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Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) are the two major neurodegenerative diseases with distinct clinical and neuropathological profiles. The aim of this report is to conduct a population-based investigation in well-characterized APP, PSEN1, PSEN2, MAPT, GRN, and C9orf72 mutation carriers/pedigrees from the north, the center, and the south of Italy. We retrospectively analyzed the data of 467 Italian individuals. We identified 21 different GRN mutations, 20 PSEN1, 11 MAPT, 9 PSEN2, and 4 APP. Moreover, we observed geographical variability in mutation frequencies by looking at each cohort of participants, and we observed a significant difference in age at onset among the genetic groups. Our study provides evidence that age at onset is influenced by the genetic group. Further work in identifying both genetic and environmental factors that modify the phenotypes in all groups is needed. Our study reveals Italian regional differences among the most relevant AD/FTD causative genes and emphasizes how the collaborative studies in rare diseases can provide new insights to expand knowledge on genetic/epigenetic modulators of age at onset.
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Doença de Alzheimer , Demência Frontotemporal , Mutação , Proteínas tau , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/epidemiologia , Itália/epidemiologia , Demência Frontotemporal/genética , Demência Frontotemporal/epidemiologia , Demência Frontotemporal/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Proteínas tau/genética , Idade de Início , Proteína C9orf72/genética , Presenilina-2/genética , Estudos Retrospectivos , Precursor de Proteína beta-Amiloide/genética , Presenilina-1/genética , Progranulinas/genética , Adulto , Idoso de 80 Anos ou mais , Predisposição Genética para DoençaRESUMO
Alzheimer's disease (AD) and Frontotemporal lobar degeneration (FTLD) represent the most common forms of neurodegenerative dementias with a highly phenotypic variability. Herein, we investigated the role of genetic variants related to the immune system and inflammation as genetic modulators in AD and related dementias. In patients with sporadic AD/FTLD (n = 300) and GRN/C9orf72 mutation carriers (n = 80), we performed a targeted sequencing of 50 genes belonging to the immune system and inflammation, selected based on their high expression in brain regions and low tolerance to genetic variation. The linear regression analyses revealed two genetic variants: (i) the rs1049296 in the transferrin (TF) gene, shown to be significantly associated with age at onset in the sporadic AD group, anticipating the disease onset of 4 years for each SNP allele with respect to the wild-type allele, and (ii) the rs7550295 in the calsyntenin-1 (CLSTN1) gene, which was significantly associated with age at onset in the C9orf72 group, delaying the disease onset of 17 years in patients carrying the SNP allele. In conclusion, our data support the role of genetic variants in iron metabolism (TF) and in the modulation of the calcium signalling/axonal anterograde transport of vesicles (CLSTN1) as genetic modulators in AD and FTLD due to C9orf72 expansions.
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Idade de Início , Doença de Alzheimer , Proteína C9orf72 , Degeneração Lobar Frontotemporal , Humanos , Doença de Alzheimer/genética , Proteína C9orf72/genética , Degeneração Lobar Frontotemporal/genética , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Expansão das Repetições de DNA/genética , Idoso de 80 Anos ou mais , Polimorfismo de Nucleotídeo Único , Transferrina/genética , Transferrina/metabolismo , Predisposição Genética para Doença , Variação GenéticaRESUMO
Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two major neurodegenerative diseases causing dementia. Due to similar clinical phenotypes, differential diagnosis is challenging without specific biomarkers. Beta-site Amyloid Precursor Protein cleaving enzyme 1 (BACE1) is a ß-secretase pivotal in AD pathogenesis. In AD and mild cognitive impairment subjects, BACE1 activity is increased in brain/cerebrospinal fluid, and plasma levels appear to reflect those in the brain. In this study, we aim to evaluate serum BACE1 activity in FTD, since, to date, there is no evidence about its role. The serum of 30 FTD patients and 30 controls was analyzed to evaluate (i) BACE1 activity, using a fluorescent assay, and (ii) Glial Fibrillary Acid Protein (GFAP) and Neurofilament Light chain (NfL) levels, using a Simoa kit. As expected, a significant increase in GFAP and NfL levels was observed in FTD patients compared to controls. Serum BACE1 activity was not altered in FTD patients. A significant increase in serum BACE1 activity was shown in AD vs. FTD and controls. Our results support the hypothesis that serum BACE1 activity is a potential biomarker for the differential diagnosis between AD and FTD.
