David Vadasz

Intravenous iron sucrose for restless legs syndrome in pregnant women with low serum ferritin

We report on two pregnant women who either had de novo restless legs syndrome (RLS) or had marked enhancement of preexisting RLS symptoms during pregnancy. Both patients had ferritin values <50 μg/L at baseline. The patients had relevant sleep disorders and daytime symptoms caused by RLS. The women were treated in an open paradigm with intravenous iron sucrose. A few weeks after therapy, both patients experienced a significant reduction or even remission of RLS symptoms. Their quality of life and sleep substantially improved and no treatment-related adverse effects were observed. According to our initial experience, intravenous iron sucrose administration appears to be an effective therapy in RLS patients with low ferritin values during pregnancy.

FDG PET, Dopamine Transporter SPECT, and Olfaction: Combining Biomarkers in REM Sleep Behavior Disorder

Idiopathic REM sleep behavior disorder is a prodromal stage of Parkinsons disease and dementia with Lewy bodies. Hyposmia, reduced dopamine transporter binding, and expression of the brain metabolic PD‐related pattern were each associated with increased risk of conversion to PD. The objective of this study was to study the relationship between the PD‐related pattern, dopamine transporter binding, and olfaction in idiopathic REM sleep behavior disorder.

The PD-associated alpha-synuclein promoter Rep1 allele 2 shows diminished frequency in restless legs syndrome

Gain-of-function mutations of alpha-synuclein (SNCA) are known to trigger Parkinson’s disease (PD) with striatal dopaminergic deficits and a reduction of spontaneous movements. The longest size variant (allele 2) of the complex microsatellite repeat Rep1 within the SNCA gene promoter is known to confer a PD risk. We now observed this Rep1 allele 2 to show significantly decreased frequency in restless legs syndrome (RLS) in a genotyping study of 258 patients versus 235 healthy controls from Germany. Given that RLS is a disease with increased spontaneous movements and with increased striatal dopamine signaling, these novel data appear plausible. The scarcity of this alpha-synuclein gain-of-function variant in RLS might suggest that a low alpha-synuclein function via the SNARE complex in presynaptic vesicle release and neurotransmission of the striatum contributes to RLS pathogenesis.

Blood RNA biomarkers in prodromal PARK4 and rapid eye movement sleep behavior disorder show role of complexin 1 loss for risk of Parkinson's disease

ABSTRACT Parkinsons disease (PD) is a frequent neurodegenerative process in old age. Accumulation and aggregation of the lipid-binding SNARE complex component α-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity have been intensely investigated. In view of the physiological roles of SNCA in blood to modulate vesicle release, we studied blood samples from a new large pedigree with SNCA gene duplication (PARK4 mutation) to identify effects of SNCA gain of function as potential disease biomarkers. Downregulation of complexin 1 (CPLX1) mRNA was correlated with genotype, but the expression of other Parkinsons disease genes was not. In global RNA-seq profiling of blood from presymptomatic PARK4 indviduals, bioinformatics detected significant upregulations for platelet activation, hemostasis, lipoproteins, endocytosis, lysosome, cytokine, Toll-like receptor signaling and extracellular pathways. In PARK4 platelets, stimulus-triggered degranulation was impaired. Strong SPP1, GZMH and PLTP mRNA upregulations were validated in PARK4. When analysing individuals with rapid eye movement sleep behavior disorder, the most specific known prodromal stage of general PD, only blood CPLX1 levels were altered. Validation experiments confirmed an inverse mutual regulation of SNCA and CPLX1 mRNA levels. In the 3′-UTR of the CPLX1 gene we identified a single nucleotide polymorphism that is significantly associated with PD risk. In summary, our data define CPLX1 as a PD risk factor and provide functional insights into the role and regulation of blood SNCA levels. The new blood biomarkers of PARK4 in this Turkish family might become useful for PD prediction. Summary: Complexin 1 is a prodromal biomarker and risk factor for REM sleep behavior disorder and PARK4-associated Parkinsons disease.

The metabolic pattern of idiopathic REM sleep behavior disorder reflects early-stage Parkinson's disease

Idiopathic REM sleep behavior disorder (iRBD) is considered a prodromal stage of Parkinson disease (PD) and other Lewy body disorders. Spatial covariance analysis of 18F-FDG PET data has disclosed a specific brain pattern of altered glucose metabolism in PD. In this study, we identify the metabolic pattern underlying iRBD and compare it with the known PD pattern. To understand the relevance of the iRBD pattern to disease progression, we studied the expression of the iRBD pattern in de novo PD patients. Methods: The iRBD-related pattern was identified in 18F-FDG PET scans of 21 patients with polysomnographically confirmed iRBD and 19 controls using spatial covariance analysis. Expression of the iRBD-related pattern was subsequently computed in 18F-FDG PET scans of 44 controls and 38 de novo, treatment-naïve PD patients. Of these 38 PD patients, 24 had probable REM sleep behavior disorder (RBD) according to the Mayo Sleep Questionnaire. Neuropsychologic evaluation showed mild cognitive impairment in 20 PD patients (PD-MCI), of whom 16 also had concomitant RBD and roughly half (11/20) had bilateral motor symptoms. Results: The iRBD-related pattern was characterized by relative hypermetabolism in the cerebellum, brain stem, thalamus, sensorimotor cortex, and hippocampus, and by relative hypometabolism in the middle cingulate, temporal, occipital, and parietal cortices. This topography partially overlapped with the PD-related pattern (PDRP). The iRBD-related pattern was significantly expressed in PD patients compared with controls (P < 0.0001). iRBD-related pattern expression was not significantly different between PD patients with and without probable RBD, or between PD patients with unilateral or bilateral parkinsonism. iRBD-related pattern (iRBDRP) expression was higher in PD-MCI patients than in PD patients with preserved cognition (P = 0.001). Subject scores on the iRBD-related pattern were highly correlated to subject scores on the PDRP (r = 0.94, P < 0.0001). Conclusion: Our results show that the iRBDRP is an early manifestation of the PDRP. Expression of both PDRP and iRBDRP was higher in patients with a more severe form of PD (PD-MCI), which indicates that expression of the 2 patterns increases with disease severity.

Is increased spinal nociception another hallmark for Parkinson’s disease?

Augmented spinal nociception during the “off” phase has been observed early in Parkinson’s disease further increasing with disease duration. To find out whether increased spinal nociception represents a premotor feature, experimental pain sensitivity was assessed in idiopathic REM-sleep behavior disorder (IRBD) patients with or without signs of a neurodegenerative disorder compared to early Parkinson’s disease (ePD) patients and healthy controls (HC). Spinal nociception as measured by the nociceptive flexion reflex (NFR) and experimental pain sensitivity as measured by heat and electrical pain thresholds were determined in 14 IRBD, 15 ePD patients in the medication-defined “off” state and 27 HC in an explorative cohort study. No significant differences between IRBD and HC were found with regard to spinal nociception (NFR) and experimental pain sensitivity. However, IRBD patient with anosmia and/or abnormal DaTSCAN tended to increased experimental pain sensitivity. In contrast, early PD patients exhibited increased NFR responses compared to HC, and a tendency for increased spinal nociception compared to IRBD patients. Increased spinal nociception may represent an early but not a premotor, non-motor feature of PD. Whether increased pain sensitivity already presents a premotor feature should be assessed in further studies.