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1.	Abelev, Betty, et al. (author) Long-range angular correlations on the near and away side in p-Pb collisions at root S-NN=5.02 TeV 2013 In: Physics Letters. Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier BV. - 0370-2693. ; 719:1-3, s. 29-41 Journal article (peer-reviewed)abstract Angular correlations between charged trigger and associated particles are measured by the ALICE detector in p-Pb collisions at a nucleon-nucleon centre-of-mass energy of 5.02 TeV for transverse momentum ranges within 0.5 < P-T,P-assoc < P-T,P-trig < 4 GeV/c. The correlations are measured over two units of pseudorapidity and full azimuthal angle in different intervals of event multiplicity, and expressed as associated yield per trigger particle. Two long-range ridge-like structures, one on the near side and one on the away side, are observed when the per-trigger yield obtained in low-multiplicity events is subtracted from the one in high-multiplicity events. The excess on the near-side is qualitatively similar to that recently reported by the CMS Collaboration, while the excess on the away-side is reported for the first time. The two-ridge structure projected onto azimuthal angle is quantified with the second and third Fourier coefficients as well as by near-side and away-side yields and widths. The yields on the near side and on the away side are equal within the uncertainties for all studied event multiplicity and p(T) bins, and the widths show no significant evolution with event multiplicity or p(T). These findings suggest that the near-side ridge is accompanied by an essentially identical away-side ridge. (c) 2013 CERN. Published by Elsevier B.V. All rights reserved.
2.	Abelev, Betty, et al. (author) Measurement of prompt J/psi and beauty hadron production cross sections at mid-rapidity in pp collisions at root s=7 TeV 2012 In: Journal of High Energy Physics. - 1029-8479. ; :11 Journal article (peer-reviewed)abstract The ALICE experiment at the LHC has studied J/psi production at mid-rapidity in pp collisions at root s = 7 TeV through its electron pair decay on a data sample corresponding to an integrated luminosity L-int = 5.6 nb(-1). The fraction of J/psi from the decay of long-lived beauty hadrons was determined for J/psi candidates with transverse momentum p(t) > 1,3 GeV/c and rapidity vertical bar y vertical bar < 0.9. The cross section for prompt J/psi mesons, i.e. directly produced J/psi and prompt decays of heavier charmonium states such as the psi(2S) and chi(c) resonances, is sigma(prompt J/psi) (p(t) > 1.3 GeV/c, vertical bar y vertical bar < 0.9) = 8.3 +/- 0.8(stat.) +/- 1.1 (syst.)(-1.4)(+1.5) (syst. pol.) mu b. The cross section for the production of b-hadrons decaying to J/psi with p(t) > 1.3 GeV/c and vertical bar y vertical bar < 0.9 is a sigma(J/psi <- hB) (p(t) > 1.3 GeV/c, vertical bar y vertical bar < 0.9) = 1.46 +/- 0.38 (stat.)(-0.32)(+0.26) (syst.) mu b. The results are compared to QCD model predictions. The shape of the p(t) and y distributions of b-quarks predicted by perturbative QCD model calculations are used to extrapolate the measured cross section to derive the b (b) over bar pair total cross section and d sigma/dy at mid-rapidity.
3.	Abelev, Betty, et al. (author) Underlying Event measurements in pp collisions at root s=0.9 and 7 TeV with the ALICE experiment at the LHC 2012 In: Journal of High Energy Physics. - 1029-8479. ; :7 Journal article (peer-reviewed)abstract We present measurements of Underlying Event observables in pp collisions at root s = 0 : 9 and 7 TeV. The analysis is performed as a function of the highest charged-particle transverse momentum p(T),L-T in the event. Different regions are defined with respect to the azimuthal direction of the leading (highest transverse momentum) track: Toward, Transverse and Away. The Toward and Away regions collect the fragmentation products of the hardest partonic interaction. The Transverse region is expected to be most sensitive to the Underlying Event activity. The study is performed with charged particles above three different p(T) thresholds: 0.15, 0.5 and 1.0 GeV/c. In the Transverse region we observe an increase in the multiplicity of a factor 2-3 between the lower and higher collision energies, depending on the track p(T) threshold considered. Data are compared to PYTHIA 6.4, PYTHIA 8.1 and PHOJET. On average, all models considered underestimate the multiplicity and summed p(T) in the Transverse region by about 10-30%.
