Clinical Value of Longitudinal Serum Neurofilament Light Chain in Prodromal Genetic Frontotemporal Dementia

BACKGROUND AND OBJECTIVES: Elevated serum neurofilament light chain (NfL) is used to identify carriers of genetic frontotemporal dementia (FTD) pathogenic variants approaching prodromal conversion. Yet, the magnitude and timeline of NfL increase are still unclear. Here, we investigated the predictive and early diagnostic value of longitudinal serum NfL for the prodromal conversion in genetic FTD. METHODS: In a longitudinal observational cohort study of genetic FTD pathogenic variant carriers, we examined the diagnostic accuracy and conversion risk associated with cross-sectional and longitudinal NfL. Time periods relative to prodromal conversion (&gt;3, 3-1.5, 1.5-0 years before; 0-1.5 years after) were compared with values of participants who did not convert. Next, we modeled longitudinal NfL and MRI volume trajectories to determine their timeline.RESULTS: We included 21 participants who converted (5 chromosome 9 open-reading frame 72 [C9orf72], 10 progranulin [GRN], 5 microtubule-associated protein tau [MAPT], and 1 TAR DNA-binding protein [TARDBP]) and 61 who did not (20 C9orf72, 30 GRN, and 11 MAPT). Participants who converted had higher NfL levels at all examined periods before prodromal conversion (median values 14.0-18.2 pg/mL; betas = 0.4-0.7, standard error [SE] = 0.1, p &lt; 0.046) than those who did not (6.5 pg/mL) and showed further increase 0-1.5 years after conversion (28.4 pg/mL; beta = 1.0, SE = 0.1, p &lt; 0.001). Annualized longitudinal NfL change was only significantly higher in participants who converted (vs. participants who did not) 0-1.5 years after conversion (beta = 1.2, SE = 0.3, p = 0.001). Diagnostic accuracy of cross-sectional NfL for prodromal conversion (vs. nonconversion) was good-to-excellent at time periods before conversion (area under the curve range: 0.72-0.92), improved 0-1.5 years after conversion (0.94-0.97), and outperformed annualized longitudinal change (0.76-0.84). NfL increase in participants who converted occurred earlier than frontotemporal MRI volume change and differed by genetic group and clinical phenotypes. Higher NfL corresponded to increased conversion risk (hazard ratio: cross-sectional = 6.7 [95% CI 3.3-13.7]; longitudinal = 13.0 [95% CI 4.0-42.8]; p &lt; 0.001), but conversion-free follow-up time varied greatly across participants. DISCUSSION: NfL increase discriminates individuals who convert to prodromal FTD from those who do not, preceding significant frontotemporal MRI volume loss. However, NfL alone is limited in predicting the exact timing of prodromal conversion. NfL levels also vary depending on underlying variant-carrying genes and clinical phenotypes. These findings help to guide participant recruitment for clinical trials targeting prodromal genetic FTD.</p

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

Research productivity and academics’ conceptions of research

This paper asks the question: do people with different levels of research productivity and identification as a researcher think of research differently? It discusses a study that differentiated levels of research productivity among English and Australian academics working in research-intensive environments in three broad discipline areas: science, engineering and technology; social science and humanities; and medicine and health sciences. The paper explores the different conceptions of research held by these academics in terms of their levels of research productivity, their levels of research training, whether they considered themselves an active researcher and a member of a research team, and their disciplinary differences

Discovery of novel CSF biomarkers to predict progression in dementia using machine learning

Providing an accurate prognosis for individual dementia patients remains a challenge since they greatly differ in rates of cognitive decline. In this study, we used machine learning techniques with the aim to identify cerebrospinal fluid (CSF) biomarkers that predict the rate of cognitive decline within dementia patients. First, longitudinal mini-mental state examination scores (MMSE) of 210 dementia patients were used to create fast and slow progression groups. Second, we trained random forest classifiers on CSF proteomic profiles and obtained a well-performing prediction model for the progression group (ROC-AUC = 0.82). As a third step, Shapley values and Gini feature importance measures were used to interpret the model performance and identify top biomarker candidates for predicting the rate of cognitive decline. Finally, we explored the potential for each of the 20 top candidates in internal sensitivity analyses. TNFRSF4 and TGF [Formula: see text]-1 emerged as the top markers, being lower in fast-progressing patients compared to slow-progressing patients. Proteins of which a low concentration was associated with fast progression were enriched for cell signalling and immune response pathways. None of our top markers stood out as strong individual predictors of subsequent cognitive decline. This could be explained by small effect sizes per protein and biological heterogeneity among dementia patients. Taken together, this study presents a novel progression biomarker identification framework and protein leads for personalised prediction of cognitive decline in dementia

