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The composition of the gut microbiome is linked to multiple diseases, including Parkinson’s disease (PD). Bacteria producing short-chain fatty acids (SCFAs) and fecal SCFA concentrations are reduced in PD. SCFAs exert various beneficial functions in humans. In the interventional, monocentric, open-label clinical trial RESISTA-PD (NCT02784145) we aimed at altering fecal SCFAs by an 8-week prebiotic intervention with resistant starch (RS). We enrolled 87 subjects in three study-arms: 32 PD patients receiving RS (PD + RS), 30 control subjects receiving RS, and 25 PD patients receiving solely dietary instructions. We performed paired-end 100 base pair length metagenomic sequencing of fecal samples using the BGISEQ platform at an average of 9.9 GB. RS was well-tolerated. In PD + RS, fecal butyrate concentrations increased significantly and fecal calprotectin concentrations dropped significantly after 8 weeks of RS. Clinically, we observed a reduction in non-motor symptoms load in PD + RS. The reference-based analysis of metagenomes highlighted stable alpha-diversity and beta-diversity across the three groups, including bacteria producing SCFAs. Reference-free analysis suggested punctual, yet pronounced differences in the metagenomic signature in PD + RS. RESISTA-PD highlights that a prebiotic treatment with RS is safe and well-tolerated in PD. The stable alpha-diversity and beta-diversity alongside altered fecal butyrate and calprotectin concentrations calls for long-term studies, also investigating whether RS is able to modify the clinical course of PD.

Background: Altered gastric motility is a frequent non-motor symptom of Parkinson’s disease (PD). It has been hypothesized that disturbed gastric motility contributes to motor fluctuations in PD due to an erratic gastro-duodenal transport and an unpredictable absorption of drugs. Objective: We investigated whether patient-reported fluctuations are associated with parameters of gastric motility visualized by real-time magnetic resonance imaging (MRI) of the stomach. Methods: We analyzed real-time MRI-scans of the stomach after an overnight fasting period in 16 PD patients and 20 controls. MRI was performed 1) in the fasting state, 2) directly after a test meal, and 3) 4 hours postprandially. Gastric motility indices were calculated and compared between groups. Results: MRI showed an attenuated gastric motility in PD patients compared to controls. The difference was most obvious in the early postprandial phase. Gastric motility was not associated with patient-reported motor fluctuations. Using an iron-containing capsule we were able to retrace retention of drugs in the stomach. Conclusion: The results of this study stress the importance of considering the phase of digestion when investigating gastric motility in PD. Despite theoretical considerations, we did not find robust evidence for an association between MRI parameters of gastric motility and patient-reported motor fluctuations. For future studies that aim to investigate gastric motility in PD by MRI, we suggest multiple short-time MRIs to better track the whole gastro-duodenal phase in PD. Such an approach would also allow to retrace the retention of drugs in the stomach as shown by our approach using an iron-containing capsule.

Seit einigen Jahren mehren sich Studien, die einen Zusammenhang zwischen dem idiopathischen Parkinson-Syndrom (IPS) und dem (Darm‑)Mikrobiom nahelegen. Der vorliegende Artikel fasst die wichtigsten Erkenntnisse zur Interaktion zwischen dem IPS und dem (Darm‑)Mikrobiom zusammen und bewertet sie. Es erfolgte eine kritische zusammenfassende Betrachtung von Studien im Bereich Parkinson und Mikrobiom. Sich daraus ergebende potenzielle Handlungsstrategien werden diskutiert. Trotz im Detail divergierender Ergebnisse zwischen den einzelnen Studien (z. T. zuruckzufuhren auf unterschiedliche Methodik und Zusammensetzung des untersuchten Kollektivs) zeigt sich eine Assoziation zwischen dem IPS und dem Mikrobiom bzw. mikrobiellen Metaboliten. Dennoch ist die Ursache-Wirkungs-Beziehung zwischen dem IPS und dem Mikrobiom bislang nicht geklart. In der Gesamtbetrachtung sprechen die Ergebnisse fur eine mogliche Relevanz des Mikrobioms sowohl fur krankheitstypische Symptome als auch fur die Pathogenese der Erkrankung. Die Evidenz in Bezug auf die Relevanz des Mikrobioms fur das IPS ist in den zuruckliegenden 5 Jahren deutlich gewachsen. Wahrend die ersten Arbeiten auf diesem Gebiet noch vorwiegend deskriptiven Charakter hatten, ermoglichen neue diagnostische Methoden inzwischen ein besseres Verstandnis der Mechanismen und der komplexen Interaktionen zwischen dem Mensch als Wirt, dem menschlichen Immunsystem, dem enterischen Nervensystem, dem Darmmikrobiom und mikrobiellen Metaboliten. Ein relativ neues und klinisch bedeutsames Forschungsfeld ist auch, wie das Darmmikrobiom den Erfolg einer oralen Pharmakotherapie beeinflussen kann bzw. ob spezifische Eingriffe in das Mikrobiom therapeutisch oder prophylaktisch eingesetzt werden konnen.

