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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.
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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
BACKGROUND: There is little consensus on how to make a diagnosis announcement of severe chronic disease in neurology. Other medical specialties, such as oncology, have developed assessment methods similar to the Objective Structured Clinical Examination (OSCE) to address this issue. Here we report the implementation of an OSCE focused on the diagnosis announcement of chronic disease in neurology by residents. OBJECTIVE: We aimed to evaluate the acceptability, feasibility and validity in routine practice of an OSCE combined with a theoretical course focused on diagnosis announcement in neurology. METHOD: Eighteen neurology residents were prospectively included between 2019 and 2022. First, they answered a questionnaire on their previous level of training in diagnosis announcement. Second, in a practical session with a simulated patient, they made a 15-min diagnosis announcement and then had 5mins of immediate feedback with an expert observer, present in the room. The OSCE consisted of 4 different stations, with standardized scenarios dedicated to the announcement of multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Third, in a theory session, expert observers covered the essential theoretical points. All residents and expert observers completed an evaluation of the "practical session" and the "theory session". RESULTS: Residents estimated their previous level of diagnosis announcement training at 3.1/5. The most feared announcements were AD and ALS. The "practical session" was rated at a mean of 4.1/5 by the residents and 4.8/5 by the expert observers, and the "theory session" at a mean of 4.7/5 by the residents and 5/5 by the expert observers. After the OSCEs, 11 residents felt more confident about making an announcement. CONCLUSION: This study has shown a benefit of using an OSCE to learn how to make a diagnosis announcement of severe chronic disease in neurology. OSCEs could be used in many departments in routine practice and seem adapted to residents.
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Induced Pluripotent Stem Cell (iPSC) lines derived from healthy individuals are helpful and essential tools for disease modelling. Here, we described the reprogramming of skin fibroblasts obtained from a healthy 59-year-old individual without Alzheimer's disease. The generated iPSC lines have a normal karyotype, expressed pluripotency markers, and demonstrated the ability to differentiate into the three germ layers. The iPSC lines will be used as controls to study Alzheimer's disease mechanisms.
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Doença de Alzheimer , Células-Tronco Pluripotentes Induzidas , Humanos , Pessoa de Meia-Idade , Células-Tronco Pluripotentes Induzidas/metabolismo , Doença de Alzheimer/metabolismo , Fibroblastos , Camadas Germinativas , Diferenciação Celular , Reprogramação CelularRESUMO
Alzheimer's disease (AD) is a progressive neurological disorder and the most common form of dementia worldwide. Sporadic Alzheimer's disease (sAD) cases are the main forms, over 95% of AD cases, but still poorly understood. Thereby there is a crucial need to develop in vitro models for studying this multifactorial disorder. Here, we report the reprogramming of skin fibroblasts from a 57-years-old male donor. The new generated iPSC cell line has a normal karyotype and, is pluripotent since it demonstrates the ability to differentiate in vitro into the three germ layers. This iPSC line will be used to understand pathological mechanisms of sAD.
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Doença de Alzheimer , Células-Tronco Pluripotentes Induzidas , Humanos , Masculino , Pessoa de Meia-Idade , Células-Tronco Pluripotentes Induzidas/metabolismo , Doença de Alzheimer/patologia , Linhagem Celular , Fibroblastos/metabolismo , Camadas Germinativas/metabolismo , Diferenciação CelularRESUMO
OBJECTIVES: Statins have been associated with an increased risk of spontaneous intracerebral hemorrhage (ICH), but without dedicated study in cerebral amyloid angiopathy (CAA). We aimed to evaluate the association between previous statin treatment and radiological hemorrhagic lesions in a CAA population during a first lobar ICH event. MATERIALS AND METHODS: We retrospectively included all patients meeting the modified Boston criteria for probable CAA and admitted for a first lobar ICH between 2010 and 2021 at Rouen University Hospital. Patients were classified as having previous statin treatment or not. We compared the ICH volume, the number of associated cerebral microbleeds (CMBs), and cortical superficial siderosis (CSS) according to previous statin treatment or not. We also compared functional outcomes and ICH recurrence during the follow-up period between the two groups. RESULTS: We included 99 patients, 27 of whom had statin treatment prior to their ICH. The ICH volume and the number of CMBs did not differ between groups. Disseminated CSS was initially more frequent in the statin group (88% versus 57%; P=0.019), but this was no longer significant after adjustment for antiplatelet treatment (P=0.13). The long-term outcome was similar between the two groups with no increased risk of ICH recurrence in the statin-treated group (29.63% versus 23.61%, P=0.54). CONCLUSIONS: Previous statin treatment was not associated with more severe hemorrhagic lesions in CAA in terms of ICH volume or number of microbleeds, but a trend for increased disseminated CSS was highlighted, which will require further larger studies.