Plasma glial fibrillary acidic protein in autosomal dominant Alzheimer\u27s disease: Associations with Aβ-PET, neurodegeneration, and cognition

Background: Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer\u27s disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. Methods: We evaluated plasma, serum, and cerebrospinal fluid (CSF) GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Results: Plasma GFAP elevations appear a decade before expected symptom onset, after amyloid beta (A ) accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished A -positive from A -negative ADAD participants and showed a stronger relationship with A load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Conclusion: Our findings support a role for plasma GFAP as a clinical biomarker of A -related astrocyte reactivity that is associated with cognitive decline and neurodegeneration. Highlights: Plasma glial fibrillary acidic protein (GFAP) elevations appear a decade before expected symptom onset in autosomal dominant Alzheimer\u27s disease (ADAD). Plasma GFAP was associated to amyloid positivity in asymptomatic ADAD. Plasma GFAP increased with clinical severity and predicted disease progression. Plasma and serum GFAP carried similar information in ADAD, while cerebrospinal fluid GFAP did not

Early maternal deprivation affects dentate gyrus structure and emotional learning in adult female rats

Rationale: Stress elicits functional and structural changes in the hippocampus. Early life stress is one of the major risk factors for stress-related pathologies like depression. Patients suffering from depression show a reduced hippocampal volume, and in women, this occurs more often when depression is preceded by childhood trauma. However, the underlying mechanisms that account for a reduced hippocampal volume are unknown. Objective: We examined the effects of maternal absence on structure and function of the hippocampus in female offspring. Methods: We studied whether 24 h of maternal deprivation (MD) on postnatal day 3 altered adult neurogenesis, individual neuronal morphology and dentate gyrus (DG) structure in young adult female rats. In addition, functional alterations were addressed by studying synaptic plasticity in vitro, and spatial as well as emotional learning was tested. Results: Adult females that were subjected to MD revealed significant reductions in DG granule cell number and density. In addition, DG neurons were altered in their dendritic arrangement. No effects on the rate of adult neurogenesis were found. Furthermore, MD did not alter synaptic plasticity in vitro, neither under normal nor high-stress conditions. In addition, spatial learning and contextual fear conditioning were comparable between control and MD animals. However, MD animals showed an improved amygdala-dependent fear memory. Conclusion: Although early life stress exposure did not impair hippocampus-dependent functioning in female offspring, it irreversibly affected DG structure by reducing cell numbers. This may be relevant for the reduced hippocampal volume observed in depression and the increased vulnerability of women to develop depression

Constraints on jet quenching in p-Pb collisions at root s(NN)=5.02 TeV measured by the event-activity dependence of semi-inclusive hadron-jet distributions

CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFINEP - FINANCIADORA DE ESTUDOS E PROJETOSFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOThe ALICE Collaboration reports the measurement of semi-inclusive distributions of charged-particle jets recoiling from a high-transverse momentum trigger hadron in p-Pb collisions at root s(NN) = 5.02TeV. Jets are reconstructed from charged-particle tracks using the anti-k(T) algorithm with resolution parameter R = 0.2 and 0.4. A data-driven statistical approach is used to correct the uncorrelated background jet yield. Recoil jet distributions are reported for jet transverse momentum 15 < p(T,jet)(ch) < 50 GeV/c and are compared in various intervals of p-Pb event activity, based on charged-particle multiplicity and zero-degree neutral energy in the forward (Pb-going) direction. The semi-inclusive observable is self-normalized and such comparisons do not require the interpretation of p-Pb event activity in terms of collision geometry, in contrast to inclusive jet observables. These measurements provide new constraints on the magnitude of jet quenching in small systems at the LHC. In p-Pb collisions with high event activity, the average medium-induced out-of-cone energy transport for jets with R = 0.4 and 15 < p(T,jet)(ch) < 50 GeV/c is measured to be less than 0.4 GeV/c at 90% confidence, which is over an order of magnitude smaller than a similar measurement for central Pb-Pb collisions at root s(NN) = 2.76 TeV. Comparison is made to theoretical calculations of jet quenching in small systems, and to inclusive jet measurements in p-Pb collisions selected by event activity at the LHC and in d-Au collisions at RHIC.78395113CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFINEP - FINANCIADORA DE ESTUDOS E PROJETOSFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFINEP - FINANCIADORA DE ESTUDOS E PROJETOSFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOSem informaçãoSem informaçãoSem informaçãoAgências de fomento estrangeiras apoiaram essa pesquisa, mais informações acesse artig

Search for a common baryon source in high-multiplicity pp collisions at the LHC

We report on the measurement of the size of the particle-emitting source from two-baryon correlations with ALICE in high-multiplicity pp collisions at s=13 TeV. The source radius is studied with low relative momentum p–p, p‾–p‾, p–Λ, and p‾–Λ‾ pairs as a function of the pair transverse mass mT considering for the first time in a quantitative way the effect of strong resonance decays. After correcting for this effect, the radii extracted for pairs of different particle species agree. This indicates that protons, antiprotons, Λ s, and Λ‾ s originate from the same source. Within the measured mT range (1.1–2.2) GeV/c2the invariant radius of this common source varies between 1.3 and 0.85 fm. These results provide a precise reference for studies of the strong hadron–hadron interactions and for the investigation of collective properties in small colliding systems. © 2020 CERN for the benefit of the ALICE CollaborationPeer reviewe

Inclusive J/ψ production at forward and backward rapidity in p-Pb collisions at √sNN=8.16 TeV

Inclusive J/psi production is studied in p-Pb interactions at a centre-of-mass energy per nucleon-nucleon collision sqrt(s_NN) = 8.16TeV, using the ALICE detector at the CERN LHC. The J/psi meson is reconstructed, via its decay to a muon pair, in the centre-of-mass rapidity intervals 2.03 < ycms < 3.53 and -4.46 < ycms < -2.96, where positive and negative ycms refer to the p-going and Pb-going direction, respectively. The transverse momentum coverage is pT < 20 GeV/c. In this paper, ycms- and pT-differential cross sections for inclusive J/psi production are presented, and the corresponding nuclear modification factors RpPb are shown. Forward results show a suppression of the J/psi yield with respect to pp collisions, concentrated in the region pT < 5 GeV/c. At backward rapidity no significant suppression is observed. The results are compared to previous measurements by ALICE in p-Pb collisions at sqrt(s_NN) = 5.02TeV and to theoretical calculations. Finally, the ratios RFB between forward- and backward-ycms RpPb values are shown and discussed

Energy dependence and fluctuations of anisotropic flow in Pb-Pb collisions at √sNN=5.02 and 2.76 TeV

Measurements of anisotropic flow coefficients with two- and multi-particle cumulants for inclusive charged particles in Pb-Pb collisions at sqrt(s_NN) = 5.02 and 2.76TeV are reported in the pseudorapidity range |eta|< 0.8 and transverse momentum 0.2 < pT < 50 GeV/c. The full data sample collected by the ALICE detector in 2015 (2010), corresponding to an integrated luminosity of 12.7 (2.0) ub^-1 in the centrality range 0-80%, is analysed. Flow coefficients up to the sixth flow harmonic (v6) are reported and a detailed comparison among results at the two energies is carried out. The pT dependence of anisotropic flow coefficients and its evolution with respect to centrality and harmonic number n are investigated. An approximate power-law scaling of the form vn(pT) ~ pT^(n/3) is observed for all flow harmonics at low pT (0.2 < pT < 3 GeV/c). At the same time, the ratios vn/vm^(n/m) are observed to be essentially independent of pT for most centralities up to about pT = 10 GeV/c. Analysing the differences among higher-order cumulants of elliptic flow (v2), which have different sensitivities to flow fluctuations, a measurement of the standardised skewness of the event-by-event v2 distribution P(v2) is reported and constraints on its higher moments are provided. The Elliptic Power distribution is used to parametrise P(v2), extracting its parameters from fits to cumulants. The measurements are compared to different model predictions in order to discriminate among initial-state models and to constrain the temperature dependence of the shear viscosity to entropy-density ratio