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Abstract Osteopontin (OPN), also known as SPP1 (secreted phosphoprotein), is an integrin binding glyco-phosphoprotein produced by a variety of tissues. In cancer patients expression of OPN has been associated with poor prognosis in several tumor types including breast, lung, and colorectal cancers. Despite wide expression in tumor cells and stroma, there is limited evidence supporting role of OPN in tumor progression and metastasis. Using phage display technology we identified a high affinity anti-OPN monoclonal antibody (hereafter AOM1). The binding site for AOM1 was identified as SVVYGLRSKS sequence which is immediately adjacent to the RGD motif and also spans the thrombin cleavage site of the human OPN. AOM1 efficiently inhibited OPNa binding to recombinant integrin αvβ3 with an IC50 of 65 nM. Due to its unique binding site, AOM1 is capable of inhibiting OPN cleavage by thrombin which has been shown to produce an OPN fragment that is biologically more active than the full length OPN. Screening of human cell lines identified tumor cells with increased expression of OPN receptors (αvβ3 and CD44v6) such as mesothelioma, hepatocellular carcinoma, breast, and non-small cell lung adenocarcinoma (NSCLC). CD44v6 and αvβ3 were also found to be highly enriched in the monocyte, but not lymphocyte, subset of human peripheral blood mononuclear cells (hPBMCs). In vitro, OPNa induced migration of both tumor and hPBMCs in a transwell migration assay. AOM1 significantly blocked cell migration further validating its specificity for the ligand. OPN was found to be enriched in mouse plasma in a number of pre-clinical tumor model of non-small cell lung cancers. To assess the role of OPN in tumor growth and metastasis and to evaluate a potential therapeutic indication for AOM1, we employed a KrasG12D-LSLp53fl/fl subcutaneously implanted in vivo model of NSCLC which possesses a high capacity to metastasize into the lung. Our data indicated that treatment of tumor bearing mice with AOM1 as a single agent or in combination with Carboplatin significantly inhibited growth of large metastatic tumors in the lung further supporting a role for OPN in tumor metastasis and progression.

Abstract Background To date, nine Parkinson disease (PD) genome-wide association studies in North American, European and Asian populations have been published. The majority of studies have confirmed the association of the previously identified genetic risk factors, SNCA and MAPT, and two studies have identified three new PD susceptibility loci/genes (PARK16, BST1 and HLA-DRB5). In a recent meta-analysis of datasets from five of the published PD GWAS an additional 6 novel candidate genes (SYT11, ACMSD, STK39, MCCC1/LAMP3, GAK and CCDC62/HIP1R) were identified. Collectively the associations identified in these GWAS account for only a small proportion of the estimated total heritability of PD suggesting that an 'unknown' component of the genetic architecture of PD remains to be identified. Methods We applied a GWAS approach to a relatively homogeneous Ashkenazi Jewish (AJ) population from New York to search for both 'rare' and 'common' genetic variants that confer risk of PD by examining any SNPs with allele frequencies exceeding 2%. We have focused on a genetic isolate, the AJ population, as a discovery dataset since this cohort has a higher sharing of genetic background and historically experienced a significant bottleneck. We also conducted a replication study using two publicly available datasets from dbGaP. The joint analysis dataset had a combined sample size of 2,050 cases and 1,836 controls. Results We identified the top 57 SNPs showing the strongest evidence of association in the AJ dataset (p < 9.9 × 10-5). Six SNPs located within gene regions had positive signals in at least one other independent dbGaP dataset: LOC100505836 (Chr3p24), LOC153328/SLC25A48 (Chr5q31.1), UNC13B (9p13.3), SLCO3A1(15q26.1), WNT3(17q21.3) and NSF (17q21.3). We also replicated published associations for the gene regions SNCA (Chr4q21; rs3775442, p = 0.037), PARK16 (Chr1q32.1; rs823114 (NUCKS1), p = 6.12 × 10-4), BST1 (Chr4p15; rs12502586, p = 0.027), STK39 (Chr2q24.3; rs3754775, p = 0.005), and LAMP3 (Chr3; rs12493050, p = 0.005) in addition to the two most common PD susceptibility genes in the AJ population LRRK2 (Chr12q12; rs34637584, p = 1.56 × 10-4) and GBA (Chr1q21; rs2990245, p = 0.015). Conclusions We have demonstrated the utility of the AJ dataset in PD candidate gene and SNP discovery both by replication in dbGaP datasets with a larger sample size and by replicating association of previously identified PD susceptibility genes. Our GWAS study has identified candidate gene regions for PD that are implicated in neuronal signalling and the dopamine pathway.

