Diagnostic and prognostic performance and longitudinal changes in plasma neurofilament light chain concentrations in adults with Down syndrome: a cohort study
Por:
Carmona-Iragui, M, Alcolea, D, Barroeta, I, Videla, L, Munoz, L, Van Pelt, KL, Schmitt, FA, Lightner, DD, Koehl, LM, Jicha, G, Sacco, S, Mircher, C, Pape, SE, Hithersay, R, Clare, ICH, Holland, AJ, Nubling, G, Levin, J, Zaman, SH, Strydom, A, Rebillat, AS, Head, E, Blesa, R, Lleo, A, Fortea, J
Publicada:
1 ago 2021
Resumen:
Background Adults with Down syndrome are at an ultra-high risk of Alzheimer's disease, but diagnosis of Alzheimer's disease in this population is challenging. We aimed to validate the clinical utility of plasma neurofilament light chain (NfL) for the diagnosis of symptomatic Alzheimer's disease in Down syndrome, assess its prognostic value, and establish longitudinal changes in adults with Down syndrome.
Methods We did a multicentre cohort study, including adults with Down syndrome (>= 18 years), recruited from six hospitals and university medical centres in France, Germany, Spain, the UK, and the USA, who had been assessed, followed up, and provided at least two plasma samples. Participants were classified by local clinicians, who were masked to biomarker data, as asymptomatic (ie, no clinical suspicion of Alzheimer's disease), prodromal Alzheimer's disease, or Alzheimer's disease dementia. We classified individuals who progressed along the Alzheimer's disease continuum during follow-up as progressors. Plasma samples were analysed retrospectively; NfL concentrations were measured centrally using commercial kits for biomarker detection. We used ANOVA to evaluate differences in baseline NfL concentrations, Cox regression to study their prognostic value, and linear mixed models to estimate longitudinal changes. To account for potential confounders, we included age, sex, and intellectual disability as covariates in the analyses.
Findings Between Aug 2, 2010, and July 16, 2019, we analysed 608 samples from 236 people with Down syndrome: 165 (70%) were asymptomatic, 32 (14%) had prodromal Alzheimer's disease, and 29 (12%) had Alzheimer's disease dementia; ten [4%] participants were excluded because their classification was uncertain. Mean follow-up was 3.6 years (SD 1.6, range 0.6-9.2). Baseline plasma NfL concentrations showed an area under the receiver operating characteristic curve of 0.83 (95% CI 0.76-0.91) in the prodromal group and 0.94 (0.90-0.97) in the dementia group for differentiating from participants who were asymptomatic. An increase of 1 pg/mL in baseline NfL concentrations was associated with a 1.04-fold risk of clinical progression (95% CI 1.01-1.07; p=0.0034). Plasma NfL concentrations showed an annual increase of 3.0% (95% CI 0.4-5.8) per year in the asymptomatic non-progressors group, 11.5% (4.9-18.5) per year in the asymptomatic progressors group, and 16.0% (8.4-24.0) per year in the prodromal Alzheimer's disease progressors group. In participants with Alzheimer's disease dementia, NfL concentrations increased by a mean of 24.3% (15.3-34.1).
Interpretation Plasma NfL concentrations have excellent diagnostic and prognostic performance for symptomatic Alzheimer's disease in Down syndrome. The longitudinal trajectory of plasma NfL supports its use as a theragnostic marker in clinical trials. Copyright (C) 2021 Elsevier Ltd. All rights reserved.
Filiaciones:
Carmona-Iragui, M:
Univ Autonoma Barcelona, Biomed Res Inst St Pau, Hosp Santa Creu & St Pau, St Pau Memory Unit,Neurol Dept, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Fundacio Catalana Sindrome, Barcelona Med Ctr, Barcelona, Spain
Horizon 21 Consortium, Paris, France
Alcolea, D:
Univ Autonoma Barcelona, Biomed Res Inst St Pau, Hosp Santa Creu & St Pau, St Pau Memory Unit,Neurol Dept, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Barroeta, I:
Univ Autonoma Barcelona, Biomed Res Inst St Pau, Hosp Santa Creu & St Pau, St Pau Memory Unit,Neurol Dept, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Videla, L:
Univ Autonoma Barcelona, Biomed Res Inst St Pau, Hosp Santa Creu & St Pau, St Pau Memory Unit,Neurol Dept, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Fundacio Catalana Sindrome, Barcelona Med Ctr, Barcelona, Spain
Horizon 21 Consortium, Paris, France
Munoz, L:
Univ Autonoma Barcelona, Biomed Res Inst St Pau, Hosp Santa Creu & St Pau, St Pau Memory Unit,Neurol Dept, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Van Pelt, KL:
Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA
Schmitt, FA:
Univ Kentucky, Dept Neurol, Lexington, KY 40536 USA
Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA
Lightner, DD:
Univ Kentucky, Dept Neurol, Lexington, KY 40536 USA
Koehl, LM:
Univ Kentucky, Dept Neurol, Lexington, KY 40536 USA
Jicha, G:
Univ Kentucky, Dept Neurol, Lexington, KY 40536 USA
Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA
Sacco, S:
Horizon 21 Consortium, Paris, France
Inst Jerome Lejeune, Paris, France
Mircher, C:
Inst Jerome Lejeune, Paris, France
Pape, SE:
Horizon 21 Consortium, Paris, France
Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England
South London & Maudsley Fdn NHS Trust, London, England
LonDownS Consortium, London, England
Hithersay, R:
Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England
LonDownS Consortium, London, England
Clare, ICH:
Univ Cambridge, Dept Psychiat, Cambridge, England
Cambridgeshire & Peterborough NHS Fdn Trust, Cambridge, England
East England, Natl Inst Hlth Res, Appl Res Collaborat, Cambridge, England
Holland, AJ:
Univ Cambridge, Dept Psychiat, Cambridge, England
Nubling, G:
Ludwig Maximilians Univ Munchen, Dept Neurol, Munich, Germany
Levin, J:
Horizon 21 Consortium, Paris, France
Ludwig Maximilians Univ Munchen, Dept Neurol, Munich, Germany
Munich Cluster Syst Neurol SyNergy, Munich, Germany
German Ctr Neurodegenerat Dis, Munich, Germany
Zaman, SH:
Horizon 21 Consortium, Paris, France
Univ Cambridge, Dept Psychiat, Cambridge, England
Cambridgeshire & Peterborough NHS Fdn Trust, Cambridge, England
Strydom, A:
Horizon 21 Consortium, Paris, France
Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England
South London & Maudsley Fdn NHS Trust, London, England
LonDownS Consortium, London, England
Rebillat, AS:
Horizon 21 Consortium, Paris, France
Inst Jerome Lejeune, Paris, France
Head, E:
Univ Calif Irvine, Dept Pathol & Lab Med, Irvine, CA USA
Blesa, R:
Univ Autonoma Barcelona, Biomed Res Inst St Pau, Hosp Santa Creu & St Pau, St Pau Memory Unit,Neurol Dept, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Lleo, A:
Univ Autonoma Barcelona, Biomed Res Inst St Pau, Hosp Santa Creu & St Pau, St Pau Memory Unit,Neurol Dept, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Fortea, J:
Univ Autonoma Barcelona, Biomed Res Inst St Pau, Hosp Santa Creu & St Pau, St Pau Memory Unit,Neurol Dept, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Fundacio Catalana Sindrome, Barcelona Med Ctr, Barcelona, Spain
Horizon 21 Consortium, Paris, France
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