RESUMO
BACKGROUND: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU). METHODS: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants' clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials. RESULTS: Survey responses were received over a sixteen-month window during 2020-2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial's demographic distribution. Participants' decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome. CONCLUSION: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4-7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden.
Assuntos
Doença de Alzheimer , Anticorpos Monoclonais Humanizados , Satisfação do Paciente , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Masculino , Feminino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/uso terapêutico , Método Duplo-Cego , Adulto , Inquéritos e Questionários , Ensaios Clínicos como AssuntoRESUMO
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is an autosomal dominant leukoencephalopathy related to CSF1R gene mutations. A growing number of clinicoradiologic phenotypes have been described. In this study, we analyzed brain imaging findings in 16 patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia to refine radiologic diagnostic clues. T2/FLAIR white matter hyperintensities were present in all patients with frontal or frontoparietal predilection, with asymmetric distribution in more than one-third. Brain atrophy and callosal involvement were almost constant, and corticospinal tract involvement was frequent. Moreover, deep white matter hyperintense dots on DWI and deep punctate calcifications on CT were often found. Conversely, deep gray matter nuclei, external capsules, and brain stem were rarely involved. Our series emphasized the great variability of MR imaging findings seen in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. A complete imaging screening including DWI, T2*, and CT is mandatory to accurately assess patients with suspected inherited adult-onset leukoencephalopathy.
Assuntos
Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/patologia , Adulto , Feminino , França , Humanos , Leucoencefalopatias/genética , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodosRESUMO
To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case-control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6-1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPT duplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-ß deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early-onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series.
Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 17/genética , Demência/genética , Idoso , Encéfalo/metabolismo , Estudos de Casos e Controles , Variações do Número de Cópias de DNA/genética , Feminino , Dosagem de Genes , Duplicação Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/patologia , Neuroimagem , Tauopatias/genética , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
The role of biomarkers in clinical research was recently highlighted in the new criteria for the diagnosis of Alzheimer's disease. Cerebro-spinal fluid (CSF) biomarkers (total Tau protein, threonine 181 phosphorylated Tau protein and amyloid Aß1-42 peptide) are associated with cerebral neuropathological lesions observed in Alzheimer's disease (neuronal death, neurofibrillary tangle with abnormal Tau deposits and amyloid plaque). Aß1-40 amyloid peptide dosage helps to interpret Aß1-42 results. As suggested in the latest international criteria and the French HAS (Haute Autorité de santé) recommendations, using theses CSF biomarkers should not be systematic but sometimes could be performed to improve confidence about the diagnostic of Alzheimer's disease in young subjects or in complex clinical situations. Future biomarkers actually in development will additionally help in diagnostic process (differential diagnosis) and in prognostic evaluation of neurodegenerative diseases.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Demência/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Pesquisa Biomédica/métodos , Pesquisa Biomédica/tendências , Demência/líquido cefalorraquidiano , Diagnóstico Diferencial , Humanos , Memória/fisiologia , Padrões de Prática Médica , Proteínas tau/líquido cefalorraquidianoRESUMO
The SORL1 protein plays a protective role against the secretion of the amyloid ß peptide, a key event in the pathogeny of Alzheimer's disease. We assessed the impact of SORL1 rare variants in early-onset Alzheimer's disease (EOAD) in a case-control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of disruptive and predicted damaging missense SORL1 variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02-14.99), P=7.49.10(-5)). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35-27.31), P=3.82.10(-7)). We conclude that predicted damaging rare SORL1 variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history.
