RESUMEN
OBJECTIVES: All categories included in the AT(N) classification can now be measured in plasma. However, their agreement with cerebrospinal fluid (CSF) markers is not fully established. A blood signature to generate the AT(N) classification would facilitate early diagnosis of patients with Alzheimer's disease (AD) through an easy and minimally invasive approach. METHODS: We measured Aß, pTau181 and neurofilament light (NfL) in 150 plasma samples of the Sant Pau Initiative on Neurodegeneration cohort including patients with mild cognitive impairment, AD dementia, frontotemporal dementia, dementia with Lewy bodies and cognitively normal participants. We classified participants in the AT(N) categories according to CSF biomarkers and studied the diagnostic value of plasma biomarkers within each category individually and in combination. RESULTS: The plasma Aß composite, pTau181 and NfL yielded areas under the curve (AUC) of 0.75, 0.78 and 0.88 to discriminate positive and negative participants in their respective A, T and N categories. The combination of all three markers did not outperform pTau181 alone (AUC=0.81) to discriminate A+T+ from A-T- participants. There was a moderate correlation between plasma Aß composite and CSF Aß1-42/Aß1-40 (Rho=-0.5, p<0.001) and between plasma pTau181 and CSF pTau181 in the entire cohort (Rho=0.51, p<0.001). NfL levels in plasma showed high correlation with those in CSF (Rho=0.78, p<0.001). CONCLUSIONS: Plasma biomarkers are useful to detect the AT(N) categories, and their use can differentiate patients with pathophysiological evidence of AD. A blood AT(N) signature may facilitate early diagnosis and follow-up of patients with AD through an easy and minimally invasive approach.
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Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/sangre , Disfunción Cognitiva/diagnóstico , Demencia Frontotemporal/diagnóstico , Enfermedad por Cuerpos de Lewy/diagnóstico , Proteínas de Neurofilamentos/sangre , Proteínas tau/sangre , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Biomarcadores/sangre , Disfunción Cognitiva/sangre , Femenino , Demencia Frontotemporal/sangre , Humanos , Enfermedad por Cuerpos de Lewy/sangre , Masculino , Persona de Mediana Edad , FosforilaciónRESUMEN
INTRODUCTION: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis. METHODS: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively. RESULTS: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis. DISCUSSION: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides/sangre , Biomarcadores/sangre , Proteínas Sanguíneas , Proteómica , Proteínas tau/sangre , Anciano , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/patología , Apolipoproteína E4/sangre , Apolipoproteína E4/genética , Disfunción Cognitiva/sangre , Disfunción Cognitiva/patología , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Pelvic irradiation in childhood may result in abnormal uterine function. Poor obstetric outcomes have been reported in these patients. CASE: A 30-year-old woman with a previous midtrimester miscarriage, G2, P0, presented at 234 weeks gestation with acute abdominal pain and signs of hemodynamic instability. The patient was treated in childhood for Ewing sarcoma of the pelvis. Spontaneous uterine rupture was diagnosed. A supracervical hysterectomy with intrauterine fetus was performed. CONCLUSION: A high index of suspicion is needed in primigravidas with risk factors for uterine rupture. Pelvic radiotherapy in childhood may be a risk factor.
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Complicaciones del Embarazo/diagnóstico , Diagnóstico Prenatal , Traumatismos por Radiación , Sobrevivientes , Rotura Uterina/diagnóstico , Dolor Abdominal/etiología , Adulto , Neoplasias Óseas , Diagnóstico Diferencial , Femenino , Humanos , Histerectomía , Ilion , Embarazo , Complicaciones del Embarazo/diagnóstico por imagen , Complicaciones del Embarazo/cirugía , Segundo Trimestre del Embarazo , Sarcoma de Ewing , Rotura Uterina/diagnóstico por imagen , Rotura Uterina/cirugíaRESUMEN
INTRODUCTION: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a "Holy Grail" of AD research and intensively sought; however, there are no well-established plasma markers. METHODS: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed. RESULTS: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOε4 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71). DISCUSSION: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation.
