Metabolic Syndrome: Is It Time to Add the Central Nervous System?
Metabolic syndrome (MS) is a set of cardio-metabolic risk factors that includes central obesity, hyperglycemia, hypertension, and dyslipidemias. The syndrome affects 25% of adults worldwide. The definition of MS has evolved over the last 80 years, with various classification systems and criteria, wh...
- Autores:
-
Rojas, Milagros
Chávez-Castillo, Mervin
Pirela, Daniela
Parra, Heliana
Nava, Manuel
Chacín, Maricarmen
Angarita, Lissé
Añez, Roberto
Salazar, Juan
Ortiz, Rina
Durán Agüero, Samuel
Gravini-Donado, Marbel
Bermúdez, Valmore
Díaz-Camargo, Edgar
- Tipo de recurso:
- Fecha de publicación:
- 2021
- Institución:
- Universidad Simón Bolívar
- Repositorio:
- Repositorio Digital USB
- Idioma:
- eng
- OAI Identifier:
- oai:bonga.unisimon.edu.co:20.500.12442/8318
- Palabra clave:
- metabolic syndrome
insulin resistance
diabetes mellitus type 2
mild cognitive impairment
Alzheimer’s disease
- Rights
- openAccess
- License
- Attribution-NonCommercial-NoDerivatives 4.0 Internacional
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Metabolic Syndrome: Is It Time to Add the Central Nervous System? |
| title |
Metabolic Syndrome: Is It Time to Add the Central Nervous System? |
| spellingShingle |
Metabolic Syndrome: Is It Time to Add the Central Nervous System? metabolic syndrome insulin resistance diabetes mellitus type 2 mild cognitive impairment Alzheimer’s disease |
| title_short |
Metabolic Syndrome: Is It Time to Add the Central Nervous System? |
| title_full |
Metabolic Syndrome: Is It Time to Add the Central Nervous System? |
| title_fullStr |
Metabolic Syndrome: Is It Time to Add the Central Nervous System? |
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Metabolic Syndrome: Is It Time to Add the Central Nervous System? |
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Metabolic Syndrome: Is It Time to Add the Central Nervous System? |
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Rojas, Milagros Chávez-Castillo, Mervin Pirela, Daniela Parra, Heliana Nava, Manuel Chacín, Maricarmen Angarita, Lissé Añez, Roberto Salazar, Juan Ortiz, Rina Durán Agüero, Samuel Gravini-Donado, Marbel Bermúdez, Valmore Díaz-Camargo, Edgar |
| dc.contributor.author.none.fl_str_mv |
Rojas, Milagros Chávez-Castillo, Mervin Pirela, Daniela Parra, Heliana Nava, Manuel Chacín, Maricarmen Angarita, Lissé Añez, Roberto Salazar, Juan Ortiz, Rina Durán Agüero, Samuel Gravini-Donado, Marbel Bermúdez, Valmore Díaz-Camargo, Edgar |
| dc.subject.eng.fl_str_mv |
metabolic syndrome insulin resistance diabetes mellitus type 2 mild cognitive impairment Alzheimer’s disease |
| topic |
metabolic syndrome insulin resistance diabetes mellitus type 2 mild cognitive impairment Alzheimer’s disease |
| description |
Metabolic syndrome (MS) is a set of cardio-metabolic risk factors that includes central obesity, hyperglycemia, hypertension, and dyslipidemias. The syndrome affects 25% of adults worldwide. The definition of MS has evolved over the last 80 years, with various classification systems and criteria, whose limitations and benefits are currently the subject of some controversy. Likewise, hypotheses regarding the etiology of MS add more confusion from clinical and epidemiological points of view. The leading suggestion for the pathophysiology of MS is insulin resistance (IR). IR can affect multiple tissues and organs, from the classic “triumvirate” (myocyte, adipocyte, and hepatocyte) to possible effects on organs considered more recently, such as the central nervous system (CNS). Mild cognitive impairment (MCI) and Alzheimer’s disease (AD) may be clinical expressions of CNS involvement. However, the association between MCI and MS is not understood. The bidirectional relationship that seems to exist between these factors raises the questions of which phenomenon occurs first and whether MCI can be a precursor of MS. This review explores shared pathophysiological mechanisms between MCI and MS and establishes a hypothesis of a possible MCI role in the development of IR and the appearance of MS. |
| publishDate |
2021 |
| dc.date.accessioned.none.fl_str_mv |
2021-09-09T21:32:18Z |
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2021-09-09T21:32:18Z |
| dc.date.issued.none.fl_str_mv |
2021-06 |
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http://purl.org/coar/version/c_970fb48d4fbd8a85 |
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Artículo científico |
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20726643 |
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https://hdl.handle.net/20.500.12442/8318 |
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https://doi.org/10.3390/nu13072254 |
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20726643 |
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https://hdl.handle.net/20.500.12442/8318 https://doi.org/10.3390/nu13072254 |
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eng |
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Attribution-NonCommercial-NoDerivatives 4.0 Internacional |
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pdf |
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MDPI |
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Nutrients |
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Vol. 13, No. 7, 2021 |
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Universidad Simón Bolívar |
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Rojas, Milagrosd07a9d4d-cce2-438c-b4a0-fc5ed4af1a67Chávez-Castillo, Mervin912e1d3d-18fb-43af-8edb-826137f74a5aPirela, Danielaf7d00476-6884-4e9b-b972-aa1b154fcf02Parra, Heliana13603b25-99ce-42ac-a469-5b65a89ce794Nava, Manuelcf0ca570-5fc3-4ec7-9913-90be952261e2Chacín, Maricarmen5c3b3d7c-4444-47e2-b2be-11f08df10409Angarita, Lissécd37d36e-0d41-457f-9dc8-1ed5b9201b16Añez, Roberto0a8ecfdc-a89a-4435-9859-b66bba8947faSalazar, Juanfbd053e7-5aea-424c-812f-92153ecb9181Ortiz, Rinab50c3253-2c29-426f-b91b-165deb110151Durán Agüero, Samuel1ec96ecd-37dc-4900-9d2c-11f00f2c2d7dGravini-Donado, Marbelf5216d16-f0e2-4742-a70b-587021000208Bermúdez, Valmore29f9aa18-16a4-4fd3-8ce5-ed94a0b8663aDíaz-Camargo, Edgare056554f-7c70-4102-b9c6-bad4ba6afb392021-09-09T21:32:18Z2021-09-09T21:32:18Z2021-0620726643https://hdl.handle.net/20.500.12442/8318https://doi.org/10.3390/nu13072254Metabolic syndrome (MS) is a set of cardio-metabolic risk factors that includes central obesity, hyperglycemia, hypertension, and dyslipidemias. The syndrome affects 25% of adults worldwide. The definition