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1. A unique common ancestor introduced P301L mutation in MAPT gene in frontotemporal dementia patients from Barcelona (Baix Llobregat, Spain).

Author

Palencia-Madrid L, Sánchez-Valle R, Fernández de Retana I, Borrego S, Grau-Rivera O, Reñé R, Hernández I, Almenar C, Rossi G, Caroppo P, Redaelli V, Le Ber I, Camuzat A, Brice A, Antonell A, Balasa M, Gelpi E, Lladó A, and de Pancorbo MM

Subjects
Humans, Spain, Frontotemporal Dementia genetics, Mutation, tau Proteins genetics
Abstract

The County of Baix Llobregat (Barcelona, Catalonia, Spain) presents a high prevalence of familial frontotemporal dementia (FTD) in the presence of P301L mutation in the MAPT gene. To evaluate a possible unique founder effect of P301L, and its age, the analysis of 20 single-nucleotide polymorphisms covering 50 kb and 12 single-nucleotide polymorphisms located along 30 Mb around the mutation was performed by developing 2 multiplex single-base extension reactions. In addition, families with affected and healthy individuals from France and Italy were analyzed. The FTD-affected individuals from Barcelona carried the same 50-kb haplotype linked to P301L mutation, suggesting a unique common ancestor, as opposed to French patients. Italian patients are also probably descendants of a unique ancestor, which would be different from that of Barcelona. Diversity of 30-Mb haplotypes found in Barcelona and the inference of the mutation age in these populations, among other reasons, suggest that prevalence of FTD linked to P301L MAPT mutation is the result of a locally originated mutation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Published
2019
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2. Altered microRNAs related to synaptic function as potential plasma biomarkers for Alzheimer's disease.

Author

Siedlecki-Wullich D, Català-Solsona J, Fábregas C, Hernández I, Clarimon J, Lleó A, Boada M, Saura CA, Rodríguez-Álvarez J, and Miñano-Molina AJ

Subjects
Aged, Aged, 80 and over, Biomarkers blood, Cohort Studies, Female, Humans, Male, Middle Aged, Up-Regulation, Alzheimer Disease blood, Cognitive Dysfunction blood, Frontotemporal Dementia blood, MicroRNAs blood
Abstract

Background: Several evidences suggest that failure of synaptic function occurs at preclinical stages of Alzheimer's disease (AD) preceding neuronal loss and the classical AD pathological hallmarks. Nowadays, there is an urgent need to identify reliable biomarkers that could be obtained with non-invasive methods to improve AD diagnosis at early stages. Here, we have examined plasma levels of a group of miRNAs related to synaptic proteins in a cohort composed of cognitive healthy controls (HC), mild cognitive impairment (MCI) and AD subjects., Methods: Plasma and brain levels of miRNAs were analysed in two different cohorts including 38 HC, 26 MCI, 56 AD dementia patients and 27 frontotemporal dementia (FTD) patients. D'Agostino and Pearson and Shapiro-Wilk tests were used to evaluate data normality. miRNA levels between groups were compared using a two-sided nonparametric Mann-Whitney test and sensitivity and specificity was determined by receiver operating characteristic curve analysis., Results: Significant upregulation of miR-92a-3p, miR-181c-5p and miR-210-3p was found in the plasma of both MCI and AD subjects. MCI patients that progress to AD showed higher plasma levels of these miRNAs. By contrast, no changes in miR-92a-3p, miR-181c-5p or miR-210-3p levels were observed in plasma obtained from a cohort of FTD., Conclusion: Our study shows that plasma miR-92a-3p, miR-181c-5p and miR-210-3p constitute a specific molecular signature potentially useful as a potential biomarker for AD.

Published
2019
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3. A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers.

Author

Zhang M, Ferrari R, Tartaglia MC, Keith J, Surace EI, Wolf U, Sato C, Grinberg M, Liang Y, Xi Z, Dupont K, McGoldrick P, Weichert A, McKeever PM, Schneider R, McCorkindale MD, Manzoni C, Rademakers R, Graff-Radford NR, Dickson DW, Parisi JE, Boeve BF, Petersen RC, Miller BL, Seeley WW, van Swieten JC, van Rooij J, Pijnenburg Y, van der Zee J, Van Broeckhoven C, Le Ber I, Van Deerlin V, Suh E, Rohrer JD, Mead S, Graff C, Öijerstedt L, Pickering-Brown S, Rollinson S, Rossi G, Tagliavini F, Brooks WS, Dobson-Stone C, Halliday GM, Hodges JR, Piguet O, Binetti G, Benussi L, Ghidoni R, Nacmias B, Sorbi S, Bruni AC, Galimberti D, Scarpini E, Rainero I, Rubino E, Clarimon J, Lleó A, Ruiz A, Hernández I, Pastor P, Diez-Fairen M, Borroni B, Pasquier F, Deramecourt V, Lebouvier T, Perneczky R, Diehl-Schmid J, Grafman J, Huey ED, Mayeux R, Nalls MA, Hernandez D, Singleton A, Momeni P, Zeng Z, Hardy J, Robertson J, Zinman L, and Rogaeva E

Subjects
Age of Onset, Aged, CpG Islands, DNA Methylation, Female, Genotype, Heterozygote, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Amyotrophic Lateral Sclerosis genetics, C9orf72 Protein genetics, Frontotemporal Dementia genetics, Gene Expression Regulation genetics
Abstract

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

Published
2018
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4. TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

Author

van der Zee J, Gijselinck I, Van Mossevelde S, Perrone F, Dillen L, Heeman B, Bäumer V, Engelborghs S, De Bleecker J, Baets J, Gelpi E, Rojas-García R, Clarimón J, Lleó A, Diehl-Schmid J, Alexopoulos P, Perneczky R, Synofzik M, Just J, Schöls L, Graff C, Thonberg H, Borroni B, Padovani A, Jordanova A, Sarafov S, Tournev I, de Mendonça A, Miltenberger-Miltényi G, Simões do Couto F, Ramirez A, Jessen F, Heneka MT, Gómez-Tortosa E, Danek A, Cras P, Vandenberghe R, De Jonghe P, De Deyn PP, Sleegers K, Cruts M, Van Broeckhoven C, Goeman J, Nuytten D, Smets K, Robberecht W, Damme PV, Bleecker J, Santens P, Dermaut B, Versijpt J, Michotte A, Ivanoiu A, Deryck O, Bergmans B, Delbeck J, Bruyland M, Willems C, Salmon E, Pastor P, Ortega-Cubero S, Benussi L, Ghidoni R, Binetti G, Hernández I, Boada M, Ruiz A, Sorbi S, Nacmias B, Bagnoli S, Sorbi S, Sanchez-Valle R, Llado A, Santana I, Rosário Almeida M, Frisoni GB, Maetzler W, Matej R, Fraidakis MJ, Kovacs GG, Fabrizi GM, and Testi S

Subjects
Aged, Alleles, Amino Acid Substitution, Amyotrophic Lateral Sclerosis diagnosis, Amyotrophic Lateral Sclerosis epidemiology, Case-Control Studies, Cohort Studies, Enzyme Activation, Female, Frontotemporal Dementia diagnosis, Frontotemporal Dementia epidemiology, Genetic Association Studies, Heterozygote, Humans, Male, Middle Aged, Mutation, NF-kappa B metabolism, Phenotype, Protein Serine-Threonine Kinases metabolism, Sequence Deletion, Amyotrophic Lateral Sclerosis genetics, Frontotemporal Dementia genetics, Protein Serine-Threonine Kinases genetics, White People genetics
Abstract

We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS., (© 2016 The Authors. **Human Mutation published by Wiley Periodicals, Inc.)

Published
2017
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5. Frontotemporal Dementia Caused by the P301L Mutation in the MAPT Gene: Clinicopathological Features of 13 Cases from the Same Geographical Origin in Barcelona, Spain.

Author

Borrego-Écija S, Morgado J, Palencia-Madrid L, Grau-Rivera O, Reñé R, Hernández I, Almenar C, Balasa M, Antonell A, Molinuevo JL, Lladó A, Martínez de Pancorbo M, Gelpi E, and Sánchez-Valle R

Subjects
Adult, Aged, Female, Founder Effect, Frontal Lobe pathology, Frontotemporal Dementia diagnosis, Frontotemporal Dementia pathology, Genetic Carrier Screening, Haplotypes, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide genetics, Retrospective Studies, Spain, Temporal Lobe pathology, Alleles, DNA Mutational Analysis, Frontotemporal Dementia genetics, tau Proteins genetics
Abstract

Background/aims: We identified and studied 13 patients carrying the P301L mutation in the MAPT gene from the same area (Baix Llobregat County) in Barcelona, Spain., Methods: The demographic and clinical features were reviewed retrospectively. Detailed neuropathological characterization was obtained in 9 subjects. To investigate the origin of the P301L mutation in these families, 20 single nucleotide polymorphisms (SNPs) in the MAPT gene were analyzed., Results: The mean age at disease onset was 51 years and the mean disease duration was 7 years. The most common initial symptoms were behavioral changes (54%), followed by language disturbances (31%) and memory loss (15%). 46% developed parkinsonism. Neuropathology showed an extensive neuronal and glial 4-repeat (4R) tauopathy with "mini-Pick"-like bodies in the dentate gyrus as the characteristic underlying pathology in all cases. In 1 subject, additional 4R globular glial inclusions were observed. All the mutation carriers showed the same haplotype for the SNPs analyzed, suggesting a common ancestor., Conclusion: These findings suggest a relative homogeneous clinicopathological phenotype in P301L MAPT mutation carriers in our series. This phenotype might help in the differential diagnosis from other tauopathies and be a morphological hint for genetic testing. The haplotype analysis results suggest a founder effect of the P301L mutation in this area., (© 2017 S. Karger AG, Basel.)

