| 1. |
- Abele, H., et al.
(author)
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Particle physics at the European Spallation Source
- 2023
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In: Physics reports. - : Elsevier. - 0370-1573 .- 1873-6270. ; 1023, s. 1-84
-
Research review (peer-reviewed)abstract
- Presently under construction in Lund, Sweden, the European Spallation Source (ESS) will be the world’s brightest neutron source. As such, it has the potential for a particle physics program with a unique reach and which is complementary to that available at other facilities. This paper describes proposed particle physics activities for the ESS. These encompass the exploitation of both the neutrons and neutrinos produced at the ESS for high precision (sensitivity) measurements (searches).
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| 2. |
- Addazi, A., et al.
(author)
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New high-sensitivity searches for neutrons converting into antineutrons and/or sterile neutrons at the HIBEAM/NNBAR experiment at the European Spallation Source
- 2021
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In: Journal of Physics G. - : Institute of Physics Publishing (IOPP). - 0954-3899 .- 1361-6471. ; 48:7
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Journal article (peer-reviewed)abstract
- The violation of baryon number, , is an essential ingredient for the preferential creation of matter over antimatter needed to account for the observed baryon asymmetry in the Universe. However, such a process has yet to be experimentally observed. The HIBEAM/NNBAR program is a proposed two-stage experiment at the European Spallation Source to search for baryon number violation. The program will include high-sensitivity searches for processes that violate baryon number by one or two units: free neutron–antineutron oscillation () via mixing, neutron–antineutron oscillation via regeneration from a sterile neutron state (), and neutron disappearance (n → n'); the effective process of neutron regeneration () is also possible. The program can be used to discover and characterize mixing in the neutron, antineutron and sterile neutron sectors. The experiment addresses topical open questions such as the origins of baryogenesis and the nature of dark matter, and is sensitive to scales of new physics substantially in excess of those available at colliders. A goal of the program is to open a discovery window to neutron conversion probabilities (sensitivities) by up to three orders of magnitude compared with previous searches. The opportunity to make such a leap in sensitivity tests should not be squandered. The experiment pulls together a diverse international team of physicists from the particle (collider and low energy) and nuclear physics communities, while also including specialists in neutronics and magnetics.
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| 3. |
- Escartin, C., et al.
(author)
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Reactive astrocyte nomenclature, definitions, and future directions
- 2021
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In: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 24, s. 312-325
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Journal article (peer-reviewed)abstract
- Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions. Good-bad binary classifications fail to describe reactive astrocytes in CNS disorders. Here, 81 researchers reach consensus on widespread misconceptions and provide definitions and recommendations for future research on reactive astrocytes.
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| 4. |
- Santoro, V., et al.
(author)
-
HighNESS conceptual design report: Volume I
- 2024
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In: Journal of Neutron Research. - 1023-8166 .- 1477-2655. ; 25:3-4, s. 85-314
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Journal article (peer-reviewed)abstract
- The European Spallation Source, currently under construction in Lund, Sweden, is a multidisciplinary international laboratory. Once completed to full specifications, it will operate the world’s most powerful pulsed neutron source. Supported by a 3 million Euro Research and Innovation Action within the EU Horizon 2020 program, a design study (HighNESS) has been completed to develop a second neutron source located below the spallation target. Compared to the first source, designed for high cold and thermal brightness, the new source has been optimized to deliver higher intensity, and a shift to longer wavelengths in the spectral regions of cold (CN, 2–20 Å), very cold (VCN, 10–120 Å), and ultracold (UCN, >500 Å) neutrons. The second source comprises a large liquid deuterium moderator designed to produce CN and support secondary VCN and UCN sources. Various options have been explored in the proposed designs, aiming for world-leading performance in neutronics. These designs will enable the development of several new instrument concepts and facilitate the implementation of a high-sensitivity neutron-antineutron oscillation experiment (NNBAR). This document serves as the Conceptual Design Report for the HighNESS project, representing its final deliverable.
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| 5. |
- Santoro, V., et al.
(author)
-
HighNESS conceptual design report: Volume II. the NNBAR experiment.
- 2024
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In: Journal of Neutron Research. - 1023-8166 .- 1477-2655. ; 25:3-4, s. 315-406
-
Journal article (peer-reviewed)abstract
- A key aim of the HighNESS project for the European Spallation Source is to enable cutting-edge particle physics experiments. This volume presents a conceptual design report for the NNBAR experiment. NNBAR would exploit a new cold lower moderator to make the first search in over thirty years for free neutrons converting to anti-neutrons. The observation of such a baryon-number-violating signature would be of fundamental significance and tackle open questions in modern physics, including the origin of the matter-antimatter asymmetry. This report shows the design of the beamline, supermirror focusing system, magnetic and radiation shielding, and anti-neutron detector necessary for the experiment. A range of simulation programs are employed to quantify the performance of the experiment and show how background can be suppressed. For a search with full background suppression, a sensitivity improvement of three orders of magnitude is expected, as compared with the previous search. Civil engineering studies for the NNBAR beamline are also shown, as is a costing model for the experiment.
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| 6. |
- Ashton, Nicholas J., et al.
(author)
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Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease
- 2022
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In: Ebiomedicine. - : Elsevier BV. - 2352-3964. ; 76
-
Journal article (peer-reviewed)abstract
- Background: Phosphorylated tau (p-tau) epitopes in cerebrospinal fluid (CSF) are accurate biomarkers for a pathological and clinical diagnosis of Alzheimer's disease (AD) and are seen to be increased in preclinical stage of the disease. However, it is unknown if these increases transpire earlier, prior to amyloid-beta (Aβ) positivity as determined by position emission tomography (PET), and if an ordinal sequence of p-tau epitopes occurs at this incipient phase Methods: We measured CSF concentrations of p-tau181, p-tau217 and p-tau231 in 171 participants across the AD continuum who had undergone Aβ ([18F]AZD4694) and tau ([18F]MK6240) position emission tomography (PET) and clinical assessment Findings: All CSF p-tau biomarkers were accurate predictors of cognitive impairment but CSF p-tau217 demonstrated the largest fold-changes in AD patients in comparison to non-AD dementias and cognitively unimpaired individuals. CSF p-tau231 and p-tau217 predicted Aβ and tau to a similar degree but p-tau231 attained abnormal levels first. P-tau231 was sensitive to the earliest changes of Aβ in the medial orbitofrontal, precuneus and posterior cingulate before global Aβ PET positivity was reached Interpretation: We demonstrate that CSF p-tau231 increases early in development of AD pathology and is a principal candidate for detecting incipient Aβ pathology for therapeutic trial application Funding: Canadian Institutes of Health Research (CIHR), Canadian Consortium of Neurodegeneration and Aging, Weston Brain Institute, Brain Canada Foundation, the Fonds de Recherche du Québec. © 2022
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| 7. |
- Bellaver, B., et al.
