Is Periodontitis Associated with Age-Related Cognitive Impairment? The Systematic Review, Confounders Assessment and Meta-Analysis of Clinical Studies
Abstract
:1. Introduction
1.1. The Bidirectional, Circumstantial Relationship, Shared Risk Factors for Periodontitis and Cognitive Impairment
1.2. Induction of Systemic Immune Response Because of Periodontal Inflammation
1.3. Rationale for the Systematic Review (SR) Project
2. Materials and Methods
2.1. Database Search Strategy
2.2. Studies Selection
2.3. Inclusion and Exclusion Criteria
2.4. Quality Assessment of Studies Risk of Bias Evaluation
2.5. Assessment of Confounding
2.6. Data synthesis and Statistical Analysis
3. Results
3.1. Characteristics of Included Studies
3.2. Comparison of Outcome Measures and Diagnostic Criteria
3.3. Quality Assessment of Reviewed, Observational Studies
3.4. Adjustment for Confounding, Measurement of Confounders
3.5. Summary of Systamatic Review Results Subgroups Analyses
3.6. Quantitative Evaluation Meta-Analysis and Sensitivity Analyses
4. Discussion
4.1. Non-Clinical Data Supporting PDS-ACI Relationship
4.2. Causal Relationship Assessment Using Koch’s Postulates and Bradford-Hill’s Criteria
4.3. Consistency of Temporality of Collected Data
4.4. Other Systematic Reviews Investigating the PDS-ACI Relationship
4.5. Strengths and Limitations
4.6. The Implication of the Obtained Findings on Public Health Strategies
5. Conclusions
Supplementary Materials
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Jaul, E.; Barron, J. Age-Related Diseases and Clinical and Public Health Implications for the 85 Years Old and over Population. Front. Public Health 2017, 5, 335. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Franceschi, C.; Garagnani, P.; Morsiani, C.; Conte, M.; Santoro, A.; Grignolio, A.; Monti, D.; Capri, M.; Salvioli, S. The Continuum of Aging and Age-Related Diseases: Common Mechanisms but Different Rates. Front. Med. 2018, 12, 61. [Google Scholar]
- World Health Organization. Global Action Plan on the Public Health Response to Dementia 2017–2025. 2017. Available online: https://www.who.int/publications/i/item/global-action-plan-on-the-public-health-response-to-dementia-2017---2025 (accessed on 20 December 2021).
- Gatz, M.; Mortimer, J.A.; Fratiglioni, L.; Johansson, B.; Berg, S.; Reynolds, C.A.; Pedersen, N.L. Potentially modifiable risk factors for dementia in identical twins. Alzheimer’s Dement. J. Alzheimer’s Assoc. 2006, 2, 110–117. [Google Scholar] [CrossRef]
- Aarabi, G.; Thomalla, G.; Heydecke, G.; Seedorf, U. Chronic oral infection: An emerging risk factor of cerebral small vessel disease? Oral Dis. 2018, 25, 710–719. [Google Scholar] [CrossRef] [PubMed]
- Kamer, A.R.; Dasanayake, A.P.; Craig, R.G.; Glodzik-Sobanska, L.; Bry, M.; de Leon, M.J. Alzheimer’s disease and peripheral infections: The possible contribution from periodontal infections, model and hypothesis. J. Alzheimers Dis. 2008, 13, 437–449. [Google Scholar] [CrossRef] [Green Version]
- Guo, H.; Chang, S.; Pi, X.; Hua, F.; Jiang, H.; Liu, C.; Du, M. The Effect of Periodontitis on Dementia and Cognitive Impairment: A Meta-Analysis. Int. J. Environ. Res. Public Health 2021, 18, 6823. [Google Scholar] [CrossRef]
- Tonsekar, P.P.; Jiang, S.S.; Yue, G. Periodontal disease, tooth loss and dementia: Is there a link? A systematic review. Gerodontology 2017, 34, 151–163. [Google Scholar] [CrossRef]
- Nangle, M.R.; Riches, J.; Grainger, S.A.; Manchery, N.; Sachdev, P.S.; Henry, J.D. Oral Health and Cognitive Function in Older Adults: A Systematic Review. Gerontology 2019, 65, 659–672. [Google Scholar] [CrossRef]
- Asher, S.; Stephen, R.; Mäntylä, P.; Suominen, A.L.; Solomon, A. Periodontal health, cognitive decline, and dementia: A systematic review and meta-analysis of longitudinal studies. J. Am. Geriatr. Soc. 2022, 70, 2695–2709. [Google Scholar] [CrossRef]
- Suhrcke, M.; Nugent, R.A.; Stuckler, D.; Rocco, L. Chronic Disease: An Economic Perspective; Oxford Health Alliance: Oxford, UK, 2006. [Google Scholar]
- Maresova, P.; Javanmardi, E.; Barakovic, S.; Barakovic Husic, J.; Tomsone, S.; Krejcar, O.; Kuca, K. Consequences of chronic diseases and other limitations associated with old age-a scoping review. BMC Public Health 2019, 19, 1431. [Google Scholar] [CrossRef]
- Sanderson, W.C.; Sergei, S.; Gerland, P. Probabilistic population aging. PLoS ONE 2017, 12, e0179171. [Google Scholar] [CrossRef] [PubMed]
- Atella, V.; Piano Mortari, A.; Kopinska, J.; Belotti, F.; Lapi, F.; Cricelli, C.; Fontana, L. Trends in age-related disease burden and healthcare utilization. Aging Cell 2019, 18, e12861. [Google Scholar] [CrossRef]
- Kennedy, B.K.; Berger, S.L.; Brunet, A.; Campisi, J.; Cuervo, A.M.; Epel, E.S.; Franceschi, C.; Lithgow, G.J.; Morimoto, R.I.; Pessin, J.E.; et al. Geroscience: Linking aging to chronic disease. Cell 2014, 159, 709–771. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hosseinpoor, A.R.; Bergen, N.; Kunst, A.; Harper, S.; Guthold, R.; Rekve, D.; D’Espaignet, E.T.; Naidoo, N.; Chatterji, S. Socioeconomic inequalities in risk factors for non communicable diseases in low-income and middle-income countries: Results from the World Health Survey. BMC Public Health 2012, 12, 912. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lago, S.; Cantarero, D.; Rivera, B.; Pascual, M.; Blázquez-Fernández, C.; Casal, B.; Reyes, F. Socioeconomic status, health inequalities and non-communicable diseases: A systematic review. Z. Gesundh. Wiss. 2018, 26, 1–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Joyce, G.F.; Keeler, E.B.; Shang, B.; Goldman, D.P. The lifetime burden of chronic disease among the elderly. Health Aff. 2005, 24 (Suppl. S2), W5R18-29. [Google Scholar] [CrossRef] [PubMed]
- Nazir, M.; Al-Ansari, A.; Al-Khalifa, K.; Alhareky, M.; Gaffar, B.; Almas, K. Global Prevalence of Periodontal Disease and Lack of Its Surveillance. Sci. World J. 2020, 2020, 2146160. [Google Scholar] [CrossRef] [PubMed]
- Petersen, P.E.; Ogawa, H. The global burden of periodontal disease: Towards integration with chronic disease prevention and control. Periodontology 2000 2012, 60, 15–39. [Google Scholar] [CrossRef]
- GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet 2017, 390, 1211–1259. [Google Scholar] [CrossRef] [Green Version]
- Eke, P.I.; Dye, B.A.; Wei, L.; Thornton-Evans, G.O.; Genco, R.J. CDC Periodontal Disease Surveillance workgroup: James Beck (University of North Carolina, Chapel Hill, USA), Gordon Douglass (Past President, American Academy of Periodontology), Roy Page (University of Washin. Prevalence of periodontitis in adults in the United States: 2009 and 2010. J. Dent. Res. 2012, 91, 914–920. [Google Scholar]