Published
2017
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6. Assessing the role of TUBA4A gene in frontotemporal degeneration.

Author

Dols-Icardo O, Iborra O, Valdivia J, Pastor P, Ruiz A, López de Munain A, Sánchez-Valle R, Álvarez V, Sánchez-Juan P, Lleó A, Fortea J, Blesa R, Cardona F, Baquero M, Alonso MD, Ortega-Cubero S, Pastor MA, Razquin C, Boada M, Hernández I, Gorostidi A, Moreno F, Zulaika M, Lladó A, Coto E, Combarros O, Pérez-Tur J, and Clarimón J

Subjects
Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis genetics, Cohort Studies, Female, Heterozygote, Humans, Male, Middle Aged, Frontotemporal Dementia genetics, Genetic Association Studies, Mutation, Tubulin genetics
Abstract

The tubulin alpha 4a (TUBA4A) gene has been recently associated with amyotrophic lateral sclerosis. Interestingly, some of the mutation carriers were also diagnosed with frontotemporal degeneration (FTD) or mild cognitive impairment. With the aim to investigate the role of TUBA4A in FTD, we screened TUBA4A in a series of 814 FTD patients from Spain. Our data did not disclose any nonsense or missense variant in the cohort, thus suggesting that TUBA4A mutations are not associated with FTD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Published
2016
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7. Analysis of the CHCHD10 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis from Spain.

Author

Dols-Icardo O, Nebot I, Gorostidi A, Ortega-Cubero S, Hernández I, Rojas-García R, García-Redondo A, Povedano M, Lladó A, Álvarez V, Sánchez-Juan P, Pardo J, Jericó I, Vázquez-Costa J, Sevilla T, Cardona F, Indakoechea B, Moreno F, Fernández-Torrón R, Muñoz-Llahuna L, Moreno-Grau S, Rosende-Roca M, Vela Á, Muñoz-Blanco JL, Combarros O, Coto E, Alcolea D, Fortea J, Lleó A, Sánchez-Valle R, Esteban-Pérez J, Ruiz A, Pastor P, López De Munain A, Pérez-Tur J, and Clarimón J

Subjects
Age of Onset, Aged, Amyotrophic Lateral Sclerosis epidemiology, Case-Control Studies, Female, Frontotemporal Dementia complications, Frontotemporal Dementia epidemiology, Humans, Male, Motor Neuron Disease complications, Motor Neuron Disease epidemiology, Mutation, Spain epidemiology, Amyotrophic Lateral Sclerosis genetics, Frontotemporal Dementia genetics, Mitochondrial Proteins genetics, Motor Neuron Disease genetics
Published
2015
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8. Association of TMEM106B rs1990622 marker and frontotemporal dementia: evidence for a recessive effect and meta-analysis.

Author

Hernández I, Rosende-Roca M, Alegret M, Mauleón A, Espinosa A, Vargas L, Sotolongo-Grau O, Tárraga L, Boada M, and Ruiz A

Subjects
Aged, Case-Control Studies, Female, Genetic Association Studies, Humans, Male, Models, Genetic, Sequence Analysis, DNA, Spain, White People genetics, Frontotemporal Dementia genetics, Genes, Recessive, Genetic Predisposition to Disease, Membrane Proteins genetics, Nerve Tissue Proteins genetics, Polymorphism, Single Nucleotide
Abstract

Transmembrane Protein 106B SNP rs1990622 was recently shown to modify the risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTD-TDP). An independent replication study of this genetic variant was performed in 381 individuals from Catalonia (Spain). By applying a recessive model, a tendency toward an association with FTD risk was observed in our case-control study (age- and gender-adjusted odds ratio = 0.57; p = 0.082). Importantly, meta-analysis of available studies also supports a recessive effect for rs1990622 CC genotype (OR = 0.70; CI 95% [0.57-0.85]; p = 0.0003) and demonstrates the existence of statistical heterogeneity due to an inherent pathological heterogeneity between series (p = 0.00014). We conclude that TMEM106B is associated with FTD, although the extent of this effect is difficult to be estimated by using clinical FTD series.

Published
2015
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9. Investigation of the role of rare TREM2 variants in frontotemporal dementia subtypes.

Author

Thelen M, Razquin C, Hernández I, Gorostidi A, Sánchez-Valle R, Ortega-Cubero S, Wolfsgruber S, Drichel D, Fliessbach K, Duenkel T, Damian M, Heilmann S, Slotosch A, Lennarz M, Seijo-Martínez M, Rene R, Kornhuber J, Peters O, Luckhaus C, Jahn H, Hüll M, Rüther E, Wiltfang J, Lorenzo E, Gascon J, Lleó A, Lladó A, Campdelacreu J, Moreno F, Ahmadzadehfar H, Fortea J, Indakoetxea B, Heneka MT, Wetter A, Pastor MA, Riverol M, Becker T, Frölich L, Tárraga L, Boada M, Wagner M, Jessen F, Maier W, Clarimón J, López de Munain A, Ruiz A, Pastor P, and Ramirez A

Subjects
Aged, Aged, 80 and over, Alzheimer Disease genetics, Female, Frontotemporal Dementia classification, Humans, Linkage Disequilibrium, Male, Middle Aged, Phenotype, Sequence Analysis, DNA, Frontotemporal Dementia genetics, Genetic Association Studies, Genetic Variation genetics, Membrane Glycoproteins genetics, Receptors, Immunologic genetics
Abstract

Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. Rare TREM2 variants have been recently identified in families affected by FTD-like phenotype. However, genetic studies of the role of rare TREM2 variants in FTD have generated conflicting results possibly because of difficulties on diagnostic accuracy. The aim of the present study was to investigate associations between rare TREM2 variants and specific FTD subtypes (FTD-S). The entire coding sequence of TREM2 was sequenced in FTD-S patients of Spanish (n = 539) and German (n = 63) origin. Genetic association was calculated using Fisher exact test. The minor allele frequency for controls was derived from in-house genotyping data and publicly available databases. Seven previously reported rare coding variants (p.A28V, p.W44X, p.R47H, p.R62H, p.T66M, p.T96K, and p.L211P) and 1 novel missense variant (p.A105T) were identified. The p.R47H variant was found in 4 patients with FTD-S. Two of these patients showed cerebrospinal fluid pattern of amyloid beta, tau, and phosphorylated-tau suggesting underlying Alzheimer's disease (AD) pathology. No association was found between p.R47H and FTD-S. A genetic association was found between p.T96K and FTD-S (p = 0.013, odds ratio = 4.23, 95% Confidence Interval [1.17-14.77]). All 6 p.T96K patients also carried the TREM2 variant p.L211P, suggesting linkage disequilibrium. The remaining TREM2 variants were found in 1 patient, respectively, and were absent in controls. The present findings provide evidence that p.T96K is associated with FTD-S and that p.L211P may contribute to its pathogenic effect. The data also suggest that p.R47H is associated with an FTD phenotype that is characterized by the presence of underlying AD pathology., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Published
2014
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10. Frontotemporal dementia and its subtypes: a genome-wide association study.

