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1.
Neurol Sci ; 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34791565

RESUMO

PURPOSE: To study for the first time the incidence of adult-onset CNS tumors in Southern Sardinia, Italy. METHODS: Clinical records of patients > 18 years old who were diagnosed with primary CNS tumors during 2016-2019 in the study area were reviewed. Meningiomas, cranial/paraspinal nerve tumors, lymphomas, and pituitary tumors were excluded. Cases were classified according to the 2016 WHO classification of CNS tumors and to the morphology codes from the International Classification of Diseases-Oncology, third edition. Age-adjusted incidence rates were calculated by the direct method to the 2011-2020 European standard population. Kulldorff's spatial scan statistic was used to identify geographic clusters of patients who shared increased/decreased tendency to develop CNS tumors. RESULTS: CNS tumors were diagnosed in 234 incident patients, but histological diagnosis was available in 222/234 patients (95%) aged 64.3 ± 13.5 years at diagnosis. Crude incidence rate was 7.1 per 100,000 persons-year (95% CI, 6.2-8.1), 6.2 per 100,000 persons-year (95% CI, 5.4-7.0) when age-adjusted. CNS tumors were more frequent in men and after age 40. Glioblastoma accounted for 76% of the total (adjusted rate, 4.7 per 100,000 persons-year; 95% CI, 4.0-5.4). Spatial analysis revealed geographic variations of glioblastoma incidence within the study area. CONCLUSION: Although the distribution of tumor diagnoses in Sardinia reflects expected age and gender-related patterns in western populations, our findings would indicate a slightly higher incidence of glial tumors, glioblastoma in particular, in Sardinia than in other European countries. The identification of spatial clusters of high/low risk will serve as a resource for etiological research.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33818195

RESUMO

C9orf72 mutation (C9+) is a common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. C9+ clinical phenotype is heterogeneous and epilepsy has been recently described in few cases. We report a 47-year-old patient who developed reflex reading epilepsy (RRE) at the age of 19. After the first years with exclusive reflex seizures, afterwards the patients developed drug-resistant, unprovoked seizures and progressive cognitive deterioration. In the last years, a progressive motor impairment with spastic tetraparesis also occurred. During the hospitalization, the patient underwent an extensive workup identifying C9+ expansion and a family history suggestive for an autosomal dominant inheritance. This report, together with the few cases already described, raises the possibility that epileptic manifestations are part of the clinical phenotype of C9ORF72 mutation and reflect hyperexcitability of cortical networks involved in neurodegeneration.

3.
Nat Genet ; 53(3): 294-303, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33589841

RESUMO

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.


Assuntos
Estudo de Associação Genômica Ampla , Doença por Corpos de Lewy/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Estudos de Casos e Controles , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano , Glucosilceramidase/genética , Humanos , Proteínas Nucleares/genética , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Proteínas Supressoras de Tumor/genética , alfa-Sinucleína/genética
4.
Neurogenetics ; 21(4): 251-257, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32458274

RESUMO

In genetic prion diseases (gPrD), five genetic variants (E200K, V210I, V180I, P102L, and D178N) are responsible for about 85% of cases. The R208H is one of the several additional rare mutations and to date, only 16 cases carrying this mutation have been reported worldwide. To describe the phenotypic features of 5 affected patients belonging to apparently unrelated Sardinian (Italian) families with R208H gPrD, and provide evidence for a possible founder effect are the aims of this study. The R208H PRNP mutation has a much higher relative frequency in Sardinia than elsewhere in Italy (72% vs. 4.4% of gCJD cases). Our cohort shared similar phenotypic features to the previously described patients with R208H-129M haplotype with most patients showing the classical Creutzfeldt-Jakob disease (CJD) phenotype. The analysis of 10 controls and 5 patients by NGS sequencing identified 4 haplotypes, 3 associated with the wild type variant, and one (H1) shared by all patients carrying the 208His variant. This is the first report of a regional cluster for R208H mutation in gPrD and the first report of the presence of a common ancestor for this Sardinian R208H cluster, confirming the probable consequences of genetic isolation process even for rare diseases.


