. 2020 Jan;16(1):37-48.

doi: 10.1016/j.jalz.2019.04.007. Epub 2020 Jan 6.

Individualized atrophy scores predict dementia onset in familial frontotemporal lobar degeneration

Adam M Staffaroni¹, Yann Cobigo¹, Sheng-Yang M Goh¹, John Kornak², Lynn Bajorek¹, Kevin Chiang¹, Brian Appleby³, Jessica Bove⁴, Yvette Bordelon⁵, Patrick Brannelly⁶, Danielle Brushaber⁷, Christina Caso⁸, Giovanni Coppola^{5

9}, Reilly Dever¹, 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, Hilary W Heuer¹, 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, Joel H Kramer¹, Walter K Kremers⁷, Walter A Kukull²⁹, Irene Litvan³⁰, Peter A Ljubenkov¹, 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, Howard J Rosen¹; ARTFL/LEFFTDS consortium

Affiliations

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

PMID: 31272932
PMCID: PMC6938544
DOI: 10.1016/j.jalz.2019.04.007

Individualized atrophy scores predict dementia onset in familial frontotemporal lobar degeneration

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

. 2020 Jan;16(1):37-48.

doi: 10.1016/j.jalz.2019.04.007. Epub 2020 Jan 6.

Authors

Affiliations

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

PMID: 31272932
PMCID: PMC6938544
DOI: 10.1016/j.jalz.2019.04.007

Abstract

Introduction: Some models of therapy for neurodegenerative diseases envision starting treatment before symptoms develop. Demonstrating that such treatments are effective requires accurate knowledge of when symptoms would have started without treatment. Familial frontotemporal lobar degeneration offers a unique opportunity to develop predictors of symptom onset.

Methods: We created dementia risk scores in 268 familial frontotemporal lobar degeneration family members by entering covariate-adjusted standardized estimates of brain atrophy into a logistic regression to classify asymptomatic versus demented participants. The score's predictive value was tested in a separate group who were followed up longitudinally (stable vs. converted to dementia) using Cox proportional regressions with dementia risk score as the predictor.

Results: Cross-validated logistic regression achieved good separation of asymptomatic versus demented (accuracy = 90%, SE = 0.06). Atrophy scores predicted conversion from asymptomatic or mildly/questionably symptomatic to dementia (HR = 1.51, 95% CI: [1.16,1.98]).

Discussion: Individualized quantification of baseline brain atrophy is a promising predictor of progression in asymptomatic familial frontotemporal lobar degeneration mutation carriers.

Keywords: Frontotemporal dementia; Genetics; Magnetic resonance imaging (MRI); TDP-43; Tau.

PubMed Disclaimer

Figures

**Fig. 1.**
Steps to create W-score maps, W-volume masks, and W-burden masks. A linear regression was performed on a healthy control group (1A and 1B). A raw W-score map was then created for each subject (1C). Finally, each patient’s W-map was thresholded to produce the W-burden and W-volume masks (1D).

**Fig. 2.**
Individual W-maps for familial FTLD mutation carriers with CDR® plus NACC FTLD = 1. Axial slices displaying W-scores for 6 f-FTLD mutation carriers with (A) *MAPT*, (B) *GRN*, and (C) *C9orf72* mutations. Abbreviations: FTLD, Frontotemporal lobar degeneration; CDR, Clinical Dementia Rating Scale; NACC, National Alzheimer’s Coordinating Center.

**Fig. 3.**
Distribution of weights in each ROI resulting from the optimization of the logistic regression model. This figure displays the fitted weights (coefficients) associated with each ROI in the logistic regression model. These weights were subsequently used to calculate prediction scores for the survival analysis. Abbreviation: ROI, Region of interest.

**Fig. 4.**
Prediction scores derived from the logistic regression model. Abbreviations: FTLD, frontotemporal lobar degeneration; CDR, Clinical Dementia Rating Scale.

**Fig. 5.**
Kaplan-Meier curve representing survival from CDR® plus NACC FTLD = (0 or 0.5) to 1+. Note: Hash marks indicate censored observations. Abbreviations: FTLD, Frontotemporal lobar degeneration; CDR, Clinical Dementia Rating Scale; NACC, National Alzheimer’s Coordinating Center.

See this image and copyright information in PMC

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Individualized atrophy scores predict dementia onset in familial frontotemporal lobar degeneration

Affiliations

Individualized atrophy scores predict dementia onset in familial frontotemporal lobar degeneration

Authors

Affiliations

Abstract

Figures

References

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MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

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Medical

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