- Okada, H.; Murakami, S. Cytokine expression in periodontal health and disease. Crit. Rev. Oral Biol. Med. 1998, 9, 248–266. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Van Dyke, T.E.; Serhan, C.N. Resolution of inflammation: A new paradigm for the pathogenesis of periodontal diseases. J. Dent. Res. 2003, 82, 82–90. [Google Scholar] [CrossRef] [PubMed]
- Graves, D.T.; Cochran, D. The contribution of interleukin-1 and tumor necrosis factor to periodontal tissue destruction. J. Periodontol. 2003, 74, 391–401. [Google Scholar] [CrossRef]
- Liu, Y.C.; Lerner, U.H.; Teng, Y.T. Cytokine responses against periodontal infection: Protective and destructive roles. Periodontology 2000 2010, 52, 163–206. [Google Scholar]
- Harrell, J.C.; Stein, S.H. Prostaglandin E2 regulates gingival mononuclear cell immunoglobulin production. J. Periodontol. 1995, 66, 222–227. [Google Scholar] [CrossRef] [PubMed]
- Garlet, G.P. Destructive and protective roles of cytokines in periodontitis: A re-appraisal from host defense and tissue destruction viewpoints. J. Dent. Res. 2010, 89, 1349–1363. [Google Scholar] [CrossRef]
- Cekici, A.; Kantarci, A.; Hasturk, H.; Van Dyke, T.E. Inflammatory and immune pathways in the pathogenesis of periodontal disease. Periodontology 2000 2014, 64, 57–80. [Google Scholar]
- Hanada, T.; Yoshimura, A. Regulation of cytokine signaling and inflammation. Cytokine Growth Factor Rev. 2002, 13, 413–421. [Google Scholar] [CrossRef]
- Nascimento, P.C.; Castro, M.M.L.; Magno, M.B.; Almeida, A.P.C.P.S.C.; Fagundes, N.C.F.; Maia, L.C.; Lima, R.R. Association Between Periodontitis and Cognitive Impairment in Adults: A Systematic Review. Front. Neurol. 2019, 10, 323. [Google Scholar] [CrossRef] [Green Version]
- de Souza Rolim, T.; Fabri, G.M.; Nitrini, R.; Anghinah, R.; Teixeira, M.J.; de Siqueira, J.T.; Cestari, J.A.; de Siqueira, S.R. Oral infections and orofacial pain in Alzheimer’s disease: A case-control study. J. Alzheimers Dis. 2014, 38, 823–829. [Google Scholar] [CrossRef]
- Teixeira, F.B.; Saito, M.T.; Matheus, F.C.; Prediger, R.D.; Yamada, E.S.; Maia, C.S.F.; Lima, R.R. Periodontitis and Alzheimer’s Disease: A Possible Comorbidity between Oral Chronic Inflammatory Condition and Neuroinflammation. Front. Aging Neurosci. 2017, 9, 327. [Google Scholar] [CrossRef] [PubMed]
- Kapellas, K.; Ju, X.; Wand, X.; Mueller, N.; Jamieson, L.M. The association between periodontal disease and dementia: A systematic review and meta-analysis. Dent. Oral Biol. Cranofacial. Res. 2019, 2, 11. [Google Scholar]
- Kamer, A.R.; Craig, R.G.; Niederman, R.; Fortea, J.; de Leon, M.J. Periodontal disease as a possible cause for Alzheimer’s disease. Periodontology 2000 2020, 83, 242–271. [Google Scholar] [CrossRef]
- Kamer, A.R.; Morse, D.E.; Holm-Pedersen, P.; Mortensen, E.L.; Avlund, K. Periodontal inflammation in relation to cognitive function in an older adult Danish population. J. Alzheimers Dis. 2012, 28, 613–624. [Google Scholar] [CrossRef]
- Martande, S.S.; Pradeep, A.R.; Singh, S.P.; Kumari, M.; Suke, D.K.; Raju, A.P.; Naik, S.B.; Singh, P.; Guruprasad, C.N.; Chatterji, A. Periodontal health condition in patients with Alzheimer’s disease. Am. J. Alzheimers Dis. Other Demen. 2014, 29, 498–502. [Google Scholar] [CrossRef]
- Foley, N.C.; Affoo, R.H.; Siqueira, W.L.; Martin, R.E. A Systematic Review Examining the Oral Health Status of Persons with Dementia. JDR Clin. Transl. Res. 2017, 2, 330–342. [Google Scholar] [CrossRef]
- Delwel, S.; Binnekade, T.T.; Perez, R.S.G.M.; Hertogh, C.M.P.M.; Scherder, E.J.A.; Lobbezoo, F. Oral hygiene and oral health in older people with dementia: A comprehensive review with focus on oral soft tissues. Clin. Oral Investig. 2018, 22, 93–108. [Google Scholar] [CrossRef] [Green Version]
- Daly, B.; Thompsell, A.; Sharpling, J.; Rooney, Y.M.; Hillman, L.; Wanyonyi, K.L.; White, K.; Gallagher, J.E. Evidence summary: The relationship between oral health and dementia. BDJ 2017, 223, 846–853. [Google Scholar] [CrossRef] [PubMed]
- Ide, M.; Harris, M.; Stevens, A.; Sussams, R.; Hopkins, V.; Culliford, D.; Fuller, J.; Ibbett, P.; Raybould, R.; Thomas, R.; et al. Periodontitis and Cognitive Decline in Alzheimer’s Disease. PLoS ONE 2016, 11, e0151081. [Google Scholar] [CrossRef] [Green Version]
- Persson, G.R. Periodontal complications with age. Periodontology 2000 2018, 78, 185–194. [Google Scholar] [CrossRef]
- Brookmeyer, R.; Johnson, E.; Ziegler-Graham, K.; Arrighi, H.M. Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement. 2007, 3, 186–191. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- AlJehani, Y.A. Risk factors of periodontal disease: Review of the literature. Int. J. Dent. 2014, 2014, 182513. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Grossi, S.G.; Zambon, J.J.; Ho, A.W.; Koch, G.; Dunford, R.G.; Machtei, E.E.; Norderyd, O.M.; Genco, R.J. Assessment of risk for periodontal disease. I. Risk indicators, for attachment loss. J. Periodontol. 1994, 65, 260–267. [Google Scholar] [CrossRef] [PubMed]
- Thorbert-Mros, S.; Cassel, B.; Berglundh, T. Age of onset of disease in subjects with severe periodontitis: A 9- to 34-year retrospective study. J. Clin. Periodontol. 2017, 44, 778–783. [Google Scholar] [CrossRef]
- Montelaro, S. Alzheimer’s disease: A growing concern in geriatric dentistry. Gen. Dent. 1985, 33, 494–497. [Google Scholar]
- Niessen, L.C.; Jones, J.A.; Zocchi, M.; Gurian, B. Dental care for the patient with Alzheimer’s disease. J. Am. Dent. Assoc. 1985, 110, 207–209. [Google Scholar] [CrossRef]
- Sanz, M.; Del Castillo, A.M.; Jepsen, S.; Juanatey, J.R.G.; D’Aiuto, F.; Bouchard, P.; Chapple, I.; Dietrich, T.; Gotsman, I.; Graziani, F.; et al. Periodontitis and cardiovascular diseases: Consensus report. J. Clin. Periodontol. 2020, 47, 268–288. [Google Scholar] [CrossRef]
- Genco, R.J. Current view of risk factors for periodontal diseases. J. Periodontol. 1996, 67, 1041–1049. [Google Scholar]
- Natto, Z.S.; Ahmad, R.; Alsharif, L.T.; Alrowithi, H.F.; AlSini, D.A.; Salih, H.A.; Bissada, N.F. Chronic Periodontitis Case Definitions and Confounders in Periodontal Research: A Systematic Assessment. Biomed. Res. Int 2018, 2018, 4578782. [Google Scholar] [CrossRef] [Green Version]
- Baima, G.; Romandini, M.; Citterio, F.; Romano, F.; Aimetti, M. Periodontitis and Accelerated Biological Aging: A Geroscience Approach. J. Dent. Res. 2021, 5, 220345211037977. [Google Scholar] [CrossRef]
- Guthmiller, J.M.; Novak, K.F. Periodontal Diseases. In Polymicrobial Diseases; Brogden, K.A., Guthmiller, J.M., Eds.; Chapter 8; ASM Press: Washington, DC, USA, 2012. Available online: https://www.ncbi.nlm.nih.gov/books/NBK2496/ (accessed on 15 September 2021).
