| 1. |
- Jansen, Iris E, et al.
(author)
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Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.
- 2022
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In: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 144:5, s. 821-842
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Journal article (peer-reviewed)abstract
- Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n=8074; replication n=5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
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| 2. |
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| 3. |
- Bergström, Sofia, et al.
(author)
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A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers : a GENFI study
- 2021
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In: Molecular Neurodegeneration. - : Springer Nature. - 1750-1326. ; 16:1
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Journal article (peer-reviewed)abstract
- Background A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD.
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| 5. |
- Bussy, Aurélie, et al.
(author)
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Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia
- 2023
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In: Human Brain Mapping. - : Wiley. - 1065-9471 .- 1097-0193. ; 44:7, s. 2684-2700
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Journal article (peer-reviewed)abstract
- Recent studies have reported early cerebellar and subcortical impact in the disease progression of genetic frontotemporal dementia (FTD) due to microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72). However, the cerebello-subcortical circuitry in FTD has been understudied despite its essential role in cognition and behaviors related to FTD symptomatology. The present study aims to investigate the association between cerebellar and subcortical atrophy, and neuropsychiatric symptoms across genetic mutations. Our study included 983 participants from the Genetic Frontotemporal dementia Initiative including mutation carriers and noncarrier first-degree relatives of known symptomatic carriers. Voxel-wise analysis of the thalamus, striatum, globus pallidus, amygdala, and the cerebellum was performed, and partial least squares analyses (PLS) were used to link morphometry and behavior. In presymptomatic C9orf72 expansion carriers, thalamic atrophy was found compared to noncarriers, suggesting the importance of this structure in FTD prodromes. PLS analyses demonstrated that the cerebello-subcortical circuitry is related to neuropsychiatric symptoms, with significant overlap in brain/behavior patterns, but also specificity for each genetic mutation group. The largest differences were in the cerebellar atrophy (larger extent in C9orf72 expansion group) and more prominent amygdalar volume reduction in the MAPT group. Brain scores in the C9orf72 expansion carriers and MAPT carriers demonstrated covariation patterns concordant with atrophy patterns detectable up to 20 years before expected symptom onset. Overall, these results demonstrated the important role of the subcortical structures in genetic FTD symptom expression, particularly the cerebellum in C9orf72 and the amygdala in MAPT carriers.
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| 6. |
- Esteve-Raventos, Fernando, et al.
(author)
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A Taxonomic and Phylogenetic Contribution on Inosperma Section Inosperma (Agaricales, Inocybaceae) in Europe: Calamistratum and Geraniodorum Groups
- 2024
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In: JOURNAL OF FUNGI. - 2309-608X. ; 10:6
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Journal article (peer-reviewed)abstract
- The aim of this study is to carry out a taxonomic revision of the groups Calamistratum and Geraniodorum of the genus Inosperma sect. Inosperma in Europe. For this purpose, a multigenic phylogenetic analysis was carried out using the ITS, LSU, RPB1 and RPB2 markers, covering a total of 111 sequences, including those generated from the existing type-material collections. This analysis led to the recognition of nine clades or terminal groups for the European continent, correlating with nine morphological species. Three of them, I. calamistratum, I. neohirsutum sp. nov. and I. turietoense sp. nov., are distributed in humid and temperate forests, whereas I. geminum sp. nov., I. geraniodorum, I. gracilentum sp. nov., I. praetermissum comb. nov., I. subhirsutum and I. veliferum seem to be restricted to the colder altimontane, boreal and alpine climates. It is concluded that the study of morphological and ecological characteristics allows the recognition of species without the need for an often-subjective interpretation of organoleptic characteristics. Inocybe hirsuta is considered a synonym of Inosperma calamistratum, Inosperma praetermissum as a different species from I. calamistratum, and Inocybe geraniodora var. gracilenta f. salicis-herbaceae as a synonym of I. praetermissum. Four new species and one new combination are proposed. A key for the recognition of the European species is provided. Illustrations and photographs of macro- and micromorphological characters and SEM spores of all species are presented.
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| 7. |
- Guzman-Parra, Jose, et al.