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Enfermedad de Alzheimer , Biomarcadores/sangre , Disfunción Cognitiva , Inflamación , Anciano , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/sangre , Disfunción Cognitiva/sangre , Disfunción Cognitiva/diagnóstico , Estudios de Cohortes , Factor B del Complemento , Factor H de Complemento , Humanos , Internacionalidad , PronósticoRESUMEN
INTRODUCTION: A critical and as-yet unmet need in Alzheimer's disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers. METHODS: This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis. RESULTS: Eight metabolites were associated with amyloid ß and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory. DISCUSSION: PFAMs have been found increased and associated with amyloid ß burden in CSF and clinical measures.
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Péptidos beta-Amiloides , Amiloidosis/sangre , Biomarcadores , Hipocampo , Memoria/fisiología , Metabolómica , Anciano , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/líquido cefalorraquídeo , Amiloidosis/líquido cefalorraquídeo , Amiloidosis/metabolismo , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Encéfalo/patología , Disfunción Cognitiva/diagnóstico , Estudios de Cohortes , Femenino , Hipocampo/metabolismo , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Proteínas tau/sangre , Proteínas tau/líquido cefalorraquídeoRESUMEN
INTRODUCTION: Cortical mean diffusivity (MD) and free water fraction (FW) changes are proposed biomarkers for Alzheimer's disease (AD). METHODS: We included healthy control subjects (N = 254), mild cognitive impairment (N = 41), and AD dementia (N = 31) patients. Participants underwent a lumbar puncture and a 3 T magnetic resonance imaging. Healthy control subjects were classified following National Institute on Aging-Alzheimer's Association stages (stage 0, N = 220; stage 1, N = 25; and stage 2/3, N = 9). We assessed the cortical MD, cortical FW, and cortical thickness (CTh) changes along the AD continuum. RESULTS: Microstructural and macrostructural changes show a biphasic trajectory. Stage 1 subjects showed increased CTh and decreased MD and FW with respect the stage 0 subjects. Stage 2/3 subjects showed decreased CTh and increased cortical MD and FW, changes that were more widespread in symptomatic stages. DISCUSSION: These results support a biphasic model of changes in AD, which could affect the selection of patients for clinical trials and the use of magnetic resonance imaging as a surrogate marker of disease modification.
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Enfermedad de Alzheimer/diagnóstico por imagen , Corteza Cerebral/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquídeo , Corteza Cerebral/patología , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/genética , Progresión de la Enfermedad , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Punción EspinalRESUMEN
INTRODUCTION: We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer's disease (AD) (early-onset AD [EOAD]). METHODS: Neuroimaging features of CAA, apolipoprotein (APOE), and cerebrospinal fluid amyloid ß (Aß) 40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68). RESULTS: CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE ε4 genotype was borderline significantly associated with CAA in sporadic EOAD (P = .06) but not with DS or ADAD. There were no differences in Aß040 levels between groups or between subjects with and without CAA. DISCUSSION: CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid Aß40 levels are not a useful biomarker for CAA in AD.
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Enfermedad de Alzheimer/complicaciones , Angiopatía Amiloide Cerebral/etiología , Síndrome de Down/complicaciones , Adulto , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteína E4/genética , Angiopatía Amiloide Cerebral/líquido cefalorraquídeo , Angiopatía Amiloide Cerebral/diagnóstico por imagen , Angiopatía Amiloide Cerebral/genética , Síndrome de Down/líquido cefalorraquídeo , Síndrome de Down/diagnóstico por imagen , Síndrome de Down/genética , Femenino , Frecuencia de los Genes , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
The H1 haplotype of the 17q21.31 inversion polymorphism has been consistently associated with progressive supranuclear palsy, corticobasal degeneration, and Parkinson's disease in Caucasians. Recently, large polymorphic segmental duplications resulting into complex rearrangements at this locus with a high diversity range in human populations have been revealed. We sought to explore whether the two multi-allelic copy number variants that are present in the H1 clade (with segmental duplications of 300 and 218 kilobases in length) could be responsible for the known H1-related risk of developing these neurodegenerative disorders. A total of 857 Spanish subjects including 330 patients with Parkinson's disease, 96 with progressive supranuclear palsy, 55 with corticobasal degeneration, 51 dementia with Lewy bodies, and 325 neurologically healthy controls, were genotyped for the H1/H2 haplotype. Subsequently, the two copy number variants that are characteristic of the H1 haplotype were evaluated through a high-resolution approach based on droplet digital polymerase chain reaction, in all H1 homozygous subjects. The H1 allele was significantly overrepresented in all diagnostic groups compared with controls (Parkinson's disease, P = 0.0001; progressive supranuclear palsy, P = 1.22 × 10(-6) ; corticobasal degeneration, P = 0.0002; and dementia with Lewy bodies, P = 0.032). However, no dosage differences were found for any of the two copy number variants analyzed. The H1 haplotype is associated with the risk of several neurodegenerative disorders, including dementia with Lewy bodies. However, common structural diversity within the 17q21.31-H1 clade does not explain this genetic association.
