J Clin Neurol.  2019 Apr;15(2):175-183. 10.3988/jcn.2019.15.2.175.

A New Metabolic Network Correlated with Olfactory and Executive Dysfunctions in Idiopathic Rapid Eye Movement Sleep Behavior Disorder

Affiliations
  • 1Department of Nuclear Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea. yk3181@snu.ac.kr
  • 2Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea.
  • 3Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Korea.
  • 4Department of Neurology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea. wieber04@snu.ac.kr
  • 5Department of Neurology, Seoul National University College of Medicine, Seoul, Korea.
  • 6Department of Neurology, Seoul National University Hospital, Seoul, Korea.

Abstract

BACKGROUND AND PURPOSE
To identify a metabolic network reflecting neurodegeneration in patients with idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD).
METHODS
We recruited a prospective cohort comprising patients with de novo Parkinson's disease (PD) with probable REM sleep behavior disorder (PDRBD, n=21), polysomnography-confirmed iRBD patients (n=28), and age-matched healthy controls (HC) (n=24). PDRBD-related spatial covariance pattern (PDRBD-RP) were determined from 18F-fluorodeoxyglucose PET images of the PDRBD group and validated by reproduction in a separate PD cohort with polysomnography-confirmed REM sleep behavior disorder (n=11). We also confirmed via 18F-N-3-fluoropropyl-2β-carboxymethoxy-3β-(4-iodophenyl)-nortropane PET that none of our iRBD patients had any loss of dopamine transporters (DATs) suggestive of PD. Differences in the PDRBD-RP across groups were compared, and the clinical significance of these metabolic patterns in iRBD patients was further evaluated based on relationships with olfactory and cognitive functions, and striatal DAT densities.
RESULTS
The PDRBD-RP reflected the previously reported PD-related covariance pattern and additionally showed relative metabolic increases in the hippocampus and premotor cortex. The PDRBD-RP gradually increased from the HC to iRBD patients and to the de novo and validation PDRBD groups. In iRBD patients, the PDRBD-RP was negatively correlated with olfactory and frontal executive functions (age-controlled p<0.01 for both), and tended to be negatively correlated with the striatal DAT density, although this was insignificant after age adjustment. During the mean follow-up period of 3.5 years, 5 of 11 iRBD patients with PDRBD-RP elevation had developed Lewy body diseases, whereas those without PDRBD-RP elevation had not.
CONCLUSIONS
Our results suggest that PDRBD-RP is an effective biomarker for monitoring the progression to neurodegenerative disease in iRBD patients.

Keyword

Parkinson's disease; rapid eye movement sleep behavior disorder; functional neuroimaging; smell; positron-emission tomography

MeSH Terms

Cognition
Cohort Studies
Dopamine
Executive Function
Follow-Up Studies
Functional Neuroimaging
Hippocampus
Humans
Lewy Bodies
Metabolic Networks and Pathways*
Motor Cortex
Neurodegenerative Diseases
Parkinson Disease
Positron-Emission Tomography
Prospective Studies
REM Sleep Behavior Disorder*
Reproduction
Sleep, REM*
Smell
Dopamine

Figure

  • Fig. 1 Disease-related metabolic patterns in the various study groups. A: The de novo Parkinson's disease with probable RBD-PDRBD-RP identified by network analysis of 18F-FDG PET scans in 21 PDRBD patients and 24 age- and gender-matched HC. Voxels with warm colors represent positive regions (metabolic increases) and those with cool colors are negative regions (metabolic decreases). B: The PDRBD-RP differed significantly among the groups, as determined by one-way ANOVA followed by post-hoc Tukey's HSD tests. The PDRBD-RP increased gradually from HC to iRBD and then to PDRBD. C: The RBD-RP identified by the network analysis of 18F-FDG PET scans of 28 iRBD patients and 24 age- and gender-matched HC. Voxels with warm colors represent positive regions (metabolic increases) and those with cool colors denote negative regions (metabolic decreases). D: The RBD-RP differed significantly among the groups, as determined by one-way ANOVA followed by post-hoc Tukey's HSD tests. The pattern was higher in both patient groups than in HC, with no difference between the two patient groups. 18F-FDG: 18F-fluorodeoxyglucose, GP: globus pallidus, HC: healthy controls, HSD: honestly significant difference, iRBD: idiopathic rapid eye movement sleep behavior disorder, PDRBD-RP: de novo Parkinson's disease with probable rapid eye movement sleep behavior disorder-related spatial covariance pattern, RBD: rapid eye movement sleep behavior disorder, RBD-RP: rapid eye movement sleep behavior disorder-related spatial covariance pattern, SMA: supplementary motor area.