4.	Alonso-Mori, Roberto, et al. (author) Energy-dispersive X-ray emission spectroscopy using an X-ray free-electron laser in a shot-by-shot mode 2012 In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:47, s. 19103-19107 Journal article (peer-reviewed)abstract The ultrabright femtosecond X-ray pulses provided by X-ray free-electron lasers open capabilities for studying the structure and dynamics of a wide variety of systems beyond what is possible with synchrotron sources. Recently, this probe-before-destroy approach has been demonstrated for atomic structure determination by serial X-ray diffraction of microcrystals. There has been the question whether a similar approach can be extended to probe the local electronic structure by X-ray spectroscopy. To address this, we have carried out femtosecond X-ray emission spectroscopy (XES) at the Linac Coherent Light Source using redox-active Mn complexes. XES probes the charge and spin states as well as the ligand environment, critical for understanding the functional role of redox-active metal sites. K beta(1,3) XES spectra of Mn-II and Mn-2(III,IV) complexes at room temperature were collected using a wavelength dispersive spectrometer and femtosecond X-ray pulses with an individual dose of up to > 100 MGy. The spectra were found in agreement with undamaged spectra collected at low dose using synchrotron radiation. Our results demonstrate that the intact electronic structure of redox active transition metal compounds in different oxidation states can be characterized with this shot-by-shot method. This opens the door for studying the chemical dynamics of metal catalytic sites by following reactions under functional conditions. The technique can be combined with X-ray diffraction to simultaneously obtain the geometric structure of the overall protein and the local chemistry of active metal sites and is expected to prove valuable for understanding the mechanism of important metalloproteins, such as photosystem II.
5.	Assi, Nada, et al. (author) A statistical framework to model the meeting-in-the-middle principle using metabolomic data : application to hepatocellular carcinoma in the EPIC study 2015 In: Mutagenesis. - : Oxford University Press (OUP). - 0267-8357 .- 1464-3804. ; 30:6, s. 743-753 Journal article (peer-reviewed)abstract Metabolomics is a potentially powerful tool for identification of biomarkers associated with lifestyle exposures and risk of various diseases. This is the rationale of the 'meeting-in-the-middle' concept, for which an analytical framework was developed in this study. In a nested case-control study on hepatocellular carcinoma (HCC) within the European Prospective Investigation into Cancer and nutrition (EPIC), serum H-1 nuclear magnetic resonance (NMR) spectra (800 MHz) were acquired for 114 cases and 222 matched controls. Through partial least square (PLS) analysis, 21 lifestyle variables (the 'predictors', including information on diet, anthropometry and clinical characteristics) were linked to a set of 285 metabolic variables (the 'responses'). The three resulting scores were related to HCC risk by means of conditional logistic regressions. The first PLS factor was not associated with HCC risk. The second PLS metabolomic factor was positively associated with tyrosine and glucose, and was related to a significantly increased HCC risk with OR = 1.11 (95% CI: 1.02, 1.22, P = 0.02) for a 1SD change in the responses score, and a similar association was found for the corresponding lifestyle component of the factor. The third PLS lifestyle factor was associated with lifetime alcohol consumption, hepatitis and smoking, and had negative loadings on vegetables intake. Its metabolomic counterpart displayed positive loadings on ethanol, glutamate and phenylalanine. These factors were positively and statistically significantly associated with HCC risk, with 1.37 (1.05, 1.79, P = 0.02) and 1.22 (1.04, 1.44, P = 0.01), respectively. Evidence of mediation was found in both the second and third PLS factors, where the metabolomic signals mediated the relation between the lifestyle component and HCC outcome. This study devised a way to bridge lifestyle variables to HCC risk through NMR metabolomics data. This implementation of the 'meeting-in-the-middle' approach finds natural applications in settings characterised by high-dimensional data, increasingly frequent in the omics generation.
6.	Barnaure, I., et al. (author) Clinicoradiologic Correlations of Cerebral Microbleeds in Advanced Age 2017 In: American Journal of Neuroradiology. - 0195-6108 .- 1936-959X. ; 38, s. 39-45 Journal article (peer-reviewed)abstract BACKGROUND AND PURPOSE: The presence of cerebral microbleeds has been associated with dementia and cognitive decline, although studies report conflicting results. Our aim was to determine the potential role of the presence and location of cerebral microbleeds in early stages of cognitive decline.MATERIALS AND METHODS: Baseline 3T MR imaging examinations including SWI sequences of 328 cognitively intact community-dwelling controls and 72 subjects with mild cognitive impairment were analyzed with respect to the presence and distribution of cerebral microbleeds. A neuropsychological follow-up of controls was performed at 18 months post inclusion and identified cases with subtle cognitive deficits were referred to as controls with a deteriorating condition. Group differences in radiologic parameters were studied by using nonparametric tests, 1-way analysis of variance, and Spearman correlation coefficients.RESULTS: Cerebral microbleed prevalence was similar in subjects with mild cognitive impairment and controls with stable and cognitively deteriorating conditions (25%-31.9%). In all diagnostic groups, lobar cerebral microbleeds were more common. They occurred in 20.1% of all cases compared with 6.5% of cases with deep cerebral microbleeds. None of the investigated variables (age, sex, microbleed number, location and depth, baseline Mini-Mental State Examination score, and the Fazekas score) were significantly associated with cognitive deterioration with the exception of education of >12 years showing a slight but significant protective effect (OR, 0.44; 95% CI, 0.22-0.92; P = .028). The Mini-Mental State Examination and the Buschke total score were correlated with neither the total number nor lobar-versus-deep location of cerebral microbleeds.CONCLUSIONS: Cerebral microbleed presence, location, and severity are not related to the early stages of cognitive decline in advanced age.
