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).

With metabolite corrected arterial input a compartmental model with spill-over correction for the right ventricular cavity can be applied to quantitate 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.

Analysis method in TPC

FUR (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.

FUR calculation can be done in Carimas™ or with CLI programs regfur for regional TTAC data and imgfur for image data.

FUR can be corrected for blood-flow -related variability by dividing it by regional MBF (Jayachandran et al., 2002; Pietilä et al., 2002):

For full quantification a reversible one-tissue compartmental model with spillover correction from RV should be considered.


See also:



References:

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DeGrado TR, Hutchins GD, Toorongian SA, Wieland DM, Schwaiger M. Myocardial kinetics of carbon-11-meta-hydroxyephedrine: retention mechanisms and effects of norepinephrine. J Nucl Med. 1993; 34(8): 1287-1293.

Harms HJ, de Haan S, Knaapen P, Allaart CP, Rijnierse MT, Schuit RC, Windhorst AD, Lammertsma AA, Huisman MC, Lubberink M. Quantification of [11C]-meta-hydroxyephepride uptake in human myocardium. EJNMMI Res. 2014; 4:52.

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Pietilä M, Malminiemi K, Vesalainen R, Jartti T, Teräs M, Någren K, Lehikoinen P, Voipio-Pulkki LM. Exercise training in chronic heart failure: beneficial effects on cardiac 11C-hydroxyephedrine PET, autonomic nervous control, and ventricular repolarization. J Nucl Med. 2002; 43(6): 773-779.

Pietilä M, Malminiemi K, Ukkonen H, Saraste M, Någren K, Lehikoinen P, Voipio-Pulkki LM. Reduced myocardial carbon-11 hydroxyephedrine retention is associated with poor prognosis in chronic heart failure. Eur J Nucl Med. 2001; 28(3): 373-376.

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Created at: 2014-05-20
Updated at: 2018-12-12
Written by: Vesa Oikonen