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Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Biomarcadores , Demência Frontotemporal , Proteína Glial Fibrilar Ácida , Humanos , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Demência Frontotemporal/sangue , Demência Frontotemporal/diagnóstico , Secretases da Proteína Precursora do Amiloide/sangue , Secretases da Proteína Precursora do Amiloide/metabolismo , Diagnóstico Diferencial , Feminino , Masculino , Biomarcadores/sangue , Idoso , Projetos Piloto , Ácido Aspártico Endopeptidases/sangue , Pessoa de Meia-Idade , Proteína Glial Fibrilar Ácida/sangue , Proteínas de Neurofilamentos/sangue , Estudos de Casos e ControlesRESUMO
The introduction of computerized medical records in hospitals has reduced burdensome activities like manual writing and information fetching. However, the data contained in medical records are still far underutilized, primarily because extracting data from unstructured textual medical records takes time and effort. Information Extraction, a subfield of Natural Language Processing, can help clinical practitioners overcome this limitation by using automated text-mining pipelines. In this work, we created the first Italian neuropsychiatric Named Entity Recognition dataset, PsyNIT, and used it to develop a Transformers-based model. Moreover, we collected and leveraged three external independent datasets to implement an effective multicenter model, with overall F1-score 84.77 %, Precision 83.16 %, Recall 86.44 %. The lessons learned are: (i) the crucial role of a consistent annotation process and (ii) a fine-tuning strategy that combines classical methods with a "low-resource" approach. This allowed us to establish methodological guidelines that pave the way for Natural Language Processing studies in less-resourced languages.
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Mineração de Dados , Idioma , Humanos , Mineração de Dados/métodos , Registros Eletrônicos de Saúde , Itália , Processamento de Linguagem Natural , Estudos Multicêntricos como AssuntoRESUMO
Dysfunctions in the endo-lysosomal system have been hypothesized to underlie neurodegeneration in major neurocognitive disorders due to Alzheimer's disease (AD), Frontotemporal Lobar Degeneration (FTLD), and Lewy body disease (DLB). The aim of this study is to investigate whether these diseases share genetic variability in the endo-lysosomal pathway. In AD, DLB, and FTLD patients and in controls (948 subjects), we performed a targeted sequencing of the top 50 genes belonging to the endo-lysosomal pathway. Genetic analyses revealed (i) four previously reported disease-associated variants in the SORL1 (p.N1246K, p.N371T, p.D2065V) and DNAJC6 genes (p.M133L) in AD, FTLD, and DLB, extending the previous knowledge attesting SORL1 and DNAJC6 as AD- and PD-related genes, respectively; (ii) three predicted null variants in AD patients in the SORL1 (p.R985X in early onset familial AD, p.R1207X) and PPT1 (p.R48X in early onset familial AD) genes, where loss of function is a known disease mechanism. A single variant and gene burden analysis revealed some nominally significant results of potential interest for SORL1 and DNAJC6 genes. Our data highlight that genes controlling key endo-lysosomal processes (i.e., protein sorting/transport, clathrin-coated vesicle uncoating, lysosomal enzymatic activity regulation) might be involved in AD, FTLD and DLB pathogenesis, thus suggesting an etiological link behind these diseases.
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Doença de Alzheimer/metabolismo , Degeneração Lobar Frontotemporal/metabolismo , Predisposição Genética para Doença , Proteínas de Choque Térmico HSP40/genética , Proteínas Relacionadas a Receptor de LDL/genética , Doença por Corpos de Lewy/metabolismo , Proteínas de Membrana Transportadoras/genética , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Feminino , Degeneração Lobar Frontotemporal/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doença por Corpos de Lewy/genética , Lisossomos/metabolismo , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNARESUMO
OBJECTIVE: To assess the diagnostic and prognostic value of serum neurofilament light (NfL) and serum phospho-Tau181 (p-Tau181) in a large cohort of patients with frontotemporal lobar degeneration (FTLD). METHODS: In this retrospective study, performed on 417 participants, we analysed serum NfL and p-Tau181 concentrations with an ultrasensitive single molecule array (Simoa) approach. We assessed the diagnostic values of serum biomarkers in the differential diagnosis between FTLD, Alzheimer's disease (AD) and healthy ageing; their role as markers of disease severity assessing the correlation with clinical variables, cross-sectional brain imaging and neurophysiological data; their role as prognostic markers, considering their ability to predict survival probability in FTLD. RESULTS: We observed significantly higher levels of serum NfL in patients with FTLD syndromes, compared with healthy controls, and lower levels of p-Tau181 compared with patients with AD. Serum NfL concentrations showed a high accuracy in discriminating between FTLD and healthy controls (area under the curve (AUC): 0.86, p<0.001), while serum p-Tau181 showed high accuracy in differentiating FTLD from patients with AD (AUC: 0.93, p<0.001). In FTLD, serum NfL levels correlated with measures of cognitive function, disease severity and behavioural disturbances and were associated with frontotemporal atrophy and indirect measures of GABAergic deficit. Moreover, serum NfL concentrations were identified as the best predictors of survival probability. CONCLUSIONS: The assessment of serum NfL and p-Tau181 may provide a comprehensive view of FTLD, aiding in the differential diagnosis, in staging disease severity and in defining survival probability.