of MS has evolved over the last 80 years, with various classification systems and criteria, whose limitations and benefits are currently the subject of some controversy. Likewise, hypotheses regarding the etiology of MS add more confusion from clinical and epidemiological points of view. The leading suggestion for the pathophysiology of MS is insulin resistance (IR). IR can affect multiple tissues and organs, from the classic “triumvirate” (myocyte, adipocyte, and hepatocyte) to possible effects on organs considered more recently, such as the central nervous system (CNS). Mild cognitive impairment (MCI) and Alzheimer’s disease (AD) may be clinical expressions of CNS involvement. However, the association between MCI and MS is not understood. The bidirectional relationship that seems to exist between these factors raises the questions of which phenomenon occurs first and whether MCI can be a precursor of MS. This review explores shared pathophysiological mechanisms between MCI and MS and establishes a hypothesis of a possible MCI role in the development of IR and the appearance of MS.pdfengMDPIAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2NutrientsVol. 13, No. 7, 2021metabolic syndromeinsulin resistancediabetes mellitus type 2mild cognitive impairmentAlzheimer’s diseaseMetabolic Syndrome: Is It Time to Add the Central Nervous System?info:eu-repo/semantics/articleArtículo científicohttp://purl.org/coar/version/c_970fb48d4fbd8a85http://purl.org/coar/resource_type/c_2df8fbb1Hennekens, C.H.; Andreotti, F. Leading Avoidable Cause of Premature Deaths Worldwide: Case for Obesity. Am. J. Med. 2013, 126, 97–98. [CrossRef] [PubMedAlberti, K.G.M.M.; Eckel, R.H.; Grundy, S.M.; Zimmet, P.Z.; Cleeman, J.I.; Donato, K.A.; Smith, S.C., Jr. Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009, 120, 1640–1645.Mente, A.; Yusuf, S.; Islam, S.; McQueen, M.J.; Tanomsup, S.; Onen, C.L.; Rangarajan, S.; Gerstein, H.C.; Anand, S.S. Metabolic syndrome and risk of acute myocardial infarction a case-control study of 26,903 subjects from 52 countries. J. Am. Coll. Cardiol. 2010, 55, 2390–2398. [CrossRef]Kerekes, G.; Nurmohamed, M.T.; González-Gay, M.A.; Seres, I.; Paragh, G.; Kardos, Z.; Baráth, Z.; Tamási, L.; Soltész, P.; Szekanecz, Z. Rheumatoid arthritis and metabolic syndrome. Nat. Rev. Rheumatol. 2014, 10, 691–696. [CrossRef] [PubMed]Uzunlulu, M.; Caklili, O.T.; Oguz, A. Association between Metabolic Syndrome and Cancer. Ann. Nutr. Metab. 2016, 68, 173–179. [CrossRef]Bangen, K.J.; Armstrong, N.M.; Au, R.; Gross, A.L. Metabolic Syndrome and Cognitive Trajectories in the Framingham Offspring Study. J. Alzheimer’s Dis. 2019, 71, 931–943. [CrossRef]Laws, S.M.; Gaskin, S.; Woodfield, A.; Srikanth, V.; Bruce, D.; Fraser, P.E.; Porter, T.; Newsholme, P.; Wijesekara, N.; Burnham, S.; et al. Insulin resistance is associated with reductions in specific cognitive domains and increases in CSF tau in cognitively normal adults. Sci. Rep. 2017, 7, 1–11. [CrossRef]Petersen, R.C.; Roberts, R.O.; Knopman, D.S.; Boeve, B.F.; Geda, Y.E.; Ivnik, R.J.; Smith, G.E.; Jack, C.R., Jr. Mild cognitive impairment: Ten years later. Arch. Neurol. 2009, 66, 1447–1455. [CrossRef] [PubMed]Sanford, A.M. Mild Cognitive Impairment. Clin. Geriatr. Med. 2017, 33, 325–337. [CrossRef] [PubMed]Biessels, G.J.; Despa, F. Cognitive decline and dementia in diabetes mellitus: Mechanisms and clinical implications. Nat. Rev. Endocrinol. 2018, 14, 591–604. [CrossRef] [PubMed]Arnold, S.E.; Arvanitakis, Z.; Macauley-Rambach, S.L.; Koenig, A.M.; Wang, H.-Y.; Ahima, R.S.; Craft, S.; Gandy, S.; Buettner, C.; Stoeckel, L.E.; et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums. Nat. Rev. Neurol. 2018, 14, 168–181. [CrossRef]Kylin, E. Hypertonie and Zuckerkrankheit. Zent. Inn. Med. 1921, 42, 873–877Marañon, G. Über Hypertonie and Zuckerkrankheit. Zent. Inn. Med. 1922, 43, 169–176Hanefeld, M.; Leonhardt, W. Das Metabolische Syndrom. Dt Gesundh Wesen. 1981, 36, 545–551. [CrossRef]Reaven, G.M. Banting lecture Role of insulin resistance in human disease. Diabetes 1988, 37, 1595–1607. [CrossRef]Reaven, G.M. Why Syndrome X? From Harold Himsworth to the Insulin Resistance Syndrome. Cell Metab. 2005, 1, 9–14. [CrossRef]Randle, P.; Garland, P.; Hales, C.; Newsholme, E. The glucose fatty-acid cycle its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963, 281, 785–789. [CrossRef]DeFronzo, R.A.; Ferrannini, E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991, 14, 173–194. [CrossRef] [PubMed]Alberti, K.G.; Zimmet, P.Z. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet. Med. J. Br. Diabet. Assoc. 1998, 15, 539–553. [CrossRef]Balkau, B.; Charles, M.A. Comment on the provisional report from the WHO consultation. Diabet. Med. 1999, 16, 442–443. [CrossRef]Reaven, G.M. The metabolic syndrome: Is this diagnosis necessary? Am. J. Clin. Nutr. 2006, 83, 1237–1247. [CrossRef]Einhorn, D.; Reaven, G.M.; Cobin, R.H.; Ford, E.; Ganda, O.P.; Handelsman, Y.; Hellman, R.; Jellinger, P.S.; Kendall, D.; Krauss, R.M.; et al. American College of Endocrinology position statement on the insulin resistance syndrome. Endocr. Pract. 2003, 9, 237–252. [CrossRef] [PubMed]Alberti, K.G.M.M.; Zimmet, P.; Shaw, J. Metabolic syndrome-a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet. Med. 2006, 23, 469–480. [CrossRef]Alegría Ezquerra, E.; Castellano Vázquez, J.M.; Alegría Barrero, A. Obesity, metabolic syndrome and diabetes: Cardiovascular implications and therapy. Rev. Esp. Cardiol. 2008, 61, 752–764. [CrossRef]Jais, A.; Brüning, J.C. Hypothalamic inflammation in obesity and metabolic disease. J. Clin. Investig. 2017, 127, 24–32. [CrossRef]Rönnemaa, E.; Zethelius, B.; Sundelöf, J.; Sundström, J.; Degerman-Gunnarsson, M.; Berne, C.; Lannfelt, L.; Kilander, L. Impaired insulin secretion increases the risk of Alzheimer disease. Neurology 2008, 71, 1065–1071. [CrossRef]Cohen, A.D.; Klunk, W.E. Early detection of Alzheimer’s disease using PiB and FDG PET. Neurobiol. Dis. 2014, 72, 117–122. [CrossRef]Segura, B.; Jurado, M.Á.; Freixenet, N.; Albuin, C.; Muniesa, J.; Junque, C. Mental slowness and executive dysfunctions in patients with metabolic syndrome. Neurosci. Lett. 2009, 462, 49–53. [CrossRef]Anstey, K.J.; Cherbuin, N.; Budge, M.; Young, J. Body mass index in midlife and late-life as a risk factor for dementia: A me-ta-analysis of prospective studies. Obes. Rev. Off. J. Int. Assoc. Study Obes. 2011, 12, 426–437. [CrossRef]Grillo, C.; Woodruff, J.L.; Macht, V.A.; Reagan, L.P. Insulin resistance and hippocampal dysfunction: Disentangling peripheral and brain causes from consequences. Exp. Neurol. 