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BACKGROUND: Dentatorubral-pallidoluysian atrophy is a hereditary neurodegenerative disease prevalently reported in Japan but rare in Caucasians. The objective of this study was to reconstruct the pedigree of Italian dentatorubral-pallidoluysian atrophy familial cases describing their clinical features. METHODS: We investigated 6 apparently unrelated dentatorubral-pallidoluysian atrophy families comprising a total of 51 affected individuals: 13 patients were clinically examined, and for 38 patients clinical data were collected from clinical sources. The dentatorubral-pallidoluysian atrophy diagnosis was genetically confirmed in 18 patients. Genealogical data from historical archives were analyzed. RESULTS: All 6 families were unified in a large pedigree deriving from a founder couple originating from Monte San Giuliano (Italy) in the late 1500s, with 51 affected subjects over the last 4 generations. Wide phenotypical variability in age at onset and clinical features was confirmed. Epilepsy was more frequent in juvenile cases than in late adults, with cognitive/psychiatric and motor disorders observed regardless of age at onset. CONCLUSIONS: We have described the largest Caucasian dentatorubral-pallidoluysian atrophy pedigree from a single founder couple. The introduction of the dentatorubral-pallidoluysian atrophy gene in Italy could have arisen as a result of trade relationships between the Spanish or Portuguese and the Japanese in the 1500s. © 2019 International Parkinson and Movement Disorder Society.
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Efecto Fundador , Mutación/genética , Epilepsias Mioclónicas Progresivas/epidemiología , Epilepsias Mioclónicas Progresivas/genética , Adolescente , Adulto , Anciano , Niño , Epilepsia/complicaciones , Epilepsia/epidemiología , Familia , Femenino , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Epilepsias Mioclónicas Progresivas/psicología , Pruebas Neuropsicológicas , Linaje , Repeticiones de Trinucleótidos , Población Blanca , Adulto JovenRESUMEN
Inherited mutations in the Prion protein (PrP), encoded by the PRNP gene, have been associated with autosomal dominant neurodegenerative disorders, such as Creutzfeldt-Jacob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and Fatal Familial Insomnia (FFI). Notably, PRNP mutations have also been described in clinical pictures resembling other neurodegenerative diseases, such as frontotemporal dementia. Regarding the pathogenesis, it has been observed that these point mutations are located in the C-terminal region of the PRNP gene and, currently, the potential significance of the N-terminal domain has largely been underestimated. The purpose of this report is to review and provide current insights into the pathogenic mechanisms of PRNP mutations, emphasizing the differences between the C- and N-terminal regions and focusing, in particular, on the lesser-known flexible N-terminal, for which recent biophysical evidence has revealed a physical interaction with the globular C-terminal domain of the cellular prion protein (PrPC).
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Síndrome de Creutzfeldt-Jakob/genética , Demencia Frontotemporal/genética , Enfermedad de Gerstmann-Straussler-Scheinker/genética , Mutación , Proteínas PrPC/genética , Proteínas Priónicas/genética , Sitios de Unión , Encéfalo/metabolismo , Encéfalo/patología , Cationes Bivalentes , Cobre/química , Cobre/metabolismo , Síndrome de Creutzfeldt-Jakob/metabolismo , Síndrome de Creutzfeldt-Jakob/patología , Demencia Frontotemporal/metabolismo , Demencia Frontotemporal/patología , Expresión Génica , Enfermedad de Gerstmann-Straussler-Scheinker/metabolismo , Enfermedad de Gerstmann-Straussler-Scheinker/patología , Humanos , Proteínas PrPC/química , Proteínas PrPC/metabolismo , Proteínas Priónicas/química , Proteínas Priónicas/metabolismo , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Zinc/química , Zinc/metabolismoAsunto(s)
Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Citodiagnóstico , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias de la Tiroides/diagnóstico , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Metástasis de la Neoplasia , Neoplasias Primarias Múltiples/patología , Glándula Tiroides/patología , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/secundarioRESUMEN
An increasing number of hereditary neurodegenerative diseases, including autosomal-dominant Alzheimer disease (AD), familial autosomal-dominant frontotemporal dementia (FTD), and heritable Lewy body disease (LBD) have been defined at the molecular level in recent years, making it possible to determine the genotype before the onset of symptoms. The identification of deterministic genes for these common adult-onset genetic diseases is moving the field of genetic counseling toward a new and challenging direction. With the identification of genes associated with AD and FTD, there is considerable interest in the clinical application of genetic information in genetic counseling and testing. Progress in the genetics of dementing disorders and the availability of clinical tests for practicing physicians therefore increases the need for a better understanding of the multifaceted issues associated with genetic testing. The aims of this systematic review are: (1) to underline the need to consider a genetic etiology of AD, FTD, and LBD; (2) to provide clinicians with information necessary to effectively translate genetic diagnosis into clinical practice; and (3) to highlight gaps and uncertainties in the field which will need to be addressed by future research.
