Relationship of 18F-SMBT-1 PET with cognition in non-demented individuals

Increased peripheral inflammation and astrogliosis, as assessed by glial fibrillary acidic protein (GFAP) associates with worse cognition. GFAP, however, does not provide regional brain information. 18 F-SMBT-1, a tracer that binds to overexpressed MAO-B in reactive astrocytes, may help overcome this limitation. Proteins related to neurotrophic or growth factor signaling (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, selected proteins related to neurotrophic or growth factor signaling, astrogliosis, and cognitive function and explored whether the relationship of astrogliosis with cognition could be mediated by these growth factors. 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 proteins related to neurotrophic or growth factor signaling. We used multivariable robust linear regression models to test the relationship of peripheral inflammation and astrogliosis and cognition. Later, in a post hoc exploratory analysis we ran a causal mediation analyses to examine the effects of BDNF and IGFR1 on the relationship between astrogliosis and cognition. Ninety-four non-demented participants were included (mean age: 69 ± 1.2 yrs, 52% women, 89%, White, 15% with MCI); among them, 76 were classified as A- and 18 as A+. 18 F-SMBT-1 binding in precuneus was higher among A+ individuals. Also, frontal, latero-temporal, posterior and occipital 18 F-SMBT-1 binding was associated with worse visual memory. Lastly, in an exploratory post hoc analysis we found that IGFR1 but not BDNF significantly mediated (suppressed) the association of 18 F-SMBT-1 with worse visual memory in A+ participants (NIE p = 4.68; p = 0.012, BH p-val:0.048). In this non-demented population of older adults with low levels of Aβ pathology and neuroinflammation, astrogliosis related with worse visual memory, particularly among A+ individuals. A post hoc exploratory analysis suggests that IGFR1 may play a suppressive role on the effect of astrogliosis on worse visual memory.