| 1. |
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| 2. |
- Aartsen, M. G., et al.
(författare)
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Searches for Sterile Neutrinos with the IceCube Detector
- 2016
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 117:7
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Tidskriftsartikel (refereegranskat)abstract
- The IceCube neutrino telescope at the South Pole has measured the atmospheric muon neutrino spectrum as a function of zenith angle and energy in the approximate 320 GeV to 20 TeV range, to search for the oscillation signatures of light sterile neutrinos. No evidence for anomalous nu(mu) or (nu) over bar (mu) disappearance is observed in either of two independently developed analyses, each using one year of atmospheric neutrino data. New exclusion limits are placed on the parameter space of the 3 + 1 model, in which muon antineutrinos experience a strong Mikheyev-Smirnov-Wolfenstein-resonant oscillation. The exclusion limits extend to sin(2)2 theta(24) <= 0.02 at Delta m(2) similar to 0.3 eV(2) at the 90% confidence level. The allowed region from global analysis of appearance experiments, including LSND and MiniBooNE, is excluded at approximately the 99% confidence level for the global best-fit value of vertical bar U-e4 vertical bar(2).
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| 3. |
- Edgecock, T. R., et al.
(författare)
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High intensity neutrino oscillation facilities in Europe
- 2013
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Ingår i: Physical Review Special Topics - Accelerators and Beams. - : American Physical Society. - 1098-4402. ; 16:2, s. 021002-
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Tidskriftsartikel (refereegranskat)abstract
- The EUROnu project has studied three possible options for future, high intensity neutrino oscillation facilities in Europe. The first is a Super Beam, in which the neutrinos come from the decay of pions created by bombarding targets with a 4 MW proton beam from the CERN High Power Superconducting Proton Linac. The far detector for this facility is the 500 kt MEMPHYS water Cherenkov, located in the Frejus tunnel. The second facility is the Neutrino Factory, in which the neutrinos come from the decay of mu(+) and mu(-) beams in a storage ring. The far detector in this case is a 100 kt magnetized iron neutrino detector at a baseline of 2000 km. The third option is a Beta Beam, in which the neutrinos come from the decay of beta emitting isotopes, in particular He-6 and Ne-18, also stored in a ring. The far detector is also the MEMPHYS detector in the Frejus tunnel. EUROnu has undertaken conceptual designs of these facilities and studied the performance of the detectors. Based on this, it has determined the physics reach of each facility, in particular for the measurement of CP violation in the lepton sector, and estimated the cost of construction. These have demonstrated that the best facility to build is the Neutrino Factory. However, if a powerful proton driver is constructed for another purpose or if the MEMPHYS detector is built for astroparticle physics, the Super Beam also becomes very attractive.
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| 4. |
- Armengaud, E., et al.
(författare)
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Physics potential of the International Axion Observatory (IAXO)
- 2019
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Ingår i: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; :6
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Tidskriftsartikel (refereegranskat)abstract
- We review the physics potential of a next generation search for solar axions: the International Axion Observatory (IAXO). Endowed with a sensitivity to discover axion-like particles (ALPs) with a coupling to photons as small as g(a gamma) similar to 10(-12) GeV-1, or to electrons g(ae) similar to 10(-13), IAXO has the potential to find the QCD axion in the 1 meV similar to 1 eV mass range where it solves the strong CP problem, can account for the cold dark matter of the Universe and be responsible for the anomalous cooling observed in a number of stellar systems. At the same time, IAXO will have enough sensitivity to detect lower mass axions invoked to explain: 1) the origin of the anomalous transparency of the Universe to gamma-rays, 2) the observed soft X-ray excess from galaxy clusters or 3) some inflationary models. In addition, we review string theory axions with parameters accessible by IAXO and discuss their potential role in cosmology as Dark Matter and Dark Radiation as well as their connections to the above mentioned conundrums.
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| 5. |
- Alemany, S., et al.