7.	Buvall, Lisa, 1976, et al. (author) Orellanine specifically targets renal clear cell carcinoma 2017 In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:53, s. 91085-91098 Journal article (peer-reviewed)abstract Renal cell carcinoma (RCC), arising from the proximal tubule in the kidney, accounts for approximately 85% of kidney cancers and causes over 140,000 annual deaths worldwide. In the last decade, several new therapies have been identified for treatment of metastatic RCC. Although these therapies increase survival time compared to standard care, none of them has curative properties. The nephrotoxin orellanine specifically targets proximal tubular epithelial cells, leaving other organs unaffected. We therefore hypothesized that the selective toxicity of orellanine extends to clear cell RCC (ccRCC) cells since they emanate from proximal tubular cells. Orellanine would thus target both primary and metastatic ccRCC in vitro and in vivo. We found that orellanine induces dose-dependent cell death in proximal tubular cells and in all ccRCC cells tested, both primary and cell lines, with no toxicity detected in control cells. The toxic action of orellanine involve decreased protein synthesis, disrupted cell metabolism and induction of apoptosis. In nude rats carrying human ccRCC xenografts, brief orellanine treatment eliminated more than 90% of viable tumor mass compared to control rats. This identifies orellanine as a potential treatment concept for ccRCC patients on dialysis, due to its unique selective toxicity towards ccRCC.
8.	Chapman, Henry N, et al. (author) Femtosecond X-ray protein nanocrystallography. 2011 In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 470:7332, s. 73-7 Journal article (peer-reviewed)abstract X-ray crystallography provides the vast majority of macromolecular structures, but the success of the method relies on growing crystals of sufficient size. In conventional measurements, the necessary increase in X-ray dose to record data from crystals that are too small leads to extensive damage before a diffraction signal can be recorded. It is particularly challenging to obtain large, well-diffracting crystals of membrane proteins, for which fewer than 300 unique structures have been determined despite their importance in all living cells. Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source. We prove this concept with nanocrystals of photosystem I, one of the largest membrane protein complexes. More than 3,000,000 diffraction patterns were collected in this study, and a three-dimensional data set was assembled from individual photosystem I nanocrystals (∼200nm to 2μm in size). We mitigate the problem of radiation damage in crystallography by using pulses briefer than the timescale of most damage processes. This offers a new approach to structure determination of macromolecules that do not yield crystals of sufficient size for studies using conventional radiation sources or are particularly sensitive to radiation damage.
9.	De Palma, Adriana, et al. (author) Predicting bee community responses to land-use changes : effects of geographic and taxonomic biases 2016 In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 6, s. 1-14 Journal article (peer-reviewed)abstract Land-use change and intensification threaten bee populations worldwide, imperilling pollination services. Global models are needed to better characterise, project, and mitigate bees' responses to these human impacts. The available data are, however, geographically and taxonomically unrepresentative; most data are from North America and Western Europe, overrepresenting bumblebees and raising concerns that model results may not be generalizable to other regions and taxa. To assess whether the geographic and taxonomic biases of data could undermine effectiveness of models for conservation policy, we have collated from the published literature a global dataset of bee diversity at sites facing land-use change and intensification, and assess whether bee responses to these pressures vary across 11 regions (Western, Northern, Eastern and Southern Europe; North, Central and South America; Australia and New Zealand; South East Asia; Middle and Southern Africa) and between bumblebees and other bees. Our analyses highlight strong regionally-based responses of total abundance, species richness and Simpson's diversity to land use, caused by variation in the sensitivity of species and potentially in the nature of threats. These results suggest that global extrapolation of models based on geographically and taxonomically restricted data may underestimate the true uncertainty, increasing the risk of ecological surprises.
10.	Filmann, Natalie, et al. (author) Prevalence of Anemia in Inflammatory Bowel Diseases in European Countries: A Systematic Review and Individual Patient Data Meta-analysis. 2014 In: Inflammatory Bowel Diseases. - 1536-4844. ; 20:5, s. 936-945 Research review (peer-reviewed)abstract The main objective is to determine the overall prevalence of anemia in inflammatory bowel diseases (IBD) in Europe.