- Meyle, J.; Chapple, I. Molecular aspects of the pathogenesis of periodontitis. Periodontology 2000 2015, 69, 7–17. [Google Scholar] [CrossRef]
- Maldonado, A.; Laugisch, O.; Bürgin, W.; Sculean, A.; Eick, S. Clinical periodontal variables in patients with and without dementia-a systematic review and meta-analysis. Clin. Oral Investig. 2018, 22, 2463–2474. [Google Scholar] [CrossRef]
- Garcia, R.I.; Henshaw, M.M.; Krall, E.A. Relationship between periodontal disease and systemic health. Periodontology 2000 2001, 25, 21–36. [Google Scholar] [CrossRef]
- Taylor, B.A.; Tofler, G.H.; Carey, H.M.; Morel-Kopp, M.C.; Philcox, S.; Carter, T.R.; Elliott, M.J.; Kull, A.D.; Ward, C.; Schenck, K. Full-mouth tooth extraction lowers systemic inflammatory and thrombotic markers of cardiovascular risk. J. Dent. Res. 2006, 85, 74–78. [Google Scholar] [CrossRef]
- Montagne, A.; Barnes, S.R.; Sweeney, M.D.; Halliday, M.R.; Sagare, A.P.; Zhao, Z.; Toga, A.W.; Jacobs, R.E.; Liu, C.Y.; Amezcua, L.; et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron 2015, 85, 296–302. [Google Scholar] [CrossRef] [Green Version]
- Gorelick, P.B. Role of inflammation in cognitive impairment: Results of observational epidemiological studies and clinical trials. Ann. N. Y. Acad. Sci. 2010, 1207, 155–162. [Google Scholar] [CrossRef]
- Kamer, A.R.; Craig, R.G.; Pirraglia, E.; Dasanayake, A.P.; Norman, R.G.; Boylan, R.J.; Nehorayoff, A.; Glodzik, L.; Brys, M.; de Leon, M.J. TNF-alpha and antibodies to periodontal bacteria discriminate between Alzheimer’s disease patients and normal subjects. J. Neuroimmunol. 2009, 216, 92–97. [Google Scholar] [CrossRef]
- Watts, A.; Crimmins, E.M.; Gatz, M. Inflammation as a potential mediator for the association between periodontal disease and Alzheimer’s disease. Neuropsychiatr. Dis. Treat 2008, 4, 865–876. [Google Scholar] [CrossRef] [Green Version]
- Rosi, S.; Ramirez-Amaya, V.; Hauss-Wegrzyniak, B.; Wenk, G.L. Chronic brain inflammation leads to a decline in hippocampal NMDA-R1 receptors. J. Neuroinflamm. 2004, 1, 12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fulop, T.; Witkowski, J.M.; Bourgade, K.; Khalil, A.; Zerif, E.; Larbi, A.; Hirokawa, K.; Pawelec, G.; Bocti, C.; Lacombe, G.; et al. Can an Infection Hypothesis Explain the Beta Amyloid Hypothesis of Alzheimer’s Disease? Front. Aging Neurosci. 2018, 10, 224. [Google Scholar] [CrossRef] [Green Version]
- Abbott, A. Are infections seeding some cases of Alzheimer’s disease? Nature 2020, 587, 22–25. [Google Scholar] [CrossRef] [PubMed]
- Olsen, I.; Singhrao, S.K. Can oral infection be a risk factor for Alzheimer’s disease? J. Oral Microbiol. 2015, 7, 29143. [Google Scholar] [CrossRef] [Green Version]
- Miklossy, J.; McGeer, P.L. Common mechanisms involved in Alzheimer’s disease and type 2 diabetes: A key role of chronic bacterial infection and inflammation. Aging 2016, 8, 575–588. [Google Scholar] [CrossRef] [Green Version]
- Gil-Montoya, J.A.; Barrios, R.; Sanchez-Lara, I.; Ramos, P.; Carnero, C.; Fornieles, F.; Montes, J.; Santana, S.; de Dios Luna, J.; Gonzalez-Moles, M.A. Systemic inflammatory impact of periodontitis on cognitive impairment. Gerodontology 2019, 37, 11–18. [Google Scholar] [CrossRef]
- Nadim, R.; Tang, J.; Dilmohamed, A.; Yuan, S.; Wu, C.; Bakre, A.T.; Partridge, M.; Ni, J.; Copeland, J.R.; Anstey, K.J.; et al. Influence of periodontal disease on risk of dementia: A systematic literature review and a meta-analysis. Eur. J. Epidemiol. 2020, 35, 821–833. [Google Scholar] [CrossRef]
- Liccardo, D.; Marzano, F.; Carraturo, F.; Guida, M.; Femminella, G.D.; Bencivenga, L.; Agrimi, J.; Addonizio, A.; Melino, I.; Valletta, A.; et al. Potential Bidirectional Relationship Between Periodontitis and Alzheimer’s Disease. Front. Physiol. 2020, 11, 683. [Google Scholar] [CrossRef]
- Poole, S.; Singhrao, S.K.; Kesavalu, L.; Curtis, M.A.; Crean, S. Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer’s disease brain tissue. J. Alzheimers Dis. 2013, 36, 665–677. [Google Scholar] [CrossRef]
- Beck, J.D.; Offenbacher, S. Systemic effects of periodontitis: Epidemiology of periodontal disease and cardiovascular disease. J. Periodontol. 2005, 76 (Suppl. S11), 2089–2100. [Google Scholar] [CrossRef] [PubMed]
- Winning, L.; Linden, G.J. Periodontitis and Systemic Disease: Association or Causality? Curr. Oral Health Rep. 2017, 4, 1–7. [Google Scholar] [CrossRef] [Green Version]
- Macedo Paizan, M.L.; Vilela-Martin, J.F. Is there an association between periodontitis and hypertension? Curr. Cardiol. Rev. 2014, 10, 355–361. [Google Scholar] [CrossRef] [Green Version]
- Martin-Cabezas, R.; Seelam, N.; Petit, C.; Agossa, K.; Gaertner, S.; Tenenbaum, H.; Davideau, J.L.; Huck, O. Association between periodontitis and arterial hypertension: A systematic review and meta-analysis. Am. Heart J. 2016, 180, 98–112. [Google Scholar] [CrossRef] [PubMed]
- Noble, J.M.; Scarmeas, N.; Celenti, R.S.; Elkind, M.S.; Wright, C.B.; Schupf, N.; Papapanou, P.N. Serum IgG antibody levels to periodontal microbiota are associated with incident Alzheimer disease. PLoS ONE 2014, 18, e114959. [Google Scholar] [CrossRef] [Green Version]
- Holmes, C.; Cunningham, C.; Zotova, E.; Woolford, J.; Dean, C.; Kerr, S.; Culliford, D.; Perry, V.H. Systemic inflammation and disease progression in Alzheimer disease. Neurology 2009, 73, 768–774. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ding, Y.; Ren, J.; Yu, H.; Yu, W.; Zhou, Y. Porphyromonas gingivalis, a periodontitis causing bacterium, induces memory impairment and age-dependent neuroinflammation in mice. Immun. Ageing 2018, 15, 6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Amor, S.; Puentes, F.; Baker, D.; van der Valk, P. Inflammation in neurodegenerative diseases. Immunology 2010, 129, 154–169. [Google Scholar] [CrossRef]
- Kannarkat, G.T.; Boss, J.M.; Tansey, M.G. The role of innate and adaptive immunity in Parkinson’s disease. J. Parkinsons Dis. 2013, 3, 493–514. [Google Scholar] [CrossRef] [Green Version]
- McGeer, E.G.; McGeer, P.L. Brain inflammation in Alzheimer disease and the therapeutic implications. Curr. Pharm. Des. 1999, 5, 821–836. [Google Scholar]
- Zhong, J.; Shi, G. Editorial: Regulation of Inflammation in Chronic Disease. Front. Immunol. 2019, 10, 737. [Google Scholar] [CrossRef]
- Singhrao, S.K.; Olsen, I. Assessing the role of Porphyromonas gingivalis in periodontitis to determine a causative relationship with Alzheimer’s disease. J. Oral Microbiol. 2019, 11, 1563405. [Google Scholar] [CrossRef] [Green Version]
- Page, R.C. The pathobiology of periodontal diseases may affect systemic diseases: Inversion of a paradigm. Ann. Periodontol. 1998, 3, 108–120. [Google Scholar] [CrossRef]
- Amar, S.; Han, X. The impact of periodontal infection on systemic diseases. Med. Sci. Monit. 2003, 9, RA291-9. [Google Scholar] [PubMed]
- D’Aiuto, F.; Parkar, M.; Andreou, G.; Suvan, J.; Brett, P.M.; Ready, D.; Tonetti, M.S. Periodontitis and systemic inflammation: Control of the local infection is associated with a reduction in serum inflammatory markers. J. Dent. Res. 2004, 83, 156–160. [Google Scholar] [CrossRef] [PubMed]
- Loos, B.G. Systemic markers of inflammation in periodontitis. J. Periodontol. 2005, 76 (Suppl. S11), 2106–2115. [Google Scholar] [CrossRef] [PubMed]
- Lio, D.; Annoni, G.; Licastro, F.; Crivello, A.; Forte, G.I.; Scola, L.; Colonna-Romano, G.; Candore, G.; Arosio, B.; Galimberti, L.; et al. Tumor necrosis factor-alpha -308A/G polymorphism is associated with age at onset of Alzheimer’s disease. Mech. Ageing Dev. 2006, 127, 567–571. [Google Scholar] [CrossRef]
- Grammas, P.; Ovase, R. Inflammatory factors are elevated in brain microvessels in Alzheimer’s disease. Neurobiol. Aging 2001, 22, 837–842. [Google Scholar] [CrossRef]
- Engelhart, M.J.; Geerlings, M.I.; Meijer, J.; Kiliaan, A.; Ruitenberg, A.; van Swieten, J.C.; Stijnen, T.; Hofman, A.; Witteman, J.C.; Breteler, M.M. Inflammatory proteins in plasma and the risk of dementia: The rotterdam study. Arch. Neurol. 2004, 61, 668–672. [Google Scholar] [CrossRef] [Green Version]
- Sheng, J.G.; Bora, S.H.; Xu, G.; Borchelt, D.R.; Price, D.L.; Koliatsos, V.E. Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid beta peptide in APPswe transgenic mice. Neurobiol. Dis. 2003, 14, 133–145. [Google Scholar] [CrossRef]
- Soscia, S.J.; Kirby, J.E.; Washicosky, K.J.; Tucker, S.M.; Ingelsson, M.; Hyman, B.; Burton, M.A.; Goldstein, L.E.; Duong, S.; Tanzi, R.E.; et al. The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS ONE 2010, 5, e9505. [Google Scholar] [CrossRef]