(författare)
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Associations between air pollution and biomarkers of Alzheimer's disease in cognitively unimpaired individuals
- 2021
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120. ; 157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Air quality contributes to incidence of Alzheimer's disease (AD) although the underlying neurobiological mechanisms are unclear. This study was aimed to examine the association between air pollution and concentrations of cerebrospinal fluid (CSF) AD biomarkers and amyloid-beta (A beta) deposition. Participants and methods The sample included 156 cognitively unimpaired adults aged 57 years (61 at biomarkers assessment) with increased risk of AD from the ALFA + Study. We examined CSF levels of A beta 42, A beta 40, p-Tau, t-Tau, neurofilament light (NfL) and cerebral amyloid load (Centiloid). A Land Use Regression model from 2009 was used to estimate residential exposure to air pollutants including nitrogen dioxide (NO2,) and particulate matter (PM2.5, PM2.5 abs, PM10). This model was considered a surrogate of long-term exposure until time of data collection in 2013-2014. Participants have resided in the same residence for at least the previous 3 years. Multiple linear regression models were used to estimate associations between air pollutants and biomarkers. The effect modification by CSF A beta status and APOE-epsilon 4 carriership was also assessed. Results: A consistent pattern of results indicated that greater exposure to NO2 and PM2.5 absorbance was associated with higher levels of brain A beta deposition, while greater exposure to PM10 and PM(2.5)was associated with higher levels of CSF NfL. Most associations were driven by individuals that were A beta-positive. Although APOE-epsilon 4 status did not significantly modify these associations, the effect of air pollutants exposure on CSF NfL levels was stronger in APOE-epsilon 4 carriers. Conclusion: In a population of cognitively unimpaired adults with increased risk of AD, long-term exposure to air pollution was associated with higher levels in biomarkers of AD pathology. While further research is granted to elucidate the mechanisms involved in such associations, our results reinforce the role of air pollution as an environmental risk factor for AD.
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| 6. |
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| 7. |
- Grau-Rivera, O., et al.
(författare)
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Association of weight change with cerebrospinal fluid biomarkers and amyloid positron emission tomography in preclinical Alzheimer's disease
- 2021
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Ingår i: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundRecognizing clinical manifestations heralding the development of Alzheimer's disease (AD)-related cognitive impairment could improve the identification of individuals at higher risk of AD who may benefit from potential prevention strategies targeting preclinical population. We aim to characterize the association of body weight change with cognitive changes and AD biomarkers in cognitively unimpaired middle-aged adults.MethodsThis prospective cohort study included data from cognitively unimpaired adults from the ALFA study (n=2743), a research platform focused on preclinical AD. Cognitive and anthropometric data were collected at baseline between April 2013 and November 2014. Between October 2016 and February 2020, 450 participants were visited in the context of the nested ALFA+ study and underwent cerebrospinal fluid (CSF) extraction and acquisition of positron emission tomography images with [F-18]flutemetamol (FTM-PET). From these, 408 (90.1%) were included in the present study. We used data from two visits (average interval 4.1years) to compute rates of change in weight and cognitive performance. We tested associations between these variables and between weight change and categorical and continuous measures of CSF and neuroimaging AD biomarkers obtained at follow-up. We classified participants with CSF data according to the AT (amyloid, tau) system and assessed between-group differences in weight change.ResultsWeight loss predicted a higher likelihood of positive FTM-PET visual read (OR 1.27, 95% CI 1.00-1.61, p=0.049), abnormal CSF p-tau levels (OR 1.50, 95% CI 1.19-1.89, p=0.001), and an A+T+ profile (OR 1.64, 95% CI 1.25-2.20, p=0.001) and was greater among participants with an A+T+ profile (p<0.01) at follow-up. Weight change was positively associated with CSF A42/40 ratio (beta =0.099, p=0.032) and negatively associated with CSF p-tau (beta=-0.141, p=0.005), t-tau (beta=-0.147 p=0.004) and neurogranin levels (beta=-0.158, p=0.002). In stratified analyses, weight loss was significantly associated with higher t-tau, p-tau, neurofilament light, and neurogranin, as well as faster cognitive decline in A+ participants only.ConclusionsWeight loss predicts AD CSF and PET biomarker results and may occur downstream to amyloid-beta accumulation in preclinical AD, paralleling cognitive decline. Accordingly, it should be considered as an indicator of increased risk of AD-related cognitive impairment.Trial registrationNCT01835717, NCT02485730, NCT02685969.
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| 8. |
- Mila-Aloma, M., et al.
(författare)
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Amyloid beta, tau, synaptic, neurodegeneration, and glial biomarkers in the preclinical stage of the Alzheimer's continuum
- 2020
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 16:10, s. 1358-1371
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The biological pathways involved in the preclinical stage of the Alzheimer's continuum are not well understood. Methods: We used NeuroToolKit and Elecsys (R) immunoassays to measure cerebrospinal fluid (CSF) amyloid-beta (A beta)42, A beta 40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100, and alpha-synuclein in cognitively unimpaired participants of the ALFA+ study, many within the Alzheimer's continuum. Results: CSF t-tau, p-tau, and neurogranin increase throughout aging only in A beta-positive individuals, whereas NfL and glial biomarkers increase with aging regardless of A beta status. We modelled biomarker changes as a function of CSF A beta 42/40, p-tau and p-tau/A beta 42 as proxies of disease progression. The first change observed in the Alzheimer's continuum was a decrease in the CSF A4 beta 42/40 ratio. This is followed by a steep increase in CSF p-tau; t-tau; neurogranin; and, to a lesser extent, in NfL and glial biomarkers. Discussion: Multiple biological pathways are altered and could be targeted very early in the Alzheimer's continuum.
