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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.
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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 RetrospectivosRESUMEN
OBJECTIVES: We aimed to define brain iron distribution patterns in subtypes of early-onset Alzheimer's disease (EOAD) by the use of quantitative susceptibility mapping (QSM). METHODS: EOAD patients prospectively underwent MRI on a 3-T scanner and concomitant clinical and neuropsychological evaluation, between 2016 and 2019. An age-matched control group was constituted of cognitively healthy participants at risk of developing AD. Volumetry of the hippocampus and cerebral cortex was performed on 3DT1 images. EOAD subtypes were defined according to the hippocampal to cortical volume ratio (HV:CTV). Limbic-predominant atrophy (LPMRI) is referred to HV:CTV ratios below the 25th percentile, hippocampal-sparing (HpSpMRI) above the 75th percentile, and typical-AD between the 25th and 75th percentile. Brain iron was estimated using QSM. QSM analyses were made voxel-wise and in 7 regions of interest within deep gray nuclei and limbic structures. Iron distribution in EOAD subtypes and controls was compared using an ANOVA. RESULTS: Sixty-eight EOAD patients and 43 controls were evaluated. QSM values were significantly higher in deep gray nuclei (p < 0.001) and limbic structures (p = 0.04) of EOAD patients compared to controls. Among EOAD subtypes, HpSpMRI had the highest QSM values in deep gray nuclei (p < 0.001) whereas the highest QSM values in limbic structures were observed in LPMRI (p = 0.005). QSM in deep gray nuclei had an AUC = 0.92 in discriminating HpSpMRI and controls. CONCLUSIONS: In early-onset Alzheimer's disease patients, we observed significant variations of iron distribution reflecting the pattern of brain atrophy. Iron overload in deep gray nuclei could help to identify patients with atypical presentation of Alzheimer's disease. KEY POINTS: ⢠In early-onset AD patients, QSM indicated a significant brain iron overload in comparison with age-matched controls. ⢠Iron load in limbic structures was higher in participants with limbic-predominant subtype. ⢠Iron load in deep nuclei was more important in participants with hippocampal-sparing subtype.
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Enfermedad de Alzheimer , Sobrecarga de Hierro , Humanos , Enfermedad de Alzheimer/patología , Atrofia/patología , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Sobrecarga de Hierro/diagnóstico por imagen , Hierro , Mapeo Encefálico/métodosRESUMEN
Objective: Predicted age difference (PAD) is a score computed by subtracting chronological age from "brain" age, which is estimated using neuroimaging data. The goal of this study was to evaluate the PAD as a marker of phenotypic heterogeneity and severity among early-onset Alzheimer's disease (EOAD) patients. Methods: We first used 3D T1-weighted (3D-T1) magnetic resonance images (MRI) of 3,227 healthy subjects aged between 18 and 85 years to train, optimize, and evaluate the brain age model. A total of 123 participants who met the criteria for early-onset (<65 years) sporadic form of probable Alzheimer's disease (AD) and presented with two distinctive clinical presentations [an amnestic form (n = 74) and a non-amnestic form (n = 49)] were included at baseline and followed-up for a maximum period of 4 years. All the participants underwent a work-up at baseline and every year during the follow-up period, which included clinical examination, neuropsychological testing and genotyping, and structural MRI. In addition, cerebrospinal fluid biomarker assay was recorded at baseline. PAD score was calculated by applying brain age model to 3D-T1 images of the EOAD patients and healthy controls, who were matched based on age and sex. At baseline, between-group differences for neuropsychological and PAD scores were assessed using linear models. Regarding longitudinal analysis of neuropsychological and PAD scores, differences between amnestic and non-amnestic participants were analyzed using linear mixed-effects modeling. Results: PAD score was significantly higher for non-amnestic patients (2.35 ± 0.91) when compared to amnestic patients (2.09 ± 0.74) and controls (0.00 ± 1). Moreover, PAD score was linearly correlated with the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating Sum of Boxes (CDR-SB), for both amnestic and non-amnestic sporadic forms. Longitudinal analyses showed that the gradual development of the disease in patients was accompanied by a significant increase in PAD score over time, for both amnestic and non-amnestic patients. Conclusion: PAD score was able to separate amnestic and non-amnestic sporadic forms. Regardless of the clinical presentation, as PAD score was a way of quantifying an early brain age acceleration, it was an appropriate method to detect the development of AD and follow the evolution of the disease as a marker of severity as MMSE and CDR-SB.
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BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is a heterogeneous pathology. Young patients with AD are particularly likely to have an atypical presentation. The objectives of the present cluster analysis were to determine whether patients with early-onset AD (EOAD) had several distinct cognitive profiles and to compare the resulting clusters with regard to clinical, neuroimaging, and laboratory characteristics. METHODS: We collected cognitive, behavioural, functional, neuroimaging, and laboratory data on 72 patients meeting the criteria for probable mild EOAD. The patients were first classified into clinical phenotype groups by a multidisciplinary board of clinicians. The patients' cognitive and functional decline was monitored for 24 months. A k-means clustering analysis was then used to determine clusters on the basis of the patients' neuropsychological test results. RESULTS: Two distinct clusters were identified: the patients in the first cluster (C1, n = 38) had a predominant memory impairment, whereas patients in the second (C2, n = 34) did not. Dyslipidaemia and the presence of É4 apolipoprotein E allele were more frequent in C1, whereas the cognitive and functional decline was faster in the patients in C2. Moreover, posterior brain abnormalities were more severe in patients in C2 than in patients in C1. CONCLUSIONS: By applying a k-means clustering analysis, we identified two clusters of patients in an EOAD cohort. The clusters differed with regard to certain clinical, imaging, and laboratory characteristics. This clustering procedure might be of value for managing patients with EOAD in general and for identifying those at risk of more rapid decline in particular.
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Enfermedad de Alzheimer , Cognición , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Humanos , Estudios Longitudinales , Neuroimagen , Pruebas NeuropsicológicasRESUMEN
BACKGROUND: Due to heterogeneous clinical presentation, difficult differential diagnosis with Alzheimer's disease (AD) and psychiatric disorders, and evolving clinical criteria, the epidemiology and natural history of frontotemporal lobar degeneration (FTD) remain elusive. In order to better characterize FTD patients, we relied on the database of a regional memory clinic network with standardized diagnostic procedures and chose AD patients as a comparator. METHODS: Patients that were first referred to our network between January 2010 and December 2016 and whose last clinical diagnosis was degenerative or vascular dementia were included. Comparisons were conducted between FTD and AD as well as between the different FTD syndromes, divided into language variants (lvFTD), behavioral variant (bvFTD), and FTD with primarily motor symptoms (mFTD). Cognitive progression was estimated with the yearly decline in Mini Mental State Examination (MMSE). RESULTS: Among the patients that were referred to our network in the 6-year time span, 690 were ultimately diagnosed with FTD and 18,831 with AD. Patients with FTD syndromes represented 2.6% of all-cause dementias. The age-standardized incidence was 2.90 per 100,000 person-year and incidence peaked between 75 and 79 years. Compared to AD, patients with FTD syndromes had a longer referral delay and delay to diagnosis. Patients with FTD syndromes had a higher MMSE score than AD at first referral while their progression was similar. mFTD patients had the shortest survival while survival in bvFTD, lvFTD, and AD did not significantly differ. FTD patients, especially those with the behavioral variant, received more antidepressants, anxiolytics, and antipsychotics than AD patients. CONCLUSIONS: FTD syndromes differ with AD in characteristics at baseline, progression rate, and treatment. Despite a broad use of the new diagnostic criteria in an organized memory clinic network, FTD syndromes are longer to diagnose and account for a low proportion of dementia cases, suggesting persistent underdiagnosis. Congruent with recent publications, the late peak of incidence warns against considering FTD as being exclusively a young-onset dementia.