(author)
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Astrocyte reactivity influences amyloid-beta effects on tau pathology in preclinical Alzheimer's disease
- 2023
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In: Nature Medicine. - 1078-8956. ; 29:7
-
Journal article (peer-reviewed)abstract
- Cross-sectional and longitudinal analyses of tau pathology in preclinical Alzheimer's disease reveal that tau tangles accumulate as a function of amyloid-beta burden only in individuals positive for an astrocyte reactivity biomarker. An unresolved question for the understanding of Alzheimer's disease (AD) pathophysiology is why a significant percentage of amyloid-beta (A beta)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash A beta effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts (n = 1,016), we tested whether astrocyte reactivity modulates the association of A beta with tau phosphorylation in CU individuals. We found that A beta was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast(+)). Cross-sectional and longitudinal tau-positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of A beta only in CU Ast(+) individuals. Our findings suggest astrocyte reactivity as an important upstream event linking A beta with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials.
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| 8. |
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| 9. |
- Backman, Filip, 1991-, et al.
(author)
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The development of the NNBAR experiment
- 2022
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In: Journal of Instrumentation. - : Institute of Physics (IOP). - 1748-0221. ; 17:10
-
Journal article (peer-reviewed)abstract
- The NNBAR experiment for the European Spallation Source will search for free neutrons converting to antineutrons with a sensitivity improvement of three orders of magnitude compared to the last such search. This paper describes progress towards a conceptual design report for NNBAR. The design of a moderator, neutron reflector, beamline, shielding and annihilation detector is reported. The simulations used form part of a model which will be used for optimisation of the experiment design and quantification of its sensitivity.
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| 10. |
- Bellaver, B., et al.
(author)
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Blood-brain barrier integrity impacts the use of plasma amyloid-beta as a proxy of brain amyloid-beta pathology
- 2023
-
In: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:9, s. 3815-3825
-
Journal article (peer-reviewed)abstract
- INTRODUCTION Amyloid-beta (A beta) and tau can be quantified in blood. However, biological factors can influence the levels of brain-derived proteins in the blood. The blood-brain barrier (BBB) regulates protein transport between cerebrospinal fluid (CSF) and blood. BBB altered permeability might affect the relationship between brain and blood biomarkers.METHODS We assessed 224 participants in research (TRIAD, n = 96) and clinical (BIODEGMAR, n = 128) cohorts with plasma and CSF/positron emission tomography A beta, p-tau, and albumin measures.RESULTS Plasma A beta(42/40) better identified CSF A beta(42/40) and A beta-PET positivity in individuals with high BBB permeability. An interaction between plasma A beta(42/40) and BBB permeability on CSF A beta(42/40) was observed. Voxel-wise models estimated that the association of positron emission tomography (PET), with plasma A beta was most affected by BBB permeability in AD-related brain regions. BBB permeability did not significantly impact the relationship between brain and plasma p-tau levels.DISCUSSION These findings suggest that BBB integrity may influence the performance of plasma A beta, but not p-tau, biomarkers in research and clinical settings.
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| 11. |
- Ferrari-Souza, J. P., et al.
(author)
-
APOEε4 associates with microglial activation independently of Aβ plaques and tau tangles
- 2023
-
In: Science Advances. - 2375-2548. ; 9:14
-
Journal article (peer-reviewed)abstract
- Animal studies suggest that the apolipoprotein E epsilon 4 (APOE epsilon 4) allele is a culprit of early microglial activation in Alzheimer's disease (AD). Here, we tested the association between APOE epsilon 4 status and microglial activation in living individuals across the aging and AD spectrum. We studied 118 individuals with positron emission tomog-raphy for amyloid-beta (A beta; [18F]AZD4694), tau ([18F]MK6240), and microglial activation ([11C]PBR28). We found that APOE epsilon 4 carriers presented increased microglial activation relative to noncarriers in early Braak stage regions within the medial temporal cortex accounting for A beta and tau deposition. Furthermore, microglial acti-vation mediated the A beta-independent effects of APOE epsilon 4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of APOE mRNA expression predicted the patterns of APOE epsilon 4-related microglial activation in our population, suggesting that APOE gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the APOE epsilon 4 genotype exerts A beta-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition.
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| 12. |
- Ferrari-Souza, J. P., et al.
(author)
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APOEε4 potentiates amyloid β effects on longitudinal tau pathology
- 2023
-
In: Nature Aging. - 2662-8465. ; 3:10
-
Journal article (peer-reviewed)abstract
- The mechanisms by which the apolipoprotein E epsilon 4 (APOE epsilon 4) allele influences the pathophysiological progression of Alzheimer's disease (AD) are poorly understood. Here we tested the association of APOE epsilon 4 carriership and amyloid-beta (A beta) burden with longitudinal tau pathology. We longitudinally assessed 94 individuals across the aging and AD spectrum who underwent clinical assessments, APOE genotyping, magnetic resonance imaging, positron emission tomography (PET) for A beta ([F-18]AZD4694) and tau ([F-18]MK-6240) at baseline, as well as a 2-year follow-up tau-PET scan. We found that APOE epsilon 4 carriership potentiates A beta effects on longitudinal tau accumulation over 2 years. The APOE epsilon 4-potentiated A beta effects on tau-PET burden were mediated by longitudinal plasma phosphorylated tau at threonine 217 (p-tau217(+)) increase. This longitudinal tau accumulation as measured by PET was accompanied by brain atrophy and clinical decline. Our results suggest that the APOE epsilon 4 allele plays a key role in A beta downstream effects on the aggregation of phosphorylated tau in the living human brain.