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Doença de Alzheimer/diagnóstico , Degeneração Lobar Frontotemporal/sangue , Degeneração Lobar Frontotemporal/diagnóstico , Proteínas de Neurofilamentos/sangue , Proteínas tau/sangue , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos Transversais , Diagnóstico Diferencial , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Motor/fisiologia , Neuroimagem , Fosforilação , Prognóstico , Estudos Retrospectivos , Estimulação Magnética TranscranianaRESUMO
Frontotemporal dementia (FTD) is a common form of dementia among early-onset cases. Several genetic factors for FTD have been revealed, but a large proportion of FTD cases still have an unidentified genetic origin. Recent studies highlighted common pathobiological mechanisms among neurodegenerative diseases. In the present study, we investigated a panel of candidate genes, previously described to be associated with FTD and/or other neurodegenerative diseases by targeted next generation sequencing (NGS). We focused our study on sporadic FTD (sFTD), devoid of disease-causing mutations in GRN, MAPT and C9orf72. Since genetic factors have a substantially higher pathogenetic contribution in early onset patients than in late onset dementia, we selected patients with early onset (<65 years). Our study revealed that, in 50% of patients, rare missense potentially pathogenetic variants in genes previously associated with Alzheimer's disease, Parkinson disease, amyotrophic lateral sclerosis and Lewy body dementia (GBA, ABCA7, PARK7, FUS, SORL1, LRRK2, ALS2), confirming genetic pleiotropy in neurodegeneration. In parallel, a synergic genetic effect on FTD is suggested by the presence of variants in five different genes in one single patient. Further studies employing genome-wide approaches might highlight pathogenic variants in novel genes that explain the still missing heritability of FTD.
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Demência Frontotemporal/genética , Mutação de Sentido Incorreto , Doença de Alzheimer/genética , Esclerose Lateral Amiotrófica/genética , Feminino , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doença por Corpos de Lewy/genética , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/genéticaRESUMO
INTRODUCTION: The goal of the present work was to assess the incidence of dementia with onset before the age of 65 years (i.e., young-onset dementia [YOD]) and define the frequencies of young-onset Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD), and dementia with Lewy bodies (DLB) in the general population. METHODS: The study was conducted from January 1, 2019 to December 31, 2019 in Brescia province (population: 1,268,455). During the study period, all new YOD cases (incident YOD) were counted, and all patients' records reviewed. The incidence was standardized to the Italian general population in 2019. RESULTS: A total of 29 YOD patients were diagnosed. The age-sex standardized incidence rate was 4.58 (95% confidence interval, 3.07-6.58) per 100,000 person-years. No difference in incidence rate between YOD due to AD or FTLD (P = 0.83) and between sexes (P = 0.81) was observed. YOD incidence increased with age, reaching its peak after 60 years. DISCUSSION: Presenting neurodegenerative YOD phenotypes encompasses both AD and FTLD. Improved knowledge on YOD epidemiology is essential to adequately plan and organize health services.
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BACKGROUND: A growing number of studies are attempting to understand how effective cognitive interventions may be for patients with amnestic mild cognitive impairment (aMCI), particularly in relation to their memory problems. METHODS: The present study aimed to explore the benefits of a working memory (WM) training program in aMCI patients. Patients (N = 20) were randomly assigned to two training programs: the experimental group practiced with a verbal WM task, while the active control group conducted educational activities on memory. RESULTS: Results showed that the aMCI patients completing the WM training obtained specific gains in the task trained with some transfer effects on other WM measures (visuospatial WM) and on processes involved in or related to WM, e.g. fluid intelligence (the Cattell test) and long-term memory. This was not the case for the aMCI control group, who experienced only a very limited improvement. CONCLUSION: This pilot study suggests that WM training could be a valuable method for improving cognitive performance in aMCI patients, possibly delaying the onset of Alzheimer's disease.
