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BACKGROUND: Although sleep disturbances are highly prevalent in patients with Parkinson's disease, sleep macroarchitecture metrics show only minor changes.OBJECTIVE: To assess alterations of the cyclic alternating pattern (CAP) as a critical feature of sleep microarchitecture in patients with prodromal, recent, and established Parkinson's disease.METHODS: We evaluated overnight polysomnography for classic sleep macroarchitecture and CAP metrics in 68 patients at various disease stages and compared results to 22 age- and sex-matched controls.RESULTS: Already at the prodromal stage, patients showed a significantly reduced CAP rate as a central characteristic of sleep microarchitecture. Temporal characteristics of CAP showed a gradual change over disease stages and correlated with motor performance. In contrast, the sleep macroarchitecture metrics did not differ between groups.CONCLUSION: Data suggest that alterations of sleep microarchitecture are an early and more sensitive characteristic of Parkinson's disease than changes in sleep macroarchitecture.

Previous studies have reported substantial involvement of the noradrenergic system in Parkinson’s disease. Neuromelanin-sensitive MRI sequences and PET tracers have become available to visualize the cell bodies in the locus coeruleus and the density of noradrenergic terminal transporters. Combining these methods, we investigated the relationship of neurodegeneration in these distinct compartments in Parkinson’s disease. We examined 93 subjects (40 healthy controls and 53 Parkinson’s disease patients) with neuromelanin-sensitive turbo spin-echo MRI and calculated locus coeruleus-to-pons signal contrasts. Voxels with the highest intensities were extracted from published locus coeruleus coordinates transformed to individual MRI. To also investigate a potential spatial pattern of locus coeruleus degeneration, we extracted the highest signal intensities from the rostral, middle, and caudal third of the locus coeruleus. Additionally, a study-specific probabilistic map of the locus coeruleus was created and used to extract mean MRI contrast from the entire locus coeruleus and each rostro-caudal subdivision. Locus coeruleus volumes were measured using manual segmentations. A subset of 73 subjects had 11C-MeNER PET to determine noradrenaline transporter density, and distribution volume ratios of noradrenaline transporter-rich regions were computed. Patients with Parkinson’s disease showed reduced locus coeruleus MRI contrast independently of the selected method (voxel approaches: P The data shed first light on the interaction between the axonal and cell body compartments and their differential susceptibility to neurodegeneration in Parkinson’s disease, which may eventually direct research towards potential novel treatment approaches.

Study Objectives Parkinson’s disease (PD) commonly involves degeneration of sleep-wake regulating brainstem nuclei; likewise, sleep-wake disturbances are highly prevalent in PD patients. As polysomnography macroparameters typically show only minor changes in PD, we investigated sleep microstructure, particularly cyclic alternating pattern (CAP), and its relation to alterations of the noradrenergic system in these patients. Methods We analyzed 27 PD patients and 13 healthy control (HC) subjects who underwent overnight polysomnography and 11C-MeNER positron emission tomography for evaluation of noradrenaline transporter density. Sleep macroparameters, as well as CAP metrics, were evaluated according to the consensus statement from 2001. Statistical analysis comprised group comparisons and correlation analysis of CAP metrics with clinical characteristics of PD patients as well as noradrenaline transporter density. Results PD patients and HC subjects were comparable in demographic characteristics (age, sex, body mass index) and polysomnography macroparameters. CAP rate as well as A index differed significantly between groups, with PD patients having a lower CAP rate (46.7 ± 6.6% versus 38.0 ± 11.6%, p = 0.015) and lower A index (49.0 ± 8.7/hour versus 40.1 ± 15.4/hour, p = 0.042). In PD patients, both CAP metrics correlated significantly with diminished noradrenaline transporter density in arousal prompting brainstem nuclei (locus coeruleus, raphe nuclei) as well as arousal propagating brain structures like thalamus and bitemporal cortex. Conclusions Sleep microstructure is more severely altered than sleep macrostructure in PD patients and is associated with widespread dysfunction of the noradrenergic arousal system.