11.	Giannakopoulos, Panteleimon, et al. (author) Alzheimer resemblance atrophy index, BrainAGE, and normal pressure hydrocephalus score in the prediction of subtle cognitive decline : added value compared to existing MR imaging markers. 2022 In: European Radiology. - : Springer Science and Business Media LLC. - 0938-7994 .- 1432-1084. ; 32:11, s. 7833-7842 Journal article (peer-reviewed)abstract OBJECTIVES: Established visual brain MRI markers for dementia include hippocampal atrophy (mesio-temporal atrophy MTA), white matter lesions (Fazekas score), and number of cerebral microbleeds (CMBs). We assessed whether novel quantitative, artificial intelligence (AI)-based volumetric scores provide additional value in predicting subsequent cognitive decline in elderly controls.METHODS: A prospective study including 80 individuals (46 females, mean age 73.4 ± 3.5 years). 3T MR imaging was performed at baseline. Extensive neuropsychological assessment was performed at baseline and at 4.5-year follow-up. AI-based volumetric scores were derived from 3DT1: Alzheimer Disease Resemblance Atrophy Index (AD-RAI), Brain Age Gap Estimate (BrainAGE), and normal pressure hydrocephalus (NPH) index. Analyses included regression models between cognitive scores and imaging markers.RESULTS: AD-RAI score at baseline was associated with Corsi (visuospatial memory) decline (10.6% of cognitive variability in multiple regression models). After inclusion of MTA, CMB, and Fazekas scores simultaneously, the AD-RAI score remained as the sole valid predictor of the cognitive outcome explaining 16.7% of its variability. Its percentage reached 21.4% when amyloid positivity was considered an additional explanatory factor. BrainAGE score was associated with Trail Making B (executive functions) decrease (8.5% of cognitive variability). Among the conventional MRI markers, only the Fazekas score at baseline was positively related to the cognitive outcome (8.7% of cognitive variability). The addition of the BrainAGE score as an independent variable significantly increased the percentage of cognitive variability explained by the regression model (from 8.7 to 14%). The addition of amyloid positivity led to a further increase in this percentage reaching 21.8%.CONCLUSIONS: The AI-based AD-RAI index and BrainAGE scores have limited but significant added value in predicting the subsequent cognitive decline in elderly controls when compared to the established visual MRI markers of brain aging, notably MTA, Fazekas score, and number of CMBs.KEY POINTS: • AD-RAI score at baseline was associated with Corsi score (visuospatial memory) decline. • BrainAGE score was associated with Trail Making B (executive functions) decrease. • AD-RAI index and BrainAGE scores have limited but significant added value in predicting the subsequent cognitive decline in elderly controls when compared to the established visual MRI markers of brain aging, notably MTA, Fazekas score, and number of CMBs.
12.	Giannakopoulos, Panteleimon, et al. (author) Less agreeable, better preserved? : A PET amyloid and MRI study in a community-based cohort 2020 In: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 89, s. 24-31 Journal article (peer-reviewed)abstract The relationship between personality profiles and brain integrity in old age is still a matter of debate. We examined the association between Big Five factor and facet scores and MRI brain volume changes on a 54-month follow-up in 65 elderly controls with 3 neurocognitive assessments (baseline, 18 months, and 54 months), structural brain MRI (baseline and 54 months), brain amyloid PET during follow-up, and APOE genotyping. Personality was assessed with the Neuroticism Extraversion Openness Personality Inventory-Revised. Regression models were used to identify predictors of volume loss including time, age, sex, personality, amyloid load, presence of APOE epsilon 4 allele, and cognitive evolution. Lower agreeableness factor scores (and 4 of its facets) were associated with lower volume loss in the hippocampus, entorhinal cortex, amygdala, mesial temporal lobe, and precuneus bilaterally. Higher openness factor scores (and 2 of its facets) were also associated with lower volume loss in the left hippocampus. Our findings persisted when adjusting for confounders in multivariable models. These data suggest that the combination of low agreeableness and high openness is an independent predictor of better preservation of brain volume in areas vulnerable to neurodegeneration. (C) 2020 Elsevier Inc. All rights reserved.
13.	Giannakopoulos, Panteleimon, et al. (author) Personality Factors' Impact on the Structural Integrity of Mentalizing Network in Old Age : A Combined PET-MRI Study 2020 In: Frontiers in Psychiatry. - : Frontiers Media SA. - 1664-0640. ; 11 Journal article (peer-reviewed)abstract The mentalizing network (MN) treats social interactions based on our understanding of other people's intentions and includes the medial prefrontal cortex (mPFC), temporoparietal junction (TPJ), posterior cingulate cortex (PCC), precuneus (PC), and amygdala. Not all elders are equally affected by the aging-related decrease of mentalizing abilities. Personality has recently emerged as a strong determinant of functional connectivity in MN areas. However, its impact on volumetric changes across the MN in brain aging is still unknown. To address this issue, we explored the determinants of volume decrease in MN components including amyloid burden, personality, and APOE genotyping in a previously established cohort of 130 healthy elders with a mean follow-up of 54 months. Personality was assessed with the Neuroticism Extraversion Openness Personality Inventory-Revised. Regression models corrected for multiple comparisons were used to identify predictors of volume loss including time, age, sex, personality, amyloid load, presence of APOE epsilon 4 allele, and cognitive evolution. In cases with higher Agreeableness scores, there were lower volume losses in PCC, PC, and amygdala bilaterally. This was also the case for the right mPFC in elders displaying lower Agreeableness and Conscientiousness. In multiple regression models, the effect of Agreeableness was still observed in left PC and right amygdala and that of Conscientiousness was still observed in right mPFC volume loss (26.3% of variability, significant age and sex). Several Agreeableness (Modesty) and Conscientiousness (order, dutifulness, achievement striving, and self-discipline) facets were positively related to increased volume loss in cortical components of the MN. In conclusion, these data challenge the beneficial role of higher levels of Agreeableness and Conscientiousness in old age, showing that they are associated with an increased rate of volume loss within the MN.