Background There is increasing evidence that Parkinson’s disease (PD) might start in the gut, thus involving and compromising also the enteric nervous system (ENS). At the clinical onset of the disease the majority of dopaminergic neurons in the midbrain is already destroyed, so that the lack of early biomarkers for the disease represents a major challenge for developing timely treatment interventions. Here, we use a transgenic A30P-α-synuclein-overexpressing PD mouse model to identify appropriate candidate markers in the gut before hallmark symptoms begin to manifest. Methods Based on a gait analysis and striatal dopamine levels, we defined 2-month-old A30P mice as pre-symptomatic (psA30P), since they are not showing any motoric impairments of the skeletal neuromuscular system and no reduced dopamine levels, but an intestinal α-synuclein pathology. Mice at this particular age were further used to analyze functional and molecular alterations in both, the gastrointestinal tract and the ENS, to identify early pathological changes. We examined the gastrointestinal motility, the molecular composition of the ENS, as well as the expression of regulating miRNAs. Moreover, we applied A30P-α-synuclein challenges in vitro to simulate PD in the ENS. Results A retarded gut motility and early molecular dysregulations were found in the myenteric plexus of psA30P mice. We found that i.e. neurofilament light chain, vesicle-associated membrane protein 2 and calbindin 2, together with the miRNAs that regulate them, are significantly altered in the psA30P, thus representing potential biomarkers for early PD. Many of the dysregulated miRNAs found in the psA30P mice are reported to be changed in PD patients as well, either in blood, cerebrospinal fluid or brain tissue. Interestingly, the in vitro approaches delivered similar changes in the ENS cultures as seen in the transgenic animals, thus confirming the data from the mouse model. Conclusions These findings provide an interesting and novel approach for the identification of appropriate biomarkers in men.

Background. Multiple Sclerosis (MS) is primarily considered as a neuro-inflammatory CNS disease. Yet, experimental data suggest a role for gut microbiota and microbial products like short chain fatty acids (SCFA) in the pathogenesis of MS. Very recently a high-ranked publication reported beneficial effects of propionate, a SCFA, in MS patients. Based on experimental and preliminary human data, we hypothesized that not only the gut microbiota but also microbial products and fecal inflammatory markers might be altered in MS.Methods. In a pilot study, we investigated fecal markers (short chain fatty acids, calprotectin) as well as clinical markers in patients with relapsing-remitting MS (RRMS) under different therapeutic regimes and compared the results to age-matched control subjects.Results. We observed a non-significant reduction in fecal SCFA in RRMS patients compared to control subjects. Fecal calprotectin concentrations did not differ significantly between MS patients and control subjects. We observed a significant reduction in fecal SCFA concentrations in women compared to men.Conclusions. We conclude that the observed sex-associated difference in fecal SCFA concentrations might be a contributing factor in the pathogenesis of MS, especially when taking into account the female predominance in MS. We suggest investigating the role of SCFA in MS in a longitudinal study (starting in drug-naïve patients) in larger cohorts of MS patients with defined therapeutic regimes. Such a study would allow to distinguish between drug effects and disease-immanent effects and might help to identify a potentially modifiable sex-associated contributing factor in MS.Trial registration. Registered by the local Ethics Committee (Reg.Nr. 81/18, Ethikkommission der Aerztekammer des Saarlandes, Saarbruecken, Germany).

In this retrospective study, we explored the clinical and stroke characteristics of patients treated with thrombolysis and/or mechanical thrombectomy for an acute stroke and experiencing early poststroke seizures within 7 days of the cerebrovascular accident. Patients with prior epilepsy, primary intracerebral hemorrhage or transient ischemic attacks, or taking antiepileptic drugs were excluded. We retrospectively identified 32 patients admitted between 2010 and 2016 (mean age 75 years; range: 49–90; 14 females and 18 males). A cortical stroke was found in more than 70% of patients. Most epileptic seizures were focal aware (46.7%) or generalized convulsive (43.3%). The median time between stroke onset and seizure occurrence was 2 days; in 75.9% of the cases, seizures occurred within the first 3 days. This retrospective case series is the largest published so far providing details on clinical features of patients with early poststroke seizures following different reperfusion therapies, not only restricted to intravenous (i.v.) thrombolysis. Early poststroke seizures following reperfusion therapies are associated with cortical stroke involvement, are usually focal without impairment of awareness or generalized convulsive, and occur mostly within the first 3 days. Further studies are needed to clarify whether the low prevalence of focal impaired awareness seizures (and nonconvulsive seizures/status) is real or reflects the failure to recognize and correctly diagnose this seizure type in the acute poststroke period (risk of underascertainment due to the lack of systematic video-electroencephalogram (EEG) recording in patients with stroke and difficulties in recognizing these seizures). This article is part of the Special Issue “Seizures & Stroke”.

