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1.
Nat Commun ; 12(1): 3417, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099642

RESUMO

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.


Assuntos
Doença de Alzheimer/genética , Herança Multifatorial , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Apolipoproteínas E/genética , Estudos de Casos e Controles , Estudos de Coortes , Conjuntos de Dados como Assunto , Feminino , Seguimentos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medição de Risco/métodos , Fatores de Risco
2.
Artigo em Inglês | MEDLINE | ID: mdl-32669313

RESUMO

OBJECTIVE: To identify transcriptomic changes, neuropathologic correlates, and cellular subpopulations in the motor cortex of sporadic amyotrophic lateral sclerosis (ALS). METHODS: We performed massive RNA sequencing of the motor cortex of patients with ALS (n = 11) and healthy controls (HCs; n = 8) and analyzed gene expression alterations, differential isoform usage, and gene coexpression networks. Furthermore, we used cell type deconvolution algorithms with human single-nucleus RNA sequencing data as reference to identify perturbations in cell type composition associated with ALS. We performed immunohistochemical techniques to evaluate neuropathologic changes in this brain region. RESULTS: We report extensive RNA expression alterations at gene and isoform levels, characterized by the enrichment of neuroinflammatory and synaptic-related pathways. The assembly of gene coexpression modules confirmed the involvement of these 2 major transcriptomic changes, which also showed opposite directions related to the disease. Cell type deconvolution revealed an overrepresentation of microglial cells in ALS compared with HC. Notably, microgliosis was driven by a subcellular population presenting a gene expression signature overlapping with the recently described disease-associated microglia (DAM). Using immunohistochemistry, we further evidenced that this microglial subpopulation is overrepresented in ALS and that the density of pTDP43 aggregates negatively correlates with the proportion of microglial cells. CONCLUSIONS: DAM has a central role in microglia-related neuroinflammatory changes in the motor cortex of patients with ALS, and these alterations are coupled with a reduced expression of postsynaptic transcripts.


Assuntos
Esclerose Amiotrófica Lateral , Microglia , Córtex Motor , Transcriptoma/genética , Idoso , Idoso de 80 Anos ou mais , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/imunologia , Feminino , Humanos , Masculino , Microglia/imunologia , Microglia/metabolismo , Pessoa de Meia-Idade , Córtex Motor/imunologia , Córtex Motor/metabolismo , Análise de Sequência de RNA , Bancos de Tecidos
3.
Neurobiol Aging ; 92: 7-11, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32335360

RESUMO

A circular-transcriptome-wide study has recently linked differential expression of circular RNAs (circRNAs) in brain tissue with Alzheimer's disease (AD). We aimed at replicating the major findings in an independent series of sporadic and familial AD. We also included cases with frontotemporal lobar degeneration (FTLD), comprising brain specimens with TDP-43 aggregates (FTLD-TDP43) and samples that presented Tau accumulation (FTLD-Tau). Using a quantitative polymerase chain reaction approach, we evaluated 8 circRNAs that surpassed the significant threshold in the former meta-analysis (circHOMER1, circDOCK1, circFMN1, circKCNN2, circRTN4, circMAN2A1, circMAP7, and circPICALM). Average expression changes between patients with AD and controls followed the same directions as previously reported. We also confirmed an exacerbated alteration in circRNA expression in the familial AD group compared with the sporadic forms. Two circRNAs (circHOMER1 and circKCNN2) also showed significant expression alterations in the group of FTLD-Tau and FTLD-TDP43, respectively. Overall, these results reinforce the conception that expression of circRNAs is different in AD, and also suggest a wider involvement of this particular class of RNA in other neurodegenerative dementias.


Assuntos
Doença de Alzheimer/genética , Degeneração Lobar Frontotemporal/genética , Expressão Gênica , RNA Circular/genética , RNA Circular/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Lobo Frontal/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase
4.
Neuropharmacology ; 168: 108014, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32097768

RESUMO

Molecular genetics has been an invaluable tool to help understand the molecular basis of neurodegenerative dementias. In this review, we provide an overview of the genetic architecture underlying some of the most prevalent causes of dementia, including Alzheimer's dementia, frontotemporal lobar degeneration, Lewy body dementia, and prion diseases. We also discuss the complexity of the human genome and how the novel technologies have revolutionized and accelerated the way we screen the variety of our DNA. Finally, we also provide some examples about how this genetic knowledge is being transferred into the clinic through personalized medicine. This article is part of the special issue entitled 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.