Author

Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JB, Dobson-Stone C, Brooks WS, Schofield PR, Halliday GM, Hodges JR, Piguet O, Bartley L, Thompson E, Haan E, Hernández I, Ruiz A, Boada M, Borroni B, Padovani A, Cruchaga C, Cairns NJ, Benussi L, Binetti G, Ghidoni R, Forloni G, Galimberti D, Fenoglio C, Serpente M, Scarpini E, Clarimón J, Lleó A, Blesa R, Waldö ML, Nilsson K, Nilsson C, Mackenzie IR, Hsiung GY, Mann DM, Grafman J, Morris CM, Attems J, Griffiths TD, McKeith IG, Thomas AJ, Pietrini P, Huey ED, Wassermann EM, Baborie A, Jaros E, Tierney MC, Pastor P, Razquin C, Ortega-Cubero S, Alonso E, Perneczky R, Diehl-Schmid J, Alexopoulos P, Kurz A, Rainero I, Rubino E, Pinessi L, Rogaeva E, St George-Hyslop P, Rossi G, Tagliavini F, Giaccone G, Rowe JB, Schlachetzki JC, Uphill J, Collinge J, Mead S, Danek A, Van Deerlin VM, Grossman M, Trojanowski JQ, van der Zee J, Deschamps W, Van Langenhove T, Cruts M, Van Broeckhoven C, Cappa SF, Le Ber I, Hannequin D, Golfier V, Vercelletto M, Brice A, Nacmias B, Sorbi S, Bagnoli S, Piaceri I, Nielsen JE, Hjermind LE, Riemenschneider M, Mayhaus M, Ibach B, Gasparoni G, Pichler S, Gu W, Rossor MN, Fox NC, Warren JD, Spillantini MG, Morris HR, Rizzu P, Heutink P, Snowden JS, Rollinson S, Richardson A, Gerhard A, Bruni AC, Maletta R, Frangipane F, Cupidi C, Bernardi L, Anfossi M, Gallo M, Conidi ME, Smirne N, Rademakers R, Baker M, Dickson DW, Graff-Radford NR, Petersen RC, Knopman D, Josephs KA, Boeve BF, Parisi JE, Seeley WW, Miller BL, Karydas AM, Rosen H, van Swieten JC, Dopper EG, Seelaar H, Pijnenburg YA, Scheltens P, Logroscino G, Capozzo R, Novelli V, Puca AA, Franceschi M, Postiglione A, Milan G, Sorrentino P, Kristiansen M, Chiang HH, Graff C, Pasquier F, Rollin A, Deramecourt V, Lebert F, Kapogiannis D, Ferrucci L, Pickering-Brown S, Singleton AB, Hardy J, and Momeni P

Subjects
Adult, Aged, Aged, 80 and over, Female, Frontotemporal Dementia classification, Humans, Male, Middle Aged, Frontotemporal Dementia diagnosis, Frontotemporal Dementia genetics, Genome-Wide Association Study methods, Genotype
Abstract

Background: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder., Methods: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10(-8)) single-nucleotide polymorphisms., Findings: We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10(-8); odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10(-9); 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10(-8), 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10(-7); 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis., Interpretation: Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD., Funding: The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Published
2014
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11. Plasma phosphorylated TDP-43 levels are elevated in patients with frontotemporal dementia carrying a C9orf72 repeat expansion or a GRN mutation.

Author

Suárez-Calvet M, Dols-Icardo O, Lladó A, Sánchez-Valle R, Hernández I, Amer G, Antón-Aguirre S, Alcolea D, Fortea J, Ferrer I, van der Zee J, Dillen L, Van Broeckhoven C, Molinuevo JL, Blesa R, Clarimón J, and Lleó A

Subjects
Aged, Aged, 80 and over, Blotting, Southern, Brain metabolism, C9orf72 Protein, Case-Control Studies, DNA-Binding Proteins cerebrospinal fluid, DNA-Binding Proteins metabolism, Enzyme-Linked Immunosorbent Assay, Female, Frontotemporal Dementia metabolism, Humans, Immunohistochemistry, Male, Middle Aged, Phosphorylation, Progranulins, Protein Precursors genetics, DNA Repeat Expansion, DNA-Binding Proteins blood, Frontotemporal Dementia blood, Frontotemporal Dementia genetics, Intercellular Signaling Peptides and Proteins genetics, Mutation, Proteins genetics
Abstract

Objectives: About a half of patients with frontotemporal dementia (FTD) has deposition of phosphorylated TDP-43 protein (pTDP-43) in the brain. We studied pTDP-43 and total TDP-43 levels in plasma and cerebrospinal fluid (CSF) in healthy controls and patients with FTD, including those carrying a repeat expansion in the C9orf72 gene or a mutation in GRN., Methods: We included 88 plasma samples of 10 C9orf72 expansion carriers, 5 GRN mutation carriers, 51 patients with FTD without a known mutation and 22 healthy controls. We also obtained CSF samples from 25 patients with FTD (2 with C9orf72 expansion and 3 with a GRN mutation) and 22 healthy controls. We measured pTDP-43 and total TDP-43 levels using sandwich ELISA., Results: Patients carrying the C9orf72 repeat expansion or a GRN mutation had significantly higher plasma and CSF levels of pTDP-43 than the remaining patients with FTD (p<0.05). In addition, plasma pTDP-43 levels were higher in patients with FTD carrying a C9orf72 expansion or GRN mutations than in healthy controls (p<0.05)., Conclusions: Our study shows that plasma pTDP-43 levels may be increased in some genetic forms of FTD known to be associated with TDP-43 proteinopathies.

Published
2014
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12. Identification of misdiagnosed fronto-temporal dementia using APOE genotype and phenotype-genotype correlation analyses.

Author

Hernández I, Mauleón A, Rosense-Roca M, Alegret M, Vinyes G, Espinosa A, Sotolongo-Grau O, Becker JT, Valero S, Tarraga L, López OL, Ruiz A, and Boada M

Subjects
Aged, Aged, 80 and over, Alzheimer Disease diagnosis, Female, Frontotemporal Dementia diagnosis, Humans, Male, Middle Aged, Alzheimer Disease genetics, Apolipoproteins E genetics, Diagnostic Errors, Frontotemporal Dementia genetics, Genetic Association Studies methods, Genotype
Abstract

Objective: Postmortem and genetic studies of clinically diagnosed Frontotemporal dementia (FTD) patients suggest that a number of clinically diagnosed FTD patients are actually "frontal variants" of Alzheimer's disease (fvAD). The purpose of this study was to evaluate this hypothesis by combining neuropathological data, genetic association studies of APOE, phenotype-APOE genotype correlations and discriminant analysis techniques., Methods: Neuropathological information on 24 FTD cases, genetic association studies of APOE (168 FTD, 3083 controls and 2528 AD), phenotypegenotype correlations and discriminant techniques (LDA, logistic regression and decision trees) were combined to identify fvAD patients within a clinical FTD series., Results: Four of 24 FTLD patients (16.6%) met criteria for definite AD. By comparing allele and genotype frequencies of APOE in controls, FTD and AD groups and by applying the Hardy- Weinberg equilibrium law (HWE), we inferred a consistent (17.2%) degree of AD contamination in clinical FTD. A penetrance analysis for APOE ε4 genotype in the FTD series identified 14 features for discrimination analysis. These features were compared between clinical AD (n=332) and clinical FTD series (n=168) and classifiers were constructed usinglinear discriminant analysis logistic regression or decision tree techniques. The classifier had 92.8% sensitivity to FTD and 93.4% sensitivity to AD relative to neuropathology (global AUC=0.939, p<<0.001). We identified 30 potential fvAD cases (17.85%) in the clinical FTD sample., Conclusion: The APOE locus association in clinical FTD might be entirely explained by the existence of "hidden" fvAD cases within an FTD sample. The degree of fvAD contamination can be inferred from APOE genotypes.

Published
2014
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13. Assessing the role of the TREM2 p.R47H variant as a risk factor for Alzheimer's disease and frontotemporal dementia.

Author

Ruiz A, Dols-Icardo O, Bullido MJ, Pastor P, Rodríguez-Rodríguez E, López de Munain A, de Pancorbo MM, Pérez-Tur J, Alvarez V, Antonell A, López-Arrieta J, Hernández I, Tárraga L, Boada M, Lleó A, Blesa R, Frank-García A, Sastre I, Razquin C, Ortega-Cubero S, Lorenzo E, Sánchez-Juan P, Combarros O, Moreno F, Gorostidi A, Elcoroaristizabal X, Baquero M, Coto E, Sánchez-Valle R, and Clarimón J

Subjects
Aged, Aged, 80 and over, Alleles, Cohort Studies, Female, Genes, Recessive genetics, Genetic Predisposition to Disease genetics, Genotype, Humans, Male, Meta-Analysis as Topic, Middle Aged, Multicenter Studies as Topic, Risk Factors, Spain, Alzheimer Disease genetics, Frontotemporal Dementia genetics, Genome-Wide Association Study, Membrane Glycoproteins genetics, Mutation, Polymorphism, Genetic genetics, Receptors, Immunologic genetics
Abstract

A non-synonymous genetic rare variant, rs75932628-T (p.R47H), in the TREM2 gene has recently been reported to be a strong genetic risk factor for Alzheimer's disease (AD). Also, rare recessive mutations have been associated with frontotemporal dementia (FTD). We aimed to investigate the role of p.R47H variant in AD and FTD through a multi-center study comprising 3172 AD and 682 FTD patients and 2169 healthy controls from Spain. We found that 0.6% of AD patients carried this variant compared to 0.1% of controls (odds ratio [OR] = 4.12, 95% confidence interval [CI] = 1.21-14.00, p = 0.014). A meta-analysis comprising 32,598 subjects from 4 previous studies demonstrated the large effect of the p.R47H variant in AD risk (OR = 4.11, 95% CI = 2.99-5.68, p = 5.27×10(-18)). We did not find an association between p.R47H and age of onset of AD or family history of dementia. Finally, none of the FTD patients harbored this genetic variant. These data strongly support the important role of p.R47H in AD risk, and suggest that this rare genetic variant is not related to FTD., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Published
2014
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14. Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia.

