Influence of periodontal disease on risk of dementia: a systematic literature review and a meta-analysis

This is an accepted manuscript of an article published by Springer in European Journal of Epidemiology on 12/06/2020, available online: https://doi.org/10.1007/s10654-020-00648-x The accepted version of the publication may differ from the final published version.Periodontal disease (PD) is common and increases cardiovascular diseases. However, it is unclear whether PD is associated with increased risk of dementia. We carried out a systematic review and meta-analysis to investigate the influence of PD on dementia. We projected the number of dementia cases to be saved by reducing PD prevalence in the world. We searched cohort and case–control studies reporting the association of PD with all dementia (or any specific type of dementia) through PubMed, MEDLINE, PsycINFO, SocINDEX, CINHAL, and CNKI until 7th November 2018. Five cohorts and seven case–control studies were identified for review. We pooled eligible data to calculate relative risk (RR) of dementia in relation to PD and computed the number of dementia cases saved through reducing PD prevalence. Of 12 studies, six were undertaken in Asia, four in Europe and two in America. Eleven studies showed a positive association between PD and the risk of dementia, of which 10 were significant, and one reported a non-significant inverse association. Overall their quality was good. Pooled RR of dementia in relation to PD from all high quality studies was 1.38 (95%CI 1.01–1.90); in the five cohorts was 1.18 (1.06–1.31) and in the two case–control studies 2.25 (1.48–3.42). A 50% reduction in the current prevalence of 20% of PD in the population could save 850,000 (630,000–1,420,000) patients with dementia in the world. PD could increase the risk of incident dementia. Preventing and treating PD could contribute to controlling the global epidemic of dementia.Professor Ruoling Chen and Dr Jie Tang thank an EU Grant from Horizon 2020 MSCA – DEMAIRPO #799247. Dr Kaarin Anstey is funded by NHMRC Fellowship #1102694. Dr Wu is the recipient of BBSRC [BB/P004695/1] and NIA [1R01AG049321-01A1] Grant for aging research. Dr Yuyou Yao, Associate Professor of Anhui Medical University, China is a visiting scholar at the Faculty of Education, Health and Wellbeing, University of Wolverhampton to support this study and has made valuable comments on the manuscript.Published versio

Structural and functional insights into oligopeptide acquisition by the RagAB transporter from Porphyromonas gingivalis

Porphyromonas gingivalis, an asaccharolytic member of the Bacteroidetes, is a keystone pathogen in human periodontitis that may also contribute to the development of other chronic inflammatory diseases. P. gingivalis utilizes protease-generated peptides derived from extracellular proteins for growth, but how these peptides enter the cell is not clear. Here, we identify RagAB as the outer-membrane importer for these peptides. X-ray crystal structures show that the transporter forms a dimeric RagA2B2 complex, with the RagB substrate-binding surface-anchored lipoprotein forming a closed lid on the RagA TonB-dependent transporter. Cryo-electron microscopy structures reveal the opening of the RagB lid and thus provide direct evidence for a ‘pedal bin’ mechanism of nutrient uptake. Together with mutagenesis, peptide-binding studies and RagAB peptidomics, our work identifies RagAB as a dynamic, selective outer-membrane oligopeptide-acquisition machine that is essential for the efficient utilization of proteinaceous nutrients by P. gingivalis

Proteomic analysis of saliva in HIV-positive heroin addicts reveals proteins correlated with cognition

The prevalence of HIV-associated neurocognitive disorders (HAND) remains high despite effective antiretroviral therapies. Multiple etiologies have been proposed over the last several years to account for this phenomenon, including the neurotoxic effects o

<i>Porphyromonas gingivalis</i> in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors

Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer's disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer's patients, and levels correlated with tau and ubiquitin pathology. Oral P. gingivalis infection in mice resulted in brain colonization and increased production of Aβ1-42, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aβ1-42 production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating P. gingivalis brain colonization and neurodegeneration in Alzheimer's disease