Brain Advance Access originally published online on November 17, 2004
Brain 2005 128(1):126-137; doi:10.1093/brain/awh322
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Brain Vol. 128 No. 1 © Guarantors of Brain 2004; all rights reserved
Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for 
-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT
1 Department of Neurology, Center for Nervous Diseases and 2 Department of Nuclear Medicine, Center of Radiology, Philipps University of Marburg and 3 Department of Neurology, Hephata-Klinik, Schwalmstadt-Treysa, Germany
Correspondence to: Karin Stiasny-Kolster, MD, Department of Neurology, Center of Nervous Diseases, Rudolf-Bultmann-Strasse 8, D-35033 Marburg, Germany E-mail: stiasny{at}staff.uni-marburg.de
REM sleep behaviour disorder (RBD) and olfactory dysfunction are common and very early features of 
-synucleinopathies, in particular Parkinson's disease. To investigate the hypothesis that these two clinical features in combination are an indicator of evolving -synucleinopathy, olfactory function was assessed in RBD. We studied 30 patients (18 male, 12 female; mean age 48 ± 14 years, range 19–78 years) with clinical (idiopathic, n = 6; symptomatic, n = 13, mostly associated with narcolepsy) or subclinical (n = 11, associated with narcolepsy) RBD according to standard criteria and 30 age- and gender-matched healthy control subjects using standardized ‘Sniffin’ Sticks'. RBD patients had a significantly higher olfactory threshold (P = 0.0001), lower discrimination score (P = 0.003), and lower identification score (P = 0.001). Compared with normative data, 97% of the RBD patients had a pathologically increased olfactory threshold, 63% an impaired odour discrimination score, and 63% a decreased identification score. On neurological examination, signs of parkinsonism were newly found in five patients with clinical RBD (not associated with narcolepsy), who usually had a long history of ‘idiopathic’ RBD. Four of the five patients fulfilled the UK Brain Bank criteria for the clinical diagnosis of Parkinson's disease. The underlying nigrostriatal degeneration of clinical Parkinson's disease was confirmed by I-123-FP-CIT SPECT in one patient and early nigrostriatal degeneration was identified by SPECT in a further two patients with ‘idiopathic’ clinical RBD out of 11 RBD patients who agreed to undergo SPECT studies. Our study shows that RBD patients have a profound impairment of olfactory function. Five patients with clinical RBD not associated with narcolepsy had clinical or imaging signs of nigrostriatal degeneration. This new clinical finding correlates with the neuropathological staging of Parkinson's disease (stages 1–3) as proposed by Braak. In stage 1, the anterior olfactory nucleus or the olfactory bulb is affected (along with the dorsal motor nucleus of the glossopharyngeal and vagal nerves). In stage 2, additional lesions consistently remain confined to the medulla oblongata and pontine tegmentum, which are critical areas for RBD. Midbrain lesions are found only in stage 3, in particular degeneration of dopaminergic neurons in the substantia nigra pars compacta. Thus, ‘idiopathic’ RBD patients with olfactory impairment might present with stage 2 preclinical -synucleinopathy. Since narcoleptic patients are not known to have an increased risk of developing parkinsonism, the pathophysiology and clinical relevance of hyposmia in RBD/narcolepsy patients requires further research.
* These authors contributed equally to the study
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