[The new Parkinson's disease pain classification system (PD-PCS)]. / Die neue Parkinson-Schmerzklassifikation (PSK).

BACKGROUND: Chronic pain is a common non-motor symptom in patients with Parkinson's disease (PD). AIM: To facilitate the diagnosis of pain in PD, we developed a new classification system the Parkinson's disease pain classification system (PD-PCS) and translated the corresponding validated questionnaire into German. METHODS: A causal relationship of the respective pain syndrome with PD can be determined by four questions before assigning it hierarchically into one of three pain categories (neuropathic, nociceptive and nociplastic). RESULTS: In the initial validation study 77% of the patients (122/159) had PD-associated pain comprising 87 (55%) with nociceptive, 36 (22%) with nociplastic and 24 (16%) with neuropathic pain. The study revealed a high validity of the questionnaire and a moderate intrarater and interrater reliability. The questionnaire has been adapted into German and employed in 30 patients. DISCUSSION: The PD-PCS questionnaire is a valid and reliable tool to determine the relationship of a pain syndrome with PD before classifying it according to the underlying category, facilitating further diagnostics and treatment.

Correction to: Advanced Robotic Therapy Integrated Centers (ARTIC): an international collaboration facilitating the application of rehabilitation technologies.

The original article [1] contains a small mistake concerning the ARTIC Team members mentioned in the Acknowledgements. The team member, Rocco Salvatore Calabrò had their name presented incorrectly. This has now been corrected in the original article.

Experimental pain sensitivity in multiple system atrophy and Parkinson's disease at an early stage.

BACKGROUND: Chronic spontaneous pain is a clinically relevant non-motor symptom in multiple system atrophy (MSA) and Parkinson's disease (PD). Experimental pain sensitivity, reflecting the mechanisms of nociception and pain perception leading to clinical pain, is known to be enhanced in both diseases at advanced stages. Also, this study aimed at investigating experimental pain sensitivity already at an early stage (i.e. symptom duration ≤5 years). METHODS: Experimental pain sensitivity was assessed by investigating the nociceptive flexion reflex (NFR, reflecting spinal nociception) and heat and electrical pain thresholds. 'Off-drug' MSA (n = 11) and PD (n = 14) patients selected at an early stage of the disease were compared to healthy controls (HC, n = 27). MSA patients had either parkinsonian (MSA-P, n = 5) or cerebellar (MSA-C, n = 6) subtypes. RESULTS: Compared to HC, MSA patients had lower heat pain sensitivity, whereas PD patients had reduced NFR threshold. MSA and PD patients did not differ from HC regarding other variables. MSA-P and MSA-C patients did not differ, either. CONCLUSIONS: Impaired sensory discrimination and attention deficits could contribute to the reduced perception of heat pain in MSA, whereas in PD, local changes in spinal excitability or a diminished dopaminergic descending inhibition might impact on the motor efference of the NFR to reduce its threshold to nociceptive afferent information. WHAT DOES THIS STUDY ADD?: This study investigated experimental pain sensitivity at an early stage in MSA and PD.

Rapid eye movement sleep behavior disorder: devising controlled active treatment studies for symptomatic and neuroprotective therapy--a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group.

