Neuroinflammation Imaging in Alzheimer's Disease

Neuroinflammation is increasingly recognised as both a driver and a marker of Alzheimer’s disease progression. In vivo imaging techniques, most notably positron emission tomography (PET), permit the visualisation and quantification of inflammatory processes in the living brain. Radioligands targeting the 18 kDa translocator protein (TSPO) have dominated this field, enabling researchers to map microglial density and activation state across cortical and subcortical regions. Complementary approaches, such as magnetic resonance imaging (MRI) with iron‐sensitive sequences or diffusion metrics, are also under development to infer glial reactivity indirectly. Advances in radiochemistry have yielded second‐ and third‐generation TSPO tracers with improved specificity and affinity profiles, though genetic polymorphisms affecting TSPO binding remain a challenge. Beyond TSPO, novel PET targets include purinergic receptors, cannabinoid receptors and enzymes of the kynurenine pathway, offering the promise of distinguishing pro‐inflammatory from reparative glial phenotypes. Multi-modal protocols that combine amyloid and tau imaging with neuroinflammatory markers are revealing how plaque and tangle burden interact with microglial responses. Together, these imaging advances are refining our understanding of when and where neuroinflammation emerges in the Alzheimer continuum, guiding both patient stratification and therapeutic development.

Research from Nature Portfolio

Recent studies have demonstrated that TSPO expression in animal models does not fully translate to the human condition. Work in rodent disease models confirms robust upregulation of TSPO in activated microglia, yet parallel investigations in non‐human primates and human post-mortem tissue show little change in TSPO levels with neurodegeneration. Genetic analyses indicate that rodent TSPO promoters carry unique regulatory elements absent in primate lineages, suggesting that TSPO-PET signals in patients reflect inflammatory cell density rather than activation per se. Such findings have prompted the identification of alternative human microglial markers—including LCP2 and TFEC—that may serve as more faithful indicators of cellular activation in clinical imaging studies.

Neuroinflammation Imaging in Alzheimer's Disease publication trend

The graph below shows the total number of articles in neuroinflammation imaging in alzheimer's disease across all publications each year (not limited to Nature Index journals).

Technical terms

TSPO: 18 kDa translocator protein expressed on mitochondrial membranes of glial cells, used as a PET target for neuroinflammation.

Microglial connectome: A network representation of interregional microglial activation synchrony assessed by PET correlation metrics.

Phagocytic phenotype: A functional state of microglia characterised by high expression of markers such as CD68 and active clearance of debris and protein aggregates.

Aβ: β-amyloid peptide that aggregates extracellularly to form plaques, one of the hallmark pathologies of Alzheimer’s disease.

Tau: Microtubule-associated protein that, upon hyperphosphorylation, forms intracellular neurofibrillary tangles contributing to neuronal dysfunction.

References

1. Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer’s disease. Molecular Neurodegeneration (2024).
2. Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases. Nature Communications (2023).
3. Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies. Molecular Psychiatry (2023).
4. The microglial translocator protein (TSPO) in Alzheimer’s disease reflects a phagocytic phenotype. Acta Neuropathologica (2024).
5. Recent Developments in TSPO PET Imaging as A Biomarker of Neuroinflammation in Neurodegenerative Disorders. International Journal of Molecular Sciences (2019).
6. Applications of amyloid, tau, and neuroinflammation PET imaging to Alzheimer's disease and mild cognitive impairment. Human Brain Mapping (2019).
7. Molecular Targets for PET Imaging of Activated Microglia: The Current Situation and Future Expectations. International Journal of Molecular Sciences (2017).