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| 9. |
- Mila-Aloma, M., et al.
(författare)
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Cognitively unimpaired individuals with a low burden of A beta pathology have a distinct CSF biomarker profile
- 2021
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Understanding the changes that occur in the transitional stage between absent and overt amyloid-beta (A beta) pathology within the Alzheimer's continuum is crucial to develop therapeutic and preventive strategies. The objective of this study is to test whether cognitively unimpaired individuals with a low burden of A beta pathology have a distinct CSF, structural, and functional neuroimaging biomarker profile. Methods: Cross-sectional study of 318 middle-aged, cognitively unimpaired individuals from the ALFA+ cohort. We measured CSF A beta 42/40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100B, and alpha-synuclein. Participants also underwent cognitive assessments, APOE genotyping, structural MRI, [F-18]-FDG, and [F-18]-flutemetamol PET. To ensure the robustness of our results, we used three definitions of low burden of A beta pathology: (1) positive CSF A beta 42/40 and < 30 Centiloids in A beta PET, (2) positive CSF A beta 42/40 and negative A beta PET visual read, and (3) 20-40 Centiloid range in A beta PET. We tested CSF and neuroimaging biomarker differences between the low burden group and the corresponding A beta-negative group, adjusted by age and sex. Results: The prevalence and demographic characteristics of the low burden group differed between the three definitions. CSF p-tau and t-tau were increased in the low burden group compared to the A beta-negative in all definitions. CSF neurogranin was increased in the low burden group definitions 1 and 3, while CSF NfL was only increased in the low burden group definition 1. None of the defined low burden groups showed signs of atrophy or glucose hypometabolism. Instead, we found slight increases in cortical thickness and metabolism in definition 2. Conclusions: There are biologically meaningful A beta-downstream effects in individuals with a low burden of A beta pathology, while structural and functional changes are still subtle or absent. These findings support considering individuals with a low burden of A beta pathology for clinical trials.
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| 10. |
- Mila-Aloma, M., et al.
(författare)
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Comparative Analysis of Different Definitions of Amyloid-beta Positivity to Detect Early Downstream Pathophysiological Alterations in Preclinical Alzheimer
- 2021
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Ingår i: Jpad-Journal of Prevention of Alzheimers Disease. - : SERDI. - 2274-5807. ; 8:1, s. 68-77
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta (A beta) positivity is defined using different biomarkers and different criteria. Criteria used in symptomatic patients may conceal meaningful early A beta pathology in preclinical Alzheimer. Therefore, the description of sensitive cutoffs to study the pathophysiological changes in early stages of the Alzheimer'scontinuumis critical. Here, we compare different A beta classification approaches and we show their performance in detecting pathophysiological changes downstream A beta pathology. We studied 368 cognitively unimpaired individuals of the ALFA+ study, many of whom in the preclinical stage of the Alzheimer'scontinuum.Participants underwent A beta PET and CSF biomarkers assessment. We classified participants as A beta -positive using five approaches: (1) CSF A beta 42 < 1098 pg/ml; (2) CSF A beta 42/40 < 0.071; (3) A beta PET Centiloid > 12; (4) A beta PET Centiloid > 30 or (5) A beta PET Positive visual read. We assessed the correlations between A beta biomarkers and compared the prevalence of A beta positivity. We determined which approach significantly detected associations between A beta pathology and tau/neurodegeneration CSF biomarkers. We found that CSF-based approaches result in a higher A beta-positive prevalence than PET-based ones. There was a higher number of discordant participants classified as CSF A beta-positive but PET A beta-negative than CSF A beta-negative but PET A beta-positive. The CSF A beta 42/40 approach allowed optimal detection of significant associations with CSF p-tau and t-tau in the A beta-positive group. Altogether, we highlight the need for sensitive A beta -classifications to study the preclinical Alzheimer'scontinuumApproaches that define A beta positivity based on optimal discrimination of symptomatic Alzheimer's disease patients may be suboptimal for the detection of early pathophysiological alterations in preclinical Alzheimer.
