Multimarker synaptic protein cerebrospinal fluid panels reflect TDP-43 pathology and cognitive performance in a pathological cohort of frontotemporal lobar degeneration
Year: 2022
Type: article
Study design: Observational Study
Abstract: 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 (rs = .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 r2 = .56, p = .007 and r2 = .57, p = .006, respectively). A multimarker panel including calsyntenin-1 was associated with TDP-43 burden (r2 = .69, p = .003) and MMSE score (r2 = .19, p = .03) in FTLD. A second multimarker synaptic panel, also including calsyntenin-1, was associated with MMSE score in FTLD-tau (r2 = .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.
Source: Molecular Neurodegeneration
Authors: Alba Cervantes González, David J. Irwin, Daniel Alcolea, Corey T. McMillan, Alice Chen-Plotkin, David Wolk, Sònia Sirisi, Oriol Dols-Icardo, Marta Querol-Vilaseca, Ignacio Illán-Gala, Miguel Angel Santos-Santos, Juan Fortea, Edward B. Lee, John Q. Trojanowski, Murray Grossman, Alberto Lleó, Olivia Belbin
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,890
Funders: Generalitat de Catalunya, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, National Institutes of Health, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, European Regional Development Fund, Departament de Salut, Generalitat de Catalunya, National Institute on Aging, National Institute of Neurological Disorders and Stroke
Awards: G1011041501, G1853423388, G1875208949, Acúmulo de Proteína Precursora de Amiloide-C99 (APP-C99) como mecanismo de enfermedad en la enfermedad de Alzheimer: implicaciones terapéuticas., Center On Alpha-synuclein Strains In Alzheimer Disease & Related Dementias, The Role of Inflammation and NGF Dysfunction in the Evolution of AlzheimerDisease Pathology in Down syndrome, G3470407348, Caracterización de la inflamación relacionada con amiloide: nuevos marcadores inflamatorios y su impacto en la macroestructural y microestructura cortical en la enfermedad de Alzheimer preclínica y prodrómica, Proteínas en sangre para la discriminación precoz de las demencias, From cells to complex syndromes: using networks to understand heterogeneity in TDP-related frontotemporal degeneration and aging, G4484208813, G4509608868, Biomarkers of cognitive decline in Parkinson's Disease, G5637347424, Estudio multimodal de nuevos biomarcadores sinápticos en cohortes de la enfermedad de Alzheimer y la demencia frontotemporal, TMEM106B in neurodegenerative disease, Estudios longitudinales de RM magnética estructural, de difusión y funcional en la enfermedad de Alzheimer preclínica esporádica y asociada al síndrome de Down, G7272457731, G742421683, Tau pathology in Down syndrome and Alzheimer's, Biological Correlates of Alzheimer in Down Syndrome., G8457359034, G8712830647, G8967586028, G9000098783, Penn Alzheimer's Disease Research Center (ADRC)
OpenAlex ID: W4223617068