Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
1.
Genet Med ; 26(5): 101082, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38281098

RESUMEN

PURPOSE: To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD). METHODS: We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients. We built a framework for risk variant interpretation and risk gradation and assessed the detection rates among early-onset AD (EOAD, age of onset (AOO) ≤65 years, n = 608) depending on AOO and pedigree structure and late-onset AD (66 < AOO < 75, n = 92). RESULTS: Twenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20 of 21 affected APP, PSEN1, or PSEN2. LP/P variant detection rates in EOAD ranged from 1.7% to 11.6% based on AOO and pedigree structure. Risk factors were found in 69.5% of the remaining 679 patients, including 83 (12.2%) being heterozygotes for rare risk variants, in decreasing order of frequency, in TREM2, ABCA7, ATP8B4, SORL1, and ABCA1, including 5 heterozygotes for multiple rare risk variants, suggesting non-monogenic inheritance, even in some autosomal-dominant-like pedigrees. CONCLUSION: We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure.


Asunto(s)
Enfermedad de Alzheimer , Secuenciación del Exoma , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Glicoproteínas de Membrana , Presenilina-2 , Receptores Inmunológicos , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/diagnóstico , Pruebas Genéticas/métodos , Femenino , Masculino , Anciano , Factores de Riesgo , Estudios Prospectivos , Persona de Mediana Edad , Presenilina-2/genética , Presenilina-1/genética , Linaje , Edad de Inicio , Precursor de Proteína beta-Amiloide/genética , Anciano de 80 o más Años
2.
Acta Neuropathol ; 142(2): 259-278, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34095977

RESUMEN

Microduplications of the 17q21.31 chromosomal region encompassing the MAPT gene, which encodes the Tau protein, were identified in patients with a progressive disorder initially characterized by severe memory impairment with or without behavioral changes that can clinically mimic Alzheimer disease. The unique neuropathological report showed a primary tauopathy, which could not be unanimously classified in a given known subtype, showing both 4R- and 3R-tau inclusions, mainly within temporal cortical subregions and basal ganglia, without amyloid deposits. Recently, two subjects harboring the same duplication were reported with an atypical extrapyramidal syndrome and gait disorder. To decipher the phenotypic spectrum associated with MAPT duplications, we studied ten carriers from nine families, including two novel unrelated probands, gathering clinical (n = 10), cerebrospinal fluid (n = 6), MRI (n = 8), dopamine transporter scan (n = 4), functional (n = 5), amyloid (n = 3) and Tau-tracer (n = 2) PET imaging data as well as neuropathological examination (n = 4). Ages at onset ranged from 37 to 57 years, with prominent episodic memory impairment in 8/10 patients, associated with behavioral changes in four, while two patients showed atypical extrapyramidal syndrome with gait disorder at presentation, including one with associated cognitive deficits. Amyloid imaging was negative but Tau imaging showed significant deposits mainly in both mesiotemporal cortex. Dopaminergic denervation was found in 4/4 patients, including three without extrapyramidal symptoms. Neuropathological examination exclusively showed Tau-immunoreactive lesions. Distribution, aspect and 4R/3R tau aggregates composition suggested a spectrum from predominantly 3R, mainly cortical deposits well correlating with cognitive and behavioral changes, to predominantly 4R deposits, mainly in the basal ganglia and midbrain, in patients with prominent extrapyramidal syndrome. Finally, we performed in vitro seeding experiments in HEK-biosensor cells. Morphological features of aggregates induced by homogenates of three MAPT duplication carriers showed dense/granular ratios graduating between those induced by homogenates of a Pick disease and a progressive supranuclear palsy cases. These results suggest that MAPT duplication causes a primary tauopathy associated with diverse clinical and neuropathological features.


Asunto(s)
Encéfalo/patología , Tauopatías/patología , Proteínas tau/metabolismo , Adulto , Edad de Inicio , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Femenino , Heterocigoto , Humanos , Cuerpos de Inclusión/patología , Masculino , Persona de Mediana Edad , Tauopatías/metabolismo , Proteínas tau/genética
3.
J Neurol Neurosurg Psychiatry ; 89(5): 499-505, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29070644

