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Background: The α-syn Origin site and Connectome model (SOC) proposes that α-synucleinopathies can be divided into two categories: the asymmetrical brain-first, and more symmetrical body-first Lewy body disease. We have hypothesized that most patients with dementia with Lewy bodies (DLB) belong to the body-first subtype, whereas patients with Parkinson's disease (PD) more often belong to the brain-first subtype. Objective: To compare asymmetry of striatal dopaminergic dysfunction in DLB and PD patients using [18F]-FE-PE2I positron emission tomography (PET). Methods: We analyzed [18F]-FE-PE2I PET data from 29 DLB patients and 76 PD patients who were identified retrospectively during a 5-year period at Dept. of Neurology, Aarhus University Hospital. Additionally, imaging data from 34 healthy controls was used for age-correction and visual comparison. Results: PD patients showed significantly more asymmetry in specific binding ratios between the most and least affected putamen (p < 0.0001) and caudate (p = 0.003) compared to DLB patients. PD patients also had more severe degeneration in the putamen compared to the caudate in comparison to DLB patients (p < 0.0001) who had a more universal pattern of striatal degeneration. Conclusion: Patients with DLB show significantly more symmetric striatal degeneration on average compared to PD patients. These results support the hypothesis that DLB patients may be more likely to conform to the body-first subtype characterized by a symmetrical spread of pathology, whereas PD patients may be more likely to conform to the brain-first subtype with more lateralized initial propagation of pathology. [ABSTRACT FROM AUTHOR]

Introduction: Most patients with isolated rapid eye movement sleep behaviour disorder (iRBD) convert to Parkinson's disease (PD), dementia with Lewy bodies, or multiple system atrophy within 15 years of diagnosis. Furthermore, iRBD patients develop non-motor symptoms similar to those of manifest PD patients and display dysfunction of the sympathetic and parasympathetic nervous system, comparable to that seen in PD. However, progression rates of autonomic dysfunction in iRBD have not been studied with objective measures in detail, which is the aim of this study.Methods: Twenty-two iRBD patients were included at baseline and 14 participated in follow-up after 3 years. Colonic transit time (CTT) was examined using radio opaque markers, colonic volume was defined on abdominal computed tomography (CT) scans, Iodine-123-metaiodobenzylguanidine ([123I]MIBG) scintigraphy was performed to assess cardiac sympathetic innervation, and 3,4-dihydroxy-6-(18F) fluoro-l-phenylalanine ([18F]FDOPA) positron emission tomography (PET) scan determined nigrostriatal dopamine storage capacity. All examinations were performed at baseline and after 3 years.Results: iRBD patients displayed increased CTT (p = 0.001) and colonic volume (p = 0.01) at follow-up compared to baseline. Furthermore, [123I]MIBG uptake and [18F]FDOPA uptake showed progressive reductions at follow-up (p = 0.02 and p = 0.002, respectively). No correlations were seen between changes in intestinal or cardiac measurements and dopaminergic function.Conclusion: Using objective markers, the present study documented that intestinal dysfunction and cardiac sympathetic degeneration worsen in the majority of iRBD patients over a 3-year period. The absent correlation between these markers and nigrostriatal dopaminergic dysfunction suggests that progressive gastrointestinal and cardiac dysfunction in iRBD is caused mainly by non-dopaminergic mechanisms. [ABSTRACT FROM AUTHOR]

Background. Nonmotor symptoms, including constipation and dysphagia, are very common in Parkinson's disease (PD) and Lewy pathology is widespread in the gastrointestinal tract, particularly in the lower esophagus. Constipation and REM sleep behavior disorder (RBD) may present prior to clinical diagnosis. Yet, little is known about esophageal dysfunction and its connection to constipation in early PD. Objective. This study aimed to investigate esophageal and colonic transit in early moderate PD and to study correlations between symptoms and objective measures. Methods. Thirty early moderate PD patients and 28 healthy controls (HC) were included in this cross-sectional study. Esophageal transit times were determined by esophageal scintigraphy and colonic transit times by CT after radio-opaque marker ingestion. Olfaction tests, clinical evaluation, and nonmotor questionnaires were also performed. Results. Distal esophageal transit times and colonic transit times were both significantly prolonged in the PD group compared to HC (p < 0.05 and p < 0.01 , respectively) and a moderate-strong positive correlation was found between colonic transit time (CTT) and RBDSQ score (r = 0.61, p < 0.001). Significant correlations were also found between CTT and SCOPA-AUT scores as well as between CTT and ROME III functional constipation scores. Conclusion. Colonic transit correlates with probable RBD and is more severely prolonged in early moderate PD than is the distal esophageal transit time. [ABSTRACT FROM AUTHOR]