- Noble, J.M.; Borrell, L.N.; Papapanou, P.N.; Elkind, M.S.; Scarmeas, N.; Wright, C.B. Periodontitis is associated with cognitive impairment among older adults: Analysis of NHANES-III. J. Neurol. Neurosurg. Psychiatry 2009, 80, 1206–1211. [Google Scholar] [CrossRef] [Green Version]
- Singhrao, S.K.; Harding, A.; Poole, S.; Kesavalu, L.; Crean, S. Porphyromonas gingivalis Periodontal Infection and Its Putative Links with Alzheimer’s Disease. Mediat. Inflamm. 2015, 2015, 137357. [Google Scholar] [CrossRef] [Green Version]
- Kornman, K.S.; Page, R.C.; Tonetti, M.S. The host response to the microbial challenge in periodontitis: Assembling the players. Periodontology 2000 1997, 14, 33–53. [Google Scholar] [CrossRef] [PubMed]
- Wilson, C.J.; Finch, C.E.; Cohen, H.J. Cytokines and cognition--the case for a head-to-toe inflammatory paradigm. J. Am. Geriatr. Soc 2002, 50, 2041–2056. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Floyd, R.A. Neuroinflammatory processes are important in neurodegenerative diseases: An hypothesis to explain the increased formation of reactive oxygen and nitrogen species as major factors involved in neurodegenerative disease development. Free Radic. Biol. Med. 1999, 26, 1346–1355. [Google Scholar] [CrossRef] [PubMed]
- Cicciù, M. Neurodegenerative Disorders and Periodontal Disease: Is There a Logical Connection? Neuroepidemiology 2016, 47, 94–95. [Google Scholar] [CrossRef]
- Akiyama, H.; Barger, S.; Barnum, S.; Bradt, B.; Bauer, J.; Cole, G.M.; Cooper, N.R.; Eikelenboom, P.; Emmerling, M.; Fiebich, B.L.; et al. Inflammation and Alzheimer’s disease. Neurobiol. Aging 2000, 21, 383–421. [Google Scholar] [CrossRef] [PubMed]
- Potter, H.; Wisniewski, T. Apolipoprotein e: Essential catalyst of the Alzheimer amyloid cascade. Int. J. Alzheimers Dis. 2012, 2012, 489428. [Google Scholar] [CrossRef] [Green Version]
- Lotz, S.K.; Blackhurst, B.M.; Reagin, K.L.; Funk, K.E. Microbial Infections Are a Risk Factor for Neurodegenerative Diseases. Front. Cell Neurosci 2021, 15, 691136. [Google Scholar]
- Dehhaghi, M.; Kazemi Shariat Panahi, H.; Guillemin, G.J. Microorganisms’ Footprint in Neurodegenerative Diseases. Front. Cell Neurosci. 2018, 12, 466. [Google Scholar] [CrossRef] [Green Version]
- Vigasova, D.; Nemergut, M.; Liskova, B.; Damborsky, J. Multi-pathogen infections and Alzheimer’s disease. Microb. Cell Fact. 2021, 20, 25. [Google Scholar] [CrossRef]
- Wang, R.P.; Ho, Y.S.; Leung, W.K.; Goto, T.; Chang, R.C. Systemic inflammation linking chronic periodontitis to cognitive decline. Brain Behav. Immun. 2019, 81, 63–73. [Google Scholar] [CrossRef]
- Zhao, Y.; Lukiw, W.J. Microbiome-generated amyloid and potential impact on amyloidogenesis in Alzheimer’s disease (AD). J. Nat. Sci. 2015, 1, e138. [Google Scholar] [PubMed]
- Miklossy, J. Bacterial Amyloid and DNA are Important Constituents of Senile Plaques: Further Evidence of the Spirochetal and Biofilm Nature of Senile Plaques. J. Alzheimers Dis. 2016, 13, 1459–1473. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pritchard, A.B.; Crean, S.; Olsen, I.; Singhrao, S.K. Periodontitis, Microbiomes and their Role in Alzheimer’s Disease. Front. Aging Neurosci. 2017, 9, 336. [Google Scholar] [CrossRef] [Green Version]
- Asti, A.; Gioglio, L. Can a bacterial endotoxin be a key factor in the kinetics of amyloid fibril formation? J. Alzheimers Dis. 2014, 39, 169–179. [Google Scholar] [CrossRef] [PubMed]
- Sampson, T.R.; Debelius, J.W.; Thron, T.; Janssen, S.; Shastri, G.G.; Ilhan, Z.E.; Challis, C.; Schretter, C.E.; Rocha, S.; Gradinaru, V.; et al. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease. Cell 2016, 167, 1469–1480.e12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pisa, D.; Alonso, R.; Carrasco, L. Parkinson’s Disease: A Comprehensive Analysis of Fungi and Bacteria in Brain Tissue. Int. J. Biol. Sci. 2020, 16, 1135–1152. [Google Scholar] [CrossRef] [PubMed]
- Silver, J.G.; Martin, A.W.; McBride, B.C. Experimental transient bacteraemias in human subjects with varying degrees of plaque accumulation and gingival inflammation. J. Clin. Periodontol. 1977, 4, 92–99. [Google Scholar] [CrossRef]
- Chukkapalli, S.; Rivera-Kweh, M.F.; Velsko, I.M.; Chen, H.; Zheng, D.; Bhattacharyya, I.; Gangula, P.R.; Lucas, A.R.; Kesavalu, L. Chronic oral infection with major periodontal bacteria Tannerella forsythia modulates systemic atherosclerosis risk factors and inflammatory markers. Pathog. Dis. 2015, 73, ftv009. [Google Scholar] [CrossRef] [Green Version]
- Scannapieco, F.A.; Bush, R.B.; Paju, S. Associations between periodontal disease and risk for nosocomial bacterial pneumonia and chronic obstructive pulmonary disease. A systematic review. Ann. Periodontol. 2003, 8, 54–69. [Google Scholar] [CrossRef]
- Reyes, L.; Getachew, H.; Dunn, W.A.; Progulske-Fox, A. Porphyromonas gingivalis W83 traffics via ICAM1 in microvascular endothelial cells and alters capillary organization in vivo. J. Oral Microbiol. 2020, 12, 1742528. [Google Scholar] [CrossRef] [Green Version]
- Erickson, M.A.; Banks, W.A. Blood-brain barrier dysfunction as a cause and consequence of Alzheimer’s disease. J. Cereb. Blood Flow Metab. 2013, 33, 1500–1513. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Velsko, I.M.; Chukkapalli, S.S.; Rivera, M.F.; Lee, J.Y.; Chen, H.; Zheng, D.; Bhattacharyya, I.; Gangula, P.R.; Lucas, A.R.; Kesavalu, L. Active invasion of oral and aortic tissues by Porphyromonas gingivalis in mice causally links periodontitis and atherosclerosis. PLoS ONE 2014, 9, e97811. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, J.; Yu, C.; Zhang, X.; Chen, H.; Dong, J.; Lu, W.; Song, Z.; Zhou, W. Porphyromonas gingivalis lipopolysaccharide induces cognitive dysfunction, mediated by neuronal inflammation via activation of the TLR4 signalling pathway in C57BL/6 mice. J. Neuroinflamm. 2018, 9, 37. [Google Scholar] [CrossRef] [PubMed]
- Dominy, S.S.; Lynch, C.; Ermini, F.; Benedyk, M.; Marczyk, A.; Konradi, A.; Nguyen, M.; Haditsch, U.; Raha, D.; Griffin, C.; et al. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci. Adv. 2019, 23, eaau3333. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chi, L.; Cheng, X.; Lin, L.; Yang, T.; Sun, J.; Feng, Y.; Liang, F.; Pei, Z.; Teng, W. Porphyromonas gingivalis-Induced Cognitive Impairment Is Associated With Gut Dysbiosis, Neuroinflammation, and Glymphatic Dysfunction. Front. Cell Infect. Microbiol. 2021, 11, 755925. [Google Scholar] [CrossRef]
- Riviere, G.R.; Riviere, K.H.; Smith, K.S. Molecular and immunological evidence of oral Treponema in the human brain and their association with Alzheimer’s disease. Oral Microbiol. Immunol. 2002, 17, 113–118. [Google Scholar] [CrossRef]
- Miklossy, J. Alzheimer’s disease-a neurospirochetosis. Analysis of the evidence following Koch’s and Hill’s criteria. J. Neuroinflamm. 2011, 8, 90. [Google Scholar] [CrossRef] [Green Version]
- Abbayya, K.; Puthanakar, N.Y.; Naduwinmani, S.; Chidambar, Y.S. Association between Periodontitis and Alzheimer’s Disease. N. Am. J. Med. Sci. 2015, 7, 241–246. [Google Scholar] [CrossRef] [Green Version]
- Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G.; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. BMJ 2009, 339, b2535. [Google Scholar] [CrossRef]
- Liberati, A.; Altman, D.G.; Tetzlaff, J.; Mulrow, C.; Gotzsche, P.C.; Ioannidis, J.P.A.; Clarke, M.; Devereaux, P.J.; Kleijnen, J.; Moher, D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: Explanation and elaboration. BMJ 2009, 339, b2700. [Google Scholar] [CrossRef] [Green Version]
- Brown, D. A Review of the PubMed PICO Tool: Using Evidence-Based Practice in Health Education. Health Promot. Pr. 2020, 21, 496–498. [Google Scholar] [CrossRef] [PubMed]
- Schardt, C.; Adams, M.B.; Owens, T.; Keitz, S.; Fontelo, P. Utilization of the PICO framework to improve searching PubMed for clinical questions. BMC Med. Inform. Decis. Mak. 2007, 15, 16. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wells, G.; Shea, B.; O’Connell, D.; Peterson, J.; Welch, V.; Losos, M.; Tugwell, P. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses. 2013. Available online: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (accessed on 20 December 2021).
- Bax, L.; Yu, L.M.; Ikeda, N.; Moons, K.G. A systematic comparison of software dedicated to meta-analysis of causal studies. BMC Med. Res. Methodol. 2007, 10, 40. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Higgins, J.P.T.; Green, S. (Eds.) Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. 2003. Available online: http://www.cochrane-handbook.org (accessed on 10 August 2022).