Assuntos
Síndrome de Creutzfeldt-Jakob/genética , Efeito Fundador , Mutação , Proteínas Priônicas/genética , Idoso , Alelos , Análise por Conglomerados , Saúde da Família , Feminino , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Fenótipo
5.
Exp Brain Res ; 237(8): 2105-2110, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31177296

RESUMO

Dementia with Lewy body is a neurodegenerative disorder affecting both cognitive and motor domains. Motor impairment manifests predominantly as a symmetrical/mild asymmetrical parkinsonian syndrome that is only mildly responsive to Levodopa. To characterize motor dysfunction in dementia with Lewy body, we quantitatively assessed upper limb movements using a motion-capture system. Ten patients and ten healthy controls were tested while performing the hand-to-mouth movement of which speed, smoothness and accuracy features were measured. The results showed that individuals with dementia with Lewy body required a longer time to complete the task, particularly due to a prolonged duration of the adjusting phase (i.e., when approaching the target/mouth). The overall motor performance of dementia with Lewy body patients closely resembled what previously observed in patients affected by both Parkinson's disease and ataxia while performing the same task. Moreover, the severity of parkinsonian symptoms as assessed by the UPDRS-III scale impacted on the velocity of movement alone whereas impairment of executive functions correlated with variables related to the phase of targeting the mouth. This study provides new information about upper limb motor dysfunction in dementia with Lewy body.


Assuntos
Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/fisiopatologia , Movimento/fisiologia , Desempenho Psicomotor/fisiologia , Extremidade Superior/fisiopatologia , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
7.
BMC Neurol ; 17(1): 78, 2017 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-28424054

RESUMO

BACKGROUND: Dementia with Lewy bodies (DLB) is the second most frequent diagnosis of progressive degenerative dementia in older people. Delusions are common features in DLB and, among them, Capgras syndrome represents the most frequent disturbance, characterized by the recurrent and transient belief that a familiar person, often a close family member or caregiver, has been replaced by an identical-looking imposter. However, other delusional conditions near to misidentification syndromes can occur in DLB patients and may represent a major psychiatric disorder, although rarely studied systematically. CASE PRESENTATION: We reported on a female patient affected by DLB who presented with an unusual delusion of duplication. Referring to the female professional caregiver engaged by her relatives for her care, the patient constantly described the presence of two different female persons, with a disorder framed in the context of a delusion of duplication. A brain 99Tc-hexamethylpropyleneamineoxime SPECT was performed showing moderate hypoperfusion in both occipital lobes, and associated with marked decreased perfusion in parieto-fronto-temporal lobes bilaterally. CONCLUSIONS: An occipital hypoperfusion was identified, although in association with a marked global decrease of perfusion in the remaining lobes. The role of posterior lobes is certainly important in all misidentification syndromes where a natural dissociation between recognition and identification is present. Moreover, the concomitant presence of severe attentional and executive deficits evocative for a frontal syndrome and the marked global decrease of perfusion in the remaining lobes at the SPECT scan also suggest a possible dysfunction in an abnormal connectivity between anterior and posterior areas.


Assuntos
Síndrome de Capgras/complicações , Doença por Corpos de Lewy/psicologia , Idoso , Córtex Cerebral/irrigação sanguínea , Feminino , Humanos , Doença por Corpos de Lewy/complicações , Neuroimagem , Oximas/metabolismo , Compostos de Tecnécio/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único
8.
Neurol Sci ; 38(2): 225-231, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27848117

RESUMO

The Capgras syndrome (CS) is a rare psychiatric disorder. CS is classified as a delusional misidentification syndrome. Initially, CS was described in paranoid schizophrenia and schizoaffective disorders. CS has also been reported in neurodegenerative diseases such as Alzheimer's disease and Lewy body dementia. To date, there are very few descriptions of the occurrence of CS in idiopathic Parkinson's disease (PD), with or without dementia. Considering the recent observation of two new cases in PD patients, a systematic overview of the literature published between 1976 and 2016 reporting CS in PD was conducted. The purpose of this article is to examine the phenomenon in people with PD with and without dementia, the psychopathologic context in which it happened, the role played by the dopaminergic medications and to define useful therapeutic strategies. Our CS cases occurred in two elderly patients with advanced PD and cognitive impairment, respectively, after an acute stressor event and after an increase of the total daily dose of levodopa. In light of our observations and the cases reported in the literature, we argue that CS is an acute or subacute psychotic disorder occurring mostly in PD with dementia. Besides, the increase in brain dopamine levels induced by acute stressful events and/or dopamine-enhancing medications should be considered as a possible causal mechanism of CS in patients with advanced stages of PD and cognitive decline.