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Angiopatia Amiloide Cerebral , Inibidores de Hidroximetilglutaril-CoA Redutases , Siderose , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Estudos Retrospectivos , Imageamento por Ressonância Magnética , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/epidemiologia , Angiopatia Amiloide Cerebral/complicações , Angiopatia Amiloide Cerebral/tratamento farmacológico , Siderose/complicações , Siderose/epidemiologia , Siderose/patologiaRESUMO
OBJECTIVE: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare manifestation related to CAA, thought to be more severe. We aimed to compare the clinical and radiological outcomes of CAA-ri and non-inflammatory CAA. MATERIALS AND METHODS: We retrospectively included all patients with CAA-ri from 13 French centers. We constituted a sex- and age-matched control cohort with non-inflammatory CAA and similar disease duration. Survival, autonomy and cognitive evolution were compared after logistic regression. Cerebral microbleeds (CMB), intracerebral hemorrhage, cortical superficial siderosis and hippocampal atrophy were analyzed as well as CSF biomarker profile and APOE genotype when available. Outcomes were compared using Kaplan-Meier curves and log-rank tests. RESULTS: Data from 48 CAA-ri patients including 28 already reported and 20 new patients were analyzed. Over a mean of 3.1 years, 11 patients died (22.9%) and 18 (37.5%) relapsed. CAA-ri patients were more frequently institutionalized than non-inflammatory CAA patients (30% vs 8.3%, p < 0.001); mortality rates remained similar. MMSE and modified Rankin scale scores showed greater severity in CAA-ri at last follow-up. MRI showed a higher number of CMB at baseline and last follow-up in CAA-ri (p < 0.001 and p = 0.004, respectively). CSF showed lower baseline levels of Aß42 in CAA-ri than non-inflammatory CAA (373.3 pg/ml vs 490.8 pg/ml, p = 0.05). CAA-ri patients more likely carried at least one APOE ε4 allele (76% vs 37.5%, adjusted p = 0.05) particularly as homozygous status (56% vs 6.2%, p < 0.001). INTERPRETATION: CAA-ri appears to be more severe than non-inflammatory CAA with a significant loss of autonomy and global higher amyloid burden, shown by more CMB and a distinct CSF profile. This burden may be partially promoted by ε4 allele.
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Angiopatia Amiloide Cerebral , Angiopatia Amiloide Cerebral/complicações , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/etiologia , Humanos , Inflamação , Imageamento por Ressonância Magnética , Estudos RetrospectivosRESUMO
Alzheimer's disease (AD) is the most common neurodegenerative disorder. Although its etiology remains incompletely understood, genetic variants are important contributors. The prediction of AD risk through individual genetic variants is an important topic of research that may have individual and societal consequences when preventive treatments will become available. However, the genetic substratum of AD is heterogeneous. In addition to the extremely rare and fully penetrant pathogenic variants of the PSEN1, PSEN2 or APP genes causing autosomal dominant AD, a large spectrum of risk factors have been identified in complex forms, including the common risk factor APOEÉ4, which is associated with a moderate-to-high risk, common polymorphisms associated with a modest individual risk, and a plethora of rare variants in genes like SORL1, TREM2 or ABCA7 with moderate to high-magnitude effect. Understanding how these genetic factors contribute to AD risk in a given individual, in additional to non-genetic factors, remains a challenge. Over the last 10 years, age-related penetrance curves have progressively incorporated advances in the knowledge of AD genetics, from APOE to common polygenic components and, currently, SORL1 rare variants, which represents an important step towards precision medicine in AD. In this review, we present the complex genetic architecture of AD and we expose the prediction of AD risk according to its underlying genetic component.
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Doença de Alzheimer , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Predisposição Genética para Doença , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , MutaçãoRESUMO
CONTEXT: Cerebrospinal fluid (CSF) biomarkers are valuable tools for the diagnosis of neurological diseases. We aimed to investigate within a retrospective multicentric study the final diagnosis associated with very high CSF Tau levels and to identify patterns of biomarkers that would differentiate them in clinical practice, to help clinical biologists into physicians' counseling. PATIENTS AND METHODS: Within the national multicentric network ePLM, we included 1743 patients from January 1, 2008, to December 31, 2013, with CSF biomarkers assayed by the same Innotest assays (protein Tau, phospho-Tau [pTau], and Aß 1-42). We identified 205 patients with protein Tau concentration higher than 1200â¯pg/mL and final diagnosis. RESULTS: Among those patients, 105 (51.2%) were suffering from Alzheimer's disease, 37 (18%) from sporadic Creuztfeldt-Jakob disease, and 63 (30.7%) from other neurological diseases including paraneoplastic/ central nervous system tumor, frontotemporal dementia, other diagnoses, amyloid angiopathy, Lewy body dementia, and infections of the central nervous system. Phospho-Tau, Aß1-42 and Aß1-42/pTau values differed significantly between the three groups of patients (pâ¯<â¯.001). An Aß1-42/pTau ratio between 4.7 and 9.7 was suggestive of other neurological diseases (threshold in AD: 8.3). CSF 14-3-3 was useful to discriminate Alzheimer's disease from Creuztfeldt-Jakob disease in case of Aß1-42 concentrations <550â¯pg/mL or pTau>60â¯pg/mL. CONCLUSION: This work emphasizes the interest of a well-thought-out interpretation of CSF biomarkers in neurological diseases, particularly in the case of high Tau protein concentrations in the CSF.
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Laboratórios , Proteínas tau/líquido cefalorraquidiano , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosfoproteínas/líquido cefalorraquidiano , Adulto Jovem , Proteínas tau/metabolismoRESUMO
Induced pluripotent stem cells (iPSC) were generated from skin fibroblasts obtained from a 58â¯year-old woman suffering from Alzheimer's disease and carrying a D694N mutation on Amyloid precursor protein (APP). Fibroblasts were reprogrammed into iPSC using the integration-free Sendai Virus which allows the expression of the Yamanaka factors. Verification of their pluripotency was achieved by demonstrating the expression of pluripotency markers and their differentiation potential into the three primary germ layers. The cells have the corresponding mutation and present a normal karyotype. The reported APP-D694N iPSC line may be used to model and study human AD pathology in vitro.
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Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Diferenciação Celular , Reprogramação Celular , Fibroblastos/patologia , Células-Tronco Pluripotentes Induzidas/patologia , Mutação , Doença de Alzheimer/patologia , Células Cultivadas , Feminino , Fibroblastos/metabolismo , Heterozigoto , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Pessoa de Meia-Idade , FenótipoRESUMO
Induced pluripotent stem cells (iPSC) were generated from skin fibroblasts obtained from a 50â¯year-old patient suffering from Alzheimer's disease and carrying a G217D causal mutation on presenilin 1 (PSEN1). iPSCs were obtained following reprogramming using the integration-free Sendai Virus system which allows expression of the Yamanaka factors. Verification of their pluripotency was achieved by demonstrating the expression of pluripotency markers and their differentiation potential into the three primary germ layers. iPS cells carry the patient G217D mutation and present a normal karyotype. The reported PS1-G217D iPSC line may be used to model and study human AD pathology in vitro.
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Doença de Alzheimer/patologia , Técnicas de Cultura de Células/métodos , Células-Tronco Pluripotentes Induzidas/patologia , Mutação/genética , Presenilina-1/genética , Animais , Sequência de Bases , Linhagem Celular , Humanos , Masculino , Camundongos , Pessoa de Meia-IdadeRESUMO
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.
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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.
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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.
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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
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.
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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.
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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/patologiaRESUMO
INTRODUCTION: White matter lesions seen on MR scan reflect small vessel disease of the brain; increasing age and high blood pressure are the main risk factors. In young patients without vascular risk factors, screening for CADASIL mutation has to be done. Our aim was to describe clinical as well as radiological features of a series of patients without NOTCH3 mutation with severe vascular leukoencephalopathy not explained by the presence of vascular risk factors. MATERIAL AND METHODS: Inclusion criteria were grade 3 leukoencephalopathy according to the Fazekas scale, age<70years at onset, and negative screening for NOTCH3 gene. Patients with severe vascular risk factors or atherosclerosis were excluded. Clinical and MRI findings were analysed. RESULTS: Eight patients (four men) were included, five did not have any vascular risk factor. Mean age at onset was 59.5years. Initial symptoms were progressive in six cases of eight cases. They consisted of astasia-abasia and progressively worsened; of note one patient died 4years after disease onset. Cerebral MRI disclosed marked atrophy in five patients out of eight, temporal lobe (two out of eight) and external capsule (five out of eight) involvement was moderate. Four patients did not have any other atherosclerosis lesion. Seven out of eight had no retinal microangiopathy. High blood pressure was identified in two patients. CONCLUSION: The identification of vascular leukoencephalopathy in young patients without any vascular risk factors should lead the clinician to perform a complete work-up to search for treatable conditions including high blood pressure. Patients with vascular leukoencephalopathy usually present with astasia-abasia. In this context, cerebral MRI, cannot perfectly discriminate between patients with CADASIL from those with acquired small-vessel disease of the brain so that sequencing of NOTCH3 gene exons 2-24 is recommended.
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Encéfalo/patologia , Doenças de Pequenos Vasos Cerebrais/patologia , Leucoencefalopatias/patologia , Imageamento por Ressonância Magnética , Idoso , Atrofia , CADASIL/diagnóstico , CADASIL/genética , Doenças de Pequenos Vasos Cerebrais/sangue , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/epidemiologia , Comorbidade , Análise Mutacional de DNA , Diagnóstico Diferencial , Progressão da Doença , Feminino , França/epidemiologia , Humanos , Hiper-Homocisteinemia/epidemiologia , Hipertensão/epidemiologia , Arteriosclerose Intracraniana/epidemiologia , Leucoencefalopatias/sangue , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Radiografia , Receptor Notch3 , Receptores Notch/genética , Vasos Retinianos/patologia , Fatores de RiscoRESUMO
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.
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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
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.