OBJECTIVES: We aimed to provide a consensus statement by the International Rapid Eye Movement Sleep Behavior Disorder Study Group (IRBD-SG) on devising controlled active treatment studies in rapid eye movement sleep behavior disorder (RBD) and devising studies of neuroprotection against Parkinson disease (PD) and related neurodegeneration in RBD. METHODS: The consensus statement was generated during the fourth IRBD-SG symposium in Marburg, Germany in 2011. The IRBD-SG identified essential methodologic components for a randomized trial in RBD, including potential screening and diagnostic criteria, inclusion and exclusion criteria, primary and secondary outcomes for symptomatic therapy trials (particularly for melatonin and clonazepam), and potential primary and secondary outcomes for eventual trials with disease-modifying and neuroprotective agents. The latter trials are considered urgent, given the high conversion rate from idiopathic RBD (iRBD) to Parkinsonian disorders (i.e., PD, dementia with Lewy bodies [DLB], multiple system atrophy [MSA]). RESULTS: Six inclusion criteria were identified for symptomatic therapy and neuroprotective trials: (1) diagnosis of RBD needs to satisfy the International Classification of Sleep Disorders, second edition, (ICSD-2) criteria; (2) minimum frequency of RBD episodes should preferably be ⩾2 times weekly to allow for assessment of change; (3) if the PD-RBD target population is included, it should be in the early stages of PD defined as Hoehn and Yahr stages 1-3 in Off (untreated); (4) iRBD patients with soft neurologic dysfunction and with operational criteria established by the consensus of study investigators; (5) patients with mild cognitive impairment (MCI); and (6) optimally treated comorbid OSA. Twenty-four exclusion criteria were identified. The primary outcome measure for RBD treatment trials was determined to be the Clinical Global Impression (CGI) efficacy index, consisting of a four-point scale with a four-point side-effect scale. Assessment of video-polysomnographic (vPSG) changes holds promise but is costly and needs further elaboration. Secondary outcome measures include sleep diaries; sleepiness scales; PD sleep scale 2 (PDSS-2); serial motor examinations; cognitive indices; mood and anxiety indices; assessment of frequency of falls, gait impairment, and apathy; fatigue severity scale; and actigraphy and customized bed alarm systems. Consensus also was established for evaluating the clinical and vPSG aspects of RBD. End points for neuroprotective trials in RBD, taking lessons from research in PD, should be focused on the ultimate goal of determining the performance of disease-modifying agents. To date no compound with convincing evidence of disease-modifying or neuroprotective efficacy has been identified in PD. Nevertheless, iRBD patients are considered ideal candidates for neuroprotective studies. CONCLUSIONS: The IRBD-SG provides an important platform for developing multinational collaborative studies on RBD such as on environmental risk factors for iRBD, as recently reported in a peer-reviewed journal article, and on controlled active treatment studies for symptomatic and neuroprotective therapy that emerged during the 2011 consensus conference in Marburg, Germany, as described in our report.

DTI reveals hypothalamic and brainstem white matter lesions in patients with idiopathic narcolepsy.

BACKGROUND: Symptomatic narcolepsy is often related to hypothalamic, pontine, or mesencephalic lesions. Despite evidence of disturbances of the hypothalamic hypocretin system in patients with idiopathic narcolepsy, neuroimaging in patients with idiopathic narcolepsy revealed conflicting results and there is limited data on possible structural brain changes that might be associated with this disorder. METHODS: We investigated with diffusion tensor imaging (DTI) whether microstructural abnormalities in the brain of eight patients with idiopathic narcolepsy with cataplexy are detectable compared to 12 healthy controls using a 1.5T MRI scanner. Whole-head DTI scans were analyzed without an a priori hypothesis. Voxelwise statistical analysis of fractional anisotropy (FA) data was performed using Tract-Based Spatial Statistics (TBSS), a non-linear analysis approach. RESULTS: Patients with narcolepsy showed microstructural white matter changes in the right hypothalamus as well as in the left mesencephalon, pons, and medulla oblongata. Additionally, areas in the left temporal lobe, the pre- and postcentral gyrus, the frontal and parietal white matter, the corona radiata, the right internal capsule, and the caudate nucleus had altered microstructure in patients with narcolepsy. CONCLUSIONS: Our study shows widespread microstructural white matter changes that are not visible on conventional MRI scans in patients with idiopathic narcolepsy. In support of the evidence from patients with symptomatic narcolepsy, we found microstructural changes in the hypothalamus, mesencephalon, pons, and medulla oblongata. Changes are in accordance with disturbances of the hypothalamic hypocretin system and its projections to mesencephalic and pontine areas regulating REM sleep.

Chronic non-bacterial osteomyelitis is associated with impaired Sp1 signaling, reduced IL10 promoter phosphorylation, and reduced myeloid IL-10 expression.

