RESUMO
The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.
RESUMO
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.
Assuntos
Demência/genética , Longevidade/genética , Mutação , Fosfolipase C gama/genética , Alelos , Doença de Alzheimer/genética , Esclerose Lateral Amiotrófica/genética , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Demência Frontotemporal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Doença por Corpos de Lewy/genética , Microglia/metabolismo , Esclerose Múltipla/genética , Neuroimagem , Doença de Parkinson/genética , RiscoRESUMO
OBJECTIVE: The assessment of individuals from families affected by familial frontotemporal dementia (FTD) allows the evaluation of preclinical or pre-diagnosis disease markers. The current work aims to investigate the existence of a cognitive phase in GRN mutation carriers before overt clinical symptoms begin. METHODS: We performed a longitudinal neuropsychological analysis (three assessments in 4 years) in a group of presymptomatic c.709-1G>A progranulin (GRN) (n=15) mutation carriers and non-carrier relatives (n=25) from seven FTD families. RESULTS: GRN mutation carriers showed subtle decline over the longitudinal follow-up in several different domains (namely, attention, facial affect recognition, decision-making, language, and memory). The differences between groups were most marked in the facial affect recognition test, with improvement in the non-carrier group and decline in the GRN mutation carrier group, with very large effect sizes. CONCLUSIONS: Facial affect recognition may decline before clinical diagnosis and makes the adapted version of the Picture of Facial Affect a potential candidate for early detection of GRN-associated FTD. (JINS, 2019, 25, 39-47).
Assuntos
Afeto/fisiologia , Disfunção Cognitiva , Expressão Facial , Reconhecimento Facial/fisiologia , Demência Frontotemporal , Progranulinas/genética , Adulto , Idoso , Biomarcadores , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Feminino , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/genética , Demência Frontotemporal/fisiopatologia , Heterozigoto , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-IdadeRESUMO
Mutations in the progranulin (PGRN) gene have been identified as a cause of frontotemporal dementia (FTD). However, little is known about the neuropsychological abilities of asymptomatic carriers of these mutations. The aim of the study was to assess cognitive functioning in asymptomatic c.709-1G>A PGRN mutation carriers. We hypothesized that poorer neuropsychological performance could be present before the development of clinically significant FTD symptoms. Thirty-two asymptomatic first-degree relatives of FTD patients carrying the c.709-1G>A mutation served as study participants, including 13 PGRN mutation carriers (A-PGRN+) and 19 non-carriers (PGRN-). A neuropsychological battery was administered. We found that the A-PGRN+ participants obtained significantly poorer scores than PGRN- individuals on tests of attention (Trail-Making Test Part A), mental flexibility (Trail-Making Test Part B), and language (Boston Naming Test). Poorer performance on these tests in asymptomatic PGRN mutation carriers may reflect a prodromal phase preceding the onset of clinically significant symptoms of FTD.
Assuntos
Transtornos Cognitivos/etiologia , Transtornos Cognitivos/genética , Demência Frontotemporal/complicações , Predisposição Genética para Doença/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação/genética , Adulto , Idoso , Atenção/fisiologia , Análise Mutacional de DNA , Função Executiva/fisiologia , Feminino , Demência Frontotemporal/genética , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Progranulinas , Estudos RetrospectivosRESUMO
Measures of social cognition have now become central in neuropsychology, being essential for early and differential diagnoses, follow-up, and rehabilitation in a wide range of conditions. With the scientific world becoming increasingly interconnected, international neuropsychological and medical collaborations are burgeoning to tackle the global challenges that are mental health conditions. These initiatives commonly merge data across a diversity of populations and countries, while ignoring their specificity. OBJECTIVE: In this context, we aimed to estimate the influence of participants' nationality on social cognition evaluation. This issue is of particular importance as most cognitive tasks are developed in highly specific contexts, not representative of that encountered by the world's population. METHOD: Through a large international study across 18 sites, neuropsychologists assessed core aspects of social cognition in 587 participants from 12 countries using traditional and widely used tasks. RESULTS: Age, gender, and education were found to impact measures of mentalizing and emotion recognition. After controlling for these factors, differences between countries accounted for more than 20% of the variance on both measures. Importantly, it was possible to isolate participants' nationality from potential translation issues, which classically constitute a major limitation. CONCLUSIONS: Overall, these findings highlight the need for important methodological shifts to better represent social cognition in both fundamental research and clinical practice, especially within emerging international networks and consortia. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
Assuntos
Emoções , Transtornos Mentais , Cognição , Escolaridade , Humanos , NeuropsicologiaRESUMO
Frontotemporal lobar degeneration because of mutations in the progranulin (PGRN) gene presents a high variability both in the clinical phenotype and age of onset of disease. Factors that influence this variability remain largely unknown. The aim of our study was to determine whether selected genetic variables modify age at onset of disease in our series of 21 patients with a single splicing mutation (c.709-1G>A) in the PGRN gene, all of whom were of Basque descent. In our analysis, we included the following genetic variables: PGRN rs5848 and rs9897526 polymorphisms, APOE and microtubule-associated protein tau genotypes, and PRNP codon 129 polymorphism. We found no association between PGRN polymorphisms, APOE and microtubule-associated protein tau genotypes, and age at onset of the disease; whereas we report evidence for an association between PRNP codon 129 polymorphism and age at onset of disease in frontotemporal dementia-PGRN(+) patients. MM homozygous carriers presented onset of disease on average 8.5 years earlier than patients who carried at least 1 valine on their PRNP codon 129 (MV or VV). The biological justification for this association remains speculative.
