010-2015). PA level changes were categorized into continuous lack of PA, decreaser, increaser, and continuous PA groups. Dementia was determined using dementia diagnosis codes and antidementia drug prescriptions. RESULTS During the median follow-up of 4.8 years, 3,240 new cases of all-cause dementia developed. Regular PA was associated with lower risks of all-cause dementia (adjusted hazard ratio [aHR] 0.82; 95% CI 0.75-0.90), Alzheimer disease (AD) (aHR 0.85; 95% CI 0.77-0.95), and vascular dementia (VaD) (aHR 0.78; 95% CI 0.61-0.99). Increasers who started to engage in regular PA had a lower risk of all-cause dementia (aHR 0.86; 95% CI 0.77-0.96). Moreover, the risk was further reduced among those with continuous regular PA: all-cause dementia (aHR 0.73; 95% CI 0.62-0.85), AD (aHR 0.74; 95% CI 0.62-0.88), and VaD (aHR 0.62; 95% CI 0.40-0.94). Consistent results were noted in various subgroup analyses. CONCLUSIONS Regular PA was independently associated with lower risks of all-cause dementia, AD, and VaD among individuals with new-onset type 2 diabetes. Those with continuous regular PA and, to a lesser extent, those who started to engage in regular PA had a lower risk of dementia. Regular PA should be encouraged to prevent dementia in high-risk populations and those with new-onset type 2 diabetes.
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Affiliation(s)
- Jung Eun Yoo
- Department of Family Medicine, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Republic of Korea
| | - Kyungdo Han
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
| | - Bongseong Kim
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
| | - Sang-Hyun Park
- Department of Medical Statistics, College of Medicine, Catholic University of Korea, Seoul, Republic of Korea
| | - Seon Mee Kim
- Department of Family Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Hye Soon Park
- Department of Family Medicine, Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea
| | - Ga Eun Nam
- Department of Family Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea
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18
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Piątkowska-Chmiel I, Gawrońska-Grzywacz M, Popiołek Ł, Herbet M, Dudka J. The novel adamantane derivatives as potential mediators of inflammation and neural plasticity in diabetes mice with cognitive impairment. Sci Rep 2022; 12:6708. [PMID: 35468904 PMCID: PMC9035983 DOI: 10.1038/s41598-022-10187-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 03/14/2022] [Indexed: 12/12/2022] Open
Abstract
Diabetes is a chronic disease leading to memory difficulties and deterioration of learning abilities. The previous studies showed that modulation of inflammatory pathways in the diabetic brain may reduce dysfunction or cell death in brain areas which are important for control of cognitive function. In the present study, we investigated the neuroprotective actions of newly synthesized adamantane derivatives on diabetes-induced cognitive impairment in mice. Our study relied on the fact that both vildagliptin and saxagliptin belong to DPP4 inhibitors and, contain adamantanyl group. Efficacy of tested compounds at reversing diabetes-induced different types of memory impairment was evaluated with the use of selected behavioural tests. The following neuroinflammatory indicators were also analyzed: neuroinflammatory indicators and the expression of genes involved in the inflammatory response of brain (Cav1, Bdnf). Our study demonstrated that new adamantane derivatives, similarly to DPP4 inhibitors, can restrict diabetes-induced cognitive deficits. We demonstrated that the overexpression of GLP-1-glucagon-like peptide as well as Bdnf, Cav1 genes translate into central blockade of pro-inflammatory synthesis of cytokines and significantly improvement on memory performance in diabetes mice. Newly synthesized adamantane derivatives might have important roles in prevention and treatment of cognitive impairment by inflammatory events in patients with diabetes or related diseases.
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Affiliation(s)
- Iwona Piątkowska-Chmiel
- Chair and Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 8b Jaczewskiego Street, 20-090, Lublin, Poland.
| | - Monika Gawrońska-Grzywacz
- Chair and Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 8b Jaczewskiego Street, 20-090, Lublin, Poland
| | - Łukasz Popiołek
- Chair and Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki Street, 20-093, Lublin, Poland
| | - Mariola Herbet
- Chair and Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 8b Jaczewskiego Street, 20-090, Lublin, Poland
| | - Jarosław Dudka
- Chair and Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 8b Jaczewskiego Street, 20-090, Lublin, Poland
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19
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Zhang R, Jiang L, Li G, Wu J, Tian P, Zhang D, Qin Y, Shi Z, Gao Z, Zhang N, Wang S, Zhou H, Xu S. Advanced Glycosylation End Products Induced Synaptic Deficits and Cognitive Decline Through ROS-JNK-p53/miR-34c/SYT1 Axis in Diabetic Encephalopathy. J Alzheimers Dis 2022; 87:843-861. [PMID: 35404278 DOI: 10.3233/jad-215589] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Background: miR-34c has been found to be implicated in the pathological process of Alzheimer’s disease, diabetes, and its complications. Objective: To investigate the underlying mechanisms of miR-34c in the pathogenesis of diabetic encephalopathy (DE). Methods: Diabetes mellitus rats were developed by incorporating a high-fat diet and streptozotocin injection. Morris water maze test and novel object recognition test were used to assess the cognitive function of rats. Expression of miR-34c were detected by fluorescence in situ hybridization and qRT-PCR. Immunofluorescence and western blot were used to evaluate synaptotagmin 1 (SYT1) and AdipoR2 or other proteins. Golgi staining was performed to investigate dendritic spine density. Results: The increased miR-34c induced by advanced glycation end-products (AGEs) was mediated by ROS-JNK-p53 pathway, but not ROS-Rb-E2F1 pathway, in hippocampus of DE rats or in HT-22 cells. miR-34c negatively regulated the expression of SYT1, but not AdipoR2, in hippocampal neurons. miR-34c inhibitor rescued the AGE-induced decrease in the density of dendritic spines in primary hippocampal neurons. Administration of AM34c by the intranasal delivery increased the hippocampus levels of SYT1 and ameliorated the cognitive function in DE rats. The serum levels of miR-34c were increased in patients with DE comparing with normal controls. Conclusion: These results demonstrated that AGE-induced oxidative stress mediated increase of miR-34c through ROS-JNK-p53 pathway, resulting in synaptic deficits and cognitive decline by targeting SYT1 in DE, and the miR-34c/SYT1 axis could be considered as a novel therapeutic target for DE patients.
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Affiliation(s)
- Rui Zhang
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P. R. China
- Hebei International Joint Research Center for Brain Science, Shijiazhuang, P. R. China
- Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, P. R. China
| | - Lei Jiang
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P. R. China
- Hebei International Joint Research Center for Brain Science, Shijiazhuang, P. R. China
- Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, P. R. China
| | - Guofeng Li
- Hebei Center for Disease Control and Prevention, Shijiazhuang, P. R. China
| | - JingJing Wu
- Clinical Laboratory, Cangzhou Central Hospital, Cangzhou, P. R. China
| | - Pei Tian
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P. R. China
- Hebei International Joint Research Center for Brain Science, Shijiazhuang, P. R. China
- Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, P. R. China
| | - Di Zhang
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P. R. China
- Hebei International Joint Research Center for Brain Science, Shijiazhuang, P. R. China
- Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, P. R. China
| | - Yushi Qin
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P. R. China
- Hebei International Joint Research Center for Brain Science, Shijiazhuang, P. R. China
- Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, P. R. China
| | - Zhongli Shi
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P. R. China
- Hebei International Joint Research Center for Brain Science, Shijiazhuang, P. R. China
- Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, P. R. China
| | - ZhaoYu Gao
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P. R. China
- Hebei International Joint Research Center for Brain Science, Shijiazhuang, P. R. China
- Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, P. R. China
| | - Nan Zhang
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P. R. China
- Hebei International Joint Research Center for Brain Science, Shijiazhuang, P. R. China
- Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, P. R. China
| | - Shuang Wang
- Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, P. R. China
| | - Huimin Zhou
- Hebei International Joint Research Center for Brain Science, Shijiazhuang, P. R. China
- Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, P. R. China
- Department of Endocrinology, The First Hospital of Hebei Medical University, Shijiazhuang, P. R. China
| | - Shunjiang Xu
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P. R. China
- Hebei International Joint Research Center for Brain Science, Shijiazhuang, P. R. China
- Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, P. R. China
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20
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De Sousa RAL. Reactive gliosis in Alzheimer's disease: a crucial role for cognitive impairment and memory loss. Metab Brain Dis 2022; 37:851-857. [PMID: 35286534 DOI: 10.1007/s11011-022-00953-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 03/08/2022] [Indexed: 01/24/2023]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder that leads to cognitive decline and memory loss. Insulin resistance in central nervous system (CNS) is a common feature in dementia. Defective insulin signaling is associated to higher levels of inflammation and to neuronal dysfunction. A reactive gliosis, a change that occurs in glial cells due to damage in CNS, seems to be one of the most important pro-inflammatory mechanisms in AD pathology. The first response to CNS injury is the migration of macrophages and microglia to the specific site of the injury. Oligodendrocytes are also recruited to to contribute with remyelination. The last component of a reactive gliosis is astrogliosis, which is the enhancement of astrocytes expression with concomitant changes in its morphology being the main cells of the glial scar. Here, we review the mechanisms by which a reactive gliosis can induce or contribute to the development and progression of AD.
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Affiliation(s)
- Ricardo Augusto Leoni De Sousa
- School of Biological Sciences and Health, Physical Education Department, Universidade Federal Dos Vales Do Jequitinhonha E Mucuri, Diamantina, Minas Gerais, Brazil.
- Multicenter Post Graduation Program in Physiological Sciences (PMPGCF), Brazilian Society of Physiology, São Paulo, Brazil.
- Neuroscience and Exercise Study Group (Grupo de Estudos em Neurociências e Exercício - GENE), Universidade Federal Dos Vales Do Jequitinhonha E Mucuri, Diamantina, Minas Gerais, Brazil.
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21
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Kim HK, Song J. Hypothyroidism and Diabetes-Related Dementia: Focused on Neuronal Dysfunction, Insulin Resistance, and Dyslipidemia. Int J Mol Sci 2022; 23:ijms23062982. [PMID: 35328405 PMCID: PMC8952212 DOI: 10.3390/ijms23062982] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/06/2022] [Accepted: 03/07/2022] [Indexed: 01/27/2023] Open
Abstract
The incidence of dementia is steadily increasing worldwide. The risk factors for dementia are diverse, and include genetic background, environmental factors, sex differences, and vascular abnormalities. Among the subtypes of dementia, diabetes-related dementia is emerging as a complex type of dementia related to metabolic imbalance, due to the increase in the number of patients with metabolic syndrome and dementia worldwide. Thyroid hormones are considered metabolic regulatory hormones and affect various diseases, such as liver failure, obesity, and dementia. Thyroid dysregulation affects various cellular mechanisms and is linked to multiple disease pathologies. In particular, hypothyroidism is considered a critical cause for various neurological problems-such as metabolic disease, depressive symptoms, and dementia-in the central nervous system. Recent studies have demonstrated the relationship between hypothyroidism and brain insulin resistance and dyslipidemia, leading to diabetes-related dementia. Therefore, we reviewed the relationship between hypothyroidism and diabetes-related dementia, with a focus on major features of diabetes-related dementia such as insulin resistance, neuronal dysfunction, and dyslipidemia.
