Jiasi Vicky Zhang1, David J Irwin1, Kaj Blennow1, Henrik Zetterberg1, Edward B Lee1, Leslie M Shaw1, Katya Rascovsky1, Lauren Massimo1, Corey T McMillan1, Alice Chen-Plotkin1, Lauren Elman1, Virginia M-Y Lee1, Leo McCluskey1, Jon B Toledo1, Daniel Weintraub1, David Wolk1, John Q Trojanowski1, Murray Grossman1. 1. Penn Frontotemporal Degeneration Center (JVZ, DJI, KR, L. Massimo, CTM, MG) and Department of Neurology (DJI, KR, L. Massimo, CTM, AC-P, LE, L. McCluskey, D. Wolk, MG), Department of Pathology and Laboratory Medicine and Center for Neurodegenerative Disease Research (EBL, LMS, VM-YL, JBT, JQT), Department of Psychiatry (D. Weintraub), University of Pennsylvania, Philadelphia; Institute of Neuroscience and Physiology (KB, HZ), Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory (KB, HZ), Sahlgrenska University Hospital, Mölndal, Sweden; UK Dementia Research Institute at UCL (HZ); and Department of Neurodegenerative Disease (HZ), UCL Institute of Neurology, UK.
Abstract
OBJECTIVE: Accurate diagnosis and prognosis of frontotemporal lobar degeneration (FTLD) during life is an urgent concern in the context of emerging disease-modifying treatment trials. Few CSF markers have been validated longitudinally in patients with known pathology, and we hypothesized that CSF neurofilament light chain (NfL) would be associated with longitudinal cognitive decline in patients with known FTLD-TAR DNA binding protein ~43kD (TDP) pathology. METHODS: This case-control study evaluated CSF NfL, total tau, phosphorylated tau, and β-amyloid1-42 in patients with known FTLD-tau or FTLD-TDP pathology (n = 50) and healthy controls (n = 65) and an extended cohort of clinically diagnosed patients with likely FTLD-tau or FTLD-TDP (n = 148). Regression analyses related CSF analytes to longitudinal cognitive decline (follow-up ∼1 year), controlling for demographic variables and core AD CSF analytes. RESULTS: In FTLD-TDP with known pathology, CSF NfL is significantly elevated compared with controls and significantly associated with longitudinal decline on specific executive and language measures, after controlling for age, disease duration, and core AD CSF analytes. Similar findings are found in the extended cohort, also including clinically identified likely FTLD-TDP. Although CSF NfL is elevated in FTLD-tau compared with controls, the association between NfL and longitudinal cognitive decline is limited to executive measures. CONCLUSION: CSF NfL is associated with longitudinal clinical decline in relevant cognitive domains in patients with FTLD-TDP after controlling for demographic factors and core AD CSF analytes and may also be related to longitudinal decline in executive functioning in FTLD-tau.
OBJECTIVE: Accurate diagnosis and prognosis of frontotemporal lobar degeneration (FTLD) during life is an urgent concern in the context of emerging disease-modifying treatment trials. Few CSF markers have been validated longitudinally in patients with known pathology, and we hypothesized that CSF neurofilament light chain (NfL) would be associated with longitudinal cognitive decline in patients with known FTLD-TAR DNA binding protein ~43kD (TDP) pathology. METHODS: This case-control study evaluated CSF NfL, total tau, phosphorylated tau, and β-amyloid1-42 in patients with known FTLD-tau or FTLD-TDP pathology (n = 50) and healthy controls (n = 65) and an extended cohort of clinically diagnosed patients with likely FTLD-tau or FTLD-TDP (n = 148). Regression analyses related CSF analytes to longitudinal cognitive decline (follow-up ∼1 year), controlling for demographic variables and core AD CSF analytes. RESULTS: In FTLD-TDP with known pathology, CSF NfL is significantly elevated compared with controls and significantly associated with longitudinal decline on specific executive and language measures, after controlling for age, disease duration, and core AD CSF analytes. Similar findings are found in the extended cohort, also including clinically identified likely FTLD-TDP. Although CSF NfL is elevated in FTLD-tau compared with controls, the association between NfL and longitudinal cognitive decline is limited to executive measures. CONCLUSION: CSF NfL is associated with longitudinal clinical decline in relevant cognitive domains in patients with FTLD-TDP after controlling for demographic factors and core AD CSF analytes and may also be related to longitudinal decline in executive functioning in FTLD-tau.
