| 1. |
- de Rojas, I., et al.
(author)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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| 6. |
- Bellenguez, C, et al.
(author)
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New insights into the genetic etiology of Alzheimer's disease and related dementias
- 2022
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:4, s. 412-436
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Journal article (peer-reviewed)abstract
- Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
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| 7. |
- Botvinik-Nezer, Rotem, et al.
(author)
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Variability in the analysis of a single neuroimaging dataset by many teams
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 582, s. 84-88
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Journal article (peer-reviewed)abstract
- Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses(1). The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset(2-5). Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed. The results obtained by seventy different teams analysing the same functional magnetic resonance imaging dataset show substantial variation, highlighting the influence of analytical choices and the importance of sharing workflows publicly and performing multiple analyses.
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| 9. |
- Borghesi, M., et al.
(author)
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Progress in proton radiography for diagnosis of ICF-relevant plasmas
- 2010
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In: Laser and particle beams (Print). - 0263-0346 .- 1469-803X. ; 28:2, s. 277-284
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Journal article (peer-reviewed)abstract
- Proton radiography using laser-driven sources has been developed as a diagnostic since the beginning of the decade, and applied successfully to a range of experimental situations. Multi-MeV protons driven from thin foils via the Target Normal Sheath Acceleration mechanism, offer, under optimal conditions, the possibility of probing laser-plasma interactions, and detecting electric and magnetic fields as well as plasma density gradients with similar to ps temporal resolution and similar to 5-10 mu m spatial resolution. In view of these advantages, the use of proton radiography as a diagnostic in experiments of relevance to Inertial Confinement Fusion is currently considered in the main fusion laboratories. This paper will discuss recent advances in the application of laser-driven radiography to experiments of relevance to Inertial Confinement Fusion. In particular we will discuss radiography of hohlraum and gasbag targets following the interaction of intense ns pulses. These experiments were carried out at the HELEN laser facility at AWE (UK), and proved the suitability of this diagnostic for studying, with unprecedented detail, laser-plasma interaction mechanisms of high relevance to Inertial Confinement Fusion. Non-linear solitary structures of relevance to space physics, namely phase space electron holes, have also been highlighted by the measurements. These measurements are discussed and compared to existing models.
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| 11. |
- Mangialasche, Francesca, et al.
(author)
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Classification and prediction of clinical diagnosis of Alzheimer's disease based on MRI and plasma measures of α-/γ-tocotrienols and γ-tocopherol.
- 2013
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 273:6, s. 602-621
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Journal article (peer-reviewed)abstract
- Background: The aim of this study was to evaluate the accuracy of combined structural magnetic resonance imaging (MRI) measures and plasma levels of vitamin E forms, including all eight natural vitamin E congeners (four tocopherols and four tocotrienols) and markers of vitamin E oxidative/nitrosative damage, in differentiating individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI) from cognitively intact control (CTL) subjects.Methods: Overall, 81 patients with AD, 86 with MCI and 86 CTL individuals were enrolled from the longitudinal multicentre AddNeuroMed study. MRI and plasma vitamin E data were acquired at baseline. MRI scans were analysed using Freesurfer, an automated segmentation scheme which generates regional volume and cortical thickness measures. Orthogonal partial least squares to latent structures (OPLS), a multivariate data analysis technique, was used to analyse MRI and vitamin E measures in relation to AD and MCI diagnosis.Results: The joint evaluation of MRI and plasma vitamin E measures enhanced the accuracy of differentiating individuals with AD and MCI from CTL subjects: 98.2% (sensitivity 98.8%, specificity 97.7%) for AD versus CTL, and 90.7% (sensitivity 91.8%, specificity 89.5%) for MCI versus CTL. This combination of measures also identified 85% of individuals with MCI who converted to clinical AD at follow-up after 1 year.Conclusions: Plasma levels of tocopherols and tocotrienols together with automated MRI measures can help to differentiate AD and MCI patients from CTL subjects, and to prospectively predict MCI conversion into AD. Our results suggest the potential role of nutritional biomarkers detected in plasma–tocopherols and tocotrienols–as indirect indicators of AD pathology, and the utility of a multimodality approach.
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| 14. |
- Boccardi, V, et al.
(author)
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Metabolic Score for Insulin Resistance (METS-IR) and Circulating Cytokines in Older Persons: The Role of Gender and Body Mass Index
- 2022
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In: Nutrients. - : MDPI AG. - 2072-6643. ; 14:15
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Journal article (peer-reviewed)abstract
- Background: Inflammation, along with aging processes, contributes to the development of insulin resistance (IR), but the roles of different inflammatory and other cytokines in this process remain unclear. Thus, we aimed to analyze the association between several plasma cytokines with IR as evaluated by the metabolic score for insulin resistance, METS-IR. Methods: We measured the plasma concentrations of thirty cytokines from a cohort of older persons and analyzed their role as independent factors for IR. We used regression analyses adjusted for known IR-associated factors (including age, gender, cholesterol levels, and BMI) to find the determinants of IR. Results: The study evaluated 132 subjects, mostly women (82F/50M), slightly overweight, and with a mean age of 78.5 ± 6.5 years. In the overall population, IL-15 significantly and negatively correlates with METS-IR (r = −0.183, p = 0.036). A regression model showed that the association between IL-15 and METS-IR was significantly modulated by gender and BMI (R2: 0.831). Only in women, EGF, Eotaxin and MCP-1 significantly correlated with METS-IR even after controlling by age (EGF, r = 0.250 p = 0.025; Eotaxin, r = 0.276 p = 0.13; MCP-1, r = 0.237, p = 0.033). Furthermore, regression models showed that these molecules were associated with METS-IR and were strongly mediated by BMI. Conclusions: Our results indicate the association between cytokines and IR has to be interpreted in a gender-specific manner. In women, EGF, Eotaxin, and MCP-1 circulating levels are associated with METS-IR being BMI a significant mediator. Understanding the role of gender in the relationship between cytokines and IR will help to define individualized preventive and treatment interventions to reduce the risk of age-related metabolic disorders.