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| 11. |
- Salvado, G., et al.
(författare)
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Centiloid cut-off values for optimal agreement between PET and CSF core AD biomarkers
- 2019
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Ingår i: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe Centiloid scale has been developed to standardize measurements of amyloid PET imaging. Reference cut-off values of this continuous measurement enable the consistent operationalization of decision-making for multicentre research studies and clinical trials. In this study, we aimed at deriving reference Centiloid thresholds that maximize the agreement against core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in two large independent cohorts.MethodsA total of 516 participants of the ALFA+ Study (N=205) and ADNI (N=311) underwent amyloid PET imaging ([F-18]flutemetamol and [F-18]florbetapir, respectively) and core AD CSF biomarker determination using Elecsys (R) tests. Tracer uptake was quantified in Centiloid units (CL). Optimal Centiloid cut-offs were sought that maximize the agreement between PET and dichotomous determinations based on CSF levels of A(42), tTau, pTau, and their ratios, using pre-established reference cut-off values. To this end, a receiver operating characteristic analysis (ROC) was conducted, and Centiloid cut-offs were calculated as those that maximized the Youden's J Index or the overall percentage agreement recorded.ResultsAll Centiloid cut-offs fell within the range of 25-35, except for CSF A(42) that rendered an optimal cut-off value of 12 CL. As expected, the agreement of tau/A(42) ratios was higher than that of CSF A(42). Centiloid cut-off robustness was confirmed even when established in an independent cohort and against variations of CSF cut-offs.ConclusionsA cut-off of 12 CL matches previously reported values derived against postmortem measures of AD neuropathology. Together with these previous findings, our results flag two relevant inflection points that would serve as boundary of different stages of amyloid pathology: one around 12 CL that marks the transition from the absence of pathology to subtle pathology and another one around 30 CL indicating the presence of established pathology. The derivation of robust and generalizable cut-offs for core AD biomarkers requires cohorts with adequate representation of intermediate levels.Trial registrationALFA+ Study, NCT02485730ALFA PET Sub-study, NCT02685969
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| 12. |
- Agarwalla, S.K., et al.
(författare)
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EUROnu-WP6 2010 Report
- 2012
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This is a summary of the work done by the Working Package 6 (Physics) of the EU project "EUROnu" during the second year of activity of the project.
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| 13. |
- Carey, L. M., et al.
(författare)
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STroke imAging pRevention and treatment (START): A longitudinal stroke cohort study: Clinical trials protocol
- 2015
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Ingår i: International Journal of Stroke. - : SAGE Publications. - 1747-4930 .- 1747-4949. ; 10:4, s. 636-644
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Tidskriftsartikel (refereegranskat)abstract
- RationaleStroke and poststroke depression are common and have a profound and ongoing impact on an individual's quality of life. However, reliable biological correlates of poststroke depression and functional outcome have not been well established in humans. AimsOur aim is to identify biological factors, molecular and imaging, associated with poststroke depression and recovery that may be used to guide more targeted interventions. DesignIn a longitudinal cohort study of 200 stroke survivors, the START - STroke imAging pRevention and Treatment cohort, we will examine the relationship between gene expression, regulator proteins, depression, and functional outcome. Stroke survivors will be investigated at baseline, 24h, three-days, three-months, and 12 months poststroke for blood-based biological associates and at days 3-7, three-months, and 12 months for depression and functional outcomes. A sub-group (n=100), the PrePARE: Prediction and Prevention to Achieve optimal Recovery Endpoints after stroke cohort, will also be investigated for functional and structural changes in putative depression-related brain networks and for additional cognition and activity participation outcomes. Stroke severity, diet, and lifestyle factors that may influence depression will be monitored. The impact of depression on stroke outcomes and participation in previous life activities will be quantified. Study OutcomesClinical significance lies in the identification of biological factors associated with functional outcome to guide prevention and inform personalized and targeted treatments. Evidence of associations between depression, gene expression and regulator proteins, functional and structural brain changes, lifestyle and functional outcome will provide new insights for mechanism-based models of poststroke depression.
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| 14. |
- Lessa Benedet, Andréa, et al.
(författare)
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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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Ingår i: Jama Neurology. - : American Medical Association (AMA). - 2168-6149. ; 78:12, s. 1471-1483
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Tidskriftsartikel (refereegranskat)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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| 15. |
- Arenaza-Urquijo, E. M., et al.