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Affiliation(s)
- Hee Kyung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chonnam National University Medical School, 264 Seoyangro, Hwasun 58128, Korea;
| | - Juhyun Song
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, 264 Seoyangro, Hwasun 58128, Korea
- Correspondence: ; Tel.: +82-61-379-2706; Fax: +82-61-375-5834
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22
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Ahmad R, Chowdhury K, Kumar S, Irfan M, Reddy GS, Akter F, Jahan D, Haque M. Diabetes Mellitus: A Path to Amnesia, Personality, and Behavior Change. BIOLOGY 2022; 11:biology11030382. [PMID: 35336756 PMCID: PMC8945557 DOI: 10.3390/biology11030382] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/20/2022] [Accepted: 02/21/2022] [Indexed: 11/16/2022]
Abstract
Simple Summary Diabetes Mellitus (DM) is a metabolic disorder resulting from a disturbance of insulin secretion, action, or both. Hyperglycemia and overproduction of superoxide induce the development and progression of chronic complications of DM. The impact of DM and its complication on the central nervous system (CNS) such as dementia and Alzheimer’s Disease (AD) still remain obscure. In dementia, there is a gradual decline in cognitive function. The incidence of dementia increases with age, and patient become socially, physically, and mentally more vulnerable and dependent. The symptoms often emerge decades after the onset of pathophysiology, thus impairing early therapeutic intervention. Most diabetic subjects who develop dementia are above the age of 65, but diabetes may also cause an increased risk of developing dementia before 65 years. Vascular dementia is the second most common form of dementia after AD. Type 2 DM (T2DM) increases the incidence of vascular dementia (since its covers the vascular system) and AD. The functional and structural integrity of the CNS is altered in T2DM due to increased synthesis of Aβ. Additionally, hyperphosphorylation of Tau protein also results from dysregulation of various signaling cascades in T2DM, thereby causing neuronal damage and AD. There is the prospect for development of a therapy that may help prevent or halt the progress of dementia resulting from T2DM. Abstract Type 2 diabetes mellitus is increasingly being associated with cognition dysfunction. Dementia, including vascular dementia and Alzheimer’s Disease, is being recognized as comorbidities of this metabolic disorder. The progressive hallmarks of this cognitive dysfunction include mild impairment of cognition and cognitive decline. Dementia and mild impairment of cognition appear primarily in older patients. Studies on risk factors, neuropathology, and brain imaging have provided important suggestions for mechanisms that lie behind the development of dementia. It is a significant challenge to understand the disease processes related to diabetes that affect the brain and lead to dementia development. The connection between diabetes mellitus and dysfunction of cognition has been observed in many human and animal studies that have noted that mechanisms related to diabetes mellitus are possibly responsible for aggravating cognitive dysfunction. This article attempts to narrate the possible association between Type 2 diabetes and dementia, reviewing studies that have noted this association in vascular dementia and Alzheimer’s Disease and helping to explain the potential mechanisms behind the disease process. A Google search for “Diabetes Mellitus and Dementia” was carried out. Search was also done for “Diabetes Mellitus”, “Vascular Dementia”, and “Alzheimer’s Disease”. The literature search was done using Google Scholar, Pubmed, Embase, ScienceDirect, and MEDLINE. Keeping in mind the increasing rate of Diabetes Mellitus, it is important to establish the Type 2 diabetes’ effect on the brain and diseases of neurodegeneration. This narrative review aims to build awareness regarding the different types of dementia and their relationship with diabetes.
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Affiliation(s)
- Rahnuma Ahmad
- Department of Physiology, Medical College for Women and Hospital, Dhaka 1230, Bangladesh;
| | - Kona Chowdhury
- Department of Pediatrics, Gonoshasthaya Samaj Vittik Medical College and Hospital, Dhaka 1344, Bangladesh;
| | - Santosh Kumar
- Department of Periodontology and Implantology, Karnavati School of Dentistry, Karnavati University, 907/A, Uvarsad Gandhinagar, Gujarat 382422, India;
| | - Mohammed Irfan
- Department of Forensics, Federal University of Pelotas, Pelotas 96020-010, RS, Brazil;
| | - Govindool Sharaschandra Reddy
- Department of Periodontics and Endodontics, School of Dental Medicine, University at Buffalo, Buffalo, NY 14214, USA;
| | - Farhana Akter
- Department of Endocrinology, Chittagong Medical College, Chattogram 4203, Bangladesh;
| | - Dilshad Jahan
- Department of Hematology, Asgar Ali Hospital, 111/1/A Distillery Road, Gandaria Beside Dhupkhola, Dhaka 1204, Bangladesh;
| | - Mainul Haque
- Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kem Perdana Sungai Besi, Kuala Lumpur 57000, Malaysia
- Correspondence: or
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23
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Li T, Cao HX, Ke D. Type 2 Diabetes Mellitus Easily Develops into Alzheimer's Disease via Hyperglycemia and Insulin Resistance. Curr Med Sci 2021; 41:1165-1171. [PMID: 34874485 DOI: 10.1007/s11596-021-2467-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 10/18/2021] [Indexed: 12/14/2022]
Abstract
With the acceleration of population aging, the incidence of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) is progressively increasing due to the age-relatedness of these two diseases. The association between T2DM and AD-like dementia is receiving much attention, and T2DM is reported to be a significant risk factor for AD. The aims of this review were to reveal the brain changes caused by T2DM as well as to explore the roles of hyperglycemia and insulin resistance in the development of AD.
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Affiliation(s)
- Ting Li
- Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Hong-Xia Cao
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Dan Ke
- Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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24
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Trout AL, McLouth CJ, Kitzman P, Dobbs MR, Bellamy L, Elkins K, Fraser JF. Hemorrhagic stroke outcomes of KApSR patients with co-morbid diabetes and Alzheimer's disease. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1371. [PMID: 34733923 PMCID: PMC8506530 DOI: 10.21037/atm-21-1451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 06/07/2021] [Indexed: 11/06/2022]
Abstract
Background Vascular risk factors, such as diabetes mellitus (DM), are associated with poorer outcomes following many neurodegenerative diseases, including hemorrhagic stroke and Alzheimer's disease (AD). Combined AD and DM co-morbidities are associated with an increased risk of hemorrhagic stroke and increased Medicare costs. Therefore, we hypothesized that patients with DM in combination with AD, termed DM/AD, would have increased hemorrhagic stroke severity. Methods Kentucky Appalachian Stroke Registry (KApSR) is a database of demographic and clinical data from patients that live in Appalachia, a distinct region with increased health disparities and stroke severity. Inpatients with a primary indication of hemorrhagic stroke were selected from KApSR for retrospective analysis and were separated into four groups: DM only, AD only, neither, or both. Results Hemorrhagic stroke patients (2,071 total) presented with either intracerebral hemorrhage (ICH), n=1,448, or subarachnoid hemorrhage (SAH), n=623. When examining all four groups, subjects with AD were significantly older (AD+, 80.9±6.6 yrs) (DM+/AD+, 77.4±10.0 yrs) than non AD subjects (DM-/AD-, 61.3±16.5 yrs) and (DM+, 66.0±12.5 yrs). A higher percentage of females were among the AD+ group and a higher percentage of males among the DM+/AD+ group. Interestingly, after adjusting for multiple comparison, DM+/AD+ subjects were ten times as likely to suffer a moderate to severe stroke based on a National Institute of Health Stroke (NIHSS) upon admission [odds ratio (95% CI)] compared to DM-/AD- [0.1 (0.02-0.55)], DM+ [0.11 (0.02-0.59)], and AD+ [0.09(0.01-0.63)]. The odds of DM+/AD+ subjects having an unfavorable discharge destination (death, hospice, long-term care) was significant (P<0.05) from DM-/AD- [0.26 (0.07-0.96)] when adjusting for sex, age, and comorbidities. Conclusions In our retrospective analysis utilizing KApSR, regardless of adjusting for age, sex, and comorbidities, DM+/AD+ patients were significantly more likely to have had a moderate or severe stroke leading to an unfavorable outcome following hemorrhagic stroke.
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Affiliation(s)
- Amanda L Trout
- Center for Advanced Translational Stroke Science, University of Kentucky, Lexington, KY, USA.,Department of Neurology, University of Kentucky, Lexington, KY, USA
| | | | - Patrick Kitzman
- Department of Behavioral Science, University of Kentucky, Lexington, KY, USA.,HealthCare Stroke Network, Norton Healthcare/UK, Lexington, KY, USA
| | - Michael R Dobbs
- Department of Neurology, University of Texas Rio Grande Valley, Edinburg, TX, USA
| | - Lisa Bellamy
- HealthCare Stroke Network, Norton Healthcare/UK, Lexington, KY, USA
| | - Kelley Elkins
- HealthCare Stroke Network, Norton Healthcare/UK, Lexington, KY, USA
| | - Justin F Fraser
- Center for Advanced Translational Stroke Science, University of Kentucky, Lexington, KY, USA.,Department of Neurology, University of Kentucky, Lexington, KY, USA.,Department of Neuroscience, University of Kentucky, Lexington, KY, USA.,Department of Neurosurgery, University of Kentucky, Lexington, KY, USA.,Department of Radiology, University of Kentucky, Lexington, KY, USA
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25
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Yassine HN, Solomon V, Thakral A, Sheikh-Bahaei N, Chui HC, Braskie MN, Schneider LS, Talbot K. Brain energy failure in dementia syndromes: Opportunities and challenges for glucagon-like peptide-1 receptor agonists. Alzheimers Dement 2021; 18:478-497. [PMID: 34647685 PMCID: PMC8940606 DOI: 10.1002/alz.12474] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 06/11/2021] [Accepted: 08/11/2021] [Indexed: 12/12/2022]
Abstract
Medications for type 2 diabetes (T2DM) offer a promising path for discovery and development of effective interventions for dementia syndromes. A common feature of dementia syndromes is an energy failure due to reduced energy supply to neurons and is associated with synaptic loss and results in cognitive decline and behavioral changes. Among diabetes medications, glucagon‐like peptide‐1 (GLP‐1) receptor agonists (RAs) promote protective effects on vascular, microglial, and neuronal functions. In this review, we present evidence from animal models, imaging studies, and clinical trials that support developing GLP‐1 RAs for dementia syndromes. The review examines how changes in brain energy metabolism differ in conditions of insulin resistance and T2DM from dementia and underscores the challenges that arise from the heterogeneity of dementia syndromes. The development of GLP‐1 RAs as dementia therapies requires a deeper understanding of the regional changes in brain energy homeostasis guided by novel imaging biomarkers.
