Plasma Glial Fibrillary Acidic Protein Is Associated with 18F-SMBT-1 PET: Two Putative Astrocyte Reactivity Biomarkers for Alzheimer’s Disease

Abstract

Background: Astrocyte reactivity is an early event along the Alzheimer’s disease (AD) continuum. Plasma glial fibrillary acidic protein (GFAP), posited to reflect astrocyte reactivity, is elevated across the AD continuum from preclinical to dementia stages. Monoamine oxidase-B (MAO-B) is also elevated in reactive astrocytes observed using 18F-SMBT-1 PET in AD. Objective: The objective of this study was to evaluate the association between the abovementioned astrocyte reactivity biomarkers. Methods: Plasma GFAP and Aβ were measured using the Simoa ® platform in participants who underwent brain 18F-SMBT-1 and Aβ–PET imaging, comprising 54 healthy control (13 Aβ–PET+ and 41 Aβ–PET–), 11 mild cognitively impaired (3 Aβ–PET+ and 8 Aβ–PET–) and 6 probable AD (5 Aβ–PET+ and 1 Aβ–PET–) individuals. Linear regressions were used to assess associations of interest. Results: Plasma GFAP was associated with 18F-SMBT-1 signal in brain regions prone to early Aβ deposition in AD, such as the supramarginal gyrus (SG), posterior cingulate (PC), lateral temporal (LT) and lateral occipital cortex (LO). After adjusting for age, sex, APOE ɛ4 genotype, and soluble Aβ (plasma Aβ 42/40 ratio), plasma GFAP was associated with 18F-SMBT-1 signal in the SG, PC, LT, LO, and superior parietal cortex (SP). On adjusting for age, sex, APOE ɛ4 genotype and insoluble Aβ (Aβ–PET), plasma GFAP was associated with 18F-SMBT-1 signal in the SG. Conclusion: There is an association between plasma GFAP and regional 18F-SMBT-1 PET, and this association appears to be dependent on brain Aβ load.

Novel brain-penetrant inhibitor of G9a methylase blocks Alzheimer’s disease proteopathology for precision medication

“…The Tau family microtubule-associated proteins 118 and STIM2 responsible for neuronal calcium homeostasis impairment 119 were MS1262-targeted components of module M7 MAPK signaling and metabolism that is highly associated with the rate of cognitive decline. Plasma glial fibrillary acidic protein, an astrocyte reactivity biomarkers for AD 120 and nitric oxide synthase 1 for synaptic transmission and neuroplasticity 121 were MS1262-targeted components of modules M5 postsynaptic density or M11 cell-ECM interaction, respectively, again, major modules strongly correlated to AD neuropathology and cognition. In addition, MS1262 reversed the phosphorylation of components of modules M29, glycosylation/ER, and M42, matrisome, that were correlated with AD endophenotypes, and elevated tau microtubule-binding domain peptide levels correlate with the other MS1262-affected components of M42 matrisome and M11 cell-ECM modules.…”

Plasma Biomarkers of Alzheimer’s Disease: A Review of Available Assays, Recent Developments, and Implications for Clinical Practice

“…Novel biomarkers are still under investigation with studies showing significant results with new PET tracers, e.g., the novel 18F MAO-B PET tracer (S)-(2-methylpyrid-5-yl)-6-[(3-18F-fluoro-2-hydroxy)propoxy] quinoline (18F-SMBT-1), binding significantly higher in the brain of Aβ+ compared with Aβ–healthy controls [ 136 ], and the combination of different genetic loci such as the coat protein complex I G2 (COPG2) and the WW domain-containing oxidoreductase (WWOX) genes with known biomarkers to develop better predictive models to diagnose AD [ 137 ].…”

Advanced brain imaging for the diagnosis of Alzheimer disease

“…Reactive astroglia has been detected in vivo by measuring [11C]-L-deprenyl or [11C]-Deuterium-L-deprenyl (11C-DED) that targets monoamine oxidase B (MAO-B) for the imaging of astrocytes [103–110]. Recently, 18F-SMBT-1 and 11C-BU99008, which bind to MAO-B and I2-imidazoline binding site (I2BS), respectively, have been developed as alternative tools to assess reactive astrogliosis in AD brains [111 ▪ ,112–114]. Recent research supports the framework that astrocyte imaging might identify early progression to AD [115 ▪ ].…”