Clinical and volumetric changes with increasing functional impairment in familial frontotemporal lobar degeneration

Nicholas T Olney¹, Elise Ong¹, Sheng-Yang M Goh¹, Lynn Bajorek¹, Reilly Dever¹, Adam M Staffaroni¹, Yann Cobigo¹, Meredith Bock¹, Kevin Chiang¹, Peter Ljubenkov¹, John Kornak¹, Hilary W Heuer¹, Ping Wang¹, Katya Rascovsky², Amelia Wolf¹, Brian Appleby³, Jessica Bove², Yvette Bordelon⁴, Patrick Brannelly⁵, Danielle Brushaber⁶, Christine Caso⁷, Giovanni Coppola⁴, Bradford C Dickerson⁸, Susan Dickinson⁹, Kimiko Domoto-Reilly⁷, Kelly Faber¹⁰, Jessica Ferrall¹¹, Julie Fields¹², Ann Fishman¹³, Jamie Fong¹, Tatiana Foroud¹⁰, Leah K Forsberg¹², Debra J Gearhart¹², Behnaz Ghazanfari¹⁴, Nupur Ghoshal^{15

16}, Jill Goldman^{17

18}, Jonathan Graff-Radford¹², Neill R Graff-Radford¹⁹, Ian Grant²⁰, Murray Grossman², Dana Haley¹⁹, Gingyuek Hsiung²¹, Edward D Huey^{17

18}, David J Irwin², David T Jones¹², Kejal Kantarci¹², Anna M Karydas¹, Daniel Kaufer¹¹, Diana Kerwin^{22

23}, David S Knopman¹², Joel H Kramer¹, Ruth Kraft¹², Walter Kremers⁶, Walter Kukull²⁴, Maria I Lapid¹², Irene Litvan²⁵, Ian R Mackenzie²⁶, Miranda Maldonado⁴, Masood Manoochehri^{17

18}, Scott M McGinnis⁸, Emily C McKinley²⁷, Mario F Mendez⁴, Bruce L Miller¹, Chiadi Onyike¹³, Alex Pantelyat²⁸, Rodney Pearlman²⁹, Len Petrucelli¹⁹, Madeleine Potter¹⁰, Rosa Rademakers¹⁹, Eliana M Ramos⁴, Katherine P Rankin¹, Erik D Roberson²⁷, Emily Rogalski²⁰, Pheth Sengdy²¹, Leslie M Shaw², Jeremy Syrjanen⁶, M Carmela Tartaglia^{14

30}, Nadine Tatton⁹, Joanne Taylor¹, Arthur Toga³¹, John Q Trojanowski², Sandra Weintraub²⁰, Bonnie Wong⁸, Zbigniew Wszolek¹⁹, Adam L Boxer¹, Brad F Boeve¹², Howard J Rosen¹; ARTFL and LEFFTDS consortia

Affiliations

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

PMID: 31784375
PMCID: PMC6988137
DOI: 10.1016/j.jalz.2019.08.196

Clinical and volumetric changes with increasing functional impairment in familial frontotemporal lobar degeneration

Nicholas T Olney et al. Alzheimers Dement. 2020 Jan.

. 2020 Jan;16(1):49-59.

doi: 10.1016/j.jalz.2019.08.196. Epub 2020 Jan 6.

Authors

Affiliations

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

PMID: 31784375
PMCID: PMC6988137
DOI: 10.1016/j.jalz.2019.08.196

Abstract

Introduction: The Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects longitudinal studies were designed to describe the natural history of familial-frontotemporal lobar degeneration due to autosomal dominant mutations.

Methods: We examined cognitive performance, behavioral ratings, and brain volumes from the first time point in 320 MAPT, GRN, and C9orf72 family members, including 102 non-mutation carriers, 103 asymptomatic carriers, 43 mildly/questionably symptomatic carriers, and 72 carriers with dementia.

Results: Asymptomatic carriers showed similar scores on all clinical measures compared with noncarriers but reduced frontal and temporal volumes. Those with mild/questionable impairment showed decreased verbal recall, fluency, and Trail Making Test performance and impaired mood and self-monitoring. Dementia was associated with impairment in all measures. All MAPT carriers with dementia showed temporal atrophy, but otherwise, there was no single cognitive test or brain region that was abnormal in all subjects.

Discussion: Imaging changes appear to precede clinical changes in familial-frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals.

Keywords: C9ORF72; Familial; Frontotemporal lobar degeneration; GRN; Genetic; MAPT.

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Figures

**Fig. 1.**
Proportion of individuals in each group with abnormal performance (z < −1.5) on each cognitive test with available norms (colored bars) superimposed on proportion of noncarriers with abnormal performance on that test. Bars extend to indicate largest observed proportion, so that bars where colors extend beyond gray indicate that mutation carrier group showed higher proportion (denoted by rightward extent of colored bar from the y-axis line) than noncarriers (whose proportion is denoted by rightward extent of gray bars from y-axis line). Abbreviations: MoCA, Montreal Cognitive Assessment; MINT, Multilingual Naming Test; MAPT, microtubule associated tau; GRN, progranulin; C9orf72, chromosome 9 open reading frame 72.

**Fig. 2.**
Proportion of individuals in each group with reduced gray matter volume (w-score < −1.5) at each gray matter voxel. Increasing color from blue to yellow in “heat map” indicates higher proportion of individuals in that group showed reduced volume at that location. Left hemisphere is displayed on the left in coronal images. Abbreviations: MAPT, microtubule associated tau; GRN, progranulin; C9orf72, chromosome 9 open reading frame 72.

See this image and copyright information in PMC

References

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Clinical and volumetric changes with increasing functional impairment in familial frontotemporal lobar degeneration

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Clinical and volumetric changes with increasing functional impairment in familial frontotemporal lobar degeneration

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