Author

Dols-Icardo O, García-Redondo A, Rojas-García R, Sánchez-Valle R, Noguera A, Gómez-Tortosa E, Pastor P, Hernández I, Esteban-Pérez J, Suárez-Calvet M, Antón-Aguirre S, Amer G, Ortega-Cubero S, Blesa R, Fortea J, Alcolea D, Capdevila A, Antonell A, Lladó A, Muñoz-Blanco JL, Mora JS, Galán-Dávila L, Rodríguez De Rivera FJ, Lleó A, and Clarimón J

Subjects
Blotting, Southern methods, C9orf72 Protein, Female, Heterozygote, Humans, Male, Middle Aged, Mutation, Twins, Monozygotic, Amyotrophic Lateral Sclerosis genetics, DNA Repeat Expansion, Frontotemporal Dementia genetics, Proteins genetics
Abstract

Hexanucleotide repeat expansions within the C9orf72 gene are the most important genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The difficulty of developing a precise method to determine the expansion size has hampered the study of possible correlations between the hexanucleotide repeat number and clinical phenotype. Here we characterize, through a new non-radioactive Southern blot protocol, the expansion size range in a series of 38 ALS and 22 FTD heterozygous carriers of >30 copies of the repeat. Maximum, median and modal hexanucleotide repeat number were higher in ALS patients than in FTD patients (P< 0.05 in all comparisons). A higher median number of repeats correlated with a bigger range of repeat sizes (Spearman's ρ = 0.743, P = 1.05 × 10(-11)). We did not find any correlation between age of onset or disease duration with the repeat size in neither ALS nor FTD mutation carriers. Clinical presentation (bulbar or spinal) in ALS patients did not correlate either with the repeat length. We finally analyzed two families with affected and unaffected repeat expansion carriers, compared the size of the repeat expansion between two monozygotic (MZ) twins (one affected of ALS and the other unaffected), and examined the expansion size in two different tissues (cerebellum and peripheral blood) belonging to the same FTD patient. The results suggested that the length of the C9orf72 repeat varies between family members, including MZ twins, and among different tissues from the same individual.

Published
2014
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15. Molecular evaluation of human ubiquilin 2 gene PXX domain in familial frontotemporal dementia patients.

Author

Hernández I, Espinosa A, Real LM, Galán JJ, Mauleón A, Roca MR, Tárraga L, Ruiz A, and Boada M

Subjects
Adaptor Proteins, Signal Transducing, Autophagy-Related Proteins, Humans, Mutation genetics, Protein Structure, Tertiary genetics, Cell Cycle Proteins genetics, Frontotemporal Dementia diagnosis, Frontotemporal Dementia genetics, Sequence Analysis, DNA methods, Ubiquitins genetics
Published
2012
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16. Expansion mutation in C9ORF72 does not influence plasma progranulin levels in frontotemporal dementia.

Author

Dols-Icardo O, Suárez-Calvet M, Hernández I, Amer G, Antón-Aguirre S, Alcolea D, Fortea J, Boada M, Tárraga L, Blesa R, Lleó A, and Clarimón J

Subjects
Adult, Female, Frontotemporal Dementia epidemiology, Genetic Markers genetics, Genetic Predisposition to Disease epidemiology, Genetic Predisposition to Disease genetics, Genetic Variation genetics, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Middle Aged, Prevalence, Progranulins, Risk Factors, Spain epidemiology, Frontotemporal Dementia blood, Frontotemporal Dementia genetics, Intercellular Signaling Peptides and Proteins blood, Mutation genetics, Polymorphism, Single Nucleotide genetics, Protein Serine-Threonine Kinases genetics, Repetitive Sequences, Nucleic Acid genetics
Abstract

A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) gene has recently been described as a cause of familial and sporadic frontotemporal lobar degeneration. The aim of this study was to assess whether plasma progranulin (GRN) levels could be modulated by the presence of this repeat expansion. Sixty-five patients diagnosed with frontotemporal dementia and 10 family members with familial aggregation of disease were screened for the presence of the hexanucleotide repeat expansion in C9ORF72 gene, using a repeat-primed polymerase chain reaction method. Plasma GRN levels were measured in all subjects through enzyme-linked immunosorbent assay. Seven individuals with the repeat expansion were identified. No differences were found between C9ORF72 repeat expansion carriers and noncarriers (116.4 ± 21 ng/mL and 131.7 ± 36 ng/mL, respectively, p = 0.3). Analysis of family members did not disclose any difference in plasma GRN levels between carriers and noncarriers. In conclusion, plasma GRN levels are not influenced by the hexanucleotide repeat expansion in C9ORF72 gene, and therefore, cannot be used as a reliable biomarker to detect mutation carriers., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Published
2012
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17. Gene Expression Imputation Across Multiple Tissue Types Provides Insight Into the Genetic Architecture of Frontotemporal Dementia and Its Clinical Subtypes

Author

Reus, Lianne M, Pasaniuc, Bogdan, Posthuma, Danielle, Boltz, Toni, Consortium, International FTD-Genomics, Ferrari, Raffaele, Hernandez, Dena G, Nalls, Michael A, Rohrer, Jonathan D, Ramasamy, Adaikalavan, Kwok, John BJ, Dobson-Stone, Carol, Brooks, William S, Schofield, Peter R, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian RA, Hsiung, Ging-Yuek R, Mann, David MA, Grafman, Jordan, Morris, Christopher M, Attems, Johannes, Griffiths, Timothy D, McKeith, Ian G, Thomas, Alan J, Pietrini, Pietro, Huey, Edward D, Wassermann, Eric M, Baborie, Atik, Jaros, Evelyn, Tierney, Michael C, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B, Schlachetzki, Johannes CM, Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Van Broeckhoven, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, and Gu, Wei

Subjects
Biological Sciences, Genetics, Acquired Cognitive Impairment, Frontotemporal Dementia (FTD), Aging, Dementia, Neurodegenerative, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Prevention, Alzheimer's Disease Related Dementias (ADRD), Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Neurological, Frontotemporal Dementia, Gene Expression, Humans, International FTD-Genomics Consortium, 17q21.31 inversion region, Dorsolateral prefrontal cortex, Expression quantitative trait loci, Frontotemporal dementia, SEC22B, Transcriptome-wide association study, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biological sciences, Biomedical and clinical sciences, Psychology
Abstract

BackgroundThe etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach.MethodsFUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold.ResultsWe identified 73 significant gene-tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed.ConclusionsWe identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.

Published
2021

18. C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts

Author

Costa, Beatrice, Manzoni, Claudia, Bernal-Quiros, Manuel, Kia, Demis A, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Andreassen, Ole, Anfossi, Maria, Bagnoli, Silvia, Benussi, Luisa, Bernardi, Livia, Binetti, Giuliano, Blackburn, Daniel, Boada, Mercè, Borroni, Barbara, Bowns, Lucy, Bråthen, Geir, Bruni, Amalia C, Chiang, Huei-Hsin, Clarimon, Jordi, Colville, Shuna, Conidi, Maria E, Cope, Tom E, Cruchaga, Carlos, Cupidi, Chiara, Di Battista, Maria Elena, Diehl-Schmid, Janine, Diez-Fairen, Monica, Dols-Icardo, Oriol, Durante, Elisabetta, Flisar, Dušan, Frangipane, Francesca, Galimberti, Daniela, Gallo, Maura, Gallucci, Maurizio, Ghidoni, Roberta, Graff, Caroline, Grafman, Jordan H, Grossman, Murray, Hardy, John, Hernández, Isabel, Holloway, Guy JT, Huey, Edward D, Illán-Gala, Ignacio, Karydas, Anna, Khoshnood, Behzad, Kramberger, Milica G, Kristiansen, Mark, Lewis, Patrick A, Lleó, Alberto, Madhan, Gaganjit K, Maletta, Raffaele, Maver, Aleš, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce, Mol, Merel O, Momeni, Parastoo, Moreno-Grau, Sonia, Morris, Chris M, Nacmias, Benedetta, Nilsson, Christer, Novelli, Valeria, Öijerstedt, Linn, Padovani, Alessandro, Pal, Suvankar, Panchbhaya, Yasmin, Pastor, Pau, Peterlin, Borut, Piaceri, Irene, Pickering-Brown, Stuart, Pijnenburg, Yolande AL, Puca, Annibale A, Rainero, Innocenzo, Rendina, Antonella, Richardson, Anna MT, Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rossi, Giacomina, Rossmeier, Carola, Rowe, James B, Rubino, Elisa, Ruiz, Agustín, Sanchez-Valle, Raquel, Sando, Sigrid B, Santillo, Alexander F, Saxon, Jennifer, Scarpini, Elio, Serpente, Maria, Smirne, Nicoletta, Sorbi, Sandro, Suh, EunRan, Tagliavini, Fabrizio, Thompson, Jennifer C, Trojanowski, John Q, Van Deerlin, Vivianna M, Van der Zee, Julie, and Van Broeckhoven, Christine

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Rare Diseases, Acquired Cognitive Impairment, Alzheimer's Disease Related Dementias (ADRD), Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Frontotemporal Dementia (FTD), Genetics, Clinical Research, Dementia, Neurological, Age of Onset, Aged, Aged, 80 and over, Aphasia, Primary Progressive, C9orf72 Protein, Cohort Studies, DNA Repeat Expansion, Europe, Female, Frontotemporal Dementia, Frontotemporal Lobar Degeneration, Geography, Humans, Male, Mediterranean Region, Middle Aged, Principal Component Analysis, Scandinavian and Nordic Countries, Syndrome, International FTD-Genetics Consortium, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveWe sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.MethodsWe evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions.ResultsWe found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10-5; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10-2; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy.ConclusionsOur results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.