- Higgins, J.P.; Thompson, S.G.; Deeks, J.J.; Altman, D.G. Measuring inconsistency in meta-analyses. BMJ 2003, 6, 557–560. [Google Scholar] [CrossRef] [Green Version]
- Kim, D.H.; Jeong, S.N.; Lee, J.H. Severe periodontitis with tooth loss as a modifiable risk factor for the development of Alzheimer, vascular, and mixed dementia: National Health Insurance Service-National Health Screening Retrospective Cohort 2002–2015. J. Periodontal. Implant. Sci. 2020, 50, 303–312. [Google Scholar] [CrossRef]
- Holmer, J.; Eriksdotter, M.; Schultzberg, M.; Pussinen, P.J.; Buhlin, K. Association between periodontitis and risk of Alzheimer’s disease, mild cognitive impairment and subjective cognitive decline: A case-control study. J. Clin Periodontol. 2018, 45, 1287–1298. [Google Scholar] [CrossRef]
- Lee, C.Y.; Chang, C.C.; Lin, C.S.; Yeh, C.C.; Hu, C.J.; Wu, C.Z.; Chen, T.L.; Liao, C.C. Risk of dementia in patients with periodontitis and related protective factors: A nationwide retrospective cohort study. J. Clin. Periodontol. 2020, 47, 1428–1436. [Google Scholar] [CrossRef]
- Chen, C.K.; Wu, Y.T.; Chang, Y.C. Association between chronic periodontitis and the risk of Alzheimer’s disease: A retrospective, population-based, matched-cohort study. Alzheimers Res. Ther. 2017, 9, 56. [Google Scholar] [CrossRef] [Green Version]
- Lee, Y.T.; Lee, H.C.; Hu, C.J.; Huang, L.K.; Chao, S.P.; Lin, C.P.; Su, E.C.; Lee, Y.C.; Chen, C.C. Periodontitis as a Modifiable Risk Factor for Dementia: A Nationwide Population-Based Cohort Study. J. Am. Geriatr. Soc. 2017, 65, 301–305. [Google Scholar] [CrossRef]
- Lee, Y.L.; Hu, H.Y.; Huang, L.Y.; Chou, P.; Chu, D. Periodontal Disease Associated with Higher Risk of Dementia: Population-Based Cohort Study in Taiwan. J. Am. Geriatr. Soc. 2017, 65, 1975–1980. [Google Scholar] [CrossRef]
- Tzeng, N.-S.; Chung, C.-H.; Yeh, C.-B.; Huang, R.-Y.; Yuh, D.-Y.; Huang, S.-Y.; Lu, R.-B.; Chang, H.-A.; Kao, Y.-C.; Chiang, W.-S.; et al. Are Chronic Periodontitis and Gingivitis Associated with Dementia? A Nationwide, Retrospective, Matched-Cohort Study in Taiwan. Neuroepidemiology 2016, 47, 82–93. [Google Scholar] [CrossRef] [PubMed]
- Choi, S.; Kim, K.; Chang, J.; Kim, S.M.; Kim, S.J.; Cho, H.J.; Park, S.M. Association of Chronic Periodontitis on Alzheimer’s Disease or Vascular Dementia. J. Am. Geriatr. Soc. 2019, 67, 1234–1239. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Iwasaki, M.; Kimura, Y.; Ogawa, H.; Yamaga, T.; Ansai, T.; Wada, T.; Sakamoto, R.; Ishimoto, Y.; Fujisawa, M.; Okumiya, K.; et al. Periodontitis, periodontal inflammation, and mild cognitive impairment: A 5-year cohort study. J. Periodontal. Res. 2019, 54, 233–240. [Google Scholar] [CrossRef] [PubMed]
- Iwasaki, M.; Yoshihara, A.; Kimura, Y.; Sato, M.; Wada, T.; Sakamoto, R.; Ishimoto, Y.; Fukutomi, E.; Chen, W.; Imai, H.; et al. Longitudinal relationship of severe periodontitis with cognitive decline in older Japanese. J. Periodontal. Res. 2016, 51, 681–688. [Google Scholar] [CrossRef] [PubMed]
- Okamoto, N.; Morikawa, M.; Tomioka, K.; Yanagi, M.; Amano, N.; Kurumatani, N. Association between tooth loss and the development of mild memory impairment in the elderly: The Fujiwara-kyo Study. J. Alzheimers Dis. 2015, 44, 777–786. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Naorungroj, S.; Schoenbach, V.J.; Wruck, L.; Mosley, T.H.; Gottesman, R.F.; Alonso, A.; Heiss, G.; Beck, J.; Slade, G.D. Tooth loss, periodontal disease, and cognitive decline in the Atherosclerosis Risk in Communities (ARIC) study. Community Dent. Oral Epidemiol. 2015, 43, 47–57. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Stewart, R.; Weyant, R.J.; Garcia, M.E.; Harris, T.; Launer, L.J.; Satterfield, S.; Simonsick, E.M.; Yaffe, K.; Newman, A.B. Adverse oral health and cognitive decline: The health, aging and body composition study. J. Am. Geriatr. Soc. 2013, 61, 177–184. [Google Scholar] [CrossRef] [Green Version]
- Kaye, E.K.; Valencia, A.; Baba, N.; Spiro, A.; Dietrich, T.; Garcia, R.I. Tooth loss and periodontal disease predict poor cognitive function in older men. J. Am. Geriatr. Soc. 2010, 58, 713–718. [Google Scholar] [CrossRef] [Green Version]
- Arrivé, E.; Letenneur, L.; Matharan, F.; Laporte, C.; Helmer, C.; Barberger-Gateau, P.; Miquel, J.L.; Dartigues, J.F. Oral health condition of French elderly and risk of dementia: A longitudinal cohort study. Community Dent. Oral Epidemiol. 2012, 40, 230–238. [Google Scholar] [CrossRef]
- Nilsson, H.; Berglund, J.S.; Renvert, S. Periodontitis, tooth loss and cognitive functions among older adults. Clin. Oral Investig. 2018, 22, 2103–2109. [Google Scholar] [CrossRef]
- Stein, P.S.; Desrosiers, M.; Donegan, S.J.; Yepes, J.F.; Kryscio, R.J. Tooth loss, dementia and neuropathology in the Nun study. J. Am. Dent. Assoc. 2007, 138, 1314–1322. [Google Scholar] [CrossRef] [PubMed]
- Gil-Montoya, J.A.; Sanchez-Lara, I.; Carnero-Pardo, C.; Fornieles, F.; Montes, J.; Vilchez, R.; Burgos, J.S.; Gonzalez-Moles, M.A.; Barrios, R.; Bravo, M. Is periodontitis a risk factor for cognitive impairment and dementia? A case-control study. J. Periodontol. 2015, 86, 244–253. [Google Scholar] [CrossRef] [PubMed]
- Begg, C.B.; Mazumdar, M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994, 50, 1088–1101. [Google Scholar] [CrossRef] [PubMed]
- Egger, M.; Davey Smith, G.; Schneider, M.; Minder, C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997, 13, 629–634. [Google Scholar] [CrossRef] [Green Version]
- Gusman, D.J.R.; Mello-Neto, J.M.; Alves, B.E.S.; Matheus, H.R.; Ervolino, E.; Theodoro, L.H.; de Almeida, J.M. Periodontal disease severity in subjects with dementia: A systematic review and meta-analysis. Arch. Gerontol. Geriatr. 2018, 76, 147–159. [Google Scholar] [CrossRef] [Green Version]
- Pollock, A.; Berge, E. How to do a systematic review. Int. J. Stroke 2018, 13, 138–156. [Google Scholar] [CrossRef] [Green Version]
- Webb, P.; Bain, C. Essential Epidemiology: An Introduction for Students and Health Professionals; Cambridge University Press: New York, NY, USA, 2011. [Google Scholar]
- Borsa, L.; Dubois, M.; Sacco, G.; Lupi, L. Analysis the Link between Periodontal Diseases and Alzheimer’s Disease: A Systematic Review. Int. J. Environ. Res. Public Health 2021, 18, 9312. [Google Scholar] [CrossRef]
- Sun, Y.Q.; Richmond, R.C.; Chen, Y.; Mai, X.M. Mixed evidence for the relationship between periodontitis and Alzheimer’s disease: A bidirectional Mendelian randomization study. PLoS ONE 2020, 24, e0228206. [Google Scholar] [CrossRef]
- Brignardello-Petersen, R. Study suggesting an association between periodontitis and periodontal inflammation and mild cognitive impairment in elderly patients has high risk of bias. J. Am. Dent. Assoc. 2019, 150, e52. [Google Scholar] [CrossRef]
- Kamala, T. TK Talk–Demystify Science. Online Blog. Available online: https://tirumalaikamala.wordpress.com/2020/03/01/what-is-the-relationship-between-alzheimers-and-the-bacteria-that-causes-gum-disease-porphyromonas-gingivalis-does-it-cause-alzheimers-sometimes-or-strongly-contribute-to-its-progression/ (accessed on 10 December 2021).