Chronic non-bacterial osteomyelitis (CNO) is an auto-inflammatory disorder that affects the skeletal system. Interleukin (IL-)10 is an immune-modulatory cytokine that controls inflammation, and limits inflammatory cytokine responses. Dysregulation of IL-10 expression has been shown to result in autoimmune and infectious diseases. We investigated IL-10 expression by monocytic cells from CNO patients and controls. In response to stimulation with LPS, IL-10 expression from CNO monocytes was reduced (p<0.001). This was independent of IL10 promoter polymorphisms. Thus, we investigated Sp1 recruitment to the IL10 promoter and saw markedly reduced binding in CNO monocytes. This was accompanied with reduced phosphorylation of histone H3 serine 10 (H3S10), an activating epigenetic mark. Impaired recruitment of Sp1 to the IL10 promoter, and reduced H3S10 phosphorylation, may be a reflection of deficient MAPK signaling in CNO monocytes in response to LPS stimulation. Thus, we have discovered a mechanism that may be central in the pathophysiology of CNO.

Parasympathetic but not sympathetic cardiac dysfunction at early stages of Parkinson's disease.

BACKGROUND: Autonomic cardiovascular dysfunction is common in Parkinson's disease (PD). Imaging studies suggest loss of cardiac sympathetic nerves even in the absence of clinical signs of autonomic dysfunction. Aim of the study was to investigate the functional significance of autonomic cardiovascular denervation at early stages of PD. METHODS: Seven PD patients (Hoehn and Yahr class 1 or 1.5) without clinical signs of autonomic dysfunction and seven age-matched healthy control subjects were studied. To evaluate the pre- and post-synaptic components of sympathetic innervation, dose-response curves of isoproterenol (no neuronal uptake) and epinephrine (neuronal uptake) on heart rate, contractility, cardiac output and systemic vascular resistance were determined echocardiographically. Additionally, measurements of baroreflex sensitivity and 24-h heart rate variability were done. RESULTS: The chronotropic and inotropic responses during stimulation with isoproterenol and epinephrine were similar in PD patients and control subjects. Assessment of baroreflex sensitivity yielded no difference. Of the parameters of 24-h heart rate variability, only measures of high-frequency heart rate variation that more purely reflect parasympathetic activity were significantly depressed in PD patients as compared with control subjects. CONCLUSIONS: The results of our study using direct determination of catecholamine-mediated chronotropic and contractile responses provide evidence against a functionally relevant sympathetic dysfunction. Possibly, sympathetic denervation is incomplete and the remaining fibers are sufficient for the maintenance of autonomic control. In contrast, the depression of several parameters of heart rate variability supports a significant change of parasympathetic activity at an early stage of PD with subclinical autonomic failure.

No significance of the COMT val158met polymorphism in restless legs syndrome.

The catechol-O-methyltransferase (COMT) val(158)met polymorphism, which codes for the substitution of valine (val) by methionine (met) leading to a reduced COMT activity in homo- or heterozygous individuals, is associated with individual pain sensitivity and dopaminergic responses in Parkinson's disease as well as with various chronic painful diseases. Recent investigations support the notion of an alteration of the medial pain pathway as well as of the descending inhibitory control system in restless legs syndrome (RLS), that both involve dopaminergic transmission as well. Thus, the distribution of the COMT val(158)met polymorphism was assessed in 298 RLS patients and compared with 135 healthy controls in relation to sex, age of onset and family history. The data revealed no significant differences in the distribution of the COMT val(158)met polymorphism in RLS patients compared with the control group, also when the heterozygous and the homozygous group containing the (158)met allele were combined. In addition, sex, age of onset and family history were not associated with the COMT val(158)met polymorphism in this German population of RLS patients. The present study adds to previous mostly negative investigations on the genetic determination of dopaminergic transmission in RLS, which have - so far - only detected an association of the MAO-A activity and RLS in females in a French-Canadian population. Further investigations assessing the different COMT haplotypes and experimental and clinical parameters are nevertheless warranted.

IL10 promoter polymorphisms are associated with systemic onset juvenile idiopathic arthritis (SoJIA).