14.	Giannakopoulos, Panteleimon, et al. (author) Personality Impact on Alzheimer's Disease - Signature and Vascular Imaging Markers : A PET-MRI Study 2022 In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 85:4, s. 1807-1817 Journal article (peer-reviewed)abstract Background: Several studies postulated that personality is an independent determinant of cognitive trajectories in old age. Objective: This study explores the impact of personality on widely used Alzheimer's disease (AD) and vascular imaging markers. Methods: We examined the association between personality and three classical AD imaging markers (centiloid-based-amyloid load, MRI volumetry in hippocampus, and media temporal lobe atrophy), and two vascular MRI parameters (Fazekas score and number of cortical microbleeds) assessed at baseline and upon a 54-month-follow-up. Personality was assessed with the Neuroticism Extraversion Openness Personality Inventory-Revised. Regression models were used to identify predictors of imaging markers including sex, personality factors, presence of APOE epsilon 4 allele and cognitive evolution over time. Results: Cortical GM volumes were negatively associated with higher levels of Conscientiousness both at baseline and follow-up. In contrast, higher scores of Openness were related to better preservation of left hippocampal volumes in these two time points and negatively associated with medial temporal atrophy at baseline. Amyloid load was not affected by personality factors. Cases with higher Extraversion scores displayed higher numbers of cortical microbleeds at baseline. Conclusion: Personality impact on brain morphometry is detected only in some among the routinely used imaging markers. The most robust associations concern the positive role of high levels of Conscientiousness and Openness on AD-signature MRI markers. Higher extraversion levels are associated with increased vulnerability to cortical microbleeds pointing to the fact that the socially favorable traits may have a detrimental effect on brain integrity in old age.
15.	Giannakopoulos, Panteleimon, et al. (author) Prediction of Subtle Cognitive Decline in Normal Aging : Added Value of Quantitative MRI and PET Imaging 2021 In: Frontiers in Aging Neuroscience. - : Frontiers Media S.A.. - 1663-4365. ; 13 Journal article (peer-reviewed)abstract Quantitative imaging processing tools have been proposed to improve clinic-radiological correlations but their added value at the initial stages of cognitive decline is still a matter of debate. We performed a longitudinal study in 90 community-dwelling elders with three neuropsychological assessments during a 4.5 year follow-up period, and visual assessment of medial temporal atrophy (MTA), white matter hyperintensities, cortical microbleeds (CMB) as well as amyloid positivity, and presence of abnormal FDG-PET patterns. Quantitative imaging data concerned ROI analysis of MRI volume, amyloid burden, and FDG-PET metabolism in several AD-signature areas. Multiple regression models, likelihood-ratio tests, and areas under the receiver operating characteristic curve (AUC) were used to compare quantitative imaging markers to visual inspection. The presence of more or equal to four CMB at inclusion and slight atrophy of the right MTL at follow-up were the only parameters to be independently related to the worst cognitive score explaining 6% of its variance. This percentage increased to 24.5% when the ROI-defined volume loss in the posterior cingulate cortex, baseline hippocampus volume, and MTL metabolism were also considered. When binary classification of cognition was made, the area under the ROC curve increased from 0.69 for the qualitative to 0.79 for the mixed imaging model. Our data reveal that the inclusion of quantitative imaging data significantly increases the prediction of cognitive changes in elderly controls compared to the single consideration of visual inspection.
16.	Haller, Sven, et al. (author) Amyloid Load, Hippocampal Volume Loss, and Diffusion Tensor Imaging Changes in Early Phases of Brain Aging 2019 In: Frontiers in Neuroscience. - : FRONTIERS MEDIA SA. - 1662-4548 .- 1662-453X. ; 13 Journal article (peer-reviewed)abstract Background and Purpose Amyloid imaging, gray matter (GM) morphometry and diffusion tensor imaging (DTI) have all been used as predictive biomarkers in dementia. Our objective was to define the imaging profile of healthy elderly controls as a function of their cognitive trajectories and explore whether amyloid burden and white matter (WM) microstructure changes are associated with subtle decrement of neuropsychological performances in old age. Materials and Methods We performed a 4.5-year longitudinal study in 133 elderly individuals who underwent cognitive testing at inclusion and follow-up, amyloid PET, MRI including DTI sequences at inclusion, and APOE epsilon 4 genotyping. All cases were assessed using a continuous cognitive score (CCS) taking into account the global evolution of neuropsychological performances. Data processing included region of interest analysis of amyloid PET analysis, GM densities and tract-based spatial statistics (TBSS)-DTI. Regression models were built to explore the association between the CCS and imaging parameters controlling for significant demographic and clinical covariates. Results Amyloid uptake was not related to the cognitive outcome. In contrast, GM densities in bilateral hippocampus were associated with worst CCS at follow-up. In addition, radial and axial diffusivities in left hippocampus were negatively associated with CCS. Amyloid load was associated with decreased VBM and increased radial and axial diffusivity in the same area. These associations persisted when adjusting for gender and APOE4 genotype. Importantly, they were absent in amygdala and neocortical areas studied. Conclusion The progressive decrement of neuropsychological performances in normal aging is associated with volume loss and WM microstructure changes in hippocampus long before the emergence of clinically overt symptoms. Higher amyloid load in hippocampus is compatible with cognitive preservation in cases with better preservation of GM densities and WM microstructure in this area.