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Amnésia/complicações , Cognição/fisiologia , Disfunção Cognitiva/psicologia , Transtornos da Memória/psicologia , Transferência de Experiência , Idoso , Idoso de 80 Anos ou mais , Amnésia/psicologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/diagnóstico , Feminino , Humanos , Masculino , Transtornos da Memória/diagnóstico , Transtornos da Memória/etiologia , Memória de Curto Prazo , Testes Neuropsicológicos , Prática Psicológica , Valor Preditivo dos Testes , Curva ROC , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Objectives: There is increasing evidence for a protective role of nutritional factors on cognitive decline. Many studies have reported a preventive effect of specific dietary patterns, in particular of the Mediterranean diet (MD), on the risk of cognitive decline, but only limited evidence is available about its effects on neuropsychological performance. The aim of this work is to evaluate the relationship between nutrition and cognitive performance in a frail elderly population living in Northern Italy. Methods: In this study we have investigated the impact of the Mediterranean dietary pattern on cognitive performance in a frail elderly population (n = 140). Structural equation modeling was applied to highlight the interrelationship between three cognitive domains: i) Verbal Fluency; ii) Attention/executive function; iii) Memory, and two MD factors: i) Nutrition; ii) Anthropometric/physical activity. In addition, the Multiple Correspondence Analysis was performed to detect the food and nutrients with the highest association with MD and nutritional status. Results: In our sample, 54% of subjects have a medium-high adherence to MD and only 4% have a risk of malnutrition. The variable Nutrition was significantly associated (p < 0.001) with the cognitive domain Attention/executive function, with an increase in Nutrition directly associated with a better performance in Attention/executive function. Conclusions: This study provides preliminary evidence of an association between good nutritional status, related to a high adherence to the MD, and cognitive performance in a non-clinical elderly population living in Northern Italy.
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Disfunção Cognitiva , Desnutrição , Humanos , Idoso , Estado Nutricional , Idoso Fragilizado , Desnutrição/epidemiologia , CogniçãoRESUMO
Population-based registries represent a unique sample to estimate survival. The aim of the present study was to assess survival rates and predictors of outcome in incidental frontotemporal lobar degeneration (FTLD). Incident cases with FTLD, included between January 1, 2017 to December 31, 2017, have been followed for five years. Median survival was 8.16 years from disease onset and 5.38 years from diagnosis. Survival rates did not differ between phenotypes. Shorter disease duration from onset to diagnosis was associated with poorer outcome (pâ=â0.01). FTLD is a relatively homogeneous disease in terms of survival. Future multinational population-based studies are needed to confirm these findings.
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Demência Frontotemporal , Degeneração Lobar Frontotemporal , Humanos , Degeneração Lobar Frontotemporal/epidemiologia , Degeneração Lobar Frontotemporal/diagnóstico , Sistema de RegistrosRESUMO
Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative syndrome. Defects of copper (Cu) and iron (Fe) homeostasis are involved in the development of several neurodegenerative diseases and their homeostasis is interconnected by the Cu-protein ceruloplasmin (Cp), responsible for Fe oxidative state. In this study we assessed Fe, transferrin (Trf), ferritin, Cp specific activity (eCp/iCp), Cp/Trf ratio, and Trf saturation in 60 FTLD patients and 43 healthy controls, and discussed the results in relation to Cu homeostasis. The significant decrease of the eCp/iCp in the FTLD patients supports the involvement of Fe imbalance in the onset and progression of FTLD.
