julilili42/papers huggingface dataset:
Targeted proteomic search reveals new actors in the synaptic and lysosomal dysfunction in genetic FTD, a GENFI study.
2023-12-01

Abstract Background At present, there are limited fluid biomarkers which measure the underlying pathophysiology of frontotemporal dementia (FTD). Approximately a third of people with FTD have a genetic cause where the pathological basis is well understood. Studying fluid biomarkers in these genetic forms therefore allows greater insight into the relationship between the measure and the underlying disease mechanism. Based on prior work identifying synaptic and lysosomal dysfunction as common mechanisms across the different forms of FTD, we performed a targeted search of proteins related with synapses and the lysosomal pathway on an unbiased proteomic dataset generated from the GENetic FTD Initiative (GENFI) study. Method The dataset was obtained from a total of 248 cerebrospinal fluid samples (CSF) from the GENFI cohort including 109 presymptomatic (44 C9orf72 , 39 GRN , 26 MAPT ) and 63 symptomatic (34 C9orf72 , 17 GRN , 12 MAPT ) mutation carriers as well as 76 mutation‐negative controls where Tandem Mass Tag (TMT) proteomics had been performed. We selected the clusters obtained from a Gene Ontology analysis that corresponded to the terms “synapse” and “lysosome” and generated a list of proteins related to each category. We then analysed the differences in each specific protein between genetic groups. Result A total of 42 of the synaptic proteins preselected were significantly changed in symptomatic MAPT mutation carriers, 70 in symptomatic GRN mutation carriers, and 92 in the symptomatic C9orf72 group. Among all of these, there were only 9 proteins that overlapped in the three genetic forms. This list included reelin, which was significantly decreased in each symptomatic group when compared to controls ( MAPT p‐value = 0.0016, GRN = 0.0008, C9orf72 = 0.0064), and calretinin, which was significantly increased in symptomatic groups compared to controls ( MAPT = 0.0260, GRN = 0.0000, C9orf72 = 0.0100). We then used the same approach to study lysosomal proteins, and found that 38 proteins were significantly changed in symptomatic MAPT , 31 in the symptomatic GRN group and 41 in symptomatic C9orf72 expansion carriers. Conclusion This study provides new insights into candidate markers to assess synaptic and lysosomal dysfunction in FTD.
A multicenter validation study on the diagnostic and prognostic value of CSF Neurogranin and BACE1
2023-12-01

Abstract Background Cerebrospinal fluid (CSF) biomarkers have immense diagnostic and prognostic potential for Alzheimer disease (AD). Currently, AD is still mostly diagnosed relatively late in the disease process, sometimes even years after the initial manifestation of cognitive symptoms. Disease‐modifying treatments should be most effective in the earliest stages, before amyloid plaques and neurodegeneration become prevalent. Thus, further identification of biomarkers is required that can detect AD in the predementia stage. This study aimed to assess the clinical utility of synaptic proteins neurogranin and beta‐secretase 1 (BACE1) in the diagnosis and prognosis of AD. Method We enrolled 530 participants from DELCODE, a multicenter prospective cohort study, including healthy controls (HC), subjective cognitive decline (SCD) subjects, mild cognitive impairment (MCI) subjects, mild AD dementia and first‐degree relatives of AD patients. Based on amyloid and tau status, we divided the participants into four groups: A−T−; A−T+; A+T−; A+T+. Neurogranin and BACE1 levels across groups were assessed by ANCOVA after adjusted for age and sex. To test the correlation of the biomarkers to cognitive performance, we used linear mixed models to model baseline biomarker levels and 7 years longitudinal MMSE and PACC5 scores. Result Regardless of amyloid status, CSF neurogranin and BACE1 levels were significantly higher in T+ group compared with T‐ (all p &lt; 0.0001). Furthermore, for participants with negative tau status, neurogranin and BACE1 levels were lower in A+ group compared with A‐ (both p &lt; 0.0001). After adjusting for covariates (Age, Sex, Education, APOEε4), linear mixed‐effect models indicated that higher neurogranin predicts faster decline in MMSE (β = ‐0.14, p &lt; 0.01) and PACC5 (β = ‐0.03, p &lt; 0.05) over 7 years. Conclusion This study reveals that neurogranin and BACE1 could offer insight into identifying patients at early stages of AD and improve prediction of cognitive decline.
Altered BOLD Signal Fluctuations in precuneus relate to inflammatory markers and vascular risk in the AD spectrum
2023-12-01