Background: Only a few studies in the general population have investigated genetic contributions to variation in levels of neurofilament light (NfL), which is a general marker of axonal damage and is predictive of Alzheimer's disease (AD). To our knowledge, no studies have examined this relation in people with Down Syndrome (DS), a population at high risk of developing AD. We performed a genome‐wide search for SNPs associated with plasma NfL levels. We paid special attention to genetic variants identified in the general population to be associated with AD risk and NfL to evaluate whether those variants contributed to AD in DS by altering NfL levels. Methods: We performed a meta‐analysis using two datasets (N = 455): the omicsADDS and ABC‐DS studies. Levels of plasma NfL were measured using the Simoa platform and genotyping was performed using an Illumina Infinium General Screening Array v2. Imputation on autosomal chromosomes other than 21 was performed using the TOPMed Imputation Server. We first assessed the association between SNPs and plasma NfL levels in each dataset using a multivariable linear regression model that included age, sex, dementia status, and genetic ancestry. We then performed meta‐analysis using sample size weighting. We restricted our meta‐analysis to variants that had study‐specific P<5×10−4, to minimize potential false positives. Results: Our genome‐wide scan, after Bonferroni correction, identified 33 novel SNPs contributing to variation in plasma NfL (28 variants with elevated plasma NfL and 5 variants with decreased plasma NfL). Three AD‐risk variants previously identified in the general population (UNC5CL/rs10947943, USP6NL/rs7912495, FOXF1/rs16941239), were found to be associated with variation in plasma NfL levels at nominal Pmeta < 0.05. Candidate variants associated with NfL in the general population were not replicated in the current meta‐analysis. The novel genes identified have been implicated in tau neuropathology, variation in lipid levels, insulin regulation, and neurotransmitter release. Conclusion: This genome‐wide meta‐analysis revealed multiple novel genetic loci associated with NfL levels in plasma in adults with DS. We additionally found supporting evidence for three known variants. The genes identified here may lead to insight into underlying mechanisms of neurodegeneration and AD in adults with DS. [ABSTRACT FROM AUTHOR]

Background: Ethno‐racial differences are observed in amyloid (A), tau (T), and neurodegeneration (N) plasma biomarkers of Alzheimer's disease (AD). In neuroimaging studies, structural and social determinant of health (SSDOH) factors and associated health outcomes may mediate observed racial differences in neurodegeneration markers. However, little is known regarding the potential effects of SSDOH and downstream comorbidities on ethno‐racial differences in AT(N) plasma biomarkers. This study A) assessed potential differences in plasma Aβ42, Aβ40, Aβ42/40, t‐tau, and NfL among Mexican Americans (MA), non‐Hispanic Blacks (NHB), and non‐Hispanic Whites (NHW); B) determined whether SSDOH and comorbidity factors mediate potential ethno‐racial differences in AD plasma biomarkers. Method: Data were obtained from the diverse and well‐characterized Health and Aging Brain Study – Health Disparities (HABS‐HD) and included MAs (n = 931), NHBs (n = 258), and NHWs (n = 942). Group differences in AT(N) plasma biomarkers were assessed using analysis of covariance. Age, sex, and cognitive status (Clinical Dementia Rating Scale Sum of Boxes) were included as covariates. Two multiple mediation models were performed with SSDOH (acculturation, chronic stress, income, area deprivation index) and comorbidity factors (body mass index [BMI], blood pressure, diabetes history) as the potential mediators, respectively. Models accounted for age, sex, and cognitive status, assumed nonlinear relationships, and allowed for mediators to be considered simultaneously. Result: Plasma Aβ42 was significantly lower in MAs compared to NHWs (p<0.05). Plasma NfL was significantly higher in MAs compared to NHBs (p<0.01) and for NHWs compared to NHBs (p<0.05). No other significant differences in plasma variables were observed (p's>0.05). Group differences in plasma Aβ42 were mediated by comorbidity factors (BMI and history of diabetes), but not SSDOH. MAs had greater BMIs and history of diabetes compared to NHWs, both of which were associated with lower plasma Aβ42 levels. SSDOH and comorbidity factors did not mediate group differences in plasma NfL. Conclusion: Using a large and diverse community‐based cohort, we demonstrate that ethno‐racial differences in AD‐specific plasma biomarkers are, in part, due to modifiable health and comorbidity factors. This work informs the conditions that give rise to ethno‐racial differences in plasma ATN biomarkers while highlighting potential ethno‐racial disparities in AD research. [ABSTRACT FROM AUTHOR]