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a rare, but severe cause of childhood disability. Systemic onset JIA (SoJIA) accounts for approximately 5.8% of all JIA cases and is associated with cytokine dysregulation, including interleukin (IL-)1, IL-6 and tumour necrosis factor (TNF-)α. IL-10 is an immuno-regulatory cytokine, which in part regulates inflammation by controlling inflammatory cytokine expression. Dysregulation in IL-10 expression and certain single nucleotide polymorphisms (SNPs) in the IL-10 promoter were shown to be associated with autoimmune and infectious diseases. METHODS: Genomic DNA-samples from SoJIA patients from two German Paediatric Rheumatology centres, and healthy controls were analysed for three well defined IL-10 promoter SNPs (-1082G>A, -819C>T, and -592C>A). These SNPs are in tight linkage disequilibrium, and result in three predominant (or 'classical') haplotypes: ATA, ACC, and GCC. ATA and ACC are associated with low and medium, GCC is associated with high IL-10 expression. RESULTS: Here, we show a strong association of IL-10 promoter polymorphisms with SoJIA. We demonstrate a significantly increased frequency of low IL-10 expressing -1082A/A alleles, the medium IL-10 expressing ACC haplotype (p=0.01), and an enrichment of the rare GTC haplotype (p<0.001) in patients with SoJIA. Heterozygous -1082G/A alleles (p<0.001), and the GCC haplotype (p<0.001) on one allele protect from developing SoJIA. CONCLUSIONS: This suggests a central role of the immuno-regulatory cytokine IL-10 in the pathogenesis of SoJIA.

Pain sensitivity and descending inhibition of pain in Parkinson's disease.

BACKGROUND: Patients suffering from Parkinson's disease (PD) often complain about painful sensations. Recent studies detected increased subjective pain sensitivity and increased spinal nociception, which appeared to be reversible by dopaminergic treatment. Possibly, reduced descending pain inhibition contributes to this finding. OBJECTIVE: Subjective pain thresholds as well as nociceptive reflex thresholds were investigated to isolate potential loci of the pathophysiological changes within the pain pathway. In addition, the diffuse noxious inhibitory control (DNIC) system as one form of descending control was assessed. METHOD: 15 patients with PD and 18 controls participated in the study. Electrical and heat pain thresholds as well as the nociceptive flexion reflex (NFR) thresholds were determined. Thereafter, the electrical pain thresholds were measured once during painful heat stimulation (conditioning stimulation) and twice during innocuous stimulation (control stimulation). RESULTS: Patients with PD exhibited lower electrical and heat pain thresholds as well as lower NFR thresholds. Suppression of the electrical pain thresholds during painful heat stimulation (conditioning stimulation) compared with control stimulation did not differ significantly between the groups. No differences in the thresholds between patients with PD with and without clinical pain were seen. CONCLUSIONS: Finding the NFR threshold to be decreased in addition to the decreased electrical and heat pain thresholds indicates that the pathophysiological changes either already reside at or reach down to the spinal level. Reduced activation of the DNIC system was apparently not associated with increased pain sensitivity, suggesting that DNIC-like mechanisms do not significantly contribute to clinical pain in PD.

[Atypical Parkinson syndromes]. / Atypische Parkinson-Syndrome.

At the moment atypical Parkinson syndromes have unfavorable prognoses and show little response to dopaminergic medication. Early differential diagnosis of these disorders from idiopathic Parkinson syndrome is of pivotal clinical relevance. In case of future causal, neuroprotective therapeutic strategies, early diagnosis will allow a timely start of therapy. In the early stage of disease, it might be difficult clinically to distinguish multiple system atrophy, progressive supranuclear palsy, and corticobasal ganglionic degeneration from idiopathic Parkinson syndrome. Additional electrophysiological, imaging, and nuclear medical investigations may support the clinical diagnosis. During disease progression clinical signs indicative of an atypical Parkinson syndrome should always warrant reevaluation of the diagnosis.

Clinical risk-benefit assessment of dopamine agonists.

