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. 2022;12(6):1921-1935.
doi: 10.3233/JPD-223201.

Progressive Olfactory Impairment and Cardiac Sympathetic Denervation in REM Sleep Behavior Disorder

Annette Janzen  1 , David Vadasz  1 , Jan Booij  2 , Markus Luster  3 , Damiano Librizzi  3 , Martin T Henrich  1   4 , Lars Timmermann  1 , Mahboubeh Habibi  1 , Elisabeth Sittig  1 , Geert Mayer  1   5 , Fanni Geibl  1   4 , Wolfgang Oertel  1
Affiliations

Progressive Olfactory Impairment and Cardiac Sympathetic Denervation in REM Sleep Behavior Disorder

Annette Janzen et al. J Parkinsons Dis. 2022.

Abstract

Background: Isolated rapid eye movement sleep behavior disorder (iRBD) is prodromal for Parkinson's disease (PD) and dementia with Lewy bodies (DLB).

Objective: We investigated the use of cardiac [123I]meta-iodo-benzyl-guanidine scintigraphy ([123I]MIBG) and olfactory testing- in comparison to [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane single photon emission computed tomography ([123I]FP-CIT-SPECT)- for identifying iRBD patients as prodromal phenotype of PD/DLB.

Methods: 37 RBD subjects underwent cardiac [123I]MIBG and brain [123I]FP-CIT-SPECT at baseline. Olfactory (Sniffin' Sticks), cognitive and motor functions were tested annually for ∼4 years.

Results: 29/37 (78.4%) subjects had a pathological [123I]MIBG, of whom 86.2% (25/29) presented at least a moderate hyposmia at baseline (threshold/discrimination/identification-(TDI-)score ≤25). 20/37 (54.1%) subjects had a pathological [123I]FP-CIT-SPECT, always combined with a pathological [123I]MIBG. In subjects with pathological [123I]MIBG, olfactory function worsened (mainly due to threshold and discrimination subscores) from baseline to follow-up (p = 0.005). Olfaction was more impaired in subjects with pathological [123I]MIBG compared to those with normal [123I]MIBG at baseline (p = 0.001) and follow-up (p < 0.001). UPDRS-III scores increased in subjects with both pathological [123I]MIBG and [123I]FP-CIT-SPECT. In this group, seven subjects phenoconverted to PD, all- except for one- presented with at least moderate hyposmia at baseline.

Conclusion: A combination of the biomarkers "pathological [123I]MIBG" and "hyposmia" likely identifies iRBD patients in an early prodromal stage of PD/DLB, i.e., before nigrostriatal degeneration is visualized. One-third of the subjects with pathological [123I]MIBG had a normal [123I]FP-CIT-SPECT. Noteworthy, in iRBD subjects with pathological [123I]MIBG, olfactory impairment is progressive independent of the [123I]FP-CIT-SPECT status.

Keywords: Biomarker; [123I]FP-CIT-SPECT; cardiac [123I]MIBG scintigraphy; hyposmia; isolated rapid eye movement sleep behavior disorder; prodromal progression marker.

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Conflict of interest statement

Annette Janzen, MD, reports grants from ParkinsonFonds Deutschland outside the submitted work. David Vadasz, MD, reports no competing interests. Jan Booij, MD, PhD, is consultant at GE healthcare (all paid to the institution). Markus Luster, MD, reports no competing interests. Damiano Librizzi, MD, reports no competing interests. Martin T. Henrich, MD, reports grants from the ParkinsonFonds Deutschland and the German Society for Parkinson and Movement Disorders outside the submitted work. Lars Timmermann, MD, received payments as a consultant for Boston Scientific between September 2018 and September 2021 and received honoraria as a speaker on symposia sponsored by UCB, Desitin, Boston Scientific, AbbVie, Novartis, GlaxoSmithKline, and DIAPLAN. The institution of L.T., not L.T. personally, received funding from Boston Scientific, the German Research Foundation, the German Ministry of Education and Research, and the Deutsche Parkinson Vereinigung. Neither Lars Timmermann nor any member of his family holds stocks, stock options, patents, or financial interests in any of the aforementioned companies or their competitors. Mahboubeh Habibi reports no competing interests. Elisabeth Sittig reports no competing interests. Geert Mayer, MD, reports no competing interests. Fanni F. Geibl, MD, PhD, reports grants from ParkinsonFonds Deutschland and P.E. Kempkes outside the submitted work. Wolfgang H. Oertel, MD, PhD, reports grants from ParkinsonFonds Deutschland, grants from Michael J Fox Foundation, grants from Deutsche Forschungsgemeinschaft (DFG), during the conduct of the study; personal fees from Adamas, MODAG, Roche and UCB; outside the submitted work. WHO is Hertie-Senior-Research Professor supported by the Charitable Hertie-Foundation, Frankfurt/Main, Germany.

Figures

Fig. 1
Fig. 1
Stratification of patients solely based on cardiac [123I]MIBG scintigraphy. Number of RBD subjects with pathological and normal [123I]MIBG uptake at baseline (n = 37) and phenoconversion rates at follow-up (n = 35) are shown. Marked is also how many subjects with abnormal cardiac [123I]MIBG uptake had an abnormal [123I]FP-CIT SPECT scan, and how many subjects were on antidepressants (and type of antidepressant). Of note, only subjects with both a pathological [123I]MIBG scan and [123I]FP-CIT-SPECT phenoconverted to PD (n = 7).
Fig. 2
Fig. 2
Olfactory and motor functions of the three subgroups according to [123I]MIBG and [123I]FP-CIT-SPECT status (N = normal, P = pathological) at baseline and follow-up (fu). A) TDI-score at baseline and follow-up. B) Threshold (T), discrimination (D) and identification (I) subscores at baseline and follow-up. C) UPDRS-III score at baseline and follow-up. p values < 0.017 were considered to be significant.
Fig. 3
Fig. 3
Algorithm for selecting patients with prodromal Parkinson’s disease in clinical trials with disease-modifying therapy based on the results of this study. Subjects with video-polysomnography confirmed RBD should be screened with olfactory testing (Sniffin’ Sticks, to determine TDI score) and [123I]MIBG scintigraphy. In the RBD subjects with abnormal [123I]MIBG scintigraphy, only four subjects presented with TDI > 25 at baseline. In all of these, the olfactory function deteriorated from baseline to follow-up to TDI ≤25 –except for one. Two RBD subjects with normal [123I]MIBG scintigraphy had a TDI ≤25 at baseline: one stayed below TDI < 25, one improved to normosmia at follow-up. In case of abnormal [123I]MIBG scintigraphy, this should be followed by [123I]FP-CIT-SPECT. RBD subjects with both, abnormal [123I]MIBG scintigraphy and [123I]FP-CIT-SPECT show an annual conversion rate between ∼9–10%.
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