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Demencia/genética , Enfermedades Neurodegenerativas/genética , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Pruebas Genéticas , HumanosRESUMEN
The V363I mutation of the microtubule-associated protein tau gene has previously been associated with a case of primary progressive nonfluent aphasia with variable penetrance. Herein, we report the finding of the V363I variation in a sporadic early onset frontotemporal dementia patient and in several members of her family. The V363I variation was associated with frontotemporal dementia only in the proband which was also homozygous for the A allele of the progranulin single-nucleotide polymorphism rs9897526 and for methionine at codon 129 of the prion protein gene. The microtubule-associated protein tau V363I variation could be considered either an incomplete penetrant mutation or a rare polymorphism; although its pathogenicity has yet to be clearly demonstrated, modifier genetic factors seem to contribute to the pathogenic effects observed in the patient underlining the great complexity existing in neurodegenerative diseases and questioning so-called sporadic cases that can potentially be caused by gene mutation.
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Demencia Frontotemporal/genética , Mutación , Polimorfismo de Nucleótido Simple , Proteínas tau/genética , Femenino , Demencia Frontotemporal/patología , Humanos , Masculino , Persona de Mediana Edad , LinajeRESUMEN
Genetic testing for Alzheimer's disease offers a molecular diagnosis to patients and their relatives and provides information on personal risk, reproductive choices, clinical trial eligibility, and treatment options. In the past, molecular testing was limited to detecting single variations in single genes. Currently, with the advent of next-generation sequencing, simultaneous analysis of more than 100 genes using the same DNA sample is possible. This approach allows the determination of gene mutations, genetic risk factors, genotypes at many pharmacogenomic loci, and the determination of a polygenic risk scores for stratification of risk. This article reviews the diagnostic genetic testing of Alzheimer's disease, from the first molecular approaches to recent advances in NGS, focusing on a precision medicine approach.
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Enfermedad de Alzheimer , Medicina de Precisión , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , FarmacogenéticaRESUMEN
BACKGROUND: The distinction between mesothelioma with epithelioid features and metastatic carcinoma may be challenging, particularly on cytology. A novel 2-hit Claudin-4 and BRCA-associated protein 1 (BAP1) panel was investigated. METHODS: The objective of this study was to determine the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the panel on cytology from pleural effusions and matched biopsies, including 49 malignant mesotheliomas on cytology with 43 matched biopsies, 49 normal/reactive mesothelial proliferations, and 49 pleural metastatic carcinomas from different primaries with 21 matched pleural biopsies. The diagnostic role of the 4 categories obtained by crossing the immunostaining results was analyzed. RESULTS: Claudin-4 strongly stained all metastatic carcinomas and tested completely negative in normal mesothelium, benign reactive mesothelial hyperplasia, and malignant mesothelioma. All normal and benign mesothelial proliferations and all carcinomas except 1 were immunoreactive for BAP1, whereas BAP1 loss was observed in 88% of malignant mesotheliomas. The expression of Claudin-4 alone excluded all benign and malignant mesothelial growth, consistently characterizing all metastatic carcinomas. Double negativity was evident in all malignant mesotheliomas, and double positivity was observed in all metastatic carcinomas. BAP1-positive/Claudin-4-negative status was observed only in malignant mesotheliomas and benign mesothelial proliferations. A single metastatic anal squamous cell carcinoma had BAP1-negative/Claudin-4-positive staining. CONCLUSIONS: Claudin-4 expression was completely specific and sensitive for metastatic carcinoma, excluding mesothelial proliferations. BAP1 staining characterized 98% of metastatic carcinomas and 100% of benign mesothelial proliferations, whereas negativity was observed almost exclusively in mesotheliomas. This 2-hit panel is probably the best compromise for differentiating malignant mesothelioma and metastatic carcinoma on either cytology or biopsy specimens.
