Multimarker synaptic protein cerebrospinal fluid panels reflect TDP-43 pathology and cognitive performance in a pathological cohort of frontotemporal lobar degeneration
Por:
Gonzalez, AC, Irwin, DJ, Alcolea, D, McMillan, CT, Chen-Plotkin, A, Wolk, D, Sirisi, S, Dols-Icardo, O, Querol-Vilaseca, M, Illan-Gala, I, Santos-Santos, MA, Fortea, J, Lee, EB, Trojanowski, JQ, Grossman, M, Lleo, A, Belbin, O
Publicada:
8 abr 2022
Resumen:
Background Synapse degeneration is an early event in pathological frontotemporal lobar degeneration (FTLD). Consequently, a surrogate marker of synapse loss could be used to monitor early pathologic changes in patients with underlying FTLD. The aim of this study was to evaluate the relationship of antemortem cerebrospinal fluid (CSF) levels of 8 synaptic proteins with postmortem global tau and TDP-43 burden and cognitive performance and to assess their diagnostic capacity in a neuropathological FTLD cohort. Methods We included patients with a neuropathological confirmation of FTLD-Tau (n = 24, mean age-at-CSF 67 years +/- 11), FTLD-TDP (n = 25, 66 years +/- 9) or AD (n = 25, 73 years +/- 6) as well as cognitively normal controls (n = 35, 69 years +/- 7) from the Penn FTD Center and ADRC. We used a semi-quantitative measure of tau and TDP-43 inclusions to quantify pathological burden across 16 brain regions. Statistical methods included Spearman rank correlations, one-way analysis of covariance, ordinal regression, step-wise multiple linear regression and receiver-operating characteristic curves. Result CSF calsyntenin-1 and neurexin-2a were correlated in all patient groups (r(s) = .55 to .88). In FTLD-TDP, we observed low antemortem CSF levels of calsyntenin-1 and neurexin-2a compared to AD (.72-fold, p = .001, .77-fold, p = .04, respectively) and controls (.80-fold, p = .02, .78-fold, p = .02, respectively), which were inversely associated with post-mortem global TDP-43 burden (regression r(2) = .56, p = .007 and r(2) = .57, p = .006, respectively). A multimarker panel including calsyntenin-1 was associated with TDP-43 burden (r(2) = .69, p = .003) and MMSE score (r(2) = .19, p = .03) in FTLD. A second multimarker synaptic panel, also including calsyntenin-1, was associated with MMSE score in FTLD-tau (r(2) = .49, p = .04) and improved diagnostic performance to discriminate FTLD-Tau and FTLD-TDP neuropathologic subtypes (AUC = .83). Conclusion These synaptic panels have potential in the differential diagnosis of FTLD neuropathologic subtypes and as surrogate markers of cognitive performance in future clinical trials targeting TDP-43 or tau.