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Affiliation(s)
- Hussein N Yassine
- Department of Medicine, University of Southern California, Keck School of Medicine USC, Los Angeles, California, USA.,Department of Neurology, University of Southern California, Keck School of Medicine USC, Los Angeles, California, USA
| | - Victoria Solomon
- Department of Medicine, University of Southern California, Keck School of Medicine USC, Los Angeles, California, USA
| | - Angad Thakral
- Department of Medicine, University of Southern California, Keck School of Medicine USC, Los Angeles, California, USA
| | - Nasim Sheikh-Bahaei
- Department of Radiology, Keck School of Medicine USC, Los Angeles, California, USA
| | - Helena C Chui
- Department of Neurology, University of Southern California, Keck School of Medicine USC, Los Angeles, California, USA
| | - Meredith N Braskie
- Imaging Genetics Center, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, USC, Los Angeles, California, USA
| | - Lon S Schneider
- Department of Neurology, University of Southern California, Keck School of Medicine USC, Los Angeles, California, USA.,Department of Psychiatry and Behavioral Sciences, Keck School of Medicine USC, Los Angeles, California, USA
| | - Konrad Talbot
- Departments of Neurosurgery, Pathology and Human Anatomy, and Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA
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26
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Yu H, Liu Y, He T, Zhang Y, He J, Li M, Jiang B, Gao Y, Chen C, Ke D, Liu J, He B, Yang X, Wang J. Platelet biomarkers identifying mild cognitive impairment in type 2 diabetes patients. Aging Cell 2021; 20:e13469. [PMID: 34528736 PMCID: PMC8520722 DOI: 10.1111/acel.13469] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/09/2021] [Accepted: 07/21/2021] [Indexed: 12/21/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is an independent risk factor of Alzheimer's disease (AD). Therefore, identifying periphery biomarkers correlated with mild cognitive impairment (MCI) is of importance for early diagnosis of AD. Here, we performed platelet proteomics in T2DM patients with MCI (T2DM‐MCI) and without MCI (T2DM‐nMCI). Pearson analysis of the omics data with MMSE (mini‐mental state examination), Aβ1‐42/Aβ1‐40 (β‐amyloid), and rGSK‐3β(T/S9) (total to Serine‐9‐phosphorylated glycogen synthase kinase‐3β) revealed that mitophagy/autophagy‐, insulin signaling‐, and glycolysis/gluconeogenesis pathways‐related proteins were most significantly involved. Among them, only the increase of optineurin, an autophagy‐related protein, was simultaneously correlated with the reduced MMSE score, and the increased Aβ1‐42/Aβ1‐40 and rGSK‐3β(T/S9), and the optineurin alone could discriminate T2DM‐MCI from T2DM‐nMCI. Combination of the elevated platelet optineurin and rGSK‐3β(T/S9) enhanced the MCI‐discriminating efficiency with AUC of 0.927, specificity of 86.7%, sensitivity of 85.3%, and accuracy of 0.859, which is promising for predicting cognitive decline in T2DM patients.
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Affiliation(s)
- Haitao Yu
- Department of Pathophysiology Key Laboratory of Ministry of Education for Neurological Disorders School of Basic Medicine Tongji Medical College Huazhong University of Science and Technology Wuhan China
- Key Laboratory of Modern Toxicology of Shenzhen Shenzhen Center for Disease Control and Prevention Shenzhen China
| | - Yanchao Liu
- Department of Pathophysiology Key Laboratory of Ministry of Education for Neurological Disorders School of Basic Medicine Tongji Medical College Huazhong University of Science and Technology Wuhan China
- Department of Neurosurgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Ting He
- Department of Pathophysiology Key Laboratory of Ministry of Education for Neurological Disorders School of Basic Medicine Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Yao Zhang
- Key Laboratory of Ministry of Education for Neurological Disorders Li Yuan Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Jiahua He
- School of Physics Huazhong University of Science and Technology Wuhan Hubei China
| | - Mengzhu Li
- Department of Neurosurgery Wuhan Central Hospital Affiliated to Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Bijun Jiang
- Department of Physiology School of Basic Medicine Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei China
| | - Yang Gao
- Department of Pathophysiology Key Laboratory of Ministry of Education for Neurological Disorders School of Basic Medicine Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Chongyang Chen
- Department of Pathophysiology Key Laboratory of Ministry of Education for Neurological Disorders School of Basic Medicine Tongji Medical College Huazhong University of Science and Technology Wuhan China
- Key Laboratory of Modern Toxicology of Shenzhen Shenzhen Center for Disease Control and Prevention Shenzhen China
| | - Dan Ke
- Department of Pathophysiology Key Laboratory of Ministry of Education for Neurological Disorders School of Basic Medicine Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Jianjun Liu
- Key Laboratory of Modern Toxicology of Shenzhen Shenzhen Center for Disease Control and Prevention Shenzhen China
| | - Benrong He
- Department of Pathophysiology Key Laboratory of Ministry of Education for Neurological Disorders School of Basic Medicine Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Xifei Yang
- Key Laboratory of Modern Toxicology of Shenzhen Shenzhen Center for Disease Control and Prevention Shenzhen China
| | - Jian‐Zhi Wang
- Department of Pathophysiology Key Laboratory of Ministry of Education for Neurological Disorders School of Basic Medicine Tongji Medical College Huazhong University of Science and Technology Wuhan China
- Co‐innovation Center of Neuroregeneration Nantong University Nantong China
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27
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Yuan CL, Yi R, Dong Q, Yao LF, Liu B. The relationship between diabetes-related cognitive dysfunction and leukoaraiosis. Acta Neurol Belg 2021; 121:1101-1110. [PMID: 33893981 DOI: 10.1007/s13760-021-01676-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 04/10/2021] [Indexed: 12/17/2022]
Abstract
Cognitive dysfunction is a degenerative disease of the central nervous system, which often associates with ageing brain as well as neurodegenerative diseases. A growing body of evidence suggests that patients with diabetes mellitus (DM) have a significantly higher risk of cognitive impairment. In recent years, studies have found that patients with diabetes-related cognitive dysfunction have an increased burden of leukoaraiosis (LA), and larger white matter hyperintensity (WMH) volume. With the recent advancement of technologies, multimodal imaging is widely exploited for the precise evaluation of central nervous system diseases. Emerging studies suggest that LA pathology can be used as a predictive signal of white matter lesions in patients with diabetes-related cognitive dysfunction, providing support for early identification and diagnosis of disease. This article reviews the findings, epidemiological characteristics, pathogenesis, imaging features, prevention and treatment of LA pathophysiology in patients with diabetes-related cognitive dysfunction.
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Affiliation(s)
- Chun-Lan Yuan
- Department of Neurology, The First Affiliated Hospital Of Harbin Medical University, No. 23 Youzheng Street, Harbin, 150001, People's Republic of China
| | - Ran Yi
- Department of Endocrine, The First Affiliated Hospital Of Harbin Medical University, No. 23 Youzheng Street, Harbin, 150001, People's Republic of China
| | - Qi Dong
- Department of Neurology, The First Affiliated Hospital Of Harbin Medical University, No. 23 Youzheng Street, Harbin, 150001, People's Republic of China.
| | - Li-Fen Yao
- Department of Neurology, The First Affiliated Hospital Of Harbin Medical University, No. 23 Youzheng Street, Harbin, 150001, People's Republic of China
| | - Bin Liu
- Department of Neurosurgery, The Fourth Affiliated Hospital Of Harbin Medical University, No. 37 Yiyuan Street, Harbin, 150001, People's Republic of China.
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28
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Chen Y, Zhou Z, Liang Y, Tan X, Li Y, Qin C, Feng Y, Ma X, Mo Z, Xia J, Zhang H, Qiu S, Shen D. Classification of type 2 diabetes mellitus with or without cognitive impairment from healthy controls using high-order functional connectivity. Hum Brain Mapp 2021; 42:4671-4684. [PMID: 34213081 PMCID: PMC8410559 DOI: 10.1002/hbm.25575] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/03/2021] [Accepted: 06/08/2021] [Indexed: 12/12/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is associated with cognitive impairment and may progress to dementia. However, the brain functional mechanism of T2DM-related dementia is still less understood. Recent resting-state functional magnetic resonance imaging functional connectivity (FC) studies have proved its potential value in the study of T2DM with cognitive impairment (T2DM-CI). However, they mainly used a mass-univariate statistical analysis that was not suitable to reveal the altered FC "pattern" in T2DM-CI, due to lower sensitivity. In this study, we proposed to use high-order FC to reveal the abnormal connectomics pattern in T2DM-CI with a multivariate, machine learning-based strategy. We also investigated whether such patterns were different between T2DM-CI and T2DM without cognitive impairment (T2DM-noCI) to better understand T2DM-induced cognitive impairment, on 23 T2DM-CI and 27 T2DM-noCI patients, as well as 50 healthy controls (HCs). We first built the large-scale high-order brain networks based on temporal synchronization of the dynamic FC time series among multiple brain region pairs and then used this information to classify the T2DM-CI (as well as T2DM-noCI) from the matched HC based on support vector machine. Our model achieved an accuracy of 79.17% in T2DM-CI versus HC differentiation, but only 59.62% in T2DM-noCI versus HC classification. We found abnormal high-order FC patterns in T2DM-CI compared to HC, which was different from that in T2DM-noCI. Our study indicates that there could be widespread connectivity alterations underlying the T2DM-induced cognitive impairment. The results help to better understand the changes in the central neural system due to T2DM.
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Affiliation(s)
- Yuna Chen
- The First School of Clinical MedicineGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Department of Radiology and BRICUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Zhen Zhou
- Department of Radiology and BRICUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Yi Liang
- Department of RadiologyThe First Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
| | - Xin Tan
- Department of RadiologyThe First Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
| | - Yifan Li
- The First School of Clinical MedicineGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
| | - Chunhong Qin
- Department of RadiologyThe First Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
| | - Yue Feng
- The First School of Clinical MedicineGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
| | - Xiaomeng Ma
- The First School of Clinical MedicineGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
| | - Zhanhao Mo
- Department of Radiology and BRICUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Department of RadiologyChina‐Japan Union Hospital of Jilin UniversityChangchunJilinChina
| | - Jing Xia
- Institute of Brain‐Intelligence Technology, Zhangjiang LabShanghaiChina
| | - Han Zhang
- Institute of Brain‐Intelligence Technology, Zhangjiang LabShanghaiChina
| | - Shijun Qiu
- Department of RadiologyThe First Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
| | - Dinggang Shen
- School of Biomedical EngineeringShanghaiTech UniversityShanghaiChina
- Shanghai United Imaging Intelligence Co., Ltd.ShanghaiChina
- Department of Artificial IntelligenceKorea UniversitySeoulRepublic of Korea
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Wang H, Lu J, Zhao X, Qin R, Song K, Xu Y, Zhang J, Chen Y. Alzheimer's disease in elderly COVID-19 patients: potential mechanisms and preventive measures. Neurol Sci 2021; 42:4913-4920. [PMID: 34550494 PMCID: PMC8455804 DOI: 10.1007/s10072-021-05616-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 09/17/2021] [Indexed: 12/13/2022]
Abstract
Advanced age correlates with higher morbidity and mortality among patients affected with the novel coronavirus disease 2019 (COVID-19). Because systemic inflammation and neurological symptoms are also common in severe COVID-19 cases, there is concern that COVID-19 may lead to neurodegenerative conditions such as Alzheimer’s disease (AD). In this review, we summarize possible mechanisms by which infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, may cause AD in elderly COVID-19 patients and describe preventive measures to mitigate risk. Potential mechanisms include NLRP3 inflammasome activation and IL-1β release, renin-angiotensin system hyperactivation, innate immune activation, oxidative stress, direct viral infection, and direct cytolytic β-cell damage. Anti-inflammatory therapies, including TNF-α inhibitors and nonsteroidal anti-inflammatory drugs, antioxidants such as the vitamin E family, nutritional intervention, physical activity, blood glucose control, and vaccination are proposed as preventive measures to minimize AD risk in COVID-19 patients. Since several risk factors for AD may converge during severe SARS-CoV-2 infection, neurologists should be alert for potential symptoms of AD and actively implement preventive measures in patients presenting with neuropsychiatric symptoms and in high-risk patients such as the elderly.
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Affiliation(s)
- Haili Wang
- Department of Clinical Medicine, Dalian Medical University, Dalian, 116000, Liaoning, China.,Department of Neurology, Clinical Medical College, Yangzhou University, Yangzhou, 225000, Jiangsu, China
| | - Juan Lu
- Department of Neuro Intensive Care Unit, Subei People's Hospital of Jiangsu Province, Yangzhou, 225000, Jiangsu, China
| | - Xia Zhao
- Department of Emergency Medicine, Subei People's Hospital of Jiangsu Province, Yangzhou, 225000, Jiangsu, China
| | - Rongyin Qin
- Department of Neurology, Shanghai General Hospital (Jiading District), Jiading, Shanghai, 201812, China
| | - Kangping Song
- Department of Neurology, Institute of Clinical Neuroscience, The First Affiliated Hospital, Jinan University, Guangzhou, 510632, Guangdong, China
| | - Yao Xu
- Department of Neurology, Clinical Medical College, Yangzhou University, Yangzhou, 225000, Jiangsu, China
| | - Jun Zhang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Jingan, Shanghai, 200040, China.
| | - Yingzhu Chen
- Department of Neurology, Clinical Medical College, Yangzhou University, Yangzhou, 225000, Jiangsu, China.