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| 13. |
- Ferrari-Souza, J. P., et al.
(author)
-
Astrocyte biomarker signatures of amyloid-beta and tau pathologies in Alzheimer's disease
- 2022
-
In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 27:11, s. 4781-4789
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Journal article (peer-reviewed)abstract
- Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimer's disease (AD) patients. Here, we studied the associations of cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) and chitinase-3-like protein 1 (YKL-40) levels with brain amyloid-beta (A beta) and tau pathologies. We assessed 121 individuals across the aging and AD clinical spectrum with positron emission tomography (PET) brain imaging for A beta ([F-18]AZD4694) and tau ([F-18]MK-6240), as well as CSF GFAP and YKL-40 measures. We observed that higher CSF GFAP levels were associated with elevated A beta-PET but not tau-PET load. By contrast, higher CSF YKL-40 levels were associated with elevated tau-PET but not A beta-PET burden. Structural equation modeling revealed that CSF GFAP and YKL-40 mediate the effects of A beta and tau, respectively, on hippocampal atrophy, which was further associated with cognitive impairment. Our results suggest the existence of distinct astrocyte biomarker signatures in response to brain A beta and tau accumulation, which may contribute to our understanding of the complex link between reactive astrogliosis heterogeneity and AD progression.
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| 14. |
- Ferreira, P. C. L., et al.
(author)
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Plasma p-tau231 and p-tau217 inform on tau tangles aggregation in cognitively impaired individuals
- 2023
-
In: Alzheimers & Dementia. - 1552-5260. ; 19:10, s. 4463-4474
-
Journal article (peer-reviewed)abstract
- INTRODUCTIONPhosphorylated tau (p-tau) biomarkers have been recently proposed to represent brain amyloid-& beta; (A & beta;) pathology. Here, we evaluated the plasma biomarkers' contribution beyond the information provided by demographics (age and sex) to identify A & beta; and tau pathologies in individuals segregated as cognitively unimpaired (CU) and impaired (CI). METHODSWe assessed 138 CU and 87 CI with available plasma p-tau231, 217(+), and 181, A & beta;42/40, GFAP and A & beta;- and tau-PET. RESULTSIn CU, only plasma p-tau231 and p-tau217(+) significantly improved the performance of the demographics in detecting A & beta;-PET positivity, while no plasma biomarker provided additional information to identify tau-PET positivity. In CI, p-tau217(+) and GFAP significantly contributed to demographics to identify both A & beta;-PET and tau-PET positivity, while p-tau231 only provided additional information to identify tau-PET positivity. DISCUSSIONOur results support plasma p-tau231 and p-tau217(+) as state markers of early A & beta; deposition, but in later disease stages they inform on tau tangle accumulation. HighlightsIt is still unclear how much plasma biomarkers contribute to identification of AD pathology across the AD spectrum beyond the information already provided by demographics (age + sex).Plasma p-tau231 and p-tau217(+) contribute to demographic information to identify brain A & beta; pathology in preclinical AD.In CI individuals, plasma p-tau231 contributes to age and sex to inform on the accumulation of tau tangles, while p-tau217(+) and GFAP inform on both A & beta; deposition and tau pathology.
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| 15. |
- Ferreira, P. C. L., et al.
(author)
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Potential Utility of Plasma P-Tau and Neurofilament Light Chain as Surrogate Biomarkers for Preventive Clinical Trials
- 2023
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In: NEUROLOGY. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 101:1, s. 38-45
-
Journal article (peer-reviewed)abstract
- ObjectiveTo test the utility of longitudinal changes in plasma phosphorylated tau 181 (p-tau181) and neurofilament light chain (NfL) as surrogate markers for clinical trials targeting cognitively unimpaired (CU) populations.MethodsWe estimated the sample size needed to test a 25% drug effect with 80% of power at a 0.05 level on reducing changes in plasma markers in CU participants from Alzheimer's Disease Neuroimaging Initiative database.ResultsWe included 257 CU individuals (45.5% males; mean age = 73 [6] years; 32% & beta;-amyloid [A & beta;] positive). Changes in plasma NfL were associated with age, whereas changes in plasma p-tau181 with progression to amnestic mild cognitive impairment. Clinical trials using p-tau181 and NfL would require 85% and 63% smaller sample sizes, respectively, for a 24-month than a 12-month follow-up. A population enrichment strategy using intermediate levels of A & beta; PET (Centiloid 20-40) further reduced the sample size of the 24-month clinical trial using p-tau181 (73%) and NfL (59%) as a surrogate.DiscussionPlasma p-tau181/NfL can potentially be used to monitor large-scale population interventions in CU individuals. The enrollment of CU with intermediate A & beta; levels constitutes the alternative with the largest effect size and most cost-effective for trials testing drug effect on changes in plasma p-tau181 and NfL.
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| 16. |
- Hiensch, Anouk E, et al.
(author)
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Design of a multinational randomized controlled trial to assess the effects of structured and individualized exercise in patients with metastatic breast cancer on fatigue and quality of life : the EFFECT study.