Assuntos
Doença de Alzheimer/genética , Degeneração Lobar Frontotemporal/genética , Doença por Corpos de Lewy/genética , Farmacogenética/métodos , Doenças Priônicas/genética , Doença de Alzheimer/diagnóstico , Animais , Demência/diagnóstico , Demência/genética , Degeneração Lobar Frontotemporal/diagnóstico , Testes Genéticos/métodos , Testes Genéticos/tendências , Humanos , Doença por Corpos de Lewy/diagnóstico , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Farmacogenética/tendências , Doenças Priônicas/diagnóstico
5.
Alzheimers Dement (N Y) ; 5: 597-609, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31650016

RESUMO

Introduction: The SPIN (Sant Pau Initiative on Neurodegeneration) cohort is a multimodal biomarker platform designed for neurodegenerative disease research following an integrative approach. Methods: Participants of the SPIN cohort provide informed consent to donate blood and cerebrospinal fluid samples, receive detailed neurological and neuropsychological evaluations, and undergo a structural 3T brain MRI scan. A subset also undergoes other functional or imaging studies (video-polysomnogram, 18F-fluorodeoxyglucose PET, amyloid PET, Tau PET). Participants are followed annually for a minimum of 4 years, with repeated cerebrospinal fluid collection and imaging studies performed every other year, and brain donation is encouraged. Results: The integration of clinical, neuropsychological, genetic, biochemical, imaging, and neuropathological information and the harmonization of protocols under the same umbrella allows the discovery and validation of key biomarkers across several neurodegenerative diseases. Discussion: We describe our particular 10-year experience and how different research projects were unified under an umbrella biomarker program, which might be of help to other research teams pursuing similar approaches.

7.
PLoS One ; 14(2): e0212647, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30794663

RESUMO

OBJECTIVE: Mutations in CD59 cause CIDP-like polyneuropathy in children with inherited chronic hemolysis. We hypothesized that mutations in CD59 might be found in a subset of sporadic CIDP patients. METHODS: 35 patients from two centers, fulfilling the EFNS/PNS diagnostic criteria for CIDP were included. CD59 coding region was amplified by PCR and Sanger sequenced. RESULTS: One rare variant was detected in a patient which resulted in a synonymous change and predicted to be neutral. Pathogenic variants were absent in our cohort. INTERPRETATION: Our pilot study suggests that mutations in CD59 are absent in adult-onset sporadic CIDP.


Assuntos
Antígenos CD59/genética , Mutação , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto
8.
Mult Scler ; 25(11): 1535-1538, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-29985092

RESUMO

The role of cerebrospinal fluid (CSF) mitochondrial DNA (mtDNA) levels as biomarker in multiple sclerosis (MS) is unknown. We determined CSF mtDNA levels in a cohort of 237 individuals, including patients with MS and clinically isolated syndrome (CIS), inflammatory and non-inflammatory neurological controls, and cognitively healthy controls (HC). mtDNA concentration was measured by droplet digital polymerase chain reaction. CSF mtDNA levels were increased in all pathological conditions compared with HC, though no differences were observed between relapse-onset and progressive MS clinical forms, CIS patients and neurological controls. These findings do not support the determination of CSF mtDNA levels as a useful biomarker in MS clinical practice.


Assuntos
DNA Mitocondrial/líquido cefalorraquidiano , Esclerose Múltipla Crônica Progressiva/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Adulto , Estudos de Casos e Controles , Doenças Desmielinizantes/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase
9.
J Neurol Neurosurg Psychiatry ; 89(2): 162-168, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28889094