RESUMEN

OBJECTIVE: To assess the clinicopathological and therapeutic features of patients with low (≥1000 to <10 000 Bühlmann Titre Units) (BTU), medium (10 000-70 000) or high (≥70 000) anti-myelin-associated glycoprotein (anti-MAG) antibody titres. METHODS: We retrospectively and prospectively analysed standardised report forms and medical records of 202 patients from 14 neuromuscular centres. RESULTS: Mean age at onset and mean time between symptom onset to last follow-up were respectively 62.6 years (25-91.4) and 8.4 years (0.3-33.3). Anti-MAG antibody titres at diagnosis were low, medium or high in 11%, 51% and 38% of patients. Patients presented with monoclonal gammopathy of undetermined significance in 68% of cases. About 17% of patients presented with 'atypical' clinical phenotype independently of anti-MAG titres, including acute or chronic sensorimotor polyradiculoneuropathies (12.4%), and asymmetric or multifocal neuropathy (3%). At the most severe disease stage, 22.4% of patients were significantly disabled. Seventy-eight per cent of patients received immunotherapies. Transient clinical worsening was observed in 12% of patients treated with rituximab (11/92). Stabilisation after rituximab treatment during the 7-12-month follow-up period was observed in 29% of patients. Clinical response to rituximab during the 6-month and/or 7-12-month follow-up period was observed in 31.5% of patients and correlated with anti-MAG titre ≥10 000 BTU. CONCLUSION: Our study highlights the extended clinical spectrum of patients with anti-MAG neuropathy, which appears unrelated to antibody titre. Besides, it may also suggest beneficial use of rituximab in the early phase of anti-MAG neuropathy.


Asunto(s)
Autoanticuerpos/sangre , Glicoproteína Asociada a Mielina/inmunología , Paraproteinemias/tratamiento farmacológico , Polineuropatías/tratamiento farmacológico , Polineuropatías/inmunología , Rituximab/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Combinada , Femenino , Humanos , Factores Inmunológicos/uso terapéutico , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Paraproteinemias/sangre , Paraproteinemias/inmunología , Polineuropatías/sangre , Estudios Prospectivos , Estudios Retrospectivos
4.
Alzheimers Res Ther ; 15(1): 93, 2023 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-37170141

RESUMEN

BACKGROUND: APP duplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes of APP duplications carriers. METHODS: Clinical, radiological, and neuropathological features of 43 APP duplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40 APP-negative CAA controls. RESULTS: Major neurocognitive disorders were found in 90.2% symptomatic APP duplication carriers, with prominent behavioral impairment in 9.7%. Symptomatic intracerebral hemorrhages were reported in 29.2% and seizures in 51.2%. CSF Aß42 levels were abnormal in 18/19 patients and 14/19 patients fulfilled MRI radiological criteria for CAA, while only 5 displayed no hemorrhagic features. We found no correlation between CAA radiological signs and duplication size. Compared to CAA controls, APP duplication carriers showed less disseminated cortical superficial siderosis (0% vs 37.5%, p = 0.004 adjusted for the delay between symptoms onset and MRI). Deep microbleeds were found in two APP duplication carriers. In addition to neurofibrillary tangles and senile plaques, CAA was diffuse and severe with thickening of leptomeningeal vessels in all 9 autopsies. Lewy bodies were found in substantia nigra, locus coeruleus, and cortical structures of 2/9 patients, and one presented vascular amyloid deposits in basal ganglia. DISCUSSION: Phenotypes associated with APP duplications were heterogeneous with different clinical presentations including dementia, hemorrhage, and seizure and different radiological presentations, even within families. No apparent correlation with duplication size was found. Amyloid burden was severe and widely extended to cerebral vessels as suggested by hemorrhagic features on MRI and neuropathological data, making APP duplication an interesting model of CAA.


Asunto(s)
Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/complicaciones , Amiloide/genética , Angiopatía Amiloide Cerebral/diagnóstico por imagen , Angiopatía Amiloide Cerebral/genética , Angiopatía Amiloide Cerebral/complicaciones , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/genética , Hemorragia Cerebral/patología , Imagen por Resonancia Magnética , Fenotipo , Estudios Retrospectivos
5.
Genome Med ; 14(1): 69, 2022 06 28.
Artículo en Inglés | MEDLINE | ID: mdl-35761418

RESUMEN

BACKGROUND: Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE-ε4, make such estimations difficult. METHODS: We proposed to estimate the age-related penetrance of SORL1-LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1-LoF variants, stratified by APOE-ε4, derived from the Rotterdam study (N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1-LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE-ε4-stratified SORL1-LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia. RESULTS: SORL1-LoF variants penetrance curves reached 100% (95% confidence interval [99-100%]) by age 70 among APOE-ε4ε4 carriers only, compared with 56% [40-72%] and 37% [26-51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1-LoF variant carriers in case-control study data. CONCLUSIONS: We conclude that SORL1-LoF variants should be interpreted in light of APOE genotypes for future clinical applications.


