Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH-EXAMINER as a potential clinical trial endpoint,Alzheimer's & Dementia

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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
Alzheimer's & Dementia ( IF 13.0 ) Pub Date : 2020-01-01 , DOI: 10.1016/j.jalz.2019.01.012
Adam M Staffaroni ₁ , Lynn Bajorek ₁ , Kaitlin B Casaletto ₁ , Yann Cobigo ₁ , Sheng-Yang M Goh ₁ , Amy Wolf ₁ , Hilary W Heuer ₁ , Fanny M Elahi ₁ , Peter A Ljubenkov ₁ , Reilly Dever ₁ , John Kornak ₂ , Brian Appleby ₃ , Jessica Bove ₄ , Yvette Bordelon ₅ , Patrick Brannelly ₆ , Danielle Brushaber ₇ , Christina Caso ₈ , Giovanni Coppola _{5,

9} , Christina Dheel ₁₀ , Bradford C Dickerson ₁₁ , Susan Dickinson ₁₂ , Sophia Dominguez ₄ , Kimiko Domoto-Reilly ₈ , Kelly Faber ₁₃ , Jessica Ferrall ₁₄ , Julie A Fields ₁₅ , Ann Fishman ₁₆ , Jamie Fong ₁ , Tatiana Foroud ₁₃ , Leah K Forsberg ₁₀ , Ralitza Gavrilova ₁₀ , Debra Gearhart ₁₀ , Behnaz Ghazanfari _{17,

18} , Nupur Ghoshal ₁₉ , Jill Goldman _{20,

21} , Jonathan Graff-Radford ₁₀ , Neill Graff-Radford ₂₂ , Ian Grant ₂₃ , Murray Grossman ₄ , Dana Haley ₂₂ , Ging-Yuek Hsiung ₂₄ , Edward D Huey _{20,

21} , David J Irwin ₄ , David T Jones ₁₀ , Lynne Jones ₂₅ , Kejal Kantarci ₂₆ , Anna Karydas ₁ , Daniel I Kaufer ₁₄ , Diana R Kerwin _{27,

28} , David S Knopman ₁₀ , Ruth Kraft ₁₀ , Walter K Kremers ₇ , Walter A Kukull ₂₉ , Irene Litvan ₃₀ , Diane Lucente ₁₁ , Codrin Lungu ₃₁ , Ian R Mackenzie ₃₂ , Miranda Maldonado ₅ , Masood Manoochehri ₂₀ , Scott M McGinnis ₁₁ , Emily McKinley ₃₃ , Mario F Mendez _{5,

9} , Bruce L Miller ₁ , Namita Multani _{17,

18} , Chiadi Onyike ₃₄ , Jaya Padmanabhan ₁₁ , Alex Pantelyat ₃₅ , Rodney Pearlman ₃₆ , Len Petrucelli ₃₇ , Madeline Potter ₁₃ , Rosa Rademakers ₃₇ , Eliana Marisa Ramos ₉ , Katherine P Rankin ₁ , Katya Rascovsky ₄ , Erik D Roberson ₃₃ , Emily Rogalski ₃₈ , Pheth Sengdy ₂₄ , Leslie M Shaw ₃₉ , Jeremy Syrjanen ₇ , M Carmela Tartaglia _{17,

18} , Nadine Tatton ₁₂ , Joanne Taylor ₁ , Arthur Toga ₄₀ , John Q Trojanowski ₃₉ , Sandra Weintraub ₂₃ , Ping Wang ₁ , Bonnie Wong ₁₁ , Zbigniew Wszolek ₂₂ , Adam L Boxer ₁ , Brad F Boeve ₁₀ , Joel H Kramer ₁ , Howard J Rosen ₁ ,

Affiliation

Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA.
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
Department of Neurology, Case Western Reserve University, Cleveland, OH, USA.
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
Tau Consortium, Rainwater Charitable Foundation, Fort Worth, TX, USA.
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Department of Neurology, University of Washington, Seattle, WA, USA.
Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Department of Neurology, Frontotemporal Disorders Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Association for Frontotemporal Degeneration, Radnor, PA, USA.
National Cell Repository for Alzheimer's Disease (NCRAD), Indiana University, Indianapolis, IN, USA.
Department of Neurology, University of North Carolina, Chapel Hill, NC, USA.
Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
School of Medicine, Department of Psychiatry, Johns Hopkins University, Baltimore, MD, USA.
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Departments of Neurology and Psychiatry, Washington University School of Medicine, Washington University, St. Louis, MO, USA.
Department of Neurology, Columbia University, New York, NY, USA.
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.
Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
Feinberg School of Medicine, Department of Neurology, Northwestern University, Chicago, IL, USA.
Division of Neurology, Deptartment of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Department of Radiology, Washington University School of Medicine, Washington University, St. Louis, MO, USA.
Department of Radiology, Mayo Clinic, Rochester, MN, USA.
Department of Neurology and Neurotherapeutics, Center for Alzheimer's and Neurodegenerative Diseases, The University of Texas, Southwestern Medical Center at Dallas, Dallas, TX, USA.
Department of Internal Medicine, The University of Texas, Southwestern Medical Center at Dallas, Dallas, TX, USA.
National Alzheimer Coordinating Center (NACC), University of Washington, Seattle, WA, USA.
Department of Neurosciences, Parkinson and Other Movement Disorders Center, University of California, San Diego, San Diego, CA, USA.
National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, MD, USA.
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Department of Neurology, Alzheimer's Disease Center, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University, Baltimore, MD, USA.
School of Medicine, Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
Bluefield Project, San Francisco, CA, USA.
Department of Neurosciences, Mayo Clinic, Jacksonville, FL, USA.
Feinberg School of Medicine, Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, IL, USA.
Perelman School of Medicine, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Departments of Ophthalmology, Neurology, Psychiatry and the Behavioral Sciences, Radiology and Engineering, Laboratory of Neuroimaging (LONI), USC, Los Angeles, CA, USA.

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.

中文翻译：

症状前和轻度症状家族性额颞叶痴呆执行功能下降的评估：NIH-EXAMINER 作为潜在的临床试验终点

简介：确定在额颞叶变性 (FTLD) 早期阶段追踪疾病的临床措施对于临床试验非常重要。家族性 FTLD 为研究早期 FTLD 提供了独特的范例。执行功能障碍是 FTLD 的临床相关标志，并且可能是疾病进展的标志。方法：93 名无症状或轻微/可疑症状的突变携带者（MAPT，n = 31；GRN，n = 28；C9orf72，n = 34；临床痴呆评定量表加 NACC FTLD 模块 <1）和 78 名非携带者通过推进额颞叶变性的研究和治疗/家族性额颞叶痴呆的纵向评估受试者研究完成了执行能力：神经行为评估和研究的措施和工具（NIH-EXAMINER）和 UDS 神经心理学电池。线性混合效应模型用于识别基线和纵向认知的群体差异。我们检查了认知、临床功能和磁共振成像体积之间的关联。结果：NIH-EXAMINER 评分检测到携带者和非携带者之间的基线和斜率差异，即使是基线临床痴呆评定量表加上 NACC FTLD 模块 = 0 的携带者。NIH-EXAMINER 评分下降与临床症状恶化和脑容量损失相关。讨论：NIH-EXAMINER 对症状前家族性 FTLD 的认知变化敏感，是一个有前途的替代终点。

更新日期：2020-01-01

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