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Proteína BRCA1/metabolismo , Claudina-4/metabolismo , Mesotelioma/diagnóstico , Metástasis de la Neoplasia/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Mesotelioma/metabolismo , Mesotelioma/patología , Persona de Mediana Edad , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Inclusion body myopathy (IBM) with Paget's disease of bone (PDB) and/or frontotemporal dementia (FTD) (IBMPFD) was recently identified as rare autosomal dominant disorder due to mutations in VCP gene. However, VCP mutations have also been documented in patients with amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth type 2 (CMT2) disease, and hereditary spastic paraplegia (HSP), underlining the heterogeneity of the phenotypes due to VCP mutations. In this study, we reported a novel missense heterozygous variant c.1184A > C (p.D395A) in exon 10 of VCP gene identified in three patients (two sisters and one brother) belonging to an Italian family. The patients underwent a detailed clinical evaluation including medical history, neurological examination, and neuropsychological assessment. Brain's morphologic and functional analysis was also performed. The whole picture was consistent with the criteria of behavioral variant frontotemporal dementia (bvFTD) without IBM and PBD. Our report confirms the high degree of heterogeneity of VCP disease. A VCP analysis should be considered for the genetic screening of familial bvFTD with an early onset also in absence of IBM or PDB signs.
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Mutation A713T in the amyloid precursor protein (APP) has been linked to cases of Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA) and cerebrovascular disease. Despite its rarity, it has been observed in several families from the same geographical area, in the Calabria region in Southern Italy. Genotyping of 720,000 genome-wide SNPs with the HumanOmniExpress BeadChip was performed for six patients that were representative of apparently unrelated Calabrian families, as well as a Belgian subject of Italian descent (all with the same A713T mutation and disease). Their genomic structure and genetic relationships were analyzed. Demographic reconstruction and coalescent theory were applied to estimate the time of the most recent common ancestor (tMRCA) among patients. Results show that all A713T carriers fell into the genetic variability of Southern Italy and were not more closely related to each other than to any other healthy Calabrian individual. However, five out of seven patients shared a 1.7 Mbp-long DNA segment centered on the A713T mutation, making it possible to estimate a tMRCA for its common origin in the Calabrian region dating back over 1000 years. The analysis of affected individuals with methodologies based on human population genomics thus provides informative insights in support of clinical observations and biomedical research.
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Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOÆ4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APOÆ4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials.
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Apolipoproteínas E/genética , Demencia Frontotemporal/genética , Estudios de Asociación Genética , Variación Genética/genética , Progranulinas/genética , Proteína p53 Supresora de Tumor/genética , Proteína C9orf72 , Femenino , Heterocigoto , Humanos , Masculino , FenotipoRESUMEN
A clinical and molecular overlap between Alzheimer's disease (AD) and frontotemporal dementia (FTD) has been reported. Presenilins have been associated with FTD or with FTD-like phenotype, while mutations in the MAPT gene have been linked to a clinical phenotype of AD. We performed a clinical and genetic examination in two FTD siblings and their family tree has been reconstructed. We identified a novel Val75Ala MAPT mutation in one patient and in the other the Arg62His Presenilin2 mutation. The DNA variations identified, defined mutations by frequency, per se are not causative of the disease. These mutations, possibly in association with other unknown environmental and genetic factors, may contribute to neurodegeneration. In this family, the disease might result from a genetically interconnected spectrum of altered pathways that could link most neurodegenerative disorders. Moreover, the novel mutation identified merits further functional studies that would contribute to the unravelling of such a complex field.