Assuntos
Síndrome de Capgras/etiologia , Disfunção Cognitiva/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Síndrome de Capgras/induzido quimicamente , Disfunção Cognitiva/etiologia , Dopaminérgicos/efeitos adversos , Fraturas do Fêmur/complicações , Humanos , Masculino , Doença de Parkinson/complicações
9.
Sci Rep ; 6: 38653, 2016 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-27924954

RESUMO

Amyotrophic Lateral Sclerosis (ALS) is one of the most severe neurodegenerative diseases, which is known to affect upper and lower motor neurons. In contrast to the classical tenet that ALS represents the outcome of extensive and progressive impairment of a fixed set of motor connections, recent neuroimaging findings suggest that the disease spreads along vast non-motor connections. Here, we hypothesised that functional network topology is perturbed in ALS, and that this reorganization is associated with disability. We tested this hypothesis in 21 patients affected by ALS at several stages of impairment using resting-state electroencephalography (EEG) and compared the results to 16 age-matched healthy controls. We estimated functional connectivity using the Phase Lag Index (PLI), and characterized the network topology using the minimum spanning tree (MST). We found a significant difference between groups in terms of MST dissimilarity and MST leaf fraction in the beta band. Moreover, some MST parameters (leaf, hierarchy and kappa) significantly correlated with disability. These findings suggest that the topology of resting-state functional networks in ALS is affected by the disease in relation to disability. EEG network analysis may be of help in monitoring and evaluating the clinical status of ALS patients.


Assuntos
Esclerose Amiotrófica Lateral/fisiopatologia , Pessoas com Deficiência , Eletroencefalografia , Idoso , Esclerose Amiotrófica Lateral/diagnóstico , Encéfalo/fisiopatologia , Mapeamento Encefálico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios Motores , Vias Neurais/fisiopatologia , Prognóstico , Índice de Gravidade de Doença
11.
Neurobiol Aging ; 43: 180.e1-5, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27156075

RESUMO

Recently, mutations in the TANK-binding kinase 1 (TBK1) gene were identified as a cause for amyotrophic lateral sclerosis (ALS) with or without comorbid frontotemporal dementia. We have assessed the frequency and clinical characteristics of TBK1 mutations in a cohort of ALS patients of Sardinian ancestry. Whole-exome sequencing was performed on Hiseq2000 platform (Illumina). Genome analysis Toolkit was used to align and to code variants according to Human Genome (UCSC hg19). Mutation was confirmed with Sanger sequence. In our screening of 186 Sardinian ALS cases, we found 3 (1.6%) patients carrying 3 distinct novel genetic variants: a nonsynonymous SNV c.1150C>T leading to a p.Arg384Thr change in exon 9; a nonsynonymous SNV c.1331G>A causes a p.Arg444Gln change in exon 11; and a frameshift deletion c.2070delG (p.Met690fs) at the exon 20 of the gene leading to a stop at 693 codon. The latter patients also carried missense mutation c.98C>T of the SQSTM1 gene causing a substitution of an arginine with a valine at the position 33 (p.Arg33Val). All variants were found to be deleterious according to in silico predictions. All cases were apparently sporadic and one of them showed frontotemporal dementia associated to ALS. These mutations were not found in 2 cohorts of 6780 ethnic-matched controls. We have found that TBK1 mutations account for 1.6% of Sardinian ALS cases. Our data support the notion that TBK1 is a novel ALS gene, providing important evidence complementary to the first descriptions.


Assuntos
Esclerose Amiotrófica Lateral/genética , Demência Frontotemporal/genética , Estudos de Associação Genética , Mutação , Idoso , Estudos de Coortes , Feminino , Humanos , Itália , Masculino
13.
Artigo em Inglês | MEDLINE | ID: mdl-26575405

RESUMO

We investigated intrafamilial phenotypic variability in carriers of the C9orf72 mutation, analysing clinical, neuropsychological and imaging characteristics of various members from a large Sardinian kindred with FTD or ALS. We compared these with those of C9 + patients in our ALS and FTD cohorts. Results showed that three patients carried the C9orf72 mutation: two with ALS and one with FTD and Parkinsonism. C9 + patients in our bvFTD Sardinian cohort had a higher frequency of Parkinsonism than non-mutated patients (75% vs. 36.3%, p <0.02). Parkinsonism was present in 2.7% of our ALS cohort and 3.3% of the C9 + patients. The prevalence of Parkinsonism in C9 + patients in the bvFTD and ALS cohorts showed a statistically significant difference (p <0.006). In conclusion, Parkinsonism was frequently associated with FTD but not ALS in a large Sardinian family, a finding reflected in the wider C9orf72 associated Sardinian ALS and FTD populations.