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Catorce MN, Gevorkian G. Evaluation of Anti-inflammatory Nutraceuticals in LPS-induced Mouse Neuroinflammation Model: An Update. Curr Neuropharmacol 2021; 18:636-654. [PMID: 31934839 PMCID: PMC7457421 DOI: 10.2174/1570159x18666200114125628] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/26/2019] [Accepted: 01/11/2020] [Indexed: 02/08/2023] Open
Abstract
It is known that peripheral infections, accompanied by inflammation, represent significant risk factors for the development of neurological disorders by modifying brain development or affecting normal brain aging. The acute effects of systemic inflammation on progressive and persistent brain damage and cognitive impairment are well documented. Anti-inflammatory therapies may have beneficial effects on the brain, and the protective properties of a wide range of synthetic and natural compounds have been extensively explored in recent years. In our previous review, we provided an extensive analysis of one of the most important and widely-used animal models of peripherally induced neuroinflammation and neurodegeneration - lipopolysaccharide (LPS)-treated mice. We addressed the data reproducibility in published research and summarized basic features and data on the therapeutic potential of various natural products, nutraceuticals, with known anti-inflammatory effects, for reducing neuroinflammation in this model. Here, recent data on the suitability of the LPS-induced murine neuroinflammation model for preclinical assessment of a large number of nutraceuticals belonging to different groups of natural products such as flavonoids, terpenes, non-flavonoid polyphenols, glycosides, heterocyclic compounds, organic acids, organosulfur compounds and xanthophylls, are summarized. Also, the proposed mechanisms of action of these molecules are discussed.
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Affiliation(s)
- Miryam Nava Catorce
- Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico (UNAM), Mexico DF, Mexico
| | - Goar Gevorkian
- Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico (UNAM), Mexico DF, Mexico
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He JT, Zhao X, Xu L, Mao CY. Vascular Risk Factors and Alzheimer's Disease: Blood-Brain Barrier Disruption, Metabolic Syndromes, and Molecular Links. J Alzheimers Dis 2021; 73:39-58. [PMID: 31815697 DOI: 10.3233/jad-190764] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder, marked by cortical and hippocampal deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles and cognitive impairment. Studies indicate a prominent link between cerebrovascular abnormalities and the onset and progression of AD, where blood-brain barrier (BBB) dysfunction and metabolic disorders play key risk factors. Pericyte degeneration, endothelial cell damage, astrocyte depolarization, diminished tight junction integrity, and basement membrane disarray trigger BBB damage. Subsequently, the altered expression of low-density lipoprotein receptor-related protein 1 and receptor for advanced glycation end products at the microvascular endothelial cells dysregulate Aβ transport across the BBB. White matter lesions and microhemorrhages, dyslipidemia, altered brain insulin signaling, and insulin resistance contribute to tau and Aβ pathogenesis, and oxidative stress, mitochondrial damage, inflammation, and hypoperfusion serve as mechanistic links between pathophysiological features of AD and ischemia. Deregulated calcium homeostasis, voltage gated calcium channel functioning, and protein kinase C signaling are also common mechanisms for both AD pathogenesis and cerebrovascular abnormalities. Additionally, APOE polymorphic alleles that characterize impaired cerebrovascular integrity function as primary genetic determinants of AD. Overall, the current review enlightens key vascular risk factors for AD and underscores pathophysiologic relationship between AD and vascular dysfunction.
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Affiliation(s)
- Jin-Ting He
- Department of Neurology, China-Japan Union Hospital, Jilin University, Changchun, Jilin Province, China
| | - Xin Zhao
- Department of Paediatrics, The First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Lei Xu
- Department of Neurology, China-Japan Union Hospital, Jilin University, Changchun, Jilin Province, China
| | - Cui-Ying Mao
- Department of Cardiology, China-Japan Union Hospital, Jilin University, Changchun, Jilin Province, China
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Leclerc M, Dudonné S, Calon F. Can Natural Products Exert Neuroprotection without Crossing the Blood-Brain Barrier? Int J Mol Sci 2021; 22:ijms22073356. [PMID: 33805947 PMCID: PMC8037419 DOI: 10.3390/ijms22073356] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/19/2021] [Accepted: 03/20/2021] [Indexed: 12/17/2022] Open
Abstract
The scope of evidence on the neuroprotective impact of natural products has been greatly extended in recent years. However, a key question that remains to be answered is whether natural products act directly on targets located in the central nervous system (CNS), or whether they act indirectly through other mechanisms in the periphery. While molecules utilized for brain diseases are typically bestowed with a capacity to cross the blood–brain barrier, it has been recently uncovered that peripheral metabolism impacts brain functions, including cognition. The gut–microbiota–brain axis is receiving increasing attention as another indirect pathway for orally administered compounds to act on the CNS. In this review, we will briefly explore these possibilities focusing on two classes of natural products: omega-3 polyunsaturated fatty acids (n-3 PUFAs) from marine sources and polyphenols from plants. The former will be used as an example of a natural product with relatively high brain bioavailability but with tightly regulated transport and metabolism, and the latter as an example of natural compounds with low brain bioavailability, yet with a growing amount of preclinical and clinical evidence of efficacy. In conclusion, it is proposed that bioavailability data should be sought early in the development of natural products to help identifying relevant mechanisms and potential impact on prevalent CNS disorders, such as Alzheimer’s disease.
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Affiliation(s)
- Manon Leclerc
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada;
- Axe Neurosciences, Centre de Recherche du CHU de Québec–Université Laval, Québec, QC G1V 4G2, Canada
- Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Québec, QC G1V 0A6, Canada;
- OptiNutriBrain-Laboratoire International Associé (NutriNeuro France-INAF Canada), Québec, QC G1V 0A6, Canada
| | - Stéphanie Dudonné
- Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Québec, QC G1V 0A6, Canada;
- OptiNutriBrain-Laboratoire International Associé (NutriNeuro France-INAF Canada), Québec, QC G1V 0A6, Canada
| | - Frédéric Calon
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada;
- Axe Neurosciences, Centre de Recherche du CHU de Québec–Université Laval, Québec, QC G1V 4G2, Canada
- Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Québec, QC G1V 0A6, Canada;
- OptiNutriBrain-Laboratoire International Associé (NutriNeuro France-INAF Canada), Québec, QC G1V 0A6, Canada
- Correspondence: ; Tel.: +1-(418)-525-4444 (ext. 48697); Fax: +1-(418)-654-2761
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Tang X, Cardoso MA, Yang J, Zhou JB, Simó R. Impact of Intensive Glucose Control on Brain Health: Meta-Analysis of Cumulative Data from 16,584 Patients with Type 2 Diabetes Mellitus. Diabetes Ther 2021; 12:765-779. [PMID: 33548021 PMCID: PMC7947088 DOI: 10.1007/s13300-021-01009-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Accepted: 01/23/2021] [Indexed: 01/11/2023] Open
Abstract
INTRODUCTION Despite growing evidence that type 2 diabetes is associated with dementia, the question of whether intensive glucose control can prevent or arrest cognitive decline remains unanswered. In the analysis reported here, we explored the effect of intensive glucose control versus standard care on brain health, including structural abnormalities of the brain (atrophy, white matter hyperintensities, lacunar infarction, and cerebral microbleeds), cognitive dysfunction, and risk of dementia. METHODS We searched the PubMed and Embase databases, the Web of Science website, and the Clinicaltrial.gov registry for studies published in English prior to July 2020. Only studies with a randomized controlled trial (RCT) design were considered. We analyzed structural abnormalities of the brain (atrophy, white matter hyperintensities, lacunar infarction, and cerebral microbleeds), cognitive function (cognitive impairment, executive function, memory, attention, and information-processing speed), and dementia (Alzheimer's disease, vascular dementia, and mixed dementia). RESULTS Six studies (5 different RCTs) with 16,584 participants were included in this meta-analysis. One study that compared structural changes between groups receiving intensive versus conventional glucose control measures reported non-significant results. The results of the five studies, comprising four cohorts, indicated a significantly poorer decline in cognitive function in the intensive glucose control group (β - 0.03, 95% confidence interval [CI] - 0.05 to - 0.02) than in the conventional glucose control group. Further subgroup analysis showed a significant difference in the change in cognitive performance in composite cognitive function (β - 0.03, 95% CI - 0.05 to - 0.01) and memory (β - 0.13, 95% CI - 0.25 to - 0.02). One trial evaluated the prevalence of cognitive impairment and dementia between groups receiving intensive and conventional glucose control, respectively, and the differences were insignificant. CONCLUSION This meta-analysis suggests that intensive glucose control in patients with type 2 diabetes can slow down cognitive decline, especially the decline in composite cognition and memory function. However, further studies are necessary to confirm the impact of strict glucose control on structural abnormalities in the brain and the risk of dementia.
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Affiliation(s)
- Xingyao Tang
- Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Marly A Cardoso
- Department of Nutrition, School of Public Health, University of Sao Paulo, Sao Paulo, Brazil
| | - Jinkui Yang
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Jian-Bo Zhou
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
| | - Rafael Simó
- Endocrinology and Nutrition Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Passeig de la Vall d'Hebron, Barcelona, Spain
- Diabetes and Metabolism Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Passeig de la Vall d'Hebron, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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Baruah P, Das A, Paul D, Chakrabarty S, Aguan K, Mitra S. Sulfonylurea Class of Antidiabetic Drugs Inhibit Acetylcholinesterase Activity: Unexplored Auxiliary Pharmacological Benefit toward Alzheimer's Disease. ACS Pharmacol Transl Sci 2021; 4:193-205. [PMID: 33615172 PMCID: PMC7887854 DOI: 10.1021/acsptsci.0c00168] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Indexed: 12/21/2022]
Abstract
Contemporary literature documents extensive research on common causative mechanisms, pathogenic pathways and dual effective remedies for Alzheimer's disease (AD) and Type 2 diabetes mellitus (T2DM). Tolbutamide (TBM), chlorpropamide (CPM), and glyburide (GLY) are three sulfonylurea antidiabetic drugs of different generations. All these drugs were found to exhibit moderate to strong inhibitory efficiency on the neurotransmitter degrading enzyme acetylcholinesterase (AChE) with GLY (IC50 = 0.74 ± 0.02 μM) being the most potent, followed by CPM (IC50 = 5.72 ± 0.24 μM) and TBM (IC50 = 28.9 ± 1.60 μM). Notably, the inhibition efficiency of GLY is even comparable with the FDA approved AD drug, donepezil (DON). The larger size of GLY spans almost the full gorge of AChE ranging from catalytic active site (CAS) to the peripheral active site (PAS) with relatively strong binding affinity (6.0 × 105 M-1) and acts as a competitive inhibitor for AChE. On the other hand, while they show relatively weak binding ((2-6) × 104 M-1), both CPM and TBM act as noncompetitive binders. While these two drugs can bind to PAS, MD simulation results predict an alternative noncompetitive inhibition mechanism for CPM. These results open the possibility of repurposing the antidiabetic drugs, particularly GLY, in the treatment of AD. The consequential side effect of excess acetylcholine production, due to the administration of these drugs to AD-unaffected patients, can be rectified by using colloidal gold and silver nanofluids as potential AChE activity boosters.