- 2022
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In: Trials. - : Springer Science and Business Media LLC. - 1745-6215. ; 23:1, s. 610-
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Journal article (peer-reviewed)abstract
- BACKGROUND: Many patients with metastatic breast cancer experience cancer- and treatment-related side effects that impair activities of daily living and negatively affect the quality of life. There is a need for interventions that improve quality of life by alleviating fatigue and other side effects during palliative cancer treatment. Beneficial effects of exercise have been observed in the curative setting, but, to date, comparable evidence in patients with metastatic breast cancer is lacking. The aim of this study is to assess the effects of a structured and individualized 9-month exercise intervention in patients with metastatic breast cancer on quality of life, fatigue, and other cancer- and treatment-related side effects.METHODS: The EFFECT study is a multinational, randomized controlled trial including 350 patients with metastatic breast cancer. Participants are randomly allocated (1:1) to an exercise or control group. The exercise group participates in a 9-month multimodal exercise program, starting with a 6-month period where participants exercise twice a week under the supervision of an exercise professional. After completing this 6-month period, one supervised session is replaced by one unsupervised session for 3 months. In addition, participants are instructed to be physically active for ≥30 min/day on all remaining days of the week, while being supported by an activity tracker and exercise app. Participants allocated to the control group receive standard medical care, general written physical activity advice, and an activity tracker, but no structured exercise program. The primary outcomes are quality of life (EORTC QLQ-C30, summary score) and fatigue (EORTC QLQ-FA12), assessed at baseline, 3, 6 (primary endpoint), and 9 months post-baseline. Secondary outcomes include physical fitness, physical performance, physical activity, anxiety, depression, pain, sleep problems, anthropometric data, body composition, and blood markers. Exploratory outcomes include quality of working life, muscle thickness, urinary incontinence, disease progression, and survival. Additionally, the cost-effectiveness of the exercise program is assessed. Adherence and safety are monitored throughout the intervention period.DISCUSSION: This large randomized controlled trial will provide evidence regarding the (cost-) effectiveness of exercise during treatment of metastatic breast cancer. If proven (cost-)effective, exercise should be offered to patients with metastatic breast cancer as part of standard care.TRIAL REGISTRATION: ClinicalTrials.gov NCT04120298 . Registered on October 9, 2019.
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| 17. |
- Leffa, D. T., et al.
(author)
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Genetic risk for attention-deficit/hyperactivity disorder predicts cognitive decline and development of Alzheimer's disease pathophysiology in cognitively unimpaired older adults
- 2023
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In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 28:3, s. 1248-1255
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Journal article (peer-reviewed)abstract
- Attention-deficit/hyperactivity disorder (ADHD) persists in older age and is postulated as a risk factor for cognitive impairment and Alzheimer's Disease (AD). However, these findings rely primarily on electronic health records and can present biased estimates of disease prevalence. An obstacle to investigating age-related cognitive decline in ADHD is the absence of large-scale studies following patients with ADHD into older age. Alternatively, this study aimed to determine whether genetic liability for ADHD, as measured by a well-validated ADHD polygenic risk score (ADHD-PRS), is associated with cognitive decline and the development of AD pathophysiology in cognitively unimpaired (CU) older adults. We calculated a weighted ADHD-PRS in 212 CU individuals without a clinical diagnosis of ADHD (55-90 years). These individuals had baseline amyloid-beta (A beta) positron emission tomography, longitudinal cerebrospinal fluid (CSF) phosphorylated tau at threonine 181 (p-tau(181)), magnetic resonance imaging, and cognitive assessments for up to 6 years. Linear mixed-effects models were used to test the association of ADHD-PRS with cognition and AD biomarkers. Higher ADHD-PRS was associated with greater cognitive decline over 6 years. The combined effect between high ADHD-PRS and brain A beta deposition on cognitive deterioration was more significant than each individually. Additionally, higher ADHD-PRS was associated with increased CSF p-tau(181) levels and frontoparietal atrophy in CU A beta-positive individuals. Our results suggest that genetic liability for ADHD is associated with cognitive deterioration and the development of AD pathophysiology. Findings were mostly observed in A beta-positive individuals, suggesting that the genetic liability for ADHD increases susceptibility to the harmful effects of A beta pathology.
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| 18. |
- Lessa Benedet, Andréa, et al.
(author)
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Differences Between Plasma and Cerebrospinal Fluid Glial Fibrillary Acidic Protein Levels Across the Alzheimer Disease Continuum
- 2021
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In: Jama Neurology. - : American Medical Association (AMA). - 2168-6149. ; 78:12, s. 1471-1483
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Journal article (peer-reviewed)abstract
- Question What are the levels of plasma glial fibrillary acidic protein (GFAP) throughout the Alzheimer disease (AD) continuum, and how do they compare with the levels of cerebrospinal fluid (CSF) GFAP? Findings In this cross-sectional study, plasma GFAP levels were elevated in the preclinical and symptomatic stages of AD, with levels higher than those of CSF GFAP. Plasma GFAP had a higher accuracy than CSF GFAP to discriminate between amyloid-beta (A beta)-positive and A beta-negative individuals, also at the preclinical stage. Meaning This study suggests that plasma GFAP is a sensitive biomarker that significantly outperforms CSF GFAP in indicating A beta pathology in the early stages of AD. Importance Glial fibrillary acidic protein (GFAP) is a marker of reactive astrogliosis that increases in the cerebrospinal fluid (CSF) and blood of individuals with Alzheimer disease (AD). However, it is not known whether there are differences in blood GFAP levels across the entire AD continuum and whether its performance is similar to that of CSF GFAP. Objective To evaluate plasma GFAP levels throughout the entire AD continuum, from preclinical AD to AD dementia, compared with CSF