Background/Objective Intestinal inflammation and increased intestinal permeability (both possibly fueled by dysbiosis) have been suggested to be implicated in the multifactorial pathogenesis of Parkinson's disease (PD). The objective of the current study was to investigate whether fecal markers of inflammation and impaired intestinal barrier function corroborate this pathogenic aspect of PD. Methods In a case-control study, we quantitatively analyzed established fecal markers of intestinal inflammation (calprotectin and lactoferrin) and fecal markers of intestinal permeability (alpha-1-antitrypsin and zonulin) in PD patients (n = 34) and controls (n = 28, group-matched for age) by enzyme-linked immunosorbent assay. The study design controlled for potential confounding factors. Results Calprotectin, a fecal marker of intestinal inflammation, and two fecal markers of increased intestinal permeability (alpha-1-antitrypsin and zonulin) were significantly elevated in PD patients compared to age-matched controls. Lactoferrin, as a second fecal marker of intestinal inflammation, showed a non-significant trend towards elevated concentrations in PD patients. None of the four fecal markers correlated with disease severity, PD subtype, dopaminergic therapy, or presence of constipation. Conclusions Fecal markers reflecting intestinal inflammation and increased intestinal permeability have been primarily investigated in inflammatory bowel disease so far. Our data indicate that calprotectin, alpha-1-antitrypsin and zonulin could be useful non-invasive markers in PD as well. Even though these markers are not disease-specific, they corroborate the hypothesis of an intestinal inflammation as contributing factor in the pathogenesis of PD. Further investigations are needed to determine whether calprotectin, alpha-1-antitrypsin and zonulin can be used to define PD subgroups and to monitor the effect of interventions in PD.

Background and Purpose— A new generation of carotid artery stents that uses a second micromesh layer to reduce embolic events during carotid artery stenting has recently been introduced. The purpose of this study was to compare acute occlusion rates of these new dual-layer stents with those of single-layer stents in the setting of emergency carotid artery stenting with intracranial mechanical thrombectomy in acute ischemic stroke. Methods— Consecutive patients with acute tandem (intra- and extracranial) lesions of the anterior circulation who were endovascularly treated at our institution were identified from our registry of neuroendovascular interventions. Clinical, angiographic, and neuroimaging data were analyzed. End points included acute occlusions of the carotid stents (within 72 hours after stenting) and symptomatic intracerebral hemorrhage. Results— Forty-seven patients were included. Dual-layer stents (n=20) had a significantly higher rate of acute occlusions than single-layer stents (n=27; 45% versus 3.7%; P =0.001; odds ratio, 21.3; 95% confidence interval, 2.4–188.4). There were no significant differences in the rates of patients who had any antiplatelet or dual antiplatelet medication before admission, in the rates of postinterventional symptomatic intracerebral hemorrhage, the mean National Institutes of Health Stroke Scale scores at admission, or the modified Rankin Scale scores at discharge. Conclusions— The recently introduced dual-layer stents have a higher risk of acute occlusion compared with single-layer stents in the treatment of acute stroke.

The ability to recognize facial emotion expressions has been reported to be impaired in Parkinson's disease (PD), yet previous studies showed inconsistent findings. The aim of this study was to further investigate facial emotion recognition (FER) in PD patients and its association with demographic and clinical parameters (including motor and nonmotor symptoms).Thirty-four nondemented PD patients and 24 age- and sex-matched healthy controls (HC) underwent clinical neurological and neuropsychological assessment, standardized olfactory testing with Sniffin' Sticks, and the Ekman 60 Faces Emotion Recognition Test.PD patients had a significantly lower score on the total FER task than HC (p = .006), even after controlling for the potential confounding factors depression and apathy. The PD group had a specific impairment in the recognition of surprise (p = .007). The recognition of anger approached statistical significance (p = .07). Increasing chronological age and age at disease onset were associated with worse performance on the FER task in PD patients. Olfactory function along with PD diagnosis predicted worse FER performance within all study participants.Facial emotion recognition and especially the recognition of surprise are significantly impaired in PD patients compared with age- and sex-matched HC. The association of FER with age and olfactory function is endorsed by common structures that undergo neurodegeneration in PD. The relevance of FER in social interaction stresses the clinical relevance and the need for further investigation in this field. Future studies should also determine whether impaired FER is already present in premotor stages of PD.

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.

Cognitive impairment and dementia are common in PD; however, no stable marker of cognitive dysfunction is available. Transcranial sonography can evaluate global and focal brain atrophy and has been widely used in the differential diagnosis of parkinsonism.225 consecutive PD patients were recruited in a two-center cross sectional study and underwent a standardized sonographic protocol assessing the third ventricle's width and substantia nigra hyperechogenicity. All subjects were evaluated with an extensive motor and cognitive battery.222 PD patients were included and classified as PD with normal cognition (PDNC; n = 130), mild cognitive impairment (PD-MCI; n = 61) and dementia (PDD; n = 31). Ventricular width correlated strongly with cognitive performance in all cognitive domains (p 0.001) while SN size did not. PDD patients had significantly wider ventricles than PD patients without dementia (p 0.001) while differences between PD-MCI and PDNC or PDD were less strong (p 0.05). There were no group differences in SN size. ROC analyses resulted in age-related cut-offs of third ventricular diameter for the prediction of PDD (6.0 and 7.5 mm for subjects and ≥70 years of age, respectively). These cut-offs significantly differentiated PDD from PDNC (p 0.001) and from all patients without dementia (PDNC + PD-MCI; p 0.001).The third ventricular diameter correlated with cognitive performance in all domains and was able to differentiate PDD patients from those without dementia. Longitudinal studies are warranted to evaluate whether transcranial sonography could identify PD patients at risk for a rapid cognitive decline.