  • Fig. 2 Validation of the PDRBD-RP in a separate Parkinson's disease cohort with rapid eye movement sleep behavior disorder confirmed by polysomnography. Compared with HC, the validation PDRBD group showed a significantly increased PDRBD-RP that was similar to that in the de novo PDRBD group. HC: healthy controls, PDRBD-RP: de novo Parkinson's disease with probable rapid eye movement sleep behavior disorder-related spatial covariance pattern, ns: not significant.

  • Fig. 3 Correlations of nonmotor Parkinson's disease features in iRBD with the PDRBD-RP and RBD-RP. Correlations of the PDRBD-RP (A) and RBD-RP (D) with olfactory function (butanol threshold test). Comparisons of the PDRBD-RP (B) and RBD-RP (E) between the normosmic and anosmic iRBD patients. Correlations of the PDRBD-RP (C) and RBD-RP (F) with the reaction time z score in trail-making test B. The correlation analysis were performed using Pearson's correlation coefficient, and the group comparisons were performed using analysis of covariance, with age as the covariate. iRBD: idiopathic rapid eye movement sleep behavior disorder, PDRBD-RP: de novo Parkinson's disease with probable rapid eye movement sleep behavior disorder-related spatial covariance pattern, RBD-RP: rapid eye movement sleep behavior disorder-related spatial covariance pattern.