Assuntos
Doença de Alzheimer/genética , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Alelos , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Estudos de Casos e Controles , Exoma , Feminino , França , Frequência do Gene , Predisposição Genética para Doença/genética , Variação Genética , Humanos , Proteínas Relacionadas a Receptor de LDL/metabolismo , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Pessoa de Meia-Idade , Razão de Chances , Fatores de RiscoRESUMO
OBJECTIVES: Familial predisposition appears as an identified risk factor for cerebrovascular disease. The primary objective of our study was to assess intracranial aneurysm (IA) recurrence rate in a population of familial IA. Secondary objectives were first to analyse the inheritance categorisation/pattern of these families and second to assess the correlation between the aortic diameter on MRI and the aneurysmal characteristics. PATIENTS AND METHODS: Over a period of 20 years (1990-2010), 26 patients from 23 families, identified from a regional register, accepted to participate in this prospective trial in order to determine, the inheritance pattern, the screening of de novo aneurysms by CT angioscan, and the aortic mensuration by MRI. The transmission pattern was categorised into autosomal dominant inheritance, autosomal recessive and autosomal dominance with incomplete penetrance. The aortic diameter was measured: anatomic coverage in the caudo-cranial direction from the iliac arteries to the ventriculo-aortic junction. RESULTS: All 26 patients [from 55.4 ± 11.2 years, sex ratio female/male: 1.36] were reviewed after a mean follow-up of 7.9 ± 6.6 years after the diagnosis of a cerebral aneurysm. The characteristics of this population were the diagnostic circumstances such as a subarachnoid hemorrhage (SAH) in 14 (53.8%), the multiple locations in 10 (38.5%) and a giant aneurysm in 4 (15.4%). Four de novo aneurysms were diagnosed in 3 patients (11.5%) after a mean follow-up of 22.3 ± 4 years, which corresponds to an annual incidence of 1.9 (95% CI 1.4-2.6%). The transmission pattern was autosomal dominant in 16 (61.5%), recessive in 3 (11.5%) and not defined in 7 (26.9%). As regards the aortic diameter, a significant decrease in the aortic diameter was observed in patients with an aneurysmal diameter superior to 10mm. CONCLUSION: The rate of de novo aneurysm justifies prolonged monitoring by imaging of these patients with familial intracranial aneurysm. The narrowing of the terminal part of the aorta could be a hemodynamic factor involved into the IA development.
Assuntos
Aorta/anatomia & histologia , Aneurisma Intracraniano/genética , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Estudos ProspectivosRESUMO
We hypothesized that de novo variants (DNV) might participate in the genetic determinism of sporadic early-onset Alzheimer disease (EOAD, onset before 65 years). We investigated 14 sporadic EOAD trios first by array-comparative genomic hybridization. Two patients carried a de novo copy number variation (CNV). We then performed whole-exome sequencing in the 12 remaining trios and identified 12 non-synonymous DNVs in six patients. The two de novo CNVs (an amyloid precursor protein (APP) duplication and a BACE2 intronic deletion) and 3/12 non-synonymous DNVs (in PSEN1, VPS35 and MARK4) targeted genes from a biological network centered on the Amyloid beta (Aß) peptide. We showed that this a priori-defined genetic network was significantly enriched in amino acid-altering DNV, compared with the rest of the exome. The causality of the APP de novo duplication (which is the first reported one) was obvious. In addition, we provided evidence of the functional impact of the following three non-synonymous DNVs targeting this network: the novel PSEN1 variant resulted in exon 9 skipping in patient's RNA, leading to a pathogenic missense at exons 8-10 junction; the VPS35 missense variant led to partial loss of retromer function, which may impact neuronal APP trafficking and Aß secretion; and the MARK4 multiple nucleotide variant resulted into increased Tau phosphorylation, which may trigger enhanced Aß-induced toxicity. Despite the difficulty to recruit Alzheimer disease (AD) trios owing to age structures of the pedigrees and the genetic heterogeneity of the disease, this strategy allowed us to highlight the role of de novo pathogenic events, the putative involvement of new genes in AD genetics and the key role of Aß network alteration in AD.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Exoma , Feminino , Redes Reguladoras de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Linhagem , Presenilina-1/genéticaRESUMO