GFAP. Design, Setting, and Participants This observational, cross-sectional study collected data from July 29, 2014, to January 31, 2020, from 3 centers. The Translational Biomarkers in Aging and Dementia (TRIAD) cohort (Montreal, Canada) included individuals in the entire AD continuum. Results were confirmed in the Alzheimer's and Families (ALFA+) study (Barcelona, Spain), which included individuals with preclinical AD, and the BioCogBank Paris Lariboisiere cohort (Paris, France), which included individuals with symptomatic AD. Main Outcomes and Measures Plasma and CSF GFAP levels measured with a Simoa assay were the main outcome. Other measurements included levels of CSF amyloid-beta 42/40 (A beta 42/40), phosphorylated tau181 (p-tau181), neurofilament light (NfL), Chitinase-3-like protein 1 (YKL40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and levels of plasma p-tau181 and NfL. Results of amyloid positron emission tomography (PET) were available in TRIAD and ALFA+, and results of tau PET were available in TRIAD. Results A total of 300 TRIAD participants (177 women [59.0%]; mean [SD] age, 64.6 [17.6] years), 384 ALFA+ participants (234 women [60.9%]; mean [SD] age, 61.1 [4.7] years), and 187 BioCogBank Paris Lariboisiere participants (116 women [62.0%]; mean [SD] age, 69.9 [9.2] years) were included. Plasma GFAP levels were significantly higher in individuals with preclinical AD in comparison with cognitively unimpaired (CU) A beta-negative individuals (TRIAD: A beta-negative mean [SD], 185.1 [93.5] pg/mL, A beta-positive mean [SD], 285.0 [142.6] pg/mL; ALFA+: A beta-negative mean [SD], 121.9 [42.4] pg/mL, A beta-positive mean [SD], 169.9 [78.5] pg/mL). Plasma GFAP levels were also higher among individuals in symptomatic stages of the AD continuum (TRIAD: CU A beta-positive mean [SD], 285.0 [142.6] pg/mL, mild cognitive impairment [MCI] A beta-positive mean [SD], 332.5 [153.6] pg/mL; AD mean [SD], 388.1 [152.8] pg/mL vs CU A beta-negative mean [SD], 185.1 [93.5] pg/mL; Paris: MCI A beta-positive, mean [SD], 368.6 [158.5] pg/mL; AD dementia, mean [SD], 376.4 [179.6] pg/mL vs CU A beta-negative mean [SD], 161.2 [67.1] pg/mL). Plasma GFAP magnitude changes were consistently higher than those of CSF GFAP. Plasma GFAP more accurately discriminated A beta-positive from A beta-negative individuals than CSF GFAP (area under the curve for plasma GFAP, 0.69-0.86; area under the curve for CSF GFAP, 0.59-0.76). Moreover, plasma GFAP levels were positively associated with tau pathology only among individuals with concomitant A beta pathology. Conclusions and Relevance This study suggests that plasma GFAP is a sensitive biomarker for detecting and tracking reactive astrogliosis and A beta pathology even among individuals in the early stages of AD. This cross-sectional cohort study evaluates plasma glial fibrillary acidic protein levels throughout the entire Alzheimer disease continuum, from preclinical Alzheimer disease to Alzheimer disease dementia, compared with cerebrospinal fluid glial fibrillary acidic protein.
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| 19. |
- Santoro, V., et al.
(author)
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DEVELOPMENT OF A HIGH INTENSITY NEUTRON SOURCE AT THE EUROPEAN SPALLATION SOURCE : THE HIGHNESS PROJECT
- 2022
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In: Proceedings of the 14th International Topical Meeting on Nuclear Applications of Accelerators, AccApp 2021, Embedded with the 2021 ANS Winter Meeting. - 9780894487842 ; , s. 11-20
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Conference paper (peer-reviewed)abstract
- The European Spallation Source (ESS), presently under construction in Lund, Sweden, is a multidisciplinary international laboratory that will operate the world’s most powerful pulsed neutron source. Supported by a 3M Euro Research and Innovation Action within the EU Horizon 2020 program, a design study (HighNESS) is now underway to develop a second neutron source below the spallation target. Compared to the first source, located above the spallation target and designed for high cold and thermal brightness, the new source will provide higher intensity, and a shift to longer wavelengths in the spectral regions of cold (2-20 Å), very cold (VCN, 10-120 Å), and ultra cold (UCN, > 500 Å) neutrons. The core of the second source will consist of a large liquid deuterium moderator to deliver a high flux of cold neutrons and to serve secondary VCN and UCN sources, for which different options are under study. The features of these new sources will boost several areas of condensed matter research and will provide unique opportunities in fundamental physics. Part of the HighNESS project is also dedicated to the development of future instruments that will make use of the new source and will complement the initial suite of instruments in construction at ESS. The HighNESS project started in October 2020. In this paper, the ongoing developments and the results obtained in the first year are described.
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| 20. |
- Santoro, V., et al.
(author)
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The HighNESS Project at the European Spallation Source : Current Status and Future Perspectives
- 2024
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In: Nuclear science and engineering. - 0029-5639 .- 1943-748X. ; 198:1, s. 31-63
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Journal article (peer-reviewed)abstract
- The European Spallation Source (ESS), presently under construction in Lund, Sweden, is a multidisciplinary international laboratory that, once completed at full specifications, will operate the world's most powerful pulsed neutron source. Supported by a 3 M Euro Research and Innovation Action within the European Union Horizon 2020 program, a design study (HighNESS) is now underway to develop a second neutron source located below the spallation target. Compared to the first source, which is located above the spallation target and designed for high cold and thermal brightness, the new source is being optimized to deliver higher intensity and a shift to longer wavelengths in the spectral regions of cold neutrons (CNs) (2 to 20 & Aring;), very cold neutrons (VCNs) (10 to 120 & Aring;), and ultracold neutrons (UCNs) (> 500 & Aring;). The second source consists of a large liquid deuterium moderator to deliver CNs and serve secondary VCN and UCN sources, for which different options are under study. These new sources will boost several areas of condensed matter research and will provide unique opportunities in fundamental physics. The HighNESS project is now entering its last year, and we are working toward the Conceptual Design Report of the ESS upgrade. In this paper, results obtained in the first 2 years, ongoing developments, and future perspectives are described.
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| 21. |
- Tissot, C., et al.