2019, 318, 71–77. [CrossRef]Lindqvist, A.; Mohapel, P.; Bouter, B.; Frielingsdorf, H.; Pizzo, D.; Brundin, P.; Erlanson-Albertsson, C. High-fat diet impairs hippocampal neurogenesis in male rats. Eur. J. Neurol. 2006, 13, 1385–1388. [CrossRef]Karimi, S.A.; Salehi, I.; Komaki, A.; Sarihi, A.; Zarei, M.; Shahidi, S. Effect of high-fat diet and antioxidants on hippocampal long-term potentiation in rats: An in vivo study. Brain Res. 2013, 1539, 1–6. [CrossRef] [PubMed]Nguyen, T.T.; Ta, Q.T.H.; Nguyen, T.T.D.; Le, T.T.; Vo, V.G. Role of Insulin Resistance in the Alzheimer’s Disease Progression. Neurochem. Res. 2020, 45, 1481–1491. [CrossRef] [PubMed]Vander Zanden, C.M.; Chi, E.Y. Passive immunotherapies targeting amyloid beta and Tau oligomers in Alzheimer’s disease. J. Pharm. Sci. 2020, 109, 68–73. [CrossRef]Hurrle, S.; Hsu, W.H. The etiology of oxidative stress in insulin resistance. Biomed. J. 2017, 40, 257–262. [CrossRef] [PubMed]Kinney, J.W.; Bemiller, S.M.; Murtishaw, A.S.; Leisgang, A.M.; Salazar, A.M.; Lamb, B.T. Inflammation as a central mechanism in Alz-heimer’s disease. Alzheimers Dement. Transl. Res. Clin. Interv. 2018, 4, 575–590. [CrossRef]Walker, J.M.; Harrison, F.E. Shared Neuropathological Characteristics of Obesity, Type 2 Diabetes and Alzheimer’s Disease: Impacts on Cognitive Decline. Nutrients 2015, 7, 7332–7357. [CrossRef]Shiiki, T.; Ohtsuki, S.; Kurihara, A.; Naganuma, H.; Nishimura, K.; Tachikawa, M.; Hosoya, K.; Terasaki, T. Brain insulin impairs amyloid-beta(1-40) clearance from the brain. J. Neurosci. Off. J. Soc. Neurosci. 2004, 24, 9632–9637. [CrossRef]Liu, Z.; Patil, I.Y.; Jiang, T.; Sancheti, H.; Walsh, J.P.; Stiles, B.L.; Yin, F.; Cadenas, E. High-Fat Diet Induces Hepatic Insulin Resistance and Impairment of Synaptic Plasticity. PLoS ONE 2015, 10, e0128274. [CrossRef]Zeng, Y.; Zhang, L.; Hu, Z. Cerebral insulin, insulin signaling pathway, and brain angiogenesis. Neurol. Sci. 2016, 37, 9–16. [CrossRef]Liang, C.; Lam, P.; Martinez, S.; Mukherjee, J. Development of [18F]FAZIN3 for PET imaging of neurofibrillary tangles in Alz-heimer’s Disease. J. Nucl. Med. 2020, 61, 1032.Benedict, C.; Grillo, C. Insulin Resistance as a Therapeutic Target in the Treatment of Alzheimer’s Disease: A State-of-the-Art Review. Front. Neurosci. 2018, 12, 215. [CrossRef]Yarchoan, M.; Toledo, J.; Lee, E.B.; Arvanitakis, Z.; Kazi, H.; Han, L.-Y.; Louneva, N.; Lee, V.M.-Y.; Kim, S.F.; Trojanowski, J.Q.; et al. Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer’s disease and tauopathies. Acta Neuropathol. 2014, 128, 679–689. [CrossRef]Starks, E.J.; Patrick O’Grady, J.; Hoscheidt, S.M.; Racine, A.M.; Carlsson, C.M.; Zetterberg, H.; Blennow, K.; Okonkwo, O.C.; Puglielli, L.; Asthana, S.; et al. Insulin resistance is associated with higher cerebrospinal fluid Tau levels in asymptomatic APOE ε4 Carriers. J. Alzheimers Dis. JAD 2015, 46, 525–533. [CrossRef]Kim, B.; Sullivan, K.A.; Backus, C.; Feldman, E.L. Cortical Neurons Develop Insulin Resistance and Blunted Akt Signaling: A Potential Mechanism Contributing to Enhanced Ischemic Injury in Diabetes. Antioxidants Redox Signal. 2011, 14, 1829–1839. [CrossRef]Zhang, Y.; Huang, N.-Q.; Yan, F.; Jin, H.; Zhou, S.-Y.; Shi, J.-S.; Jin, F. Diabetes mellitus and Alzheimer’s disease: GSK-3β as a potential link. Behav. Brain Res. 2018, 339, 57–65. [CrossRef]Esposito, G.; Scuderi, C.; Lu, J.; Savani, C.; De Filippis, D.; Iuvone, T.; Steardo, L., Jr.; Sheen, V.; Steardo, L. S100B induces tau protein hyperphosphorylation via Dickopff-1 up-regulation and disrupts the Wnt pathway in human neural stem cells. J. Cell. Mol. Med. 2008, 12, 914–927. [CrossRef]van der Harg, J.M.; Eggels, L.; Bangel, F.N.; Ruigrok, S.R.; Zwart, R.; Hoozemans, J.J.M.; la Fleur, S.E.; Scheper, W. Insulin deficiency results in reversible protein kinase A activation and tau phosphorylation. Neurobiol. Dis. 2017, 103, 163–173. [CrossRef]Gratuze, M.; Julien, J.; Petry, F.R.; Morin, F.; Planel, E. Insulin deprivation induces PP2A inhibition and tau hyperphosphorylation in hTau mice, a model of Alzheimer’s disease-like tau pathology. Sci. Rep. 2017, 7, srep46359. [CrossRef]Kins, S.; Crameri, A.; Evans, D.R.; Hemmings, B.A.; Nitsch, R.M.; Gotz, J. Reduced protein phosphatase 2A activity induces hyper-phosphorylation and altered compartmentalization of tau in transgenic mice. J. Biol. Chem. 2001, 276, 38193–38200. [CrossRef]Planel, E.; Tatebayashi, Y.; Miyasaka, T.; Liu, L.; Wang, L.; Herman, M.; Yu, W.H.; Luchsinger, J.A.; Wadzinski, B.; Duff, K.E.; et al. Insulin dysfunction induces in vivo tau hyperphos-phorylation through distinct mechanisms. J. Neurosci. Off. J. Soc. Neurosci. 2007, 27, 13635–13648. [CrossRef]Zilka, N.; Filipcik, P.; Koson, P.; Fialova, L.; Skrabana, R.; Zilkova, M.; Rolkova, G.P.; Kontsekova, E.; Novak, M. Truncated tau from sporadic Alzheimer’s disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett. 2006, 580, 3582–3588. [CrossRef]Kim, B.; Backus, C.; Oh, S.; Hayes, J.M.; Feldman, E.L. Increased Tau Phosphorylation and Cleavage in Mouse Models of Type 1 and Type 2 Diabetes. Endocrinology 2009, 150, 5294–5301. [CrossRef]Kim, B.; Backus, C.; Oh, S.; Feldman, E.L. Hyperglycemia-Induced Tau Cleavage in vitro and in vivo: A Possible Link Between Diabetes and Alzheimer’s Disease. J. Alzheimer’s Dis. 2013, 34, 727–739. [CrossRef]Forny-Germano, L.; De Felice, F.G.; Vieira, M.N.D.N. The Role of Leptin and Adiponectin in Obesity-Associated Cognitive Decline and Alzheimer’s Disease. Front. Neurosci. 2019, 12, 1027. [CrossRef]Suyama, S.; Maekawa, F.; Maejima, Y.; Kubota, N.; Kadowaki, T.; Yada, T. Glucose level determines excitatory or inhibitory effects of adiponectin on arcuate POMC neuron activity and feeding. Sci. Rep. 2016, 6, 30796. [CrossRef]Friedman, J. The long road to leptin. J. Clin. Investig. 2016, 126, 4727–4734. [CrossRef]Bouret, S.G. Neurodevelopmental actions of leptin. Brain Res. 2010, 1350, 2–9. [CrossRef]Pousti, F.; Ahmadi, R.; Mirahmadi, F.; Hosseinmardi, N.; Rohampour, K. Adiponectin modulates synaptic plasticity in hippocampal dentate gyrus. Neurosci. Lett. 2018, 662, 227–232. [CrossRef]Thundyil, J.; Pavlovski, D.; Sobey, C.G.; Arumugam, T.V. Adiponectin receptor signalling in the brain. Br. J. Pharmacol. 2011, 165, 313–327. [CrossRef]Li, X.-L.; Aou, S.; Oomura, Y.; Hori, N.; Fukunaga, K.; Hori, T. Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents. Neuroscience 2002, 113, 607–615. [CrossRef]Pérez-González, R.; Alvira-Botero, M.X.; Robayo, O.; Antequera, D.; Garzón, M.; Martín-Moreno, A.M.; Brera, B.; De Ceballos, M.L.; Carro, E. Leptin gene therapy attenuates neuronal damages evoked by amyloid-β and rescues memory deficits in APP/PS1 mice. Gene Ther. 2014, 21, 298–308. [CrossRef]Fewlass, D.C.; Noboa, K.; Pi-Sunyer, F.X.; Johnston, J.M.; Yan, S.D.; Tezapsidis, N. Obesity-related leptin regulates Alzheimer’s Abeta. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2004, 18, 1870–1878.Holden, K.F.; Lindquist, K.; Tylavsky, F.A.; Rosano, C.; Harris, T.B.; Yaffe, K. Serum leptin level and cognition in the elderly: Findings from the Health ABC Study. Neurobiol. Aging 2009, 30, 1483–1489. [CrossRef]Ng, R.C.-L.; Chan, K.-H. Potential Neuroprotective Effects of Adiponectin in Alzheimer’s Disease. Int. J. Mol. Sci. 2017, 18, 592. [CrossRef]Kim, M.W.; Abid N bin Jo, M.H.; Jo, M.G.; Yoon, G.H.; Kim, M.O. Suppression of adiponectin receptor 1 promotes memory dysfunction and Alzheimer’s disease-like pathologies. Sci. Rep. 2017, 7, 12435. [CrossRef]Viswanathan, A.; Rocca, W.A.; Tzourio, C. Vascular risk factors and dementia: How to move forward? Neurology 2009, 72, 368–374. [CrossRef]Borshchev, Y.Y.; Uspensky, Y.P.; Galagudza, M.M. Pathogenetic pathways of cognitive dysfunction and dementia in metabolic syndrome. Life Sci. 2019, 237, 116932. [CrossRefPantoni, L. Cerebral small vessel disease: From pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010, 9, 689–701. [CrossRef]Moss, M.B.; Jonak, E. Cerebrovascular disease and dementia: A primate model of hypertension and cognition. Alzheimer’s Dement. 2007, 3, S6–S15. [CrossRef]Veglio, F.; Paglieri, C.; Rabbia, F.; Bisbocci, D.; Bergui, M.; Cerrato, P. Hypertension and cerebrovascular damage. Atherosclerosis 2009, 205, 331–341. [CrossRef]Frisardi, V.; Solfrizzi, V.; Seripa, D.; Capurso, C.; Santamato, A.; Sancarlo, D.; Vendemiale, G.; Pilotto, A.; Panza, F. Metaboliccognitive syndrome: A cross-talk between metabolic syndrome and Alzheimer’s disease. Ageing Res. Rev. 2010, 9, 399–417. [CrossRef]Reynolds, C.H.; Garwood, C.J.; Wray, S.; Price, C.; Kellie, S.; Perera, T.; Zvelebil, M.; Yang, A.; Sheppard, P.W.; Varndell, I.M.; et al. Phosphorylation Regulates Tau Interactions with Src Homology 3 Domains of Phosphatidylinositol 3-Kinase, Phospholipase Cγ1, Grb2, and Src Family Kinases. J. Biol. Chem. 2008, 283, 18177–18186. [CrossRef]Marciniak, E.; Leboucher, A.; Caron, E.; Ahmed, T.; Tailleux, A.; Dumont, J.; Issad, T.; Gerhardt, E.; Pagesy, P.; Vileno, M.; et al. Tau deletion promotes brain insulin resistance. J. Exp. Med. 2017, 214, 2257–2269. [CrossRef] [PubMed]Obici, S.; Feng, Z.; Karkanias, G.; Baskin, D.G.; Rossetti, L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat. Neurosci. 2002, 5, 566–572. [CrossRef] [PubMed]Brüning, J.C.; Gautam, D.; Burks, D.J.; Gillette, J.; Schubert, M.; Orban, P.C.; Klein, R.; Krone, W.; Müller-Wieland, D.; Kahn, C.R. Role of brain insulin receptor in control of body weight and reproduction. Science 2000, 289, 2122–2125. [CrossRef]Bharadwaj, P.; Wijesekara, N.; Liyanapathirana, M.; Newsholme, P.; Ittner, L.; Fraser, P.; Verdile, G. The Link between Type 2 Diabetes and Neurodegeneration: Roles for Amyloid-β, Amylin, and Tau Proteins. J. Alzheimer’s Dis. 2017, 59, 421–432. [CrossRef]Wijesekara, N.; Ahrens, R.; Sabale, M.; Wu, L.; Ha, K.; Verdile, G.; Fraser, P.E. Amyloid-β and islet amyloid pathologies link Alzheimer’s disease and type 2 diabetes in a transgenic model. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2017, 31, 5409–5418. [CrossRef]Wijesekara, N.; Gonçalves, R.A.; Ahrens, R.; De Felice, F.G.; Fraser, P.E. Tau ablation in mice leads to pancreatic β cell dysfunction and glucose intolerance. FASEB J. 2018, 32, 3166–3173. [CrossRef]Xie, L.; Helmerhorst, E.; Taddei, K.; Plewright, B.; Van Bronswijk, W.; Martins, R. Alzheimer’s beta-amyloid peptides compete for insulin binding to the insulin receptor. J. Neurosci. Off. J. Soc. Neurosci. 2002, 22, 221. [CrossRef]Zhang, Y.; Zhou, B.; Zhang, F.; Wu, J.; Hu, Y.; Liu, Y.; Zhai, Q. Amyloid-β induces hepatic insulin resistance by activating JAK2/STAT3/SOCS-1 signaling pathway. Diabetes 2012, 61, 1434–1443. [CrossRef]De Felice, F.G.; Velasco, P.T.; Lambert, M.P.; Viola, K.; Fernandez, S.J.; Ferreira, S.T.; Klein, W.L. Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J. Biol. Chem. 2007, 282, 11590–11601. [CrossRef]Kim, J.-A.; Wei, Y.; Sowers, J.R. Role of Mitochondrial Dysfunction in Insulin Resistance. Circ. Res. 2008, 102, 401–414. [CrossRef] [PubMed]Zhao, W.; De Felice, F.G.; Fernandez, S.; Chen, H.; Lambert, M.P.; Quon, M.J.; Krafft, G.A.; Klein, W.L. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. 2007, 22, 246–260. [CrossRef]McClean, P.L.; et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers. J. Clin. Investig. 2012, 122, 1339–1353. [CrossRef]Bonda, D.J.; Stone, J.G.; Torres, S.L.; Siedlak, S.L.; Perry, G.; Kryscio, R.; Jicha, G.; Casadesus, G.; Smith, M.A.; Zhu, X.; et al. Dysregulation of leptin signaling in Alzheimer disease: Evidence for neuronal leptin resistance. J. Neurochem. 2014, 128, 162–172. [CrossRef]Kanoski, S.E.; Hayes, M.R.; Greenwald, H.S.; Fortin, S.M.; Gianessi, C.A.; Gilbert, J.R.; Grill, H.J. Hippocampal Leptin Signaling Reduces Food Intake and Modulates Food-Related Memory Processing. Neuropsychopharmacology 2011, 36, 1859–1870. [CrossRef]Meakin, P.J.; Jalicy, S.M.; Montagut, G.; Allsop, D.J.P.; Cavellini, D.L.; Irvine, S.W.; McGinley, C.; Liddell, M.K.; McNeilly, A.D.; Parmionova, K.; et al. Bace1-dependent amyloid processing regulates hypothalamic leptin sensitivity in obese mice. Sci. Rep. 2018, 8, 55. [CrossRef] [PubMed]Brief, D.J.; Davis, J.D. Reduction of food intake and body weight by chronic intraventricular insulin infusion. Brain Res. Bull. 1984, 12, 571–575. [CrossRef]Panza, F.; Solfrizzi, V.; Logroscino, G.; Maggi, S.; Santamato, A.; Seripa, D.; Pilotto, A. Current epidemiological approaches to the met-abolic-cognitive syndrome. J. Alzheimers Dis. 2012, 30, S31–S75. [CrossRef] [PubMed]Irimata, K.E.; Dugger, B.N.; Wilson, J.R. Impact of the Presence of Select Cardiovascular Risk Factors on Cognitive Changes among Dementia Subtypes. Curr. Alzheimer Res. 2018, 15, 1032–1044. [CrossRef] [PubMed]Case, C.C.; Jones, P.H.; Nelson, K.; Smith, E.O.; Ballantyne, C.M. Impact of weight loss on the metabolic syndrome. Diabetes Obes. Metab. 