CSF proteomics in autosomal dominant Alzheimer's disease highlights parallels with sporadic disease

Autosomal dominant Alzheimer's disease (ADAD) offers a unique opportunity to study pathophysiological changes in a relatively young population with few comorbidities. A comprehensive investigation of proteome changes occurring in ADAD could provide valuable insights into AD-related biological mechanisms and uncover novel biomarkers and therapeutic targets. Furthermore, ADAD might serve as a model for sporadic AD, but in-depth proteome comparisons are lacking. We aimed to identify dysregulated CSF proteins in ADAD and determine the degree of overlap with sporadic AD. We measured 1472 proteins in CSF of PSEN1 or APP mutation carriers (n = 22) and age- and sex-matched controls (n = 20) from the Amsterdam Dementia Cohort using proximity extension-based immunoassays (PEA). We compared protein abundance between groups with two-sided t-tests and identified enriched biological pathways. Using the same protein panels in paired plasma samples, we investigated correlations between CSF proteins and their plasma counterparts. Finally, we compared our results with recently published PEA data from an international cohort of sporadic AD (n = 230) and non-AD dementias (n = 301). All statistical analyses were false discovery rate-corrected. We detected 66 differentially abundant CSF proteins (65 increased, 1 decreased) in ADAD compared to controls (q &lt; 0.05). The most strongly upregulated proteins (fold change &gt;1.8) were related to immunity (CHIT1, ITGB2, SMOC2), cytoskeletal structure (MAPT, NEFL) and tissue remodelling (TMSB10, MMP-10). Significant CSF-plasma correlations were found for the upregulated proteins SMOC2 and LILR1B. Of the 66 differentially expressed proteins, 36 had been measured previously in the sporadic dementias cohort, 34 of which (94%) were also significantly upregulated in sporadic AD, with a strong correlation between the fold changes of these proteins in both cohorts (rs = 0.730, P &lt; 0.001). Twenty-nine of the 36 proteins (81%) were also upregulated among non-AD patients with suspected AD co-pathology. This CSF proteomics study demonstrates substantial biochemical similarities between ADAD and sporadic AD, suggesting involvement of the same biological processes. Besides known AD-related proteins, we identified several relatively novel proteins, such as TMSB10, MMP-10 and SMOC2, which have potential as novel biomarkers. With shared pathophysiological CSF changes, ADAD study findings might be translatable to sporadic AD, which could greatly expedite therapy development.</p

Gender and leprosy-related stigma in endemic areas: A systematic review

Background: The social impact of leprosy is said to exacerbate existing gender inequalities, but what is the evidence for this? What are the differences and similarities in leprosy-related stigma experiences between men and women? Methods: A systematic search was done in PubMed, Web of Science, PsycInfo and CINAHL databases, using the web-based version of Mendeley and following PRISMA guidelines. Search terms used in the search syntaxes involved synonyms for leprosy, stigma, and sex or gender. Criteria for eligibility were articles providing data on leprosy-related stigma separate for men and/or women, Dutch or English language, access to full-text copy, information based on primary data (excluding reviews), and a sample group of leprosy-affected subjects above 15 years old, living in leprosy-endemic areas. Case reports were excluded. Findings: 18 articles met the criteria and were reviewed. They demonstrated a female gender disadvantage, in the social, health and/or psychological domain. This was evidenced by a higher percentage of women experiencing stigma, a lower quality of life score for women, and a higher mental burden among women compared to controls. Only one article indicated higher perceived stigma in men compared to women, in society and in social institutions. Overall, it was found that women's inferior position results in more rejection at family and community level, more difficulties in their marital position, more social avoidance, more concealment and treatment delay, and more self-stigmatisation. All these factors and the lower female social status mutually reinforce each other. It is argued that this gender inequality is the case in other neglected tropical diseases and stigmatising conditions as well. Conclusion: The consensus that female leprosy patients are more severely affected by leprosy-related stigma than male patients is supported by 12 of the 18 reviewed articles, and by other literature. These findings highlight a need for gender sensitivity in leprosy interventions to reduce leprosy-related stigma and its impact, especially among women and girls