- Carter, C.J.; France, J.; Crean, S.; Singhrao, S.K. The Porphyromonas gingivalis/Host Interactome Shows Enrichment in GWASdb Genes Related to Alzheimer’s Disease, Diabetes and Cardiovascular Diseases. Front. Aging Neurosci. 2017, 1, 408. [Google Scholar] [CrossRef] [Green Version]
- Cerajewska, T.; Davies, M.; West, N. Periodontitis: A potential risk factor for Alzheimer’s disease. BDJ Team 2016, 3, 16062. [Google Scholar] [CrossRef] [Green Version]
- Hill, A.B. The environment and disease: Association or causation? Proc. R. Soc. Med. 1965, 58, 295–300. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Laugisch, O.; Johnen, A.; Maldonado, A.; Ehmke, B.; Bürgin, W.; Olsen, I.; Potempa, J.; Sculean, A.; Duning, T.; Eick, S. Periodontal Pathogens and Associated Intrathecal Antibodies in Early Stages of Alzheimer’s Disease. J. Alzheimers Dis. 2018, 66, 105–114. [Google Scholar] [CrossRef] [PubMed]
- Leira, Y.; Domínguez, C.; Seoane, J.; Seoane-Romero, J.; Pías-Peleteiro, J.M.; Takkouche, B.; Blanco, J.; Aldrey, J.M. Is Periodontal Disease Associated with Alzheimer’s Disease? A Systematic Review with Meta-Analysis. Neuroepidemiology 2017, 48, 21–31. [Google Scholar] [CrossRef]
- Dioguardi, M.; Crincoli, V.; Laino, L.; Alovisi, M.; Sovereto, D.; Mastrangelo, F.; Russo, L.L.; Muzio, L.L. The Role of Periodontitis and Periodontal Bacteria in the Onset and Progression of Alzheimer’s Disease: A Systematic Review. J. Clin. Med. 2020, 11, 495. [Google Scholar] [CrossRef] [Green Version]
- Alvarenga, M.O.P.; Frazão, D.R.; de Matos, I.G.; Bittencourt, L.O.; Fagundes, N.C.F.; Rösing, C.K.; Maia, L.C.; Lima, R.R. Is There Any Association Between Neurodegenerative Diseases and Periodontitis? A Systematic Review. Front. Aging Neurosci. 2021, 13, 651437. [Google Scholar] [CrossRef]
- Caton, J.G.; Armitage, G.; Berglundh, T.; Chapple, I.L.C.; Jepsen, S.; Kornman, K.S.; Mealey, B.L.; Papapanou, P.N.; Sanz, M.; Tonetti, M.S. A new classification scheme for periodontal and peri-implant diseases and conditions-Introduction and key changes from the 1999 classification. J. Clin. Periodontol. 2018, 45 (Suppl. S20), S1–S8. [Google Scholar] [CrossRef]
- Sparks Stein, P.; Steffen, M.J.; Smith, C.; Jicha, G.; Ebersole, J.L.; Abner, E.; Dawson, D., 3rd. Serum antibodies to periodontal pathogens are a risk factor for Alzheimer’s disease. Alzheimers Dement. 2012, 8, 196–203. [Google Scholar] [CrossRef] [Green Version]
- Liu, Y.; Wu, Z.; Nakanishi, Y.; Ni, J.; Hayashi, Y.; Takayama, F.; Zhou, Y.; Kadowaki, T.; Nakanishi, H. Infection of microglia with Porphyromonas gingivalis promotes cell migration and an inflammatory response through the gingipain-mediated activation of protease-activated receptor-2 in mice. Sci. Rep. 2017, 18, 11759. [Google Scholar] [CrossRef]
- Ishida, N.; Ishihara, Y.; Ishida, K.; Tada, H.; Funaki-Kato, Y.; Hagiwara, M.; Ferdous, T.; Abdullah, M.; Mitani, A.; Michikawa, M.; et al. Periodontitis induced by bacterial infection exacerbates features of Alzheimer’s disease in transgenic mice. NPJ Aging Mech. Dis. 2017, 6, 15. [Google Scholar] [CrossRef] [Green Version]
- Hayashi, K.; Hasegawa, Y.; Takemoto, Y.; Cao, C.; Takeya, H.; Komohara, Y.; Mukasa, A.; Kim-Mitsuyama, S. Continuous intracerebroventricular injection of Porphyromonas gingivalis lipopolysaccharide induces systemic organ dysfunction in a mouse model of Alzheimer’s disease. Exp. Gerontol. 2019, 120, 1–5. [Google Scholar] [CrossRef] [PubMed]
- Nie, R.; Wu, Z.; Ni, J.; Zeng, F.; Yu, W.; Zhang, Y.; Kadowaki, T.; Kashiwazaki, H.; Teeling, J.L.; Zhou, Y. Porphyromonas gingivalis Infection Induces Amyloid-β Accumulation in Monocytes/Macrophages. J. Alzheimers Dis. 2019, 72, 479–494. [Google Scholar] [CrossRef] [PubMed]
- Díaz-Zúñiga, J.; More, J.; Melgar-Rodríguez, S.; Jiménez-Unión, M.; Villalobos-Orchard, F.; Muñoz-Manríquez, C.; Monasterio, G.; Valdés, J.L.; Vernal, R.; Paula-Lima, A. Alzheimer’s Disease-Like Pathology Triggered by Porphyromonas gingivalis in Wild Type Rats Is Serotype Dependent. Front. Immunol. 2020, 11, 588036. [Google Scholar] [CrossRef] [PubMed]
Authors Year | Country, Settings | Sample Size (N) Gender | Age | Follow-Up (Years) | Primary Outcome |
---|---|---|---|---|---|
Controlled Cohort studies | |||||
Lee, 2020 [132] | Taiwan, National Health Insurance Database | 56,018 with newly diagnosed periodontitis, 56,018 without periodontitis | >50 | 13 | Incidence of dementia. |
Choi, 2019 [137] | South Korea, Korean National Health Insurance Service—Health database | Total 262,349; 46,344 with chronic periodontitis, 216,005 without periodontitis | >50; 60.2 mean age chronic periodontitis, 60.4 mean age healthy | 10 | Incident of Alzheimer’s disease and vascular dementia. |
Iwasaki, 2019 [138] | Japan, Tosa Longitudinal Aging Study, Community-dwelling individuals | Total 179 | >75; average 80.1 | 5 | Diagnosis of mild cognitive impairment. |
Nilsson, 2018 [145] | Sweden, Swedish National Study on Aging and Care | Total 715 (704 available for examination) | >60 | 6 | Cognitive function deterioration |
Chen, 2017 [133] | Taiwan, National Health Insurance Research Database | Total 18,672; 9291 with chronic periodontitis, 18,672 without chronic periodontitis (1:2 ratio) | >50; mean age 54.1 exposed cohort, mean age 54.2 unexposed cohort | 10 | Incidence of Alzheimer’s disease. |
Lee, 2017 [134] | Taiwan, National Health Insurance Research Database | Total 6056; 3028 with periodontitis 3028 without periodontitis (age- and sex-matched) | >65; median age 72.42 | 10 | New-onset dementia |
Lee, 2017 [135] | Taiwan, National Health Insurance Research Database | 182,747; 6133 with dementia | >45 | 10 | Risk of newly developed dementia in individuals undergoing periodontal treatment |
Tzeng, 2016 [136] | Taiwan, National Health Insurance Database | Total 8828 2207 with newly diagnosed periodontitis 6621 without periodontitis Sex and index year-matched control | >20 | 10 | Risk of developing dementia |
Iwasaki, 2016 [139] | Japan, Community-dwelling individuals | 85; 21 with severe periodontitis 64 without severe periodontitis | >75; average 79.3, 79.5 with severe periodontitis, 79.3 without severe periodontitis | 3 | Cognitive function decline |
Naorungroj, 2015 [141] | USA, Atherosclerosis Risk in Communities study | Total 911 | 52–75 | 8 | Cognitive function change |
Okamoto2015 [140] | Japan, Fujiwara-kyo study, Nara Prefecture | Total 2335; 241 developed mild memory impairment | >65; median age 71.0 | 5 | Development of mild memory impairment |
Stewart, 2013 [142] | USA, Health, Aging and Body Composition Random sample from Medicare databases | Total 3075; 1053 sample with full dental examination and cognitive assessment at Years 1 and 3, 2022 remainder of the baseline sample | 70–79; mean 73.5–73.7 | 5 | A primary outcome: global cognitive function decline |
Arrive, 2012 [144] | France, Community based of elderly population | 405; 72 developed dementia during the follow-up, 333 diagnosed with no dementia at the end of the follow-up | 66–80; median age at baseline 70 | 15 | The occurrence of dementia. |
Kaye, 2010 [143] | USA, Veterans Affairs Dental Longitudinal Study | 597 Men | 28–84; median age: 45.5 at baseline | 32 Dental examination conducted every 3 years | The cognitive function loss |
Cross-sectional | |||||
Holmer, 2018 [131] | Sweden, Huddinge muncipality | 154 patients with Alzheimer’s disease (52), mild cognitive impairment (51), and subjective cognitive decline (51) 76 controls | 50–80; median age 70 year—cases, medical age 67 years—controls | 3 | The risk of mild cognitive impairment, Alzheimer’s disease, and subjective cognitive decline |
Case-control | |||||
Stein, 2007 [146] | USA, Nun Study (Milwaukee) | Total 144; females, 76 cases with available radiographs to assess bone loss | 75–98 years; Mean 84 years | 10 Ten annual cognitive assessments | Cognitive function loss, neuropathological changes, and apolipoprotein E allele genotyping |
Gil-Montoya, 2015 [147] | Spain, Granada, Neurology Departments, two hospitals | Total 409; 180 with cognitive impairment, 229 without cognitive impairment | 51–98; mean age 77.00 cases, mean age 78.5 controls | 2 | The risk of cognitive impairment/dementia in newly diagnosed persons with and without periodontitis |
Authors Year | Aim(s) of the Study | Main Results and Conclusions |
---|---|---|
Cohort studies | ||
Lee, 2020 [132] | “To compare the long-term risk of dementia in persons without and with periodontitis and its related factors” | “Higher incidence of dementia in patients with periodontitis, than without (5.19 vs. 3.02 per 1000 person/years) in men and females, especially among persons aged above 80 years (HR: 4.30) Estimated hazard ratio (HR) = 1.73 (95% CI: 1.61–1.86)”. |
Choi, 2019 [137] | “To assess the effect of chronic periodontitis on Alzheimer’s disease and vascular dementia occurrence” | “Patients with periodontitis had an increased risk of dementia and Alzheimer’s disease incident (adjusted HR 1.06 vs. 1.05, respectively). Chronic periodontitis associated with dementia after considering smoking, alcohol intake, and physical activity”. |