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Demencia Frontotemporal/genética , Mutación Missense , Presenilina-2/genética , Proteínas tau/genética , Adulto , Edad de Inicio , Familia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Análisis de Secuencia de ADN , HermanosRESUMEN
Alzheimer's disease (AD) is an age related neurodegenerative disorder causing severe disability and important socio-economic burden, but with no cure available to date. To disentangle this puzzling disease genetic studies represented an important way for the comprehension of pathogenic mechanisms. Abnormal processing and accumulation of amyloid-ß peptide (Aß) has been considered the main cause and trigger factor of the disease. The amyloid cascade theory has fallen into crisis because the failure of several anti-amyloid drugs trials and because of the simple equation AD = abnormal Aß deposition is not always the case. We now know that multiple neurodegenerative diseases share common pathogenic mechanisms leading to accumulation of misfolded protein species. Genome Wide Association studies (GWAS) led to the identification of large numbers of DNA common variants (SNPs) distributed on different chromosomes and modulating the Alzheimer's risk. GWAS genes fall into several common pathways such as immune system and neuroinflammation, lipid metabolism, synaptic dysfunction and endocytosis, all of them addressing to novel routes for different pathogenic mechanisms. Other hints could be derived from epidemiological and experimental studies showing some lifestyles may have a major role in the pathogenesis of many age-associated diseases by modifying cell metabolism, proteostasis and microglia mediated neuroinflammation.
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Enfermedad de Alzheimer , Amiloidosis , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Humanos , Microglía/metabolismo , ProteostasisRESUMEN
We analyzed the frequency of intermediate alleles (IAs) in the ATXN1, ATXN2, and HTT genes in several neurodegenerative diseases. The study included 1126 patients with Alzheimer's disease (AD), 440 patients with frontotemporal dementia (FTD), and 610 patients with Parkinson's disease. In all cohorts, we genotyped ATXN1 and ATXN2 CAG repeats. In addition, in the FTD cohort, we determined the number of HTT CAG repeats. The frequency of HTT IAs was higher in patients with FTD (6.9%) versus controls (2.9%) and in the C9orf72 expansion noncarriers (7.2%) versus controls (2.9%), although the difference was nonsignificant after correction for multiple testing. Compared with controls, progressive nonfluent aphasia (PNFA) groups showed a significantly higher frequency of HTT IAs (13.6% vs. 2.9% controls). For the ATXN2 gene, we observed an increase in IA frequency in AD cases (AD 4.1% vs. controls 1.8%) and in the behavioral FTD group (4.8% vs. 1.8%). For the ATXN1 gene, we found a significant increase of IAs in patients with PNFA (18.6%) versus controls (6.7%). In conclusion, our work suggests that the HTT and ATXN1 IAS may contribute to PNFA pathogenesis and point to a link between ATXN2 IAS and AD.
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Enfermedad de Alzheimer/genética , Ataxina-1/genética , Ataxina-2/genética , Demencia Frontotemporal/genética , Proteína Huntingtina/genética , Enfermedad de Parkinson/genética , Repeticiones de Trinucleótidos , Proteína C9orf72/genética , Estudios de Cohortes , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Expansión de Repetición de TrinucleótidoRESUMEN
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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Afasia Progresiva Primaria/genética , Proteína C9orf72/genética , Degeneración Lobar Frontotemporal/genética , Edad de Inicio , Anciano , Anciano de 80 o más Años , Afasia Progresiva Primaria/fisiopatología , Estudios de Cohortes , Expansión de las Repeticiones de ADN , Europa (Continente) , Femenino , Demencia Frontotemporal/genética , Demencia Frontotemporal/fisiopatología , Degeneración Lobar Frontotemporal/fisiopatología , Geografía , Humanos , Masculino , Región Mediterránea , Persona de Mediana Edad , Análisis de Componente Principal , Países Escandinavos y Nórdicos , SíndromeRESUMEN
BACKGROUND: Several genetic variants playing a key role in cholesterol levels, blood pressure, and vascular dysfunction influence the risk of Alzheimer's disease (AD) and vascular dementia (VaD). The many meta-analysis studies carried out on large numbers of samples in different populations have not provided clear results to date, because a trans-ethnic shift of risk genotypes in different populations is often observed. OBJECTIVES: To determine genotypes allele frequencies of the polymorphisms most frequently identified to be correlated with cardio-cerebrovascular disease and AD in a Southern Italy population and to investigate their possible association with dementia. METHODS: The genotype and allele frequencies of 13 cardio-cerebrovascular risk polymorphisms were assessed and their possible association with dementia was investigated in a case-control study, including 221 consecutive unrelated subjects diagnosed with dementia (120 subjects affected by AD, 55 by frontotemporal dementia, and 33 by vascular dementia) and 218 matched controls of Calabrian origin. RESULTS: Carriers of at least one APOEÉ4 allele resulted to be at higher risk of AD [OR(95% CI)â=â2.721(1.477-5.011)] and VaD [OR(95% CI)â=â6.205(2.356-16.342)] compared to non-carriers. Individuals with the IV genotype of the CETP polymorphism were more likely to have AD [OR(95% CI)â=â2.427(1.364-4.319)] and VaD [OR(95% CI)â=â3.649(1.455-9.152)] compared to subjects with the II-VV genotypes. CONCLUSION: CETP I405V polymorphism is likely a risk factor for AD and VaD in our cohort, independent of APOEÉ4 status. Unmodifiable genetic risk factors should be taken into account to promote a healthy lifestyle to prevent dementia.