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Cromosomas Humanos Par 17/genética , Variaciones en el Número de Copia de ADN/genética , Enfermedades Neurodegenerativas/genética , Anciano , Estudios de Casos y Controles , Demografía , Femenino , Frecuencia de los Genes/genética , Humanos , MasculinoRESUMEN
OBJECTIVE: To assess the relationships between core cerebrospinal fluid (CSF) biomarkers and cortical thickness (CTh) in preclinical Alzheimer disease (AD). METHODS: In this cross-sectional study, normal controls (n = 145) from the Alzheimer's Disease Neuroimaging Initiative underwent structural 3T magnetic resonance imaging (MRI) and lumbar puncture. CSF ß-amyloid1-42 (Aß) and phospho-tau181p (p-tau) levels were measured by Luminex assays. Samples were dichotomized using published cutoffs (Aß(+) /Aß(-) and p-tau(+) /ptau(-)). CTh was measured by Freesurfer. CTh difference maps were derived from interaction and correlation analyses. Clusters from the interaction analysis were isolated to analyze the directionality of the interaction by analysis of covariance. RESULTS: We found a significant biomarker interaction between CSF Aß and CSF p-tau levels affecting brain structure. Cortical atrophy only occurs in subjects with both Aß(+) and p-tau(+). The stratified correlation analyses showed that the relationship between p-tau and CTh is modified by Aß status and the relationship between Aß and CTh is modified by p-tau status. p-Tau-dependent thinning was found in different cortical regions in Aß(+) subjects but not in Aß(-) subjects. Cortical thickening was related to decreasing CSF Aß values in the absence of abnormal p-tau, but no correlations were found in p-tau(+) subjects. INTERPRETATION: Our data suggest that interactions between biomarkers in AD result in a 2-phase phenomenon of pathological cortical thickening associated with low CSF Aß, followed by atrophy once CSF p-tau becomes abnormal. These interactions should be considered in clinical trials in preclinical AD, both when selecting patients and when using MRI as a surrogate marker of efficacy.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides/líquido cefalorraquídeo , Corteza Cerebral/patología , Fragmentos de Péptidos/líquido cefalorraquídeo , Síntomas Prodrómicos , Proteínas tau/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Atrofia/líquido cefalorraquídeo , Atrofia/patología , Biomarcadores/líquido cefalorraquídeo , Estudios Transversales , Femenino , Humanos , MasculinoRESUMEN
OBJETIVE: To study the characteristics and evolution of group B Streptococcus (GBS) late-onset diseases, over a period of 15years in 8hospitals the Barcelona area and analyze the possible impact of prophylactic measures for the prevention of early-onset neonatal infections. METHODS: Retrospective review of all patients diagnosed with late-onset neonatal disease due to GBS from 1996 to 2010. RESULTS: A total of 143 patients were diagnosed. Of these, 51 were born in others hospitals. The overalll incidence was 0.42 per 1000 live births, varying between 0.14 in the year 2000 and 0.80 in 2009. A slight but sustained tendency of increased risk was observed over the years, 6.9% in the overall disease (with no statistical significance). Sepsis/bacteremia was detected in 63.6% of the newborns, meningitis in 32.8%, and arthritis/osteomyelitis in 3.5%. In cases with known obstetrics dates, 53% of mothers had been colonized by GBS during pregnancy, 53.8% received intrapartum antibiotic prophylaxis, and 41.2% had some obstetric risk factors, particularly premature birth in 35.9%. There was a 2.8% mortality rate in the neonates, and predominant serotypes were III and Ia. CONCLUSIONS: The incidence of GBS late-onset disease has not decreased despite the control practices of early-onset disease, and possibility of this appearing must be taken into account.