(författare)
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Association of years to parent's sporadic onset and risk factors with neural integrity and Alzheimer biomarkers
- 2020
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 95:15
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Tidskriftsartikel (refereegranskat)abstract
- Objective To evaluate the hypothesis that proximity to parental age at onset (AAO) in sporadic Alzheimer disease (AD) is associated with greater AD and neural injury biomarker alterations during midlife and to assess the role of nonmodifiable and modifiable factors. Methods This observational study included 290 cognitively unimpaired (CU) participants with a family history (FH) of clinically diagnosed sporadic AD (age 49-73 years) from the Alzheimer's and Families (ALFA) study. [F-18]flutemetamol-PET standardized uptake value ratios, CSF beta-amyloid(42/40) ratio, and phosphorylated tau were used as AD biomarkers. Hippocampal volumes and CSF total tau were used as neural injury biomarkers. Mental and vascular health proxies were calculated. In multiple regression models, we assessed the effect of proximity to parental AAO and its interaction with age on AD and neural injury biomarkers. Then, we evaluated the effects of FH load (number of parents affected), sex, APOE epsilon 4, education, and vascular and mental health. Results Proximity to parental AAO was associated with beta-amyloid, but not with neural injury biomarkers, and interacted with sex and age, showing that women and older participants had increased beta-amyloid. FH load and APOE epsilon 4 showed independent contributions to beta-amyloid load. Education and vascular and mental health proxies were not associated with AD biomarkers. However, lower mental health proxies were associated with decreased hippocampal volumes with age. Conclusion The identification of the earliest biomarker changes and modifiable factors to be targeted in early interventions is crucial for AD prevention. Proximity to parental AAO may offer a timeline for detection of incipient beta-amyloid changes in women. In risk-enriched middle-aged cohorts, mental health may be a target for early interventions.
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| 16. |
- Cacciaglia, R., et al.
(författare)
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Age, sex and APOE-epsilon 4 modify the balance between soluble and fibrillar beta-amyloid in non-demented individuals: topographical patterns across two independent cohorts
- 2022
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 27, s. 2010-2018
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid (A beta) pathology is the earliest detectable pathophysiological event along the Alzheimer's continuum, which can be measured both in the cerebrospinal fluid (CSF) and by Positron Emission Tomography (PET). Yet, these biomarkers identify two distinct A beta pools, reflecting the clearance of soluble A beta as opposed to the presence of A beta fibrils in the brain. An open question is whether risk factors known to increase Alzheimer's' disease (AD) prevalence may promote an imbalance between soluble and deposited A beta. Unveiling such interactions shall aid our understanding of the biological pathways underlying A beta deposition and foster the design of effective prevention strategies. We assessed the impact of three major AD risk factors, such as age, APOE-epsilon 4 and female sex, on the association between CSF and PET A beta, in two independent samples of non-demented individuals (ALFA: n = 320, ADNI: n = 682). We tested our hypotheses both in candidate regions of interest and in the whole brain using voxel-wise non-parametric permutations. All of the assessed risk factors induced a higher A beta deposition for any given level of CSF A beta 42/40, although in distinct cerebral topologies. While age and sex mapped onto neocortical areas, the effect of APOE-epsilon 4 was prominent in the medial temporal lobe, which represents a target of early tau deposition. Further, we found that the effects of age and APOE-epsilon 4 was stronger in women than in men. Our data indicate that specific AD risk factors affect the spatial patterns of cerebral A beta aggregation, with APOE-epsilon 4 possibly facilitating a co-localization between A beta and tau along the disease continuum.
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| 17. |
- Cacciaglia, R, et al.
(författare)
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Age, sex and APOE-ε4 modify the balance between soluble and fibrillar β-amyloid in non-demented individuals: topographical patterns across two independent cohorts
- 2022
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 27:4, s. 2010-2018
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid (Aβ) pathology is the earliest detectable pathophysiological event along the Alzheimer’s continuum, which can be measured both in the cerebrospinal fluid (CSF) and by Positron Emission Tomography (PET). Yet, these biomarkers identify two distinct Aβ pools, reflecting the clearance of soluble Aβ as opposed to the presence of Aβ fibrils in the brain. An open question is whether risk factors known to increase Alzheimer’s’ disease (AD) prevalence may promote an imbalance between soluble and deposited Aβ. Unveiling such interactions shall aid our understanding of the biological pathways underlying Aβ deposition and foster the design of effective prevention strategies. We assessed the impact of three major AD risk factors, such as age, APOE-ε4 and female sex, on the association between CSF and PET Aβ, in two independent samples of non-demented individuals (ALFA: n = 320, ADNI: n = 682). We tested our hypotheses both in candidate regions of interest and in the whole brain using voxel-wise non-parametric permutations. All of the assessed risk factors induced a higher Aβ deposition for any given level of CSF Aβ42/40, although in distinct cerebral topologies. While age and sex mapped onto neocortical areas, the effect of APOE-ε4 was prominent in the medial temporal lobe, which represents a target of early tau deposition. Further, we found that the effects of age and APOE-ε4 was stronger in women than in men. Our data indicate that specific AD risk factors affect the spatial patterns of cerebral Aβ aggregation, with APOE-ε4 possibly facilitating a co-localization between Aβ and tau along the disease continuum.
