Title: Effect of Off-Target Binding on ¹⁸F-Flortaucipir Variability in Healthy Controls Across the Life Span

Abstract

Measuring early tau accumulation is important in studying aging and Alzheimer disease and is only as accurate as the signal-to-noise ratio of the tracer. Along with aggregated tau in the form of neurofibrillary tangles, ¹⁸F-flortaucipir has been reported to bind to neuromelanin, monoamine oxidase, calcifications, iron, leptomeningeal melanocytes, and microhemorrages. Although ¹⁸F-flortaucipir successfully differentiates healthy controls (HCs) from subjects with Alzheimer disease, variability exists in the cortical signal in amyloid-negative HCs. We aimed to explore the relationship between off-target binding signal and variability in the cortical signal in HCs. Methods: Subjects ($$n$$ = 139) received ¹¹C-Pittsburgh compound B (PIB) and ¹⁸F-flortaucipir PET scans and a magnetization-prepared rapid gradient echo MRI scan. PET frames were realigned and coregistered to the MR images, which were segmented using FreeSurfer. In amyloid-negative HCs ($$n$$ = 90; age range, 21-94 y), 7 nonspecific or off-target binding regions were considered: caudate, pallidum, putamen, thalamus, cerebellar white matter, hemispheric white matter, and choroid plexus. These regions of interest were assigned to 3 similarly behaving groups using principle components analysis, exploratory factor analysis, and Pearson correlations for caudate, putamen, and pallidum (also correlated with age); thalamus and white matter; and choroid plexus. In amyloid-negative HCs with ¹¹C-PIB and ¹⁸F-flortaucipir scans, correlations were calculated between white and gray matter before and after partial-volume correction. Results: The correlation between white and gray matter disappeared after partial-volume correction in ¹¹C-PIB (r² = 0) but persisted for ¹⁸F-flortaucipir (r² = 0.27), demonstrating that the correlation between white and gray matter signal in ¹⁸F-flortaucipir is not solely due to partial-volume effects. A linear regression showed that off-target signal from putamen and thalamus together explained 64% of the variability in the cortical signal in amyloid-negative HCs (not seen in amyloid-positive HCs). Variability in amyloid-negative HCs but not amyloid-positive HCs correlated with white matter signal (unrelated to partial-volume effects) and age-related off-target signal (possibly related to iron load). Conclusion: The noise in the ¹⁸F-flortaucipir measurement could pose challenges when studying early tau accumulation.

Authors:

Baker, Suzanne L ^[1]; Harrison, Theresa M ^[2]; Maass, Anne ^[3]; La Joie, Renaud ^[4]; Jagust, William J ^[5]

---

+ Show Author Affiliations

1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
2. Univ. of California, Berkeley, CA (United States)
3. Univ. of California, Berkeley, CA (United States); German Center for Neurodegenerative Diseases, Magdeburg (Germany)
4. Univ. of California, San Francisco, CA (United States)
5. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of California, Berkeley, CA (United States)

Publication Date:

Fri Mar 15 00:00:00 EDT 2019

Research Org.:

Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

Sponsoring Org.:

USDOE Office of Science (SC)

OSTI Identifier:

1580852

Grant/Contract Number:  

AC02-05CH11231

Resource Type:

Accepted Manuscript

Journal Name:

Journal of Nuclear Medicine

Additional Journal Information:

Journal Volume: 60; Journal Issue: 10; Journal ID: ISSN 0161-5505

Publisher:

Society of Nuclear Medicine and Molecular Imaging

Country of Publication:

United States

Language:

English

Subject:

62 RADIOLOGY AND NUCLEAR MEDICINE; tau; 18F-flortaucipir PET; off-target binding