Objective: To investigate the long-term effects of the adrenergic blocker carvedilol on I-MIBG myocardial uptake in subjects with
REM sleep behavior disorder (RBD) and other premotor symptoms that increase the risk for Parkinson’s disease (PD).

Background: 123I-MIBG myocardial scintigraphy, a marker of cardiac sympathetic innervation, is abnormal in PD patients, with a
characteristic reduction of early and late heart/mediastinum (H/M) ratio and increased Washout Rate (WR). These
abnormalities are also typical in pre-motor PD, at a stage where there is no imaging evidence of dopaminergic dysfunction
or pathological confirmation of cardiac sympathetic denervation. We hypothesized that I-MIBG defects at the pre-motor
stage of PD are driven by sympathetic nervous system (SNS) hyperactivity and are therefore reversible with adrenergic
blockers.

Method: Six subjects with idiopathic RBD and at least one other pre-motor PD symptom were tested for I-MIBG and I
Ioflupane uptake at baseline, 26 and 52 weeks after treatment with carvedilol 12.5mg or 25mg twice daily. Early and late
H/M ratios, as well as WR, were calculated.

Results: Five men and one woman (age 67±8.5) were enrolled. Two subjects were unable to tolerate study medication but were
equally tested at 52 weeks. All subjects had reduced early and late H/M ratios at baseline, and 5/6 had abnormally
increased WR (>20%). In treated subjects, early H/M ratio decreased from 1.70±0.32 to 1.65±0.28, while late H/M ratio
improved from 1.65±0.35 to 1.71±0.39. WR decreased significantly on average in all treated subjects (40.8%±15.3 vs
23.1%±15.1) and normalized in 3/4. The two subjects not taking carvedilol showed WR at 52 weeks well above the normal
threshold (51.6%±7.14). I-Ioflupane uptake was normal at baseline and at 26 weeks in all subjects.

Conclusion: In the pre-motor phase of PD-associated neurodegeneration, I-MIBG impairment, and in particular WR, appears to be
reversible after 12 months of adrenergic blocker therapy, suggesting SNS hyperactivity and not denervation. This
observation may provide relevant information for the timing and nature of disease modifying efforts in PD and other
synucleinopathies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/reversible-mibg-abnormalities-in-subjects-at-risk-for-synucleinopathy-12-months-data/