Towards precision diagnostics for asymptomatic bacteriuria-related cognitive decline

Background

Bacteria in the urinary tract are a major risk factor for urinary tract infections (UTI), accounting for over 400 million cases every year globally. UTIs are the second leading cause of hospitalisation in later life and the most common infection for long term care facility residents, for whom UTIs are the most common infection often linked to cognitive issues such as delirium. Moreover, asymptomatic bateriuria (ABU; bacteria without classical UTI symptoms) is very common in older women. Acute and chronic infections, and their associated immune response, are increasingly linked to poorer brain and cognitive decline [2]. Early studies showed a clear correlation of ABU with early inflammatory immune activity in elderly patients [3], while urinary inflammatory biomarkers, including IL-6, NGAL, TIMP-2 and CXCL9, are elevated for symptomatic UTI [1].

We postulate that persistent or recurrent ABU contributes to a chronic low grade inflammatory state, increasing the risk of cognitive and cerebrovascular decline in the elderly. Testing this requires repeated urine sampling alongside deep longitudinal phenotyping in exclusively older adults. The Lothian Birth Cohort 1936 (LBC1936) provides this opportunity; 1,091 individuals followed since age 11 with repeated cognitive assessment and stored urine samples across 8 waves (70-90yrs) and health-record linkage. These data will be complimented with clinical discovery samples. Prior work in the LBC1936 has already linked persistent infection-related exposures, such as cytomegalovirus seropositivity, to cognitive ability in old age [4]. Furthermore, infection is an established driver of ischaemic stroke.

This project will study if urinary biomarkers associated with ABU can be linked to cognitive decline. The presence of both premorbid cognitive ability and longitudinal later life measures allows us to more directly test the (partly adversarial) hypotheses that ABU-cognitive correlations could reflect either i) poorer cognitive functioning leading to ABU, ii) ABU leads to subsequent cognitive decline. Urinary markers are of immense interest for non-invasive testing and home monitoring of disease risk markers, offering the potential for precision medicine interventions. 

Aims

Investigate the link of asymptomatic bacteriuria with cognitive decline (data + laboratory analysis). Using LBC1936, the student will quantify bacterial load in stored urine (2ml, stored at –40C) by qPCR and integrate this with longitudinal cognitive trajectories, MRI measures, stroke outcomes and linked clinical data. Analyses will test directionality using premorbid cognitive ability and repeated later-life measures, including lead-lag and mediation approaches. Existing blood proteomics (SomaScan 11k; Alamar NULISA) will test whether systemic inflammatory pathways mediate associations between urinary bacterial burden and cognitive or cerebrovascular outcomes. Initial findings will inform targeted proteomics, metabolomics, RNA profiling, lipidomics studies in informative participant subsets.

Develop a rapid diagnostic test (biomedical engineering + laboratory analysis). Biomarkers from Aim 1 will be translated towards a prototype rapid test for risk assessment ABU-related risk stratification for cognitive ageing. Depending on biomarker class, select the most suitable in-house test platform (such as paper-based, electrochemical or microfluidic detection) and develop ABU test building on in-house expertise for urinary diagnostics. The most promising approach will be tested and validated with contrived and clinical samples, and made available as accompanying test for future, prospective longitudinal studies.

Training Outcomes

The student will receive integrated training in longitudinal and structural equation modelling of cognitive trajectories, linked-data epidemiology, laboratory biomarker science, and high-dimensional data analysis and diagnostic assay development. The student will be co-embedded in CIR and LBC, with access to weekly research meetings, statistics courses and immunology support. Complementary training in R programming, research ethics, public and patient involvement and science communication will support an independent academic trajectory, producing a rare combined skillset in infection, immunology, brain-ageing, and diagnostics, aligned with the early-diagnosis priorities of the Precision Medicine DTP.

References: 

[1]   Bilsen MP, Treep MM, Aantjes MJ, van Andel E, Stalenhoef JE, van Nieuwkoop C, Leyten EMS, Delfos NM, van Uhm JIM, Sijbom M, Akintola AA, Numans ME, Achterberg WP, Mooijaart SP, van der Beek MT, Cobbaert CM, Conroy SP, Visser LG, Lambregts MMC. Diagnostic accuracy of urine biomarkers for urinary tract infection in older women: a case-control study. Clin Microbiol Infect. 2024 Feb;30(2):216-222.  https://doi.org/10.1016/j.cmi.2023.09.023

[2]   Hernandez-Ruiz V, Letenneur L, Fülöp T, Helmer C, Roubaud-Baudron C, Avila-Funes JA, Amieva H. Infectious diseases and cognition: do we have to worry? Neurol Sci. 2022 Nov;43(11):6215-6224. https://doi.org/10.1007/s10072-022-06280-9 

[3]   Priø TK, Bruunsgaard H, Røge B, Pedersen BK. Asymptomatic bacteriuria in elderly humans is associated with increased levels of circulating TNF receptors and elevated numbers of neutrophils. Exp Gerontol. 2002 May;37(5):693-9. https://doi.org/10.1016/s0531-5565(02)00002-5

[4]   Gow AJ, Firth CM, Harrison R, Starr JM, Moss P, Deary IJ. Cytomegalovirus infection and cognitive abilities in old age. Neurobiol Aging. 2013 Jul;34(7):1846-52. https://doi.org/10.1016/j.neurobiolaging.2013.01.011