17.	Haller, Sven, et al. (author) APOEE4 Is Associated with Gray Matter Loss in the Posterior Cingulate Cortex in Healthy Elderly Controls Subsequently Developing Subtle Cognitive Decline 2017 In:* American Journal of Neuroradiology. - 0195-6108 .- 1936-959X. ; 38:7, s. 1335-1342 Journal article (peer-reviewed)abstract BACKGROUND AND PURPOSE: The presence of apolipoprotein E4 (APOEE4) is the strongest currently known genetic risk factor for Alzheimer disease and is associated with brain gray matter loss, notably in areas involved in Alzheimer disease pathology. Our objective was to assess the effect of APOEE4 on brain structures in healthy elderly controls who subsequently developed subtle cognitive decline.MATERIALS AND METHODS: This prospective study included 382 community-dwelling elderly controls. At baseline, participants underwent MR imaging at 3T, extensive neuropsychological testing, and genotyping. After neuropsychological follow-up at 18 months, participants were classified into cognitively stable controls and cognitively deteriorating controls. Data analysis included whole-brain voxel-based morphometry and ROI analysis of GM.RESULTS: APOEE4-related GM loss at baseline was found only in the cognitively deteriorating controls in the posterior cingulate cortex. There was no APOEE4-related effect in the hippocampus, mesial temporal lobe, or brain areas not involved in Alzheimer disease pathology. Controls in the cognitively deteriorating group had slightly lower GM concentration in the hippocampus at baseline. Higher GM densities in the hippocampus, middle temporal lobe, and amygdala were associated with a decreased risk for cognitively deteriorating group status at follow-up.CONCLUSIONS: APOEE4-related GM loss in the posterior cingulate cortex (an area involved in Alzheimer disease pathology) was found only in those elderly controls who subsequently developed subtle cognitive decline but not in cognitively stable controls. This finding might explain the partially conflicting results of previous studies that typically did not include detailed neuropsychological assessment and follow-up. Most important, APOEE4 status had no impact on GM density in areas affected early by neurofibrillary tangle formation such as the hippocampus and mesial temporal lobe.
18.	Haller, Sven, et al. (author) Automatic MRI volumetry in asymptomatic cases at risk for normal pressure hydrocephalus 2023 In: Frontiers in Aging Neuroscience. - : Frontiers Media S.A.. - 1663-4365. ; 15 Journal article (peer-reviewed)abstract The occurrence of significant Alzheimer's disease (AD) pathology was described in approximately 30% of normal pressure hydrocephalus (NPH) cases, leading to the distinction between neurodegenerative and idiopathic forms of this disorder. Whether or not there is a specific MRI signature of NPH remains a matter of debate. The present study focuses on asymptomatic cases at risk for NPH as defined with automatic machine learning tools and combines automatic MRI assessment of cortical and white matter volumetry, risk of AD (AD-RAI), and brain age gap estimation (BrainAge). Our hypothesis was that brain aging and AD process-independent volumetric changes occur in asymptomatic NPH-positive cases. We explored the volumetric changes in normal aging-sensitive (entorhinal cortex and parahippocampal gyrus/PHG) and AD-signature areas (hippocampus), four control cortical areas (frontal, parietal, occipital, and temporal), and cerebral and cerebellar white matter in 30 asymptomatic cases at risk for NPH (NPH probability >30) compared to 30 NPH-negative cases (NPH probability <5) with preserved cognition. In univariate regression models, NPH positivity was associated with decreased volumes in the hippocampus, parahippocampal gyrus (PHG), and entorhinal cortex bilaterally. The strongest negative association was found in the left hippocampus that persisted when adjusting for AD-RAI and Brain Age values. A combined model including the three parameters explained 36.5% of the variance, left hippocampal volumes, and BrainAge values, which remained independent predictors of the NPH status. Bilateral PHG and entorhinal cortex volumes were negatively associated with NPH-positive status in univariate models but this relationship did not persist when adjusting for BrainAge, the latter remaining the only predictor of the NPH status. We also found a negative association between bilateral cerebral and cerebellar white matter volumes and NPH status that persisted after controlling for AD-RAI or Brain Age values, explaining between 50 and 65% of its variance. These observations support the idea that in cases at risk for NPH, as defined by support vector machine assessment of NPH-related MRI markers, brain aging-related and brain aging and AD-independent volumetric changes coexist. The latter concerns volume loss in restricted hippocampal and white matter areas that could be considered as the MRI signature of idiopathic forms of NPH.