Assuntos
Idade de Início , Demência Frontotemporal/genética , Predisposição Genética para Doença/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação , Polimorfismo de Nucleotídeo Único , Príons/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Proteínas Priônicas , Progranulinas , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Many factors may converge in healthy aging in the oldest old, but their association and predictive power on healthy or functionally impaired aging has yet to be demonstrated. By detecting healthy aging and in turn, poor aging, we could take action to prevent chronic diseases associated with age. We conducted a pilot study comparing results of a set of markers (peripheral blood mononuclear cell or PBMC telomere length, circulating Aß peptides, anti-Aß antibodies, and ApoE status) previously associated with poor aging or cognitive deterioration, and their combinations, in a cohort of "neurologically healthy" (both motor and cognitive) nonagenarians (n = 20) and functionally impaired, institutionalized nonagenarians (n = 38) recruited between 2014 and 2015. We recruited 58 nonagenarians (41 women, 70.7%; mean age: 92.37 years in the neurologically healthy group vs. 94.13 years in the functionally impaired group). Healthy nonagenarians had significantly higher mean PBMC telomere lengths (mean = 7, p = 0.001), this being inversely correlated with functional impairment, and lower circulating Aß40 (total in plasma fraction or TP and free in plasma fraction or FP), Aß42 (TP and FP) and Aß17 (FP) levels (FP40 131.35, p = 0.004; TP40 299.10, p = 0.007; FP42 6.29, p = 0.009; TP42 22.53, p = 0.019; FP17 1.32 p = 0.001; TP17 4.47, p = 0.3), after adjusting by age. Although healthy nonagenarians had higher anti-Aß40 antibody levels (net adsorbed signal or NAS ± SD: 0.211 ± 0.107), the number of participants that pass the threshold (NAS > 3) to be considered as positive did not show such a strong association. There was no association with ApoE status. Additionally, we propose a "Composite Neurologically Healthy Aging Score" combining TP40 and mean PBMC telomere length, the strongest correlation of measured biomarkers with neurologically healthy status in nonagenarians (AUC = 0.904).
RESUMO
BACKGROUND: The co-occurrence of the c.709-1G>A GRN mutation and the p.A152T MAPT variant has been identified in 18 Basque families affected by frontotemporal dementia (FTD). We aimed to investigate the influence of the p.A152T MAPT variant on the clinical and neuropathological features of these Basque GRN families. METHODS AND FINDINGS: We compared clinical characteristics of 14 patients who carried the c.709-1G>A GRN mutation (GRN+/A152T-) with 21 patients who carried both the c.709-1G>A GRN mutation and the p.A152T MAPT variant (GRN+/A152T+). Neuropsychological data (n = 17) and plasma progranulin levels (n = 23) were compared between groups, and 7 subjects underwent neuropathological studies. We genotyped six short tandem repeat markers in the two largest families. By the analysis of linkage disequilibrium decay in the haplotype block we estimated the time when the first ancestor to carry both genetic variants emerged. GRN+/A152T+ and GRN+/A152T- patients shared similar clinical and neuropsychological features and plasma progranulin levels. All were diagnosed with an FTD disorder, including behavioral variant FTD or non fluent / agrammatic variant primary progressive aphasia, and shared a similar pattern of neuropsychological deficits, predominantly in executive function, memory, and language. All seven participants with available brain autopsies (6 GRN+/A152T+, 1 GRN+/A152T-) showed frontotemporal lobar degeneration with TDP-43 inclusions (type A classification), which is characteristic of GRN carriers. Additionally, all seven showed mild to moderate tau inclusion burden: five cases lacked ß-amyloid pathology and two cases had Alzheimer's pathology. The co-occurrence of both genes within one individual is recent, with the birth of the first GRN+/A152T+ individual estimated to be within the last 50 generations (95% probability). CONCLUSIONS: In our sample, the p.A152T MAPT variant does not appear to show a discernible influence on the clinical phenotype of GRN carriers. Whether p.A152T confers a greater than expected propensity for tau pathology in these GRN carriers remains an open question.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação/genética , Proteínas tau/genética , Proteínas de Ligação a DNA , Demografia , Família , Feminino , Demência Frontotemporal/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Testes Neuropsicológicos , Fenótipo , Progranulinas , Espanha , Proteínas tau/metabolismoRESUMO
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)â=â2.03; pâ=â0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (ORâ=â1.12; pâ=â0.0005). Stratification analysis showed that this association was mainly driven by APOE É4 noncarriers (ORâ=â1.14; pâ=â0.0025). MAPT H1 was also associated with risk for PD (ORâ=â1.30; pâ=â0.0003) and PSP (ORâ=â3.18; pâ=â8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE É4 AD.
Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas tau/genética , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E4/genética , Feminino , Demência Frontotemporal/genética , Haplótipos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , EspanhaAssuntos
Proteínas Reguladoras de Apoptose/genética , Arginina/genética , Proteínas de Ligação a DNA/genética , Distonia/genética , Mutação/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Criança , Éxons/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
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.
Assuntos
Demência Frontotemporal/genética , Estudos de Associação Genética , Variação Genética/genética , Glicoproteínas de Membrana/genética , Receptores Imunológicos/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Feminino , Demência Frontotemporal/classificação , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Fenótipo , Análise de Sequência de DNARESUMO
Studies in asymptomatic granulin gene (GRN) mutation carriers are essential to improve our understanding of the pattern and timing of early morphologic brain changes in frontotemporal lobar degeneration. The main objectives of this study were to assess the effect of age in cortical thickness changes (CTh) in preclinical GRN mutation carriers and to study the relationship of CTh with cognitive performance in GRN mutation carriers. We calculated CTh maps in 13 asymptomatic carriers of the c.709-1G>A GRN mutation and 13 age- and sex-matched healthy subjects. Asymptomatic GRN mutation carriers presented different patterns of age-related cortical thinning in the right superior temporal and middle temporal gyri and the banks of the superior temporal sulcus bilaterally when compared with controls. Cortical thickness was correlated with neuropsychological test scores: Trail Making Tests A and B, and the Boston Naming Test. Distinctive age-related cortical thinning in asymptomatic GRN mutation carriers in lateral temporal cortices suggests an early and disease-specific effect in these areas.
Assuntos
Envelhecimento/genética , Envelhecimento/patologia , Córtex Cerebral/patologia , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Adulto , Idoso , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , ProgranulinasRESUMO
Gerstmann-Sträussler-Scheinker (GSS) disease is a prion disease associated with prion protein gene (PRNP) mutations. We report a novel PRNP mutation (Y218N) associated with GSS disease in a pathologically confirmed case and in two other affected family members. The clinical features of these cases met criteria for possible Alzheimer disease and possible frontotemporal dementia. Neuropathologic analysis revealed deposition of proteinase K-resistant prion protein (PrP(res)), widespread hyperphosphorylated tau pathology, abnormal accumulation of mitochondria in the vicinity of PrP deposits, and expression of mutant ubiquitin (UBB(+1)) in neurofibrillary tangles and dystrophic neurites. Prion protein immunoblotting using 3F4 and 1E4 antibodies disclosed multiple bands ranging from approximately 20 kd to 80 kd and lower bands of 15 kd and approximately 10 kd, the latter only seen after a long incubation. These bands were partially resistant to proteinase K pretreatment. This pattern differs from those seen in Creutzfeldt-Jakob disease andresembles those reported in other GSS cases. The approximately 10kd band was recognized with anti-PrP C-terminus antibodies but not with anti-N terminus antibodies, suggesting PrP truncation at the N terminal. This new mutation extends the list of known mutations responsible for GSS disease and reinforces its clinical heterogeneity. Genetic examination of the PRNP gene should be included in the workup of patients with poorly classifiable dementia.