Clinical and histopathological studies indicate involvement of the gastrointestinal tract in idiopathic RBD. Gastrointestinal signs and symptoms as well as histopathological findings in idiopathic RBD resemble findings in Parkinson’s disease.

There are many superficial similarities between diabetes mellitus (DM) and Parkinson disease (PD). In both cases, clinical manifestations are primarily attributable to the decrement and then absence of a biological product (insulin and dopamine) with diminution and ultimately substantial or near-complete loss of cells in specialized tissue that produce the agent. The diseases affect multiple organ systems and can be treated by agonists and by replacement of the agent. Other options include stimulators, tissue transplants, and pumps. But deep down, there are biologically plausible cellular mechanisms that intertwine both of these conditions. Insulin receptors are relatively plentiful in substantia nigra neurons,1 and hyperglycemia suppresses substantia nigra dopaminergic neuronal firing as well as decreases dopamine turnover. Attention has increasingly focused on mitochondria as a link between DM and PD. Insulin resistance has been associated with mitochondrial dysfunction, while MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a toxin that caused numerous cases of parkinsonism, leads to mitochondrial dysfunction. Insulin resistance is associated with decreased genetic expression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1 Alpha), a key regulator of mitochondrial genesis and functioning, with resultant organelle destruction (mitophagy), as well as increased oxidative stress and toxic mitochondrial mutations. Evidence suggests there may be diminished expression of PGC1 Alpha genes in PD as well.2

Objective To assess whether risk factors for Parkinson disease and dementia with Lewy bodies increase rate of defined neurodegenerative disease in idiopathic rapid eye movement (REM) sleep behavior disorder (RBD). Methods Twelve centers administered a detailed questionnaire assessing risk factors for neurodegenerative synucleinopathy to patients with idiopathic RBD. Variables included demographics, lifestyle factors, pesticide exposures, occupation, comorbid conditions, medication use, family history, and autonomic/motor symptoms. After 4 years of follow-up, patients were assessed for dementia or parkinsonism. Disease risk was assessed with Kaplan–Meier analysis, and epidemiologic variables were compared between convertors and those still idiopathic using logistic regression. Results Of 305 patients, follow-up information was available for 279, of whom 93 (33.3%) developed defined neurodegenerative disease. Disease risk was 25% at 3 years and 41% after 5 years. Patients who converted were older (difference = 4.5 years, p

The polypeptide ghrelin is an endogenous ligand at the growth hormone secretagogue receptor 1a. To ghrelin multiple functions have been ascribed including promotion of gastrointestinal motility. Postprandial ghrelin levels have been reported to be reduced in patients suffering from Parkinson disease (PD). Experimental studies revealed neuroprotective effects of ghrelin in different PD models. The purpose of the present study was (i) to further elucidate the mechanism underlying the neuroprotective action of ghrelin and (ii) to determine whether these effects occur with both the acylated and the unacylated form. The study was conducted in primary mesencephalic cultures treated with mitochondrial complex I and complex II inhibitors. We show that protective effects of ghrelin against complex I inhibition with MPP+ were independent of the acylation status of ghrelin, although acylated ghrelin appeared to be more potent. Protection by both forms was also observed when neurons were exposed to the complex II inhibitor 3-NP. Both forms led to higher oxygen consumption rates upon electron transport chain uncoupling, indicating that the two peptides may exert uncoupling effects themselves. We demonstrate that the rescue provided by ghrelin required calcium influx through L-type voltage-gated calcium channels. Whereas the protective effects of acylated ghrelin required receptor binding, effects of the unacylated form remained unaffected by treatment with a ghrelin receptor antagonist. Importantly, inhibition of ghrelin O-acyltransferase failed to reduce the activity of unacylated ghrelin. Overall, our data suggest that both acylated and unacylated ghrelin afford protection to dopamine neurons but through mechanisms that only partially overlap.

Hintergrund Ghrelin und andere Peptidhormone des Gastrointestinaltrakts beeinflussen Stoffwechselprozesse und die Motilitat des Verdauungstraktes. Viele dieser Peptidhormone wirken zusatzlich uber eine Bindung an spezifische Rezeptoren im zentralen Nervensystem (ZNS) auf Prozesse wie Gedachtnisfunktion, Stimmung, Belohnungsverhalten und Schlaf. Die Ausschuttung der Peptidhormone des Gastrointestinaltrakts wird uber unterschiedliche Mechanismen gesteuert. Der N. vagus spielt hierbei eine wichtige Rolle.