RESUMO

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a clinical, pathological and genetic continuum. OBJECTIVES: The purpose of the present study was to assess the mutation burden that is present in patients with concurrent ALS and FTD (ALS/FTD) not carrying the chromosome 9 open reading frame 72 (C9orf72) hexanucleotide repeat expansion, the most important genetic cause in both diseases. METHODS: From an initial group of 973 patients with ALS, we retrospectively selected those patients fulfilling diagnostic criteria of concomitant ALS and FTD lacking the repeat expansion mutation in C9orf72. Our final study group consisted of 54 patients clinically diagnosed with ALS/FTD (16 with available postmortem neuropathological diagnosis). Data from whole exome sequencing were used to screen for mutations in known ALS and/or FTD genes. RESULTS: We identified 11 patients carrying a probable pathogenic mutation, representing an overall mutation frequency of 20.4%. TBK1 was the most important genetic cause of ALS/FTD (n=5; 9.3%). The second most common mutated gene was SQSTM1, with three mutation carriers (one of them also harboured a TBK1 mutation). We also detected probable pathogenic genetic alterations in TAF15, VCP and TARDBP and possible pathogenic mutations in FIG4 and ERBB4. CONCLUSION: Our results indicate a high genetic burden underlying the co-occurrence of ALS and FTD and expand the phenotype associated with TAF15, FIG4 and ERBB4 to FTD. A systematic screening of ALS and FTD genes could be indicated in patients manifesting both diseases without the C9orf72 expansion mutation, regardless of family history of disease.


Assuntos
Esclerose Amiotrófica Lateral/genética , Demência Frontotemporal/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Amiotrófica Lateral/complicações , Proteínas de Ligação a DNA/genética , Feminino , Flavoproteínas/genética , Demência Frontotemporal/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Monoéster Fosfórico Hidrolases/genética , Receptor ErbB-4/genética , Estudos Retrospectivos , Proteína Sequestossoma-1/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Proteína com Valosina/genética
10.
Neurobiol Aging ; 53: 192.e1-192.e4, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28089353

RESUMO

Low levels of cell-free mitochondrial DNA (mtDNA) in the cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients have been identified and proposed as a novel biomarker for the disease. The lack of validation studies of previous results prompted us to replicate this finding in a comprehensive series of patients and controls. We applied droplet digital polymerase chain reaction in CSF specimens from 124 patients representing the AD spectrum and 140 neurologically healthy controls. The following preanalytical and analytical parameters were evaluated: the effect of freeze-thaw cycles on mtDNA, the linearity of mtDNA load across serial dilutions, and the mtDNA levels in the diagnostic groups. We found a wide range of mtDNA copies, which resulted in a high degree of overlap between groups. Although the AD group presented significantly higher mtDNA counts, the receiver-operating characteristic analysis disclosed an area under the curve of 0.715 to distinguish AD patients from controls. MtDNA was highly stable with low analytical variability. In conclusion, mtDNA levels in CSF show a high interindividual variability, with great overlap within phenotypes and presents low sensitivity for AD.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , DNA Mitocondrial/líquido cefalorraquidiano , Idoso , Biomarcadores/líquido cefalorraquidiano , Feminino , Marcadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , Curva ROC
11.
Mov Disord ; 32(1): 165-169, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28124432

RESUMO

BACKGROUND: The analysis of coverage depth in next-generation sequencing data allows the detection of gene dose alterations. We explore the frequency of such structural events in a Spanish cohort of sporadic PD cases. METHODS: Gene dose alterations were detected with the eXome-Hidden Markov Model (XHMM) software from depth of coverage in resequencing data available for 38 Mendelian and other risk PD loci in 394 individuals (249 cases and 145 controls) and subsequently validated by quantitative PCR. RESULTS: We identified 10 PD patients with exon dosage alterations in PARK2, GBA-GBAP1, and DJ1. Additional functional variants, including 2 novel nonsense mutations (p.Arg1552Ter in LRRK2 and p.Trp90Ter in PINK1), were confirmed by Sanger sequencing. This combined approach disclosed the genetic cause of 12 PD cases. CONCLUSIONS: Gene dose alterations related to PD can be correctly identified from targeting resequencing data. This approach substantially improves the detection rate of cases with causal genetic alterations. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Doença de Parkinson/genética , Análise de Sequência de DNA/métodos , Estudos de Coortes , Variações do Número de Cópias de DNA , Humanos , Espanha
12.
J Alzheimers Dis ; 50(2): 539-46, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26682689

RESUMO

BACKGROUND: Progranulin is implicated in frontotemporal dementia (FTD), but its role in other neurodegenerative disorders is unknown. OBJECTIVE: To investigate the levels of progranulin (PGRN) in cerebrospinal fluid (CSF) in different neurodegenerative dementias and their correlation with levels in plasma in cognitively normal subjects. METHODS: We measured PGRN in CSF in 229 patients with amnestic mild cognitive impairment, Alzheimer's disease dementia, sporadic FTD, dementia with Lewy bodies, corticobasal syndrome, or progressive supranuclear palsy. We also measured PGRN in CSF and plasma in 74 cognitively normal individuals. We examined the correlation between PGRN levels in CSF and diagnosis, cortical thickness, genetic factors and other CSF biomarkers. We also investigated the correlation between plasma and CSF levels of PGRN in cognitively normal individuals. RESULTS: CSF levels did not differ across diagnoses or correlate with cortical thickness. Polymorphism rs5848 in GRN influenced CSF PGRN levels, but APOEɛ4 allele did not. Amyloid-ß42, t-tau, p-tau, and YKL-40 levels correlated weakly with PGRN in CSF. We found a weak correlation (r = 0.362) between plasma and CSF PGRN levels in cognitively normal individuals. CONCLUSIONS: Our findings do not support a diagnostic value of CSF PGRN in neurodegenerative diseases. Our data confirm that levels of PGRN in plasma do not reflect accurately levels in CSF in cognitively normal controls. These data should be considered in clinical trials aiming to increase PGRN.


Assuntos
Demência/líquido cefalorraquidiano , Peptídeos e Proteínas de Sinalização Intercelular/líquido cefalorraquidiano , Doenças Neurodegenerativas/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Progranulinas , Proteínas tau/líquido cefalorraquidiano
13.
Am J Med Genet B Neuropsychiatr Genet ; 171B(2): 175-80, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26453547

RESUMO

The H1 haplotype of the 17q21.31 inversion polymorphism has been consistently associated with progressive supranuclear palsy, corticobasal degeneration, and Parkinson's disease in Caucasians. Recently, large polymorphic segmental duplications resulting into complex rearrangements at this locus with a high diversity range in human populations have been revealed. We sought to explore whether the two multi-allelic copy number variants that are present in the H1 clade (with segmental duplications of 300 and 218 kilobases in length) could be responsible for the known H1-related risk of developing these neurodegenerative disorders. A total of 857 Spanish subjects including 330 patients with Parkinson's disease, 96 with progressive supranuclear palsy, 55 with corticobasal degeneration, 51 dementia with Lewy bodies, and 325 neurologically healthy controls, were genotyped for the H1/H2 haplotype. Subsequently, the two copy number variants that are characteristic of the H1 haplotype were evaluated through a high-resolution approach based on droplet digital polymerase chain reaction, in all H1 homozygous subjects. The H1 allele was significantly overrepresented in all diagnostic groups compared with controls (Parkinson's disease, P = 0.0001; progressive supranuclear palsy, P = 1.22 × 10(-6) ; corticobasal degeneration, P = 0.0002; and dementia with Lewy bodies, P = 0.032). However, no dosage differences were found for any of the two copy number variants analyzed. The H1 haplotype is associated with the risk of several neurodegenerative disorders, including dementia with Lewy bodies. However, common structural diversity within the 17q21.31-H1 clade does not explain this genetic association.


Assuntos
Cromossomos Humanos Par 17/genética , Variações do Número de Cópias de DNA/genética , Doenças Neurodegenerativas/genética , Idoso , Estudos de Casos e Controles , Demografia , Feminino , Frequência do Gene/genética , Humanos , Masculino
14.
Hum Mol Genet ; 24(7): 2023-34, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25504046

RESUMO

Parkinson's disease (PD) can be divided into familial (Mendelian) and sporadic forms. A number of causal genes have been discovered for the Mendelian form, which constitutes 10-20% of the total cases. Genome-wide association studies have successfully uncovered a number of susceptibility loci for sporadic cases but those only explain a small fraction (6-7%) of PD heritability. It has been observed that some genes that confer susceptibility to PD through common risk variants also contain rare causing mutations for the Mendelian forms of the disease. These results suggest a possible functional link between Mendelian and sporadic PD and led us to investigate the role that rare and low-frequency variants could have on the sporadic form. Through a targeting approach, we have resequenced at 49× coverage the exons and regulatory regions of 38 genes (including Mendelian and susceptibility PD genes) in 249 sporadic PD patients and 145 unrelated controls of European origin. Unlike susceptibility genes, Mendelian genes show a clear general enrichment of rare functional variants in PD cases, observed directly as well as with Tajima's D statistic and several collapsing methods. Our findings suggest that rare variation on PD Mendelian genes may have a role in the sporadic forms of the disease.


Assuntos
Doença de Parkinson/genética , Adulto , Idoso , Estudos de Casos e Controles , Éxons , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , /genética
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