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. 2024 Mar 13;6(2):fcae088.
doi: 10.1093/braincomms/fcae088. eCollection 2024.

Helicobacter pylori, persistent infection burden and structural brain imaging markers

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Helicobacter pylori, persistent infection burden and structural brain imaging markers

May A Beydoun et al. Brain Commun. .

Abstract

Persistent infections, whether viral, bacterial or parasitic, including Helicobacter pylori infection, have been implicated in non-communicable diseases, including dementia and other neurodegenerative diseases. In this cross-sectional study, data on 635 cognitively normal participants from the UK Biobank study (2006-21, age range: 40-70 years) were used to examine whether H. pylori seropositivity (e.g. presence of antibodies), serointensities of five H. pylori antigens and a measure of total persistent infection burden were associated with selected brain volumetric structural MRI (total, white, grey matter, frontal grey matter (left/right), white matter hyperintensity as percent intracranial volume and bi-lateral sub-cortical volumes) and diffusion-weighted MRI measures (global and tract-specific bi-lateral fractional anisotropy and mean diffusivity), after an average 9-10 years of lag time. Persistent infection burden was calculated as a cumulative score of seropositivity for over 20 different pathogens. Multivariable-adjusted linear regression analyses were conducted, whereby selected potential confounders (all measures) and intracranial volume (sub-cortical volumes) were adjusted, with stratification by Alzheimer's disease polygenic risk score tertile when exposures were H. pylori antigen serointensities. Type I error was adjusted to 0.007. We report little evidence of an association between H. pylori seropositivity and persistent infection burden with various volumetric outcomes (P > 0.007, from multivariable regression models), unlike previously reported in past research. However, H. pylori antigen serointensities, particularly immunoglobulin G against the vacuolating cytotoxin A, GroEL and outer membrane protein antigens, were associated with poorer tract-specific white matter integrity (P < 0.007), with outer membrane protein serointensity linked to worse outcomes in cognition-related tracts such as the external capsule, the anterior limb of the internal capsule and the cingulum, specifically at low Alzheimer's disease polygenic risk. Vacuolating cytotoxin A serointensity was associated with greater white matter hyperintensity volume among individuals with mid-level Alzheimer's disease polygenic risk, while among individuals with the highest Alzheimer's disease polygenic risk, the urease serointensity was consistently associated with reduced bi-lateral caudate volumes and the vacuolating cytotoxin A serointensity was linked to reduced right putamen volume (P < 0.007). Outer membrane protein and urease were associated with larger sub-cortical volumes (e.g. left putamen and right nucleus accumbens) at middle Alzheimer's disease polygenic risk levels (P < 0.007). Our results shed light on the relationship between H. pylori seropositivity, H. pylori antigen levels and persistent infection burden with brain volumetric structural measures. These data are important given the links between infectious agents and neurodegenerative diseases, including Alzheimer's disease, and can be used for the development of drugs and preventive interventions that would reduce the burden of those diseases.

Keywords: Helicobacter pylori; brain imaging; cognitive aging; persistent infection.

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Conflict of interest statement

The authors report no competing interests. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of Fort Belvoir Community Hospital, the Defense Health Agency, the Department of Defense or the U.S. Government. Reference to any commercial products within this publication does not create or imply any endorsement by Fort Belvoir Community Hospital, the Defense Health Agency, the Department of Defense or the U.S. Government.

