Laura-Alejandra Ramirez-Tirado, Ann D Cohen, Brian J Lopresti, Milos D Ikonomovic, Alexandra Gogola, Cristy Matan, Xuemei Zeng, Thomas K Karikari, Oscar L Lopez, Beth E Snitz, C Elizabeth Shaaban, Victor L Villemagne
Background Increased peripheral inflammation and astrogliosis, as assessed by glial fibrillary acidic protein (GFAP) associates with worse cognition. GFAP, however, does not provide brain spatial information. 18 F-SMBT-1, a tracer that binds to overexpressed MAO-B in reactive astrogliosis, may help overcome this limitation. Neuroprotective growth factors (e.g. BDNF, VGF, VEGFA, VEGFD, IGF1R and IGFBP7) usually accompany astrogliosis and could mediate the pathways between AD pathology and cognitive impairment. We evaluated the relationships among peripheral inflammatory markers, growth factors, astrogliosis, and cognitive function and explored whether the relationship of astrogliosis with cognition could be mediated by these growth factors. Methods In a sample of older adults without dementia, we evaluated the relationship of astrogliosis with overall and domain-specific cognitive performance (verbal memory, visual memory, executive function and attention). 11 C-PiB and 18 F-SMBT-1 radiotracers were used to assess Aβ status and astrogliosis, respectively. The NULISAseq CNS disease panel was used to assess GFAP, markers of peripheral inflammation and selected growth factors. We used multivariable robust linear regression models to test the relationship of peripheral inflammation and astrogliosis and cognition. Later, we ran causal mediation analyses stratified by Aβ status to address the effects of BDNF and IGFR1 on the relationship between astrogliosis and cognition. Results Ninety-four non-demented participants were included (mean age: 68 ± 7 yrs, 52% women, 89%, White); among them, 76 were classified as A- and 18 as A+. 18 F-SMBT-1 binding in precuneus was higher among A+ individuals. Also, among A+ individuals, regional 18 F-SMBT-1 binding was associated with worse verbal and visual memory and executive function. Lastly, we found that IGFR1 but not BDNF significantly mediated (suppressed) the association of 18 F-SMBT-1 with worse visual memory, but only among A+ individuals (p<.0001). Conclusion In this non-demented population of older adults with low levels of Aβ pathology and neuroinflammation, astrogliosis related with worse cognitive functions, but only among A+ individuals. Further, IGFR1 may play a suppressive role decreasing by more than 50% the effect of astrogliosis on worse visual memory.