INTRODUCTION: Cerebrotendinous xanthomatosis, a metabolic leukodystrophy with an autosomal recessive inheritance, is secondary to deficiency of sterol 27-hydroxylase, an enzyme involved in cholesterol catabolism. Classical symptoms include clinical or infraclinical xanthomas affecting the skin and tendons, early cataracts, neurological signs and diarrhea. Brain imaging reveals involvement of the dentate nuclei and periventricular white matter hyperintensities. The diagnosis is based on an increased cholestanol level in serum, confirmed by the presence of a mutation in the CYP27A1 gene. Treatment is based on chenodeoxycholic acid. METHOD: We report a retrospective multicentric study of 15 cases of cerebrotendinous xanthomatosis diagnosed in French adults. Clinical, molecular and MRI findings were recorded in all patients. RESULTS: The average age at diagnosis was 39years (range 27-65). Disease onset occurred in childhood in 73% of patients and in adulthood in 27%. All patients with a pediatric onset were diagnosed during adulthood (age range 28-65years). Clinical symptoms variably associated cerebellar syndrome, pyramidal syndrome, cognitive decline, epilepsy, neuropathy (sought in 10 of our patients, present in forms in 8), psychiatric disorders, cataract and xanthomas. One patient had an atypical presentation: monoparesis associated with xanthomas. Brain MRI was abnormal in all: findings consisted in T2-weighted hyperintensity of the dentate nuclei (47%), periventricular leuoencephalopathy (73%) which preferentially involved the posterior cerebral part (60%), leucoencephalopathy with a vascular pattern (7%), hyperintensity of the cortico-spinal tracts (53%), globi pallidi, corpus callosum and cerebral atrophy (33%). Serum cholestanol was elevated in 93% of patients. The most frequent mutation was 1183C>T (n=5/15). Under treatment with chenodeoxycholic acid, eight patients improved initially, followed by stabilization in five of them, and worsening in the others. Four patients died. CONCLUSION: Patients with the xanthoma-neurological disorder association should be tested for cerebrotendinous xanthomatosis. The disease often begins in childhood with a diagnostic delay but also in adulthood. Involvement of the dentate nuclei is specific but not sensitive and the supratentorial leucoencephalopathy is not specific but with an antero-posterior gradient. A vascular distribution and involvement of the corpus callosum are possible. Serum cholestanol assay is very reliable: an elevated level provides the diagnosis, which must nevertheless be confirmed by molecular biology.
Assuntos
Xantomatose Cerebrotendinosa , Adulto , Idade de Início , Idoso , Substituição de Aminoácidos , Encéfalo/patologia , Ácido Quenodesoxicólico/uso terapêutico , Colestanotriol 26-Mono-Oxigenase/deficiência , Colestanotriol 26-Mono-Oxigenase/genética , Feminino , Genes Recessivos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Estudos Retrospectivos , Avaliação de Sintomas , Xantomatose Cerebrotendinosa/tratamento farmacológico , Xantomatose Cerebrotendinosa/epidemiologia , Xantomatose Cerebrotendinosa/patologiaAssuntos
Congressos como Assunto , Demência , Objetivos , Doença de Alzheimer/etiologia , Doença de Alzheimer/terapia , Formação de Conceito , Demência/etiologia , Demência/terapia , Demência Vascular/etiologia , Demência Vascular/terapia , Degeneração Lobar Frontotemporal/etiologia , Degeneração Lobar Frontotemporal/terapia , HumanosRESUMO
Dysphagia is one of the most important complications encountered in amyotrophic lateral sclerosis (ALS). Our aim was to determine whether oropharyngeal dysphagia impacted the quality of life (QoL) of patients with ALS. Thirty consecutive patients were recruited (31-82 years, 18 men). Swallowing function was evaluated using a standardised videofluoroscopic barium swallow. All the patients completed a specific questionnaire on quality of life in dysphagia (SWAL-QoL) immediately after the videofluoroscopy. The results of dysphagia outcome severity scale separated 14 patients with oropharyngeal dysphagia and 16 with normal swallowing function. There was no difference in the average age, weight and body mass index of the two groups (dysphagic patients: 68 ± 11 kg versus non-dysphagic patients: 69 ± 14 kg). Most of the dysphagic patients had a bulbar affection based on their Norris scores which determine the importance of cranial nerves illness (20 ± 8), significantly lower than those of the non-dysphagic patients (35 ± 5) (P < 0·0001). There was no difference in the neurological peripheral symptoms evaluated by Amyotrophic Lateral Sclerosis Functional Rating Scale scores (dysphagic patients: 26 ± 7 versus non-dysphagic patients: 27 ± 8) (ns). The swallowing quality of life questionnaire revealed that the dysphagic patients had significant burden (P < 0·001). They were affected by the necessity to applied a food selection (P < 0·01), by the increase in eating duration (P < 0·05) and described a decrease in eating desire (P < 0·05). They complained of fear regarding the risk of dysphagia (P < 0·05). They also described difficulties with oral communication (P < 0·001). All of those complained about dysphagia which impacted directly mental health (P < 0·05) and social life (P < 0·05). In conclusion, oropharyngeal dysphagia is a common symptom accompanying ALS, which alters the patient's QoL, especially social health.