Reduced noradrenaline levels have been reported to occur in the motor cortices of PD patients postmortem. Imaging techniques have recently become available to specifically study noradrenergic terminal function in vivo using PET. The objective of this study was to evaluate cortical 11 C-MeNER binding in PD patients. Thirty PD patients and 12 healthy control subjects comparable in age, sex, and cognitive performance underwent PET imaging with 11 C-MeNER, a specific ligand of the noradrenaline transporter. Cortical noradrenaline transporter binding was compared at a voxel level using Statistical Parametric Mapping, whereas cortical thickness was assessed using FreeSurfer software with MRI. PD patients showed reduced 11 C-MeNER binding in the primary motor cortex unrelated to cortical thickness; other cortical regions did not differ between groups. In a subgroup analysis, patients with higher Hoehn & Yahr stage exhibited more pronounced 11 C-MeNER binding reductions. Loss of cortical noradrenergic projections to the primary motor cortex occurs in PD associated with disease stage. © 2018 International Parkinson and Movement Disorder Society.

Introductory paragraphThe ability of gut bacterial pathogens to escape immunity by antigenic variation, particularly via changes to surface-exposed antigens, is a major barrier to immune clearance1. However, not all variants are equally fit in all environments2, 3. It should therefore be possible to exploit such immune escape mechanisms to direct an evolutionary trade-off. Here we demonstrated this phenomenon using Salmonella enterica subspecies enterica serovar Typhimurium (S.Tm). A dominant surface antigen of S.Tm is its O-antigen: A long, repetitive glycan that can be rapidly varied by mutations in biosynthetic pathways or by phase-variation4, 5. We quantified the selective advantage of O-antigen variants in the presence and absence of O-antigen specific IgA and identified a set of evolutionary trajectories allowing immune escape without an associated fitness cost in naïve mice. Through the use of oral vaccines, we rationally induced IgA responses blocking all of these trajectories, which selected for Salmonella mutants carrying deletions of the O-antigen polymerase wzyB. Due to their short O-antigen, these evolved mutants were more susceptible to environmental stressors (detergents, complement), predation (bacteriophages), and were impaired in gut colonization and virulence in mice. Therefore, a rationally induced cocktail of intestinal antibodies can direct an evolutionary trade-off in S.Tm. This lays the foundations for the exploration of mucosal vaccines capable of setting evolutionary traps as a prophylactic strategy.

Noradrenergic neurons in both the peripheral nervous system and in the central nervous system (CNS) undergo severe degeneration in patients with Parkinson's disease (PD). This loss of noradrenaline may play essential roles in the occurrence of a wide range of prevalent non-motor symptoms and can further complicate the lives of PD patients. In vivo molecular imaging of noradrenaline may provide insights into to the extent of degeneration of noradrenergic neurons and subsequent depletion of noradrenergic projections. Molecular imaging methods exist to quantify the noradrenergic deficiency in peripheral autonomic terminals, such as [

This is a case report of a 54-year-old male, who was admitted twice with transient ischaemic attacks and eventually stroke due to cerebral vasculitis because of an underlying borrelial infection. He did not have any preceding symptoms of neuroborreliosis (Bannwarth syndrome) or erythema migrans. This report underlines the importance of performing a broad neurological evaluation of patients, who present with atypical neurological symptoms.

Pathological involvement of the noradrenergic locus coeruleus occurs early in Parkinson's disease, and widespread noradrenaline reductions are found at post-mortem. Rapid eye movement sleep behaviour disorder (RBD) accompanies Parkinson's disease and its presence predicts an unfavourable disease course with a higher propensity to cognitive impairment and orthostatic hypotension. MRI can detect neuromelanin in the locus coeruleus while 11C-MeNER PET is a marker of noradrenaline transporter availability. Here, we use both imaging modalities to study the association of RBD, cognition and autonomic dysfunction in Parkinson's disease with loss of noradrenergic function. Thirty non-demented Parkinson's disease patients [16 patients with RBD and 14 without RBD, comparable across age (66.6 ± 6.7 years), sex (22 males), and disease stage (Hoehn and Yahr, 2.3 ± 0.5)], had imaging of the locus coeruleus with neuromelanin sensitive MRI and brain noradrenaline transporter availability with 11C-MeNER PET. RBD was confirmed with polysomnography; cognitive function was assessed with a neuropsychological test battery, and blood pressure changes on tilting were documented; results were compared to 12 matched control subjects. We found that Parkinson's disease patients with RBD showed decreased locus coeruleus neuromelanin signal on MRI (P < 0.001) and widespread reduced binding of 11C-MeNER (P < 0.001), which correlated with amount of REM sleep without atonia. Parkinson's disease with RBD was also associated with a higher incidence of cognitive impairment, slowed EEG activity, and orthostatic hypotension. Reduced 11C-MeNER binding correlated with EEG slowing, cognitive performance, and orthostatic hypotension. In conclusion, reduced noradrenergic function in Parkinson's disease was linked to the presence of RBD and associated with cognitive deterioration and orthostatic hypotension. Noradrenergic impairment may contribute to the high prevalence of these non-motor symptoms in Parkinson's disease, and may be of relevance when treating these conditions in Parkinson's disease.

