Alpha-synuclein co-pathology in Down syndrome-associated Alzheimer's disease
Por:
Bernhardt, AM, Rodríguez-Baz, I, Aldecoa, I, Arranz, J, Arriola-Infante, JE, Maure-Blesa, L, Carmona-Iragui, M, Longen, S, Trossbach, SV, Giese, A, Matthias, T, Benejam, B, Videla, L, Soriano, LD, Barroeta, I, Sanjuan, A, Fernandez, S, Vaqué-Alcázar, L, Aranha, MR, Morcillo-Nieto, AO, Nübling, G, Wagemann, O, Stockbauer, A, Tondo, M, Bejanin, A, Lleó, A, Alcolea, D, Molina-Porcel, L, Fortea, J, Levin, J
Publicada:
1 jun 2025
Resumen:
INTRODUCTION: Alpha-synuclein (alpha Syn) seed amplification assay (SAA) enables in vivo study of alpha Syn but remains underexplored in Down syndrome-associated Alzheimer's disease (DSAD). METHODS: We analyzed alpha Syn-SAA in cerebrospinal fluid (CSF) from 270 adults with Down syndrome, from the Down Alzheimer Barcelona Neuroimaging Initiative and from the AD21 cohort from the Department of Neurology at the University Hospital, Ludwig Maximilian University of Munich, Germany. Neuropathological examinations were conducted in 19 brain donors (five with ante mortem CSF). Participants were classified as asymptomatic or symptomatic (prodromal/dementia) Alzheimer's disease (AD). CSF A beta 1-42/1-40, CSF and plasma p-Tau181, and neurofilament light chain (NfL) levels were measured. Neuropathological evaluations assessed AD neuropathological changes and Lewy body pathology (LBP). RESULTS: Alpha Syn-SAA was positive in 9.2% of cases, independent of age or cognitive status. Symptomatic alpha Syn-positive cases exhibited higher plasma NfL levels than alpha Syn-negative cases (31 vs 21 pg/mL, p = 0.027). LBP was observed in 47% of necropsies. The individual with severe neocortical LBP was alpha Syn-SAA-positive. DISCUSSION: These findings highlight LBP prevalence in DSAD but suggest current SAA may fail to detect limited alpha Syn deposition. Highlights center dot alpha Syn-SAA positivity in DSAD is 9.2%, similar to ADAD but lower than sporadic AD. center dot Misfolded alpha Syn was detectable from early ages in individuals with DS. center dot Positivity rates did not vary with age or clinical status in DS. center dot Plasma NfL levels are higher in symptomatic alpha Syn-SAA positive versus negative cases. center dot CSF alpha Syn seeding activity was associated with high neocortical LBP at necropsy.
Filiaciones:
Bernhardt, AM:
Ludwig Maximilians Univ Munchen, Dept Neurol, Munich, Germany
German Ctr Neurodegenerat Dis DZNE, Site Munich, Munich, Germany
Rodríguez-Baz, I:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau IR SANT PAU, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
Inst Salud Carlos III, Ctr Biomed Invest Network Neurodegenerat Dis CIBER, Madrid, Spain
Aldecoa, I:
Hosp Clin Barcelona, Inst Invest Biomed August Pi I Sunyer IDIBAPS FCRB, Neurol Tissue Bank Biobanc, Barcelona, Spain
Univ Barcelona, Hosp Clin Barcelona, Biomed Diagnost Ctr, Pathol Dept, Barcelona, Spain
Arranz, J:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau IR SANT PAU, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
Arriola-Infante, JE:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau IR SANT PAU, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
Inst Salud Carlos III, Ctr Biomed Invest Network Neurodegenerat Dis CIBER, Madrid, Spain
Maure-Blesa, L:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau IR SANT PAU, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
Inst Salud Carlos III, Ctr Biomed Invest Network Neurodegenerat Dis CIBER, Madrid, Spain
Carmona-Iragui, M:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau IR SANT PAU, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
Inst Salud Carlos III, Ctr Biomed Invest Network Neurodegenerat Dis CIBER, Madrid, Spain
Barcelona Med Ctr, Fundacio Catalana Sindrome, Barcelona, Spain
Longen, S:
Aesku Diagnost GmbH, Wendelsheim, Germany
Trossbach, SV:
MODAG GmbH, Mikroforum Ring 3, Wendelsheim, Germany
Giese, A:
MODAG GmbH, Mikroforum Ring 3, Wendelsheim, Germany
Matthias, T:
Aesku Diagnost GmbH, Wendelsheim, Germany
MODAG GmbH, Mikroforum Ring 3, Wendelsheim, Germany
Benejam, B:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau IR SANT PAU, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
Inst Salud Carlos III, Ctr Biomed Invest Network Neurodegenerat Dis CIBER, Madrid, Spain
Barcelona Med Ctr, Fundacio Catalana Sindrome, Barcelona, Spain
Videla, L:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau IR SANT PAU, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
Inst Salud Carlos III, Ctr Biomed Invest Network Neurodegenerat Dis CIBER, Madrid, Spain
Barcelona Med Ctr, Fundacio Catalana Sindrome, Barcelona, Spain
Soriano, LD:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau IR SANT PAU, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
Barroeta, I:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau IR SANT PAU, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
Inst Salud Carlos III, Ctr Biomed Invest Network Neurodegenerat Dis CIBER, Madrid, Spain
Sanjuan, A:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau IR SANT PAU, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
Fernandez, S:
Barcelona Med Ctr, Fundacio Catalana Sindrome, Barcelona, Spain
Vaqué-Alcázar, L:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau IR SANT PAU, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
Univ Barcelona, Inst Neurosci, Fac Med & Hlth Sci, Dept Med, Barcelona, Spain
Inst Invest Biomed August Pi I Sunyer IDIBAPS, Barcelona, Spain
Aranha, MR:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau IR SANT PAU, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
Morcillo-Nieto, AO:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau IR SANT PAU, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
Nübling, G:
Ludwig Maximilians Univ Munchen, Dept Neurol, Munich, Germany
German Ctr Neurodegenerat Dis DZNE, Site Munich, Munich, Germany
Wagemann, O:
Ludwig Maximilians Univ Munchen, Dept Neurol, Munich, Germany
German Ctr Neurodegenerat Dis DZNE, Site Munich, Munich, Germany
Stockbauer, A:
Ludwig Maximilians Univ Munchen, Dept Neurol, Munich, Germany
German Ctr Neurodegenerat Dis DZNE, Site Munich, Munich, Germany
Tondo, M:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Serv Bioquim & Biol Mol, IR SANT PAU, Barcelona, Spain
Inst Salud Carlos III, Spanish Biomed Res Ctr Diabet & Associated Metab D, Madrid, Spain
Bejanin, A:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau IR SANT PAU, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
Inst Salud Carlos III, Ctr Biomed Invest Network Neurodegenerat Dis CIBER, Madrid, Spain
Lleó, A:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau IR SANT PAU, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
Inst Salud Carlos III, Ctr Biomed Invest Network Neurodegenerat Dis CIBER, Madrid, Spain
Alcolea, D:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau IR SANT PAU, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
Inst Salud Carlos III, Ctr Biomed Invest Network Neurodegenerat Dis CIBER, Madrid, Spain
Molina-Porcel, L:
Hosp Clin Barcelona, Inst Invest Biomed August Pi I Sunyer IDIBAPS FCRB, Neurol Tissue Bank Biobanc, Barcelona, Spain
Hosp Clin Barcelona, Neurol Serv, Alzheimers Dis & Other Cognit Disorders Unit, Barcelona, Spain
Fortea, J:
Hosp Santa Creu & Sant Pau, Inst Recerca St Pau IR SANT PAU, Dept Neurol, St Pau Memory Unit, Barcelona, Spain
Inst Salud Carlos III, Ctr Biomed Invest Network Neurodegenerat Dis CIBER, Madrid, Spain
Barcelona Med Ctr, Fundacio Catalana Sindrome, Barcelona, Spain
Levin, J:
Ludwig Maximilians Univ Munchen, Dept Neurol, Munich, Germany
German Ctr Neurodegenerat Dis DZNE, Site Munich, Munich, Germany
MODAG GmbH, Mikroforum Ring 3, Wendelsheim, Germany
Munich Cluster Syst Neurol SyNergy, Munich, Germany
Green Submitted, hybrid
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