Reference

1. Boeve BF. Idiopathic REM sleep behaviour disorder in the development of Parkinson’s disease. Lancet Neurol. 2013; 12:469–482. PMID: 23578773.
Article
2. Eckert T, Van Laere K, Tang C, Lewis DE, Edwards C, Santens P, et al. Quantification of Parkinson’s disease-related network expression with ECD SPECT. Eur J Nucl Med Mol Imaging. 2007; 34:496–501. PMID: 17096095.
Article
3. Ma Y, Tang C, Spetsieris PG, Dhawan V, Eidelberg D. Abnormal metabolic network activity in Parkinson’s disease: test-retest reproducibility. J Cereb Blood Flow Metab. 2007; 27:597–605. PMID: 16804550.
Article
4. Wu P, Yu H, Peng S, Dauvilliers Y, Wang J, Ge J, et al. Consistent abnormalities in metabolic network activity in idiopathic rapid eye movement sleep behaviour disorder. Brain. 2014; 137:3122–3128. PMID: 25338949.
Article
5. Meles SK, Vadasz D, Renken RJ, Sittig-Wiegand E, Mayer G, Depboylu C, et al. FDG PET, dopamine transporter SPECT, and olfaction: combining biomarkers in REM sleep behavior disorder. Mov Disord. 2017; 32:1482–1486. PMID: 28734065.
Article
6. Holtbernd F, Gagnon JF, Postuma RB, Ma Y, Tang CC, Feigin A, et al. Abnormal metabolic network activity in REM sleep behavior disorder. Neurology. 2014; 82:620–627. PMID: 24453082.
Article
7. Meles SK, Renken RJ, Janzen A, Vadasz D, Pagani M, Arnaldi D, et al. The metabolic pattern of idiopathic REM sleep behavior disorder reflects early-stage Parkinson’s disease. J Nucl Med. 2018; 59:1437–1444. PMID: 29476004.
8. Postuma RB, Gagnon JF, Vendette M, Charland K, Montplaisir J. REM sleep behaviour disorder in Parkinson’s disease is associated with specific motor features. J Neurol Neurosurg Psychiatry. 2008; 79:1117–1121. PMID: 18682443.
Article
9. Postuma RB, Adler CH, Dugger BN, Hentz JG, Shill HA, Driver-Dunckley E, et al. REM sleep behavior disorder and neuropathology in Parkinson’s disease. Mov Disord. 2015; 30:1413–1417. PMID: 26265105.
Article
10. Lim JS, Shin SA, Lee JY, Nam H, Lee JY, Kim YK. Neural substrates of rapid eye movement sleep behavior disorder in Parkinson’s disease. Parkinsonism Relat Disord. 2016; 23:31–36. PMID: 26678512.
Article
11. Li D, Huang P, Zang Y, Lou Y, Cen Z, Gu Q, et al. Abnormal baseline brain activity in Parkinson’s disease with and without REM sleep behavior disorder: a resting-state functional MRI study. J Magn Reson Imaging. 2017; 46:697–703. PMID: 27880010.
Article
12. Stiasny-Kolster K, Mayer G, Schäfer S, Möller JC, Heinzel-Gutenbrunner M, Oertel WH. The REM sleep behavior disorder screening questionnaire--a new diagnostic instrument. Mov Disord. 2007; 22:2386–2393. PMID: 17894337.
Article
13. American Academy of Sleep Medicine. The International Classification of Sleep Disorder: diagnostic and coding manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine;2005.
14. Doty RL, Marcus A, Lee WW. Development of the 12-item Cross-Cultural Smell Identification Test (CC-SIT). Laryngoscope. 1996; 106:353–356. PMID: 8614203.
15. Kim BG, Oh JH, Choi HN, Park SY. Simple assessment of olfaction in patients with chronic rhinosinusitis. Acta Otolaryngol. 2015; 135:258–263. PMID: 25625195.
Article
16. Kang Y, Na DL. Seoul Neuropsychological Screening Battery. Seoul: Human Brain Research & Consulting Co.;2003.
17. Habeck C, Foster NL, Perneczky R, Kurz A, Alexopoulos P, Koeppe RA, et al. Multivariate and univariate neuroimaging biomarkers of Alzheimer’s disease. Neuroimage. 2008; 40:1503–1515. PMID: 18343688.
Article
18. Dang-Vu TT, Gagnon JF, Vendette M, Soucy JP, Postuma RB, Montplaisir J. Hippocampal perfusion predicts impending neurodegeneration in REM sleep behavior disorder. Neurology. 2012; 79:2302–2306. PMID: 23115214.
Article
19. Calabresi P, Castrioto A, Di Filippo M, Picconi B. New experimental and clinical links between the hippocampus and the dopaminergic system in Parkinson’s disease. Lancet Neurol. 2013; 12:811–821. PMID: 23867199.
Article
20. Ma Y, Tang C, Moeller JR, Eidelberg D. Abnormal regional brain function in Parkinson’s disease: truth or fiction? Neuroimage. 2009; 45:260–266. PMID: 18992824.
Article
21. Sabatini U, Boulanouar K, Fabre N, Martin F, Carel C, Colonnese C, et al. Cortical motor reorganization in akinetic patients with Parkinson’s disease: a functional MRI study. Brain. 2000; 123:394–403. PMID: 10648446.
22. Doty RL. Olfactory dysfunction in Parkinson disease. Nat Rev Neurol. 2012; 8:329–339. PMID: 22584158.
Article
23. Fantini ML, Postuma RB, Montplaisir J, Ferini-Strambi L. Olfactory deficit in idiopathic rapid eye movements sleep behavior disorder. Brain Res Bull. 2006; 70:386–390. PMID: 17027774.
Article
24. Mahlknecht P, Iranzo A, Högl B, Frauscher B, Müller C, Santamaría J, et al. Olfactory dysfunction predicts early transition to a Lewy body disease in idiopathic RBD. Neurology. 2015; 84:654–658. PMID: 25609758.
Article
25. Massicotte-Marquez J, Décary A, Gagnon JF, Vendette M, Mathieu A, Postuma RB, et al. Executive dysfunction and memory impairment in idiopathic REM sleep behavior disorder. Neurology. 2008; 70:1250–1257. PMID: 18216303.
Article
26. Gagnon JF, Vendette M, Postuma RB, Desjardins C, Massicotte-Marquez J, Panisset M, et al. Mild cognitive impairment in rapid eye movement sleep behavior disorder and Parkinson’s disease. Ann Neurol. 2009; 66:39–47. PMID: 19670440.
Article
27. Rodrigues Brazète J, Montplaisir J, Petit D, Postuma RB, Bertrand JA, Génier Marchand D, et al. Electroencephalogram slowing in rapid eye movement sleep behavior disorder is associated with mild cognitive impairment. Sleep Med. 2013; 14:1059–1063. PMID: 24095264.
Article
28. Vendette M, Montplaisir J, Gosselin N, Soucy JP, Postuma RB, Dang-Vu TT, et al. Brain perfusion anomalies in rapid eye movement sleep behavior disorder with mild cognitive impairment. Mov Disord. 2012; 27:1255–1261. PMID: 22791632.
Article
29. Génier Marchand D, Montplaisir J, Postuma RB, Rahayel S, Gagnon JF. Detecting the cognitive prodrome of dementia with Lewy bodies: a prospective study of REM sleep behavior disorder. Sleep. 2017; 40:zsw014.
Article
30. Tröster AI. Neuropsychological characteristics of dementia with Lewy bodies and Parkinson’s disease with dementia: differentiation, early detection, and implications for “mild cognitive impairment” and biomarkers. Neuropsychol Rev. 2008; 18:103–119. PMID: 18322801.
Article
31. Halliday GM, Holton JL, Revesz T, Dickson DW. Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol. 2011; 122:187–204. PMID: 21720849.
Article
32. Chahine LM, Daley J, Horn S, Colcher A, Hurtig H, Cantor C, et al. Questionnaire-based diagnosis of REM sleep behavior disorder in Parkinson’s disease. Mov Disord. 2013; 28:1146–1149. PMID: 23519694.
Article
Full Text Links
  • JCN
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr