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

Alzheimers Dement. 2020 Jan;16(1):11-21. doi: 10.1016/j.jalz.2019.01.012.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Biomarkers
  • C9orf72 Protein / genetics
  • Disease Progression*
  • Executive Function / physiology*
  • Female
  • Frontotemporal Dementia* / diagnosis
  • Frontotemporal Dementia* / genetics
  • Humans
  • Longitudinal Studies
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Mutation
  • Neuropsychological Tests / statistics & numerical data*


  • Biomarkers
  • C9orf72 Protein
  • C9orf72 protein, human

Grant support