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Affiliation(s)
- Prayasee Baruah
- Centre
for Advanced Studies in Chemistry and Department of Biotechnology &
Bioinformatics, North-Eastern Hill University, Shillong 793022, India
| | - Abhinandan Das
- Department
of Chemical, Biological & Macromolecular Sciences, S. N. Bose National Centre for Basic Sciences, Salt Lake City, Kolkata 700106, India
| | - Debojit Paul
- Department
of Chemistry, Indian Institute of Technology
Guwahati, Guwahati 781039, India
| | - Suman Chakrabarty
- Department
of Chemical, Biological & Macromolecular Sciences, S. N. Bose National Centre for Basic Sciences, Salt Lake City, Kolkata 700106, India
| | - Kripamoy Aguan
- Centre
for Advanced Studies in Chemistry and Department of Biotechnology &
Bioinformatics, North-Eastern Hill University, Shillong 793022, India
| | - Sivaprasad Mitra
- Centre
for Advanced Studies in Chemistry and Department of Biotechnology &
Bioinformatics, North-Eastern Hill University, Shillong 793022, India
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Perticone M, Di Lorenzo C, Arabia G, Arturi F, Caroleo B, Tassone B, Pujia R, Fiorentino TV, Chiriaco C, Sesti G, Quattrone A, Perticone F. One Hour-Post-load Plasma Glucose ≥155 mg/dl in Healthy Glucose Normotolerant Subjects Is Associated With Subcortical Brain MRI Alterations and Impaired Cognition: A Pilot Study. Front Aging Neurosci 2021; 13:608736. [PMID: 33613266 PMCID: PMC7891177 DOI: 10.3389/fnagi.2021.608736] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 01/07/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Glucose alterations are associated with impaired cognition. The 1-h-post-load plasma glucose ≥155 mg/dl in non-diabetic subjects confers an increased risk of cardiovascular events and diabetes. This pilot study aimed to investigate whether the 1-h-post-load plasma glucose ≥155 mg/dl negatively affects the subcortical regions of the brain and the cognitive functions. Methods: We enrolled 32 non-diabetic subjects. Patients were divided into two groups based on 1-h- post-load plasma glucose value > or < 155 mg/dl: normal glucose tolerance (NGT) 1-h-high and NGT 1-h-low subjects. All subjects underwent 3 Tesla MRI and standard neuropsychological tests. Results: NGT 1-h-high subjects showed significantly lower values of both right (4.9 ± 0.9 vs. 5.1 ± 0.9 ml) and left (4.8 ± 1.1 vs. 5.1 ± 1.1 ml) hippocampal hemisphere volume, while right hemisphere hippocampal diffusivity was lower in the NGT 1-h-high group (10.0 ± 0.6 vs. 10.6 ± 0.5 10-4 mm2s-1). NGT 1-h-high subjects also showed a poorer memory performance. In particular, for both Rey Auditory Verbal Learning Task (RAVLT)-immediate-recall and Free and Cued Selective Reminding Test (FCSRT)-delayed total recall, we found lower cognitive test scores in the NGT-1 h-high group (26.5 ± 6.3 and 10.4 ± 0.3, respectively). Conclusions: One-hour-post-load hyperglycemia is associated with morpho-functional subcortical brain alterations and poor memory performance tests.
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Affiliation(s)
- Maria Perticone
- Geriatrics Division, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Cherubino Di Lorenzo
- Department of Medico-Surgical Sciences and Biotechnologies, La Sapienza University Polo Pontino, Latina, Italy
| | - Gennarina Arabia
- Neurology Division, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Franco Arturi
- Internal Medicine Division, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Benedetto Caroleo
- Geriatric Division, Azienda Ospedaliero-Universitaria Mater Domini, Catanzaro, Italy
| | - Bruno Tassone
- Internal Medicine Division, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Roberta Pujia
- Internal Medicine Division, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Teresa Vanessa Fiorentino
- Internal Medicine Division, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Carmelina Chiriaco
- Institute of Molecular Bioimaging and Physiology, National Research Council, Catanzaro, Italy
| | - Giorgio Sesti
- Department of Clinical and Molecular Medicine, La Sapienza University, Rome, Italy
| | - Aldo Quattrone
- Institute of Molecular Bioimaging and Physiology, National Research Council, Catanzaro, Italy
| | - Francesco Perticone
- Geriatrics Division, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
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Yulug B, Saatci O, Işıklar A, Hanoglu L, Kilic U, Ozansoy M, Cankaya S, Cankaya B, Kilic E. The Association between HbA1c Levels, Olfactory Memory and Cognition in Normal, Pre-Diabetic and Diabetic Persons. Endocr Metab Immune Disord Drug Targets 2020; 20:198-212. [PMID: 31203811 DOI: 10.2174/1871530319666190614121738] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 03/26/2019] [Accepted: 05/10/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Recent data have shown that olfactory dysfunction is strongly related to Alzheimer's Disease (AD) that is often preceded by olfactory deficits suggesting that olfactory dysfunction might represent an early indicator of future cognitive in prediabetes. METHODS We have applied to a group of normal (n=15), prediabetic (n=16) and type 2 diabetic outpatients (n=15) olfactory testing, 1.5-T MRI scanner and detailed cognitive evaluation including the standard Mini-Mental State Examination (MMSE) form, Short Blessed Test (SBT), Letter Fluency Test (LFT) and the category fluency test with animal, Fruit and Vegetable Naming (CFT). RESULTS We have shown that Odour Threshold (OT), Discrimination (OD), and Identification (OI) scores and most cognitive test results were significantly different in the prediabetes and diabetes group compared to those in the control group. OD and OT were significantly different between the prediabetes and diabetes group, although the cognitive test results were only significantly different in the prediabetes and diabetes group compared to those in the control group. In evaluating the association between OI, OT, OD scores and specific cognitive tests, we have found, that impaired olfactory identification was the only parameter that correlated significantly with the SBT both in the pre-diabetes and diabetes group. Although spot glucose values were only correlated with OT, HbA1c levels were correlated with OT, OD, and OI, as well as results of the letter fluency test suggesting that HbA1c levels rather than the spot glucose values play a critical role in specific cognitive dysfunction. CONCLUSION To the best of our knowledge, this is the first prospective study to demonstrate a strong association between olfactory dysfunction and specific memory impairment in a population with prediabetes and diabetes suggesting that impaired olfactory identification might play an important role as a specific predictor of memory decline.
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Affiliation(s)
- Burak Yulug
- Department of Neurology, Alanya AlaaddinKeykubat University, Antalya/Alanya, Turkey.,Istanbul Medipol University, Restorative and Regenerative Medicine Center, Istanbul, Turkey
| | - Ozlem Saatci
- Department of Otorhinolaryngology, Istanbul Sancaktepe, Education and Research Hospital, Istanbul, Turkey
| | - Aysun Işıklar
- Department of Internal Medicine, Istanbul Sancaktepe, Education and Research Hospital, Istanbul, Turkey
| | - Lutfu Hanoglu
- Department of Neurology, Istanbul Medipol University, Istanbul, Turkey
| | - Ulkan Kilic
- Department of Medical Biology, University of Health Sciences, Faculty of Medicine, Istanbul, Turkey
| | - Mehmet Ozansoy
- Istanbul Medipol University, Restorative and Regenerative Medicine Center, Istanbul, Turkey
| | - Seyda Cankaya
- Department of Neurology, Alanya AlaaddinKeykubat University, Antalya/Alanya, Turkey
| | - Baris Cankaya
- Department of Anesthesiology and Reanimation, Marmara University Pendik Education and Research Hospital, Istanbul, Turkey
| | - Ertugrul Kilic
- Istanbul Medipol University, Restorative and Regenerative Medicine Center, Istanbul, Turkey.,Department of Physiology, Istanbul Medipol University, International School of Medicine, Istanbul, Turkey
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Lee H, Kim E. Repositioning medication for cardiovascular and cerebrovascular disease to delay the onset and prevent progression of Alzheimer's disease. Arch Pharm Res 2020; 43:932-960. [PMID: 32909178 DOI: 10.1007/s12272-020-01268-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Accepted: 08/31/2020] [Indexed: 02/08/2023]
Abstract
Alzheimer's disease (AD) is a complex, progressive, neurodegenerative disorder. As with other common chronic diseases, multiple risk factors contribute to the onset and progression of AD. Many researchers have evaluated the epidemiologic and pathophysiological association between AD, cardiovascular diseases (CVDs), and cerebrovascular diseases (CBVDs), including commonly reported risk factors such as diabetes, hypertension, and dyslipidemia. Relevant therapies of CVDs/CBVDs for the attenuation of AD have also been empirically investigated. Considering the challenges of new drug development, in terms of cost and time, multifactorial approaches such as therapeutic repositioning of CVD/CBVD medication should be explored to delay the onset and progression of AD. Thus, in this review, we discuss our current understanding of the association between cardiovascular risk factors and AD, as revealed by clinical and non-clinical studies, as well as the therapeutic implications of CVD/CBVD medication that may attenuate AD. Furthermore, we discuss future directions by evaluating ongoing trials in the field.
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Affiliation(s)
- Heeyoung Lee
- Department of Clinical Medicinal Sciences, Konyang University, 121 Daehakro, Nonsan, 32992, Republic of Korea
| | - EunYoung Kim
- Evidence-Based Research Laboratory, Division of Clinical Pharmacotherapy, College of Pharmacy, Chung-Ang University, Seoul, 156-756, Republic of Korea.
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38
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De Sousa RAL, Harmer AR, Freitas DA, Mendonça VA, Lacerda ACR, Leite HR. An update on potential links between type 2 diabetes mellitus and Alzheimer's disease. Mol Biol Rep 2020; 47:6347-6356. [PMID: 32740795 DOI: 10.1007/s11033-020-05693-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 07/26/2020] [Indexed: 12/14/2022]
Abstract
Alzheimer's disease (AD) and type 2 diabetes (T2D) major feature is insulin resistance. Brain and peripheral insulin resistance lead to hyperglycemia, which contributes to the development of T2D-linked comorbidities, such as obesity and dyslipidemia. Individuals with hyperglycemia in AD present with neuronal loss, formation of plaques and tangles and reduced neurogenesis. Inflammation seems to play an essential role in the development of insulin resistance in AD and T2D. We conducted a literature review about the links between AD and T2D. Alterations in glucose metabolism result from changes in the expression of the insulin receptor substrates 1 and 2 (IRS-1 and IRS-2), and seem to be mediated by several inflammatory pathways being present in both pathologies. Although there are some similarities in the insulin resistance of AD and T2D, brain and peripheral insulin resistance also have their discrete features. Failure to activate IRS-1 is the hallmark of AD, while inhibition of IRS-2 is the main feature in T2D. Inflammation mediates the alterations in glucose metabolism in AD and T2D. Targeting inflammation and insulin receptors may be a successful strategy to prevent and ameliorate T2D and AD symptoms.
