Abstract
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Introduction: To explore the neuroinflammatory theory of Alzheimer Disease (AD) To understand neuroinflammatory manifestations of AD. To evaluate the role of radiotracer imaging of neuroinflammation in Alzheimer Disease (AD)
Methods: A literature review was conducted to collect published prospective and retrospective studies using PubMed, MeSH, Google Scholar, and Web of Science with the keywords “Alzheimer Disease”, “AD”, “Neuroinflammation”, “Molecular Imaging”, “TSPO-PET”, “Microglia”, “FDG”, etc., in various combinations.
Results: Chronic neuroinflammation as a result of Aβ peptide accumulation leading to persistent microglial activation, release of pro-inflammatory cytokines, and decrease of pro-resolution factors is a feature of many neurodegenerative diseases including AD. This inflammation has been explored as a primary driver of Aβ plaque and neurofibrillary tangle pathologies that are observed in AD. Translocator protein 18-kDa (TSPO) is a protein found in the outer mitochondrial matrix that has been extensively studied in the context of neuroinflammatory processes; most notably, its upregulation and overexpression in microglia after injury.
Radiotracers have been developed to exclusively target the TSPO protein to assess neuroinflammatory processes via TSPO-PET, which is currently the predominant modality for imaging neuroinflammation. One major disadvantage of TSPO being the main marker of neuroinflammation is that there are polymorphisms in the (rs6971) gene coding for TSPO in humans leading to variable binding affinity of tracers across the population. These obstacles have made it difficult to precisely quantify neuroinflammation. However, there is research that suggests cerebellar gray matter could be a reliable reference region across individuals.
Multiple clinical studies show an overexpression of brain TSPO on PET imaging in patients with AD, however, the pattern differs greatly in different regions of the brain. An example of this can be seen with the hippocampus; a region in the temporal lobe known to be affected greatly in AD. Multiple studies show an increase in TSPO activity in the hippocampus while other studies have not found any significant difference in this region, though the discrepancies in these temporal changes of inflammation may play a role in determining disease phenotype. This variance exists in other regions as well and is not limited to the hippocampus.
Conclusions: Multiple studies show clear evidence of chronic neuroinflammation in patients with AD. The prognostic value of TSPO-PET imaging is uncertain, with some studies suggesting that increased activity is directly correlated to disease severity while others show an inverse relationship. The presence of genetic polymorphisms in the gene for TSPO as well as the lack of an accurate reference region have made precise quantification of neuroinflammation difficult. Future studies and the development of additional tracers or target proteins are necessary in order to accurately assess neuroinflammation in AD.