Reduced noradrenaline levels have been reported to occur in the motor cortices of PD patients postmortem. Imaging techniques have recently become available to specifically study noradrenergic terminal function in vivo using PET. The objective of this study was to evaluate cortical

OBJECTIVES: Rapid eye movement (REM) sleep behavior disorder (RBD) is defined by dream enactment due to a failure of normal muscle atonia. Visual assessment of this muscle activity is time consuming and rater-dependent.METHODS: An EMG computer algorithm for scoring 'tonic', 'phasic' and 'any' submental muscle activity during REM sleep was evaluated compared with human visual ratings. Subsequently, 52 subjects were analyzed with the algorithm. Duration and maximal amplitude of muscle activity, and self-awareness of RBD symptoms were assessed.RESULTS: The computer algorithm showed high congruency with human ratings and all subjects with RBD were correctly identified by excess of submental muscle activity, when artifacts were removed before analysis. Subjects with RBD exhibited prolonged bouts of 'phasic' muscle activity with high amplitude. Self-awareness of RBD symptoms correlated with amount of REM sleep without atonia.CONCLUSIONS: Our proposed algorithm was able to detect and rate REM sleep without atonia allowing identification of RBD. Increased duration and amplitude of muscle activity bouts were characteristics of RBD. Quantification of REM sleep without atonia represents a marker of RBD severity.SIGNIFICANCE: Our EMG computer algorithm can support a diagnosis of RBD while the quantification of altered muscle activity provides a measure of its severity.

659 Purpose: Although texture features have shown potential of being quantitative biomarkers for assessing intratumoral heterogeneity, one needs to be confident that they can detect meaningful changes reflecting clinical response. The objective was to introduce and evaluate response-to-repeatability (R/R) of PET texture features as a measure to assess the range of detectable, significant feature changes. Methods: Response-to-repeatability (R/R) of texture features was assessed in individual lesions in metastatic castration-resistant prostate cancer patients. Lesions were segmented and matched across three scans: two baseline and one on-treatment follow-up 18F-NaF PET/CT using Quantitative Total Bone Imaging (QTBI) software. For each lesion, 47 PET-based texture features representing 5 matrix groups were measured across voxel patches: 6 histogram-based first-order metrics, 22 second-order metrics from grey-level co-occurrence matrix, 11 grey-level run-length features, 5 neighboring grey-level dependence features, and 3 metrics from neighborhood grey-tone difference matrices. Test-retest repeatability was assessed with coefficient of variation (CV), intra-class correlation coefficient (ICC), and 95% limits of agreement (LOA). R/R of each feature was evaluated as the proportion of changes from baseline to follow-up that were beyond repeatability margins (i.e., outside of LOA). Results A total of 265 NaF-avid bone lesions were identified in 18 patients who received double baseline scans. R/R varied within and across matrix groups: 41/47 (87%) features demonstrated R/R > 5%; 21/47 (45%) features demonstrated R/R > 10%, and 11/47 (23%) features demonstrated R/R > 20%. Magnitude of R/R at follow-up did not correlate with its magnitude of repeatability, which also varied greatly across features: 26/47 (55%) features demonstrated low variability (CV 0.75). 39/47 (83%) features demonstrated both high ICC and significant R/R (R/R > 5%). Conclusion Although texture features may demonstrate high test-retest repeatability, a commonly evaluated index of quantitative biomarkers, features may not effectively detect meaningful change at follow-up (i.e. low R/R). We present a method to evaluate response-to-repeatability as criteria for identifying quantitative imaging biomarkers of response for use in treatment assessment.