Figures

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Graphical abstract
Figure 1
Figure 1
Participant flowchart. The flowchart shows sample selection starting from the total UK Biobank study sample of over 500 000, selection of participants with neuroimaging sMRI and dMRI and finally inclusion of those who had complete data on serology, including Hp seropositivity, serointensities and PIB components, and on Alzheimer’s disease PGS. AD, Alzheimer’s disease; PGS, polygenic score; PIB, persistent infection burden; UK, United Kingdom.
Figure 2
Figure 2
Hp antigen serointensities and measures of WM integrity: UK Biobank 2006–21. Colour schemes are directions (A–E) of regression coefficients (exposures versus outcomes) from OLS multiple linear regression models, with alternative outcomes being tract-specific FA and MD and main alternative exposures being Hp serointensities (Cat, GroeL, OMP, UreA and VacA). Models were adjusted for age, sex, race (non-White versus White), Alzheimer’s disease PGS, time elapsed between baseline and neuroimaging visit (days) and the IMR. Sample size for all analyses is N = 635. Outcomes and exposures are standardized Z-scores. Cold colour represents inverse relationships (β < 0, P < 0.007), while warm colour represents positive relationships (β > 0, P < 0.007) for parts A–E. Image in part F includes all WM JHU tracts. Full results are presented in Supplementary Table 9. Cat, catalase; FA, fractional anisotropy; JHU, Johns Hopkins University; MD, mean diffusivity; OLS, ordinary least square; OMP, outer membrane protein; PGS, polygenic score; ROI, region of interest; VacA, vacuolating cytotoxin A (see Supplementary Table 1 for full list of ROIs/tracts linked to FA and MD dMRI analysis and Supplementary Table 9 for quantitative findings).
Figure 3
Figure 3
Heat map for Hp antigen serointensities and measures of WM integrity (MD) across Alzheimer’s disease polygenic risk level: UK Biobank 2006–21. Values and directions of regression coefficients (exposures versus outcomes) from OLS multiple linear regression models, with alternative outcomes being tract-specific MD and main alternative exposures being Hp serointensities (Cat, GroeL, OMP, UreA and VacA). Models were adjusted for age, sex, race (non-White versus White), Alzheimer’s disease PGS, time elapsed between baseline and neuroimaging visit (days) and the IMR. Models were stratified by Alzheimer’s disease PGS tertile. Outcomes and exposures are standardized Z-scores. Means of MD were also entered as two alternative outcomes. Sample sizes for Alzheimer’s disease PGS T1, T2 and T3 were 212, 212 and 211, respectively. Cold colours represent inverse statistically significant standardized effect sizes (β < 0, P < 0.05), while warmer colours represent positive statistically significant standardized effect sizes (β > 0, P < 0.05). Size of the circle is inversely proportional to the P-value. Depth of the colour is proportional to the absolute standardized effect size. ACR, anterior corona radiata; ALIC, anterior limb of the internal capsule; BCC, body of the corpus callosum; Cat, catalase; CCG, cingulum cingulate gyrus; CH, cingulum hippocampus; CP, cerebral peduncle; CR, superior corona radiata; CT, corticospinal tract; EC, external capsule; FA, fractional anisotropy; FCST, fornix cres–stria terminalis; FO, fornix; FOF, superior fronto-occipital fasciculus; GCC, genu of the corpus callosum; ICP, inferior cerebellar peduncle; MD, mean diffusivity; ML, medial lemniscus; MCP, middle cerebellar peduncle; OLS, ordinary least square; OMP, outer membrane protein; PC, pontine crossing; PCR, posterior corona radiata; PGS, polygenic score; PLIC, posterior limb of the internal capsule; PTR, posterior thalamic radiation; ROI, region of interest; RPIC, retrolenticular part of the internal capsule; SS, sagittal striatum; SCC, splenium of the corpus callosum; SCP, superior cerebellar peduncle; SLF, superior longitudinal fasciculus; TP, tapetum; UNC, uncinate; UreA, urease; VacA, vacuolating cytotoxin A (see Supplementary Table 1 for full list of ROIs/tracts linked to FA and MD dMRI analysis).
Figure 4
Figure 4
Heat map for Hp antigen serointensities and measures of WM integrity (FA) across Alzheimer’s disease polygenic risk level: UK Biobank 2006–21. Values and directions of regression coefficients (exposures versus outcomes) from OLS multiple linear regression models, with alternative outcomes being tract-specific FA and main alternative exposures being Hp serointensities (Cat, GroeL, OMP, UreA and VacA). Models were adjusted for age, sex, race (non-White versus White), Alzheimer’s disease PGS, time elapsed between baseline and neuroimaging visit (days) and the IMR. Models were stratified by Alzheimer’s disease PGS tertile. Outcomes and exposures are standardized Z-scores. Means of FA were also entered as two alternative outcomes. Sample sizes for Alzheimer’s disease PGS T1, T2 and T3 were 212, 212 and 211, respectively. Cold colours represent inverse statistically significant standardized effect sizes (β < 0, P < 0.05), while warmer colours represent positive statistically significant standardized effect sizes (β > 0, P < 0.05). Size of the circle is inversely proportional to the P-value. Depth of the colour is proportional to the absolute standardized effect size. ACR, anterior corona radiata; ALIC, anterior limb of the internal capsule; BCC, body of the corpus callosum; Cat, catalase; CCG, cingulum cingulate gyrus; CH, cingulum hippocampus; CP, cerebral peduncle; CT, corticospinal tract; EC, external capsule; FA, fractional anisotropy; FCST, fornix cres–stria terminalis; FO, fornix; FOF, superior fronto-occipital fasciculus; GCC, genu of the corpus callosum; ICP, inferior cerebellar peduncle; MD, mean diffusivity; ML, medial lemniscus; MCP, middle cerebellar peduncle; OLS, ordinary least square; OMP, outer membrane protein; PC, pontine crossing; PCR, posterior corona radiata; PGS, polygenic score; PLIC, posterior limb of the internal capsule; PTR, posterior thalamic radiation; ROI, region of interest; RPIC, retrolenticular part of the internal capsule; SS, sagittal striatum; SCC, splenium of the corpus callosum; SCP, superior cerebellar peduncle; SLF, superior longitudinal fasciculus; TP, tapetum; UNC, uncinate; UreA, urease; VacA, vacuolating cytotoxin A (see Supplementary Table 1 for full list of ROIs/tracts linked to FA and MD dMRI analysis).

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