Assuntos
Esclerose Amiotrófica Lateral/genética , Saúde da Família , Demência Frontotemporal/genética , Mutação/genética , Proteínas/genética , Idoso , Esclerose Amiotrófica Lateral/diagnóstico por imagem , Ataxina-2/genética , Proteína C9orf72 , Estudos de Coortes , Feminino , Demência Frontotemporal/complicações , Demência Frontotemporal/diagnóstico por imagem , Genótipo , Humanos , Itália/epidemiologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtornos Parkinsonianos/etiologia , Fenótipo , Proteínas tau/genética
14.
J Alzheimers Dis ; 47(3): 535-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26401689

RESUMO

Cerebral microbleeds (CMB) might reflect specific underlying vascular pathologies like cerebral amyloid angiopathy (CAA). In the present study we report the gradient-echo MRI pattern of two siblings with P284S PSEN1 mutation. T2* gradient-echo images of the two subjects demonstrated multiple microbleeds in lobar regions. The role and causes of CMB in sporadic Alzheimer's disease (AD) patients have not been clearly established and useful contributions could derive from familial AD studies. Furthermore, since CAA is a potential risk factor for developing adverse events in AD immunization trials, the identification in vivo of CAA through non-invasive MRI methods could be useful to monitoring side effects.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Encéfalo/patologia , Angiopatia Amiloide Cerebral/patologia , Leucoencefalopatias/patologia , Presenilina-1/genética , Doença de Alzheimer/fisiopatologia , Angiopatia Amiloide Cerebral/fisiopatologia , Feminino , Humanos , Leucoencefalopatias/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Mutação , Linhagem , Irmãos
15.
Neurobiol Aging ; 36(10): 2906.e1-5, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26208502

RESUMO

Intermediate-length CAG expansions (encoding 27-33 glutamines, polyQ) of the Ataxin2 (ATXN2) gene represent a risk factor for amyotrophic lateral sclerosis (ALS). Recently, it has been proposed that ≥31 CAG expansions may influence ALS phenotype. We assessed whether ATXN2 intermediate-length polyQ expansions influence ALS phenotype in a series of 375 patients of Sardinian ancestry. Controls were 247 neurologically healthy subjects, resident in the study area, age- and gender-matched to cases. The frequency of ≥31 polyQ ATNX2 repeats was significantly more common in ALS cases (4 patients vs. no control, p = 0.0001). All patients with ≥31 polyQ repeats had a spinal onset versus 73.3% of patients with <31 polyQ repeats. Patients with an increased number of polyQ repeats have a shorter survival than those with <31 repeats (1.2 vs. 4.2 years, p = 0.035). In this large series of ALS patients of Sardinian ancestry, we have found that ≥31 polyQ repeats of the ATXN2 gene influenced patients' phenotype, being associated to a spinal onset and a significantly shorter survival.


Assuntos
Esclerose Amiotrófica Lateral/genética , Ataxina-2/genética , Estudos de Associação Genética , Fenótipo , Esclerose Amiotrófica Lateral/mortalidade , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Taxa de Sobrevida , Expansão das Repetições de Trinucleotídeos/genética
16.
J Neurol ; 262(2): 375-84, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25408367

RESUMO

It has been shown that different genes could be associated with distinctive clinical and radiological phenotypes of FTD. TARDBP gene has been described worldwide in few cases of FTD so its phenotype is still unclear. The objective is to study the clinical and radiological characteristics of TARDBP-related FTD. In the present study, we report clinical, neuropsychological and radiological features of five new Sardinian non-related cases of FTD carriers of the p.A382T TARDBP mutation. Furthermore, we reviewed non-related FTD cases with TARDBP mutations previously described in literature. The p.A382T missense mutation of TARDBP was present in the 21.7 % of familial cases of our FTD cohort (5/23) and in no one of the sporadic patients. 3 of 5 patients showed a temporal variant FTD and 4/5 a predominant temporal involvement at MRI. The review of the literature of FTD cases with TARDBP mutations showed that in 5 of 16 cases, the clinical phenotype was consistent with temporal variant of FTD or semantic dementia (31 %) and in 7 of 16 cases neuroimaging showed predominant temporal lobe involvement (43.7 %). Our study further supports the pathogenetic role of TARDBP mutations in pure FTD and in the full spectrum of FTD/ALS. The presence of a predominant temporal lobe involvement in a high percentage of FTD mutated patients with a peculiar clinical pattern could be useful in the differential diagnosis with other forms of dementia/FTD both sporadic and familial.