Asunto(s)
Enfermedad de Alzheimer , Proteínas Relacionadas con Receptor de LDL , Proteínas de Transporte de Membrana , Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Estudios de Casos y Controles , Genotipo , Humanos , Proteínas Relacionadas con Receptor de LDL/genética , Proteínas de Transporte de Membrana/genética , Penetrancia
6.
J Alzheimers Dis ; 87(2): 791-802, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35367960

RESUMEN

BACKGROUND: There is no consensus regarding the diagnostic value of cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers in cerebral amyloid angiopathy (CAA). OBJECTIVE: To describe the CSF levels of Aß42, Aß40, total protein Tau, and phosphorylated-Tau (p-Tau) in a large series of probable CAA patients and to compare with AD patients in order to identify a specific pattern in CAA but also to look for correlations with the neuroimaging profile. METHODS: We retrospectively included from 2 French centers probable CAA patients according to modified Boston criteria who underwent lumbar puncture (LP) with CSF AD biomarker quantifications. Two neurologists independently analyzed all MRI sequences. A logistic regression and Spearman's correlation coefficient were used to identify correlation between MRI and CSF biomarkers in CAA. RESULTS: We included 63 probable CAA and 27 AD patients. Among CAA 50.8% presented with decreased Aß42 level associated with elevated p-Tau and/or Tau, 34.9% with isolated decreased Aß42 level and 14.3% patients with normal Aß42 level. Compared to AD, CAA showed lower levels of Tau (p = 0.008), p-Tau (p = 0.004), and Aß40 (p = 0.001) but similar Aß42 level (p = 0.07). No correlation between Aß42 or Aß40 levels and neuroimaging was found. CONCLUSION: CSF biomarkers may improve the accuracy of the modified Boston criteria with altered profile in 85% of the patients fulfilling revised Boston criteria for probable CAA. Aß40 appears as an interesting selective biomarker in differential diagnosis.


Asunto(s)
Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Angiopatía Amiloide Cerebral/complicaciones , Humanos , Fragmentos de Péptidos/líquido cefalorraquídeo , Estudios Retrospectivos , Proteínas tau/líquido cefalorraquídeo
7.
J Alzheimers Dis ; 86(2): 525-530, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34974434

RESUMEN

This multicenter study was conducted in French memory clinics during the first COVID-2019 lockdown (March-May 2020). The objective was to evaluate the effect of a telemedicine consultation on treatment modification in dementia care. Among 874 patients who had a telemedicine consultation, 103 (10.7%) had treatment modifications, in particular those living with a relative or diagnosed with Alzheimer's disease. A control group of patients referred March-May 2019 was also included. Treatment modification rate was similar between periods with an adjusted percentage difference of -4% (p = 0.27). Telemedicine consultations allowed treatment modifications with only a minor short-term negative impact on therapeutic strategies.


Asunto(s)
COVID-19 , Telemedicina , Control de Enfermedades Transmisibles , Humanos , Pandemias , SARS-CoV-2
8.
BMJ Open ; 9(10): e032265, 2019 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-31594904

RESUMEN

INTRODUCTION: The number of older people diagnosed with amnestic mild cognitive impairment (aMCI), the prodromal state of Alzheimer's disease (AD), is increasing worldwide. However, some patients with aMCI never convert to the AD type of dementia, with some remaining stable and others reverting to normal. This overdiagnosis bias has been largely overlooked and gone unexplained. There is ample evidence in the laboratory that negative ageing stereotypes (eg, the culturally shared belief that ageing inescapably causes severe cognitive decline) contribute to the deteriorating cognitive performances of healthy older adults, leading them to perform below their true abilities. The study described here is intended to test for the first time whether such stereotypes also impair patients' cognitive performances during neuropsychological examinations in memory clinics, resulting in overdiagnosis of aMCI. METHODS AND ANALYSIS: The ongoing study is a 4-year randomised clinical trial comparing patients' physiological stress and cognitive performances during neuropsychological testing in memory clinics. A total of 260 patients attending their first cognitive evaluation will be randomised to either a standard condition of test administration, assumed here to implicitly activate negative ageing stereotypes or a reduced-threat instruction condition designed to alleviate the anxiety arising from these stereotypes. Both groups will be tested with the same test battery and stress biomarkers. For 30 patients diagnosed with aMCI in each group (n=60), biomarkers of neurodegeneration and amyloidopathy will be used to distinguish between aMCI with normal versus abnormal AD biomarkers. A 9-month follow-up will be performed on all patients to identify those whose cognitive performances remain stable, deteriorate or improve. ETHICS AND DISSEMINATION: This protocol has been approved by the French National Agency for Medicines and Health Products Safety and the Sud-Est I French Ethics Committee (2017-A00946-47). Results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03138018.