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Enfermedad de Alzheimer , Demencia Frontotemporal , Preescolar , Demencia Frontotemporal/diagnóstico , Demencia Frontotemporal/epidemiología , Humanos , Memoria , Pruebas NeuropsicológicasRESUMEN
PURPOSE: To examine and compare longitudinal changes of cortical glucose metabolism in amnestic and non-amnestic sporadic forms of early-onset Alzheimer's disease and assess potential associations with neuropsychological performance over a 3-year period time. METHODS: Eighty-two participants meeting criteria for early-onset (< 65 years) sporadic form of probable Alzheimer's disease and presenting with a variety of clinical phenotypes (47 amnestic and 35 non-amnestic forms) were included at baseline and followed up for 1.44 ± 1.23 years. All of the participants underwent a work-up at baseline and every year during the follow-up period, which includes clinical examination, neuropsychological testing, genotyping, cerebrospinal fluid biomarker assays, and structural MRI and 18F-FDG PET. Vertex-wise partial volume-corrected glucose metabolic maps across the entire cortical surface were generated and longitudinally assessed together with the neuropsychological scores using linear mixed-effects modeling as a function of amnestic and non-amnestic sporadic forms of early-onset Alzheimer's disease. RESULTS: Similar evolution patterns of glucose metabolic decline between amnestic and non-amnestic forms were observed in widespread neocortical cortices. However, only non-amnestic forms appeared to have a greater reduction of glucose metabolism in lateral orbitofrontal and bilateral medial temporal cortices associated with more severe declines of neuropsychological performance compared with amnestic forms. Furthermore, results suggest that glucose metabolic decline in amnestic forms would progress along an anterior-to-posterior axis, whereas glucose metabolic decline in non-amnestic forms would progress along a posterior-to-anterior axis. CONCLUSIONS: We found differences in spatial distribution and temporal trajectory of glucose metabolic decline between amnestic and non-amnestic early-onset Alzheimer's disease groups, suggesting that one might want to consider treating the two forms of the disease as two separate entities.
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Enfermedad de Alzheimer , Fluorodesoxiglucosa F18 , Enfermedad de Alzheimer/diagnóstico por imagen , Encéfalo , Humanos , Imagen por Resonancia Magnética , Pruebas Neuropsicológicas , Tomografía de Emisión de PositronesRESUMEN
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 (pâ<â0.0001) and associated neurologic symptoms more frequently (pâ<â0.002). 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.
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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 ExomaRESUMEN
PURPOSE: One can reasonably suppose that cerebrospinal spinal fluid (CSF) biomarkers can identify distinct subgroups of Alzheimer's disease (AD) patients. In order to better understand differences in CSF biomarker patterns, we used FDG PET to assess cerebral metabolism in CSF-based subgroups of AD patients. METHODS: Eighty-five patients fulfilling the criteria for probable early-onset AD (EOAD) underwent lumbar puncture, brain 18F-FDG PET and MRI. A cluster analysis was performed, with the CSF biomarkers for AD as variables. Vertex-wise, partial-volume-corrected metabolic maps were computed for the patients and compared between the clusters of patients. Linear correlations between each CSF biomarker and the metabolic maps were assessed. RESULTS: Three clusters emerged. The "Aß42" cluster contained 32 patients with low levels of Aß42, while tau and p-tau remained within the normal range. The "Aß42 + tau" cluster contained 41 patients with low levels of Aß42 and high levels of tau and p-tau. Lastly, the "tau" cluster contained 12 patients with very high levels of tau and p-tau and low-normal levels of Aß42. There were no inter-cluster differences in age, sex ratio, educational level, APOE genotype, disease duration or disease severity. The "Aß42 + tau" and "tau" clusters displayed more marked frontal hypometabolism than the "Aß42" cluster did, and frontal metabolism was significantly negatively correlated with the CSF tau level. The "Aß42" and "Aß42 + tau" clusters displayed more marked hypometabolism in the left occipitotemporal region than the "tau" cluster did, and metabolism in this region was significantly and positively correlated with the CSF Aß42 level. CONCLUSION: The CSF biomarkers can be used to identify metabolically distinct subgroups of patients with EOAD. Future research should seek to establish whether these biochemical differences have clinical consequences.