Background: Down syndrome (DS) is a complex neurological disorder manifested by triplication of chromosome 21, which includes the amyloid precursor protein (APP) gene. Triplication of APP which is known for the buildup of Amyloid Beta plaques, a hallmark of Alzheimer's disease (AD) pathology. Although researchers have studied genetic factors of AD risk in DS, the overall genetic contribution of AD in DS is still not clear. While the polygenic risk score (PRS) explains the overall genetic architecture and overlap between complex traits, no study has used PRS to understand the relative burden of AD risk variants in DS. Methods: We constructed PRS using Bellenguez et al (2022) summary statistics for five different cohorts: DS (n = 282), sporadic early‐onset (sEOAD, n = 395), sporadic late‐onset (sLOAD, n = 2259), familiar early‐onset (fEOAD, n = 196), familial late‐onset (fLOAD, n = 1413). Unrelated European ancestry samples were selected for analysis (4,545 cases, 2,890 controls). To understand AD risk beyond APOE, PRS including and excluding APOE region was calculated using PRSiceV2.3. Chromosome 21 was excluded from the analysis. We tested the association of PRS with clinical status in each cohort and compared it between cohorts. We further tested association of neuropsychological batteries for cognition/memory, and cerebrospinal fluid (CSF) biomarkers with the AD PRS for DS individuals. Results: The PRS of AD was associated with sEOAD, fLOAD and sLOAD, but not with fEOAD. DS status was significantly associated with the AD PRS including APOE (OR = 0.62, P = 1.86×10−3). Down Syndrome Mental Status Examination (DSMSE) memory score was associated with AD PRS regardless of APOE inclusion (P = 8.61×10−4 with APOE, and P = 4.94×10−2 without APOE). In addition, DSMSE total score (P = 4.53×10−3), Dementia Questionnaire for People with Learning Disabilities (DLD) cognitive score (P = 1.46×10−2), CSF Aβ40 (P = 1.28×10−2), and Aβ42 (P = 4.21×10−2) were associated with the AD PRS including APOE. Conclusions: Our study suggests that even if DS individuals were depleted with AD risk variants, the overall genetic architecture for AD is still associated with cognitive and memory phenotypes, as well as AD biomarkers. This suggests that AD risk modulates APP metabolism/Aβ formation and tau protein binding, thus playing a role in the onset and progression of dementia in DS. [ABSTRACT FROM AUTHOR]