Background: We have hypothesized that Parkinson's disease (PD) comprises two subtypes. Brain-first, where pathogenic α-synuclein initially forms unilaterally in one hemisphere leading to asymmetric nigrostriatal degeneration, and body-first with initial enteric pathology, which spreads through overlapping vagal innervation leading to more symmetric brainstem involvement and hence more symmetric nigrostriatal degeneration. Isolated REM sleep behaviour disorder has been identified as a strong marker of the body-first type. Objective: To analyse striatal asymmetry in [18F]FDOPA PET and [123I]FP-CIT DaT SPECT data from iRBD patients, de novo PD patients with RBD (PD+RBD) and de novo PD patients without RBD (PD-RBD). These groups were defined as prodromal body-first, de novo body-first, and de novo brain-first, respectively. Methods: We included [18F]FDOPA PET scans from 21 iRBD patients, 11 de novo PD+RBD, 22 de novo PD-RBD, and 18 controls subjects. Also, [123I]FP-CIT DaT SPECT data from iRBD and de novo PD patients with unknown RBD status from the PPPMI dataset was analysed. Lowest putamen specific binding ratio and putamen asymmetry index (AI) was defined. Results: Nigrostriatal degeneration was significantly more symmetric in patients with RBD versus patients without RBD or with unknown RBD status in both FDOPA (p = 0.001) and DaT SPECT (p = 0.001) datasets. Conclusion: iRBD subjects and de novo PD+RBD patients present with significantly more symmetric nigrostriatal dopaminergic degeneration compared to de novo PD-RBD patients. The results support the hypothesis that body-first PD is characterized by more symmetric distribution most likely due to more symmetric propagation of pathogenic α-synuclein compared to brain-first PD. [ABSTRACT FROM AUTHOR]

Background. Patients with Parkinson's disease (PD) often show peripheral autonomic dysfunction and depositions of pathological alpha-synuclein aggregates in the skin. However, functional consequences of this skin involvement have received little attention. Objective. To determine thermographic differences in the skin between healthy controls (HCs) and PD patients on hands, feet, and trunk and to correlate findings with symptoms and signs of dysautonomia. Between-group differences in autonomic parameters and questionnaires were explored. Methods. Twenty-one PD patients and 19 HCs were examined by thermographic infrared imaging of standardized anatomical locations on the trunk and upper and lower extremities at baseline and after exposure to cold stress test (CST). Thermal recovery rates (RRs) were determined on the basis of thermograms. Correlation analyses between alterations in skin temperature and autonomic dysfunction were performed. Results. The most significant RR difference between PD patients and HCs was seen on the fifth distal phalanx 10 minutes post-CST (mean RR ± SD: 51 ± 18% vs. 70 ± 23%, p = 0.003). No between-group differences were seen in baseline or post-CST values of the feet. No correlations were seen between thermal parameters and clinical and autonomic data. In the HC group, a positive, moderate correlation was seen between post-CST recovery values on the 3rd and 5th phalanx and body mass index (BMI) (r = 0.661, p = 0.002). Conclusions. The PD patients exhibited significant reduction in RR compared to HC and patients also displayed altered thermal responses in multiple anatomical locations. Thus, infrared thermography could become an important future tool in investigation of autonomic deficiency in PD. [ABSTRACT FROM AUTHOR]

Isolated REM sleep behaviour disorder (iRBD) is a predictive marker of prodromal Lewy body disease. iRBD prevalence in the general population is around 1%, but it remains under-diagnosed, even though symptoms are alleviated by medication. We developed a population screening strategy and identified 16 iRBD patients by conducting telephone interviews and polysomnography examinations. We compared our population-screened cohort with sleep-center referred patients and found higher MoCA scores and lower MDS-UPDRS-III scores in our patients. In conclusion, screening can be used to identify iRBD patients in a cost-effective manner with the benefit of identifying patients at a very early disease stage. [ABSTRACT FROM AUTHOR]

