Ageing is known to impact the cerebral vasculature and impacts nutrient delivery, waste clearance and the regulatory functions of the blood-brain barrier (BBB). Evidence indicates that the BBB undergoes measurable changes during healthy or normal ageing, even in the absence of overt neurodegenerative disease (Cummins et al., 2024). Mapping these changes across the lifespan is essential for understanding the biology of healthy brain ageing and for identifying early biomarkers of vulnerability. Rodent models remain central to experimental studies of the BBB in ageing, and brain ageing in general. Observations of increased permeability in aged animals and humans are common, but the magnitude, time of onset, species or sex-effects and regional specificity of these changes vary widely between studies. The present systematic review and meta-analysis aims to quantify age-associated changes in BBB permeability (integrity failure/ loss of selective permeability/ increase in permeability rate), in healthy and modified ageing rodent models, and across multiple tracer types, species and sex. This will allow us to assess heterogeneity in effect sizes attributable to methodological and biological moderators, including tracer properties, detection method, (brain region, species, strain,) and age definition. This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement (Page et al., 2021). Inclusion and exclusion criteria were determined and appropriate literature searches conducted from which data including PS/PA (permeability–surface area product), K_trans (DCE-MRI), Tex (water exchange time from ASL MRI), tracer Ki (unidirectional transfer constant), Evans blue–albumin extravasation and endogenous IgG or albumin leakage was collected. Overall, we identified 14 for studies meeting the inclusion criteria for quantitative effect size analysis which included 8 studies reporting BBB permeability dysfunction and 6 studies reporting BBB permeability transport changes. Aged mice (typically ~18–30 months), tended to have higher rates of permeability, as well as showing higher levels of large molecule extravasation across the BBB when compared to younger controls (typically ~2–4 months), based on data using a variety of tracer methods including, but not limited to; PS/PA of Sucrose C14, Ktrans DCE-MRI, Evans blue dye, endogenous IgG, and albumin/IgG-depleted signal. Further analysis will determine the efficacy of different tracing methods and compare changes in BBB permeability according to species, strain (where possible), sex, tracer method and comparing healthy ageing with modified ageing models. Age-related BBB permeability increases may contribute to neuroinflammation, neuronal stress and cognitive decline. However, it is important to assess, the comparability of using healthy aged animals with modified ageing models and understand changes according to sex, species and methodological approach. Healthy ageing models require substantial investment in terms of resources, both time and financial whereas modified ageing models, if similar changes in BBB permeability are seen, can offer a more efficient route to experimental data. Additionally, it is important to consider sex-specific effects and the efficacy across a variety of tracers to determine the optimal experimental designs for exploring mechanistic changes in BBB permeability and function.
Microvasculature as a Key Regulator of Health and Disease in the Brain and Beyond (Sainsbury Wellcome Centre, London, UK) (2026) Proc Physiol Soc 69, C13
Oral Communications: Blood-brain barrier permeability during ageing in rodent models – a systematic review and meta-analysis
Mitchell Hudson1, Claire L Gibson2
1School of Psychology, University of Nottingham Unitedd Kingdom, 2School of Psychology, University of Nottingham United Kingdom
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Where applicable, experiments conform with Society ethical requirements.