Background: Pancreatic polypeptide is released immediately after food ingestion. The release is operated by vagal-abdominal projections and has therefore been suggested as a test for vagal nerve integrity. Pathoanatomical and clinical studies indicate vagal dysfunction in early Parkinson's disease (PD). Methods: We assessed the postprandial secretion of pancreatic polypeptide and motilin in healthy controls (n = 18) and patients with idiopathic rapid-eye-movement sleep behavior disorder (iRBD, n = 10), a potential premotor stage of PD, as well as in drug-naive (n = 19) and treated (n = 19) PD patients. Results: The postprandial pancreatic polypeptide secretion showed a physiological pattern in all groups and even an enhanced response in drug-naive PD and iRBD. Motilin concentrations correlated with pancreatic polypeptide concentrations. Conclusions: Postprandial pancreatic polypeptide secretion is not a suitable test for vagal nerve integrity in PD. The unimpaired pancreatic polypeptide response in iRBD and PD might be explained by partially intact vagal-abdominal projections or compensatory mechanisms substituting a defective neuronal brain–gut axis. © 2012 Movement Disorder Society

Idiopathic REM sleep behavior disorder is a parasomnia characterized by dream enactment and is commonly a prediagnostic sign of parkinsonism and dementia. Since risk factors have not been defined, we initiated a multicenter case-control study to assess environmental and lifestyle risk factors for REM sleep behavior disorder.Cases were patients with idiopathic REM sleep behavior disorder who were free of dementia and parkinsonism, recruited from 13 International REM Sleep Behavior Disorder Study Group centers. Controls were matched according to age and sex. Potential environmental and lifestyle risk factors were assessed via standardized questionnaire. Unconditional logistic regression adjusting for age, sex, and center was conducted to investigate the environmental factors.A total of 694 participants (347 patients, 347 controls) were recruited. Among cases, mean age was 67.7 ± 9.6 years and 81.0% were male. Cases were more likely to smoke (ever smokers = 64.0% vs 55.5%, adjusted odds ratio [OR] = 1.43, p = 0.028). Caffeine and alcohol use were not different between cases and controls. Cases were more likely to report previous head injury (19.3% vs 12.7%, OR = 1.59, p = 0.037). Cases had fewer years of formal schooling (11.1 ± 4.4 years vs 12.7 ± 4.3, p0.001), and were more likely to report having worked as farmers (19.7% vs 12.5% OR = 1.67, p = 0.022) with borderline increase in welding (17.8% vs 12.1%, OR = 1.53, p = 0.063). Previous occupational pesticide exposure was more prevalent in cases than controls (11.8% vs 6.1%, OR = 2.16, p = 0.008).Smoking, head injury, pesticide exposure, and farming are potential risk factors for idiopathic REM sleep behavior disorder.

REM sleep behavior disorder (RBD) is a parasomnia characterized by dream-enactment behavior, diagnosed by clinical history in combination with video-polysomnography to document REM atonia loss. Idiopathic RBD (iRBD) is receiving increased attention as an important risk factor for neurodegenerative diseases, especially alpha-synucleinopathies.2–4 Despite increasing recognition of its importance, knowledge of RBD epidemiology is limited. Except for two studies, which primarily screened for sleep injury (a subtype of RBD)5,6 no large-scale epidemiologic surveys have estimated RBD prevalence. A major barrier to conducting prevalence studies is that RBD is probably uncommon, thus requiring very large epidemiologic surveys. Such large surveys are generally broad, assessing many nonsleep outcomes, with strict limitations upon the time demands upon respondents. This precludes the use of polysomnographic diagnosis and lengthy screening questionnaires. Therefore, simple (i.e., one- or two-question) screens are needed to assess RBD in large-scale epidemiologic surveys. To meet this need, we designed the RBD Single-Question Screen (RBD1Q) a single “yes-no” question that queries the classic dream-enactment behavior of RBD. We present here the validation results of this question, in relation to gold-standard polysomnographic diagnosis, in a 12-center case-control study.

Background: Delayed gastric emptying is a non-motor symptom of Parkinson's disease. Few data exist on gastric emptying in early-stage Parkinson's disease. In idiopathic rapid-eye-movement sleep behavior disorder, a presumable pre-motor stage of Parkinson's disease, gastric emptying has not yet been investigated. Methods: Twenty healthy controls, 13 patients with idiopathic rapid-eye-movement sleep behavior disorder, and 39 patients with Parkinson's disease patients underwent standardized testing for gastric emptying with the 13C-octanoate breath test. Results: Gastric emptying was significantly delayed in drug-naive (P < .001) and in treated Parkinson's disease patients (P < .001), but normal in patients with idiopathic rapid-eye-movement sleep behavior disorder. Conclusions: Our study confirms delayed gastric emptying in drug-naive, early-stage Parkinson's disease. Normal gastric emptying in idiopathic rapid-eye-movement sleep behavior disorder might be explained by the fact that neurodegenerative changes in structures modulating gastric motility are not severe enough to cause a functional deficit that can be detected by the 13C-octanoate breath test. © 2011 Movement Disorder Society

