👤 Stefania Vetrano

Olfactory impairment is common in older age and is a known early feature of several dementia diseases. Blood-based biomarkers of Alzheimer's disease (AD) now offer a scalable method for detecting pathophysiological mechanisms related to olfactory decline in the general population. However, few studies have examined how these biomarkers relate to long-term olfactory trajectories. Most existing work has been limited to cross-sectional settings. In this population-based study, we used biomarker data collected at baseline and followed participants for up to 15 years, enabling us to test whether early biological changes are temporally linked to subsequent olfactory decline. Data came from the ongoing Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study with baseline assessments from March 21, 2001, through August 30, 2004. We included participants without prevalent neurodegenerative diseases who completed olfactory assessment at baseline. The 15-year follow-up was finished in December 2019. Data were analysed from December 2023 to April 2024. Serum-derived biomarkers of tau phosphorylated at threonine 217 (p-tau217) and at theorine181 (p-tau181), total tau (t-tau), amyloid-β ratio (Aβ42/Aβ40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were obtained at baseline. Linear mixed models examined associations between biomarker quartiles and Sniffin' Sticks odor identification performance over 15 years, adjusting for demographics, health conditions, and semantic knowledge. We included 1868 participants (mean [SD] age 71.3 [9.9] years; 1122 females [60.1%]). In fully adjusted models, higher quartiles of p-tau217, p-tau181, NfL, and GFAP, and lower quartiles of Aβ42/Aβ40, were associated with steeper olfactory decline, with the steepest decline among participants in the highest quartiles (β for Q4 vs Q1: -0.20 [95% CI: -0.26 to -0.15] for p-tau217; -0.19 [95% CI: -0.25 to -0.13] for p-tau181; -0.23 [95% CI: -0.29 to -0.17] for NfL; β = -0.17 [95% CI: -0.23 to -0.11] for GFAP. Participants in the lowest Aβ42/Aβ40 quartile declined more steeply than those in the highest (β = -0.09 [95% CI: -0.14 to -0.04]). Associations appeared stronger in the oldest participants, in APOE ε4 carriers for p-tau181, in non-carriers for NfL and GFAP, and among former smokers for NfL. Blood-based biomarkers of AD were consistently associated with faster olfactory decline in older adults, particularly in the highest biomarker quartiles. These results provide large-scale longitudinal evidence, across up to 15 years of follow-up, that olfactory decline in the general population is linked to AD-related blood biomarkers, supporting the hypothesis that common olfactory losses in ageing partly reflect dementia-related processes. Show less

Perianal fistula represents one of the most disabling manifestations of Crohn's disease (CD) due to complete destruction of the affected mucosa, which is replaced by granulation tissue and associated with changes in tissue organization. To date, the molecular mechanisms underlying perianal fistula formation are not well defined. Here, we dissected the tissue changes in the fistula area and addressed whether a dysregulation of extracellular matrix (ECM) homeostasis can support fistula formation. Surgical specimens from perianal fistula tissue and the surrounding region of fistulizing CD were analyzed histologically and by RNA sequencing. Genes significantly modulated were validated by real-time polymerase chain reaction, Western blot, and immunofluorescence assays. The effect of the protein product of TNF-stimulated gene-6 (TSG-6) on cell morphology, phenotype, and ECM organization was investigated with endogenous lentivirus-induced overexpression of TSG-6 in Caco-2 cells and with exogenous addition of recombinant human TSG-6 protein to primary fibroblasts from region surrounding fistula. Proliferative and migratory assays were performed. A markedly different organization of ECM was found across fistula and surrounding fistula regions with an increased expression of integrins and matrix metalloproteinases and hyaluronan (HA) staining in the fistula, associated with increased newly synthesized collagen fibers and mechanosensitive proteins. Among dysregulated genes associated with ECM, TNFAI6 (gene encoding for TSG-6) was as significantly upregulated in the fistula compared with area surrounding fistula, where it promoted the pathological formation of complexes between heavy chains from inter-alpha-inhibitor and HA responsible for the formation of a crosslinked ECM. There was a positive correlation between TNFAI6 expression and expression of mechanosensitive genes in fistula tissue. The overexpression of TSG-6 in Caco-2 cells promoted migration, epithelial-mesenchymal transition, transcription factor SNAI1, and HA synthase (HAs) levels, while in fibroblasts, isolated from the area surrounding the fistula, it promoted an activated phenotype. Moreover, the enrichment of an HA scaffold with recombinant human TSG-6 protein promoted collagen release and increase of SNAI1, ITGA4, ITGA42B, and PTK2B genes, the latter being involved in the transduction of responses to mechanical stimuli. By mediating changes in the ECM organization, TSG-6 triggers the epithelial-mesenchymal transition transcription factor SNAI1 through the activation of mechanosensitive proteins. These data point to regulators of ECM as new potential targets for the treatment of CD perianal fistula. Show less