Decoding blood-brain barrier dysfunction in Alzheimer's Disease: Innovations and challenges in multimodal MRI and PET imaging biomarkers.

Alzheimer's disease (AD), a leading neurodegenerative disorder, involves blood-brain barrier (BBB) dysfunction as a critical contributor to its pathogenesis. This review synthesizes current advancements in in vivo magnetic resonance imaging (MRI) and positron emission tomography (PET) techniques for imaging BBB breakdown in AD. The BBB, a dynamic neurovascular interface, regulates amyloid-beta (Aβ) and tau clearance through specialized transporters and cellular interactions. BBB dysfunction, driven by tight junction disruption, transporter deficits, and pericyte degeneration, exacerbates Aβaccumulation and neuroinflammation. Dynamic contrast-enhanced MRI quantifies subtle leakage via gadolinium kinetics, while water-exchange MRI probes trans-BBB water dynamics without contrast agents. Dynamic glucose-enhanced MRI maps glucose transport anomalies linked to glucose transporter- 1 dysfunction. PET imaging with tracers like [18F]-fluorodeoxyglucose and [11C]-verapamil evaluates glucose metabolism and efflux transporter activity, revealing early metabolic deficits and impaired Aβ clearance. Challenges include low sensitivity for subtle leakage, model-dependent quantification, and spatial-temporal resolution trade-offs. Emerging strategies emphasize multimodal integration, ultrahigh-field systems, and artificial intelligence-driven analytics to decode region-specific BBB pathology. Longitudinal studies correlating imaging biomarkers with clinical progression and novel PET tracer development are pivotal for early diagnosis and personalized therapies. These innovations promise to elucidate BBB's role and promote a paradigm shift in diagnostic and therapeutic strategies from solely targeting amyloid proteins to multi-target interventions in AD.