2-Year Natural Decline of Cardiac Sympathetic Innervation in Idiopathic Parkinson Disease Studied with 11C-Hydroxyephedrine PET

Abstract

The objective of this study was to detect regional patterns of cardiac sympathetic denervation in idiopathic Parkinson disease (IPD) using ¹¹C-hydroxyephedrine (¹¹C-HED) PET and determine the denervation rate over 2 y.

Methods: We obtained 62 cardiac ¹¹C-HED PET scans in 39 patients (30 men and 9 women; mean age ± SD, 61.9 ± 5.9 y), including 23 patients with follow-up scans at 2 y. We derived ¹¹C-HED retention indices (RIs; mL of blood/min/mL of tissue) reflecting nerve density and integrity for 480 left ventricular (LV) sectors. We compared IPD patients with 33 healthy controls using z score analysis; RI values ≤ 2.5 SDs were considered abnormal. We expressed global and regional LV denervation as the percentage extent of z score severity and severity-extent product (SEP) on 9-segment bullseye maps and decline in cardiac sympathetic innervation as the 2-y difference in SEP (diff-SEP).

Results: Baseline ¹¹C-HED PET in the 39 IPD patients revealed an RI mean of 0.052 ± 0.022 mL of blood/min/mL of tissue. In comparison with data from normal controls, 12 patients had normal ¹¹C-HED PET, 5 showed mild denervation (percentage extent < 30%), and 22 had moderate to severe denervation (percentage extent > 30%, z score ≤ 2.5 SD). In the 23 paired PET scans, worsening cardiac denervation (global diff-SEP > 9) occurred in 14 of 23 (60.9%) patients over 2 y, including percentage LV abnormality (59% increasing to 66%), z-severity (-2.4 down to -2.5), and SEP (-195 to -227) (P = 0.0062). We found a mean annual decline of 4.6% ± 5.6 (maximum, 13%) in ¹¹C-HED retention from a baseline global RI mean of 0.0481 ± 0.0218 to 0.0432 ± 0.0220 (P = 0.0009). At baseline, 5 patients with normal uptake had no interval change; 3 with mild denervation developed interval decline in lateral and inferior segments (diff-SEP -82 to -99) compared with anterior and septal segments (-65 to -79), whereas the reverse pattern occurred in 15 patients with severe baseline denervation.

Conclusion: Progressive decline in cardiac sympathetic neural integrity in IPD patients occurs at a modest rate over 2 y on ¹¹C-HED scans with marked heterogeneity and a regional pattern of involvement and decline.

Keywords: 11C-hydroxyephedrine PET; Parkinson disease; autonomic nervous system; cardiac sympathetic denervation.

FIGURE 1.

Bullseye plots using 9-segment model summarizing segmental distribution of sympathetic denervation with respect to mean percentage extent, z score severity, and SEP, in comparison to global mean measurements in 23 patients, comparing baseline measurements with 2-y follow-up. There is a decline in global LV RI per annum of 4.6% translating to increasing abnormalities of LV segmental extent, z score severity, and SEP. Over 2 y, changes in percentage LV abnormality (59% increasing to 66%), z score severity (–2.4 down to –2.5), and SEP (–195 down to –227) indicate worsening cardiac sympathetic innervation. There is a general proximal-to-distal gradient, with basal segments being relatively spared compared with distal segments.

FIGURE 2.

Bullseye plots summarizing decline in sympathetic denervation with respect to SEP, in 23 patients, comparing differences in baseline measurements with 2-y follow-up of SEP, based on starting category at baseline, either mild abnormality or severe. In patients with severe denervation at baseline preferentially affecting lateral wall, anterior and septal walls showed relatively greater decline, whereas patients with mild abnormality on PET scans at baseline had relatively greater progression in lateral, inferior, and apical walls. Patients with normal baseline ¹¹C-HED PET had small changes that were not considered significant within margin of test–retest error for ¹¹C-HED PET. Formal reproducibility analysis of ¹¹C-HED is an area of future research.

FIGURE 3.

Comparison polar maps of normal control patients’ (n = 33) mean ¹¹C-HED RIs (A) and baseline IPD patients’ (n = 23) mean ¹¹C-HED RIs (B), demonstrating severe, global cardiac sympathetic denervation. (C) Mean difference in RI between baseline studies and 2-y follow-up studies demonstrating preferentially decline in anteroseptal and septal walls. (D) Segmental z score severity polar map, generated by sector-to-sector comparison of IPD and normal control ¹¹C-HED RI, representing characteristic regional pattern of sympathetic denervation in IPD. Proximal lateral wall is most severely affected, with relative sparing of anterior and proximal septal walls. (E) There is concordance in segmental distribution on both z score severity polar map and frequency polar map representing percentage of IPD patients (i.e., n/23 × 100) with abnormal sector z score ≤ 2.5 displayed on color scale ranging from 0% to 100%.

FIGURE 4.

Examples of ¹¹C-HED decline in IPD patients showing baseline ¹¹C-HED RI (left), 2-y follow-up ¹¹C-HED RI (middle), and difference ¹¹C-HED RI (right) polar maps. (A) Partial ¹¹C-HED denervation at baseline ¹¹C-HED scan, with decline in ¹¹C-HED uptake at 2 y, after initial sparing of anterior and septal walls. (B) Severe ¹¹C-HED denervation at baseline, with mild further decline at 2 y, in septum and inferior LV walls.