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Ceruloplasmina/metabolismo , Ferritinas/sangue , Degeneração Lobar Frontotemporal/sangue , Ferro/sangue , Transferrina/metabolismo , Idoso , Afasia Primária Progressiva/sangue , Afasia Primária Progressiva/metabolismo , Estudos de Casos e Controles , Feminino , Demência Frontotemporal/sangue , Demência Frontotemporal/metabolismo , Humanos , Ferro/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
Eating behavior can change during aging due to physiological, psychological, and social changes. Modifications can occur at different levels: (1) in food choice, (2) in eating habits, and (3) in dietary intake. A good dietary behavior, like the Mediterranean dietary pattern, can be a protective factor for some aging related pathologies, such as dementia, while a worse eating behavior can lead to pathological conditions such as malnutrition. Changes in eating behavior can also be linked to the onset of dementia: for some types of dementia, such as frontotemporal dementia, dietary changes are one of the key clinical diagnostic feature, for others, like Alzheimer's disease, weight loss is a clinical reported feature. For these reasons, it is important to be able to assess eating behavior in a proper way, considering that there are normal age-related changes. An adequate assessment of dietary behavior can help to plan preventive intervention strategies for heathy aging or can help to identify abnormal behaviors that underline aging related-diseases. In this review, we have analyzed normal age-related and dementia-related changes and the tools that can be used to assess eating behavior. Thus, we make recommendations to screening and monitoring eating behavior in aging and dementia, and to adopt these tools in clinical practice.
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BACKGROUND: A consensus protocol for genetic counselling and testing of familial dementia, the Italian Dominantly Inherited Alzheimer's and Frontotemporal Network (IT-DIAfN) protocol, has been developed in Italy by a network of expert dementia centres. The aim of this study is to evaluate feasibility and acceptability of the genetic counselling and testing process, as undertaken according to the IT-DIAfN protocol in one of the IT-DIAfN dementia research centres. METHODS: The protocol was tested by a multidisciplinary team at the IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy, on affected individuals with suspected inherited forms of Alzheimer's disease (AD) or frontotemporal dementia (FTD), and to healthy at-risk relatives. The genetic counselling and testing process consisted of (i) pre-test consultation and psychological assessment (ii) genetic testing, (iii) genetic test result disclosure and (iv) follow-up consultation and psychological assessment. RESULTS: Twenty affected individuals from 17 families fulfilled the family history criteria of the IT-DIAfN protocol for suspected inherited dementia (17 for AD, 2 for FTD, 1 for inclusion body myopathy with Paget disease of bone and frontotemporal dementia) and were included in the protocol. Nineteen out of 20 affected individuals received the genetic test result (one left after the pre-test consultation being not ready to cope with an unfavourable outcome). A pathogenic mutation was found in 6 affected individuals (1 in PSEN1, 2 in PSEN2, 1 in GRN, 1 in MAPT, 1 in VCP). Eleven healthy at-risk relatives asked to undergo predictive testing and were included in the protocol. Three completed the protocol, including follow-up; one did not ask for the genetic test result after genetic testing; and eight withdrew before the genetic testing, mainly due to an increased awareness about the possible consequences of an unfavourable test result. To date, no catastrophic reactions were reported at the follow-up. CONCLUSIONS: Our case series shows that a structured genetic counselling and testing protocol for inherited dementia can be implemented in both affected individuals and at-risk relatives in a research setting. The procedure was shown to be safe in terms of occurrence of catastrophic events. A formal validation in larger cohorts is needed.
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Doença de Alzheimer , Demência Frontotemporal , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Consenso , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/genética , Aconselhamento Genético , Humanos , ItáliaRESUMO
BACKGROUND: It is still unknown if serum glial fibrillary acidic protein (GFAP) is a useful marker in frontotemporal lobar degeneration (FTLD). OBJECTIVE: To assess the diagnostic and prognostic value of serum GFAP in a large cohort of patients with FTLD. METHODS: In this retrospective study, performed on 406 participants, we measured serum GFAP concentration with an ultrasensitive Single molecule array (Simoa) method in patients with FTLD, Alzheimer's disease (AD), and in cognitively unimpaired elderly controls. We assessed the role of GFAP as marker of disease severity by analyzing the correlation with clinical variables, neurophysiological data, and cross-sectional brain imaging. Moreover, we evaluated the role of serum GFAP as a prognostic marker of disease survival. RESULTS: We observed significantly higher levels of serum GFAP in patients with FTLD syndromes, except progressive supranuclear palsy, compared with healthy controls, but not compared with AD patients. In FTLD, serum GFAP levels correlated with measures of cognitive dysfunction and disease severity, and were associated with indirect measures of GABAergic deficit. Serum GFAP concentration was not a significant predictor of survival. CONCLUSION: Serum GFAP is increased in FTLD, correlates with cognition and GABAergic deficits, and thus shows promise as a biomarker of disease severity in FTLD.