Abstract Background Inflammation, vascular disease and Alzheimer’s Disease (AD) appear to be closely linked. We recently showed that increased vascular risk relates to certain inflammatory profiles in CSF in the DELCODE cohort (Hayek et al, AAIC 2022). Moreover, we found cerebrovascular alterations in posterior‐midline regions including precuneus in subjects at risk for AD and with cognitive impairment relative to controls (Behrenbruch et al). Here, we examined the contributions of vascular risk and related inflammatory markers to alterations in resting‐state fMRI BOLD fluctuations that are sensitive to cerebrovascular reactivity (CVR)—a proposed marker of cerebrovascular dysfunction. Method Leveraging resting‐state fMRI BOLD signal, we mapped voxel‐wise relative CVR (rCVR), using mean global signal as regressor, and the relative coefficient of variation (rCV). See Figure 1 for methodological details. We derived average rCV/rCVR from the precuneus as region of interest. Inflammation‐related CSF markers and AD markers (ptau181 and Aβ42/40) from CSF were available in 205 subjects with rCVR/rCV maps. A Principal component (PC) analysis on 16 inflammation‐related CSF markers previously revealed 4 PCs. PC2 and PC3 were related to higher vascular risk scores (covering hypertension, diabetes and abnormal fat metabolism based on medical reports). We used linear regression models to assess how inflammation PC scores and AD biomarkers related to precuneus rCVR or rCV (controlling for age, sex, site, education and mean framewise displacement). We also tested if rCVR/rCV was related to vascular risk or memory. Result Lower precuneus rCVR was predicted by higher values of the inflammatory component PC2 (mainly driven by markers CRP, C1q and FactorB), with no additional effect of other PCs or AD markers. Lower precuneus rCV was predicted by higher values of the inflammatory component PC3 (mainly driven by IP10, MCP1, MIF, CRP, C4) and by higher ptau. Lower precuneus rCVR was also related to higher vascular risk. Lower rCVR and rCV related to worse memory. Figure 2 shows supplementary correlations of individual inflammation markers. Conclusion Lower rCVR and rCV in the precuneus that are thought to reflect vascular dysfunction, relate to higher vascular‐risk related inflammatory markers beyond AD pathology. Their concurrent dynamics requires further investigation to understand their unique contributions to microvascular pathology.
Associations Between Lifetime Musical Activity and Resting‐State Functional Connectivity in Higher‐Order Brain Networks
2023-12-01

Abstract Background Engagement in complex leisure activities, such as playing a musical instrument, may help preserve cognitive and brain health in older age (e.g. Böttcher et al., 2022). In this study, we investigated the associations between leisure‐time musical activity and resting‐state functional connectivity (RSFC) in three higher‐order networks, the Default Mode. Fronto‐Parietal and Salience Networks, in older adults. Method In total, 130 cognitively unimpaired older (aged 60 years and older) participants of the DZNE ‐ DELCODE (Jessen et al., 2018) were assessed. Two groups matched for their reserve proxies were identified (with musical activity during life: n = 65 and controls: n = 65) based on self‐reported musical instrument playing during life, as measured by the Lifetime of Experiences Questionnaire. The two groups were compared in global and local (seed‐to‐voxel) RSFC patterns using pre‐specified seeds of the three brain networks. A mediation analysis explored the interrelations between lifetime musical activity, RSFC, and cognitive composites (Wolfsgruber et al., 2020). Result Older participants with musical activity showed higher local RSFC between the medial prefrontal cortex (Default Mode Network seed) and temporal regions, namely the bilateral temporal poles as well as the right inferior and middle temporal gyrus, compared to controls (see Figure 1). There were no group differences in global RSFC of the three networks and no mediation effects of musical activity‐related RSFC on global and domain‐specific cognition. Conclusion We show that self‐reported lifetime musical activity relates to higher RSFC between frontal and temporal core regions of the Default Mode Network in older adults. The finding implies that playing a musical instrument during life may help preserve neural functioning in a key network that is vulnerable to aging and AD. References : Böttcher et al. Frontiers in Psychology 2022. Jessen et al. Alzheimer’s Research &amp; Therapy 2018. Wolfsgruber et al. Neurology 2020.
A longitudinal analysis of the frontotemporal dementia rating scale as a sensitive measure of disease trajectory
2023-12-01

Abstract Background Previous research in genetic frontotemporal dementia (FTD) has suggested that the FTD Rating Scale (FRS) may be a more sensitive measure of disease severity than the Clinical Dementia Rating scale plus National Alzheimer’s Coordinating Centre Frontotemporal Lobar Degeneration score (CDR+NACC FTLD). This study aims to assess the potential of longitudinal measurement of the FRS to track disease trajectory, using data from the Genetic FTD Initiative (GENFI). Method 119 mutation negative controls and 270 mutation carriers (52 MAPT , 107 GRN , 111 C9orf72) from the GENFI cohort completed the FRS at their baseline and follow‐up visits. Participants were grouped by disease severity according to their CDR+NACC FTLD global score at the baseline visit, which generated five mutation groups: asymptomatic (0), prodromal (0.5), mild (1), moderate (2), and severe (3), plus the control group. Annualised FRS change scores were generated for each participant (mean interval between visits = 1.3 years, standard deviation = 0.6). For each of the genetic groups, correlations with annualised change score for the MMSE and the CDR+NACC FTLD SOB were performed. Result As disease becomes more severe, the annualised change in FRS was larger, peaking at the moderate stage: asymptomatic 0.6 (8.0), prodromal ‐5.1, (23.2), mild ‐7.2 (24.8), moderate ‐7.8 (11.6), severe ‐1.8 (8.2). The moderate group was significantly different from controls (p = 0.018) and the asymptomatic group (p = 0.030). The annualised change in FRS negatively correlated with the annualised change in CDR+NACC FTLD Sum of Boxes (Rho = ‐0.4, p&lt;0.001) and positively correlated with the annualised change in MMSE (Rho = 0.3, p = 0.001) in GRN MCs but not in MAPT or C9orf72 . Conclusion The FRS shows promise as a sensitive clinical outcome measure, but only at certain stages of the disease. More sophisticated modelling utilising the wider GENFI cohort will help to establish the real potential for use in clinical settings.
DTI changes of thalamic subregions in genetic frontotemporal dementia: findings from the GENFI cohort
2023-12-01

Abstract Background Atrophy of thalamic subregions has been observed across the spectrum of frontotemporal dementia (FTD). To gain better insight into underlying tissue changes, we investigated how thalamic subregional fractional anisotropy (FA) and mean diffusivity (MD) derived from diffusion tensor imaging (DTI) are altered in genetic FTD. Method We used our newly developed thalamus segmentation tool, which jointly combines structural and diffusion input MRI data, to segment thalami and extract thalamic subregional FA and MD values for 163 genetic mutation carriers and 126 non‐carriers with suitable 3T MRI data from the GENetic FTD Initiative (GENFI). Mutation carriers were divided according to their genetic diagnosis and CDR®+NACC FTLD global scores into presymptomatic/prodromal (≤0.5: 41 C9orf72 , 59 GRN , 34 MAPT ) and symptomatic (≥1: 8 C9orf72 , 11 GRN , 10 MAPT ) groups. Mean FA and MD values for thalamic subregions were obtained using diffusion tensors interpolated in the log domain and weighted by segmentation posterior probabilities. Thalamic subregional FA and MD values for presymptomatic and symptomatic mutation carriers within each genetic group were compared with non‐carriers using analysis of covariance with bootstrapping, where age, scanner type, and sex were covariates. We corrected for multiple comparisons and calculated percentage changes in adjusted FA and MD mean values for mutation carriers relative to non‐carriers. Result The only significant change at the presymptomatic stage was found for C9orf72 expansion carriers, who showed FA reduction in the intralaminar subregion (5%) (Figure 1, Table 1). In symptomatic C9orf72 expansion carriers, FA was reduced in the laterodorsal (21%), lateral posterior (13%), anteroventral (13%) and intralaminar (11%) subregions. Symptomatic MAPT mutation carriers also showed FA reduction in the laterodorsal (15%) and anteroventral (11%) subregions. No significant FA reductions were found for GRN mutation carriers and no significant MD changes were observed for any group after correction for multiple comparisons. Conclusion We detected FA reductions of thalamic subregions only for C9orf72 expansion carriers at the presymptomatic stage, and for C9orf72 and MAPT mutation carriers at the symptomatic stage. Combined with the lack of robust MD changes, our findings may warrant further assessment of thalamic microstructure with more advanced diffusion models.
Getting the facts right: focus on adverbial verum marking in German
2023-12-01