Published
2020

19. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

Author

van der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till FM, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart NM, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank), EADB (Alzheimer Disease European DNA biobank), IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia), Netherlands Brain Bank (NBB), Boeve, Bradley F, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel JT, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande AL, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild IA, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, and Clarimón, Jordi

Subjects
DESGESCO (Dementia Genetics Spanish Consortium), EADB, EADB, IFGC (International FTD-Genomics Consortium), IPDGC, IPDGC, RiMod-FTD, Netherlands Brain Bank, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Alzheimer’s disease, Amyotrophic lateral sclerosis, Dementia with Lewy bodies, Frontotemporal dementia, Longevity, Multiple sclerosis, Neurodegenerative disease, PLCG2, Parkinson’s disease, Phospholipase C Gamma 2, Progressive supranuclear palsy, Alzheimer's disease, Parkinson's disease, Alzheimer's Disease, frontotemporal dementia, dementia with Lewy-bodies, progressive suprauclear palsy, Parkinson's Disease, amyotrophic lateral sclerosis, multiple sclerosis, neurodegenerative disease, longevity, Clinical Sciences, Neurosciences, Neurology & Neurosurgery
Abstract

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

Published
2019

20. Exploring Links Between Psychosis and Frontotemporal Dementia Using Multimodal Machine Learning: Dementia Praecox Revisited

Author

Koutsouleris, Nikolaos, Pantelis, Christos, Kambeitz, Joseph, Toivonen, Anna, Turtonen, Otto, Botterweck, Sonja, Kluthausen, Norman, Antoch, Gerald, Caspers, Julian, Wittsack, Hans-Jörg, Blasi, Giuseppe, Pergola, Giulio, Caforio, Grazia, Salokangas, Raimo K R, Fazio, Leonardo, Quarto, Tiziana, Gelao, Barbara, Romano, Raffaella, Andriola, Ileana, Falsetti, Andrea, Barone, Marina, Passiatore, Roberta, Sangiuliano, Marina, Surmann, Marian, Hietala, Jarmo, Bienek, Olga, Dannlowski, Udo, Solana, Ana Beatriz, Abraham, Manuela, Schirmer, Timo, Ferro, Adele, Re, Marta, Sberna, Maurizio, D'Agostino, Armando, Del Fabro, Lorenzo, Bertolino, Alessandro, Perna, Giampaolo, Nobile, Maria, Balestrieri, Matteo, Bonivento, Carolina, Cabras, Giuseppe, Fabbro, Franco, Delvecchio, Giuseppe, Maggioni, Eleonora, Squarcina, Letizia, Gritti, Davide, Brambilla, Paolo, Rossetti, Maria Gloria, Ferrari, Raffaele, Hernandez, Dena Michelle Godwin, Nalls, Michael, Rohrer, Jonathan, Ramasamy, Adaikalavan, Kwok, John, Dobson-Stone, Carol, Brooks, William, Schofield, Peter, Upthegrove, Rachel, Halliday, Glenda, Hodges, John, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Wood, Stephen J, Cruchaga, Carlos, Cairns, Nigel, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Albani, Diego, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Lencer, Rebekka, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Landqvist Waldö, Maria, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R.A., Hsiung, Ging-Yuek, Mann, David, Borgwardt, Stefan, Grafman, Jordan, Morris, Christopher, Attems, Johannes, McKeith, Ian, Thomas, Alan, Pietrini, Pietro, Huey, Edward, Wassermann, Eric, Baborie, Atik, Jaros, Evelyn, Maj, Carlo, Tierney, Michael, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Velakoulis, Dennis, Nöthen, Markus M., Pinessi, Lorenzo, Rogaeva, Ekaterina, George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James, Schlachetzki, Johannes, Uphill, James, Collinge, John, Degenhardt, Franziska, Mead, Simon, Van Deerlin, Vivianna, Marschhauser, Anke, Regenbrecht, Frank, Thoene-Otto, Angelika, Gordulla, Jannis, Ballarini, Tommaso, Engel, Annerose, Pino, Daniele, Leuthold, Dominique, Polyakova, Maryna, Naumann, Heike, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Van Broeckhofen, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Mueller, Karsten, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Villringer, Arno, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N, Fox, Nick C, Warren, Jason D, Spillantini, Maria Grazia, Morris, Huw R, Rizzu, Patrizia, Heutink, Peter, Danek, Adrian, Snowden, Julie S, Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C, Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Fassbender, Klaus, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W, Graff-Radford, Neill R, Petersen, Ronald C, Knopman, David S, Josephs, Keith A, Fliessbach, Klaus, Boeve, Bradley F, Parisi, Joseph E, Seeley, William W, Miller, Bruce L, Karydas, Anna M, Rosen, Howard, van Swieten, John C, Dopper, Elise Gp, Seelaar, Harro, Pijnenburg, Yolande Al, Jahn, Holger, Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A, Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Kornhuber, Johannes, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebouvier, Thibaud, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B, McGuire, Philip, Landwehrmeyer, Bernhard, Hardy, John, Momeni, Parastoo, Barthel, Henryk, Elisa, Semler, Jolina, Lombardi, Christine, von Arnim, Felix, Oberahauser, Kai, Schumacher, Jan, Lehmbeck, Juan-Manuel, Maler, Anderl-Straub, Sarah, Tanja, Richter-Schmidinger, Anke, Hammer-Kaspereit, Timo, Oberstein, Felix, Müller-Sarnowski, Carola, Roßmeier, Albert, Ludolph, Jan, Kassubek, Anja, Schneider, Johannes, Levin, Prudlo, Johannes, Synofzik, Matthis, Wiltfang, Jens, Riedl, Lina, Diehl-Schmid, Janine, Otto, Markus, Meisenzahl, Eva, Falkai, Peter, Dwyer, Dominic B, Schroeter, Matthias L, Consortium, the PRONIA, Haas, Shalaila, Hasan, Alkomiet, Hoff, Claudius, Khanyaree, Ifrah, Melo, Aylin, Muckenhuber-Sternbauer, Susanna, Köhler, Yanis, Urquijo-Castro, Maria-Fernanda, Öztürk, Ömer, Penzel, Nora, Rangnick, Adrian, von Saldern, Sebastian, Spangemacher, Moritz, Tupac, Ana, Weiske, Johanna, Wosgien, Antonia, Krämer, Camilla, Blume, Karsten, Paul, Riya, Hedderich, Dennis, Julkowski, Dominika, Kaiser, Nathalie, Lichtenstein, Thorsten, Milz, Ruth, Nikolaides, Alexandra, Pilgram, Tanja, Seves, Mauro, Wassen, Martina, Andreou, Christina, Dong, Sen, Egloff, Laura, Harrisberger, Fabienne, Heitz, Ulrike, Lenz, Claudia, Leanza, Letizia, Mackintosh, Amatya, Smieskova, Renata, Studerus, Erich, Walter, Anna, Widmayer, Sonja, Popovic, David, Day, Chris, Lowri Griffiths, Sian, Iqbal, Mariam, Pelton, Mirabel, Mallikarjun, Pavan, Stainton, Alexandra, Lin, Ashleigh, Lalousis, Paris, Denissoff, Alexander, Ellilä, Anu, Oeztuerk, Oemer, From, Tiina, Heinimaa, Markus, Ilonen, Tuula, Jalo, Päivi, Laurikainen, Heikki, Luutonen, Antti, Mäkela, Akseli, Paju, Janina, Pesonen, Henri, Säilä, Reetta-Liina, International FTD-Genetics Consortium (IFGC), German Frontotemporal Lobar Degeneration (FTLD) Consortium, PRONIA Consortium, and International FTD-Genetics Consortium Consortium