Assuntos
Esclerose Lateral Amiotrófica/psicologia , Transtornos de Deglutição/psicologia , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/fisiopatologia , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/fisiopatologia , Feminino , Fluoroscopia/métodos , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and Aß plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aß42/Aß40 ratio (best signal, P=5.4 × 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Haplótipos/genética , Doença de Alzheimer/sangue , Peptídeos beta-Amiloides/sangue , Estudos de Casos e Controles , Humanos , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
OBJECTIVE: It is a major issue to diagnose and detect oropharyngeal dysphagia in the early stage of ALS in order to avoid pulmonary and nutritional complications. The aim of this study was to validate a simple clinical test, the Volume-Viscosity Swallow Test (V-VST), to detect oropharyngeal dysphagia in this population. PATIENTS AND METHODS: Twenty patients were included in this study (mean age: 66.1 ± 8.13, six women). All patients had their swallowing function assessed by videofluoroscopy and V-VST. RESULTS: Among these 20 patients, 15 presented oropharyngeal dysphagia, diagnosed by videofluoroscopy, and five had normal swallowing. Norris score was lower in patients with oropharyngeal dysphagia compared to the patients with normal swallowing (27 ± 6 versus 36 ± 2; P=0.003). Among the 15 patients with oropharyngeal dysphagia, 14 had abnormal V-VST, and only one had normal V-VST. The sensibility of V-VST to detect oropharyngeal dysphagia in these patients with ALS was of 93%, and the specificity was of 80% (P=0.007). There was no significant difference between the two populations for ALSFRS score (22 ± 6 versus 20 ± 6) and body mass index (BMI) (26 ± 6 versus 26 ± 6 kg/m(2)). CONCLUSION: The V-VST presented good sensibility and specificity. It may be interesting to use it systematically for the detection of oropharyngeal dysphagia in ALS, after confirming these results on a wider patient sample.
Assuntos
Esclerose Lateral Amiotrófica/complicações , Transtornos de Deglutição/diagnóstico , Orofaringe/fisiopatologia , Idoso , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/fisiopatologia , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e EspecificidadeRESUMO
Performing exome sequencing in 14 autosomal dominant early-onset Alzheimer disease (ADEOAD) index cases without mutation on known genes (amyloid precursor protein (APP), presenilin1 (PSEN1) and presenilin2 (PSEN2)), we found that in five patients, the SORL1 gene harbored unknown nonsense (n=1) or missense (n=4) mutations. These mutations were not retrieved in 1500 controls of same ethnic origin. In a replication sample, including 15 ADEOAD cases, 2 unknown non-synonymous mutations (1 missense, 1 nonsense) were retrieved, thus yielding to a total of 7/29 unknown mutations in the combined sample. Using in silico predictions, we conclude that these seven private mutations are likely to have a pathogenic effect. SORL1 encodes the Sortilin-related receptor LR11/SorLA, a protein involved in the control of amyloid beta peptide production. Our results suggest that besides the involvement of the APP and PSEN genes, further genetic heterogeneity, involving another gene of the same pathway is present in ADEOAD.
Assuntos
Doença de Alzheimer/genética , Códon sem Sentido/genética , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Mutação de Sentido Incorreto/genética , Idoso , Estudos de Casos e Controles , Exoma/genética , Feminino , Predisposição Genética para Doença/genética , Predisposição Genética para Doença/psicologia , Humanos , MasculinoRESUMO
The Floating Harbor syndrome is a rare genetic disease characterized by a triad of clinical signs: specific dysmorphic facial features, short stature with delayed bone age, and language and speech disorders. These signs are, in most cases, associated with borderline normal intelligence to moderate delay concerning intellectual functioning. We report an extensive neuropsychological evaluation for an adult female patient and show, in particular, a severe visuospatial impairment. We discuss this deficit in the light of the previous reported cases and suggest that visuospatial abilities should be explored more systematically.