Parkinson's disease is associated with early parasympathetic dysfunction leading to constipation and gastroparesis. It has been suggested that pathological α-synuclein aggregations originate in the gut and ascend to the brainstem via the vagus. Our understanding of the pathogenesis and time course of parasympathetic denervation in Parkinson's disease is limited and would benefit from a validated imaging technique to visualize the integrity of parasympathetic function. The positron emission tomography tracer 5-[11C]-methoxy-donepezil was recently validated for imaging acetylcholinesterase density in the brain and peripheral organs. Donepezil is a high-affinity ligand for acetylcholinesterase—the enzyme that catabolizes acetylcholine in cholinergic synapses. Acetylcholinesterase histology has been used for many years for visualizing cholinergic neurons. Using 5-[11C]-methoxy-donepezil positron emission tomography, we studied 12 patients with early-to-moderate Parkinson's disease (three female; age 64 ± 9 years) and 12 age-matched control subjects (three female; age 62 ± 8 years). We collected clinical information about motor severity, constipation, gastroparesis, and other parameters. Heart rate variability measurements and gastric emptying scintigraphies were performed in all subjects to obtain objective measures of parasympathetic function. We detected significantly decreased 11C-donepezil binding in the small intestine (−35%; P = 0.003) and pancreas (−22%; P = 0.001) of the patients. No correlations were found between the 11C-donepezil signal and disease duration, severity of constipation, gastric emptying time, and heart rate variability. In Parkinson's disease, the dorsal motor nucleus of the vagus undergoes severe degeneration and pathological α-synuclein aggregations are also seen in nerve fibres innervating the gastro-intestinal tract. In contrast, the enteric nervous system displays little or no loss of cholinergic neurons. Decreases in 11C-donepezil binding may, therefore, represent a marker of parasympathetic denervation of internal organs, but further validation studies are needed. * Abbreviations : AChE : acetylcholinesterase DMV : dorsal motor nucleus of the vagus RR : distance in ms between consecutive normal R waves in QRS complexes SUV : standardized uptake value

Brain cholinergic function has been previously studied with PET but little effort has been devoted to imaging peripheral organs. Many disorders, including diabetes and Parkinson disease, are associated with autonomic dysfunction including parasympathetic denervation. Nonneuronal cholinergic signaling is also involved in immune responses to infections and in cancer pathogenesis. 5-(11)C-methoxy-donepezil, a noncompetitive acetylcholinesterase ligand, was previously validated for imaging cerebral levels of acetylcholinesterase. In the present study, we explored the utility of (11)C-donepezil for imaging acetylcholinesterase densities in peripheral organs, including the salivary glands, heart, stomach, intestine, pancreas, liver, and spleen.METHODS: With autoradiography, we determined binding affinities and levels of nonspecific (11)C-donepezil binding to porcine tissues. Radiation dosimetry was estimated by whole-body PET of a single human volunteer. Biodistribution and kinetic analyses of (11)C-donepezil time-activity curves were assessed with dynamic PET scans of 6 healthy human volunteers. A single pig with bacterial abscesses was PET-scanned to explore (11)C-donepezil uptake in infections.RESULTS: Autoradiography showed high (11)C-donepezil binding (dissociation constant, 6-39 nM) in pig peripheral organs with low nonspecific signal. Radiation dosimetry was favorable (effective dose, 5.2 μSv/MBq). Peripheral metabolization of (11)C-donepezil was low (>90% unchanged ligand at 60 min). Slow washout kinetics were seen in the salivary glands, heart, intestines, pancreas, and prostate. A linear correlation was seen between (11)C-donepezil volumes of distribution and standardized uptake values, suggesting that arterial blood sampling may not be necessary for modeling uptake kinetics in future (11)C-donepezil PET studies. High standardized uptake values and slow washout kinetics were seen in bacterial abscesses.CONCLUSION: (11)C-donepezil PET is suitable for imaging acetylcholinesterase densities in peripheral organs. Its uptake may potentially be quantitated with static whole-body PET scans not requiring arterial blood sampling. We also demonstrated high (11)C-donepezil binding in bacterial abscesses. We propose that (11)C-donepezil PET imaging may be able to quantify the parasympathetic innervation of organs but also detect nonneuronal cholinergic activity in infections.