Subjects
Adult, Male, Medizin, genetics [Alzheimer Disease], genetics [Psychotic Disorders], Neuropsychological Tests, diagnostic imaging [Frontotemporal Dementia], diagnostic imaging [Psychotic Disorders], Machine Learning, methods [Magnetic Resonance Imaging], Brain, Female, Humans, Magnetic Resonance Imaging, Alzheimer Disease, Frontotemporal Dementia, Psychotic Disorders, Schizophrenia, pathology [Brain], genetics [Schizophrenia], ddc:610, diagnostic imaging [Brain], genetics [Frontotemporal Dementia], Settore MED/25 - Psichiatria, Psychiatry and Mental health, diagnostic imaging [Schizophrenia], diagnostic imaging [Alzheimer Disease]
Abstract

Weitere Nicht-UDE Autoren sind nicht genannt. Importance: The behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far. Objective: To use machine learning to compare the expression of structural magnetic resonance imaging (MRI) patterns of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer disease (AD), and schizophrenia; estimate predictability in patients with bvFTD and schizophrenia based on sociodemographic, clinical, and biological data; and examine prognostic value, genetic underpinnings, and progression in patients with clinical high-risk (CHR) states for psychosis or recent-onset depression (ROD). Design, Setting, and Participants: This study included 1870 individuals from 5 cohorts, including (1) patients with bvFTD (n = 108), established AD (n = 44), mild cognitive impairment or early-stage AD (n = 96), schizophrenia (n = 157), or major depression (n = 102) to derive and compare diagnostic patterns and (2) patients with CHR (n = 160) or ROD (n = 161) to test patterns' prognostic relevance and progression. Healthy individuals (n = 1042) were used for age-related and cohort-related data calibration. Data were collected from January 1996 to July 2019 and analyzed between April 2020 and April 2022. Main Outcomes and Measures: Case assignments based on diagnostic patterns; sociodemographic, clinical, and biological data; 2-year functional outcomes and genetic separability of patients with CHR and ROD with high vs low pattern expression; and pattern progression from baseline to follow-up MRI scans in patients with nonrecovery vs preserved recovery. Results: Of 1870 included patients, 902 (48.2%) were female, and the mean (SD) age was 38.0 (19.3) years. The bvFTD pattern comprising prefrontal, insular, and limbic volume reductions was more expressed in patients with schizophrenia (65 of 157 [41.2%]) and major depression (22 of 102 [21.6%]) than the temporo-limbic AD patterns (28 of 157 [17.8%] and 3 of 102 [2.9%], respectively). bvFTD expression was predicted by high body mass index, psychomotor slowing, affective disinhibition, and paranoid ideation (R2= 0.11). The schizophrenia pattern was expressed in 92 of 108 patients (85.5%) with bvFTD and was linked to the C9orf72 variant, oligoclonal banding in the cerebrospinal fluid, cognitive impairment, and younger age (R2= 0.29). bvFTD and schizophrenia pattern expressions forecasted 2-year psychosocial impairments in patients with CHR and were predicted by polygenic risk scores for frontotemporal dementia, AD, and schizophrenia. Findings were not associated with AD or accelerated brain aging. Finally, 1-year bvFTD/schizophrenia pattern progression distinguished patients with nonrecovery from those with preserved recovery. Conclusions and Relevance: Neurobiological links may exist between bvFTD and psychosis focusing on prefrontal and salience system alterations. Further transdiagnostic investigations are needed to identify shared pathophysiological processes underlying the neuroanatomical interface between the 2 disease spectra.

Published
2022

21. Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

Author

Swarup, Vivek, Hinz, Flora I., Rexach, Jessica E., Noguchi, Ken-ichi, Toyoshiba, Hiroyoshi, Oda, Akira, Hirai, Keisuke, Sarkar, Arjun, Seyfried, Nicholas T., Cheng, Chialin, Haggarty, Stephen J., Ferrari, Raffaele, Rohrer, Jonathan D., Ramasamy, Adaikalavan, Hardy, John, Hernandez, Dena G., Nalls, Michael A., Singleton, Andrew B., Kwok, John B. J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cairns, Nigel J., Cruchaga, Carlos, Binetti, Giuliano, Ghidoni, Roberta, Benussi, Luisa, Forloni, Gianluigi, Albani, Diego, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Grafman, Jordan, Morris, Christopher M., Attems, Johannes, Griffiths, Timothy D., McKeith, Ian G., Thomas, Alan J., Jaros, Evelyn, Pietrini, Pietro, Huey, Edward D., Wassermann, Eric M., Tierney, Michael C., Baborie, Atik, Pastor, Pau, Ortega-Cubero, Sara, Razquin, Cristina, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, George-Hyslop, Peter St., Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C. M., Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., Pickering-Brown, Stuart, Momeni, Parastoo, van der Zee, Julie, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F., Leber, Isabelle, Brice, Alexis, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E., Hjermind, Lena E., Riemenschneider, Matthias, Mayhaus, Manuel, Gasparoni, Gilles, Pichler, Sabrina, Ibach, Bernd, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Gerhard, Alexander, Richardson, Anna, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, Seeley, William W., van Swieten, John C., Dopper, Elise G. P., Seelaar, Harro, Pijnenburg, Yolande A. L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebouvier, Thibaud, Ferrucci, Luigi, Kapogiannis, Dimitrios, Lah, James J., Levey, Allan I., Kondou, Shinichi, Geschwind, Daniel H., Int Frontotemporal Dementia Gen, Swarup, Vivek, Hinz, Flora I., Rexach, Jessica E., Noguchi, Ken-ichi, Toyoshiba, Hiroyoshi, Oda, Akira, Hirai, Keisuke, Sarkar, Arjun, Seyfried, Nicholas T., Cheng, Chialin, Haggarty, Stephen J., Ferrari, Raffaele, Rohrer, Jonathan D., Ramasamy, Adaikalavan, Hardy, John, Hernandez, Dena G., Nalls, Michael A., Singleton, Andrew B., Kwok, John B. J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cairns, Nigel J., Cruchaga, Carlo, Binetti, Giuliano, Ghidoni, Roberta, Benussi, Luisa, Forloni, Gianluigi, Albani, Diego, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Grafman, Jordan, Morris, Christopher M., Attems, Johanne, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Jaros, Evelyn, Pietrini, Pietro, Huey, Edward D., Wassermann, Eric M., Tierney, Michael C., Baborie, Atik, Pastor, Pau, Ortega-Cubero, Sara, Razquin, Cristina, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagioti, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, George-Hyslop, Peter St., Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C. M., Uphill, Jame, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., Pickering-Brown, Stuart, Momeni, Parastoo, van der Zee, Julie, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F., Leber, Isabelle, Brice, Alexi, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E., Hjermind, Lena E., Riemenschneider, Matthia, Mayhaus, Manuel, Gasparoni, Gille, Pichler, Sabrina, Ibach, Bernd, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Gerhard, Alexander, Richardson, Anna, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, Seeley, William W., van Swieten, John C., Dopper, Elise G. P., Seelaar, Harro, Pijnenburg, Yolande A. L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebouvier, Thibaud, Ferrucci, Luigi, Kapogiannis, Dimitrio, Lah, James J., Levey, Allan I., Kondou, Shinichi, and Geschwind, Daniel H.

Subjects
Proteomics, Genetics and Molecular Biology (all), 0301 basic medicine, Messenger, Gene regulatory network, Inbred C57BL, Biochemistry, Transgenic, Mice, 0302 clinical medicine, Gene Regulatory Networks, Regulation of gene expression, Cell Death, Drug discovery, Neurodegeneration, Neurodegenerative Diseases, General Medicine, Chemistry, Frontotemporal Dementia, 030220 oncology & carcinogenesis, Frontotemporal dementia, Evolution, Systems biology, Genetic Vectors, Animals, Dementia, Disease Models, Animal, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs, RNA, Messenger, Reproducibility of Results, Transcriptome, tau Proteins, Evolution, Molecular, Computational biology, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, microRNA, medicine, Biochemistry, Genetics and Molecular Biology (all), Animal, Molecular, medicine.disease, 030104 developmental biology, Disease Models, RNA, Human medicine
Abstract

Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.