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Affiliation(s)
- Ricardo Augusto Leoni De Sousa
- Programa Multicêntrico de Pós-Graduação em Ciências Fisiológicas- Sociedade Brasileira de Fisiologia (SBFis), Universidade Federal dos Vales do Jequitinhonha E Mucuri (UFVJM), Campus JK, Rodovia MGT 367, Km 583, Alto da Jacuba, no 5000, Diamantina, MG, CEP 39100-000, Brazil.
| | - Alison R Harmer
- Faculty of Medicine and Health, Sydney School of Health Sciences, The University of Sydney, Sydney, Australia
| | - Daniel Almeida Freitas
- Programa Multicêntrico de Pós-Graduação em Ciências Fisiológicas- Sociedade Brasileira de Fisiologia (SBFis), Universidade Federal dos Vales do Jequitinhonha E Mucuri (UFVJM), Campus JK, Rodovia MGT 367, Km 583, Alto da Jacuba, no 5000, Diamantina, MG, CEP 39100-000, Brazil
| | - Vanessa Amaral Mendonça
- Programa Multicêntrico de Pós-Graduação em Ciências Fisiológicas- Sociedade Brasileira de Fisiologia (SBFis), Universidade Federal dos Vales do Jequitinhonha E Mucuri (UFVJM), Campus JK, Rodovia MGT 367, Km 583, Alto da Jacuba, no 5000, Diamantina, MG, CEP 39100-000, Brazil
| | - Ana Cristina Rodrigues Lacerda
- Programa Multicêntrico de Pós-Graduação em Ciências Fisiológicas- Sociedade Brasileira de Fisiologia (SBFis), Universidade Federal dos Vales do Jequitinhonha E Mucuri (UFVJM), Campus JK, Rodovia MGT 367, Km 583, Alto da Jacuba, no 5000, Diamantina, MG, CEP 39100-000, Brazil
| | - Hércules Ribeiro Leite
- Programa Multicêntrico de Pós-Graduação em Ciências Fisiológicas- Sociedade Brasileira de Fisiologia (SBFis), Universidade Federal dos Vales do Jequitinhonha E Mucuri (UFVJM), Campus JK, Rodovia MGT 367, Km 583, Alto da Jacuba, no 5000, Diamantina, MG, CEP 39100-000, Brazil
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Roy B, Ehlert L, Mullur R, Freeby MJ, Woo MA, Kumar R, Choi S. Regional Brain Gray Matter Changes in Patients with Type 2 Diabetes Mellitus. Sci Rep 2020; 10:9925. [PMID: 32555374 PMCID: PMC7303156 DOI: 10.1038/s41598-020-67022-5] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 05/29/2020] [Indexed: 02/06/2023] Open
Abstract
Patients with Type 2 diabetes mellitus (T2DM) show cognitive and mood impairment, indicating potential for brain injury in regions that control these functions. However, brain tissue integrity in cognition, anxiety, and depression regulatory sites, and their associations with these functional deficits in T2DM subjects remain unclear. We examined gray matter (GM) changes in 34 T2DM and 88 control subjects using high-resolution T1-weighted images, collected from a 3.0-Tesla magnetic resonance imaging scanner, and assessed anxiety [Beck Anxiety Inventory], depressive symptoms [Beck Depression Inventory-II], and cognition [Montreal Cognitive Assessment]. We also investigated relationships between GM status of cognitive and mood control sites and these scores in T2DM. Significantly increased anxiety (p = 0.003) and depression (p = 0.001), and reduced cognition (p = 0.002) appeared in T2DM over controls. Decreased GM volumes appeared in several regions in T2DM patients, including the prefrontal, hippocampus, amygdala, insular, cingulate, cerebellum, caudate, basal-forebrain, and thalamus areas (p < 0.01). GM volumes were significantly associated with anxiety (r = -0.456,p = 0.009), depression (r = -0.465,p = 0.01), and cognition (r = 0.455,p = 0.009) scores in regions associated with those regulations (prefrontal cortices, hippocampus, para hippocampus, amygdala, insula, cingulate, caudate, thalamus, and cerebellum) in T2DM patients. Patients with T2DM show brain damage in regions that are involved in cognition, anxiety, and depression control, and these tissue alterations are associated with functional deficits. The findings indicate that mood and cognitive deficits in T2DM patients has brain structural basis in the condition.
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Affiliation(s)
- Bhaswati Roy
- Department of Anesthesiology, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Luke Ehlert
- Department of Anesthesiology, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Rashmi Mullur
- Department of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Matthew J Freeby
- Department of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Mary A Woo
- UCLA School of Nursing, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Rajesh Kumar
- Department of Anesthesiology, University of California Los Angeles, Los Angeles, CA, 90095, USA. .,Department of Radiology, University of California Los Angeles, Los Angeles, CA, 90095, USA. .,Department of Bioengineering, University of California Los Angeles, Los Angeles, CA, 90095, USA. .,Brain Research Institute, University of California Los Angeles, Los Angeles, CA, 90095, USA.
| | - Sarah Choi
- UCLA School of Nursing, University of California Los Angeles, Los Angeles, CA, 90095, USA
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Screening of Some Sulfonamide and Sulfonylurea Derivatives as Anti-Alzheimer’s Agents Targeting BACE1 and PPARγ. J CHEM-NY 2020. [DOI: 10.1155/2020/1631243] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/08/2022] Open
Abstract
In the last few decades, Alzheimer’s disease (AD) has emerged as a serious global problem, and it has been considered as the most common type of dementia. PPARγ and beta-secretase 1 (BACE1) are considered as potential targets for Alzheimer’s disease management. In the same time, sulfonylureas and sulfonamides have been confirmed to have PPARγ agonistic activity. Aiming to obtain new anti-AD agents, thirty-five compounds of sulfonamide and sulfonylurea derivatives having the same essential pharmacophoric features of the reported PPARγ agonists have been subjected to virtual screening. Docking studies revealed that five compounds (1, 2, 3, 4, and 5) have promising affinities to PPARγ. They were also docked into the binding site of BACE1. In addition, ADMET and physicochemical properties of these compounds were considered. Additionally, these compounds were further evaluated against BACE1 and PPARγ. Compound 2 showed IC50 value of 1.64 μM against BACE1 and EC50 value of 0.289 μM against PPARγ.
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De Sousa RAL, Improta-Caria AC, Jesus-Silva FMD, Magalhães CODE, Freitas DA, Lacerda ACR, Mendonça VA, Cassilhas RC, Leite HR. High-intensity resistance training induces changes in cognitive function, but not in locomotor activity or anxious behavior in rats induced to type 2 diabetes. Physiol Behav 2020; 223:112998. [PMID: 32505787 DOI: 10.1016/j.physbeh.2020.112998] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 03/12/2020] [Accepted: 06/01/2020] [Indexed: 10/24/2022]
Abstract
Type 2 diabetes (T2D) is a metabolic disorder that can lead to cognitive decline through impairment of insulin signaling. Resistance training, a type of physical exercise, is a non-pharmacological approach used to improve insulin resistance in T2D. The aim of our study was to evaluate the effects of high-intensity resistance training (HIRT) over cognitive function, locomotor activity, and anxious behavior in rats induced to T2D. Thirty young adult male wistar rats were distributed into 3 groups (n = 10): Control; dexamethasone (D); and dexamethasone + exercise (DE), that performed the HIRT during 4 weeks. Blood glucose, water intake, and total body fat were measured. Locomotor activity, and anxious behavior where evaluated through the open field task. Cognitive function was assessed through the novel object recognition task. Insulin resistance and neuronal death were evaluated through western blot analysis. Rats induced to T2D had higher blood glucose levels, and consumed more water when compared to control group, but DE had better blood glucose levels than D. Total body fat was reduced in DE compared to D. Locomotor activity, and anxious behavior were not significantly altered. T2D rats which performed HIRT maintained cognitive function, while those induced to T2D that did not exercise developed cognitive decline. DE group showed a reduction in the inhibition of the activation of hippocampal IRS-1 and higher expression of GSk3β phosphorylated in serine compared to D group, revealing insulin signaling impairment, and neuronal death were identified in the hippocampus of D group. Lifestyle intervention through the regular practice of HIRT plays a fundamental role in the treatment of T2D preventing cognitive decline.
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Affiliation(s)
- Ricardo Augusto Leoni De Sousa
- Programa Multicêntrico de Pós-Graduação em Ciências Fisiológicas (PMPGCF), UFVJM, Sociedade Brasileira de Fisiologia, Diamantina, MG, Brazil.
| | | | | | - Caique Olegário Diniz E Magalhães
- Programa Multicêntrico de Pós-Graduação em Ciências Fisiológicas (PMPGCF), UFVJM, Sociedade Brasileira de Fisiologia, Diamantina, MG, Brazil
| | - Daniel Almeida Freitas
- Programa Multicêntrico de Pós-Graduação em Ciências Fisiológicas (PMPGCF), UFVJM, Sociedade Brasileira de Fisiologia, Diamantina, MG, Brazil
| | - Ana Cristina Rodrigues Lacerda
- Programa Multicêntrico de Pós-Graduação em Ciências Fisiológicas (PMPGCF), UFVJM, Sociedade Brasileira de Fisiologia, Diamantina, MG, Brazil
| | - Vanessa Amaral Mendonça
- Programa Multicêntrico de Pós-Graduação em Ciências Fisiológicas (PMPGCF), UFVJM, Sociedade Brasileira de Fisiologia, Diamantina, MG, Brazil
| | - Ricardo Cardoso Cassilhas
- Programa Multicêntrico de Pós-Graduação em Ciências Fisiológicas (PMPGCF), UFVJM, Sociedade Brasileira de Fisiologia, Diamantina, MG, Brazil
| | - Hércules Ribeiro Leite
- Programa Multicêntrico de Pós-Graduação em Ciências Fisiológicas (PMPGCF), UFVJM, Sociedade Brasileira de Fisiologia, Diamantina, MG, Brazil
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Chau ACM, Cheung EYW, Chan KH, Chow WS, Shea YF, Chiu PKC, Mak HKF. Impaired cerebral blood flow in type 2 diabetes mellitus - A comparative study with subjective cognitive decline, vascular dementia and Alzheimer's disease subjects. NEUROIMAGE-CLINICAL 2020; 27:102302. [PMID: 32521474 PMCID: PMC7284123 DOI: 10.1016/j.nicl.2020.102302] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 04/27/2020] [Accepted: 05/25/2020] [Indexed: 12/21/2022]
Abstract
CBF impairment is found in T2DM and SCD individuals, which might suggest a preclinical stage of dementia. Comparing to HC, lower CBF in T2DM was due to higher rate of multiple cerebrovascular risk factors. Unlike T2DM, CBF reduction in AD and VD was due to amyloid deposition and microangiopathy respectively. Significant negative correlation between adjusted CBF and HbA1c in all cortical regions in healthy control and T2DM. The link between non-demented type 2 diabetes mellitus (T2DM) and different types of cognitive impairment is controversial. By controlling for co-morbidities such as cerebral macrovascular and microvascular changes, cerebral atrophy, amyloid burden, hypertension or hyperlipidemia, the current study investigated the cerebral blood flow of T2DM individuals as compared to cognitively impaired subjects recruited from a memory clinic. 15 healthy control (71.8 ± 6.1 years), 18 T2DM (62.5 ± 3.7 years), as well as 8 Subjective Cognitive Decline (69.5 ± 7.5 years), 12 Vascular Dementia (79.3 ± 4.2 years) and 17 Alzheimer’s Disease (75.1 ± 8.2 years) underwent multi-parametric MRI brain scanning. Subjects with T2DM and from the memory clinic also had 18-F Flutametamol PET-CT scanning to look for any amyloid burden. Pseudocontinuous Arterial Spin Labeling (PCASL), MR Angiography Head, 3D FLAIR and 3D T1-weighted sequences were used to quantify cerebral blood flow, cerebrovascular changes, white matter hyperintensities and brain atrophy respectively. Vascular risk factors were retrieved from the medical records. The 37 subjects from memory clinic were classified into subjective cognitive decline (SCD), vascular dementia (VD) and Alzheimer’s disease (AD) subgroups by a multi-disciplinary panel consisting of a neuroradiologist, and 2 geriatricians. Absolute cortical CBF in our cohort of T2DM, SCD, VD and AD was significantly decreased (p < 0.01) as compared to healthy controls (HC) in both whole brain and eight paired brain regions, after age, normalized grey matter volume and gender adjustment and Bonferroni correction. Subgroup analysis between T2DM, SCD, VD, and AD revealed that CBF of T2DM was not significantly different from AD, VD or SCD. By controlling for co-morbidities, impaired cortical CBF in T2DM was not related to microangiopathy or amyloid deposition, but to the interaction of triple risk factors (such as diabetes mellitus, hypertension, and hyperlipidemia). There was statistically significant negative correlation (p ≤ 0.05) between adjusted CBF and HbA1c in all brain regions of T2DM and HC (with partial correlation ranging from −0.30 to −0.46). Taken together, altered cerebral blood flow in T2DM might be related to disruption of cerebrovascular autoregulation related to vascular risk factors, and such oligemia occurred before clinical manifestation due to altered glycemic control.