2002, 4, 407–414. [CrossRef] [PubMed]Yaffe, K.; Kanaya, A.; Lindquist, K.; Simonsick, E.M.; Harris, T.; Shorr, R.I.; Tylavsky, F.A.; Newman, A.B. The Metabolic Syndrome, Inflammation, and Risk of Cognitive Decline. JAMA 2004, 292, 2237–2242. [CrossRef] [PubMed]Panza, F.; D’Introno, A.; Colacicco, A.M.; Capurso, C.; Del Parigi, A.; Capurso, S.A.; Caselli, R.J.; Pilotto, A.; Scafato, E.; Capurso, A.; et al. Cognitive frailty: Predementia syndrome and vascular risk factors. Neurobiol. Aging 2006, 27, 933–940. [CrossRef]Dregan, A.; Stewart, R.; Gulliford, M.C. Cardiovascular risk factors and cognitive decline in adults aged 50 and over: A popula-tion-based cohort study. Age Ageing 2013, 42, 338–345. [CrossRef]Harrison, S.L.; Ding, J.; Tang, E.Y.H.; Siervo, M.; Robinson, L.; Jagger, C.; Stephan, B.C.M. Cardiovascular Disease Risk Models and Longitudinal Changes in Cognition: A Systematic Review. PLoS ONE 2014, 9, e114431. [CrossRef] [PubMed]Harrison, S.L.; De Craen, A.J.M.; Kerse, N.; Teh, R.; Granic, A.; Davies, K.; Wesnes, K.A.; Elzen, W.D.; Gussekloo, J.; Kirkwood, T.B.L.; et al. Predicting Risk of Cognitive Decline in Very Old Adults Using Three Models: The Framingham Stroke Risk Profile; the Cardiovascular Risk Factors, Aging, and Dementia Model; and Oxi-Inflammatory Biomarkers. J. Am. Geriatr. Soc. 2017, 65, 381–389. [CrossRef] [PubMed]Purnell, C.; Gao, S.; Callahan, C.M.; Hendrie, H.C. Cardiovascular risk factors and incident Alzheimer disease: A systematic review of the literature. Alzheimer Dis. Assoc. Disord. 2009, 23, 1–10. [CrossRef]Prasad, K.; Wiryasaputra, L.; Ng, A.; Kandiah, N. White Matter Disease Independently Predicts Progression from Mild Cognitive Impairment to Alzheimer’s Disease in a Clinic Cohort. Dement. Geriatr. Cogn. Disord. 2011, 31, 431–434. [CrossRef]Iadecola, C.; Yaffe, K.; Biller, J.; Bratzke, L.C.; Faraci, F.M.; Gorelick, P.B.; Gulati, M.; Kamel, H.; Knopman, D.S.; Launer, L.J.; et al. Impact of Hypertension on Cognitive Function: A Scientific Statement from the American Heart Association. Hypertension 2016, 68, e67–e94. [CrossRef] [PubMed]McDonald, C.; Pearce, M.S.; Kerr, S.R.J.; Newton, J.L. Blood pressure variability and cognitive decline in older people: A 5-year longitudinal study. J. Hypertens. 2017, 35, 140–147. [CrossRef]Tzourio, C.; Dufouil, C.; Ducimetiere, P.; Alperovitch, A. Cognitive decline in individuals with high blood pressure: A longitudinal study in the elderly. Neurology 1999, 53, 1948. [CrossRef]Haring, B.; Wu, C.; Coker, L.H.; Seth, A.; Snetselaar, L.; Manson, J.E.; Rossouw, J.E.; Wassertheil-Smoller, S. Hypertension, Dietary Sodium, and Cognitive Decline: Results from the Women’s Health Initiative Memory Study. Am. J. Hypertens. 2015, 29, 202–216. [CrossRef]Tarraf, W.; Rodríguez, C.J.; Daviglus, M.L.; Lamar, M.; Schneiderman, N.; Gallo, L.; Talavera, G.A.; Kaplan, R.C.; Fornage, M.; Conceicao, A.; et al. Blood Pressure and Hispanic/Latino Cognitive Function: Hispanic Community Health Study/Study of Latinos Results. J. Alzheimer’s Dis. 2017, 59, 31–42. [CrossRef]Kilander, L.; Nyman, H.; Boberg, M.; Hansson, L.; Lithell, H. Hypertension is related to cognitive impairment: A 20-year follow-up of 999 men. Hypertension 1998, 31, 780–786. [CrossRef] [PubMed]Launer, L.J. The association between midlife blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study. JAMA 1995, 274, 1846–1851. [CrossRef] [PubMed]Walker, K.A.; Sharrett, A.R.; Wu, A.; Schneider, A.L.C.; Albert, M.; Lutsey, P.L.; Bandeen-Roche, K.; Coresh, J.; Gross, A.L.; Windham, B.G.; et al. Association of Midlife to Late-Life Blood Pressure Patterns with Incident Dementia. JAMA 2019, 322, 535–545. [CrossRef] [PubMed]Reitz, C.; Tang, M.-X.; Manly, J.; Mayeux, R.; Luchsinger, J.A. Hypertension and the Risk of Mild Cognitive Impairment. Arch. Neurol. 2007, 64, 1734–1740. [CrossRef] [PubMed]Elias, M.F.; Elias, P.K.; Sullivan, L.M.; Wolf, P.A.; D’Agostino, R.B. Lower cognitive function in the presence of obesity and hyper-tension: The Framingham heart study. Int. J. Obes. Relat. Metab. Disord. J. Int. Assoc. Study Obes. 2003, 27, 260–268. [CrossRef] [PubMed]Cournot, M.; Marquie, J.C.; Ansiau, D.; Martinaud, C.; Fonds, H.; Ferrieres, J.; Ruidavets, J.B. Relation between body mass index and cognitive function in healthy middle-aged men and women. Neurology 2006, 67, 1208–1214. [CrossRef]Kloppenborg, R.P.; Berg, E.V.D.; Kappelle, L.J.; Biessels, G.J. Diabetes and other vascular risk factors for dementia: Which factor matters most? A systematic review. Eur. J. Pharmacol. 2008, 585, 97–108. [CrossRef]Sabia, S.; Kivimaki, M.; Shipley, M.J.; Marmot, M.; Singh-Manoux, A. Body mass index over the adult life course and cognition in late midlife: The Whitehall II Cohort Study. Am. J. Clin. Nutr. 2008, 89, 601–607. [CrossRef]Beydoun, M.A.; Wang, Y. Obesity and central obesity as risk factors for incident dementia and its subtypes: A systematic review and meta-analysis. Obes. Rev. 2008, 9, 204–218. [CrossRef] [PubMed]Blom, K.; Emmelot-Vonk, M.H.; Koek, H.L. The influence of vascular risk factors on cognitive decline in patients with dementia: A systematic review. Maturitas 2013, 76, 113–117. [CrossRef]de Frias, C.M.; Bunce, D.; Wahlin, A.; Adolfsson, R.; Sleegers, K.; Cruts, M.; van Broeckhoven, C.; Nilsson, L. Cholesterol and triglycerides moderate the effect of apolipoprotein E on memory functioning in older adults. J. Gerontol. B Psychol. Sci. Soc. Sci. 2007, 62, 112–118. [CrossRef] [PubMed]Sims, R.; Madhere, S.; Callender, C.; Campbell, A. Patterns of Relationships between Cardiovascular Disease Risk Factors and Neurocognitive Function in African Americans. Ethn. Dis. 2008, 18, 471–476. [PubMed]Singh-Manoux, A.; Gimeno, D.; Kivimaki, M.; Brunner, E.; Marmot, M.G. Low HDL cholesterol is a risk factor for deficit and decline in memory in midlife: The Whitehall II study. Arterioscler Thromb. Vasc. Biol. 2008, 28, 1556–1562. [CrossRef]Zuliani, G.; Cavalieri, M.; Galvani, M.; Volpato, S.; Cherubini, A.; Bandinelli, S.; Corsi, A.M.; Lauretani, F.; Guralnik, J.M.; Fellin, R.; et al. Relationship Between Low Levels of High-Density Lipoprotein Cholesterol and Dementia in the Elderly. The InChianti Study. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2010, 65, 559–564. [CrossRef] [PubMed]van Vliet, P.; van de Water, W.; de Craen, A.J.M.; Westendorp, R.G.J. The influence of age on the association between cholesterol and cognitive function. Exp. Gerontol. 