RAPID EYE MOVEMENT (REM) SLEEP BEHAVIOR DISORDER (RBD) IS A REM-PARASOMNIA THAT CLINICALLY PRESENTS WITH NOCTURNAL SPEECH AND motor activity reflecting the dream content of the patient during REM sleep.1,2 Idiopathic RBD (iRBD), i.e., the occurrence of RBD in the absence of other medical (neurologic) conditions, is considered to represent a clinical risk marker, with the—at present—highest positive predictive value for the subsequent development of an α-synucleinopathy, i.e., for Parkinson disease (PD), dementia with Lewy bodies, or multiple system atrophy.3 In the context of evolving PD, iRBD is thought to be an early clinical correlate of a slowly progressing neurodegenerative process in the brainstem. Identification of such a neurodegenerative process with a routinely available technique such as magnetic resonance imaging (MRI) could be of value for the preclinical (premotor) detection of PD and other α-synucleinopathies. During physiologic REM sleep, the activity of spinal α-motor neurons is suppressed by a complex interaction of superordinate brainstem nuclei (REM-on and REM-off areas, including the sublaterodorsal nucleus4). In RBD, this interaction between REM-on and REM-off areas is considered to be disturbed, leading to a disinhibition of spinal α-motor neurons and, subsequently, to movements during the dream phase. The sublaterodorsal nucleus is presumably one major efferent pathway for mediating muscle atonia during REM sleep,5 pointing to the brainstem as a potential area to be investigated for structural changes in iRBD. Until now, structural brain changes have not been described in patients with iRBD. Functional imaging studies have reported normal or conflicting findings: a single-photon emission computed tomography (SPECT) study showed that decreased blood flow in the pons and in the superior frontal lobes of patients with iRBD,6 whereas other studies have confirmed the decreased perfusion in the frontal cortices, they have also found an increased perfusion in the pons, putamina, and right hippocampus.7 SPECT studies using ligands to visualize the presynaptic dopamine transporter have reported that tracer uptake in the striatum is frequently reduced in patients with iRBD.8–11 The latter finding must be interpreted in the context of iRBD as a putative “preclinical (premotor)” stage of the α-synucleinopathy PD, rather than as a finding that directly relates to the disruptive nocturnal behavior of RBD-related pathophysiology. The results of previous magnetic resonance spectroscopy studies are conflicting, reporting either no metabolic changes12 or a pathologic choline/creatine ratio in the brainstem.13 Recently, transcranial sonography has revealed hyperechogenicity in the substantia nigra in a group of patients with iRBD,11,14 a sonographic marker that is seen in 90% of all patients with PD. In summary, in vivo imaging studies have not consistently demonstrated disease-specific structural abnormalities in patients with iRBD. Diffusion tensor imaging (DTI) is a novel MRI technique that enables noninvasive in vivo visualization of brain white-matter microstructure. DTI has been applied successfully to several neurodegenerative disorders, providing insights into the pathophysiology of the respective disorders.15–18 Most DTI studies have focused on fractional anisotropy (FA) as an unspecific summary measure of brain-tissue integrity. More recently, 2 components of the diffusion signal, namely axial diffusivity (AD) and radial diffusivity (RD), have been used to describe different aspects of mechanisms of degeneration. In the current study, the microstructural properties of the brains of patients with iRBD and age-matched healthy volunteers were examined using an automated whole-head analysis of the DTI measures of FA, RD, and AD.

Gastrointestinal motility is frequently affected in Parkinson's disease (PD) and has even been reported in early stages of PD. We hypothesized that gastric motility can be assessed in vivo by real-time magnetic resonance imaging (MRI), an established, noninvasive method. After an overnight fast and a standardized test meal, 10 patients with PD (six drug naive, four treated) and 10 healthy volunteers underwent real-time MRI scanning of the stomach. Gastric motility was quantified by calculating the gastric motility indices (GMI) from transversal oblique und sagittal oblique MRI scans. There was a trend toward a decreased gastric motility in patients with PD compared with healthy controls (Mann-Whitney test, P 0.059). This difference in peristalsis was due to a significant reduction in the amplitude of peristaltic contractions (P 0.029) and not to a decelerated velocity of the peristaltic waves (P 0.97). Real-time MRI allows direct visualization of gastric motility in PD. In this pilot study, a relatively high interindividual variability impaired accurate separation of our PD sample from healthy controls. The trend toward decreased gastric motility is in accordance with previous studies that investigated gastric motility in patients with PD using other methods. Our study provides first demonstration of a possible underlying mechanism for disturbed gastric motility in PD (reduced amplitude of contractions versus altered velocity of peristaltic waves). Further studies in drug-naive PD patients are required to determine the discriminatory power and validity of this technique in PD.

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.

Idiopathic rapid-eye-movement (REM) sleep behavior disorder (iRBD) has been suggested to be a risk factor for subsequent development of neurodegenerative disorders, especially Parkinson's disease (PD) and other alpha-synucleinopathies. At present, it is not possible to predict whether or not an iRBD patient will eventually develop PD. Here, we report 5 iRBD patients who underwent a test battery comprising a neurological examination (including UPDRS rating), mini mental state examination testing, transcranial sonography, olfactory function testing, and presynaptic dopamine transporter imaging with FP-CIT-SPECT. Our preliminary data show the diverse pattern of individual combinations of pathological findings when a multimodal assessment approach is applied in this patient group. Large-size longitudinal studies in iRBD patients are required to evaluate the usefulness of diagnostic tests to identify the subgroup of iRBD patients that is prone to develop PD.