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Affiliation(s)
- Anson C M Chau
- The University of Hong Kong (Shenzhen) Teaching Hospital Limited, The University of Hong Kong, Pokfulam Road, Hong Kong.
| | - Eva Y W Cheung
- Department of Diagnostic Radiology, LKS Faculty of Medicine, The University of Hong Kong, K406, Queen Mary Hospital, Pokfulam Road, Hong Kong
| | - K H Chan
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, 405B, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong.
| | - W S Chow
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, 405B, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong.
| | - Y F Shea
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, 405B, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong
| | - Patrick K C Chiu
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, 405B, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong
| | - Henry K F Mak
- Department of Diagnostic Radiology, LKS Faculty of Medicine, The University of Hong Kong, K406, Queen Mary Hospital, Pokfulam Road, Hong Kong; State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong; Alzheimer's Disease Research Network, The University of Hong Kong, Hong Kong.
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Abstract
Diabetes can take a tremendous toll on physical and psychological health. Given the growing evidence of the benefits of humor, this study examined the association between diabetes and humor. The sample consisted of 249 participants: 72.3% with type 1 diabetes, 70.3% female, 89.5% Caucasian, and 70.9% college educated. Participants completed the Humor Styles Questionnaire (HSQ) and were compared with HSQ norms. On the affiliative humor scale, the diabetes group did not differ from the norm (P >0.05), nor did those with type 1 diabetes (P >0.05). Scores of those with type 2 diabetes were lower than the norm (P <0.05). On the self-enhancing humor scale, the diabetes group did not differ from the norm (P >0.05), nor did the subgroups with type 1 diabetes (P >0.05) or type 2 diabetes (P >0.05). The diabetes group was lower than the norm on aggressive humor (P <0.01), as were the subgroups with type 1 diabetes (P <0.01) and type 2 diabetes (P <0.05). The diabetes group was higher than the norm on self-defeating humor (P <0.01), as were the subgroups with type 1 diabetes (P <0.01) and type 2 diabetes (P <0.01). Results suggest that people with either type of diabetes are more inclined toward self-enhancing humor, are less inclined toward aggressive humor, and score higher on self-defeating humor, and those with type 1 diabetes are also inclined toward affiliative humor. Results are discussed relative to the sample being comprised of individuals with good glycemic control (mean A1C 7.06 ± 1.39%). This study offers a preliminary comparison of humor among people with diabetes versus those in a healthy norm group without diabetes.
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Zhou J, Tang X, Han Y, Luo F, Cardoso MA, Qi L. Prediabetes and structural brain abnormalities: Evidence from observational studies. Diabetes Metab Res Rev 2020; 36:e3261. [PMID: 31856401 PMCID: PMC7685098 DOI: 10.1002/dmrr.3261] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 11/12/2019] [Accepted: 11/15/2019] [Indexed: 12/24/2022]
Abstract
Type 2 diabetes mellitus has been linked to structural brain abnormalities, but evidence of the association among prediabetes and structural brain abnormalities has not been systematically evaluated. Comprehensive searching strategies and relevant studies were systematically retrieved from PubMed, Embase, Medline and web of science. Twelve articles were included overall. Stratified analyses and regression analyses were performed. A total of 104 468 individuals were included. The risk of infarct was associated with continuous glycosylated haemoglobin (HbA1c ) [adjusted odds ratio (OR) 1.19 (95% confidence interval [CI]: 1.05-1.34)], or prediabetes [adjusted OR 1.13 (95% CI: 1.00-1.27)]. The corresponding ORs associated with white matter hyperintensities were 1.08 (95%CI: 1.04-1.13) for prediabetes, and 1.10 (95%CI: 1.08-1.12) for HbA1c . The association was significant between the decreased risk of brain volume with continuous HbA1c (the combined OR 0.92, 95% CI: 0.87-0.98). Grey matter volume and white matter volume were inversely associated with prediabetes [weighted mean deviation (WMD), -9.65 (95%CI: -15.25 to -4.04) vs WMD, -9.25 (95%CI: -15.03 to -3.47)]. There were no significant association among cerebral microbleeds, hippocampal volume, continuous total brain volume, and prediabetes. Our findings demonstrated that (a) both prediabetes and continuous HbA1c were significantly associated with increasing risk of infarct or white matter hyperintensities; (b) continuous HbA1c was associated with a decreased risk of brain volume; (c) prediabetes was inversely associated with grey matter volume and white matter volume. To confirm these findings, further studies on early diabetes onset and structural brain abnormalities are needed.
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Affiliation(s)
- Jian‐Bo Zhou
- Department of Endocrinology, Beijing Tongren HospitalCapital Medical UniversityBeijingChina
- Department of Epidemiology, School of Public Health and Tropical MedicineTulane UniversityNew OrleansLA
| | - Xing‐Yao Tang
- Beijing Tongren HospitalCapital Medical UniversityBeijingChina
| | - Yi‐Peng Han
- Beijing Tongren HospitalCapital Medical UniversityBeijingChina
| | - Fu‐qiang Luo
- Beijing Tongren HospitalCapital Medical UniversityBeijingChina
| | - Marly Augusto Cardoso
- Department of Nutrition, School of Public HealthUniversity of São PauloSão PauloBrazil
| | - Lu Qi
- Department of Epidemiology, School of Public Health and Tropical MedicineTulane UniversityNew OrleansLA
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BenAri O, Efrati S, Sano M, Bendlin BB, Lin H, Liu X, Sela I, Almog G, Livny A, Sandler I, Ben‐Haim S, Sagi R, LeRoith D, Schnaider Beeri M, Ravona‐Springer R. A double-blind placebo-controlled clinical trial testing the effect of hyperbaric oxygen therapy on brain and cognitive outcomes of mildly cognitively impaired elderly with type 2 diabetes: Study design. ALZHEIMER'S & DEMENTIA (NEW YORK, N. Y.) 2020; 6:e12008. [PMID: 32296731 PMCID: PMC7153432 DOI: 10.1002/trc2.12008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 12/26/2019] [Indexed: 12/30/2022]
Abstract
INTRODUCTION Type 2 diabetes (T2D) is a risk factor for dementia. Ischemia due to vascular pathology is hypothesized to be an underlying mechanism for this association. Hyperbaric oxygen therapy (HBOT) is a treatment in which oxygen-enriched air (up to 100%) is administered to patients in a chamber at a pressure above one atmosphere absolute. HBOT is approved for the treatment of T2D ischemic non-healing wounds. Evidence from animal studies and small clinical trials suggests that HBOT improves hypoxic/ischemic brain injuries, consequently inducing brain angiogensis, leading to cognitive improvement. METHODS We present the design of the first double-blind, placebo-controlled, clinical trial on brain and cognitive outcomes in elderly (n = 154) with T2D and mild cognitive impairment to compare the effects of HBOT versus sham (normal air with 1.1 ATA pressure in the first and last 5 minutes of the session). Eligible candidates are randomized with equal probability to HBOT and sham. Outcomes are assessed before and after treatment, and at 6- and 12-month follow-up. The primary cognitive outcome is global cognitive change, indexed by a composite sum of z-scores of four executive functions and four episodic memory tests. The primary neurobiological outcome is cerebral blood flow (CBF; via arterial spin labeling magnetic resonance imaging [ASL-MRI]) and cerebral glucose utilization via fluorodeoxyglucose positron emission tomography (FDG-PET). Secondary outcome measures are specific cognitive domains (executive function and episodic memory) and functional measures (Clinical Dementia Rating sum of boxes, activities of daily living). Efficacy analyses will be performed for the intent-to-treat sample. DISCUSSION Recent studies suggest that HBOT induces neuroplasticity and improves cognition in post-stroke and traumatic brain injury patients. However, its effect on cognition, cerebral blood flow, and brain glucose utilization in T2D patients at high dementia risk is yet to be determined. If effective, this study may provide strong evidence for the brain and cognitive benefits of HBOT in this population.
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Affiliation(s)
- Ori BenAri
- The Joseph Sagol Neuroscience CenterSheba Medical CenterTel‐HashomerRamat‐GanIsrael
- Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
| | - Shai Efrati
- Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
- Sagol center for Hyperbaric Medicine & ResearchShamir (Assaf Harofeh) Medical CenterBe'er Ya'akovIsrael
| | - Mary Sano
- Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Barbara B. Bendlin
- Wisconsin Alzheimer's Disease Research CenterUniversity of Wisconsin‐Madison School of Medicine and Public HealthMadisonWisconsinUSA
| | - HungMo Lin
- Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Xiaoyu Liu
- Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Inbar Sela
- The Joseph Sagol Neuroscience CenterSheba Medical CenterTel‐HashomerRamat‐GanIsrael
| | - Ganit Almog
- The Joseph Sagol Neuroscience CenterSheba Medical CenterTel‐HashomerRamat‐GanIsrael
| | - Abigail Livny
- The Joseph Sagol Neuroscience CenterSheba Medical CenterTel‐HashomerRamat‐GanIsrael
- Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
- Division of Diagnostic ImagingSheba Medical CenterTel‐HashomerRamat‐GanIsrael
| | - Israel Sandler
- Department of Nuclear MedicineSheba Medical CenterTel‐HashomerRamat‐GanIsrael
| | - Simona Ben‐Haim
- Department of Biophysics and Nuclear MedicineHadassah University HospitalEin KeremJerusalemIsrael
- Institute of Nuclear MedicineUniversity College London HospitalsNHS TrustLondonUK
| | - Roy Sagi
- Sagol center for Hyperbaric Medicine & ResearchShamir (Assaf Harofeh) Medical CenterBe'er Ya'akovIsrael
| | - Derek LeRoith
- Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Michal Schnaider Beeri
- The Joseph Sagol Neuroscience CenterSheba Medical CenterTel‐HashomerRamat‐GanIsrael
- Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Ramit Ravona‐Springer
- The Joseph Sagol Neuroscience CenterSheba Medical CenterTel‐HashomerRamat‐GanIsrael
- Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
- Department of PsychiatrySheba Medical CenterTel‐HashomerRamat‐GanIsrael
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Shi S, Yin H, Li J, Wang L, Wang W, Wang X. Studies of pathology and pharmacology of diabetic encephalopathy with KK-Ay mouse model. CNS Neurosci Ther 2020; 26:332-342. [PMID: 31401815 PMCID: PMC7052806 DOI: 10.1111/cns.13201] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 07/11/2019] [Accepted: 07/12/2019] [Indexed: 11/28/2022] Open
Abstract
AIMS Pathogenesis of diabetic encephalopathy (DE) is not completely understood until now. The purposes of this study were to illustrate the changes in morphology, function, and important transporters in neurons and glia during DE, as well as to reveal the potential therapeutic effects of medicines and the diet control on DE. METHODS Spontaneous obese KK-Ay mice were used to investigate diabetes-induced cognitive disorder, the morphology, function, and protein expression changes in impact animal and the cell level studies. The new drug candidate PHPB, donepezil, and low-fat food were used to observe the therapeutic effects. RESULTS KK-Ay mice at 5 months of age showed typical characteristics of type 2 diabetes mellitus (T2DM） and appeared significant cognitive deficits. Morphological study showed microtubule-associated protein 2 (MAP2) expression was increased in hippocampal neurons and glial fibrillary acidic protein (GFAP) expression decreased in astrocytes. Meanwhile, the vesicular glutamate transporter 1 (vGLUT1) expression was increased and glucose transporter 1 (GLUT1) decreased, and the expression of brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) was also reduced in KK-Ay mice. Microglia were activated, and IL-1β and TNF-α were increased obviously in the brains of the KK-Ay mice. Most of the above changes in the KK-Ay mice at 5 months of age could be relieved by diet intervention (DR) or by treatment of donepezil or new drug candidate PHPB. CONCLUSION KK-Ay mouse is a useful animal model for studying DE. The alterations of morphology, structure, and function of astrocyte and microglia in KK-Ay mice might be rescued by DR and by treatment of medicine. The proteins we reported in this study could be used as biomarkers and the potential drug targets for DE study and treatment.