19.	Haller, Sven, et al. (author) Hippocampal Volume Loss, Brain Amyloid Accumulation, and APOE Status in Cognitively Intact Elderly Subjects 2019 In: Neurodegenerative Diseases. - : S. Karger AG. - 1660-2854 .- 1660-2862. ; 19:3-4, s. 139-147 Journal article (peer-reviewed)abstract BACKGROUND: Hippocampal volume loss (HVL), PET-documented brain amyloid accumulation, and APOE-ε4 status are predictive biomarkers of the transition from mild cognitive impairment to Alzheimer disease (AD). In asymptomatic cases, the role of these biomarkers remains ambiguous. In contrast to the idea that HVL occurs in late phases of neurodegeneration, recent contributions indicate that it might occur before abnormal amyloid PET occurrence in elderly subjects and that its severity could be only marginally related to APOE variants. Using a longitudinal design, we examined the determinants of HVL in our sample, i.e., brain amyloid burden and the presence of APOE-ε4, and made a longitudinal assessment of cognitive functions.METHODS: We performed a 4.5-year longitudinal study on 81 elderly community dwellers (all right-handed;, 48 (59.3%) women; mean age 73.7 ± 3.7 years) including MRI at baseline and follow-up, PET amyloid during follow-up, neuropsychological assessment at 18 and 54 months, and APOE genotyping. All cases were assessed using a continuous cognitive score (CCS) that took into account the global evolution of neuropsychological performance. Linear regression models were used to identify predictors of HVL.RESULTS: There was a negative association between the CCS and HVL bilaterally. In multivariate models adjusting for demographic variables, the presence of APOE-ε4 was related to increased HVL bilaterally. A trend of significance was observed with respect to the impact of amyloid positivity on HVL in the left hemisphere. No significant interaction was found between amyloid positivity and the APOE-ε4 allele.CONCLUSION: The progressive decrement of neuropsychological performance is associated with HVL long before the emergence of clinically overt symptoms. In this cohort of healthy individuals, the presence of the APOE-ε4 allele was shown to be an independent predictor of worst hippocampal integrity in asymptomatic cases independently of amyloid positivity.
20.	Haller, Sven, et al. (author) Impact of Coffee, Wine, and Chocolate Consumption on Cognitive Outcome and MRI Parameters in Old Age 2018 In: Nutrients. - : MDPI AG. - 2072-6643. ; 10:10 Journal article (peer-reviewed)abstract Coffee, wine and chocolate are three frequently consumed substances with a significant impact on cognition. In order to define the structural and cerebral blood flow correlates of self-reported consumption of coffee, wine and chocolate in old age, we assessed cognition and brain MRI measures in 145 community-based elderly individuals with preserved cognition (69 to 86 years). Based on two neuropsychological assessments during a 3-year follow-up, individuals were classified into stable-stable (52 sCON), intermediate (61 iCON) and deteriorating-deteriorating (32 dCON). MR imaging included voxel-based morphometry (VBM), tract-based spatial statistics (TBSS) and arterial spin labelling (ASL). Concerning behavior, moderate consumption of caffeine was related to better cognitive outcome. In contrast, increased consumption of wine was related to an unfavorable cognitive evolution. Concerning MRI, we observed a negative correlation of wine and VBM in bilateral deep white matter (WM) regions across all individuals, indicating less WM lesions. Only in sCON individuals, we observed a similar yet weaker association with caffeine. Moreover, again only in sCON individuals, we observed a significant positive correlation between ASL and wine in overlapping left parietal WM indicating better baseline brain perfusion. In conclusion, the present observations demonstrate an inverse association of wine and coffee consumption with cognitive performances. Moreover, low consumption of wine but also moderate to heavy coffee drinking was associated with better WM preservation and cerebral blood-flow notably in cognitively stable elders.
21.	Haller, Sven, et al. (author) MRI detection of cerebral microbleeds : size matters 2019 In: Neuroradiology. - : Springer Science and Business Media LLC. - 0028-3940 .- 1432-1920. ; 61:10, s. 1209-1213 Journal article (peer-reviewed)abstract PURPOSE: Cerebral microbleeds (CMB) play an important role as an imaging biomarker notably in vascular and neurodegenerative diseases. Current clinical brain MRI underestimates the number of CMB with respect to histopathology. It is expected that small CMBs are more likely to be false-negatives, yet this has not been demonstrated and the average size of false-negative and true-positive CMBs have not been established.METHODS: The radiologic-histopathologic correlation study was approved by the local review board and included 42 consecutive cases (mean age at death, 80.7 ± 10.0 years; 23 females and 19 men) between 12 January 2012 and 10 December 2012 having undergone brain autopsy. Postmortem SWI (susceptibility-weighted imaging) images were acquired on a clinical 3T system using parameters similar to clinical routine. The detection of CMB on postmortem MRI was compared with corresponding histopathological slices.RESULTS: Postmortem MRI detected 23 true-positive CMB. Histopathology additionally detected 68 CMBs (false-negative MRI CMBs). The average size true-positive MRI CMBs had on histopathology was 3.6 ± 7.1 mm3. The average size false-negative MRI CMBs was significantly smaller (p < 0.05), measuring 0.3 ± 1.2 mm3 on histopathology.CONCLUSION: Size matters. As expected, the average size of true-positive MRI CMB was around 10 times larger as compared with false-negative MRI CMB. Evidently, in addition to size, other factors will influence the detectability of CMB, including iron content, ratio of Fe2+/Fe3+, spatial configuration, and location, yet this remains to be elucidated in future studies.