Published
2018

22. Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

Author

van der Lee, Sven J, Conway, Olivia J, Zettergren, Anna, Christensen, Kaare, Ertekin-Taner, Nilüfer, Scholz, Sonja W, Ramirez, Alfredo, Ruiz, Agustín, Slagboom, Eline, van der Flier, Wiesje M, Holstege, Henne, Mead, S., Synofzik, M., Andlauer, Till F M, van Swieten, J. C., Leber, I., Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Diez-Fairen, Monica, Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Simon-Sanchez, Javier, Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Blesa, R., Landqvist Waldö, M., Lleó, Alberto, Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G-Y R, Mann, D. M. A., Grafman, J., Morris, C. M., Attems, J., Griffiths, T. D., McKeith, I. G., Zetterberg, Henrik, Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Razquin, C., Ortega-Cubero, S., Alonso, E., Nygaard, Marianne, Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Blauwendraat, Cornelis, Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., Savage, Jeanne E, van der Zee, J., Van Broeckhoven, C., Cappa, S. F., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Mengel-From, Jonas, Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Jansen, Iris, Moreno-Grau, Sonia, Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Wagner, Michael, Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Baker, M., Josephs, K. A., Fortea, Juan, Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., Dopper, E. G. P., Seelaar, H., Logroscino, G., Capozzo, R., Novelli, V., Keogh, Michael J, Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H-H, Graff, C., Pasquier, F., Rollin, A., Blennow, Kaj, Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Coppola, G., Skoog, Ingmar, Varpetian, A., Foroud, T. M., Levey, A. I., Kukull, W. A., Mendez, M. F., Ringman, J., Chui, H., Cotman, C., DeCarli, C., Friese, Manuel A, Geschwind, D. H., Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, Carrasquillo, Minerva M, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Kleineidam, Luca, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart N M, Alcolea, Daniel, Wiendl, Heinz, van den Akker, Erik, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO, EADB, IFGC, IPDGC, RiMod-FTD, Bank, Netherlands Brain, Boeve, Bradley F, Hernández, Isabel, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel J T, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, van Eijk, Kristel R, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Stringa, Najada, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande A L, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Chen, Jason A, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild I A, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT, and Clarimón, Jordi

Subjects
0301 basic medicine, Dementia with Lewy bodies, Disease, Bioinformatics, Neurodegenerative disease, 0302 clinical medicine, Missense mutation, media_common, 2. Zero hunger, Longevity, Brain, Parkinson Disease, Phospholipase C Gamma 2, Biobank, 3. Good health, ddc, Frontotemporal Dementia, Microglia, Alzheimer's disease, Alzheimer’s disease, Amyotrophic lateral sclerosis, Frontotemporal dementia, Multiple sclerosis, PLCG2, Parkinson’s disease, Progressive supranuclear palsy, Lewy Body Disease, Risk, Multiple Sclerosis, media_common.quotation_subject, education, Neuroimaging, Genomics, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Alzheimer Disease, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Alleles, Phospholipase C gamma, business.industry, Amyotrophic Lateral Sclerosis, Correction, medicine.disease, 030104 developmental biology, Mutation, Dementia, Neurology (clinical), business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target. The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

Published
2019

23. A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers

Author

Zhang, Ming, Ferrari, Raffaele, Tartaglia, Maria Carmela, Keith, Julia, Surace, Ezequiel I, Wolf, Uri, Sato, Christine, Grinberg, Mark, Liang, Yan, Xi, Zhengrui, Dupont, Kyle, McGoldrick, Philip, Weichert, Anna, McKeever, Paul M, Schneider, Raphael, McCorkindale, Michael D, Manzoni, Claudia, Rademakers, Rosa, Graff-Radford, Neill R, Dickson, Dennis W, Parisi, Joseph E, Boeve, Bradley F, Petersen, Ronald C, Miller, Bruce L, Seeley, William W, Van Swieten, John C, Van Rooij, Jeroen, Pijnenburg, Yolande, Van Der Zee, Julie, Van Broeckhoven, Christine, Le Ber, Isabelle, Van Deerlin, Vivianna, Suh, EunRan, Rohrer, Jonathan D, Mead, Simon, Graff, Caroline, Öijerstedt, Linn, Pickering-Brown, Stuart, Rollinson, Sara, Rossi, Giacomina, Tagliavini, Fabrizio, Brooks, William S, Dobson-Stone, Carol, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Binetti, Giuliano, Benussi, Luisa, Ghidoni, Roberta, Nacmias, Benedetta, Sorbi, Sandro, Bruni, Amalia C, Galimberti, Daniela, Scarpini, Elio, Rainero, Innocenzo, Rubino, Elisa, Clarimon, Jordi, Lleó, Alberto, Ruiz, Agustin, Hernández, Isabel, Pastor, Pau, Diez-Fairen, Monica, Borroni, Barbara, Pasquier, Florence, Deramecourt, Vincent, Lebouvier, Thibaud, Perneczky, Robert, Diehl-Schmid, Janine, Grafman, Jordan, Huey, Edward D, Mayeux, Richard, Nalls, Michael A, Hernandez, Dena, Singleton, Andrew, Momeni, Parastoo, Zeng, Zhen, Hardy, John, Robertson, Janice, Zinman, Lorne, Rogaeva, Ekaterina, International FTD-Genomics Consortium (IFGC), Schneider, Raphael [0000-0003-1776-2418], Manzoni, Claudia [0000-0001-5367-4023], Diez-Fairen, Monica [0000-0003-1882-0309], and Apollo - University of Cambridge Repository

Subjects
Male, Aging, amyotrophic lateral sclerosis, Heterozygote, genetic association, Genotype, Neurodegenerative, Medical and Health Sciences, frontotemporal dementia, Polymorphism, Single Nucleotide, Rare Diseases, age of onset, Clinical Research, C9orf72, Acquired Cognitive Impairment, Genetics, 2.1 Biological and endogenous factors, Humans, Polymorphism, Aetiology, Age of Onset, Aged, Neurology & Neurosurgery, C9orf72 Protein, International FTD-Genomics Consortium, Human Genome, Psychology and Cognitive Sciences, Amyotrophic Lateral Sclerosis, Neurosciences, Single Nucleotide, DNA Methylation, Middle Aged, Brain Disorders, Gene Expression Regulation, Frontotemporal Dementia, Neurological, Dementia, CpG Islands, Female, ALS, Biotechnology
Abstract

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

Published
2019
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24. MAPT H1 haplotype is associated with late-onset Alzheimer's disease risk in APOE ε 4 noncarriers: Results from the dementia genetics Spanish consortium

Author

Pastor, Pau, Moreno, Fermín, Antonell, Anna, Elcoroaristizabal, Xabier, Lleó, Alberto, Blesa, Rafael, Fortea, Juan, Belbin, Olivia, Alcolea, Daniel, Carmona-Iragui, María, Sánchez-Saudinós, M Belén, Sala, Isabel, Anton-Aguirre, Sofía, Coto, Eliecer, Morenas, Estrella, Ribosa, Roser, Colom-Cadena, Martí, Cervera, Laura, Muñoz, Laia, Dols-Icardo, Oriol, Clarimón, Jordi, Ortega-Cubero, Sara, Hernandez, Isabel, Tárraga, Lluís, Boada, Mercè, Kulisevsky, Jaime, Vázquez-Higuera, José Luis, Infante, Jon, Rábano, Alberto, Fernández-Blázquez, Miguel Ángel, Valentí, Meritxell, Indakoetxea, Begoña, Barandiarán, Myriam, Gorostidi, Ana, Frank-García, Ana, Sastre, Isabel, Lorenzo, Elena, Ruiz, Agustín, Pastor, María A, Lennarz, Martina, Maier, Wolfgang, Rámirez, Alfredo, Serrano-Ríos, Manuel, Lee, Suzee E, Sánchez-Juan, Pascual, Consortium, Dementia Genetic Spanish, Combarros, Onofre, Lorenzo-Betancor, Oswaldo, Pastor, Maria A, Hernández, Isabel, Lafuente, Asunción, Rosende-Roca, Maitée, Mauleón, Ana, Vargas, Liliana, Rodríguez, Octavio, Calero, Miguel, Abdelnour, Carla, Alegret, Montserrat, Espinosa, Ana, Ortega, Gemma, Sanabria, Ángela, Ibarria, Marta, Diego, Susana, Canyabate, Pilar, Moreno, Mariola, Buendía, Mar, López de Munain, Adolfo, Pancho, Ana, Palacio, María Eugenia, Ruiz, Susana, Tantinya, Natalia, Tarragona, Marina, Morera, América, Guitart, Marina, Sotolongo Grau, Oscar, Martín, Elvira, Fernández, Victòria, Bullido, Maria J, Sánchez-Valle, Raquel, Molinuevo, José Luis, Lladó, Albert, Rami, Lorena, Alvarez, Victoria, de Pancorbo, Marian M, Pozueta, Ana, González Suarez, Andrea, Carro, Eva, Rodriguez-Rodriguez, Eloy, Mateo, Ignacio, Berciano, José, Bullido, María J, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Universidad Pública de Navarra, Universidad del País Vasco, Universidad Autónoma de Madrid, Fundació ACE. Institut Català de Neurociències Aplicades, University of Bonn, University of California, Universitat de Barcelona, Universitat Autònoma de Barcelona, and Universitat Oberta de Catalunya (UOC)