Iwasaki, 2019 [138] | “To explore the association between a mild cognitive impairment and periodontitis and periodontal inflammation in older adults” | “Severe periodontitis was associated with mild cognitive impairment after adjusting for follow-up period, age, gender, smoking, education, physical activity, obesity, depression, and diabetes (adjusted OR 2.61; 95% CI: 1.08–6.28)”. |
Nilsson, 2018 [145] | “To determine whether a diagnosis of periodontitis in individuals >60 years of age was associated with cognitive decline” | “A history of periodontal disease was an independent risk indicator for cognitive decline. Bone loss >4 mm at >30% of sites associated with cognitive decline after adjustment of main confounding factors. The unadjusted OR 2.8, 95% CI: 1.7–4.5, fully adjusted OR 2.2, 95% CI: 1.2–3.8 for age, education, and BMI”. |
Chen, 2017 [133] | “To determine whether patients with chronic periodontitis are at risk of developing Alzheimer’s disease” | “Patients with periodontitis exposure exhibit a higher risk of Alzheimer’s disease occurrence (1.707-fold increase in the risk of developing Alzheimer’s disease, 95% CI: 1.152–2.528, adjusted HR)”. |
Lee, 2017 [134] | “To determine whether periodontitis is a modifiable risk factor for dementia” | “Risk of dementia was higher in individuals with periodontitis (HR 1.16; 95% CI: 1.01–1.32) after adjustment for sociodemographic factors”. |
Lee, 2017 [135] | “To determine the magnitude and temporal aspects of the effect of the poor oral health and periodontal disease on dementia” | “The incidence of dementia was significantly higher in persons with periodontal disease who did not receive treatment (0.76%) and who had teeth extracted due to periodontal disease (0.57%), compared to group that received intensive periodontal treatment (0.35%) and prophylaxis (0.39%) (HR 1.14, 95%, CI:1.04–1.24). Higher risk of dementia in persons with periodontitis who did not undergo periodontal treatmen”. |
Tzeng, 2016 [136] | “To identify the association between chronic periodontitis and gingivitis, and the risk of developing dementia” | “The HR for dementia was 2.54 (95% CI: 1.297–3.352) after adjusting for main confounders: gender, age, income, urbanisation level, geographical region, and comorbiditites”. |
Iwasaki, 2016 [139] | “To investigate whether periodontitis in elderly Japanese people could be a risk factor for cognitive decline” | “Severe periodontitis was significantly associated with risk of cognitive function decline (adjusted RR 2.2; 95% CI: 1.1–4.5). A 1.8-point greater decrease in MMSE score was observed in severe periodontitis (95%, CI: 3.3–0.2)”. |
Naorungroj, 2015 [141] | “To determine whether tooth loss and current inflammatory state of periodontal disease predicted 8-year changes in cognitive function” | “Periodontal disease did not predict cognitive decline and was not associated with cognitive performance”. |
Okamoto, 2015 [140] | “To investigate the effect of tooth loss on the development of mild memory impairment among elderly” | “No association between CPI code 0–3, code 4, and mild memory impairment”. |
Stewart, 2013 [142] | “To investigate the relationship between periodontal disease and cognitive decline”. | “Worse periodontal status associated with cognitive impairment based on MMSE. Strong association between PPD/alveolar bone loss and cognitive impairment after adjustment for age and gender (OR 1.50 PPD vs 1.34 alveolar bone loss)”. |
Arrive, 2012 [144] | “To examine the relationship between oral condition and occurrence of dementia in French older community dwellers” | “Periodontal condition was not associated with the risk of dementia”. |
Kaye, 2010 [143] | “To determine whether tooth loss, periodontal disease, and caries incidence predict cognitive decline in men” | “The risk of low MMSE increased from 2% to 5% for each tooth with progression of alveolar bone loss or probing pocket depth”. |
Cross-sectional studies | ||
Holmer, 2018 [131] | “To investigate the putative association among marginal periodontitis, cognitive impairment, and Alzheimer’s disease”. | “Alzheimer’s disease, mild cognitive impairment, and subjective cognitive decline were associated with more alveolar bone loss (OR 5.81; 95% CI: 1.14–29.68) and deep periodontal pockets (OR 8.43; 95% CI: 4.00–17.76). The strongest association was found between Alzheimer’s disease and the presence of one or more deep pockets > 6 mm (OR 15.12; 95% CI: 5.93–38.58)”. |
Case-control studies | ||
Gil-Montoya, 2015 [147] | “To determine whether periodontitis is associated with the diagnosis of cognitive impairment/dementia after controlling for risk factors: age, gender, and education level”. | “Periodontitis indicators such as PPD and alveolar bone loss were significantly associated with diagnosis of cognitive impairment. The risk of cognitive impairment was above 3-fold higher in persons with severe periodontitis versus group with no or mild periodontitis after controlling for age, gender, and education”. |
Stein, 2007 [146] | “To investigate the potential relationship between tooth loss and development of dementia” | “Alveolar bone loss was not associated with dementia at first cognitive examination (OR 1.5, 95% CI: 0.37–5.8) or incidence of dementia (HR 2.4, 95% CI: 0.86–6.6) after adjusting for age, education, and APOE4”. |
Authors Year | Periodontitis Diagnosis; Criteria | Cognitive Impairment Diagnosis; Criteria |
---|---|---|
Cohort studies | ||
Lee, 2020 [132] | International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM): ICD-9-CM 523.4, | International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM): dementia code 290 and 331.0 |
Choi, 2019 [137] | International Classification of Diseases, 10th Revision (ICD-10): K05.3. At least one chronic periodontitis-related treatment such as: subgingival curettage, periodontal flap operation, gingivectomy, odontectomy | International Classification of Diseases, 10th Revision (ICD-10): codes F00, G30 for Alzheimer’s Disease or ICD-10 code F01 for vascular dementia |
Iwasaki, 2019 [138] | Case definitions of periodontitis according to European Workshop in Periodontology Group C (EWP definition) and Centers for Disease Control/American Academy of Periodontology (CDC/AAP definition): | MMSE range from 0 to 30. Dementia is diagnosed according to the criteria of the DSM-IV. Patients diagnosed with mild cognitive impairment if they fulfilled criteria: (1) subjective cognitive complaints, (2) memory problems that were abnormal for the patient’s age, (3) preserved functional activity of daily living, (4) failure to meet the DSM-IV criteria for dementia |
Nilsson, 2018 [145] | PPD at four sited of existing teeth > 5 mm on 30% of teeth Alveolar bone loss >4 mm from CAJ to marginal bone level on >30% of readable sites. | Mini-Mental Stage Examination (MMSE) as cognitive outcome variable |
Chen, 2017 [133] | ICD-9-CM code 523.4 (chronic periodontitis). | ICD-9-CM code 331.0, Alzheimer’s disease, dementia |
Tzeng, 2016 [134] | ICD-9-CM, codes 523.1 (chronic gingivitis), and 523.4. (chronic periodontitis). | ICD-9-CM, codes for dementia: 290.20–290.10–290.13, 290.20–290.21, 290.3, 331.0, 290.41–290.43, 290.8–290.9. Alzheimer-type dementia: ICD-9-CM 290.0, 290.10–290.13, 290.20–290.21, 290.3, 331.0. Vascular dementia: ICD-9-CM 290.41–290.43. Non-vascular dementia: ICD-9-CM 290.8–290.9 Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Revised (DSM-IV) |
Iwasaki, 2016 [135] | Case definitions of periodontitis according to Centers for Disease Control/American Academy of Periodontology (CDC/AAP definition): - severe periodontitis: >2 interproximal sites with AL of >6 mm (not on the same tooth) and >1 interproximal site with PPD > 5 mm. | MMSE as cognitive functioning test by trained psychologists Cognitive decline if <24 score |
Lee, 2017 [136] | ICD-9-CM, codes 523.3-5 | ICD-9-CM, codes 290.0-290.4, 294.1, 331.0-331.2 |
Lee, 2017 [139] | ICD-9-CM code 523.0–523.5, subjects diagnosed with gingivitis, gingival recession, acute, or chronic periodontitis. Four groups: Group 1—only dental prophylaxis (scaling) required, Group 2—intensive periodontal treatment (subgingival curettage, root planning, periodontal flap operation) required. Group 3—tooth extraction required due to periodontal disease, Group 4—subjects who did not receive any of these treatments | ICD-9-CM code 290.X, 331.0. Subjects with diagnosis of presenile dementia, vascular dementia, senile dementia, Alzheimer’s disease. |
Naorungroj, 2015 [141] | PPD, BOP BGI based on PPD and BOP | Delayed word test (DWT), Digital symbol substitution (DSS), Word fluency (WF) |
Okamoto, 2015 [140] | CPI (baseline code 0–3 and code 4) | MMSE score assessed by a specialist psychiatrist or clinical psychologists |
Stewart, 2013 [142] | PPD (mean value and proportion with >3 mm depth) AL (>3 mm; defined as the mean number of sites affected and the proportion of sites examined that were affected) | Modified Mini-Mental State Examination (3MSE) used for an assessment of global function. Digit Symbol Substitution test measuring attention, psychomotor speed, and executive function. Clock drawing test used to measure executive function |
Arrive, 2012 [144] | CPI (cut-off code 3 and 4) | Neuropsychological testing: DSM-III R for dementia. National Institute of Neurological and Communication Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association (Alzheimer’s disease criteria) Hachinski score (vascular dementia criteria) |