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Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Proteínas de Transferencia de Ésteres de Colesterol/genética , Demencia Vascular/genética , Demencia Frontotemporal/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Frecuencia de los Genes , Humanos , Italia , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Factores de RiesgoRESUMEN
BACKGROUND: Several neurological and systemic diseases can cause dementia, beyond Alzheimer's disease. Rare genetic causes are often responsible for dementia with atypical features. Recently, mutations causative for Niemann-Pick type C disease (NPC) have also been implicated in neurodegenerative diseases. NPC is an autosomal recessive lipid storage disorder caused by mutations in NPC1 and NPC2 genes. In adults, clinical presentation mimicking other neurodegenerative diseases makes diagnosis difficult. Recent evidence suggests that heterozygous mutations in NPC genes may take on etiological significance. OBJECTIVE: To investigate the presence of NPC1 and NPC2 mutations in adults affected by neurodegenerative dementia plus. METHODS: We performed a genetic screening on 50 patients using a wide clinical and biochemical approach to characterize the phenotype of mutated patients. RESULTS: Sequencing analysis revealed four different and known heterozygous mutations in NPC1 and NPC2 genes. Patient 1 carried the p. F284LfsX26 in NPC1 and was affected by progressive supranuclear palsy-like syndrome. The remaining three patients showed a corticobasal syndrome and harbored the c.441+1G>A variant of NPC2 (patient 2), the missense p.N222âS mutation associated with the c.1947+8G>C variant in the splice region of intron 12 in NPC1 (patient 3), and the p.V30M mutation in NPC2 (patient 4), respectively. Filipin staining was abnormal in patients 1 and 2. mRNA analysis revealed an altered splicing of the NPC2 gene in patient 2. CONCLUSIONS: Heterozygous mutations of NPC1 and NPC2 genes could contribute to dementia plus, at least in a subset of patients. We highlight the occurrence of NPC1 and NPC2 heterozygous variants in dementia-plus as pathological event.
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Proteínas Portadoras/genética , Demencia/genética , Glicoproteínas/genética , Glicoproteínas de Membrana/genética , Mutación/genética , Anciano , Animales , Encéfalo/diagnóstico por imagen , Análisis Mutacional de ADN , Demencia/diagnóstico por imagen , Demencia/patología , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Proteína Niemann-Pick C1 , Tomografía Computarizada de Emisión de Fotón Único , Proteínas de Transporte VesicularRESUMEN
In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by -3.86 (95% CI: -4.64 to -3.07, pâ<â2×10-16) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5% of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted.
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Demencia Frontotemporal/genética , Sitios Genéticos , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Demencia Frontotemporal/epidemiología , Estudios de Asociación Genética , Humanos , Italia , Modelos Lineales , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Análisis de Componente PrincipalRESUMEN
We identified the novel PSEN1 pathogenic mutation M84V in 3 patients belonging to a large kindred affected by autosomal dominant Alzheimer's disease (AD). The clinical phenotype was characterized by early onset dementia in 14 affected subjects over 3 generations. Detailed clinical, imaging and genetic assessment was performed. We highlighted the presence of unusual symptoms such as frontal executive syndrome, psychosis and spastic paraparesis in these patients. Spastic paraparesis has been reported in other PSEN1 mutations in adjacent codons, suggesting that the position of the genetic defect may affect the clinical expression, although this phenotype can occur in mutations throughout the whole PSEN1 gene. Brain magnetic resonance imaging showed diffuse cortical atrophy, but also atrophy of cerebellar lobules, mainly involving Crus I, in 2 patients without cerebellar motor deficits. These neuroimaging results were consistent with recent findings about the association between sporadic AD and distinct and circumscribed cerebellar atrophy. The present work acknowledged the novel PSEN1 pathogenic mutation M84V and might contribute to the ongoing debate about the involvement of cerebellum in AD.