Assuntos
Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Anormalidades Craniofaciais/complicações , Transtornos do Crescimento/complicações , Comunicação Interventricular/complicações , Testes Neuropsicológicos , Anormalidades Múltiplas/psicologia , Adulto , Atenção/fisiologia , Anormalidades Craniofaciais/psicologia , Função Executiva/fisiologia , Feminino , Transtornos do Crescimento/psicologia , Comunicação Interventricular/psicologia , Humanos , Inteligência , Transtornos da Linguagem/diagnóstico , Transtornos da Linguagem/etiologia , Memória/fisiologia , Transtornos do Humor/etiologia , Personalidade , Percepção Espacial/fisiologiaRESUMO
INTRODUCTION: Fabry's disease is a X-linked lysosomal storage disorder caused by an alpha-galactosidase A deficiency responsible for the accumulation of glycosphingolipids. Males are more severely and frequently affected than females. We report the case of a female who presented a stroke revealing Fabry's disease. CASE REPORT: An 53-year-old woman, with cardiovascular risk factors and two previous transient ischemic attacks, was admitted with a brutal right hemiparisia. Cerebral MRI showed multiple white matter lesions in the cerebral hemispheres with multiple lacunar infarcts and ectatic vessels, cardiac echography revealed a hypertrophic concentric cardiomyopathy, and slit-lamp examination demonstrated a cornea verticillata. The sequencing of the alpha-galactosidase gene (GLA) revealed the c.150_151del mutation responsible for a loss of function. DISCUSSION: As in the present case, ophthalmological examination is very useful to determine Fabry's disease as a cause of young onset stroke. Females may be affected by X-linked disease, as the Fabry's disease. Fabry's disease among females is mainly characterized by the involvement of the nervous and cardiovascular systems. The specific treatment is based on an enzyme replacement therapy by recombinant enzyme with cardiovascular benefit. Despite the presence of cardiovascular risk factors, this case demonstrates the importance of thorough standardized investigations including ophthalmological examination of young patients with stroke.
Assuntos
Doenças da Córnea/complicações , Doença de Fabry/complicações , Doença de Fabry/diagnóstico , Ataque Isquêmico Transitório/complicações , Acidente Vascular Cerebral/complicações , Doenças da Córnea/diagnóstico , Doenças da Córnea/etiologia , Diagnóstico Diferencial , Feminino , Humanos , Ataque Isquêmico Transitório/diagnóstico , Ataque Isquêmico Transitório/etiologia , Pessoa de Meia-Idade , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologiaRESUMO
BACKGROUND: For suprasellar meningioma, the fronto-basal exposure is considered the standard approach. The superior interhemispheric (IH) approach is less described in the literature. OBJECTIVE: To assess the surgical complications, functional outcome (visual, olfaction), morbidity and mortality rates and late recurrence, after resection by superior IH approach of midline skull base meningioma. METHODS: Between 1998 and 2008, 52 consecutive patients with midline meningioma on the anterior portion of the skull base (mean age: 63.8 ± 13.1; sex ratio F/M: 3.7) were operated on via the superior IH approach. After a mean follow-up of 56.9 ± 32.9 months, an independent neurosurgeon proposed a prospective examination of functional outcome to each patient, as well as a visual and olfactory function assessment. RESULTS: Fifty-two patients were divided into a group with olfactory groove meningioma (n=34) and another with tuberculum sellae meningioma (n=18). The outcome was characterized by postoperative complications in 13 patients (25%), mortality rate in two (3.8%) and long-term morbidity at in 17 (37%) of 50 surviving patients. Based on multivariate analysis, no prognosis factor was significant as regards the favorable outcome. The mean postoperative KPS score (86.6 ± 9.4) was significantly improved. However, dysexecutive syndrome was observed in four patients (8%), hyposmia-anosmia in 34 (68%) and visual acuity deteriorated in one (2%). CONCLUSION: The superior IH approach could be considered a safe anteriorly orientated midline approach for removal OGM and TSM meningioma.