Authors: Edoardo G Spinelli; Maria Luisa Mandelli; Zachary A Miller; Miguel A Santos-Santos; Stephen M Wilson; Federica Agosta; Lea T Grinberg; Eric J Huang; John Q Trojanowski; Marita Meyer; Maya L Henry; Giancarlo Comi; Gil Rabinovici; Howard J Rosen; Massimo Filippi; Bruce L Miller; William W Seeley; Maria Luisa Gorno-Tempini Journal: Ann Neurol Date: 2017-03-20 Impact factor: 10.422
Authors: Daniel Alcolea; Eduard Vilaplana; Marc Suárez-Calvet; Ignacio Illán-Gala; Rafael Blesa; Jordi Clarimón; Albert Lladó; Raquel Sánchez-Valle; José L Molinuevo; Guillermo García-Ribas; Yaroslau Compta; María José Martí; Gerard Piñol-Ripoll; Guillermo Amer-Ferrer; Aina Noguera; Ana García-Martín; Juan Fortea; Alberto Lleó Journal: Neurology Date: 2017-06-07 Impact factor: 9.910
Authors: John L Robinson; Edward B Lee; Sharon X Xie; Lior Rennert; EunRan Suh; Colin Bredenberg; Carrie Caswell; Vivianna M Van Deerlin; Ning Yan; Ahmed Yousef; Howard I Hurtig; Andrew Siderowf; Murray Grossman; Corey T McMillan; Bruce Miller; John E Duda; David J Irwin; David Wolk; Lauren Elman; Leo McCluskey; Alice Chen-Plotkin; Daniel Weintraub; Steven E Arnold; Johannes Brettschneider; Virginia M-Y Lee; John Q Trojanowski Journal: Brain Date: 2018-07-01 Impact factor: 13.501
Authors: Leslie M Shaw; Hugo Vanderstichele; Malgorzata Knapik-Czajka; Christopher M Clark; Paul S Aisen; Ronald C Petersen; Kaj Blennow; Holly Soares; Adam Simon; Piotr Lewczuk; Robert Dean; Eric Siemers; William Potter; Virginia M-Y Lee; John Q Trojanowski Journal: Ann Neurol Date: 2009-04 Impact factor: 10.422
Authors: Claire Bridel; Wessel N van Wieringen; Henrik Zetterberg; Betty M Tijms; Charlotte E Teunissen; José C Alvarez-Cermeño; Ulf Andreasson; Markus Axelsson; David C Bäckström; Ales Bartos; Maria Bjerke; Kaj Blennow; Adam Boxer; Lou Brundin; Joachim Burman; Tove Christensen; Lenká Fialová; Lars Forsgren; Jette L Frederiksen; Magnus Gisslén; Elizabeth Gray; Martin Gunnarsson; Sara Hall; Oskar Hansson; Megan K Herbert; Joel Jakobsson; Jan Jessen-Krut; Shorena Janelidze; Gudmundur Johannsson; Michael Jonsson; Ludwig Kappos; Mohsen Khademi; Michael Khalil; Jens Kuhle; Mikael Landén; Ville Leinonen; Giancarlo Logroscino; Ching-Hua Lu; Jan Lycke; Nadia K Magdalinou; Andrea Malaspina; Niklas Mattsson; Lieke H Meeter; Sanjay R Mehta; Signe Modvig; Tomas Olsson; Ross W Paterson; Josué Pérez-Santiago; Fredrik Piehl; Yolande A L Pijnenburg; Okko T Pyykkö; Oskar Ragnarsson; Julio C Rojas; Jeppe Romme Christensen; Linda Sandberg; Carole S Scherling; Jonathan M Schott; Finn T Sellebjerg; Isabella L Simone; Tobias Skillbäck; Morten Stilund; Peter Sundström; Anders Svenningsson; Rosanna Tortelli; Carla Tortorella; Alessandro Trentini; Maria Troiano; Martin R Turner; John C van Swieten; Mattias Vågberg; Marcel M Verbeek; Luisa M Villar; Pieter Jelle Visser; Anders Wallin; Andreas Weiss; Carsten Wikkelsø; Edward J Wild Journal: JAMA Neurol Date: 2019-09-01 Impact factor: 18.302
Authors: Lorenzo Gaetani; Kina Höglund; Lucilla Parnetti; Fani Pujol-Calderon; Bruno Becker; Paolo Eusebi; Paola Sarchielli; Paolo Calabresi; Massimiliano Di Filippo; Henrik Zetterberg; Kaj Blennow Journal: Alzheimers Res Ther Date: 2018-01-23 Impact factor: 6.982