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Infecciones Estreptocócicas/microbiología , Streptococcus agalactiae/aislamiento & purificación , Edad de Inicio , Profilaxis Antibiótica , Artritis Infecciosa/epidemiología , Artritis Infecciosa/microbiología , Bacteriemia/epidemiología , Bacteriemia/microbiología , Infección Hospitalaria/epidemiología , Infección Hospitalaria/microbiología , Femenino , Humanos , Incidencia , Recién Nacido , Enfermedades del Prematuro/epidemiología , Enfermedades del Prematuro/microbiología , Meningitis Bacterianas/epidemiología , Meningitis Bacterianas/microbiología , Osteomielitis/epidemiología , Osteomielitis/microbiología , Embarazo , Complicaciones Infecciosas del Embarazo/epidemiología , Complicaciones Infecciosas del Embarazo/microbiología , Estudios Retrospectivos , Riesgo , Factores de Riesgo , España/epidemiología , Infecciones Estreptocócicas/congénito , Infecciones Estreptocócicas/epidemiología , Infecciones Estreptocócicas/prevención & controlRESUMEN
Diagnosis of rapidly progressive dementia (RPD) poses a complex medical challenge that requires an exhaustive evaluation. Although prion diseases, in particular Creutzfeldt-Jakob disease (CJD), are often suspected, many other nonprion diseases may present as RPD. Our aim was to review the causes of RPD in our center to better understand the underlying conditions. We reviewed clinical, neuroimaging, and cerebrospinal fluid data from patients with RPD admitted to our hospital from 1994 to 2009. Forty-nine patients (mean age at onset 72.4 y) with RPD were admitted to our center during the study period. The mean interval between the onset of symptoms and admission was 4.6 months. The final clinical diagnoses were as follows: nonprion neurodegenerative diseases (36.8%), CJD (30.6%), vascular dementia (8.2%), toxic-metabolic conditions (8.2%), and other disorders (16.2%). Among cases with informed death (n = 19), the average survival time was 8.6 ± 9.5 months. Survival was shorter among patients with prion disease (n = 10) than in those with other diagnoses (n = 9, P = 0.004). In conclusion, nonprion neurodegenerative diseases are the most common cause of RPD in our center. Our results suggest that although CJD is often suspected as a cause of RPD, its frequency depends on the referral differences across specialized centers.
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Demencia/etiología , Demencia/mortalidad , Demencia/patología , Anciano , Síndrome de Creutzfeldt-Jakob/complicaciones , Síndrome de Creutzfeldt-Jakob/epidemiología , Demencia Vascular/complicaciones , Demencia Vascular/epidemiología , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Enfermedades Neurodegenerativas/complicaciones , Enfermedades Neurodegenerativas/epidemiología , Centros de Atención TerciariaRESUMEN
BACKGROUND: Cerebrospinal fluid (CSF) Aß1-42 levels and the Aß1-42/Aß1-40 ratio are markers of amyloid pathology, but previous studies suggest that their levels might be influenced by additional pathophysiological processes. AIMS: To compare Aß1-42 and the Aß1-42/Aß1-40 ratio in CSF in different neurodegenerative disorders and study their association with other biomarkers (tTau, pTau181, and NfL) and with cognitive and functional progression. METHODS: We included all participants from the Sant Pau Initiative on Neurodegeneration (SPIN) with CSF Aß1-42 and Aß1-42/Aß1-40. Participants had diagnoses of Alzheimer's disease (AD), dementia