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Degeneração Lobar Frontotemporal/sangue , Degeneração Lobar Frontotemporal/diagnóstico por imagem , Proteína Glial Fibrilar Ácida/sangue , Índice de Gravidade de Doença , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Degeneração Lobar Frontotemporal/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
OBJECTIVE: The goal of the present work, based on a collaborative research registry in Italy (the Salento-Brescia Registry), was to assess the incidence of frontotemporal lobar degeneration (FTLD) and to define the frequencies of different FTLD phenotypes in the general population. METHODS: The study was conducted from January 1, 2017, to December 31, 2017, in 2 Italian provinces: Lecce (in Puglia) in the south (area 2,799.07 km2, inhabitants 802,082) and Brescia (in Lombardy) in the north (area 4,785.62 km2, inhabitants 1,262,678). During the study period, all new cases of FTLD (incident FTLD) were counted, and all patients' records were reviewed. The incidence was standardized to the Italian general population in 2017. RESULTS: In the 2 provinces, 63 patients with FTLD were diagnosed. The incidence rate for FTLD was 3.05 (95% confidence interval [CI] 2.34-3.90) per 100,000 person-years (py), while the age-sex standardized incidence rate was 3.09 (95% CI 2.95-3.23) per 100,000 py. In the Italian population, the lifetime risk was 1:400. There was a progressive increase in FTLD incidence across age groups, reaching its peak in the 75- to 79-year-old group, with an incidence rate of 15.97 (95% CI 8.94-26.33) per 100,000 py. The behavioral variant of frontotemporal dementia was the most common phenotype (37%). No difference in crude incidence rate between the 2 provinces was observed. CONCLUSION: FTLD is a more common form of dementia than previously recognized, with a risk spanning in a wide age range and with maximum incidence in the mid-70s. Improved knowledge of FTLD epidemiology will help to provide appropriate public health service policies.
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Demência Frontotemporal/epidemiologia , Afasia Primária Progressiva não Fluente/epidemiologia , Paralisia Supranuclear Progressiva/epidemiologia , Idoso , Esclerose Lateral Amiotrófica/epidemiologia , Feminino , Degeneração Lobar Frontotemporal/epidemiologia , Humanos , Incidência , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Sistema de RegistrosRESUMO
BACKGROUND: Early onset dementias (EOD) are rare neurodegenerative dementias that present before 65 years. Genetic factors have a substantially higher pathogenetic contribution in EOD patients than in late onset dementia. OBJECTIVE: To identify known and/or novel rare variants in major candidate genes associated to EOD by high-throughput sequencing. Common-risk variants of apolipoprotein E (APOE) and prion protein (PRNP) genes were also assessed. METHODS: We studied 22 EOD patients recruited in Memory Clinics, in the context of studies investigating genetic forms of dementia. Two methodological approaches were applied for the target-Next Generation Sequencing (NGS) analysis of these patients. In addition, we performed progranulin plasma dosage, C9Orf72 hexanucleotide repeat expansion analysis, and APOE genotyping. RESULTS: We detected three rare known pathogenic mutations in the GRN and PSEN2 genes and eleven unknown-impact mutations in the GRN, VCP, MAPT, FUS, TREM2, and NOTCH3 genes. Six patients were carriers of only common risk variants (APOE and PRNP), and one did not show any risk mutation/variant. Overall, 69% (nâ=â9) of our early onset Alzheimer's disease (EAOD) patients, compared with 34% (nâ=â13) of sporadic late onset Alzheimer's disease (LOAD) patients and 27% (nâ=â73) of non-affected controls (ADNI, whole genome data), were carriers of at least two rare/common risk variants in the analyzed candidate genes panel, excluding the full penetrant mutations. CONCLUSION: This study suggests that EOD patients without full penetrant mutations are characterized by higher probability to carry polygenic risk alleles that patients with LOAD forms. This finding is in line with recently reported evidence, thus suggesting that the genetic risk factors identified in LOAD might modulate the risk also in EOAD.