(author)
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Attitudes and use of information and communication technologies in older adults with mild cognitive impairment or early stages of dementia and their caregivers : cross-sectional study
- 2020
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In: Journal of Medical Internet Research. - : JMIR Publications. - 1438-8871. ; 22:6
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Journal article (peer-reviewed)abstract
- BACKGROUND: Information and communication technologies are promising tools to increase the quality of life of people with dementia or mild cognitive impairment and that of their caregivers. However, there are barriers to their use associated with sociodemographic factors and negative attitudes, as well as inadequate knowledge about technologies. OBJECTIVE: The aim of this study was to analyze technophilia (attitudes toward new technologies) and the use of smartphones and tablets along with associated factors in people with dementia/mild cognitive impairment and their caregivers. METHODS: Data from the first visit of the Support Monitoring and Reminder for Mild Dementia (SMART4MD) randomized multicenter clinical trial were used for this analysis. Data were obtained from two European countries, Spain and Sweden, and from three centers: Consorci Sanitari de Terrassa (Catalonia, Spain), Servicio Andaluz de Salud (Andalusia, Spain), and the Blekinge Institute of Technology (Sweden). Participants with a score between 20 and 28 in the Mini Mental State Examination, with memory problems (for more than 6 months), and who were over the age of 55 years were included in the study, along with their caregivers. The bivariate Chi square and Mann-Whitney tests, and multivariate linear and logistic regression models were used for statistical analysis. RESULTS: A total of 1086 dyads were included (N=2172). Overall, 299 (27.53%) of people with dementia/mild cognitive impairment had a diagnosis of dementia. In addition, 588 (54.14%) of people with dementia/mild cognitive impairment reported using a smartphone almost every day, and 106 (9.76%) used specific apps or software to support their memory. Among the caregivers, 839 (77.26%) used smartphones and tablets almost every day, and 181 (16.67%) used specific apps or software to support their memory. The people with dementia/mild cognitive impairment showed a lower level of technophilia in comparison to that of their caregivers after adjusting for confounders (B=0.074, P=.02) with differences in technology enthusiasm (B=0.360, P<.001), but not in technology anxiety (B=-0.042, P=.37). Technophilia was associated with lower age (B=-0.009, P=.004), male gender (B=-0.160, P<.001), higher education level (P=.01), living arrangement (living with children vs single; B=-2.538, P=.01), country of residence (Sweden vs Spain; B=0.256, P<.001), lower depression (B=-0.046, P<.001), and better health status (B=0.004, P<.001) in people with dementia/mild cognitive impairment. Among caregivers, technophilia was associated with comparable sociodemographic factors (except for living arrangement), along with a lower caregiver burden (B=-0.005, P=.04) and better quality of life (B=0.348, P<.001). CONCLUSIONS: Technophilia was associated with a better quality of life and sociodemographic variables in people with dementia/mild cognitive impairment and caregivers, suggesting potential barriers for technological interventions. People with dementia/mild cognitive impairment frequently use smartphones and tablets, but the use of specific apps or software to support memory is limited. Interventions using these technologies are needed to overcome barriers in this population related to sociodemographic characteristics and the lack of enthusiasm for new technologies. TRIAL REGISTRATION: ClinicalTrials.gov NCT03325699; https://clinicaltrials.gov/ct2/show/NCT03325699. ©Jose Guzman-Parra, Pilar Barnestein-Fonseca, Gloria Guerrero-Pertiñez, Peter Anderberg, Luis Jimenez-Fernandez, Esperanza Valero-Moreno, Jessica Marian Goodman-Casanova, Antonio Cuesta-Vargas, Maite Garolera, Maria Quintana, Rebeca I García-Betances, Evi Lemmens, Johan Sanmartin Berglund, Fermin Mayoral-Cleries.
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| 9. |
- Le Guen, Yann, et al.
(author)
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Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.
- 2023
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 1091-6490 .- 0027-8424. ; 120:36
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Journal article (peer-reviewed)abstract
- Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
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| 10. |
- Linnemann, Christoph, et al.
(author)
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NfL reliability across laboratories, stage-dependent diagnostic performance and matrix comparability in genetic FTD: a large GENFI study
- 2024
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In: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY. - 0022-3050 .- 1468-330X.
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Journal article (peer-reviewed)abstract
- BackgroundBlood neurofilament light chain (NfL) is increasingly considered as a key trial biomarker in genetic frontotemporal dementia (gFTD). We aimed to facilitate the use of NfL in gFTD multicentre trials by testing its (1) reliability across labs; (2) reliability to stratify gFTD disease stages; (3) comparability between blood matrices and (4) stability across recruiting sites.MethodsComparative analysis of blood NfL levels in a large gFTD cohort (GENFI) for (1)-(4), with n=344 samples (n=148 presymptomatic, n=11 converter, n=46 symptomatic subjects, with mutations in C9orf72, GRN or MAPT; and n=139 within-family controls), each measured in three different international labs by Simoa HD-1 analyzer.ResultsNfL revealed an excellent consistency (intraclass correlation coefficient (ICC) 0.964) and high reliability across the three labs (maximal bias (pg/mL) in Bland-Altman analysis: 1.12 +/- 1.20). High concordance of NfL across laboratories was moreover reflected by high areas under the curve for discriminating conversion stage against the (non-converting) presymptomatic stage across all three labs. Serum and plasma NfL were largely comparable (ICC 0.967). The robustness of NfL across 13 recruiting sites was demonstrated by a linear mixed effect model.ConclusionsOur results underline the suitability of blood NfL in gFTD multicentre trials, including cross-lab reliable stratification of the highly trial-relevant conversion stage, matrix comparability and cross-site robustness.
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