with Lewy bodies, frontotemporal lobar degeneration-related syndromes, non-neurodegenerative conditions, or were cognitively normal. We classified participants as "positive" or "negative" according to each marker. We compared CSF levels of tTau, pTau181, and NfL between concordant and discordant groups through ANCOVA and assessed differences in cognitive (MMSE, FCSRT) and functional (GDS, CDR-SOB) progression using Cox regression and linear-mixed models. RESULTS: In the 1791 participants, the agreement between Aß1-42 and Aß1-42/Aß1-40 was 78.3%. The Aß1-42/Aß1-40 ratio showed a stronger correlation with tTau and pTau181 than Aß1-42 and an agreement with tTau and pTau181 of 73.1% and 77.1%, respectively. Participants with a low Aß1-42/Aß1-40 ratio showed higher tTau and pTau181 and worse cognitive and functional prognosis, regardless of whether they were positive or negative for Aß1-42. The results were consistent across stages, diagnostic categories, and use of different cutoffs. CONCLUSION: Although Aß1-42 and Aß1-42/Aß1-40 are considered markers of the same pathophysiological pathway, our findings provide evidence favoring the use of the Aß1-42/Aß1-40 ratio in clinical laboratories in the context of AD.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Proteínas tau , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Humanos , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeoRESUMEN
BACKGROUND: Astrocytes play an essential role in neuroinflammation and are involved in the pathogenesis of neurodenegerative diseases. Studies of glial fibrillary acidic protein (GFAP), an astrocytic damage marker, may help advance our understanding of different neurodegenerative diseases. In this study, we investigated the diagnostic performance of plasma GFAP (pGFAP), plasma neurofilament light chain (pNfL) and their combination for frontotemporal dementia (FTD) and Alzheimer's disease (AD) and their clinical utility in predicting disease progression. METHODS: pGFAP and pNfL concentrations were measured in 72 FTD, 56 AD and 83 cognitively normal (CN) participants using the Single Molecule Array technology. Of the 211 participants, 199 underwent cerebrospinal (CSF) analysis and 122 had magnetic resonance imaging. We compared cross-sectional biomarker levels between groups, studied their diagnostic performance and assessed correlation between CSF biomarkers, cognitive performance and cortical thickness. The prognostic performance was investigated, analyzing cognitive decline through group comparisons by tertile. RESULTS: Unlike pNfL, which was increased similarly in both clinical groups, pGFAP was increased in FTD but lower than in AD (all P < 0.01). Combination of both plasma markers improved the diagnostic performance to discriminate FTD from AD (area under the curve [AUC]: combination 0.78; pGFAP 0.7; pNfL 0.61, all P < 0.05). In FTD, pGFAP correlated with cognition, CSF and plasma NfL, and cortical thickness (all P < 0.05). The higher tertile of pGFAP was associated with greater change in MMSE score and poor cognitive outcome during follow-up both in FTD (1.40 points annually, hazard ratio [HR] 3.82, P < 0.005) and in AD (1.20 points annually, HR 2.26, P < 0.005). CONCLUSIONS: pGFAP and pNfL levels differ in FTD and AD, and their combination is useful for distinguishing between the two diseases. pGFAP could also be used to track disease severity and predict greater cognitive decline during follow-up in patients with FTD.
