MRI-assessed locus coeruleus integrity is heritable and associated with multiple cognitive domains, mild cognitive impairment, and daytime dysfunction

Jeremy A Elman; Olivia K Puckett; Asad Beck; Christine Fennema-Notestine; Latonya K Cross; Anders M Dale; Graham M L Eglit; Lisa T Eyler; Nathan A Gillespie; Eric L Granholm; Daniel E Gustavson; Donald J Hagler Jr; Sean N Hatton; Richard Hauger; Amy J Jak; Mark W Logue; Linda K McEvoy; Ruth E McKenzie; Michael C Neale; Matthew S Panizzon; Chandra A Reynolds; Mark Sanderson-Cimino; Rosemary Toomey; Xin M Tu; Nathan Whitsel; McKenna E Williams; Hong Xian; Michael J Lyons; Carol E Franz; William S Kremen

doi:10.1002/alz.12261

MRI-assessed locus coeruleus integrity is heritable and associated with multiple cognitive domains, mild cognitive impairment, and daytime dysfunction

Alzheimers Dement. 2021 Jun;17(6):1017-1025. doi: 10.1002/alz.12261. Epub 2021 Feb 13.

Authors

Jeremy A Elman^{1

2}, Olivia K Puckett^{1

2}, Asad Beck³, Christine Fennema-Notestine^{1

4}, Latonya K Cross⁵, Anders M Dale^{4

6}, Graham M L Eglit^{1

2}, Lisa T Eyler^{1

7}, Nathan A Gillespie⁸, Eric L Granholm^{1

9}, Daniel E Gustavson¹⁰, Donald J Hagler Jr⁴, Sean N Hatton^{2

6}, Richard Hauger^{1

9}, Amy J Jak^{1

9}, Mark W Logue^{11

12

13}, Linda K McEvoy⁴, Ruth E McKenzie¹⁴, Michael C Neale⁸, Matthew S Panizzon^{1

2}, Chandra A Reynolds¹⁵, Mark Sanderson-Cimino^{2

16}, Rosemary Toomey¹⁷, Xin M Tu¹⁸, Nathan Whitsel^{1

2}, McKenna E Williams^{2

16}, Hong Xian¹⁹, Michael J Lyons¹⁷, Carol E Franz^{1

2}, William S Kremen^{1

2

9}

Affiliations

¹ Department of Psychiatry, University of California San Diego, La Jolla, California, USA.
² Center for Behavior Genetics of Aging, University of California San Diego, La Jolla, California, USA.
³ Graduate Program in Neuroscience, University of Washington, Seattle, Washington, USA.
⁴ Department of Radiology, University of California San Diego, La Jolla, California, USA.
⁵ Department of Psychology, University of Hawaii Hilo, Hilo, Hawaii, USA.
⁶ Department of Neuroscience, University of California San Diego, La Jolla, California, USA.
⁷ Desert Pacific Mental Illness Research Education and Clinical Center, VA San Diego Healthcare System, San Diego, California, USA.
⁸ Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.
⁹ VA San Diego Healthcare System, San Diego, California, USA.
¹⁰ Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹¹ National Center for PTSD: Behavioral Science Division, VA Boston Healthcare System, Boston, Massachusetts, USA.
¹² Department of Psychiatry and the Biomedical Genetics Section, Boston University School of Medicine, Boston, Massachusetts, USA.
¹³ Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
¹⁴ School of Education and Public Policy, Merrimack College, Andover, Massachusetts, USA.
¹⁵ Department of Psychology, University of California Riverside, Riverside, California, USA.
¹⁶ Joint Doctoral Program in Clinical Psychology, San Diego State/University of California, San Diego, California, USA.
¹⁷ Department of Psychological and Brain Sciences, Boston University, Boston, Massachusetts, USA.
¹⁸ Family Medicine and Public Health, University of California San Diego, La Jolla, California, USA.
¹⁹ Department of Epidemiology & Biostatistics, St. Louis University, St. Louis, Missouri, USA.

Abstract

Introduction: The locus coeruleus (LC) undergoes extensive neurodegeneration in early Alzheimer's disease (AD). The LC is implicated in regulating the sleep-wake cycle, modulating cognitive function, and AD progression.

Methods: Participants were 481 men (ages 62 to 71.7) from the Vietnam Era Twin Study of Aging. LC structural integrity was indexed by neuromelanin-sensitive magnetic resonance imaging (MRI) contrast-to-noise ratio (LC_CNR ). We examined LC_CNR , cognition, amnestic mild cognitive impairment (aMCI), and daytime dysfunction.

Results: Heritability of LC_CNR was .48. Participants with aMCI showed greater daytime dysfunction. Lower LC_CNR was associated with poorer episodic memory, general verbal fluency, semantic fluency, and processing speed, as well as increased odds of aMCI and greater daytime dysfunction.

Discussion: Reduced LC integrity is associated with widespread differences across cognitive domains, daytime sleep-related dysfunction, and risk for aMCI. These findings in late-middle-aged adults highlight the potential of MRI-based measures of LC integrity in early identification of AD risk.

Keywords: Alzheimer's disease; heritability; locus coeruleus; mild cognitive impairment; neuromelanin magnetic resonance imaging; sleep-wake disturbance.

Publication types

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

MeSH terms

Aged
Aging / physiology
Cognition / physiology*
Cognitive Dysfunction / diagnostic imaging
Cognitive Dysfunction / pathology*
Disease Progression
Humans
Locus Coeruleus / pathology*
Magnetic Resonance Imaging
Male
Memory Disorders
Neuropsychological Tests / statistics & numerical data
Sleep

Abstract

Publication types

MeSH terms

Grants and funding