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 18 F-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 18 F-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 18 F-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 18 F-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 18 F-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.

Getting to the heart of Lewy body disease

“…More broadly, the application of such a detailed and thorough longitudinal, prospective protocol as that used in Goldstein et al ( 7 ), with highly compelling results, will stimulate not only an extension of this study but also the further development of available biomarker detection tools ( 11 ). For example, 123 I-MIBG SPECT, skin and gut α-synuclein immunofluorescence, or seed amplification assays from cerebrospinal fluid or nasal secretions also have the potential to identify prodromal or early disease in at-risk individuals, accelerating the development and testing of new disease-modifying therapies for the central Lewy body diseases.…”

“…In this issue of the JCI, Goldstein et al ( 7 ) report the results of the prospective, longitudinal PDRisk study (ClinicalTrials.gov NCT00775853) investigating an NIH-developed positron emission tomography (PET) tracer, 18 F-dopamine, to assess dysfunction of the cardiac noradrenergic system as a prelude to the development of PD and DLB. Though relatively small, this study demonstrated a remarkably accurate predictive value of low cardiac uptake of 18 F-dopamine for central Lewy body disease.…”

“…However, Goldstein et al are the first to our knowledge to demonstrate this relationship in a longitudinal, long-term prospective study of cardiac noradrenergic imaging in individuals with specific, self-reported nonmotor risk factors for PD (genetics, olfactory changes, dream enactment, orthostasis). Goldstein et al ( 7 ) should pave the way for its use in identifying patients with peripheral synucleinopathies before they develop substantial central nervous system disease, thus optimizing the use of disease-modifying therapeutics.…”

“…Goldstein et al ( 7 ) demonstrate that a combination of cardiac noradrenergic cell loss and inefficient sequestration of catecholamines in residual cardiac sympathetic nerves precedes the onset of central Lewy body diseases, at least in a population with several identified nonmotor PD risk factors. The precise timing of cardiac noradrenergic cell loss to central nervous system dopaminergic cell loss remains to be elucidated.…”

“…The precise timing of cardiac noradrenergic cell loss to central nervous system dopaminergic cell loss remains to be elucidated. As the authors acknowledge, this paradigm may be more effective in identifying preclinical disease in patients with “body-first” rather than “brain-first” central Lewy body disease ( 10 ), since the choice of nonmotor risk factors for entry into the PDRisk study probably biases toward the “body-first” paradigm ( 7 ). Regardless, there is an increasing role for cardiac 18 F-dopamine PET in identifying early or clinically prodromal disease in a substantial proportion of patients.…”