22.	Haller, Sven, et al. (author) PET amyloid in normal aging : direct comparison of visual and automatic processing methods 2020 In: Scientific Reports. - : NATURE RESEARCH. - 2045-2322. ; 10 Journal article (peer-reviewed)abstract Assessment of amyloid deposits is a critical step for the identification of Alzheimer disease (AD) signature in asymptomatic elders. Whether the different amyloid processing methods impacts on the quality of clinico-radiological correlations is still unclear. We directly compared in 155 elderly controls with extensive neuropsychological testing at baseline and 4.5 years follow-up three approaches: (i) operator-dependent standard visual reading, (ii) operator-independent automatic SUVR with four different reference regions, and (iii) novel operator and region of reference-independent automatic A beta-index. The coefficient of variance was used to examine inter-individual variability for each processing method. Using visually-established amyloid positivity as the gold standard, the area under the receiver operating characteristic curve (ROC) was computed. Linear regression models were used to assess the association between changes in continuous cognitive score and amyloid uptake values. In SUVR analyses, the coefficient of variance varied from 1.718 to 1.762 according to the area of reference and was of - 3.045 for the A beta-index method. Compared to the visual rating, A beta-index method showed the largest area under the ROC curve [0.9568 (95% CI 0.9252, 0.98833)]. The best cut-off score was of - 0.3359 with sensitivity and specificity values of 0.97 and 0.83, respectively. Only the A beta-index was related to more severe decrement of cognitive performances [regression coefficient: 9.103 (95% CI 1.148, 17.058)]. The A beta-index is considered as preferred option in asymptomatic elders, since it is operator-independent, avoids the selection of reference area, is closer to established visual scoring and correlates with the evolution of cognitive performances.
23.	Haller, Sven, et al. (author) Radiologic-Histopathologic Correlation of Cerebral Microbleeds Using Pre-Mortem and Post-Mortem MRI 2016 In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:12 Journal article (peer-reviewed)abstract INTRODUCTION: Cerebral microbleeds (CMB), also known as cerebral microhemorrhages, are small areas of susceptibility on brain magnetic resonance imaging (MRI), that are increasingly detected due to the higher availability of high-field MRI systems and dedicated pulse sequences. The prevalence of CMBs increases in cases with cognitive decline. The current investigation assessed the poorly investigated radiologic-histopathologic correlation of CMBs on MRI.METHODS: The local ethical committee approved the current investigation. We retrospectively assessed a consecutive series of 1303 autopsy cases hospitalized in Geneva University Hospitals between 2000-2014. Of 112 cases with pre-mortem T2* sequences, we included 25 cases (mean age 77.3 ± 9.6, 9 females) with at least one CMB. We compared pre-mortem CMBs with targeted histopathology and post-mortem MRI.RESULTS: 25 cases had 31 CMB lesions detected by pre-mortem MRI. 25 additional CMB were detected on histopathology. 4 CMBs on pre-mortem MRI were false positives, resulting in a total of 52 CMBs. 27 CMBs on pre-mortem MRI were confirmed on histopathology, corresponding to a sensitivity or true positive rate of 51.9% (95% CI 37.6-66.0%). The false negative rate of pre-mortem MRI was 48.1% (95% CI 34.0-62.4%). Post-mortem MRI showed only 3 cases with additional CMBs. Overall, pre-mortem MRI significantly underestimated CMBs (p = 0.0001).CONCLUSIONS: Routine clinical brain MRI underestimates the prevalence of CMBs by approximately 50%, and 12% of radiologic pre-mortem MRI CMBs were false positives. Post-mortem MRI confirmed that this discordance is not explained by microbleeds occurring after the pre-mortem MRI.
24.	Herrmann, Björn, et al. (author) Chlamydophila abortus in a Brown skua (Catharacta antarctica, lonnbergi) from a sub-Antarctic island 2000 In: Applied and Environmental Microbiology. ; 66, s. 3654- Journal article (peer-reviewed)
25.	Herrmann, Björn, et al. (author) Chlamydophila abortus in a Brown skua (Catharacta antarctica, lonnbergi) from a sub-Antarctic island 2000 In: Applied and Environmental Microbiology. - Washington, DC, United States : American Society for Microbiology. - 0099-2240 .- 1098-5336. ; 66:8, s. 3654-3656 Journal article (peer-reviewed)abstract On Bird Island, South Georgia, a new strain of Chlamydophila abortus was detected in one Brown skua out of 37 specimens from six different seabird species. Phylogenetic analysis of thernpB and omp1 genes indicated the strain to be more closely related to C. abortus than to 6BC, the type strain of Chlamydophila psittaci.

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