Assuntos
Meningioma/cirurgia , Procedimentos Neurocirúrgicos/métodos , Neoplasias da Base do Crânio/cirurgia , Base do Crânio/cirurgia , Idoso , Função Executiva/fisiologia , Feminino , Seguimentos , Humanos , Avaliação de Estado de Karnofsky , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Meningioma/mortalidade , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Procedimentos Neurocirúrgicos/efeitos adversos , Transtornos do Olfato/etiologia , Percepção Olfatória/fisiologia , Complicações Pós-Operatórias/epidemiologia , Prognóstico , Qualidade de Vida , Estudos Retrospectivos , Base do Crânio/anatomia & histologia , Neoplasias da Base do Crânio/mortalidade , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Testes Visuais , Acuidade Visual/fisiologiaRESUMO
OBJECTIVE: Oropharyngeal dysphagia is frequent in chronic neurological disorders and increases mortality, mainly due to pulmonary complications. Our aim was to show that submental sensitive transcutaneous electrical stimulation (SSTES) applied during swallowing at home can improve swallowing function in patients with chronic neurological disorders. METHODS: Thirteen patients were recruited for the study (4 f, 68 ± 12 years). They all suffered from neurogenic oropharyngeal dysphagia. We first compared the swallowing of paste and liquid with and without SSTES. Thereafter, the patients were asked to perform SSTES at home with each meal. Swallowing was evaluated before and after six weeks of SSTES using the SWAL-QoL questionnaire. RESULTS: With the stimulator switch turned on, swallowing coordination improved, with a decrease in swallow reaction time for the liquid (P<0.05) and paste boluses (P<0.01). Aspiration scores also decreased significantly with the electrical stimulations (P<0.05), with no change in stasis. At-home compliance was excellent and most patients tolerated the electrical stimulations with no discomfort. A comparison of the SWAL-QoL questionnaires after 6 weeks revealed an improvement in the burden (P=0.001), fatigue (P<0.05), and pharyngeal symptom (P<0.001) scales. CONCLUSION: The present study demonstrated that SSTES is easy to use at home and improves oropharyngeal dysphagia quality of life.
Assuntos
Transtornos de Deglutição/terapia , Assistência Domiciliar/métodos , Estimulação Elétrica Nervosa Transcutânea/métodos , Idoso , Idoso de 80 Anos ou mais , Obstrução das Vias Respiratórias/prevenção & controle , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/fisiopatologia , Transtornos de Deglutição/psicologia , Feminino , Fluoroscopia , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/complicações , Esclerose Múltipla/complicações , Aceitação pelo Paciente de Cuidados de Saúde , Cooperação do Paciente , Projetos Piloto , Pneumonia Aspirativa/prevenção & controle , Qualidade de Vida , Acidente Vascular Cerebral/complicações , Inquéritos e Questionários , Estimulação Elétrica Nervosa Transcutânea/instrumentaçãoRESUMO
Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.
Assuntos
Doença de Alzheimer/genética , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Predisposição Genética para Doença/genética , Hereditariedade/genética , Fatores Etários , Idoso , Alelos , Doença de Alzheimer/epidemiologia , Estudos de Casos e Controles , Feminino , França/epidemiologia , Genótipo , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estados Unidos/epidemiologiaRESUMO
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disorder due to a deficiency of the mitochondrial enzyme sterol 27-hydroxylase (CYP 27) with reduced or no chenodeoxycholic synthesis. This deficiency leads to an accumulation of cholestanol in different sites such as the eye lens, central nervous system or tendons. We report a 64-year-old female patient with a progressive gait disorder associated with cognitive decline since the age of 59. The patient had no mental retardation, cataract or chronic diarrhea. Her family reported increasing behavioral modifications 10 years previously. Clinical examination revealed a spastic paraplegia and bilateral xanthomas on the Achilles tendons. Cerebral magnetic resonance imaging (MRI) revealed diffuse hyperintense T2 abnormalities in the pyramidal tracts from the internal capsules to the cerebral peduncles also Technetium-99m-ECD brain SPECT showed a severe cerebellar hypoperfusion. Serum cholestanol analysis was 7 µmol/l (N). After 2 years, she was bedridden and died of aspiration pneumonia. The neuropathological study confirmed the CTX diagnosis and the sequencing analysis revealed that she was compound heterozygous for two mutations in the CYP27A1 gene: 1435 C > T (exon 7) on one allele and a new mutation, 1017 G > C (exon 5) on the other. The interest of the present case is to report neuropathology findings strongly correlated with the MRI and SPECT abnormalities.