Quantification of sympathetic nerve density with [11C]HED
[11C]‑(–)‑m‑hydroxyephedrine ([11C]HED) is a widely used PET tracer for cardiac neuronal imaging (Knuuti & Sipola, 2005; Lautamäki et al., 2007). [11C]HED can also be used to measure the sympathetic nerve density in other tissues, such as brown adipose tissue (Muzik et al., 2017). [11C]HED can be used in imaging of neuroblastomas (Shulkin et al. 1996) and pheochromocytomas (Trampal et al. 2004).
[11C]HED is a catecholamine analogue, and it is actively transported into presynaptic sympathetic nerve terminals by the norepinephrine transporter (NET). Inside neurons, tracer is taken up into norepinephrine storage vesicles by VMAT2. [11C]HED is not metabolized by MAO or COMT.
The uptake of [11C]HED is very rapid and flow-limited (Jang et al., 2013). Retention is also dependent on the NET density of the heart (Raffel et al., 2006), with a balance between continuous release and reuptake (DeGrado et al., 1993). A semiquantitative method, FUR, has been used to analyze [11C]HED PET data, although it and SUV show a non-linear relationship with the distribution volume. FUR is traditionally called Retention Index (RI) in analysis of [11C]HED data. The flow-limited neuronal uptake causes the FUR to be insensitive to substantial nerve losses as long as myocardial perfusion is not reduced (Jang et al., 2013).
Plasma metabolite fractions have been fitted with exponential function (Bernacki et al., 2016). In myocardial studies, with metabolite corrected arterial input, a compartmental model with spill-over correction for the right ventricular cavity can be applied to quantify the distribution volume (Harms et al., 2014). Although the reversible two-tissue compartmental model provided better fits, Harms et al (2014) proposed using one-tissue compartmental model instead, because of its robustness. Separately assessed myocardial perfusion can be included in the model (Caldwell et al., 1998; Link et al., 2003).
In diagnostics of regional cardiac sympathetic denervation, static scans (starting 20 min after injection) are scaled to maximal uptake in myocardium, and scored based on a threshold value. With appropriate software, excellent inter-rater reliability can be achieved (Wang et al., 2021).
Analysis method in TPCFUR (retention index, RI) is calculated as the myocardial activity at a late time (30–40 min p.i.) divided by the integral of metabolite corrected arterial blood activity curve, derived from a small ROI drawn in the LV cavity, and parent tracer fractions that can be measured from separate venous blood samples collected during the PET study (Vesalainen et al., 1999). Usually, blood TAC is not corrected for metabolites.
For full quantification a reversible one-tissue compartmental model with spillover correction from RV should be considered.
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Updated at: 2022-01-15
Created at: 2014-05-20
Written by: Vesa Oikonen