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Demencia Frontotemporal , Proteína Ácida Fibrilar de la Glía , Estudios Transversales , Demencia Frontotemporal/diagnóstico por imagen , Proteína Ácida Fibrilar de la Glía/análisis , Humanos , Filamentos Intermedios , PronósticoRESUMEN
Lifelong bilingualism may contribute to cognitive reserve (CR) in neurodegenerative diseases as shown by a delay of the age at symptom onset in bilinguals with Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI). However, some studies have failed to show this bilingual advantage, suggesting that it might depend on the type and degree of bilingualism. In the present study, we tested the hypothesis that active bilingualism, defined as the continuous use of the two languages as opposed to second language exposition only, may protect against cognitive decline. Moreover, we investigated whether bilingualism as a CR factor may be explained by an advantage within the executive control (EC) system. To do so, we collected clinical measures (age at onset of cognitive symptoms, age at the first medical visit for cognitive impairments, and age at diagnosis) in patients with MCI and patients with AD with different degrees of language experience and usage of Catalan and Spanish. Additionally, all participants were tested on four EC tasks and one long-term memory recognition task. First, results from multiple regression analyses showed that active bilingualism was a significant predictor of delay in the age at onset for all the clinical measures in MCI, but not AD patients. Second, the effect of active bilingualism was independent of occupation, educational level and job attainment across the individuals' lifespan. Finally, although we did not find an effect of active bilingualism across all EC tasks, we did find an effect for conflict resolution. These results are discussed in the context of CR hypotheses, suggesting that compensatory mechanisms may play a role in protecting against cognitive decline.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Reserva Cognitiva , Multilingüismo , Humanos , LenguajeRESUMEN
OBJECTIVE: To characterize the cortical macrostructure and microstructure of behavioral and cognitive changes along the amyotrophic lateral sclerosis (ALS)-frontotemporal dementia (FTD) continuum. METHODS: We prospectively recruited 88 participants with a 3T MRI structural and diffusion-weighted imaging sequences: 31 with ALS, 20 with the behavioral variant of FTD (bvFTD), and 37 cognitively normal controls. Participants with ALS underwent a comprehensive cognitive and behavioral assessment and were dichotomized into ALS without cognitive or behavioral impairment (ALSno-cbi; n = 12) and ALS with cognitive or behavioral impairment (ALScbi; n = 19). We computed cortical thickness and cortical mean diffusivity using a surface-based approach and explored the cortical correlates of cognitive impairment with the Edinburgh Cognitive and Behavioral ALS Screen. RESULTS: The ALSno-cbi and ALScbi groups showed different patterns of reduced cortical thickness and increased cortical mean diffusivity. In the ALSno-cbi group, cortical thinning was restricted mainly to the dorsal motor cortex. In contrast, in the ALScbi group, cortical thinning was observed primarily on frontoinsular and temporal regions bilaterally. There were progressive cortical mean diffusivity changes along the ALSno-cbi, ALScbi, and bvFTD clinical continuum. Participants with ALS with either cognitive or behavioral impairment showed increased cortical mean diffusivity in the prefrontal cortex in the absence of cortical thickness. CONCLUSIONS: Cortical mean diffusivity might be a useful biomarker for the study of extramotor cortical neurodegeneration in the ALS-FTD clinical spectrum. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that the cortical microstructure correlates with cognitive impairment in the ALS-FTD continuum.
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Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/psicología , Corteza Cerebral/patología , Trastornos del Conocimiento/patología , Trastornos del Conocimiento/psicología , Demencia Frontotemporal/patología , Demencia Frontotemporal/psicología , Anciano , Esclerosis Amiotrófica Lateral/complicaciones , Trastornos del Conocimiento/complicaciones , Femenino , Demencia Frontotemporal/complicaciones , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Pruebas Neuropsicológicas , Problema de Conducta/psicologíaRESUMEN
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aß) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aß42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aß38 and CSF-Aß40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aß and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.
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Enfermedad de Alzheimer , Anciano , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/genética , Biomarcadores , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Fragmentos de Péptidos , Proteínas tau/genéticaRESUMEN
We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E É4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.
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Enfermedad de Alzheimer/sangre , Biomarcadores/sangre , Proteínas Sanguíneas/análisis , Angiopatía Amiloide Cerebral/sangre , Proteómica , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Apolipoproteína E4/genética , Carga Corporal (Radioterapia) , Angiopatía Amiloide Cerebral/diagnóstico por imagen , Disfunción Cognitiva/sangre , Disfunción Cognitiva/diagnóstico por imagen , Estudios de Cohortes , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Curva ROC , Proteínas tau/líquido cefalorraquídeoRESUMEN
INTRODUCTION: The aetiological agent of erythema infectiosum is Erythrovirus B19 (also known as parvovirus B19), frequently found in children and adolescents, but also associated with arthropathy, aplastic crisis, and abortion in adults. MATERIAL AND METHODS: A retrospective study of Erythrovirus B19 cases in the years 2010-2015. RESULTS: Of the 56 cases of Erythrovirus B19 diagnosed, 34 were adults (32 women and 2 men) and 22 younger than 18 years (12 girls and 10 boys). Six cases were in pregnant women. Infections mainly occurred between spring and summer. In childhood, fever (64%), rash (50%), and anaemia (55%) were the most frequent symptoms. However, arthralgia (59%) was the most frequent symptom in adults, and less frequent were anaemia (41%), fever (32%), and rash (29%). CONCLUSIONS: The characteristic clinical presentation in childhood was rash and fever, whereas in adults it was arthralgia. Anaemia is also frequent, but only severe in previous haematological disease. It should be pointed out that Erythrovirus B19 infection during pregnancy could severely affect the foetus.