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| 18. |
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| 19. |
- Mila-Aloma, M., et al.
(författare)
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Plasma p-tau231 and p-tau217 as state markers of amyloid-beta pathology in preclinical Alzheimer's disease
- 2022
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 28, s. 1797-1801
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Tidskriftsartikel (refereegranskat)abstract
- A comprehensive comparison of Alzheimer's disease blood biomarkers in cognitively unimpaired individuals reveals that plasma p-tau231 and p-tau217 capture very early A beta changes, showing promise as markers to enrich a preclinical population for Alzheimer's disease clinical trials Blood biomarkers indicating elevated amyloid-beta (A beta) pathology in preclinical Alzheimer's disease are needed to facilitate the initial screening process of participants in disease-modifying trials. Previous biofluid data suggest that phosphorylated tau231 (p-tau231) could indicate incipient A beta pathology, but a comprehensive comparison with other putative blood biomarkers is lacking. In the ALFA+ cohort, all tested plasma biomarkers (p-tau181, p-tau217, p-tau231, GFAP, NfL and A beta 42/40) were significantly changed in preclinical Alzheimer's disease. However, plasma p-tau231 reached abnormal levels with the lowest A beta burden. Plasma p-tau231 and p-tau217 had the strongest association with A beta positron emission tomography (PET) retention in early accumulating regions and associated with longitudinal increases in A beta PET uptake in individuals without overt A beta pathology at baseline. In summary, plasma p-tau231 and p-tau217 better capture the earliest cerebral A beta changes, before overt A beta plaque pathology is present, and are promising blood biomarkers to enrich a preclinical population for Alzheimer's disease clinical trials.
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| 20. |
- Reynolds, A., et al.
(författare)
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Evidence-based European recommendations for the dietary management of diabetes
- 2023
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Ingår i: Diabetologia. - 0012-186X. ; 66:6, s. 965-985
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Tidskriftsartikel (refereegranskat)abstract
- Diabetes management relies on effective evidence-based advice that informs and empowers individuals to manage their health. Alongside other cornerstones of diabetes management, dietary advice has the potential to improve glycaemic levels, reduce risk of diabetes complications and improve health-related quality of life. We have updated the 2004 recommendations for the nutritional management of diabetes to provide health professionals with evidence-based guidelines to inform discussions with patients on diabetes management, including type 2 diabetes prevention and remission. To provide this update we commissioned new systematic reviews and meta-analyses on key topics, and drew on the broader evidence available. We have strengthened and expanded on the previous recommendations to include advice relating to dietary patterns, environmental sustainability, food processing, patient support and remission of type 2 diabetes. We have used the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach to determine the certainty of evidence for each recommendation based on findings from the commissioned and identified systematic reviews. Our findings indicate that a range of foods and dietary patterns are suitable for diabetes management, with key recommendations for people with diabetes being largely similar for those for the general population. Important messages are to consume minimally processed plant foods, such as whole grains, vegetables, whole fruit, legumes, nuts, seeds and non-hydrogenated non-tropical vegetable oils, while minimising the consumption of red and processed meats, sodium, sugar-sweetened beverages and refined grains. The updated recommendations reflect the current evidence base and, if adhered to, will improve patient outcomes.
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| 21. |
- Salvado, G., et al.
