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

Author information

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.

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

PMID:
31914230
PMCID:
PMC6842665
[Available on 2021-01-01]
DOI:
10.1016/j.jalz.2019.01.012

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