Filiaciones:
Gonzalez, AC:
Univ Autonoma Barcelona, Hosp La Santa Creu & St Pau, Barcelona, Spain
Ctr Biomed Invest Network Neurodegenerat Dis CIBE, Madrid, Spain
IIB St Pau, Memory Unit, C St Quinti 77, Barcelona 08041, Spain
IIB St Pau, Biomed Res Inst, C St Quinti 77, Barcelona 08041, Spain
Irwin, DJ:
Univ Penn, Penn FTD Ctr, Dept Neurol, Perelman Sch Med, Philadelphia, PA USA
Alcolea, D:
Univ Autonoma Barcelona, Hosp La Santa Creu & St Pau, Barcelona, Spain
Ctr Biomed Invest Network Neurodegenerat Dis CIBE, Madrid, Spain
IIB St Pau, Memory Unit, C St Quinti 77, Barcelona 08041, Spain
IIB St Pau, Biomed Res Inst, C St Quinti 77, Barcelona 08041, Spain
McMillan, CT:
Univ Penn, Penn FTD Ctr, Dept Neurol, Perelman Sch Med, Philadelphia, PA USA
Chen-Plotkin, A:
Univ Penn, Penn Alzheimers Dis Res Ctr, Dept Neurol, Perelman Sch Med, Philadelphia, PA USA
Wolk, D:
Univ Penn, Penn Alzheimers Dis Res Ctr, Dept Neurol, Perelman Sch Med, Philadelphia, PA USA
Sirisi, S:
Univ Autonoma Barcelona, Hosp La Santa Creu & St Pau, Barcelona, Spain
Ctr Biomed Invest Network Neurodegenerat Dis CIBE, Madrid, Spain
IIB St Pau, Memory Unit, C St Quinti 77, Barcelona 08041, Spain
IIB St Pau, Biomed Res Inst, C St Quinti 77, Barcelona 08041, Spain
Dols-Icardo, O:
Univ Autonoma Barcelona, Hosp La Santa Creu & St Pau, Barcelona, Spain
Ctr Biomed Invest Network Neurodegenerat Dis CIBE, Madrid, Spain
IIB St Pau, Memory Unit, C St Quinti 77, Barcelona 08041, Spain
IIB St Pau, Biomed Res Inst, C St Quinti 77, Barcelona 08041, Spain
Querol-Vilaseca, M:
Univ Autonoma Barcelona, Hosp La Santa Creu & St Pau, Barcelona, Spain
Ctr Biomed Invest Network Neurodegenerat Dis CIBE, Madrid, Spain
IIB St Pau, Memory Unit, C St Quinti 77, Barcelona 08041, Spain
IIB St Pau, Biomed Res Inst, C St Quinti 77, Barcelona 08041, Spain
Illan-Gala, I:
Univ Autonoma Barcelona, Hosp La Santa Creu & St Pau, Barcelona, Spain
Ctr Biomed Invest Network Neurodegenerat Dis CIBE, Madrid, Spain
IIB St Pau, Memory Unit, C St Quinti 77, Barcelona 08041, Spain
IIB St Pau, Biomed Res Inst, C St Quinti 77, Barcelona 08041, Spain
Santos-Santos, MA:
Univ Autonoma Barcelona, Hosp La Santa Creu & St Pau, Barcelona, Spain
Ctr Biomed Invest Network Neurodegenerat Dis CIBE, Madrid, Spain
IIB St Pau, Memory Unit, C St Quinti 77, Barcelona 08041, Spain
IIB St Pau, Biomed Res Inst, C St Quinti 77, Barcelona 08041, Spain
Fortea, J:
Univ Autonoma Barcelona, Hosp La Santa Creu & St Pau, Barcelona, Spain
Ctr Biomed Invest Network Neurodegenerat Dis CIBE, Madrid, Spain
IIB St Pau, Memory Unit, C St Quinti 77, Barcelona 08041, Spain
IIB St Pau, Biomed Res Inst, C St Quinti 77, Barcelona 08041, Spain
Lee, EB:
Univ Penn, Ctr Neurodegenerat Dis Res, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA
Trojanowski, JQ:
Univ Penn, Ctr Neurodegenerat Dis Res, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA
Grossman, M:
Univ Penn, Penn FTD Ctr, Dept Neurol, Perelman Sch Med, Philadelphia, PA USA
Lleo, A:
Univ Autonoma Barcelona, Hosp La Santa Creu & St Pau, Barcelona, Spain
Ctr Biomed Invest Network Neurodegenerat Dis CIBE, Madrid, Spain
IIB St Pau, Memory Unit, C St Quinti 77, Barcelona 08041, Spain
IIB St Pau, Biomed Res Inst, C St Quinti 77, Barcelona 08041, Spain
Belbin, O:
Univ Autonoma Barcelona, Hosp La Santa Creu & St Pau, Barcelona, Spain
Ctr Biomed Invest Network Neurodegenerat Dis CIBE, Madrid, Spain
IIB St Pau, Memory Unit, C St Quinti 77, Barcelona 08041, Spain
IIB St Pau, Biomed Res Inst, C St Quinti 77, Barcelona 08041, Spain
gold, Green Published, All Open Access, Gold, Green
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