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Encéfalo/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Encéfalo/diagnóstico por imagen , Análisis por Conglomerados , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Fosfoproteínas/líquido cefalorraquídeo , Tomografía de Emisión de Positrones , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/metabolismoRESUMEN
BACKGROUND: Determinants of early-onset Alzheimer's disease (EOAD) are not well known. In late-onset AD, vascular risk factors (VRFs) are associated with earlier clinical manifestation. OBJECTIVE: The objective of this study was to assess the putative association between VRFs and EOAD. METHODS: We studied participants with dementia meeting criteria for EOAD (recruited into the French CoMAJ prospective cohort study from 1 June 2009 to 28 February 2014) and age-, gender-matched controls (ratio 1:3, drawn randomly from the French MONA-LISA population-based survey between 2005 and 2007). Demographic data, VRFs, comorbidities, treatments, and APOE genotypes were compared in multivariable logistic regression analyses. RESULTS: We studied 102 participants with dementia (mean±standard deviation age: 59.5±3.8; women: 59.8%) and 306 controls. Compared with controls, EOAD participants had spent less time in formal education (9.9±2.9 versus 11.7±3.8 y; pâ<â0.0001), were less likely to be regular alcohol consumers (pâ<â0.0001), had a lower body mass index (-2âkg/m2; pâ<â0.0004), and a lower mean systolic blood pressure (-6.2 mmHg; pâ=â0.0036). The prevalence of APOE É4 allele was higher in participants with dementia than in controls (50% versus 29.4%; pâ=â0.0002), as was the prevalence of depression (48% versus 32%; pâ<â0.001). Similar results were observed in multivariable analysis. Compared with EOAD participants lacking VRFs, EOAD participants with at least one VRF had a higher prevalence of depression (29.6% versus 53.3%, respectively; pâ=â0.03). CONCLUSION: The prevalence of VRFs is not elevated in EOAD patients (in contrast to older AD patients). Extensive genetic testing should be considered more frequently in the context of EOAD.
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Enfermedad de Alzheimer/epidemiología , Enfermedades Cardiovasculares/epidemiología , Edad de Inicio , Enfermedad de Alzheimer/genética , Animales , Apolipoproteínas E/genética , Enfermedades Cardiovasculares/genética , Comorbilidad , Femenino , Francia/epidemiología , Humanos , Modelos Logísticos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Prevalencia , Estudios Prospectivos , Factores de RiesgoRESUMEN
Until now, hypometabolic patterns and their correlations with neuropsychological performance have not been assessed as a function of the various presentations of sporadic early-onset Alzheimer's disease (EOAD). Here, we processed and analyzed the patients' metabolic maps at the vertex and voxel levels by using a nonparametric, permutation method that also regressed out the effects of cortical thickness and gray matter volume, respectively. The hypometabolism patterns in several areas of the brain were significantly correlated with the clinical manifestations. These areas included the paralimbic regions for typical presentations of sporadic EOAD. For atypical presentations, the hypometabolic regions included Broca's and Wernicke's areas and the pulvinar in language forms, bilateral primary and higher processing visual regions (with right predominance) in visuospatial forms, and the bilateral prefrontal cortex in executive forms. Similar hypometabolism patterns were also observed in a correlation analysis of the 18F-FDG PET data versus domain-specific, neuropsychological test scores. These heterogeneities might reflect different underlying pathophysiological processes in particular clinical presentations of sporadic EOAD and should be taken into account in future longitudinal and therapeutic studies.
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Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/psicología , Cognición , Tomografía de Emisión de Positrones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Atrofia , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Femenino , Fluorodesoxiglucosa F18 , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Tamaño de los Órganos , RadiofármacosRESUMEN
We performed whole-exome and whole-genome sequencing in 927 late-onset Alzheimer disease (LOAD) cases, 852 early-onset AD (EOAD) cases, and 1273 controls from France. We assessed the evidence for gene-based association of rare variants with AD in 6 genes for which an association with such variants was previously claimed. When aggregating protein-truncating and missense-predicted damaging variants, we found exome-wide significant association between EOAD risk and rare variants in SORL1, TREM2, and ABCA7. No exome-wide significant signal was obtained in the LOAD sample, and significance of the order of 10-6 was observed in the whole AD group for TREM2. Our study confirms previous gene-level results for TREM2, SORL1, and ABCA7 and provides a clearer insight into the classes of rare variants involved. Despite different effect sizes and varying cumulative minor allele frequencies, the rare protein-truncating and missense-predicted damaging variants in TREM2, SORL1, and ABCA7 contribute similarly to the heritability of EOAD and explain between 1.1% and 1.5% of EOAD heritability each, compared with 9.12% for APOE ε4.
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Transportadoras de Casetes de Unión a ATP/genética , Enfermedad de Alzheimer/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Estudio de Asociación del Genoma Completo , Proteínas Relacionadas con Receptor de LDL/genética , Glicoproteínas de Membrana/genética , Proteínas de Transporte de Membrana/genética , Receptores Inmunológicos/genética , Adulto , Anciano , Anciano de 80 o más Años , Apolipoproteína E4/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Secuenciación Completa del Genoma , Adulto JovenRESUMEN
BACKGROUND: Amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series. METHODS AND FINDINGS: We report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers-total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid ß (Aß)42-in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification. CONCLUSIONS: Our findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.
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Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Presenilina-1/genética , Presenilina-2/genética , Adulto , Edad de Inicio , Femenino , Francia , Pruebas Genéticas , Humanos , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
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.
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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 JovenRESUMEN
OBJECTIVE: To study the association between ABCA7 rare coding variants and Alzheimer disease (AD) in a case-control setting. METHODS: We conducted a whole exome analysis among 484 French patients with early-onset AD and 590 ethnically matched controls. RESULTS: After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of ABCA7 loss of function (LOF) and predicted damaging missense variants in cases (odds ratio [OR] 3.40, 95% confidence interval [CI] 1.68-7.35, p = 0.0002). Performing a meta-analysis with previously published data, we found that in a combined sample of 1,256 patients and 1,347 controls from France and Belgium, the OR was 2.81 (95% CI 1.89-4.20, p = 3.60 × 10(-7)). CONCLUSIONS: These results confirm that ABCA7 LOF variants are enriched in patients with AD and extend this finding to predicted damaging missense variants.
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Transportadoras de Casetes de Unión a ATP/genética , Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad , Mutación , Anciano , Bélgica , Estudios de Casos y Controles , Exoma , Francia , Frecuencia de los Genes , Estudios de Asociación Genética , HumanosRESUMEN
Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of late-onset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.
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Enfermedad de Alzheimer/genética , Exoma , Pruebas Genéticas/métodos , Precursor de Proteína beta-Amiloide/genética , Estudios de Casos y Controles , Femenino , Pruebas Genéticas/normas , Humanos , Masculino , Persona de Mediana Edad , Mutación , Linaje , Presenilina-1/genética , Presenilina-2/genética , Procesamiento Proteico-Postraduccional/genéticaAsunto(s)
Encéfalo/patología , Angiopatía Amiloide Cerebral/patología , Meninges/patología , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Complejo CD3/metabolismo , Progresión de la Enfermedad , Electroencefalografía , Femenino , Humanos , Imagen por Resonancia Magnética , Persona de Mediana EdadRESUMEN
BACKGROUND: There are many reports of cognitive dysfunction in patients receiving chemotherapy or targeted therapies. Many antineoplastic agents may be involved in the condition also known as "chemo brain" or "chemo fog". CASE PRESENTATION: Two male patients (aged 41 and 70) with multiple myeloma developed severe, rapidly progressing cognitive impairment (mostly involving episodic memory) and loss of independence in activities of daily living during lenalidomide-based treatment. On withdrawal of the drug, one patient recovered normal cognitive function and independence in activities of daily living, whereas mild cognitive impairment persisted in the other patient. The Naranjo Adverse Drug Reaction Probability Scale score was 6 out of 13 for the first patient and 5 out of 13 for the second, suggesting a probable causal relationship between the adverse event and lenalidomide administration. CONCLUSION: Lenalidomide may induce particular cognitive disorders (notably episodic memory impairments) in some patients. The drug's putative neurotoxicity is probably promoted by specific risk factors (such as previous chemotherapy, prior mild cognitive impairment, age and the presence of cerebrovascular lesions).
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Inhibidores de la Angiogénesis/efectos adversos , Factores Inmunológicos/efectos adversos , Trastornos de la Memoria/inducido químicamente , Talidomida/análogos & derivados , Adulto , Anciano , Humanos , Lenalidomida , Masculino , Mieloma Múltiple/diagnóstico por imagen , Mieloma Múltiple/tratamiento farmacológico , Talidomida/efectos adversos , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
The rs75932628-T variant of the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has recently been identified as a rare risk factor for late-onset Alzheimer's disease (AD). In this study we examined the association between TREM2 exon 2 variants and early-onset AD in a sample of Caucasian subjects of French origin including 726 patients with age of onset ≤65 years and 783 controls. Only the rs75932628-T variant (predicted to cause an R47H substitution) conferred a significant risk for early-onset AD (OR, 4.07; 95% CI, 1.3 to 16.9; p = 0.009). These results confirm the association between this variant and AD and underline its involvement in early-onset cases.
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Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Variación Genética/genética , Glicoproteínas de Membrana/genética , Receptores Inmunológicos/genética , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
AIM: To assess reasons that prevent Alzheimer's disease (AD) patients from being included in clinical trials. METHODS: In 2009, we reviewed the Lille Memory Clinic's case database to identify patients suitable for inclusion in four AD clinical trials. An initial selection was made on the basis of four criteria: (i) a diagnosis of AD (with or without white matter lesions [WML]), (ii) age, (iii) mini mental state examination (MMSE) score and (iv) symptomatic treatment of AD (cholinesterase inhibitors/memantine). Next, data on patients fulfilling these criteria were reviewed against all the inclusion/exclusion criteria for four clinical trials performed in 2009 at the Memory Clinic. Reasons for non-inclusion were analyzed. RESULTS: Two hundred and five patients were selected according to the four initial criteria. Reasons for subsequently not including some of patients in clinical trials were abnormalities on MRI (56.9%, 88.9% of which were WML), unauthorized medication (37.3%), the lack of a study partner/informant (37.1%), the presence of a non-authorized disease (24.4%), contraindication to MRI (9%), a change in diagnosis over time (3.9%), visual/auditory impairments (2.9%), alcohol abuse (2%) and an insufficient educational level (1%). CONCLUSION: A high proportion of AD patients presented with vascular abnormalities on MRI. This was not unexpected, since the patients were selected from the database and, as shown in epidemiologic studies, cerebrovascular diseases are frequently associated with AD. The presence of a study partner is essential for enabling a patient to participate in clinical trials because of the need to record reliably primary and secondary outcomes.
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Enfermedad de Alzheimer/diagnóstico , Selección de Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto/normas , Anciano , Anciano de 80 o más Años , Método Doble Ciego , Humanos , Persona de Mediana EdadRESUMEN
We describe 56 novel autosomal dominant early-onset Alzheimer disease (ADEOAD) families with PSEN1, PSEN2, and AßPP mutations or duplications, raising the total of families with mutations on known genes to 111 (74 PSEN1, 8 PSEN2, 16 AßPP, and 13 AßPP duplications) in the French series. In 33 additional families (23% of the series), the genetic determinism remained uncharacterized after this screening. Cerebrospinal fluid (CSF) biomarker levels were obtained for patients of 58 families (42 with known mutations and 16 without genetic characterization). CSF biomarkers profile was consistent with an AD diagnosis in 90% of families carrying mutations on known genes. In families without mutation, CSF biomarkers were consistent with AD diagnosis in 14/16 cases. Overall, these results support further genetic heterogeneity in the determinism of ADEOAD and suggest that other major genes remain to be characterized.