Asunto(s)
Envejecimiento/psicología , Enfermedad de Alzheimer/diagnóstico , Disfunción Cognitiva/diagnóstico , Estereotipo , Humanos , Memoria , Pruebas Neuropsicológicas , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de Regresión
9.
J Alzheimers Dis ; 71(1): 227-243, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31381512

RESUMEN

BACKGROUND: Pathogenic variants in the autosomal dominant genes PSEN1, PSEN2, or APP, APOE4 alleles, and rare variants within TREM2, SORL1, and ABCA7 contribute to early-onset Alzheimer's disease (EOAD). However, sporadic EOAD patients have been insufficiently studied to define the probability of being a carrier of one of these variants. OBJECTIVE: To describe the proportion of each genetic variation among patients with very young-onset sporadic AD. METHODS: We first screened PSEN1, PSEN2, and APP in 154 EOAD patients with an onset before 51 years and a negative family history. Among 99 patients with no mutation (NMC), whole exome sequencing (WES) was performed. We analyzed the APOE genotype and rare protein-truncating or missense predicted damaging variants of TREM2, SORL1, and ABCA7. Neurological examination and cerebrospinal fluid (CSF) biomarkers were systematically retrieved. RESULTS: Nineteen (12.3%) mutation carriers (MC) harbored an APP or PSEN1 pathogenic or likely pathogenic variant. Among the NMC, 54/99 carried at least one genetic risk factor, including 9 APOE4/E4 homozygous, 37 APOE4 heterozygous, and 14 with a rare variant in another risk factor gene: 3 SORL1, 4 TREM2, and 9 ABCA7. MC presented an earlier disease onset (p < 0.0001) and associated neurologic symptoms more frequently (p < 0.002). All but one patient had at least 2 CSF biomarkers in abnormal ranges. CONCLUSION: The genetic component of very early sporadic EOAD gathers a substantial proportion of pathogenic variants in autosomal dominant genes and an even higher proportion of patients carrying genetic risk factors, suggesting an oligogenic determinism, even at this range of ages.


Asunto(s)
Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad/genética , Mutación/genética , Precursor de Proteína beta-Amiloide/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Presenilina-1/genética , Presenilina-2/genética , Factores de Riesgo , Secuenciación del Exoma
11.
Neurology ; 87(9): 912-9, 2016 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-27466472

RESUMEN

OBJECTIVE: To assess seizure frequency in a large French cohort of autosomal dominant early-onset Alzheimer disease (ADEOAD) and to determine possible correlations with causative mutations. METHODS: A national multicentric study was performed in patients with ADEOAD harboring a pathogenic mutation within PSEN1, PSEN2, APP, or a duplication of APP, and a minimal follow-up of 5 years. Clinical, EEG, and imaging data were systematically recorded. RESULTS: We included 132 patients from 77 families: 94 PSEN1 mutation carriers (MCs), 16 APP duplication carriers, 15 APP MCs, and 7 PSEN2 MCs. Seizure frequency was 47.7% after a mean follow-up of 8.4 years (range 5-25). After 5-year follow-up and using a Cox model analysis, the percentages of patients with seizures were respectively 19.1% (10.8%-26.7%) for PSEN1, 28.6% (0%-55.3%) for PSEN2, 31.2% (4.3%-50.6%) for APP duplications, and no patient for APP mutation. APP duplication carriers showed a significantly increased seizure risk compared to both APP MCs (hazard ratio [HR] = 5.55 [95% confidence interval 1.87-16.44]) and PSEN1 MCs (HR = 4.46 [2.11-9.44]). Among all PSEN1 mutations, those within the domains of protein hydrophilic I, transmembrane II (TM-II), TM-III, TM-IV, and TM-VII were associated with a significant increase in seizure frequency compared to other domains (HR = 4.53 [1.93-10.65], p = 0.0005). CONCLUSIONS: Seizures are a common feature of ADEOAD. In this population, risk was significantly higher in the APP duplication group than in all other groups. Within PSEN1, 5 specific domains were associated with a higher seizure risk indicating specific correlations between causative mutation and seizures.


Asunto(s)
Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Epilepsia/epidemiología , Adulto , Edad de Inicio , Anciano , Precursor de Proteína beta-Amiloide/genética , Estudios de Cohortes , Análisis Mutacional de ADN , Epilepsia/genética , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Presenilina-1/genética , Presenilina-2/genética , Estadísticas no Paramétricas , Adulto Joven
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA