Mechanistic Disruption of the Blood-Brain Barrier and Neurovascular Unit by Lead, Manganese, and Cadmium: A WHO-WHY-WHAT-WHEN-WHERE-HOW Structured Review

Abstract:

Environmental exposure to lead (Pb), manganese (Mn), and cadmium (Cd) damages the Blood-Brain Barrier (BBB) and the Neurovascular Unit (NVU) through a combination of pathways, including endothelial and astrocyte remodeling, transport dysregulation, oxidative and inflammatory signaling, and altered astrocyte-pericyte control of capillary tone. These changes lead to impaired neurovascular coupling and reduced cerebral blood flow. We collated and synthesized mechanistic evidence from experimental and clinical studies conducted over the 30 years from 1995 to 2025, focusing on studies that reported quantitative environmental exposure data and measured neuroimaging correlates of NVU/BBB injury. Cognitive deficits are associated with low-level blood lead levels (<5-10 μg/dL); blood manganese (Mn) levels of 4-15 μg/L are associated with neurodegeneration. Cadmium (Cd) is a cumulative neurotoxicity biomarker linked to cognitive deficits. Hair Mn tracks chronic inhalation exposure more closely than blood Mn does, and the gap between the two measures suggests that cerebral targets receive more manganese than systemic concentrations imply. Neuroimaging corroborates these mechanistic pathways, documenting region-specific cortical and subcortical volume loss, altered brain perfusion, and changes consistent with inflammatory signaling and with endothelial and astrocyte remodeling. Pallidal T1-weighted MRI and Arterial Spin-Labeling (ASL) perfusion MRI both perform well as neuroimaging biomarkers. Multimetal exposure biomarkers are more indicative of the mixture effect than single metal biomarkers. Longitudinal, mechanistic, and quantitative analyses indicate potential to develop interventions in exposed populations.