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Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH-EXAMINER as a potential clinical trial endpoint.

  • Author(s): Staffaroni, Adam M
  • Bajorek, Lynn
  • Casaletto, Kaitlin B
  • Cobigo, Yann
  • Goh, Sheng-Yang M
  • Wolf, Amy
  • Heuer, Hilary W
  • Elahi, Fanny M
  • Ljubenkov, Peter A
  • Dever, Reilly
  • Kornak, John
  • Appleby, Brian
  • Bove, Jessica
  • Bordelon, Yvette
  • Brannelly, Patrick
  • Brushaber, Danielle
  • Caso, Christina
  • Coppola, Giovanni
  • Dheel, Christina
  • Dickerson, Bradford C
  • Dickinson, Susan
  • Dominguez, Sophia
  • Domoto-Reilly, Kimiko
  • Faber, Kelly
  • Ferrall, Jessica
  • Fields, Julie A
  • Fishman, Ann
  • Fong, Jamie
  • Foroud, Tatiana
  • Forsberg, Leah K
  • Gavrilova, Ralitza
  • Gearhart, Debra
  • Ghazanfari, Behnaz
  • Ghoshal, Nupur
  • Goldman, Jill
  • Graff-Radford, Jonathan
  • Graff-Radford, Neill
  • Grant, Ian
  • Grossman, Murray
  • Haley, Dana
  • Hsiung, Ging-Yuek
  • Huey, Edward D
  • Irwin, David J
  • Jones, David T
  • Jones, Lynne
  • Kantarci, Kejal
  • Karydas, Anna
  • Kaufer, Daniel I
  • Kerwin, Diana R
  • Knopman, David S
  • Kraft, Ruth
  • Kremers, Walter K
  • Kukull, Walter A
  • Litvan, Irene
  • Lucente, Diane
  • Lungu, Codrin
  • Mackenzie, Ian R
  • Maldonado, Miranda
  • Manoochehri, Masood
  • McGinnis, Scott M
  • McKinley, Emily
  • Mendez, Mario F
  • Miller, Bruce L
  • Multani, Namita
  • Onyike, Chiadi
  • Padmanabhan, Jaya
  • Pantelyat, Alex
  • Pearlman, Rodney
  • Petrucelli, Len
  • Potter, Madeline
  • Rademakers, Rosa
  • Ramos, Eliana Marisa
  • Rankin, Katherine P
  • Rascovsky, Katya
  • Roberson, Erik D
  • Rogalski, Emily
  • Sengdy, Pheth
  • Shaw, Leslie M
  • Syrjanen, Jeremy
  • Tartaglia, M Carmela
  • Tatton, Nadine
  • Taylor, Joanne
  • Toga, Arthur
  • Trojanowski, John Q
  • Weintraub, Sandra
  • Wang, Ping
  • Wong, Bonnie
  • Wszolek, Zbigniew
  • Boxer, Adam L
  • Boeve, Brad F
  • Kramer, Joel H
  • Rosen, Howard J
  • ARTFL/LEFFTDS consortium
  • et al.
Abstract

INTRODUCTION:Identifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression. METHODS:Ninety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes. RESULTS:NIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss. DISCUSSION:The NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint.

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