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International audience; BACKGROUND:Diagnosis of Alzheimer's disease in Down syndrome is challenging because of the absence of validated diagnostic biomarkers. We investigated the diagnostic performance of plasma and CSF biomarkers in this population.METHODS:We did a cross-sectional study of adults aged 18 years and older with Down syndrome enrolled in a population-based health plan in Catalonia, Spain. Every person with Down syndrome assessed in the health plan was eligible to enter the Down Alzheimer Barcelona Neuroimaging Initiative, and those with a plasma or CSF sample available were included in this study. Participants underwent neurological and neuropsychological examination and blood sampling, and a subset underwent a lumbar puncture. Adults with Down syndrome were classified into asymptomatic, prodromal Alzheimer's disease, or Alzheimer's disease dementia groups by investigators masked to biomarker data. Non-trisomic controls were a convenience sample of young (23-58 years) healthy people from the Sant Pau Initiative on Neurodegeneration. Amyloid-β (Aβ)1-40, Aβ1-42, total tau (t-tau), 181-phosphorylated tau (p-tau; only in CSF), and neurofilament light protein (NfL) concentrations were measured in plasma with a single molecule array assay and in CSF with ELISA. Plasma and CSF biomarker concentrations were compared between controls and the Down syndrome clinical groups. Diagnostic performance was assessed with receiver operating characteristic curve analyses between asymptomatic participants and those with prodromal Alzheimer's disease and between asymptomatic participants and those with Alzheimer's disease dementia.FINDINGS:Between Feb 1, 2013, and Nov 30, 2017, we collected plasma from 282 participants with Down syndrome (194 asymptomatic, 39 prodromal Alzheimer's disease, 49 Alzheimer's disease dementia) and 67 controls; CSF data were available from 94 participants (54, 18, and 22, respectively) and all 67 controls. The diagnostic performance of plasma biomarkers was poor (area under the curve [AUC] between 0·53 [95% CI 0·44-0·62] and 0·74 [0·66-0·82]) except for plasma NfL concentrations, which had an AUC of 0·88 (0·82-0·93) for the differentiation of the asymptomatic group versus the prodromal Alzheimer's disease group and 0·95 (0·92-0·98) for the asymptomatic group versus the Alzheimer's disease dementia group. In CSF, except for Aβ1-40 concentrations (AUC 0·60, 95% CI 0·45-0·75), all biomarkers had a good performance in the asymptomatic versus prodromal Alzheimer's disease comparison: AUC 0·92 (95% CI 0·85-0·99) for Aβ1-42, 0·81 (0·69-0·94) for t-tau, 0·80 (0·67-0·93) for p-tau, and 0·88 (0·79-0·96) for NfL. Performance of the CSF biomarkers was optimal in the asymptomatic versus Alzheimer's disease dementia comparison (AUC ≥0·90 for all except Aβ1-40 [0·59, 0·45-0·72]). Only NfL concentrations showed a strong correlation between plasma and CSF biomarker concentrations in participants with Down syndrome (rho=0·80; p

Introduction In the general population, the current trend is to diagnose Autism Spectrum Disorders (ASD) at an early stage, which is crucial to improve the prognosis. In contrast, in the Down's syndrome (DS) population, ASD diagnosis is frequently delayed, having negative consequences on the overall development of the children who suffer the condition. Objective To identify “early warning signs” for the detection of ASD in DS in the first years of life (0 to 4 years). Methods Retrospective cohort study: DS with an ASD diagnosis (DS-ASD) and healthy-DS (DS-noASD) matched by sex and age. Early warning signs were identified and selected from different questionnaires on ASD in the general population: 1. Lack of social smile; 2. lack of shared attention; 3. Lack of seeking comfort/protection; 4. Lack of complaint; 5. Little interest in others; 6. No pointing; 7. Absence of -imitation; 8. Lack of babbling/vocalisation; 9. Inappropriate facial expression; 10. Presence of rituals as repetitive actions or repetitive sentences; 11. Mannerisms hands/fingers; 12. Stereotypies; 13. Lack of sensory interest; and 14. Absence of gaze integration. Six investigators, who did not participate in the identification of the “early warning signals”, selected those that would guide a diagnosis of ASD (qualitative analysis). Parents were asked for videos of people with DS in ‘activity’ between 0 and 4 years. The same investigators, blinded to the diagnosis of ASD and after watching the videos, scored the “early warning signals” in three categories: presence/absence/non-evaluable (quantitative analysis). Results During 2013, 12 videos of 12 people with SD were obtained: 6 from the SD-ASD group and 6 from the SD-noASD group. The qualitative analysis identified as early warning signals related to the diagnosis of ASD: “Absence of gaze integration”, “absence of imitation”, “presence of rituals as repetitive actions or repetitive sentences” and “stereotypies”, and the quantitative analysis: “lack of shared attention” and “little interest in others”. Conclusion Certain “warning signs” may lead to a diagnosis of ASD in the first years of life in children with DS.

Resumen Introduccion En la poblacion general, el diagnostico de trastornos del espectro autista (TEA) se realiza generalmente en una etapa temprana, mejorandose asi el pronostico. En las personas con sindrome de Down (SD), la falta de instrumentos especificos y adaptados para el diagnostico, y la falta de experiencia de los profesionales, hace que el diagnostico de TEA suela pasar desapercibido. Objetivo Identificar senales de alarma «tempranas» de un posible diagnostico de TEA en ninos con SD en los primeros anos de vida (de 0 a 4 anos). Metodos Estudio retrospectivo de cohortes: ninos con SD y TEA (SD-TEA) y ninos con SD y sin TEA (SD-noTEA) emparejados por sexo y edad. Se identificaron las siguientes senales de alarma tempranas: 1) ausencia de sonrisa social; 2) falta atencion compartida; 3) falta de busqueda de consuelo/proteccion; 4) ausencia de queja; 5) poco interes por el otro; 6) no senala; 7) no imita; 8) ausencia de balbuceo, vocalizacion; 9) expresion facial inapropiada; 10) rituales verbales o acciones repetitivas; 11) manierismos manos/dedos; 12) estereotipias; 13) interes sensorial, y 14) no integracion de la mirada y la conducta. Seis investigadores, quienes no participaron en la identificacion de las senales de alarma tempranas, seleccionaron aquellas que orientarian a un diagnostico de TEA (analisis cualitativo). Se solicito a los padres videos de las personas con SD en «actividad» entre los 0 y 4 anos. Los mismos investigadores, cegados al diagnostico de TEA y tras visualizar los videos, puntuaron las senales de alarma tempranas en 3 categorias: presencia/ausencia/no evaluable (analisis cuantitativo). Resultados Durante el ano 2013, se obtuvieron 12 videos de 12 personas con SD: 6 del grupo SD-TEA y 6 del grupo SD-noTEA. El analisis cualitativo identifico como senales de alarma temprana relacionadas con el diagnostico de TEA: «no integracion de la mirada», «no imita», «rituales verbales o acciones repetitivas» y «estereotipias»; y el analisis cuantitativo identifico: «falta de atencion compartida» y «falta de interes por el otro». Conclusion Ciertas «senales de alarma» pueden orientar hacia un diagnostico de TEA en los primeros anos de vida en ninos con SD.