Assuntos
Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Proteínas de Ligação a DNA/genética , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Mutação , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo
17.
Artigo em Inglês | MEDLINE | ID: mdl-25285776

RESUMO

In our study we analysed clinical and neuropsychological data in a cohort of 57 Sardinian patients with FTD (55 apparently unrelated and two belonging to the same family), who underwent genetic screening for the C9orf72 mutation. Eight out of 56 patients were found positive for the C9orf72 mutation representing 14% of the entire cohort and 31.6% of the familial cases (6/19). C9orf72 mutated patients differed from the other FTD cases of the cohort for a younger age of onset, higher frequency of familial history for FTD and higher prevalence of delusional psychotic symptoms and hallucinations. In the neuropsychological assessment, C9orf72 mutated patients differed from non-mutated for the high frequency of visuospatial dysfunction regarding constructional apraxia (p = 0.02). In conclusion, our study confirms that Sardinian FTD patients have peculiar genetic characteristics and that C9orf72 mutated patients have a distinctive clinical and neuropsychological profile that could help differentiate them from other FTD patients. In our cohort we found that constructional apraxia, rarely reported in FTD, can properly discriminate between C9orf72 mutated and non-mutated patients and contribute to broaden the neuropsychological profile in frontotemporal dementia associated with this mutation.


Assuntos
Apraxias/etiologia , Apraxias/genética , Demência Frontotemporal/complicações , Demência Frontotemporal/genética , Mutação/genética , Proteínas/genética , Idoso , Encéfalo/diagnóstico por imagem , Proteína C9orf72 , Estudos de Coortes , Feminino , Demência Frontotemporal/diagnóstico por imagem , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Transtornos da Percepção/etiologia , Transtornos da Percepção/genética , Fenótipo , Estimulação Luminosa , Tomografia Computadorizada de Emissão de Fóton Único
18.
Neurobiol Aging ; 35(12): 2882.e7-2882.e12, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25123918

RESUMO

Conserved populations, such as Sardinians, displaying elevated rates of familial or sporadic amyotrophic lateral sclerosis (ALS) provide unique information on the genetics of the disease. Our aim was to describe the genetic profile of a consecutive series of ALS patients of Sardinian ancestry. All ALS patients of Sardinian ancestry, identified between 2008 and 2013 through the Italian ALS Genetic Consortium, were eligible to be included in the study. Patients and controls underwent the analysis of TARDBP, C9ORF72, SOD1, and FUS genes. Genetic mutations were identified in 155 out of 375 Sardinian ALS cases (41.3%), more commonly the p.A382T and p.G295S mutations of TARDBP and the GGGGCC hexanucleotide repeat expansion of C9ORF72. One patient had both p.G295S and p.A382T mutations of TARDBP and 8 carried both the heterozygous p.A382T mutation of TARDBP and a repeat expansion of C9ORF72. Patients carrying the p.A382T and the p.G295S mutations of TARDBP and the C9ORF72 repeat expansion shared distinct haplotypes across these loci. Patients with cooccurrence of C9ORF72 and TARDBP p.A382T missense mutation had a significantly lower age at onset and shorter survival. More than 40% of all cases on the island of Sardinia carry a mutation of an ALS-related gene, representing the highest percentage of ALS cases genetically explained outside of Scandinavia. Clinical phenotypes associated with different genetic mutations show some distinctive characteristics, but the heterogeneity between and among families carrying the same mutations implies that ALS manifestation is influenced by other genetic and nongenetic factors.


Assuntos
Esclerose Amiotrófica Lateral/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Mutação , Idade de Início , Esclerose Amiotrófica Lateral/epidemiologia , Proteína C9orf72 , Expansão das Repetições de DNA , Proteínas de Ligação a DNA/genética , Genótipo , Humanos , Itália/epidemiologia , Penetrância , Fenótipo , Proteínas/genética , Proteína FUS de Ligação a RNA/genética , Superóxido Dismutase/genética , Superóxido Dismutase-1
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