Almost 200 years ago, James Parkinson1 described constipation as a frequent and clinically relevant nonmotor symptom in shaking palsy. Recent studies have shown that constipation can precede the motor manifestation of Parkinson disease (PD)2,3 and that constipation is more frequent in idiopathic REM sleep behavior disorder (iRBD) (a potential prodromal stage of PD) compared to controls.4 Even though the causal relationship between constipation and the neurodegenerative process that underlies PD remains debatable, constipation is considered as a risk marker for a subsequent diagnosis of PD.3 One potential pathoanatomical correlate for constipation in PD is Lewy bodies, the pathohistologic hallmark of PD, in the enteric nervous system (ENS). Lewy body pathology is found throughout the gastrointestinal tract with a rostral to caudal gradient. While early work on Lewy body pathology in the ENS was postmortem,5 recent studies have shown that the ENS is also easily amenable to in vivo pathohistologic assessment using endoscopy.6,7 The presence of ENS Lewy body pathology in PD led to the hypothesis that the ENS might be one of the first sites where Lewy body pathology occurs in PD.8 Few in vivo data exist on ENS pathology in early-stage PD.

Objective: This controlled study investigated associations between comorbidity and medication in patients with polysomnographically confirmed idiopathic REM sleep behavior disorder (iRBD), using a large multicenter clinic-based cohort. Methods: Data of a self-administered questionnaire on comorbidity and medication use of 318 patients with iRBD and 318 matched controls were analyzed. Comparisons between cases and controls were made using logistic regression analysis. Results: Patients with iRBD were more likely to report depression (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.3–2.9) and concomitant antidepressant use (OR 2.2, 95% CI 1.4–3.6). Subanalysis of antidepressant agents revealed that the increased use of antidepressants in iRBD was due to selective serotoninergic reuptake inhibitors (OR 3.6, 95% CI 1.8–7.0) and not due to other antidepressant classes. Patients with iRBD reported more lifetime antidepressant use than comorbid depression (antidepressant use: OR 1.9, 95% CI 1.1–3.3; depression: OR 1.6, 95% CI 1.0–2.5). Patients with iRBD reported more ischemic heart disease (OR 1.9, 95% CI 1.1–3.1). This association did not change substantially when adjusting for cardiovascular risk factors (OR 2.3, 95% CI 1.3–3.9). The use of inhaled glucocorticoids was higher in patients with iRBD compared to controls (OR 5.3, 95% CI 1.8–15.8), likely reflecting the higher smoking rate in iRBD (smoking: OR 15.3, 95% CI 2.0–118.8; nonsmoking: OR 2.4, 95% CI 0.4–13.2) and consequent pulmonary disease. Conclusions: This large study confirms the association between comorbid depression and antidepressant use in iRBD. In addition, there was an unexpected association of iRBD with ischemic heart disease that was not explained by cardiovascular risk factors.

The peptide ghrelin regulates gastrointestinal motility and energy homeostasis. Ghrelin is also a modulator of higher brain functions like mood, cognition, sleep, and reward-associated behaviour. Some of these functions regulated by ghrelin are disturbed in the neurodegenerative disorder Parkinson’s disease. The link between ghrelin and Parkinson’s disease is further endorsed by the finding that ghrelin receptors are expressed in brain regions that undergo neurodegeneration in Parkinson’s disease and by the finding of an altered postprandial ghrelin secretion in patients with Parkinson’s disease. In addition, ghrelin has shown protective effects in neurodegenerative disorders including experimental models of Parkinson’s disease. This chapter reviews the potential link between the gastric peptide ghrelin and the movement disorder Parkinson’s disease.

The relationship between Restless Legs Syndrome (RLS) and Parkinson's disease (PD) is still controversial. Most genetic, pathological, and imaging data argue against a close association of these two disorders. Still, many studies reported an increased prevalence of RLS in PD patients. These studies are difficult to interpret because the current diagnostic criteria for RLS have not been validated in PD patients. Although many PD patients suffer from motor restlessness due to parkinsonism and may thus mimic RLS, the risk for (secondary) RLS in PD patients is probably slightly increased. This review provides an overview of the current pertinent literature and discusses the possible association between RLS and PD.

Objective: To compare the frequency of proxy-reported REM sleep behavior disorder (RBD) among relatives of patients with polysomnogram-diagnosed idiopathic RBD (iRBD) in comparison to controls using a large multicenter clinic-based cohort. Methods: A total of 316 patients with polysomnography-confirmed iRBD were recruited from 12 RBD study group centers, along with 316 controls matched on sex and age group. All subjects completed a self-administered questionnaire that collected proxy-reported information on family history of tremor, gait trouble, balance trouble, Parkinson disease, memory loss, and Alzheimer disease. The questionnaire also included a single question that asked about possible symptoms of RBD among first-degree relatives (siblings, parents, and children). Results: A positive family history of dream enactment was reported in 13.8% of iRBD cases compared to 4.8% of controls (odds ratio [OR] = 3.9, 95% confidence interval [CI] 2.0–7.7). ORs were increased for both siblings (OR = 6.1, 95% CI 2.1–18.1) and parents (OR = 3.2, 95% CI 1.4–7.8). We found no significant difference in sex, current age (65.3 ± 10.2 vs 66.9 ± 10.2 years), or age at self-reported RBD onset (55.2 ± 11.7 vs 56.6 ± 15.1 years) in possible familial vs sporadic iRBD. No differences were found in family history of tremor, walking and balance troubles, Parkinson disease, memory loss, or Alzheimer disease. Conclusion: We found increased odds of proxy-reported family history of presumed RBD among individuals with confirmed iRBD. This suggests the possibility of a genetic contribution to RBD.