2009, 44, 112–122. [CrossRef]Kinno, R.; Mori, Y.; Kubota, S.; Nomoto, S.; Futamura, A.; Shiromaru, A.; Kuroda, T.; Yano, S.; Ishigaki, S.; Murakami, H.; et al. High serum high-density lipoprotein-cholesterol is associated with memory function and gyrification of insular and frontal opercular cortex in an elderly memory-clinic pop-ulation. NeuroImage Clin. 2019, 22, 101746. [CrossRef]Bonarek, M.; Barberger-Gateau, P.; Letenneur, L.; Deschamps, V.; Iron, A.; Dubroca, B.; Dartigues, J.F. Relationships between cholesterol, apolipoprotein E polymorphism and dementia: A cross-sectional analysis from the PAQUID study. Neuroepidemiology 2000, 19, 141–148. [CrossRef]Sanz, C.; Andrieu, S.; Sinclair, A.; Hanaire, H.; Vellas, B. For the REAL.FR Study Group Diabetes is associated with a slower rate of cognitive decline in Alzheimer disease. Neurology 2009, 73, 1359–1366. [CrossRef]Solimany, F.; Mohammadi, E.; Omidfar, F. Comparison of cognitive abilities, depression and anxiety of type II diabetic patients with healthy individuals in Isfahan province in 2015. Rev. Latinoam. Hipertens. 2018, 13, 8.Marseglia, A.; Fratiglioni, L.; Kalpouzos, G.; Wang, R.; Bäckman, L.; Xu, W. Prediabetes and diabetes accelerate cognitive decline and predict microvascular lesions: A population-based cohort study. Alzheimer’s Dement. 2019, 15, 25–33. [CrossRef]Rouch, I.; Roche, F.; Dauphinot, V.; Laurent, B.; Antérion, C.T.; Celle, S.; Krolak-Salmon, P.; Barthélémy, J.-C. Diabetes, impaired fasting glucose, and cognitive decline in a population of elderly community residents. Aging Clin. Exp. Res. 2012, 24, 377–383. [CrossRef] [PubMed]Yaffe, K.; Blackwell, T.; Kanaya, A.M.; Davidowitz, N.; Barrett-Connor, E.; Krueger, K. Diabetes, impaired fasting glucose, and development of cognitive impairment in older women. Neurology 2004, 63, 658–663. [CrossRef] [PubMed]Vanhanen, M.; Koivisto, K.; Kuusisto, J.; Mykkänen, L.; Helkala, E.-L.; Hänninen, T.; Riekkinen, P.; Soininen, H.; Laakso, M. Cognitive function in an elderly population with persistent impaired glucose tolerance. Diabetes Care 1998, 21, 398–402. [CrossRef] [PubMed]Kanaya, A.M.; Barrett-Connor, E.; Gildengorin, G.; Yaffe, K. Change in cognitive function by glucose tolerance status in older adults: A 4-year prospective study of the Rancho Bernardo study cohort. Arch. Intern. Med. 2004, 164, 1327–1333. [CrossRef]Miles, W.R.; Root, H.F. Psychologic Tests Applied to Diabetic Patients. Arch. Intern. Med. 1922, 30, 767–777. [CrossRef]Grodstein, F.; Chen, J.; Wilson, R.S.; Manson, J.E. Nurses’ Health Study. Type 2 diabetes and cognitive function in communi-tydwelling elderly women. Diabetes Care. 2001, 24, 1060–1065. [CrossRef] [PubMed]Cukierman, T.; Gerstein, H.C.; Williamson, J.D. Cognitive decline and dementia in diabetes—systematic overview of prospective observational studies. Diabetologia 2005, 48, 2460–2469. [CrossRef]Saczynski, J.S.; Jónsdóttir, M.K.; Garcia, M.E.; Jonsson, P.V.; Peila, R.; Eiriksdottir, G.; Olafsdottir, E.; Harris, T.B.; Gudnason, V.; Launer, L.J. Cognitive Impairment: An Increasingly Important Complication of Type 2 Diabetes: The Age, Gene/Environment Susceptibility-Reykjavik Study. Am. J. Epidemiol. 2008, 168, 1132–1139. [CrossRef]Cukierman-Yaffe, T.; Gerstein, H.C.; Williamson, J.D.; Lazar, R.M.; Lovato, L.; Miller, M.E.; Coker, L.H.; Murray, A.; Sullivan, M.D.; Marcovina, S.M.; et al. Relationship between baseline gly-cemic control and cognitive function in individuals with type 2 diabetes and other cardiovascular risk factors: The action to control cardiovascular risk in diabetes-memory in diabetes (ACCORD-MIND) trial. Diabetes Care 2009, 32, 221–226. [CrossRef]Elias, M.F.; Elias, P.K.; Sullivan, L.M.; Wolf, P.A.; D’Agostino, R.B. Obesity, diabetes and cognitive deficit: The Framingham Heart Study. Neurobiol. Aging 2005, 26, 11–16. [CrossRef] [PubMed]Roberts, R.O.; Geda, Y.E.; Knopman, D.S.; Cha, R.H.; Boeve, B.F.; Ivnik, R.J.; Pankratz, V.S.; Tangalos, E.G.; Petersen, R.C. Metabolic syndrome, inflammation, and nonamnestic mild cognitive impairment in older persons: A population-based study. Alzheimer Dis. Assoc. Disord. 2010, 24, 11–18. [CrossRef] [PubMed]Yaffe, K.; Weston, A.L.; Blackwell, T.; Krueger, K.A. The Metabolic Syndrome and Development of Cognitive Impairment Among Older Women. Arch. Neurol. 2009, 66, 324–328. [CrossRef]Pal, K.; Mukadam, N.; Petersen, I.; Cooper, C. Mild cognitive impairment and progression to dementia in people with diabetes, prediabetes and metabolic syndrome: A systematic review and meta-analysis. Soc. Psychiatry Psychiatr. Epidemiol. 2018, 53, 1149–1160. [CrossRef] [PubMed]Atti, A.R.; Valente, S.; Iodice, A.; Caramella, I.; Ferrari, B.; Albert, U.; Mandelli, L.; De Ronchi, D. Metabolic Syndrome, Mild Cognitive Impairment, and Dementia: A Meta-Analysis of Longitudinal Studies. Am. J. Geriatr. Psychiatry 2019, 27, 625–637. [CrossRef] [PubMed]Yau, P.L.; Javier, D.C.; Ryan, C.; Tsui, W.H.; Ardekani, B.A.; Ten, S.; Convit, A. Preliminary evidence for brain complications in obese adolescents with type 2 diabetes mellitus. Diabetologia 2010, 53, 2298–2306. [CrossRef]Verdejo-Garcia, A.; Pérez-Expósito, M.; Schmidt-Río-Valle, J.; Fernández-Serrano, M.J.; Cruz, F.; Pérez-García, M.; López-Belmonte, G.; Martín-Matillas, M.; Martín-Lagos, J.A.; Marcos, A.; et al. Selective Alterations Within Executive Functions in Adolescents With Excess Weight. Obesity 2010, 18, 1572–1578. [CrossRef]. Lande, M.B.; Kaczorowski, J.M.; Auinger, P.; Schwartz, G.J.; Weitzman, M. Elevated blood pressure and decreased cognitive function among school-age children and adolescents in the United States. J. Pediatr. 2003, 143, 720–724. [CrossRef]Li, Y.; Dai, Q.; Jackson, J.C.; Zhang, J. Overweight Is Associated with Decreased Cognitive Functioning Among School-age Children and Adolescents. Obesity 2008, 16, 1809–1815. [CrossRef]Bourdel-Marchasson, I.; Lapre, E.; Laksir, H.; Puget, E. Insulin resistance, diabetes and cognitive function: Consequences for pre-ventative strategies. Diabetes Metab. 2010, 36, 173–181. [CrossRef]Frederiksen, K.S.; Verdelho, A.; Madureira, S.; Bäzner, H.; O’Brien, J.T.; Fazekas, F.; Scheltens, P.; Schmidt, R.; Wallin, A.; Wahlund, L.; et al. Physical activity in the elderly is associated with improved executive function and processing speed: The LADIS Study: Physical activity and cognitive function. Int. J. Geriatr. Psychiatry. 2015, 30, 744–750. [CrossRef] [PubMed]Karssemeijer, E.G.A.; Aaronson, J.A.; Bossers, W.J.; Smits, T.; Olde Rikkert, M.G.M.; Kessels, R.P.C. Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A me-ta-analysis. Ageing Res. Rev. 2017, 40, 75–83. [CrossRef] [PubMed]Groot, C.; Hooghiemstra, A.; Raijmakers, P.; Van Berckel, B.; Scheltens, P.; Scherder, E.; van der Flier, W.; Ossenkoppele, R. The effect of physical activity on cognitive function in patients with dementia: A meta-analysis of randomized control trials. Ageing Res. Rev. 2016, 25, 13–23. [CrossRef]Lautenschlager, N.T.; Cox, K.L.; Ellis, K.A. Physical activity for cognitive health: What advice can we give to older adults with subjective cognitive decline and mild cognitive impairment? Dialogues Clin. Neurosci. 2019, 21, 61–68. [PubMed]McGrattan, A.M.; McEvoy, C.; McGuinness, B.; McKinley, M.C.; Woodside, J.V. Effect of dietary interventions in mild cognitive impairment: A systematic review. Br. J. Nutr. 2018, 120, 1388–1405. [CrossRef] [PubMed]Singh, B.; Parsaik, A.K.; Mielke, M.; Erwin, P.J.; Knopman, D.S.; Petersen, R.C.; Roberts, R.O. Association of Mediterranean Diet with Mild Cognitive Impairment and Alzheimer’s Disease: A Systematic Review and Meta-Analysis. J. Alzheimer’s Dis. 2014, 39, 271–282. [CrossRef] [PubMed]Hosking, D.E.; Eramudugolla, R.; Cherbuin, N.; Anstey, K.J. MIND not Mediterranean diet related to 12-year incidence of cognitive impairment in an Australian longitudinal cohort study. Alzheimer’s Dement. 2019, 15, 581–589. [CrossRef]Krikorian, R.; Shidler, M.D.; Dangelo, K.; Couch, S.C.; Benoit, S.C.; Clegg, D.J. Dietary ketosis enhances memory in mild cognitive impairment. Neurobiol. Aging 2012, 33, 425.e19–425.e27. [CrossRef] [PubMed]Zhang, Y.; Chen, J.; Qiu, J.; Li, Y.; Wang, J.; Jiao, J. Intakes of fish and polyunsaturated fatty acids and mild-to-severe cognitive impairment risks: A dose-response meta-analysis of 21 cohort studies1–3. Am. J. Clin. Nutr. 2015, 103, 330–340. [CrossRef] [PubMed]Rouch, L.; Cestac, P.; Hanon, O.; Cool, C.; Helmer, C.; Bouhanick, B.; Chamontin, B.; Dartigues, J.-F.; Vellas, B.; Andrieu, S. Antihypertensive Drugs, Prevention of Cognitive Decline and Dementia: A Systematic Review of Observational Studies, Randomized Controlled Trials and Meta-Analyses, with Discussion of Potential Mechanisms. CNS Drugs 2015, 29, 113–130. [CrossRef] [PubMed]Levi Marpillat, N.; Macquin-Mavier, I.; Tropeano, A.I.; Bachoud-Levi, A.-C.; Maison, P. Antihypertensive classes, cognitive decline and incidence of dementia: A network meta-analysis. J. Hypertens. 2013, 31, 1073–1082. [CrossRef]Guo, Z.; Fratiglioni, L.; Zhu, L.; Fastbom, J.; Winblad, B.; Viitanen, M. Occurrence and progression of dementia in a community population aged 75 years and older: Relationship of antihypertensive medication use. Arch. Neurol. 1999, 56, 991–996. [CrossRef]Zhang, Q.Q.; Li, W.S.; Liu, Z.; Zhang, H.L.; Ba, Y.G.; Zhang, R.X. Metformin therapy and cognitive dysfunction in patients with type 2 diabetes: A meta-analysis and systematic review. Medicine 2020, 99, 19378. [CrossRef]Ng, T.P.; Feng, L.; Yap, K.B.; Lee, T.S.; Tan, C.H.; Winblad, B. Long-Term Metformin Usage and Cognitive Function among Older Adults with Diabetes. J. Alzheimer’s Dis. 2014, 41, 61–68. [CrossRef]Borzì, A.M.; Condorelli, G.; Biondi, A.; Basile, F.; Vicari, E.S.D.; Buscemi, C.; Luca, S.; Vacante, M. Effects of vildagliptin, a DPP-4 inhibitor, in elderly diabetic patients with mild cognitive impairment. Arch. Gerontol. Geriatr. 2019, 84, 103896. [CrossRef]Areosa Sastre, A.; Vernooij, R.W.; González-Colaço Harmand, M.; Martínez, G. Effect of the treatment of Type 2 diabetes mellitus on the development of cognitive impairment and dementia. Cochrane Database Syst. Rev. 2017, 6, 003804. [CrossRef]Koo, B.K.; Kim, L.; Lee, J.; Moon, M.K. Taking metformin and cognitive function change in older patients with diabetes. Geriatr. Gerontol. Int. 2019, 19, 755–761. [CrossRef] [PubMed]Wennberg, A.M.V.; Hagen, C.E.; Edwards, K.; Roberts, R.O.; Machulda, M.M.; Knopman, D.S.; Petersen, R.C.; Mielke, M.M. Association of antidiabetic medi-cation use, cognitive decline, and risk of cognitive impairment in older people with type 2 diabetes: Results from the pop-ulation-based Mayo Clinic Study of Aging. Int. J. Geriatr. Psychiatry. 2018, 33, 1114–1120. [CrossRef] [PubMed]Fink, H.A.; Jutkowitz, E.; McCarten, J.R.; Hemmy, L.S.; Butler, M.; Davila, H.; Ratner, E.; Calvert, C.; Barclay, T.R.; Brasure, M. Pharmacologic interventions to prevent cognitive decline, mild cognitive impairment, and clinical Alzheimer-type dementia: A systematic review. Ann. Intern. Med. 2018, 168, 39–51. [CrossRef]Ligthart, S.A.; Moll van Charante, E.P.; Van Gool, W.A.; Richard, E. Treatment of cardiovascular risk factors to prevent cognitive decline and dementia: A systematic review. Vasc. Health Risk Manag. 2010, 6, 775–785. [CrossRef] [PubMed]Bosch, J.; O’Donnell, M.; Swaminathan, B.; Lonn, E.M.; Sharma, M.; Dagenais, G.; Diaz, R.; Khunit, K.; Lewis, B.S.; Avezum, A.; et al. Effects of blood pressure and lipid lowering on cognition: Results from the HOPE-3 study. Neurology 2019, 92, 1435–1446. [CrossRef]Bettermann, K.; Arnold, A.M.; Williamson, J.; Rapp, S.; Sink, K.; Toole, J.F.; Carlson, M.C.; Yasar, S.; DeKosky, S.; Burke, G.L. Statins, Risk of Dementia, and Cognitive Function: Secondary Analysis of the Ginkgo Evaluation of Memory Study. J. Stroke Cerebrovasc. Dis. 2012, 21, 436–444. [CrossRef]Zandi, P.P.; Sparks, D.L.; Khachaturian, A.S.; Tschanz, J.; Norton, M.; Steinberg, M.; Welsh-Bohmer, K.A.; Breitner, J.C.S. Do Statins Reduce Risk of Incident Dementia and Alzheimer Disease? The Cache County Study. Arch. Gen. Psychiatry 2005, 62, 217–224. [CrossRef]Rea, T.D.; Breitner, J.C.; Psaty, B.M.; Fitzpatrick, A.L.; Lopez, O.L.; Newman, A.B.; Hazzard, W.R.; Zandi, P.P.; Burke, G.L.; Lyketsos, C.G.; et al. Statin use and the risk of incident dementia: The cardiovascular health study. Arch. Neurol. 2005, 62, 1047–1051. [CrossRef]Bae, S.; Shimada, H.; Lee, S.; Makizako, H.; Lee, S.; Harada, K.; Doi, T.; Tsutsumimoto, K.; Hotta, R.; Nakakubo, S.; et al. The Relationships Between Components of Metabolic Syndrome and Mild Cognitive Impairment Subtypes: A Cross-Sectional Study of Japanese Older Adults. J. Alzheimer’s Dis. 2017, 60, 913–921. [CrossRef]Steen, E.; Terry, B.M.; Rivera, E.J.; Cannon, J.L.; Neely, T.R.; Tavares, R.; Xu, X.J.; Wands, J.R.; De La Monte, S.M. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—Is this type 3 diabetes? J. Alzheimer’s Dis. 2005, 7, 63–80. [CrossRef] [PubMed]Frölich, L.; Blum-Degen, D.; Bernstein, H.-G.; Engelsberger, S.; Humrich, J.; Laufer, S.; Muschner, D.; Thalheimer, A.; Türk, A.; Hoyer, S.; et al. Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J. Neural Transm. 