Cardiac noradrenergic deficiency revealed by 18F-dopamine positron emission tomography identifies preclinical central Lewy body diseases
David S. Goldstein, … , Tianxia Wu, Yehonatan Sharabi
David S. Goldstein, … , Tianxia Wu, Yehonatan Sharabi
Published October 26, 2023
Citation Information: J Clin Invest. 2024;134(1):e172460. https://doi.org/10.1172/JCI172460.
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Cardiac noradrenergic deficiency revealed by 18F-dopamine positron emission tomography identifies preclinical central Lewy body diseases

Abstract

BACKGROUND. In Lewy body diseases (LBDs) Parkinson disease (PD), and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests clinically, substantial neurodegeneration has already occurred. Biomarkers are needed to identify central LBDs in a preclinical phase, when neurorescue strategies might forestall symptomatic disease. This phase may involve catecholamine deficiency in the autonomic nervous system. We analyzed data from the prospective, observational, long-term PDRisk study to assess the predictive value of low versus normal cardiac 18F-dopamine positron emission tomography (PET), an index of myocardial content of the sympathetic neurotransmitter norepinephrine, in at-risk individuals. METHODS. Participants self-reported risk factor information (genetics, olfactory dysfunction, dream enactment behavior, and orthostatic intolerance or hypotension) at a protocol-specific website. Thirty-four with 3 or more confirmed risk factors underwent serial cardiac 18F-dopamine PET at 1.5-year intervals for up to 7.5 years or until PD was diagnosed. RESULTS. Nine participants had low initial myocardial 18F-dopamine–derived radioactivity (<6,000 nCi-kg/cc-mCi) and 25 had normal radioactivity. At 7 years of follow-up, 8 of 9 with low initial radioactivity and 1 of 11 with normal radioactivity were diagnosed with a central LBD (LBD+) (P = 0.0009 by Fisher’s exact test). Conversely, all 9 LBD+ participants had low 18F-dopamine–derived radioactivity before or at the time of diagnosis of a central LBD, whereas among 25 participants without a central LBD only 1 (4%) had persistently low radioactivity (P < 0.0001 by Fisher’s exact test). CONCLUSION. Cardiac 18F-dopamine PET highly efficiently distinguishes at-risk individuals who are diagnosed subsequently with a central LBD from those who are not. TRIAL REGISTRATION. ClinicalTrials.gov NCT00775853. FUNDING. Division of Intramural Research, NIH, NINDS.

Authors

David S. Goldstein, Courtney Holmes, Patti Sullivan, Grisel Lopez, Janna Gelsomino, Sarah Moore, Risa Isonaka, Tianxia Wu, Yehonatan Sharabi

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Figure 7

Modeling uptake and subsequent loss of 18F-dopamine–derived radioactivity.

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Modeling uptake and subsequent loss of 18F-dopamine–derived radioactivit...
Individual observed values (A and B) and predicted curves of best fit (C and D) for interventricular septal myocardial 18F-dopamine–derived radioactivity as a function of time from initiation of 3-minute intravenous administration of the tracer in healthy volunteers (HV) and in at-risk individuals subsequently diagnosed with a central Lewy body disease (LBD+) or not diagnosed with a central Lewy body disease during follow-up (LBD–). (A and C) Data from 1 minute after initiation of 3-minute intravenous administration of the tracer to the maximum radioactivity. (B and D) Data from maximum radioactivity to 25 minutes after initiation of administration of the tracer, expressed as percentage of maximum radioactivity. In A and C, the early increase in radioactivity was slower in the LBD+ than LBD– and HV groups. In B and D, the LBD+ group had more rapid loss of radioactivity than the LBD– and HV groups between the maximum radioactivity and 13 minutes. The outlier data at 3 minutes for patient LBD– no. 11 and the data at 4 minutes for HV no. 4 were excluded from the analysis. From peak to 25 minutes the excluded outlier time point data are at 5 and 13 minutes for LBD+ no. 9, 5 minutes for LBD+ no. 10, 4 and 5 minutes for LBD– no. 3, and peak to 25 minutes for LBD+ no. 4.