(author)
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The Association of Age-Related and Off-Target Retention with Longitudinal Quantification of 18F MK6240 Tau PET in Target Regions
- 2023
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In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 64:3, s. 452-459
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Journal article (peer-reviewed)abstract
- 6-(fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([18F] MK6240) tau PET tracer quantifies the brain tau neurofibrillary tangle load in Alzheimer disease. The aims of our study were to test the stabil-ity of common reference region estimates in the cerebellum over time and across diagnoses and evaluate the effects of age-related and off -target retention on the longitudinal quantification of [18F]MK6240 in tar-get regions. Methods: We assessed reference, target, age-related, and off-target regions in 125 individuals across the aging and Alzhei-mer disease spectrum with longitudinal [18F]MK6240 SUVs and SUV ratios (SUVRs) (mean +/- SD, 2.25 +/- 0.40 y of follow-up). We obtained SUVR from meninges, exhibiting frequent off-target retention with [18F]MK6240. Additionally, we compared tracer uptake between 37 cognitively unimpaired young (CUY) (mean age, 23.41 +/- 3.33 y) and 27 cognitively unimpaired older (CU) adults (amyloid-P-negative and tau-negative, 58.50 +/- 9.01 y) to identify possible nonvisually apparent, age-related signal. Two-tailed t testing and Pearson correlation testing were used to determine the difference between groups and associa-tions between changes in region uptake, respectively. Results: Inferior cerebellar gray matter SUV did not differ on the basis of diagnosis and amyloid-P status, cross-sectionally and over time. [18F]MK6240 uptake significantly differed between CUY and CU adults in the puta-men or pallidum (affecting-75% of the region) and in the Braak II region (affecting-35%). Changes in meningeal and putamen or palli-dum SUVRs did not significantly differ from zero, nor did they vary across diagnostic groups. We did not observe significant correlations between longitudinal changes in age-related or meningeal off-target retention and changes in target regions, whereas changes in all target regions were strongly correlated. Conclusion: Inferior cerebellar gray matter was similar across diagnostic groups cross-sectionally and sta-ble over time and thus was deemed a suitable reference region for quantification. Despite not being visually perceptible, [18F]MK6240 has age-related retention in subcortical regions, at a much lower magnitude but topographically colocalized with significant off-target signal of the first-generation tau tracers. The lack of correlation between changes in age-related or meningeal and target retention suggests little influence of possible off-target signals on longitudinal tracer quantification. Nev-ertheless, the age-related retention in the Braak II region needs to be further investigated. Future postmortem studies should elucidate the source of the newly reported age-related [18F]MK6240 signal, and in vivo studies should further explore its impact on tracer quantification.
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| 22. |
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| 23. |
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| 24. |
- Brum, Wagner S., et al.
(author)
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A two-step workflow based on plasma p-tau217 to screen for amyloid β positivity with further confirmatory testing only in uncertain cases
- 2023
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In: Nature Aging. - 2662-8465. ; 3:9, s. 1079-1090
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Journal article (peer-reviewed)abstract
- Cost-effective strategies for identifying amyloid-beta (A beta) positivity in patients with cognitive impairment are urgently needed with recent approvals of anti-A beta immunotherapies for Alzheimer's disease (AD). Blood biomarkers can accurately detect AD pathology, but it is unclear whether their incorporation into a full diagnostic workflow can reduce the number of confirmatory cerebrospinal fluid (CSF) or positron emission tomography (PET) tests needed while accurately classifying patients. We evaluated a two-step workflow for determining A beta-PET status in patients with mild cognitive impairment (MCI) from two independent memory clinic-based cohorts (n = 348). A blood-based model including plasma tau protein 217 (p-tau217), age and APOE epsilon 4 status was developed in BioFINDER-1 (area under the curve (AUC) = 89.3%) and validated in BioFINDER-2 (AUC = 94.3%). In step 1, the blood-based model was used to stratify the patients into low, intermediate or high risk of A beta-PET positivity. In step 2, we assumed referral only of intermediate-risk patients to CSF A beta 42/A beta 40 testing, whereas step 1 alone determined A beta-status for low-and high-risk groups. Depending on whether lenient, moderate or stringent thresholds were used in step 1, the two-step workflow overall accuracy for detecting A beta-PET status was 88.2%, 90.5% and 92.0%, respectively, while reducing the number of necessary CSF tests by 85.9%, 72.7% and 61.2%, respectively. In secondary analyses, an adapted version of the BioFINDER-1 model led to successful validation of the two-step workflow with a different plasma p-tau217 immunoassay in patients with cognitive impairment from the TRIAD cohort (n = 84). In conclusion, using a plasma p-tau217-based model for risk stratification of patients with MCI can substantially reduce the need for confirmatory testing while accurately classifying patients, offering a cost-effective strategy to detect AD in memory clinic settings.
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| 25. |
- Correa, J., et al.
(author)
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The PERCIVAL detector : first user experiments
- 2023
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In: Journal of Synchrotron Radiation. - 0909-0495 .- 1600-5775. ; 30, s. 242-250
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Journal article (peer-reviewed)abstract
- The PERCIVAL detector is a CMOS imager designed for the soft X-ray regime at photon sources. Although still in its final development phase, it has recently seen its first user experiments: ptychography at a free-electron laser, holographic imaging at a storage ring and preliminary tests on X-ray photon correlation spectroscopy. The detector performed remarkably well in terms of spatial resolution achievable in the sample plane, owing to its small pixel size, large active area and very large dynamic range; but also in terms of its frame rate, which is significantly faster than traditional CCDs. In particular, it is the combination of these features which makes PERCIVAL an attractive option for soft X-ray science.
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| 26. |
- Ferreira, Pamela C. L., et al.
(author)
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Endocannabinoid System Biomarkers in Alzheimer's Disease
- 2023
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In: CANNABIS AND CANNABINOID RESEARCH. - : Mary Ann Liebert Inc. - 2578-5125 .- 2378-8763. ; 8:1, s. 77-91
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Journal article (peer-reviewed)abstract
- Background: Alterations in the endocannabinoid system (ES) have been described in Alzheimer's disease (AD) pathophysiology. In the past years, multiple ES biomarkers have been developed, promising to advance our understanding of ES changes in AD.Discussion: ES biomarkers, including positron emission tomography with cannabinoid receptors tracers and biofluid-based endocannabinoids, are associated with AD disease progression and pathological features.Conclusion: Although not specific enough for AD diagnosis, ES biomarkers hold promise for prognosis, drug-target engagement, and a better understanding of the disease. Here, we summarize currently available ES biomarker findings and discuss their potential applications in the AD research field.
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| 27. |
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| 28. |
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| 29. |
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| 30. |
- Lessa Benedet, Andréa, et al.