1998, 105, 423–438. [CrossRef] [PubMed]Craft, S.; Peskind, E.; Schwartz, M.W.; Schellenberg, G.D.; Raskind, M.; Porte, D. Cerebrospinal fluid and plasma insulin levels in Alzheimer’s disease: Relationship to severity of dementia and apolipoprotein E genotype. Neurology 1998, 50, 164–168. [CrossRef]Mody, N.; Agouni, A.; Mcilroy, G.D.; Platt, B.; Delibegovic, M. Susceptibility to diet-induced obesity and glucose intolerance in the APP SWE/PSEN1 A246E mouse model of Alzheimer’s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein. Diabetologia 2011, 54, 2143–2151. [CrossRef] [PubMed]Janson, J.; Laedtke, T.; Parisi, J.E.; O’Brien, P.; Petersen, R.C.; Butler, P.C. Increased Risk of Type 2 Diabetes in Alzheimer Disease. Diabetes 2004, 53, 474–481. [CrossRef] [PubMed]Altschul, D.M.; Starr, J.M.; Deary, I.J. Cognitive function in early and later life is associated with blood glucose in older individuals: Analysis of the Lothian Birth Cohort of 1936. Diabetologia 2018, 61, 1946–1955. [CrossRef]Peng, X.; Xu, Z.; Mo, X.; Guo, Q.; Yin, J.; Xu, M.; Peng, Z.; Sun, T.; Zhou, L.; Peng, X.; et al. Association of plasma β-amyloid 40 and 42 concentration with type 2 diabetes among Chinese adults. Diabetologia 2020, 63, 954–963. [CrossRef]Lipton, S.A. Paradigm shift in NMDA receptor antagonist drug development: Molecular mechanism of uncompetitive inhi-bition by memantine in the treatment of Alzheimer’s disease and other neurologic disorders. J. Alzheimers Dis. 2004, 6, 61–74. [CrossRef]Ettcheto, M.; Sanchez-Lopez, E.; Gómez-Mínguez, Y.; Cabrera, H.; Busquets, O.; Beas-Zárate, C.; García, M.L.; Carro, E.; Casadesus, G.; Auladell, C.; et al. Peripheral and Central Effects of Memantine in a Mixed Preclinical Mice Model of Obesity and Familial Alzheimer’s Disease. Mol. Neurobiol. 2018, 55, 7327–7339. [CrossRefAhmed, A.S.; Elgharabawy, R.; Al-Najjar, A.H. Ameliorating effect of anti-Alzheimer’s drugs on the bidirectional association between type 2 diabetes mellitus and Alzheimer’s disease. Exp. Biol. Med. 2017, 242, 1335–1344. [CrossRef] [PubMed]Meakin, P.J.; Harper, A.J.; Hamilton, D.L.; Gallagher, J.; McNeilly, A.D.; Burgess, L.A.; Vaanholt, L.M.; Bannon, K.A.; Latcham, J.; Hussain, I.; et al. Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice. Biochem. J. 2011, 441, 285–296. [CrossRef] [PubMed]Wessels, A.M.; Tariot, P.N.; Zimmer, J.A.; Selzler, K.J.; Bragg, S.M.; Andersen, S.W.; Landry, J.; Krull, J.H.; Downing, A.M.; Willis, B.A.; et al. Efficacy and safety of Lanabecestat for treatment of early and mild Alzheimer disease: The AMARANTH and DAYBREAK-ALZ randomized clinical trials. JAMA Neurol. 2020, 77, 199–209. [CrossRef] [PubMed]Zhang, Y.; Zhou, B.; Deng, B.; Zhang, F.; Wu, J.; Wang, Y.; Le, Y.; Zhai, Q. Amyloid-β Induces Hepatic Insulin Resistance In Vivo via JAK2. Diabetes 2012, 62, 1159–1166. [CrossRef] [PubMed]Gunstad, J.; Spitznagel, M.B.; Paul, R.H.; Cohen, R.A.; Kohn, M.; Luyster, F.S.; Clark, R.; Williams, L.M.; Gordon, E. Body mass index and neuropsychological function in healthy children and adolescents. Appetite 2008, 50, 246–251. [CrossRef]Muller, M.; Tang, M.-X.; Schupf, N.; Manly, J.J.; Mayeux, R.; Luchsinger, J.A. Metabolic Syndrome and Dementia Risk in a Multiethnic Elderly Cohort. Dement. Geriatr. Cogn. Disord. 2007, 24, 185–192. [CrossRef]Forti, P.; Pisacane, N.; Rietti, E.; Lucicesare, A.; Olivelli, V.; Mariani, E.; Mecocci, P.; Ravaglia, G. Metabolic Syndrome and Risk of Dementia in Older Adults. J. Am. Geriatr. Soc. 2010, 58, 487–492. [CrossRef]Feinkohl, I.; Janke, J.; Hadzidiakos, D.; Slooter, A.; Winterer, G.; Spies, C.; Pischon, T. Associations of the metabolic syndrome and its components with cognitive impairment in older adults. BMC Geriatr. 2019, 19, 1–11. [CrossRef]Bermúdez, V.; Añez, R.; Salazar, J.J.; Sanchez, H.; Castellanos, B.; Bello, L.; Villalobos, M. Comportamiento Epidemiológico del síndrome metabólico en el municipio Maracaibo-Venezuela. Síndrome Cardiometabólico 2013, 3, 31–42.Morales Aguilar, R.; Lastre-Amell, G.; Pardo Vásquez, A. Estilos de vida relacionados con factores de riesgo cardiovascular. Arch. Venez. Farmacol. Ter. 2018, 38, 9Espinoza Diaz, C.I.E.; Morocho Zambrano, A.A.; Pesantez Placencia, L.F.; Toala Guerrero, J.E.; Bravo Rey, P.J.; Garavito Martinez, A.M.; Carbo Tapia, A.D.; García Vargas, J.J. Prevalencia de síndrome metabólico y factores asociados en adultos mayores de la parroquia de Baños, Cuenca. Arch. Venez. Farmacol. Ter. 2018, 39, 6.Vanegas, H. Buscando las bases moleculares de la enfermedad de Alzheimer. Gac. Médica Caracas 2017, 125, 4–11Gunczler, P. Síndrome de resistencia a la insulina en niños y adolescentes. Gac. Médica. Caracas 2006, 114, 99–103.Després, J.-P.; Lemieux, I.; Bergeron, J.; Pibarot, P.; Mathieu, P.; LaRose, E.; Rodés-Cabau, J.; Bertrand, O.F.; Poirier, P. Abdominal Obesity and the Metabolic Syndrome: Contribution to Global Cardiometabolic Risk. Arter. Thromb. Vasc. Biol. 2008, 28, 1039–1049. [CrossRef]Narváez López, E.J.; Bravo Peláez, J.A.; Almeida Lozano, K.A.; Alvarez Rivera, C.G.; Mendoza Argandoña, C.A.; Morales Sánchez, A.M.; Godos Rivera, D.T.; Del Salto Ocaña, T.E.; Catota Camacho, M.M. Implicación de polimorfismos de apolipoproteína en la fisiopatología de la ateroesclerosis y enfermedad de Alzheimer. Rev. Latinoam. Hipertens. 2018, 13, 6.Avila Vinueza, J.P.; Avila Vinueza, T.L.; Pesantez Calle, M.F.; Guaraca Pino, A.C.; Durazno Montesdeoca, G.C.; Cobos Alvarracin, M.Y. Frecuencia, factores de riesgo y hallazgos neuroimagenológicos de deterioro cognitivo leve en pacientes con hipertensión arterial. Arch. Venez. Farmacol. Ter. 2019, 38, 12.Chacón, O.; Riaño-Garzón, M.E.; Bermúdez, V.; Quintero Sanguino, M.; Hernández Lalinde, J.D.; Mendoza Bernal, M.I. ¿Es la obesidad un factor de riesgo para el trastorno de déficit de atención con hiperactividad (TDAH)? Rev. Latinoam Hipertens. 2018, 13, 89–97.Lozada, M.; Machado, S.; Manrique, M.; Martínez, D.; Suárez, O.; Guevara, H. Factores de riesgo asociados al síndrome metabólico en adolescentes. Gac. Médica Caracas 2008, 116, 323–329Pinillos Patiño, Y.; Herazo Beltrán, Y.; Vidarte Claros, J.A.; Quiroz, E.; Suarez Palacio, D. Niveles de Actividad Física y sus Deter-minantes en Mujeres Adultas de Barranquilla. Cienc. Innov. Salud 2014, 2, 10–17.De La Cruz Vargas, J.A.; Dyzinger, W.; Herzog, S.; dos Santos, F.; Villegas, H.; Ezinga, M. Medicina del Estilo de Vida: Trabajando juntos para revertir la epidemia de las enfermedades crónicas en Latinoamérica. Cienc. Innov. Salud 2017, 4, 1–7. [CrossRef]Díaz Cárdenas, S. Fomento de la Salud Física en Pacientes de la Facultad de Odontología de la Universidad de Cartagena: Sistematización de Experiencias. Cienc. Innov. Salud 2013, 1, 52–56. 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