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

Adam M Staffaroni¹, Lynn Bajorek¹, Kaitlin B Casaletto¹, Yann Cobigo¹, Sheng-Yang M Goh¹, Amy Wolf¹, Hilary W Heuer¹, Fanny M Elahi¹, Peter A Ljubenkov¹, Reilly Dever¹, John Kornak², Brian Appleby³, Jessica Bove⁴, Yvette Bordelon⁵, Patrick Brannelly⁶, Danielle Brushaber⁷, Christina Caso⁸, Giovanni Coppola^{5

9}, Christina Dheel¹⁰, Bradford C Dickerson¹¹, Susan Dickinson¹², Sophia Dominguez⁴, Kimiko Domoto-Reilly⁸, Kelly Faber¹³, Jessica Ferrall¹⁴, Julie A Fields¹⁵, Ann Fishman¹⁶, Jamie Fong¹, Tatiana Foroud¹³, Leah K Forsberg¹⁰, Ralitza Gavrilova¹⁰, Debra Gearhart¹⁰, Behnaz Ghazanfari^{17

18}, Nupur Ghoshal¹⁹, Jill Goldman^{20

21}, Jonathan Graff-Radford¹⁰, Neill Graff-Radford²², Ian Grant²³, Murray Grossman⁴, Dana Haley²², Ging-Yuek Hsiung²⁴, Edward D Huey^{20

21}, David J Irwin⁴, David T Jones¹⁰, Lynne Jones²⁵, Kejal Kantarci²⁶, Anna Karydas¹, Daniel I Kaufer¹⁴, Diana R Kerwin^{27

28}, David S Knopman¹⁰, Ruth Kraft¹⁰, Walter K Kremers⁷, Walter A Kukull²⁹, Irene Litvan³⁰, Diane Lucente¹¹, Codrin Lungu³¹, Ian R Mackenzie³², Miranda Maldonado⁵, Masood Manoochehri²⁰, Scott M McGinnis¹¹, Emily McKinley³³, Mario F Mendez^{5

9}, Bruce L Miller¹, Namita Multani^{17

18}, Chiadi Onyike³⁴, Jaya Padmanabhan¹¹, Alex Pantelyat³⁵, Rodney Pearlman³⁶, Len Petrucelli³⁷, Madeline Potter¹³, Rosa Rademakers³⁷, Eliana Marisa Ramos⁹, Katherine P Rankin¹, Katya Rascovsky⁴, Erik D Roberson³³, Emily Rogalski³⁸, Pheth Sengdy²⁴, Leslie M Shaw³⁹, Jeremy Syrjanen⁷, M Carmela Tartaglia^{17

18}, Nadine Tatton¹², Joanne Taylor¹, Arthur Toga⁴⁰, John Q Trojanowski³⁹, Sandra Weintraub²³, Ping Wang¹, Bonnie Wong¹¹, Zbigniew Wszolek²², Adam L Boxer¹, Brad F Boeve¹⁰, Joel H Kramer¹, Howard J Rosen¹; ARTFL/LEFFTDS consortium

Affiliations

¹ Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA.
² Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
³ Department of Neurology, Case Western Reserve University, Cleveland, OH, USA.
⁴ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Tau Consortium, Rainwater Charitable Foundation, Fort Worth, TX, USA.
⁷ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁸ Department of Neurology, University of Washington, Seattle, WA, USA.
⁹ Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁰ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
¹¹ Department of Neurology, Frontotemporal Disorders Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹² Association for Frontotemporal Degeneration, Radnor, PA, USA.
¹³ National Cell Repository for Alzheimer's Disease (NCRAD), Indiana University, Indianapolis, IN, USA.
¹⁴ Department of Neurology, University of North Carolina, Chapel Hill, NC, USA.
¹⁵ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
¹⁶ School of Medicine, Department of Psychiatry, Johns Hopkins University, Baltimore, MD, USA.
¹⁷ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
¹⁸ Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
¹⁹ Departments of Neurology and Psychiatry, Washington University School of Medicine, Washington University, St. Louis, MO, USA.
²⁰ Department of Neurology, Columbia University, New York, NY, USA.
²¹ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.
²² Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
²³ Feinberg School of Medicine, Department of Neurology, Northwestern University, Chicago, IL, USA.
²⁴ Division of Neurology, Deptartment of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
²⁵ Department of Radiology, Washington University School of Medicine, Washington University, St. Louis, MO, USA.
²⁶ Department of Radiology, Mayo Clinic, Rochester, MN, USA.
²⁷ Department of Neurology and Neurotherapeutics, Center for Alzheimer's and Neurodegenerative Diseases, The University of Texas, Southwestern Medical Center at Dallas, Dallas, TX, USA.
²⁸ Department of Internal Medicine, The University of Texas, Southwestern Medical Center at Dallas, Dallas, TX, USA.
²⁹ National Alzheimer Coordinating Center (NACC), University of Washington, Seattle, WA, USA.
³⁰ Department of Neurosciences, Parkinson and Other Movement Disorders Center, University of California, San Diego, San Diego, CA, USA.
³¹ National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, MD, USA.
³² Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
³³ Department of Neurology, Alzheimer's Disease Center, University of Alabama at Birmingham, Birmingham, AL, USA.
³⁴ Department of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University, Baltimore, MD, USA.
³⁵ School of Medicine, Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
³⁶ Bluefield Project, San Francisco, CA, USA.
³⁷ Department of Neurosciences, Mayo Clinic, Jacksonville, FL, USA.
³⁸ Feinberg School of Medicine, Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, IL, USA.
³⁹ Perelman School of Medicine, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴⁰ Departments of Ophthalmology, Neurology, Psychiatry and the Behavioral Sciences, Radiology and Engineering, Laboratory of Neuroimaging (LONI), USC, Los Angeles, CA, USA.