Kaye, 2010 [143] | PPD, Alveolar bone loss Number of teeth with PPD > 4 mm Number of teeth with Alveolar bone loss | MMSE: low cognitive status, mild cognitive impairment < 25 points of the age or education—specific median on the MMSE Spatial Coping Task—Developmental Test of Visual-Motor Integration |
Cross-sectional studies | ||
Holmer, 2018 [131] | PPD Number of teeth with PPD 4–5 mm and with PPD > 6 mm Alveolar bone loss based on OPT: no or mild, localised, generalised | ICD, 10th Revision. MMSE > 20 for patients diagnosed with Alzheimer’s disease. Winblad criteria for patients diagnosed with mild cognitive impairment. Pre-Mental Cognitive Impairment criteria for patients diagnosed with subjective cognitive decline |
Case-control studies | ||
Gil-Montoya, 2015 [147] | PPD, AL Degree of periodontitis—percentage of sites with AL > 3 mm | Behavioural assessment (neuropsychiatric inventory scale) Clinical dementia rating scale. DSM—IV for dementia from National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association |
Stein, 2007 [146] | Alveolar bone loss based on OPT: moderate and severe bone loss due to low number of subjects with severe periodontitis | Cognitive function assessed annually by MMSE and Activities of Daily Living, Delayed Word Recall Test, Boston Naming Test, verbal fluency test, construction praxis test. Criteria considered to be diagnosed with dementia: impairment in memory, impairment in at least one other area of cognition, impairment in social or daily function |
Study | Selection of Cohort | Comparability of Cohorts | Outcome | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Representativeness of the Exposed Cohort | Selection of the Non-Exposed Cohort | Ascertainment of Exposure | Demonstration that Outcome of the Interest Was Not Present at Start of Study | Age and Gender/ Additional Factor | Assessment of Outcome | Long Enough Follow-Up for Outcome to Occur | Adequacy of Follow-Up of Cohorts | Total | ||
Lee, 2020 [132] | * | * | * | * | * | * | 6/9 | |||
Choi, 2019 [137] | * | * | * | * | * | * | * | 7/9 | ||
Iwasaki, 2019 [138] | * | * | * | * | * | * | * | 7/9 | ||
Chen, 2017 [133] | * | * | * | * | * | * | 6/9 | |||
Lee, 2017 [134] | * | * | * | * | * | 5/9 | ||||
Tzeng, 2016 [136] | * | * | * | * | * | 5/9 | ||||
Iwasaki, 2016 [139] | * | * | * | * | * | 5/9 | ||||
Stewart, 2013 [142] | * | * | * | * | * | 5/9 | ||||
Naorungroj, 2015 [141] | * | * | * | * | * | * | 6/9 | |||
Okamoto, 2015 [140] | * | * | * | * | * | * | 6/9 | |||
Arrive, 2012 [144] | * | * | * | * | * | 5/9 | ||||
Kaye, 2010 [143] | * | * | * | * | * | * | 6/9 |
Study | Selection | Comparability | Outcome | ||||||
---|---|---|---|---|---|---|---|---|---|
Representativeness of the Sample | Sample Size | Non-Respondents | Ascertainment of the Exposure (Absence or Exclusion) | The Subjects in Different Outcome Groups Are Comparable, Based on the Study Design or Analysis. Confounding Factors are Controlled. | Assessment of Outcome | Statistical Test | Total | ||
Lee, 2017 [134] | * | * | * | * | * | * | 6/8 | ||
Holmer, 2018 [131] | * | * | * | * | * | 5/8 |
Study | Selection of Case-Control | Comparability | Exposure | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Is the Case Definition Adequate? | Representativeness of the Cases | Selection of Control | Definition of Control | Comparability of Cases and Controls on the Basis of the Design or Analysis | Ascertainment of Exposure | Same Method of Ascertainment for Cases and Controls | Non-Response Rate | Total | ||
Gill-Montoya, 2015 [147] | * | * | * | * | * | 5/9 | ||||
Stein, 2007 [146] | * | * | * | * | * | 5/9 |
Confounders Accounted for | Methods to Account | |
---|---|---|
Cohort studies | ||
Lee, 2020 [132] | Age, gender, income, coexisting medical conditions, period of follow-up | Stratification |
Choi, 2019 [137] | Smoking, physical activity, alcohol consumption | Stratification |
Iwasaki, 2019 [138] | Age, gender, smoking status, educational level, physical activity, obesity, depression, diabetes | Multilevel mixed-effects logistic regression |
Nilsson, 2018 [145] | Age, gender, level of education, use of interdental aids, frequency of dental visits, living alone, diabetes, ischaemic heart disease, BMI, dental caries | Logistic regression |
Chen, 2017 [133] | Age, gender, comorbidities, Charlson comorbidity index, and urbanisation level. Patients were matched according to gender, age, and index years | Cox regression models adjusted for Alzheimer’s disease-related comorbidities, CCI, and urbanisation level |
Lee, 2017 [134] | Adjustment for age, gender, for socio-demographic characteristics and comorbidities | Age and gender-matched control groups |
Lee, 2017 [135] | Age, gender, socio-economic status, comorbidities | Cox regression model |
Tzeng, 2016 [136] | Adjustment for age, gender, income, urbanisation level, geographic region, comorbidities | Age and gender-matched control Multivariate Cox proportional hazards regression analysis |
Iwasaki, 2016 [139] | Age, gender, smoking, alcohol, education, depression, BMI, exercise, comorbidities | Multivariable regression |
Naorungroj, 2015 [141] | Age, gender, smoking, alcohol, education, comorbidities, BMI, APOE4 allele genotype | Logistic regression, bivariate analysis |
Okamoto, 2015 [140] | Age, gender, smoking, alcohol, education, comorbidities | Multivariable logistic regression |
Stewart, 2013 [142] | Adjustment for age, gender, education, race, depressive symptoms, cardiovascular risk. Separate exploratory adjustments for inflammatory markers, BMI, anticholinergic medications use | Initial logistic regression models, followed by further adjustments. Stratification to investigate effect modification according to apolipoprotein E genotype |
Arrive, 2012 [144] | Age, gender, smoking, alcohol intake, vascular risk factors, depressive symptoms | Multivariate analyses |
Kaye, 2010 [143] | Age, years of education, smoking, alcohol intake, BMI, comorbidities | Multivariable models Cox proportional hazards regression models stratified according to median age |
Cross-sectional studies | ||
Holmer, 2018 [131] | Age, gender, education, smoking, marital status, BMI, diabetes | Age- and gender-matched controls Multivariable regression models Sensitivity analysis for unmeasured confounding |
Case-control studies | ||
Stein, 2007 [146] | Age, gender, education | Multivariable logistic regression |
Gil-Montoya, 2015 [147] | Age, gender, education level, oral hygiene habits adjusted for main potential confounders | Multiple logistic regression |
Study | Smoking | Alcohol | Education | Socio-Economic Status |
---|---|---|---|---|
Cohort studies | ||||
Lee, 2020 [132] | - | - | - | Low income: yes/no |
Choi, 2019 [137] | Never smoker Past smoker Current smoker | [Times per week]. None. 0–1, 1–2, 3–4, >5 | - | Household income: first, second, third, fourth quartile |
Iwasaki, 2019 [138] | Never smoker Previous smoker Current smoker | Not. Daily drinker | Less education, 6 years of school attendance | - |
Nilsson, 2018 [145] | Never smoker Current, Former | Yes/No | Elementary Higher | - |
Lee, 2017 [134] | - | - | - | - |
Lee, 2017 [135] | - | - | - | <20,000, 20,000–39,999 >40,000 |
Chen, 2017 [133] | - | - | - | - |
Tzeng, 2016 [136] | - | - | - | Monthly income |
Iwasaki, 2016 [139] | Never Former smoker Current smoker | Yes/No | Lower education: school attendance for less than 7 years | - |
Naurungroj, 2015 [141] | Cigarette use Current Former Never | Current Former Never | Less than high school High school completion Postsecondary education | Refused <25,000$ $25 < 50,000 $50,000 or more |
Okamoto, 2015 [140] | Never Former smoker Current | Hardly drink Drink at least one day a week | Less than 12 years, more than 12 years | - |
Stewart, 2013 [142] | Never Former smoker Current smoker | - | <High school. High school graduate. Postsecondary | - |
Arrive, 2012 [144] | Tobacco consumption: yes/no | Alcohol intake: yes/no | Higher school level: yes/no | - |
Kaye, 2010 [143] | Never Ever smoked | Alcohol intake [g/day] | Years of education | - |
Cross-sectional studies | ||||
Holmer, 2018 [131] | Never Previous smoker Current smoker | - | 1–2 years University | Annual income |
Case-control studies | ||||
Stein, 2007 [146] | - | - | Similar level of education (nuns) | - |
Gil-Montoya, 2015 [147] | Tobacco: yes/no, <20 and >20 cig./day | Alcohol intake: yes/no, 1–6 times a week, >1 times/day | High. Primary. Primary incomplete | - |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Dziedzic, A. Is Periodontitis Associated with Age-Related Cognitive Impairment? The Systematic Review, Confounders Assessment and Meta-Analysis of Clinical Studies. Int. J. Mol. Sci. 2022, 23, 15320. https://doi.org/10.3390/ijms232315320
Dziedzic A. Is Periodontitis Associated with Age-Related Cognitive Impairment? The Systematic Review, Confounders Assessment and Meta-Analysis of Clinical Studies. International Journal of Molecular Sciences. 2022; 23(23):15320. https://doi.org/10.3390/ijms232315320
Chicago/Turabian StyleDziedzic, Arkadiusz. 2022. "Is Periodontitis Associated with Age-Related Cognitive Impairment? The Systematic Review, Confounders Assessment and Meta-Analysis of Clinical Studies" International Journal of Molecular Sciences 23, no. 23: 15320. https://doi.org/10.3390/ijms232315320