Abstract Two types of analyses of verum can be distinguished: either it is decomposed into focus and a focused verum element or it is a single, non-decomposable specialized lexical element which operates on discourse conditions. This paper argues for the former by investigating adverbs like tatsächlich , echt , wirklich in German that overtly realize a truth related predicate by illustrating the parallel between verb-verum and these adverbs for which their lexical contribution and the contribution of focus can be distinguished. It is shown, however, that this predicate does not encode polarity but factuality, which is analyzed in terms of a modal object. The syntactic location is determined to be between polarity and speaker-oriented categories. Other effects regarding commitment and evidentiality come as a by-product of highlighting factuality.
OA-99 Evaluation of the safety and efficacy of dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in HIV-infected pregnant women: a multi-centre, double-blind, placebo-controlled trial (MAMAH project)
2023-12-01

<h3>Background</h3> Malaria during pregnancy is an important driver of maternal and neonatal health especially among HIV-infected women. In Africa, at least one million pregnant women are annually co-infected with Plasmodium and HIV. The interaction between the two infections is particularly deleterious during pregnancy, leading to an increased risk of malaria and HIV viral load. Intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine is recommended for malaria prevention in HIV-uninfected women but it is contraindicated in those HIV-infected women on cotrimoxazole prophylaxis (CTXp). <h3>Methods</h3> A randomized, double-blind, two-arm, placebo-controlled trial to evaluate the safety and efficacy of dihydroartemisinin-piperaquine (DHA-PPQ) for IPTp was conducted in HIV-infected pregnant women receiving CTXp, antiretroviral drugs and long lasting insecticide treated nets in five sites from Gabon and Mozambique. Women attending the first antenatal care clinic visit, resident in the study area and with a gestational age ≤28 weeks were randomized to receive either monthly IPTp with DHA-PPQ or placebo. The three day IPTp administration was always done under direct observation. Women were followed up until one month after the end of pregnancy. <h3>Results</h3> A total of 666 HIV-infected pregnant women were enrolled in the trial between September 2019 and November 2021. The prevalence of maternal peripheral parasitemia at delivery (primary study endpoint) was unexpectedly low during the study period and no significant differences were found between groups. However, the composite of Plasmodium infection (detected by any diagnostic test during pregnancy or delivery) was significantly decreased in the DHA-PPQ group (RR=0.48, 95CI 0.27–0.84; p=0.010). There were no differences in the prevalence of adverse pregnancy outcomes and serious adverse events across groups. <h3>Conclusion</h3> In a context of low malaria transmission, adding monthly IPTp- DHA-PPQ to CTXp in HIV-pregnant women is safe and it is associated with a decreased risk of clinical malaria and overall Plasmodium infection in pregnancy.
PA-201 Species identification and drug susceptibility testing of non-tuberculous mycobacteria isolated among presumptive tuberculosis patients in Lambaréné, Gabon
2023-12-01

<h3>Background</h3> Non-tuberculous mycobacteria are increasingly recognised as causative agents of opportunistic and device-associated infections in humans. In Gabon, data is scarce, as species identification and drug susceptibility are not performed in most laboratories. The objectives of our study were to identify the relative frequencies of non-tuberculous mycobacteria species circulating and to determine their genotypic susceptibility pattern regarding the antibiotics most commonly used to treat NTM infections among presumptive tuberculosis patients. <h3>Methods</h3> This cross-sectional prospective study was conducted at the CERMEL TB laboratory from January 2020 to December 2022 to generate drug susceptibility data on NTM species identified from presumptive TB patient specimen sent to the National TB Reference Laboratory. The drug susceptibility to macrolides and aminoglycosides and the NTM subspecies identification were performed using the genotype NTM-DR kit. <h3>Results</h3> Among 524 culture-positive specimen, 146 (28%) were NTM. The predominant group was Mycobacterium avium complex, MAC 80/146 (54.8%), of which M. intracellular 53/146 (36.3%) and M. avium 27/146 (18.5%)); followed by Mycobacterium abscessus complex, MABC 38/146 (26.0%), of which M. abscessus subsp. abscessus 20/146 (13.6%); M. abscessus subsp. massiliense 10/146 (7.0%); and M. abscessus subsp. bolletii 8/146 (5.4%)). All MAC were genotypically fully susceptible to macrolides and aminoglycosides. All five isolates of MABC showed polymorphisms both of the erm (41) and rrl genes, both coding for macrolide resistance. <h3>Conclusion</h3> All MAC isolates were fully susceptible to macrolides and aminoglycosides, thus confirming their role in NTM treatment. However, resistance-conferring polymorphisms indicate limited susceptibility of M. abscessus complex isolates against both drug classes; requiring further investigation to comprehensively determine M. abscessus drug susceptibility. The study results presented here shall guide clinicians to better manage treatment. Routine susceptibility testing is not available.
OA-196 Development of a CAA/CCA duplex test for improved diagnosis of human schistosomiasis
2023-12-01