PMID: 31914230
PMCID: PMC6842665
DOI: 10.1016/j.jalz.2019.01.012

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

Adam M Staffaroni et al. Alzheimers Dement. 2020 Jan.

. 2020 Jan;16(1):11-21.

doi: 10.1016/j.jalz.2019.01.012.

Authors

Affiliations

¹ Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA.
² Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
³ Department of Neurology, Case Western Reserve University, Cleveland, OH, USA.
⁴ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Tau Consortium, Rainwater Charitable Foundation, Fort Worth, TX, USA.
⁷ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁸ Department of Neurology, University of Washington, Seattle, WA, USA.
⁹ Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁰ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
¹¹ Department of Neurology, Frontotemporal Disorders Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹² Association for Frontotemporal Degeneration, Radnor, PA, USA.
¹³ National Cell Repository for Alzheimer's Disease (NCRAD), Indiana University, Indianapolis, IN, USA.
¹⁴ Department of Neurology, University of North Carolina, Chapel Hill, NC, USA.
¹⁵ Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
¹⁶ School of Medicine, Department of Psychiatry, Johns Hopkins University, Baltimore, MD, USA.
¹⁷ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
¹⁸ Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
¹⁹ Departments of Neurology and Psychiatry, Washington University School of Medicine, Washington University, St. Louis, MO, USA.
²⁰ Department of Neurology, Columbia University, New York, NY, USA.
²¹ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.
²² Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
²³ Feinberg School of Medicine, Department of Neurology, Northwestern University, Chicago, IL, USA.
²⁴ Division of Neurology, Deptartment of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
²⁵ Department of Radiology, Washington University School of Medicine, Washington University, St. Louis, MO, USA.
²⁶ Department of Radiology, Mayo Clinic, Rochester, MN, USA.
²⁷ Department of Neurology and Neurotherapeutics, Center for Alzheimer's and Neurodegenerative Diseases, The University of Texas, Southwestern Medical Center at Dallas, Dallas, TX, USA.
²⁸ Department of Internal Medicine, The University of Texas, Southwestern Medical Center at Dallas, Dallas, TX, USA.
²⁹ National Alzheimer Coordinating Center (NACC), University of Washington, Seattle, WA, USA.
³⁰ Department of Neurosciences, Parkinson and Other Movement Disorders Center, University of California, San Diego, San Diego, CA, USA.
³¹ National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, MD, USA.
³² Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
³³ Department of Neurology, Alzheimer's Disease Center, University of Alabama at Birmingham, Birmingham, AL, USA.
³⁴ Department of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University, Baltimore, MD, USA.
³⁵ School of Medicine, Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
³⁶ Bluefield Project, San Francisco, CA, USA.
³⁷ Department of Neurosciences, Mayo Clinic, Jacksonville, FL, USA.
³⁸ Feinberg School of Medicine, Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, IL, USA.
³⁹ Perelman School of Medicine, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴⁰ Departments of Ophthalmology, Neurology, Psychiatry and the Behavioral Sciences, Radiology and Engineering, Laboratory of Neuroimaging (LONI), USC, Los Angeles, CA, USA.

PMID: 31914230
PMCID: PMC6842665
DOI: 10.1016/j.jalz.2019.01.012

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.

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Figures

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

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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

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