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Enfermedad de Alzheimer/genética , Cerebelo/patología , Función Ejecutiva , Genes Dominantes/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad/genética , Mutación , Paraparesia Espástica/genética , Presenilina-1/genética , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Atrofia , Cerebelo/diagnóstico por imagen , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Paraparesia Espástica/diagnóstico por imagen , Linaje , Trastornos Psicóticos/diagnóstico por imagen , Trastornos Psicóticos/genética , SíndromeRESUMEN
BACKGROUND: Genetic testing of familial Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) is attracting interest thanks to innovative primary prevention clinical trials and increased request for information by at-risk individuals. However, ethical, social, and psychological implications are paramount and genetic testing must be supported by structured genetic counseling. In Italy, practice parameters and guidelines for genetic counseling in dementia are not available. OBJECTIVE: To develop a nationally harmonized protocol for genetic counseling and testing of familial AD and FTLD. METHODS: Activities were carried out in the context of the Italian Dominantly Inherited Alzheimer's and Frontotemporal Network (IT-DIAfN) project, a national network of centers of excellence with expertise in managing patients with familial AD and FTLD. A survey of the literature on genetic counseling protocols and guidelines was conducted. Local protocols for genetic counseling were surveyed. Differences and commonalities among protocols were identified and discussed among project partners. Consensus was reached following implicit aggregation methods. RESULTS: Consensus was reached on a protocol for patients with clinically diagnosed familial AD or FTLD and a distinct protocol for their at-risk relatives. Genetic counseling should be provided by a multidisciplinary team including a geneticist, a neurologist/geriatrician, and a psychologist/psychiatrist, according to the following schedule: (i) initial consultation with tailored information on the genetics of the dementias; (ii) clinical, psychological, and cognitive assessment; if deemed appropriate (iii) genetic testing following a structured decision tree for gene mutation search; (iv) genetic testing result disclosure; (v) psychological support follow-up. CONCLUSION: This genetic counseling protocol provides Italian centers with a line of shared practice for dealing with the requests for genetic testing for familial AD and FTLD from patients and at-risk relatives, who may also be eligible participants for novel prevention clinical trials.
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Enfermedad de Alzheimer/genética , Degeneración Lobar Frontotemporal/genética , Asesoramiento Genético/métodos , Pruebas Genéticas , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Consenso , Femenino , Estudios de Seguimiento , Degeneración Lobar Frontotemporal/líquido cefalorraquídeo , Humanos , Italia , Masculino , Fragmentos de Péptidos/líquido cefalorraquídeo , Escalas de Valoración PsiquiátricaRESUMEN
BACKGROUND: The receptor for advanced glycation end products (RAGE) is a cell surface receptor that has been implicated in vascular disease and neurodegeneration. Low levels of its secreted isoform, soluble RAGE (sRAGE), have been regarded as a putative risk factor for atherosclerosis. In addition, administration of sRAGE has been shown to reduce development of cerebral beta-amyloidosis in an Alzheimer disease mouse model. OBJECTIVE: To investigate the role of sRAGE as a biological marker for Alzheimer disease and vascular dementia. DESIGN: Cross-sectional study of 152 patients with a clinical diagnosis of Alzheimer disease, 91 with vascular dementia and 161 control subjects. MAIN OUTCOME MEASURE: Plasma levels of sRAGE. RESULTS: Levels of sRAGE were significantly reduced in the plasma of patients with Alzheimer disease compared with that for those with either vascular dementia (P<.05) or with controls (P<.001). CONCLUSIONS: Patients with Alzheimer disease have reduced levels of sRAGE in plasma compared with patients with vascular dementia and controls. The striking reduction of circulating sRAGE in Alzheimer disease further supports a role for the RAGE axis in this clinical entity and requires further investigation.