Dopamine agonists (DAs) have proven efficacy as monotherapy in early Parkinson's disease (PD) for preventing motor complications such as dyskinesia and as adjunct therapy as the disease progresses. Further, it is increasingly evident that at least some DAs may provide additional benefits, such as reduction in depressive symptoms and treatment of refractory tremor. Different side-effect profiles have been associated with levodopa and ergot or non-ergot DA treatment, such as sudden onset of sleep, reduced impulse control, hallucination, and cardiovascular fibrosis. This paper discusses the evidence for specific associations between particular treatments and side effects as well as the clinical implications for patient care. Ultimately, the choice depends on the risk-benefit assessment as it applies to the individual patient's clinical profile and the physician's preference.

Immunophenotyping in Tourette syndrome--a pilot study.

BACKGROUND AND PURPOSE: The cause of Tourette syndrome (TS) is not precisely known, although several lines of evidence point at an involvement of the immune system in its pathogenesis. RESULTS: Here, we report the results of a pilot study investigating frequently analysed lymphocyte surface markers in 20 adult patients with TS (16 males; 37.3 +/- 15.8 years) and 20 matched controls (16 males; 37.5 +/- 15.3 years). Statistical analysis revealed significant differences for the investigated lymphocyte surface markers. The difference in CD69+/CD22+-B cells (23.0 +/- 10.5% vs. 13.1 +/- 6.1%; P = 0.001) and in CD95+/CD4+-T cells (41.5 +/- 12.1% vs. 24.6 +/- 10.0%; P = 0.0001) was still significant after Bonferroni-Holm correction. CONCLUSION: Our preliminary data indicate that TS may be associated with an increased peripheral immune activity.

The prevalence of the G2019S and R1441C/G/H mutations in LRRK2 in German patients with Parkinson's disease.

BACKGROUND AND PURPOSE: The prevalence of the heterozygous G2019S and R1441C/G/H mutations in LRRK2 in patients with Parkinson's disease (PD) has shown a great variability depending on the sample population. Here we investigated the prevalence of these mutations in a large cohort of German PD patients (n = 1049). RESULTS: We observed heterozygous G2019S mutations in five patients with apparently sporadic late-onset PD (LOPD; n = 3) and young-onset PD (YOPD) (one sporadic and one familial), respectively, resulting in an overall prevalence of 0.5%. No R1441C/G/H mutation was found in our sample. DISCUSSION: In summary, the overall prevalence of the G2019S mutation in German PD patients is apparently somewhat lower than in patients from other nearby European countries. In contrast to previous reports, the G2019S mutation was also observed in apparently sporadic German LOPD patients.

Olfactory dysfunction in patients with narcolepsy with and without REM sleep behaviour disorder.

Patients with idiopathic rapid eye movement sleep behaviour disorder (RBD) frequently develop Parkinson's disease and the majority present with hyposmia, which is a potential preclinical non-motor sign of Parkinson's disease. Accordingly, it has been proposed that the clinical symptoms of hyposmia and RBD in combination have to be considered as very early symptoms of Parkinson's disease. Since not only patients with idiopathic RBD but also patients in whom RBD is associated with narcolepsy present with an olfactory dysfunction we investigated if hyposmia in RBD patients with concomitant narcolepsy is RBD specific or if narcolepsy per se is associated with olfactory dysfunction. We studied olfactory function in 20 narcoleptic patients each with RBD (9 male and 11 female; mean age 45.4 +/- 14.0 years, range 20-75 years) and without associated RBD (8 male and 12 female; mean age 44.4 +/- 13.40 years, range 20-70 years) and 40 age- and gender-matched healthy control subjects using standardized 'Sniffin' Sticks'. Both, narcoleptics with (Narc/+RBD) and without RBD (Narc/-RBD) had a significantly higher olfactory threshold (Narc/+RBD, P = 0.0001; Narc/-RBD, P = 0.0001), lower discrimination scores (P = 0.001; P = 0.014) and lower identification scores (P = 0.057; P = 0.003) than controls. There were no symptoms or signs for early parkinsonism in both patient groups. Our results show for the first time that narcolepsy per se is associated with olfactory dysfunction. In contrast to patients with idiopathic RBD, hyposmia in patients with RBD associated with narcolepsy is unlikely to be a predictor for developing parkinsonism.