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Eritema Infeccioso/epidemiología , Parvovirus B19 Humano/aislamiento & purificación , Complicaciones Infecciosas del Embarazo/virología , Adulto , Factores de Edad , Artralgia/epidemiología , Artralgia/virología , Niño , Preescolar , Eritema Infeccioso/fisiopatología , Exantema/epidemiología , Exantema/virología , Femenino , Fiebre/epidemiología , Fiebre/virología , Estudios de Seguimiento , Humanos , Lactante , Masculino , Persona de Mediana Edad , Embarazo , Estudios RetrospectivosRESUMEN
The role of innate immunity in dementia with Lewy bodies (DLB) has been little studied. We investigated the levels in cerebrospinal fluid (CSF) of glial proteins YKL-40, soluble TREM2 (sTREM2) and progranulin in DLB and their relationship with Alzheimer's disease (AD) biomarkers. We included patients with DLB (n = 37), prodromal DLB (prodDLB, n = 23), AD dementia (n = 50), prodromal AD (prodAD, n = 53), and cognitively normal subjects (CN, n = 44). We measured levels of YKL-40, sTREM2, progranulin, Aß1-42, total tau (t-tau) and phosphorylated tau (p-tau) in CSF. We stratified the group DLB according to the ratio t-tau/Aß1-42 (≥0.52, indicative of AD pathology) and the A/T classification. YKL-40, sTREM2 and progranulin levels did not differ between DLB groups and CN. YKL-40 levels were higher in AD and prodAD compared to CN and to DLB and prodDLB. Patients with DLB with a CSF profile suggestive of AD copathology had higher levels of YKL-40, but not sTREM2 or PGRN, than those without. T+ DLB patients had also higher YKL-40 levels than T-. Of these glial markers, only YKL-40 correlated with t-tau and p-tau in DLB and in prodDLB. In contrast, in prodAD, sTREM2 and PGRN also correlated with t-tau and p-tau. In conclusion, sTREM2 and PGRN are not increased in the CSF of DLB patients. YKL-40 is only increased in DLB patients with an AD biomarker profile, suggesting that the increase is driven by AD-related neurodegeneration. These data suggest a differential glial activation between DLB and AD.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad por Cuerpos de Lewy/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Proteína 1 Similar a Quitinasa-3/líquido cefalorraquídeo , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/patología , Masculino , Glicoproteínas de Membrana/líquido cefalorraquídeo , Persona de Mediana Edad , Neuroglía/patología , Fragmentos de Péptidos/líquido cefalorraquídeo , Progranulinas/líquido cefalorraquídeo , Receptores InmunológicosRESUMEN
INTRODUCTION: The SPIN (Sant Pau Initiative on Neurodegeneration) cohort is a multimodal biomarker platform designed for neurodegenerative disease research following an integrative approach. METHODS: Participants of the SPIN cohort provide informed consent to donate blood and cerebrospinal fluid samples, receive detailed neurological and neuropsychological evaluations, and undergo a structural 3T brain MRI scan. A subset also undergoes other functional or imaging studies (video-polysomnogram, 18F-fluorodeoxyglucose PET, amyloid PET, Tau PET). Participants are followed annually for a minimum of 4 years, with repeated cerebrospinal fluid collection and imaging studies performed every other year, and brain donation is encouraged. RESULTS: The integration of clinical, neuropsychological, genetic, biochemical, imaging, and neuropathological information and the harmonization of protocols under the same umbrella allows the discovery and validation of key biomarkers across several neurodegenerative diseases. DISCUSSION: We describe our particular 10-year experience and how different research projects were unified under an umbrella biomarker program, which might be of help to other research teams pursuing similar approaches.