(author)
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The accuracy and robustness of plasma biomarker models for amyloid PET positivity
- 2022
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In: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 14:1
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Journal article (peer-reviewed)abstract
- Background Plasma biomarkers for Alzheimer's disease (AD) have broad potential as screening tools in primary care and disease-modifying trials. Detecting elevated amyloid-beta (A beta) pathology to support trial recruitment or initiating A beta-targeting treatments would be of critical value. In this study, we aimed to examine the robustness of plasma biomarkers to detect elevated A beta pathology at different stages of the AD continuum. Beyond determining the best biomarker-or biomarker combination-for detecting this outcome, we also simulated increases in inter-assay coefficient of variability (CV) to account for external factors not considered by intra-assay variability. With this, we aimed to determine whether plasma biomarkers would maintain their accuracy if applied in a setting which anticipates higher variability (i.e., clinical routine). Methods We included 118 participants (cognitively unimpaired [CU, n = 50], cognitively impaired [CI, n = 68]) from the ADNI study with a full plasma biomarker profile (A beta 42/40, GFAP, p-tau181, NfL) and matched amyloid imaging. Initially, we investigated how simulated CV variations impacted single-biomarker discriminative performance of amyloid status. Then, we evaluated the predictive performance of models containing different biomarker combinations, based both on original and simulated measurements. Plasma A beta 42/40 was represented by both immunoprecipitation mass spectrometry (IP-MS) and single molecule array (Simoa) methods in separate analyses. Model selection was based on a decision tree which incorporated Akaike information criterion value, likelihood ratio tests between the best-fitting models and, finally, and Schwartz's Bayesian information criterion. Results Increasing variation greatly impacted the performance of plasma A beta 42/40 in discriminating A beta status. In contrast, the performance of plasma GFAP and p-tau181 remained stable with variations >20%. When biomarker models were compared, the models "AG" (A beta 42/40 + GFAP; AUC = 86.5), "A" (A beta 42/40; AUC = 82.3), and "AGP" (A beta 42/40 + GFAP + p-tau181; AUC = 93.5) were superior in determining A beta burden in all participants, within-CU, and within-CI groups, respectively. In the robustness analyses, when repeating model selection based on simulated measurements, models including IP-MS A beta 42/40 were also most often selected. Simoa A beta 42/40 did not contribute to any selected model when used as an immunoanalytical alternative to IP-MS A beta 42/40. Conclusions Plasma A beta 42/40, as quantified by IP-MS, shows high performance in determining A beta positivity at all stages of the AD continuum, with GFAP and p-tau181 further contributing at CI stage. However, between-assay variations greatly impacted the performance of A beta 42/40 but not that of GFAP and p-tau181. Therefore, when dealing with between-assay CVs that exceed 5%, plasma GFAP and p-tau181 should be considered for a more robust determination of A beta burden in CU and CI participants, respectively.
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| 31. |
- Lima, R. A. S., et al.
(author)
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Association of the fibronectin type III domain-containing protein 5 rs1746661 single nucleotide polymorphism with reduced brain glucose metabolism in elderly humans
- 2023
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In: Brain Communications. ; 5:4
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Journal article (peer-reviewed)abstract
- Lima-Filho et al. reported that cognitively unimpaired elders carrying the FNDC5 rs1746661(T) allele develop low brain glucose metabolism and increased amyloid deposition. These findings indicate that FNDC5 may contribute to regional glucose metabolism in the human brain. Fibronectin type III domain-containing protein 5 (FNDC5) and its derived hormone, irisin, have been associated with metabolic control in humans, with described FNDC5 single nucleotide polymorphisms being linked to obesity and metabolic syndrome. Decreased brain FNDC5/irisin has been reported in subjects with dementia due to Alzheimer's disease. Since impaired brain glucose metabolism develops in ageing and is prominent in Alzheimer's disease, here, we examined associations of a single nucleotide polymorphism in the FNDC5 gene (rs1746661) with brain glucose metabolism and amyloid-& beta; deposition in a cohort of 240 cognitively unimpaired and 485 cognitively impaired elderly individuals from the Alzheimer's Disease Neuroimaging Initiative. In cognitively unimpaired elderly individuals harbouring the FNDC5 rs1746661(T) allele, we observed a regional reduction in low glucose metabolism in memory-linked brain regions and increased brain amyloid-& beta; PET load. No differences in cognition or levels of cerebrospinal fluid amyloid-& beta;(42), phosphorylated tau and total tau were observed between FNDC5 rs1746661(T) allele carriers and non-carriers. Our results indicate that a genetic variant of FNDC5 is associated with low brain glucose metabolism in elderly individuals and suggest that FNDC5 may participate in the regulation of brain metabolism in brain regions vulnerable to Alzheimer's disease pathophysiology. Understanding the associations between genetic variants in metabolism-linked genes and metabolic brain signatures may contribute to elucidating genetic modulators of brain metabolism in humans.
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| 32. |
- Marras, Alessandro, et al.
(author)
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Characterization of the Percival detector with soft X-rays
- 2021
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In: Journal of Synchrotron Radiation. - 0909-0495 .- 1600-5775. ; 28, s. 131-145
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Journal article (peer-reviewed)abstract
- In this paper the back-side-illuminated Percival 2-Megapixel (P2M) detector is presented, along with its characterization by means of optical and X-ray photons. For the first time, the response of the system to soft X-rays (250 eV to 1 keV) is presented. The main performance parameters of the first detector are measured, assessing the capabilities in terms of noise, dynamic range and single-photon discrimination capability. Present limitations and coming improvements are discussed.
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| 33. |
- Santoro, V, et al.
(author)
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Development of high intensity neutron source at the European Spallation Source
- 2020
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In: Journal of Neutron Research. - 1023-8166 .- 1477-2655. ; 22:2-3, s. 209-219
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Journal article (peer-reviewed)abstract
- The European Spallation Source being constructed in Lund, Sweden will provide the user community with a neutron source of unprecedented brightness. By 2025, a suite of 15 instruments will be served by a high-brightness moderator system placed above the spallation target. The ESS infrastructure, consisting of the proton linac, the target station, and the instrument halls, allows for implementation of a second source below the spallation target. We propose to develop a second neutron source with a high-intensity moderator able to (1) deliver a larger total cold neutron flux, (2) provide high intensities at longer wavelengths in the spectral regions of Cold (4–10 Å), Very Cold (10–40 Å), and Ultra Cold (several 100 Å) neutrons, as opposed to Thermal and Cold neutrons delivered by the top moderator. Offering both unprecedented brilliance, flux, and spectral range in a single facility, this upgrade will make ESS the most versatile neutron source in the world and will further strengthen the leadership of Europe in neutron science. The new source will boost several areas of condensed matter research such as imaging and spin-echo, and will provide outstanding opportunities in fundamental physics investigations of the laws of nature at a precision unattainable anywhere else. At the heart of the proposed system is a volumetric liquid deuterium moderator. Based on proven technology, its performance will be optimized in a detailed engineering study. This moderator will be complemented by secondary sources to provide intense beams of Very- and Ultra-Cold Neutrons.