Subjects
Gerontology, Male, associació genètica, genetic association, Apolipoprotein E4, A152T, enfermedad de Alzheimer, genetics [Alzheimer Disease], frontotemporal dementia, MAPT, Alzheimer, Enfermedad de, genetics [Genetic Predisposition to Disease], genetics [Frontotemporal Dementia], genetics [Apolipoprotein E4], Aged, 80 and over, General Neuroscience, General Medicine, demencia frontotemporal, Middle Aged, Alzheimer's disease, Psychiatry and Mental health, Clinical Psychology, demència frontotemporal, genetics [Polymorphism, Single Nucleotide], Christian ministry, Female, Alzheimer’s disease, Frontotemporal dementia, Late onset, MAPT protein, human, tau Proteins, Polymorphism, Single Nucleotide, asociación genética, Alzheimer Disease, malaltia d'Alzheimer, mental disorders, medicine, Dementia, Humans, Genetic Predisposition to Disease, ddc:610, Genetic association, Aged, business.industry, Haplotype, medicine.disease, nervous system diseases, H1H2, genetics [tau Proteins], Alzheimer, Malaltia d', Logistic Models, Haplotypes, Spain, Disease risk, Geriatrics and Gerontology, business
Abstract

The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR)=2.03; p=0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR=1.12; p=0.0005). Stratification analysis showed that this association was mainly driven by APOE ε4 noncarriers (OR=1.14; p=0.0025). MAPT H1 was also associated with risk for PD (OR=1.30; p=0.0003) and PSP (OR=3.18; p=8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ε4 AD., Spanish Ministry of Science and Innovation SAF 2006-10126 (2006–2009) and SAF2010-22329-C02-01 (2011–2013) to P.P and by the UTE project FIMA to P.P. Grants from the Ministry of Science (SAF2010-15558) and CIBERNED. Agust´ın Ruiz is supported by grant PI13/02434 (Acción Estratégica en Salud. Instituto de Salud Carlos III. Ministerio de Economía y Competitividad, Spain). Grant: Consolider (CSD2010-00045).

Published
2015

25. Frontotemporal dementia and its subtypes: a genome-wide association study

Author

Ferrari, Raffaele, Hernandez, Dena G, Nalls, Michael A, Rohrer, Jonathan D, Ramasamy, Adaikalavan, Kwok, John BJ, Dobson-Stone, Carol, Brooks, William S, Schofield, Peter R, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian RA, Hsiung, Ging-Yuek R, Mann, David MA, Grafman, Jordan, Morris, Christopher M, Attems, Johannes, Griffiths, Timothy D, McKeith, Ian G, Thomas, Alan J, Pietrini, P, Huey, Edward D, Wassermann, Eric M, Baborie, Atik, Jaros, Evelyn, Tierney, Michael C, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B, Schlachetzki, Johannes CM, Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Deschamps, William, Van Langenhove, Tim, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, and Rossor, Martin N

Subjects
Adult, Male, Aging, Genotype, Clinical Sciences, Neurodegenerative, Rare Diseases, Clinical Research, 80 and over, Genetics, Acquired Cognitive Impairment, Humans, 2.1 Biological and endogenous factors, Aetiology, Alzheimer's Disease Related Dementias (ADRD), Aged, Neurology & Neurosurgery, Human Genome, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Middle Aged, Brain Disorders, Frontotemporal Dementia (FTD), Frontotemporal Dementia, Neurological, Female, Dementia, Genome-Wide Association Study
Abstract

BackgroundFrontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.MethodsWe did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p

Published
2014

26. Analysis of the CHCHD10 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis from Spain.

Author

Dols-Icardo, Oriol, Nebot, Irene, Gorostidi, Ana, Ortega-Cubero, Sara, Hernández, Isabel, Rojas-García, Ricard, García-Redondo, Alberto, Povedano, Monica, Lladó, Albert, Álvarez, Victoria, Sánchez-Juan, Pascual, Pardo, Julio, Jericó, Ivonne, Vázquez-Costa, Juan, Sevilla, Teresa, Cardona, Fernando, Indakoechea, Begoña, Moreno, Fermín, Fernández-Torrón, Roberto, and Muñoz-Llahuna, Laia

Subjects
FRONTOTEMPORAL dementia, AMYOTROPHIC lateral sclerosis, MOLECULAR genetics, NEUROSCIENCES, ALZHEIMER'S patients, PATIENTS
Published
2015
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27. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

Author

Van Der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, Van Den Akker, Erik, Hernández, Isabel, Van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till FM, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, De Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, Van Berckel, Bart NM, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA Biobank), EADB (Alzheimer Disease European DNA Biobank), IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), RiMod-FTD (Risk And Modifying Factors In Fronto-Temporal Dementia), Netherlands Brain Bank (NBB), Boeve, Bradley F, Petersen, Ronald C, Ferman, Tanis J, Van Gerpen, Jay A, Reinders, Marcel JT, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, Van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, De Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande AL, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild IA, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT (Genetic Investigation In Frontotemporal Dementia And Alzheimer’s Disease) Study Group, Clarimón, Jordi, Christensen, Kaare, Ertekin-Taner, Nilüfer, Scholz, Sonja W, Ramirez, Alfredo, Ruiz, Agustín, Slagboom, Eline, Van Der Flier, Wiesje M, and Holstege, Henne

Subjects
Lewy Body Disease, Risk, Multiple Sclerosis, Dementia with Lewy bodies, Longevity, Neuroimaging, Neurodegenerative disease, PLCG2, Alzheimer Disease, Humans, Genetic Predisposition to Disease, Alleles, Phospholipase C gamma, Progressive supranuclear palsy, Amyotrophic Lateral Sclerosis, Brain, Parkinson Disease, Phospholipase C Gamma 2, 3. Good health, Frontotemporal Dementia, Mutation, Parkinson’s disease, Dementia, Microglia, Alzheimer’s disease, Genome-Wide Association Study
Abstract

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

28. C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts

Author

Costa, Beatrice, Manzoni, Claudia, Bernal-Quiros, Manuel, Kia, Demis A, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Andreassen, Ole, Anfossi, Maria, Bagnoli, Silvia, Benussi, Luisa, Bernardi, Livia, Binetti, Giuliano, Blackburn, Daniel, Boada, Mercè, Borroni, Barbara, Bowns, Lucy, Bråthen, Geir, Bruni, Amalia C, Chiang, Huei-Hsin, Clarimon, Jordi, Colville, Shuna, Conidi, Maria E, Cope, Tom E, Cruchaga, Carlos, Cupidi, Chiara, Di Battista, Maria Elena, Diehl-Schmid, Janine, Diez-Fairen, Monica, Dols-Icardo, Oriol, Durante, Elisabetta, Flisar, Dušan, Frangipane, Francesca, Galimberti, Daniela, Gallo, Maura, Gallucci, Maurizio, Ghidoni, Roberta, Graff, Caroline, Grafman, Jordan H, Grossman, Murray, Hardy, John, Hernández, Isabel, Holloway, Guy JT, Huey, Edward D, Illán-Gala, Ignacio, Karydas, Anna, Khoshnood, Behzad, Kramberger, Milica G, Kristiansen, Mark, Lewis, Patrick A, Lleó, Alberto, Madhan, Gaganjit K, Maletta, Raffaele, Maver, Aleš, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce, Mol, Merel O, Momeni, Parastoo, Moreno-Grau, Sonia, Morris, Chris M, Nacmias, Benedetta, Nilsson, Christer, Novelli, Valeria, Öijerstedt, Linn, Padovani, Alessandro, Pal, Suvankar, Panchbhaya, Yasmin, Pastor, Pau, Peterlin, Borut, Piaceri, Irene, Pickering-Brown, Stuart, Pijnenburg, Yolande AL, Puca, Annibale A, Rainero, Innocenzo, Rendina, Antonella, Richardson, Anna MT, Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rossi, Giacomina, Rossmeier, Carola, Rowe, James B, Rubino, Elisa, Ruiz, Agustín, Sanchez-Valle, Raquel, Sando, Sigrid B, Santillo, Alexander F, Saxon, Jennifer, Scarpini, Elio, Serpente, Maria, Smirne, Nicoletta, Sorbi, Sandro, Suh, EunRan, Tagliavini, Fabrizio, Thompson, Jennifer C, Trojanowski, John Q, Van Deerlin, Vivianna M, Van Der Zee, Julie, Van Broeckhoven, Christine, Van Rooij, Jeroen, Van Swieten, John C, Veronesi, Arianna, Vitale, Emilia, Waldö, Maria L, Woodward, Cathy, Yokoyama, Jennifer, Escott-Price, Valentina, Polke, James M, Ferrari, Raffaele, and International FTD-Genetics Consortium

Subjects
Aged, 80 and over, Male, Principal Component Analysis, DNA Repeat Expansion, C9orf72 Protein, Geography, Mediterranean Region, Syndrome, Middle Aged, Scandinavian and Nordic Countries, Cohort Studies, Europe, Aphasia, Primary Progressive, Frontotemporal Dementia, Humans, Female, Age of Onset, Frontotemporal Lobar Degeneration, 10. No inequality, Aged
Abstract

OBJECTIVE: We sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases. METHODS: We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions. RESULTS: We found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10-5; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10-2; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy. CONCLUSIONS: Our results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.

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