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

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

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.

Keywords: Behavioral variant; Cognition; Corticobasal syndrome; Fluency; Genetic; Inhibition; Neuropsychology; Nonfluent variant; Primary progressive aphasia; Progranulin; Progressive supranuclear palsy; Semantic variant; Set-shifting; Tau; Working memory.

© 2019 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.

Figures

Fig. 1.
Fig. 1.
Baseline differences and longitudinal executive function declines are detectable in presymptomatic and mildly/questionably symptomatic familial FTLD using the NIH-EXAMINER. NOTE. These figures display fitted regression lines of each group’s mean trajectory estimated by the fixed, carrier status by time interaction term in the linear mixed-effects model. Error bars represent the 95% confidence intervals. * indicates baseline differences (P = .016). *** indicates longitudinal differences (P<.009). (A) This sample includes 93 mutation carriers with a global CDR® plus NACC FTLD = 0 or 0.5 at their baseline visit. Mutation carriers are compared with 78 noncarrier controls using linear mixed-effects models. This figure displays the fitted results of the mutation status by time interaction from a linear mixed-effects model, showing mutation carriers had a significantly more negative slope on the Executive Composite than noncarriers and significantly poorer performance at baseline. EXAMINER Executive Composite scores are displayed on the y-axis in z-score units. The arrow indicates that lower scores are associated with poorer performance. (B) This sample includes 66 mutation carriers with a global CDR® plus NACC FTLD = 0 at their baseline visit, compared with 64 noncarrier controls. This figure displays the fitted results of the mutation status by time interaction from a linear mixed-effects model. Mutation carriers showed a significantly more negative slope on the Executive Composite than noncarriers. Baseline performance did not differ significantly. The y-axis is in z-score units; the arrow signifies that lower scores on this composite indicate poorer performance. Abbreviations: FTLD, frontotemporal lobar degeneration; CDR® plus NACC FTLD, Clinical Dementia Rating scale plus National Alzheimer Coordinating Center FTLD Module; NIH-EXAMINER, NIH–Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research.

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Source: PubMed

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