(författare)
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Brain alterations in the early Alzheimer's continuum with amyloid-beta, tau, glial and neurodegeneration CSF markers
- 2022
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Ingår i: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 4:3
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Tidskriftsartikel (refereegranskat)abstract
- Higher grey matter volumes/cortical thickness and fluorodeoxyglucose uptake have been consistently found in cognitively unimpaired individuals with abnormal Alzheimer's disease biomarkers compared with those with normal biomarkers. It has been hypothesized that such transient increases may be associated with neuroinflammatory mechanisms triggered in response to early Alzheimer's pathology. Here, we evaluated, in the earliest stages of the Alzheimer's continuum, associations between grey matter volume and fluorodeoxyglucose uptake with CSF biomarkers of several pathophysiological mechanisms known to be altered in preclinical Alzheimer's disease stages. We included 319 cognitively unimpaired participants from the ALFA+ cohort with available structural MRI, fluorodeoxyglucose PET and CSF biomarkers of amyloid-beta and tau pathology (phosphorylated tau and total tau), synaptic dysfunction (neurogranin), neuronal and axonal injury (neurofilament light), glial activation (soluble triggering receptor on myeloid cells 2, YKL40, GFAP, interleukin-6 and S100b) and alpha-synuclein using the Roche NeuroToolKit. We first used the amyloid-beta/tau framework to investigate differences in the neuroimaging biomarkers between preclinical Alzheimer's disease stages. Then, we looked for associations between the neuroimaging markers and all the CSF markers. Given the non-negative nature of the concentrations of CSF biomarkers and their high collinearity, we clustered them using non-negative matrix factorization approach (components) and sought associations with the imaging markers. By groups, higher grey matter volumes were found in the amyloid-beta-positive tau-negative participants with respect to the reference amyloid-beta-negative tau-negative group. Both amyloid-beta and tau-positive participants showed higher fluorodeoxyglucose uptake than tau-negative individuals. Using the obtained components, we observed that tau pathology accompanied by YKL-40 (astrocytic marker) was associated with higher grey matter volumes and fluorodeoxyglucose uptake in extensive brain areas. Higher grey matter volumes in key Alzheimer-related regions were also found in association with two other components characterized by a higher expression of amyloid-beta in combination with different glial markers: one with higher GFAP and S100b levels (astrocytic markers) and the other one with interleukin-6 (pro-inflammatory). Notably, these components' expression had different behaviours across amyloid-beta/tau stages. Taken together, our results show that CSF amyloid-beta and phosphorylated tau, in combination with different aspects of glial response, have distinctive associations with higher grey matter volumes and increased glucose metabolism in key Alzheimer-related regions. These mechanisms combine to produce transient higher grey matter volumes and fluorodeoxyglucose uptake at the earliest stages of the Alzheimer's continuum, which may revert later on the course of the disease when neurodegeneration drives structural and metabolic cerebral changes. Salvado et al. show that amyloid-beta and tau pathologies, in combination with different aspects of glial response, have distinctive associations with brain's structure and function in key Alzheimer-related regions. These mechanisms combine to produce transient higher grey matter volumes and glucose metabolism at the earliest stages of the Alzheimer's continuum.
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| 22. |
- Salvado, G., et al.
(författare)
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Reactive astrogliosis is associated with higher cerebral glucose consumption in the early Alzheimer's continuum
- 2022
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 49, s. 4567-4579
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Glial activation is one of the earliest mechanisms to be altered in Alzheimer's disease (AD). Glial fibrillary acidic protein (GFAP) relates to reactive astrogliosis and can be measured in both cerebrospinal fluid (CSF) and blood. Plasma GFAP has been suggested to become altered earlier in AD than its CSF counterpart. Although astrocytes consume approximately half of the glucose-derived energy in the brain, the relationship between reactive astrogliosis and cerebral glucose metabolism is poorly understood. Here, we aimed to investigate the association between fluorodeoxyglucose ([F-18]FDG) uptake and reactive astrogliosis, by means of GFAP quantified in both plasma and CSF for the same participants. Methods We included 314 cognitively unimpaired participants from the ALFA + cohort, 112 of whom were amyloid-beta (A beta) positive. Associations between GFAP markers and [F-18]FDG uptake were studied. We also investigated whether these associations were modified by A beta and tau status (AT stages). Results Plasma GFAP was positively associated with glucose consumption in the whole brain, while CSF GFAP associations with [F-18]FDG uptake were only observed in specific smaller areas like temporal pole and superior temporal lobe. These associations persisted when accounting for biomarkers of A beta pathology but became negative in A beta-positive and tau-positive participants (A + T +) in similar areas of AD-related hypometabolism. Conclusions Higher astrocytic reactivity, probably in response to early AD pathological changes, is related to higher glucose consumption. With the onset of tau pathology, the observed uncoupling between astrocytic biomarkers and glucose consumption might be indicative of a failure to sustain the higher energetic demands required by reactive astrocytes.
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| 23. |
- Brugulat-Serrat, Anna, et al.