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Affiliation(s)
- Si Shi
- Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Hua‐Jing Yin
- Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Jiang Li
- Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Ling Wang
- Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Wei‐Ping Wang
- Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Xiao‐Liang Wang
- Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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Diabetes mellitus in the young and the old: Effects on cognitive functioning across the life span. Neurobiol Dis 2020; 134:104608. [DOI: 10.1016/j.nbd.2019.104608] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 08/06/2019] [Accepted: 09/04/2019] [Indexed: 01/12/2023] Open
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Ciudin A, Ortiz-Zuñiga AM, Fidilio E, Romero D, Sánchez M, Comas M, Gonzalez O, Vilallonga R, Simó-Servat O, Hernández C, Simó R. Retinal Microperimetry: A Useful Tool for Detecting Insulin Resistance-Related Cognitive Impairment in Morbid Obesity. J Clin Med 2019; 8:jcm8122181. [PMID: 31835729 PMCID: PMC6947364 DOI: 10.3390/jcm8122181] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 12/04/2019] [Accepted: 12/05/2019] [Indexed: 01/04/2023] Open
Abstract
Background: There is clear association between type 2 diabetes (T2D) and cognitive decline. Retinal microperimetry is a useful tool for detecting cognitive impairment in T2D. Morbid obesity (MO) has been associated with cognitive impairment. Insulin resistance (IR) seems a major determinant, but the data are unclear. The aim of this study was to evaluate the cognitive impairment in MO as well as the utility of retinal microperimetry in identifying these alterations. Methods: In total, 50 consecutive patients with MO were matched by age and gender with 30 healthy controls. All patients underwent cognitive evaluation (Montreal Cognitive Assessment Test-MoCA) and retinal microperimetry, using MAIA microperimeter 3rd generation. Retinal sensitivity and gaze fixation parameters were used for the evaluation of the analysis. Results: MO patients showed a significantly lower neurocognitive performance than the controls: MoCA score 24.94 ± 2.74 vs. 28.95 ± 1.05, p < 0.001. Cognitive function inversely correlated with the HOMA-IR (r = −0.402, p = 0.007). The AUROC for cognitive impairment using microperimetry was 0.807, CI 95% (0.592–0.947), p = 0.017. Conclusions: (1) Systemic insulin resistance is a major underlying mechanism accounting for the higher prevalence of cognitive impairment detected in young MO subjects. (2) Retinal microperimetry is a useful tool for identifying MO patients with cognitive impairment.
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Affiliation(s)
- Andreea Ciudin
- Institut de Recerca Vall d’Hebron, Universitat Autònoma de Barcelona (VHIR-UAB), Plaça Cívica, Barcelona 08193, Spain; (A.M.O.-Z.); (E.F.); (D.R.); (O.S.-S.); (C.H.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid 28020, Spain
- Department of Endocrinology, Vall d’Hebron University Hospital. Passeig Vall d’Hebron 119-139, Barcelona 08035, Spain; (M.S.); (M.C.)
- Correspondence: (A.C.); (R.S.); Tel.: +34-934-894-172 (A.C.); +34-934-894-172 (R.S.)
| | - Angel Michael Ortiz-Zuñiga
- Institut de Recerca Vall d’Hebron, Universitat Autònoma de Barcelona (VHIR-UAB), Plaça Cívica, Barcelona 08193, Spain; (A.M.O.-Z.); (E.F.); (D.R.); (O.S.-S.); (C.H.)
- Department of Endocrinology, Vall d’Hebron University Hospital. Passeig Vall d’Hebron 119-139, Barcelona 08035, Spain; (M.S.); (M.C.)
| | - Enzamaria Fidilio
- Institut de Recerca Vall d’Hebron, Universitat Autònoma de Barcelona (VHIR-UAB), Plaça Cívica, Barcelona 08193, Spain; (A.M.O.-Z.); (E.F.); (D.R.); (O.S.-S.); (C.H.)
- Department of Endocrinology, Vall d’Hebron University Hospital. Passeig Vall d’Hebron 119-139, Barcelona 08035, Spain; (M.S.); (M.C.)
| | - Diana Romero
- Institut de Recerca Vall d’Hebron, Universitat Autònoma de Barcelona (VHIR-UAB), Plaça Cívica, Barcelona 08193, Spain; (A.M.O.-Z.); (E.F.); (D.R.); (O.S.-S.); (C.H.)
| | - Marta Sánchez
- Department of Endocrinology, Vall d’Hebron University Hospital. Passeig Vall d’Hebron 119-139, Barcelona 08035, Spain; (M.S.); (M.C.)
| | - Marta Comas
- Department of Endocrinology, Vall d’Hebron University Hospital. Passeig Vall d’Hebron 119-139, Barcelona 08035, Spain; (M.S.); (M.C.)
| | - Oscar Gonzalez
- Department of Surgery. Vall d’Hebron University Hospital. Passeig Vall d’Hebron 119-139, Barcelona 08035, Spain; (O.G.); (R.V.)
| | - Ramon Vilallonga
- Department of Surgery. Vall d’Hebron University Hospital. Passeig Vall d’Hebron 119-139, Barcelona 08035, Spain; (O.G.); (R.V.)
| | - Olga Simó-Servat
- Institut de Recerca Vall d’Hebron, Universitat Autònoma de Barcelona (VHIR-UAB), Plaça Cívica, Barcelona 08193, Spain; (A.M.O.-Z.); (E.F.); (D.R.); (O.S.-S.); (C.H.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid 28020, Spain
- Department of Endocrinology, Vall d’Hebron University Hospital. Passeig Vall d’Hebron 119-139, Barcelona 08035, Spain; (M.S.); (M.C.)
| | - Cristina Hernández
- Institut de Recerca Vall d’Hebron, Universitat Autònoma de Barcelona (VHIR-UAB), Plaça Cívica, Barcelona 08193, Spain; (A.M.O.-Z.); (E.F.); (D.R.); (O.S.-S.); (C.H.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid 28020, Spain
- Department of Endocrinology, Vall d’Hebron University Hospital. Passeig Vall d’Hebron 119-139, Barcelona 08035, Spain; (M.S.); (M.C.)
| | - Rafael Simó
- Institut de Recerca Vall d’Hebron, Universitat Autònoma de Barcelona (VHIR-UAB), Plaça Cívica, Barcelona 08193, Spain; (A.M.O.-Z.); (E.F.); (D.R.); (O.S.-S.); (C.H.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid 28020, Spain
- Department of Endocrinology, Vall d’Hebron University Hospital. Passeig Vall d’Hebron 119-139, Barcelona 08035, Spain; (M.S.); (M.C.)
- Correspondence: (A.C.); (R.S.); Tel.: +34-934-894-172 (A.C.); +34-934-894-172 (R.S.)
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Lee ATC, Richards M, Chan WC, Chiu HFK, Lee RSY, Lam LCW. Higher dementia incidence in older adults with type 2 diabetes and large reduction in HbA1c. Age Ageing 2019; 48:838-844. [PMID: 31574142 DOI: 10.1093/ageing/afz108] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 07/14/2019] [Accepted: 07/29/2019] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND although type 2 diabetes increases risk of dementia by 2-fold, whether optimizing glycemic level in late life can reduce risk of dementia remains uncertain. We examined if achieving the glycemic goal recommended by the American Diabetes Association (ADA) within a year was associated with lower risk of dementia in 6 years. METHODS in this population-based observational study, we examined 2246 community-living dementia-free Chinese older adults with type 2 diabetes who attended the Elderly Health Centres in Hong Kong at baseline and followed their HbA1c level and cognitive status for 6 years. In line with the ADA recommendation, we defined the glycemic goal as HbA1c < 7.5%. The study outcome was incident dementia in 6 years, diagnosed according to the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) or Clinical Dementia Rating of 1-3. RESULTS those with HbA1c ≥ 7.5% at baseline and HbA1c < 7.5% in 1 year were associated with higher rather than lower incidence of dementia, independent of severe hypoglycemia, glycemic variability and other health factors. Sensitivity analyses showed that a relative reduction of ≥10%, but not 5-10%, in HbA1c within a year was associated with higher incidence of dementia in those with high (≥8%) and moderate (6.5-7.9%) HbA1c at baseline. CONCLUSION a large reduction in HbA1c could be a potential predictor and possibly a risk factor for dementia in older adults with type 2 diabetes. Our findings suggest that optimizing or intensifying glycemic control in this population requires caution.
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Affiliation(s)
- Allen T C Lee
- Department of Psychiatry, The Chinese University of Hong Kong, Hong Kong SAR, China
| | | | - Wai C Chan
- Department of Psychiatry, The University of Hong Kong, Hong Kong SAR, China
| | - Helen F K Chiu
- Department of Psychiatry, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ruby S Y Lee
- Department of Health, Elderly Health Service, The Government of Hong Kong SAR, Hong Kong SAR, China
| | - Linda C W Lam
- Department of Psychiatry, The Chinese University of Hong Kong, Hong Kong SAR, China
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50
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Ghisletta P, Mason F, Dahle CL, Raz N. Metabolic risk affects fluid intelligence changes in healthy adults. Psychol Aging 2019; 34:912-920. [PMID: 31589057 DOI: 10.1037/pag0000402] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Metabolic syndrome affects persons of all ages and has been associated with cognitive decline. In a sample of 221 healthy adults (18.57 to 85.33 years), assessed up to 3 times (over up to 6.33 years), we applied a second-order bivariate dual-change-score model with strong factorial invariance to estimate the effects of previous levels of metabolic risk (MR) and fluid intelligence (Gf) on subsequent changes in both constructs. The results indicated that MR levels affect subsequent changes in Gf, whereas Gf does not affect changes in MR. This suggests that control of MR may be related to the change in a person's cognitive status, making early intervention, starting in young adulthood, a promising approach. To our knowledge, this is the first long-term study with such evidence. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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Affiliation(s)
| | - Fabio Mason
- Faculty of Psychology and Educational Sciences
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