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| 15. |
- Boccardi, V, et al.
(author)
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miRNAs and Alzheimer's Disease: Exploring the Role of Inflammation and Vitamin E in an Old-Age Population
- 2023
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In: Nutrients. - : MDPI AG. - 2072-6643. ; 15:3
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Journal article (peer-reviewed)abstract
- Alzheimer’s disease (AD) is the most frequent cause of dementia worldwide and represents one of the leading factors for severe disability in older persons. Although its etiology is not fully known yet, AD may develop due to multiple factors, including inflammation and oxidative stress, conditions where microRNAs (miRNAs) seem to play a pivotal role as a molecular switch. All these aspects may be modulated by nutritional factors. Among them, vitamin E has been widely studied in AD, given the plausibility of its various biological functions in influencing neurodegeneration. From a cohort of old-aged people, we measured eight vitamin E forms (tocopherols and tocotrienols), thirty cytokines/chemokines, and thirteen exosome-extracted miRNAs in plasma of subjects suffering from subjects affected by AD and age-matched healthy controls (HC). The sample population included 80 subjects (40 AD and 40 HC) with a mean age of 77.6 ± 3.8 years, mostly women (45; 56.2%). Of the vitamin E forms, only α-tocopherol differed between groups, with significantly lower levels in AD. Regarding the examined inflammatory molecules, G-CSF, GM-CSF, INF-α2, IL-3, and IL-8 were significantly higher and IL-17 lower in AD than HC. Among all miRNAs examined, AD showed downregulation of miR-9, miR-21, miR29-b, miR-122, and miR-132 compared to controls. MiR-122 positively and significantly correlated with some inflammatory molecules (GM-CSF, INF-α2, IL-1α, IL-8, and MIP-1β) as well as with α-tocopherol even after correction for age and gender. A final binary logistic regression analysis showed that α-tocopherol serum levels were associated with a higher AD probability and partially mediated by miR-122. Our results suggest an interplay between α-tocopherol, inflammatory molecules, and microRNAs in AD, where miR-122 may be a good candidate as modulating factor.
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| 17. |
- Flex, Elisabetta, et al.
(author)
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Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis
- 2014
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:16, s. 4315-4327
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Journal article (peer-reviewed)abstract
- RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2(S2G) mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease.
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| 19. |
- Polidori, M. C., et al.
(author)
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Association of increased carotid intima-media thickness and lower plasma levels of vitamin C and vitamin E in old age subjects : implications for Alzheimer's disease
- 2015
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In: Journal of neural transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 122:4, s. 523-530
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Journal article (peer-reviewed)abstract
- In light of the recent advances regarding the role of vascularity in Alzheimer's disease (AD) pathophysiology, the relationship between plasma levels and activities of the major antioxidant molecules and the carotid intima-media thickness (C-IMT) of older persons with no or very mild cognitive impairment was evaluated. The underlying hypothesis is that the IMT may be an indirect index of vascular damage in persons with low levels of plasma antioxidants. Plasma levels of vitamins A, C, E, of uric acid as well as activities of the plasma antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) were measured. Plasma levels of vitamins C and E significantly decreased among participants from the first to the fourth IMT quartile, with a linear slope only for vitamin C. Compared to participants in the lowest vitamin C quartile, the probability to have IMT > 1.2 mm significantly decreased among persons from the second to the fourth quartile independent of confounders. In conclusion, only vitamin C plasma levels appear to be selectively associated with the risk of increasing C-IMT. An adequate vitamin C status might be particularly important for protection against AD and other clinical manifestations of vascular and cognitive ageing.
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| 20. |
- Sarri, Gianluca, et al.
(author)
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Observation and characterization of laser-driven phasespace electron holes
- 2010
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In: Physics of Plasmas. - : AIP Publishing. - 1070-664X .- 1089-7674. ; 17:1, s. 010701-
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Journal article (peer-reviewed)abstract
- The direct observation and full characterization of a phase space electron hole (EH) generated during laser-matter interaction is presented. This structure, propagating in a tenuous, nonmagnetized plasma, has been detected via proton radiography during the irradiation with a ns laser pulse (I21014 W/cm2) of a gold hohlraum. This technique has allowed the simultaneous detection of propagation velocity, potential, and electron density spatial profile across the EH with fine spatial and temporal resolution allowing a detailed comparison with theoretical and numerical models.
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| 21. |
- Sarri, G, et al.
(author)
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The application of laser-driven proton beams to the radiography of intense laser–hohlraum interactions
- 2010
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In: New Journal of Physics. - : IOP Publishing Ltd. - 1367-2630. ; 12:4, s. 045006-
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Journal article (peer-reviewed)abstract
- Plasma expansion following the interaction of an intense laser beam with the inner surface of gold hohlraums, emulating conditions relevant to indirect drive inertial confinement fusion (ICF), has been investigated by a radiographic technique which employs a beam of laser-accelerated protons. This probing technique has made it possible to measure the electric field distribution associated with the plasma front and its propagation throughout the interior of the hohlraum with a temporal and spatial resolution of the order of a few ps and μm, respectively. The data indicate that the expanding plasma slows down approaching the opposite walls, possibly due to the interaction with x-ray heated plasma from the non-irradiated walls. The electric field at the plasma front shows a bipolar structure, suggesting the presence of ion-acoustic soliton-like structures cotraveling with the front. Data obtained using enclosed hohlraums suggest the feasibility of this type of diagnosis in gas-filled hohlraums, as currently employed in ICF experiments.
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