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Demência/genética , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Idade de Início , Idoso , Alelos , Apolipoproteínas E/genética , Proteína C9orf72/genética , Feminino , Estudos de Associação Genética , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Presenilina-2/genética , Proteínas Priônicas/genética , Estudos Retrospectivos , Medição de RiscoRESUMO
A large portion of frontotemporal lobar degeneration (FTLD) patients has a family history of disease and the presence of a pathogenic mutation confirms the clinical diagnosis. Recently, standardized criteria to evaluate FTLD pedigree, based on first- and second-degree affected relatives, their age at onset, and clinical phenotype, were proposed and validated in an American cohort. Herein we applied these criteria to 402 Italian FTLD pedigrees and assessed mutation frequencies in GRN, C9orf72, and MAPT genes with the aim of validating these criteria. Moreover, we evaluated whether genetic counseling requests reflect the estimated family risk. 12.4% of pedigrees had high family history, 6.5% medium, 15.4% low; 39% were apparent sporadic cases and 26.6% had family history of unknown significance. Mutations frequencies were in line with the categorization proposed: the highest rate was found in the most at-risk families (74%) and decreased in other categories (medium: 15.4%; low: 9.7%; sporadic: 1.3%). Mutation carriers with unknown family history (5.6%) were mostly early-onset patients. Detected mutation frequency was comparable with the US-cohort (13.7%), but mutations distribution among genes was different, with higher frequency of GRN mutations (9.4%) in our cohort. An elevated proportion of FTLD patients belonging to "high risk" pedigrees asked for genetic counseling (42%); requests decreased according to the estimated family risk (medium: 26.9%; low: 17.7%; sporadic: 5.1%). In conclusion, the proposed pedigree classification criteria, herein further validated, should be incorporated in the FTLD diagnostic work-up. Moreover, our data suggest to extend genetic screening to early-onset patients with unknown family history.
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Degeneração Lobar Frontotemporal/classificação , Degeneração Lobar Frontotemporal/genética , Testes Genéticos/normas , Linhagem , Idade de Início , Idoso , Proteína C9orf72/genética , Estudos de Coortes , Feminino , Degeneração Lobar Frontotemporal/diagnóstico , Aconselhamento Genético , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Mutação , Progranulinas/genética , Proteínas tau/genéticaRESUMO
Frontotemporal lobar degeneration (FTLD) is a group of complex neurodegenerative disease characterized by progressive deterioration of the frontal and anterior temporal lobes of the brain resulting in different heterogeneous conditions, mainly characterized by personality changes, behavioral disturbances, such as binge eating, and deficits in language and executive functions. Null mutations in progranulin gene (GRN) are one of the most frequent genetic determinants in familial frontotemporal dementia. Recently, progranulin was recognized as an adipokine involved in diet-induced obesity and insulin resistance revealing its metabolic function. Increasing evidence suggests that neurodegenerative dementias are associated with a higher prevalence of metabolic changes than in the general population. According to these findings, the aim of this study is to investigate putative alterations in markers linked to metabolic functions (i.e., C-peptide, ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, glucagon, insulin, resistin, and three adipokines as visfatin, leptin, and plasminogen activator inhibitor-1 total) in sporadic and GRN-related FTLD. We found that 1) C-peptide is increased in sporadic and GRN-mutated FTLD patients; in addition, we demonstrated an anticipation of the disease in patients with the highest C-peptide concentrations; 2) visfatin is slightly reduced in the whole FTLD group; 3) resistin, an adipokine involved in inflammatory-related diseases, is specifically increased in FTLD due to GRN null mutations; 4) ghrelin concentration is specifically increased in pre-symptomatic subjects and FTLD patients with GRN mutations. These findings support the hypothesis that alterations in metabolic pattern are involved in FTLD progression highlighting novel putative targets for the development of preventive and personalized therapies.
Assuntos
Biomarcadores/sangue , Degeneração Lobar Frontotemporal/sangue , Degeneração Lobar Frontotemporal/genética , Progranulinas/genética , Idoso , Peptídeo C/sangue , Feminino , Grelina/sangue , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Nicotinamida Fosforribosiltransferase/sangue , Resistina/sangueRESUMO
Meta-analyses show copper dyshomeostasis in Alzheimer's disease. However, a study evaluating copper changes in other neurodegenerative forms of dementia has not yet been performed. In this study, we assessed copper, ceruloplasmin, copper not bound to ceruloplasmin, and copper to ceruloplasmin ratio in 85 patients affected by frontotemporal lobar degeneration (FTLD) and 55 healthy controls. Data were analyzed through multivariate ANOVA models taking into account age and sex as covariates and the stratification for FTLD variants, after calculating power analysis to ensure the reliability of the conclusions drawn. The study revealed no difference between the groups.