CNS involvement in hereditary neuropathy with pressure palsies (HNPP).

We assessed seven patients with hereditary neuropathy with liability to pressure palsies (HNPP) with 16 electrophysiological tests and cranial MRI for CNS abnormalities. Mean latencies differed between patients with HNPP and controls for the blink reflex, the jaw-opening reflex, and acoustic evoked potentials. MRI abnormalities were observed in four patients. Our study suggests subclinical but functionally relevant CNS myelin damage in HNPP.

The alpha-synuclein gene in multiple system atrophy.

BACKGROUND: The formation of alpha-synuclein aggregates may be a critical event in the pathogenesis of multiple system atrophy (MSA). However, the role of this gene in the aetiology of MSA is unknown and untested. METHOD: The linkage disequilibrium (LD) structure of the alpha-synuclein gene was established and LD patterns were used to identify a set of tagging single nucleotide polymorphisms (SNPs) that represent 95% of the haplotype diversity across the entire gene. The effect of polymorphisms on the pathological expression of MSA in pathologically confirmed cases was also evaluated. RESULTS AND CONCLUSION: In 253 Gilman probable or definite MSA patients, 457 possible, probable, and definite MSA cases and 1472 controls, a frequency difference for the individual tagging SNPs or tag-defined haplotypes was not detected. No effect was observed of polymorphisms on the pathological expression of MSA in pathologically confirmed cases.

The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA Study Group.

The recent identification of fragile X-associated tremor ataxia syndrome (FXTAS) associated with premutations in the FMR1 gene and the possibility of clinical overlap with multiple system atrophy (MSA) has raised important questions, such as whether genetic testing for FXTAS should be performed routinely in MSA and whether positive cases might affect the specificity of current MSA diagnostic criteria. We genotyped 507 patients with clinically diagnosed or pathologically proven MSA for FMR1 repeat length. Among the 426 clinically diagnosed cases, we identified four patients carrying FMR1 premutations (0.94%). Within the subgroup of patients with probable MSA-C, three of 76 patients (3.95%) carried premutations. We identified no premutation carriers among 81 patients with pathologically proven MSA and only one carrier among 622 controls (0.16%). Our results suggest that, with proper application of current diagnostic criteria, FXTAS is very unlikely to be confused with MSA. However, slowly progressive disease or predominant tremor are useful red flags and should prompt the consideration of FXTAS. On the basis of our data, the EMSA Study Group does not recommend routine FMR1 genotyping in typical MSA patients.

Pharmacotherapy of Parkinson's disease in Germany.

Treatment standards or guidelines have been developed for most features of Parkinson's disease (PD). However, data on the actual treatment that is put into practice are scarce. In 2000, a nationwide survey on the topic of sudden onset of sleep (SOS) in PD was initiated among the members of the German patient support group (deutsche Parkinson-Vereinigung, dPV). A part of this mailed questionnaire survey covering the antiparkinsonian and concomitant medication of the participants is presented here. This study analyses data sets from more than 6,500 PD patients. The mean dopaminergic dose was equivalent to 599 +/- 387 mg levodopa/die. The most frequently administered drugs were levodopa (94.2 %), dopamine agonists (DA) (71.7 %), amantadine (40.1 %), selegiline (27.6 %), entacapone (20.4 %), budipine (12.3 %), and anticholinergics (11.8 %). Costs of pharmacotherapy were estimated to be approximately 399 million/year in Germany. PD drug therapy in general strongly depended on age, disease duration, and the level of care. The treatment guidelines were apparently not consistently followed underlining the need for their continuous propagation throughout the medical community. In addition our data suggest that non-motor symptoms in PD are not adequately treated and that concomitant sedative medication contributes to the occurrence of SOS.

Combination of 'idiopathic' REM sleep behaviour disorder and olfactory dysfunction as possible indicator for alpha-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT.

REM sleep behaviour disorder (RBD) and olfactory dysfunction are common and very early features of alpha-synucleinopathies, in particular Parkinson's disease. To investigate the hypothesis that these two clinical features in combination are an indicator of evolving alpha-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 alpha-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.