(författare)
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APOE -ε4 modulates the association between regional amyloid deposition and cognitive performance in cognitively unimpaired middle-aged individuals
- 2023
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To determine whether the APOE-ε4 allele modulates the relationship between regional β-amyloid (Aβ) accumulation and cognitive change in middle-aged cognitively unimpaired (CU) participants. Methods: The 352 CU participants (mean aged 61.1 [4.7] years) included completed two cognitive assessments (average interval 3.34 years), underwent [18F]flutemetamol Aβ positron emission tomography (PET), T1w magnetic resonance imaging (MRI), as well as APOE genotyping. Global and regional Aβ PET positivity was assessed across five regions-of-interest by visual reading (VR) and regional Centiloids. Linear regression models were developed to examine the interaction between regional and global Aβ PET positivity and APOE-ε4 status on longitudinal cognitive change assessed with the Preclinical Alzheimer’s Cognitive Composite (PACC), episodic memory, and executive function, after controlling for age, sex, education, cognitive baseline scores, and hippocampal volume. Results: In total, 57 participants (16.2%) were VR+ of whom 41 (71.9%) were APOE-ε4 carriers. No significant APOE-ε4*global Aβ PET interactions were associated with cognitive change for any cognitive test. However, APOE-ε4 carriers who were VR+ in temporal areas (n = 19 [9.81%], p = 0.04) and in the striatum (n = 8 [4.14%], p = 0.01) exhibited a higher decline in the PACC. The temporal areas findings were replicated when regional PET positivity was determined with Centiloid values. Regionally, VR+ in the striatum was associated with higher memory decline. As for executive function, interactions between APOE-ε4 and regional VR+ were found in temporal and parietal regions, and in the striatum. Conclusion: CU APOE-ε4 carriers with a positive Aβ PET VR in regions known to accumulate amyloid at later stages of the Alzheimer’s disease (AD) continuum exhibited a steeper cognitive decline. This work supports the contention that regional VR of Aβ PET might convey prognostic information about future cognitive decline in individuals at higher risk of developing AD. ClinicalTrials.gov Identifier: NCT02485730. Registered 20 June 2015 https://clinicaltrials.gov/ct2/show/NCT02485730 and ClinicalTrials.gov Identifier:NCT02685969. Registered 19 February 2016 https://clinicaltrials.gov/ct2/show/NCT02685969.
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| 24. |
- Collij, Lyduine E., et al.
(författare)
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Spatial-Temporal Patterns of beta-Amyloid Accumulation A Subtype and Stage Inference Model Analysis
- 2022
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 98:17, s. E1692-E1703
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives beta-amyloid (A beta) staging models assume a single spatial-temporal progression of amyloid accumulation. We assessed evidence for A beta accumulation subtypes by applying the data-driven Subtype and Stage Inference (SuStaIn) model to amyloid-PET data. Methods Amyloid-PET data of 3,010 participants were pooled from 6 cohorts (ALFA+, EMIF-AD, ABIDE, OASIS, and ADNI). Standardized uptake value ratios were calculated for 17 regions. We applied the SuStaIn algorithm to identify consistent subtypes in the pooled dataset based on the cross-validation information criterion and the most probable subtype/stage classification per scan. The effects of demographics and risk factors on subtype assignment were assessed using multinomial logistic regression. Results Participants were mostly cognitively unimpaired (n = 1890 [62.8%]), had a mean age of 68.72 (SD 9.1) years, 42.1% were APOE epsilon 4 carriers, and 51.8% were female. A 1-subtype model recovered the traditional amyloid accumulation trajectory, but SuStaIn identified 3 optimal subtypes, referred to as frontal, parietal, and occipital based on the first regions to show abnormality. Of the 788 (26.2%) with strong subtype assignment (>50% probability), the majority was assigned to frontal (n = 415 [52.5%]), followed by parietal (n = 199 [25.3%]) and occipital subtypes (n = 175 [22.2%]). Significant differences across subtypes included distinct proportions of APOE epsilon 4 carriers (frontal 61.8%, parietal 57.1%, occipital 49.4%), participants with dementia (frontal 19.7%, parietal 19.1%, occipital 31.0%), and lower age for the parietal subtype (frontal/occipital 72.1 years, parietal 69.3 years). Higher amyloid (Centiloid) and CSF p-tau burden was observed for the frontal subtype; parietal and occipital subtypes did not differ. At follow-up, most participants (81.1%) maintained baseline subtype assignment and 25.6% progressed to a later stage. Discussion Whereas a 1-trajectory model recovers the established pattern of amyloid accumulation, SuStaIn determined that 3 subtypes were optimal, showing distinct associations with Alzheimer disease risk factors. Further analyses to determine clinical utility are warranted.
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| 25. |
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