Background: Venezuela is in the throes of a complex humanitarian crisis that is one of the worst in decades to impact any country outside of wartime. This case analysis describes the challenges faced by the ongoing Maracaibo Aging Study (MAS) during the deteriorating conditions in Venezuela. When the MAS began in 1997, it focused on memory-related disorders. Since then, strategic planning and proactive community participation allowed us to anticipate and address logistical, funding, and ethical challenges, and facilitated the enrollment and retention of more than 2500 subjects over 55 years of age. All participants, who are residents of the city of Maracaibo, Venezuela, underwent various assessments on several occasions. Here, we discuss how our approach to implementing a longitudinal, population-based study of age-related conditions has allowed our research program to continue throughout this period of political, economic, and social upheaval.Discussion: As the social context in Venezuela became more complicated, new challenges emerged, and strategies to sustain the study and participation were refined. We identified five main mechanisms through which the evolving humanitarian crisis has affected implementation of the MAS: 1) community dynamics; 2) morale of researchers, staff, and participants; 3) financial feasibility; 4) components of the research process; and 5) impact on the health of staff, participants, and their families. Strategies to compensate for the impact on these components were implemented, based on inputs from community members and staff. Improved communication, greater involvement of stakeholders, broadening the scope of the project, and strengthening international collaboration have been the most useful strategies. Particular demands emerged, related to the increased mortality and comorbidities of participants and staff, and deterioration of basic services and safety.Conclusion: Although the MAS has faced numerous obstacles, it has been possible to continue a longitudinal research project throughout the humanitarian crisis, because our research team has engaged the community deeply and developed a sense of mutual commitment, and also because our project has provided funding to help keep researchers employed, somewhat attenuating the brain drain. [ABSTRACT FROM AUTHOR]

Objective: Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology by their 5th decade. Compared with the general population, traditional vascular risks in adults with DS are rare, allowing examination of cerebrovascular disease in this population and insight into its role in AD without the confound of vascular risk factors. We examined in vivo magnetic resonance imaging (MRI)‐based biomarkers of cerebrovascular pathology in adults with DS, and determined their cross‐sectional relationship with age, beta‐amyloid pathology, and mild cognitive impairment or clinical AD diagnostic status. Methods: Participants from the Biomarkers of Alzheimer's Disease in Down Syndrome study (n = 138, 50 ± 7 years, 39% women) with MRI data and a subset (n = 90) with amyloid positron emission tomography (PET) were included. We derived MRI‐based biomarkers of cerebrovascular pathology, including white matter hyperintensities (WMH), infarcts, cerebral microbleeds, and enlarged perivascular spaces (PVS), as well as PET‐based biomarkers of amyloid burden. Participants were characterized as cognitively stable (CS), mild cognitive impairment–DS (MCI‐DS), possible AD dementia, or definite AD dementia based on in‐depth assessments of cognition, function, and health status. Results: There were detectable WMH, enlarged PVS, infarcts, and microbleeds as early as the 5th decade of life. There was a monotonic increase in WMH volume, enlarged PVS, and presence of infarcts across diagnostic groups (CS < MCI‐DS < possible AD dementia < definite AD dementia). Higher amyloid burden was associated with a higher likelihood of an infarct. Interpretation: The findings highlight the prevalence of cerebrovascular disease in adults with DS and add to a growing body of evidence that implicates cerebrovascular disease as a core feature of AD and not simply a comorbidity. ANN NEUROL 2020;88:1165–1177 [ABSTRACT FROM AUTHOR]

Background: Phenotypic expression of pathogenic variants in individuals with no family history of inherited disorders remains unclear. Methods: We evaluated the prevalence of pathogenic variants in 25 genes associated with Mendelian-inherited disorders in 3015 participants from 485 families in the Long Life Family Study (LLFS). Boot-strapping and Fisher's exact test were used to determine whether allele frequencies in LLFS were significantly different from the allele frequencies reported in publicly available genomic databases. Results: The proportions of pathogenic autosomal dominant mutation carriers in BRCA1 and SDHC in LLFS study participants were similar to those reported in publicly available genomic databases (0.03% vs. 0.0008%, p = 1 for BRCA1, and 0.08% vs. 0.003%, p = 0.05 for SDHC). The frequency of carriers of pathogenic autosomal recessive variants in CPT2, ACADM, SUMF1, WRN, ATM, and ACADVL were also similar in LLFS as compared to those reported in genomic databases. The lack of clinical disease among LLFS participants with well-established pathogenic variants in BRCA1 and SDHC suggests that penetrance of pathogenic variants may be different in long lived families. Conclusion: Further research is needed to better understand the penetrance of pathogenic variants before expanding large scale genomic testing to asymptomatic individuals. [ABSTRACT FROM AUTHOR]