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| 34. |
- Schaffer Aguzzoli, Cristiano, et al.
(author)
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Neuropsychiatric Symptoms and Microglial Activation in Patients with Alzheimer Disease
- 2023
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In: JAMA network open. - 2574-3805. ; 6:11
-
Journal article (peer-reviewed)abstract
- Importance: Neuropsychiatric symptoms are commonly encountered and are highly debilitating in patients with Alzheimer disease. Understanding their underpinnings has implications for identifying biomarkers and treatment for these symptoms. Objective: To evaluate whether glial markers are associated with neuropsychiatric symptoms in individuals across the Alzheimer disease continuum. Design, Setting, and Participants: This cross-sectional study was conducted from January to June 2023, leveraging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University, Canada. Recruitment was based on referrals of individuals from the community or from outpatient clinics. Exclusion criteria included active substance abuse, major surgery, recent head trauma, safety contraindications for positron emission tomography (PET) or magnetic resonance imaging, being currently enrolled in other studies, and having inadequately treated systemic conditions. Main Outcomes and Measures: All individuals underwent assessment for neuropsychiatric symptoms (Neuropsychiatry Inventory Questionnaire [NPI-Q]), and imaging for microglial activation ([11C]PBR28 PET), amyloid-β ([18F]AZD4694 PET), and tau tangles ([18F]MK6240 PET). Results: Of the 109 participants, 72 (66%) were women and 37 (34%) were men; the median age was 71.8 years (range, 38.0-86.5 years). Overall, 70 had no cognitive impairment and 39 had cognitive impairment (25 mild; 14 Alzheimer disease dementia). Amyloid-β PET positivity was present in 21 cognitively unimpaired individuals (30%) and in 31 cognitively impaired individuals (79%). The NPI-Q severity score was associated with microglial activation in the frontal, temporal, and parietal cortices (β=7.37; 95% CI, 1.34-13.41; P=.01). A leave-one-out approach revealed that irritability was the NPI-Q domain most closely associated with the presence of brain microglial activation (β=6.86; 95% CI, 1.77-11.95; P=.008). Furthermore, we found that microglia-associated irritability was associated with study partner burden measured by NPI-Q distress score (β=5.72; 95% CI, 0.33-11.10; P=.03). Conclusions and Relevance: In this cross-sectional study of 109 individuals across the AD continuum, microglial activation was associated with and a potential biomarker of neuropsychiatric symptoms in Alzheimer disease. Moreover, our findings suggest that the combination of amyloid-β- and microglia-targeted therapies could have an impact on relieving these symptoms.
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| 35. |
- Therriault, J., et al.
(author)
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Staging of Alzheimer?s disease: past, present and future perspectives
- 2022
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In: Trends in Molecular Medicine. - : Elsevier BV. - 1471-4914. ; 28:9, s. 726-741
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Journal article (peer-reviewed)abstract
- For many years Alzheimer's disease (AD) was associated with the dementia stage of the disease, the tail end of a pathophysiological process that lasts approximately two decades. Whereas early disease staging assessments focused on progressive deterioration of clinical functioning, brain imaging with positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarker studies highlighted the long preclinical phase of AD in which a cascade of detectable biological abnormalities precede cognitive decline. The recent pro-liferation of imaging and fluid biomarkers of AD pathophysiology provide an opportunity for the identification of several biological stages in the preclinical phase of AD. We discuss the use of clinical and biomarker information in past, present, and future staging of AD. We highlight potential applications of PET, CSF, and plasma biomarkers for staging AD severity in vivo.
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| 36. |
- Wagner, R., et al.
(author)
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Design of an optimized nested-mirror neutron reflector for a NNBAR experiment
- 2023
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In: Nuclear Instruments and Methods in Physics Research, Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 1051
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Journal article (peer-reviewed)abstract
- The NNBAR experiment for the European Spallation Source will search for free neutrons converting to antineutrons with an expected sensitivity improvement of three orders of magnitude compared to the last such search. This paper describes both the simulations of a key component for the experiment, the neutron optical reflector and the expected gains in sensitivity.
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| 37. |
- Zimmer, Christine L., et al.
(author)
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A biliary immune landscape map of primary sclerosing cholangitis reveals a dominant network of neutrophils and tissue-resident T cells
- 2021
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In: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 13:599
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Journal article (peer-reviewed)abstract
- The human biliary system, a mucosal barrier tissue connecting the liver and intestine, is an organ often affected by serious inflammatory and malignant diseases. Although these diseases are linked to immunological processes, the biliary system represents an unexplored immunological niche. By combining endoscopy-guided sampling of the biliary tree with a high-dimensional analysis approach, comprehensive mapping of the human biliary immunological landscape in patients with primary sclerosing cholangitis (PSC), a severe biliary inflammatory disease, was conducted. Major differences in immune cell composition in bile ducts compared to blood were revealed. Furthermore, biliary inflammation in patients with PSC was characterized by high presence of neutrophils and T cells as compared to control individuals without PSC. The biliary T cells displayed a CD103(+)CD69(+) effector memory phenotype, a combined gut and liver homing profile, and produced interleukin-17 (IL-17) and IL-22. Biliary neutrophil infiltration in PSC associated with CXCL8, possibly produced by resident T cells, and CXCL16 was linked to the enrichment of T cells. This study uncovers the immunological niche of human bile ducts, defines a local immune network between neutrophils and biliary-resident T cells in PSC, and provides a resource for future studies of the immune responses in biliary disorders.
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