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.

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 1.5 T 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.

Luigi Ferini-Strambi • Wolfgang Oertel • Yves Dauvilliers • Ronald B. Postuma • Sara Marelli • Alex Iranzo • Isabelle Arnulf • Birgit Hogl • Raffaele Manni • Tomoyuki Miyamoto • Maria-Livia Fantini • Monica Puligheddu • Poul Jennum • Karel Sonka • Joan Santamaria • Marco Zucconi • Paola M. V. Rancoita • Smeranda Leu-Semenescu • Birgit Frauscher • Michele Terzaghi • Masayuki Miyamoto • Marcus Unger • Karin Stiasny-Kolster • Alex Desautels • Christina Wolfson • Amelie Pelletier • Jacques Montplaisir

Ghrelin, an orexigenic peptide, has multiple functions, which include promoting gastrointestinal motility and influencing higher brain functions. Experimental data suggest that ghrelin has neuroprotective potential in the MPTP mouse model of Parkinson’s disease (PD). PD patients show delayed gastric emptying and other symptoms that may relate to disturbed excretion of ghrelin. No data are available on postprandial ghrelin response in patients with PD and idiopathic REM sleep behaviour disorder (iRBD)––a condition considered a putative preclinical stage of PD. We measured fasting and postprandial ghrelin serum concentrations in 20 healthy controls, 39 (including 19 drug-naive) PD patients and 11 iRBD patients using a commercial radioimmunoassay for total ghrelin. For statistical analysis we employed ANCOVA and post-hoc testing with Bonferroni’s method. Controls showed a decrease of mean fasting ghrelin serum concentrations in the early postprandial phase, followed by a recuperation starting 60 min after the test meal and reaching a maximum at 300 min. This recuperation was less pronounced in PD and iRBD; the slope of relative postprandial ghrelin recovery was different between the investigated groups (p = 0.007). Post-hoc testing showed a difference between controls and PD patients (p = 0.002) and between controls and iRBD patients (p = 0.037). The dynamic regulation of ghrelin in response to food intake is partially impaired in subjects at putative preclinical (iRBD) and clinical stages of PD. Reduced ghrelin excretion might increase the vulnerability of nigrostriatal dopaminergic neurons as suggested by animal studies. The impaired ghrelin excretion might qualify as a peripheral biomarker and be of diagnostic or therapeutic value.

Substantia nigra (SN) hyperechogenicity--a sonographic vulnerability marker for Parkinson's disease (PD)--has been recently described in patients with idiopathic REM sleep behaviour disorder (RBD). It is not known whether subjects with narcolepsy (who frequently have associated RBD) also show SN hyperechogenicity. The aim of this study was to (1) evaluate SN echogenicity in narcolepsy and (2) determine whether transcranial sonography (TCS) differs in narcoleptic subjects with and without RBD. A total of 16 patients with narcolepsy-cataplexy (7 had a concomitant, video-polysomnographically based diagnosis of RBD) were examined with TCS by two investigators blinded to the clinical data. The size of the SN echogenic area in both subgroups was within the range previously described for healthy subjects. The brainstem raphe, however, was reduced in five of seven narcoleptic subjects with RBD, whereas only two of nine narcoleptic subjects without RBD exhibited this TCS finding. We conclude that evaluation of SN echogenicity does not discriminate between both subgroups. The absence of SN hyperechogenicity in narcoleptic patients with RBD supports the hypothesis that SN hyperechogenicity in patients with presumed idiopathic RBD is an additional risk marker for subsequent evolvement of PD rather than an RBD-immanent finding. Reduced echogenicity of the brainstem raphe might indicate an involvement of the serotonergic system in narcoleptic subjects with RBD.

Background/Aims: In 1998, the European Medicines Agency suspended the approval for tolcapone in Parkinson’s disease (PD) with motor complications due to the drug’s implication in fulminant liver failure and the consequent death of 3 patients. Clinical data obtained by ongoing use of tolcapone in other countries proved that adequate safety can be achieved if liver enzymes are strictly monitored. In 2005, tolcapone was relaunched in the European Union under the prerequisite of biweekly liver enzyme monitoring. The objective of this study was to evaluate the compliance with mandatory drug safety monitoring under real-life conditions. Methods: Twenty-one Parkinson’s disease patients receiving tolcapone were analyzed with regard to their compliance in performing and reporting the required laboratory tests. Results: Tolcapone was effective and well tolerated. Yet, less than 25% of the patients regularly performed and reported the required laboratory tests and the compliance declined when comparing the first and second half-years of therapy. Conclusions: Our data shed light on the incongruity between requirements of postmarketing drug surveillance and every-day reality. The depicted noncompliance is most likely a general problem in postmarketing drug surveillance with an impact for physicians, manufacturers and legal authorities. Practical, legal and ethical aspects will be discussed.