<h3>Background</h3> Schistosomiasis is caused by infection with parasitic worms, schistosomes, and affects hundreds of millions people worldwide. The detection of schistosome circulating cathodic and anodic antigens (CCA and CAA) has proven to be highly valuable in diagnosing intestinal and urinary schistosomiasis. Within the freeBILy project, a CCA/CAA duplex test was developed which detects both antigens simultaneously to improve the diagnostic accuracy and potentially identify Schistosoma spp based on CAA/CCA ratios. <h3>Methods</h3> CAA and CCA were incorporated into the current laboratory-based UCP-LF test platform utilizing a duplex test-format; i.e. a single prototype device with two parallel lateral flow (LF) strips. Test performance was evaluated using banked sample sets (serum and urine) from two different Schistosoma endemic areas using standardized protocols. Samples were available from both cross-sectional as well as school-age children based population studies. In a subset, CCA/CAA ratios were determined. <h3>Results</h3> CAA-levels in urine were lower compared to CAA-levels in serum, both for S. mansoni (Sm) and S. haematobium (Sh). Significantly more CCA was observed in Sm urines compared to Sh urines. In urine the CCA/CAA ratio for Sm was significantly higher compared to the CAA/CCA ratio for Sh, while no differences were observed in serum. Species could not be identified unequivocally based on the CCA/CAA ratio. <h3>Conclusion</h3> Combined detection of CAA and CCA improved diagnostic accuracy and showed added value compared to detection either antigen separately, particularly in Sh settings where the POC-CCA performance is limited. Identification of Schistosoma species based on the CCA/CAA ratio seems challenging due to multiple factors. Generally, CAA and CCA levels in serum and urine show marked differences which would benefit from further focused in-depth studies.
PA-166 Circulating anodic antigen (CAA) detection in pregnant women and their child during Schistosoma haematobium infections in Lambaréné, Gabon
2023-12-01

<h3>Background</h3> The detection of schistosome-derived antigens in urine is a highly effective diagnostic approach for controlling schistosomiasis. It offers greater sensitivity compared to parasitological methods and involves a more convenient, user-friendly lab-based method. This diagnostic approach is particularly advantageous for pregnant women and young children, as early detection of active infections can lead to prompt treatment with Praziquantel (PZQ). The freeBILy clinical trial in Gabon (NCT03779347) evaluated the accuracy of the circulating anodic antigen (CAA) test for detecting Schistosoma haematobium (Sh) infections in pregnant women as well as an endpoint measure for PZQ efficacy. <h3>Methods</h3> The accuracy of the upconverting particle lateral flow (UCP-LF) CAA urine test was comprehensively evaluated using a cross-sectional design and comparing it against urine filtration (UF) and PCR. Subsequently, Sh-positive pregnant women were enrolled in sub-study and received a single dose of PZQ either immediately (intervention) or after delivery (control) to assess the safety of PZQ use during pregnancy and to monitor the kinetics of CAA levels following PZQ administration. Finally, in an observational, longitudinal study mothers and their newborns were followed to determine the incidence of schistosomiasis in infants with accurate diagnostics. <h3>Results</h3> A total of 733 pregnant women were enrolled in this study with mean age 25.3 years. The prevalence of schistosomiasis measured by the respective tests was 18% (UF), 19% (UCP-LF CAA), and 12% (PCR). Compared to the composite reference standard, the sensitivity of UCP-LF CAA was 71.8%, with 64% and 68% for UF and PCR, resp. <h3>Conclusion</h3> Preliminary data show a high prevalence of schistosomiasis among pregnant women. Furthermore, the UCP-LF-CAA test was more sensitive than conventional microscopy, which contributed to the improved health of pregnant women as they were treated during pregnancy. PZQ treatment had no deleterious effects on mother nor child, and administrating it to pregnant women can be considered to be safe.