Assuntos
Asparagina/genética , Demência Frontotemporal/genética , Doença de Gerstmann-Straussler-Scheinker/genética , Emaranhados Neurofibrilares/patologia , Príons/genética , Tirosina/genética , Encéfalo/metabolismo , Encéfalo/patologia , Análise Mutacional de DNA/métodos , Progressão da Doença , Saúde da Família , Feminino , Demência Frontotemporal/complicações , Doença de Gerstmann-Straussler-Scheinker/complicações , Humanos , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/genética , Proteínas Priônicas , Príons/metabolismo , Ubiquitina/metabolismo , Canais de Ânion Dependentes de Voltagem/metabolismoRESUMO
BACKGROUND: There is an increasing interest in the clinico-pathological correlation of mutations in progranulin (PGRN) and frontotemporal lobar degeneration (FTLD) complex diseases. We aim to study the PGRN expression variability in patients with different clinical features for a better understanding of its roles in FTLD disease. METHODS: We sequenced the PGRN gene in 72 patients suffering from FTLD (25 familial and 47 sporadic cases) and in 24 asymptomatic at-risk relatives. We also analyzed PGRN expression in blood by quantitative real-time polymerase chain reaction from 37 patients, 8 asymptomatic mutation carriers, and 10 control subjects as well as in brain tissue from 16 patients and 9 control subjects. RESULTS: Four novel mutations were associated with familial and sporadic FTLD and familial dementia associated with amyotrophic lateral sclerosis. We identified a close association between the IVS6-1G>A mutation in PGRN and corticobasal syndrome. Brain tissue was available for carriers of two of the four mutations (IVS6-1 G>A and P357HfsX3). Immunohistochemical analysis revealed ubiquitin- and TDP-43positive and tau/alpha-synuclein negative immunoreactive neuronal intranuclear inclusions. The relative expression of PGRN in the clinical sample was significantly lower in carriers of the IVS6-1 G>A than in control subjects. CONCLUSIONS: Progranulopathies are a major cause of the main phenotypes included in the FTLD complex. According to our results, the level of expression of PGRN in blood could be a useful marker both for diagnostics of part of the spectrum of FTLD conditions and for monitoring future treatments that might boost the level of PGRN in this disorder.
Assuntos
Demência/genética , Expressão Gênica/fisiologia , Predisposição Genética para Doença , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação/genética , RNA/metabolismo , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Proteínas de Ligação a DNA/metabolismo , Demência/metabolismo , Demência/patologia , Feminino , Humanos , Corpos de Inclusão Intranuclear/patologia , Masculino , Testes Neuropsicológicos , Progranulinas , Estudos Retrospectivos , Análise de Sequência , Ubiquitina/metabolismo , alfa-Sinucleína/metabolismo , Proteínas tau/genéticaRESUMO
Rapid-onset dystonia-parkinsonism is a hereditary disease characterized by a combination of dystonic and parkinsonian symptoms. Bulbar musculature is predominantly affected by dystonia. The onset is usually abrupt and the progression of the disease over years is minimal or absent. Homovanillic acid levels in cerebrospinal fluid can be diminished, suggesting that the pathogenesis of the disease is related to some dysfunction in dopaminergic neurotransmission. However, no abnormality has been found in positron emission tomography studies and levodopa does not improve symptoms. The genetic abnormality is not known, but evidence for linkage to markers on chromosome 19q13 has been reported. We describe the case of a woman with a clinical picture highly suggestive of rapid onset dystonia-parkinsonism (RDP) and no family history of the disease.
Assuntos
Distúrbios Distônicos/diagnóstico , Doença de Parkinson/diagnóstico , Adulto , Dopamina/metabolismo , Distúrbios Distônicos/etiologia , Feminino , Ácido Homovanílico/líquido cefalorraquidiano , Humanos , Doença de Parkinson/etiologia , Fatores de Tempo , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
Levodopa-induced ocular dyskinesias are very uncommon. Usually they occur simultaneously with limb peak-dose choreatic dyskinesias. We report on a patient with leftward and upward deviations of gaze during the peak effect of levodopa, and hypothesize that a severe dopaminergic denervation in the caudate nucleus is needed for the appearance of these levodopa-induce ocular dyskinesias.
Assuntos
Antiparkinsonianos/uso terapêutico , Levodopa/uso terapêutico , Transtornos da Motilidade Ocular/induzido quimicamente , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/efeitos adversos , Diagnóstico Diferencial , Humanos , Levodopa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Transtornos da Motilidade Ocular/diagnósticoRESUMO
Limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by any of over 150 mutations in the calpain-3 (CAPN3) gene. Of those, 2362AG --> TCATCT is particularly prevalent in Basque patients, and this mutation was hypothesized to have arisen in the Basque Country. To explore the natural history of this mutation, we genotyped 65 Basque and non-Basque patients with LGMD2A who carry the 2362AG --> TCATCT mutation for four microsatellites within or flanking the gene. A particular haplotype was found in three-fourths of the patients and was assumed to be ancestral. From the average number of recombinations and mutations accumulated from this ancestral haplotype, the age of the 2362AG ----> TCATCT mutation was estimated to be 50 generations (i.e., 1,250 years), which is more recent than the Paleolithic Basque heritage. The subsequent spread of the 2362AG --> TCATCT mutation can be related to gene flow out of the Basque Country, even across a cultural border.