Background: Parasympathetic neuropathy is a key feature in many common disorders, including diabetes, neurological disorders, and cancers, but few objective methods exist for assessing damage to the parasympathetic nervous system, particularly in the gastrointestinal system. This study aimed to validate the use of 11C‐donepezil positron emission tomography (PET) to assess parasympathetic integrity in a group of vagotomized patients. Methods: Sixteen healthy controls and 12 patients, vagotomized due to esophagectomy, underwent 11C‐donepezil PET, measurement of colonic transit time, quantification of plasma pancreatic polypeptide (PP), and assessment of subjective long‐term symptoms. Key Results: Vagotomized patients had significantly decreased PET signal in the small intestine and colon compared with healthy controls (5.7 [4.4‐7.9] vs 7.4 [4.5‐11.3], P =.01 and 1.4 [1.1‐2.1] vs 1.6 [1.4‐2.4], P <.01, respectively). Vagotomized patients also displayed a significantly increased colonic transit time (2.9 ± 0.9 h vs 1.9 ± 0.8 h), P <.01 and increased volumes of the small intestine and colon (715 ccm [544‐1177] vs 443 ccm [307‐613], P <.01 and 971 ccm [713‐1389] vs 711 ccm [486‐1394], P =.01, respectively). Patients and controls did not differ in PP ratio levels after sham feeding, but PP ratio at 10 minutes. after sham feeding and PET signal intensity in the small intestine was positively correlated (P =.03). Conclusions and Inferences: We found significantly decreased 11C‐donepezil signal in the intestine of vagotomized patients, supporting that 11C‐donepezil PET is a valid measure of intestinal parasympathetic denervation. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease is characterized by pathological α-synuclein accumulation and cell death, which has been hypothesized to originate in peripheral nerve terminals and subsequently spread via autonomic nerves. Supporting this, most Parkinson's disease patients experience autonomic non-motor symptoms such as constipation, often years prior to diagnosis.Objective: We aimed to study gastrointestinal transit time, colonic volume, and peristaltic movements in idiopathic REM Sleep Behavior Disorder patients, a prodromal marker of Parkinson's disease or Dementia with Lewy bodies.Methods: Twenty-two patients were included and compared to previously published data from Parkinson's disease patients and controls. Gastrointestinal transit time, computed tomography-based volume estimation, and colonic motility were performed as markers of gastrointestinal function and autonomic involvement. Subjective constipation symptoms were evaluated with two different questionnaires.Results: Gastrointestinal transit time was increased in 33% (p = 0.039) and colonic volume in 48% (p = 0.0049) of patients. Colonic transit time measured by the 3D-Transit system was increased in 70% (p = 0.0326) and the number of fast peristaltic colonic movements was reduced (p = 0.015). Mean small intestinal transit time was comparable to Parkinson's disease patients, although not significantly different compared to controls (p = 0.18). Subjective constipation symptoms were present in 18 or 41%, depending on type of questionnaire.Conclusions: Total gastrointestinal transit time, colonic volume, and 3D-Transit colonic transit time were significantly increased compared to controls, although not to the extent seen in medicated Parkinson's patients. Limited correlation was seen between subjective constipation and objective markers. The findings support that marked GI dysfunction is present in the early prodromal PD phase. [ABSTRACT FROM AUTHOR]

Patients with Parkinson's disease (PD) experience a range of non-motor symptoms, including constipation and other gastrointestinal problems. These symptoms are sometimes present in the prodromal disease phase. An improved understanding of the underlying pathophysiology is needed considering that PD has been hypothesized to originate in the gut. Delayed gastric emptying time (GET) is often listed as a prevalent gastrointestinal symptom in PD, but the true prevalence is controversial. The aim of this short review was to investigate if GET in PD is dependent on the applied measuring methodology. A systemic search of Pubmed identified 15 relevant studies, including six using gold standard method gastric scintigraphy and nine using 13C-octanoate breath tests. Overall, gastric scintigraphy studies showed a non-significant GET delay (standardized mean difference (SMD) 0.42) in PD patients. After exclusion of one outlier study, GET was significantly increased (SMD 0.59). In contrast, highly significant GET delay (SMD 1.70) was seen in breath test studies. A limitation of the meta-analyses was reuse of the same control group in some studies. In summary, the marked GET delay observed in breath test studies is not confirmed by gold standard gastric scintigraphy studies. This discrepancy can perhaps be explained by breath test being an indirect GET measure, depending not only on mechanic stomach emptying but also intestinal absorption and liver metabolism. Thus, multi-modality studies under standardized conditions are needed to elucidate the prevalence and severity of gastric dysmotility in PD, along with contributions from other factors including intestinal absorption and permeability. [ABSTRACT FROM AUTHOR]

Summary Background Accumulating evidence suggests that α-synuclein aggregates—a defining pathology of Parkinson's disease—display cell-to-cell transmission. α-synuclein aggregation is hypothesised to start in autonomic nerve terminals years before the appearance of motor symptoms, and subsequently spread via autonomic nerves to the spinal cord and brainstem. To assess this hypothesis, we investigated sympathetic, parasympathetic, noradrenergic, and dopaminergic innervation in patients with idiopathic rapid eye movement (REM) sleep behaviour disorder, a prodromal phenotype of Parkinson's disease. Methods In this prospective, case-control study, we recruited patients with idiopathic REM sleep behaviour disorder, confirmed by polysomnography, without clinical signs of parkinsonism or dementia, via advertisement and through sleep clinics in Denmark. We used 11 C-donepezil PET and CT to assess cholinergic (parasympathetic) gut innervation, 123 I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure integrity of pigmented neurons of the locus coeruleus, 11 C-methylreboxetine (MeNER) PET to assess noradrenergic nerve terminals originating in the locus coeruleus, and 18 F-dihydroxyphenylalanine (DOPA) PET to assess nigrostriatal dopamine storage capacity. For each imaging modality, we compared patients with idiopathic REM sleep behaviour disorder with previously published reference data of controls without neurological disorders or cognitive impairment and with symptomatic patients with Parkinson's disease. We assessed imaging data using one-way ANOVA corrected for multiple comparisons. Findings Between June 3, 2016, and Dec 19, 2017, we recruited 22 consecutive patients with idiopathic REM sleep behaviour disorder to the study. Compared with controls, patients with idiopathic REM sleep behaviour disorder had decreased colonic 11 C-donepezil uptake (−0·322, 95% CI −0·112 to −0·531; p=0·0020), 123 I-MIBG heart:mediastinum ratio (−0·508, −0·353 to −0·664; p<0·0001), neuromelanin-sensitive MRI locus coeruleus:pons ratio (−0·059, −0·019 to −0·099; p=0·0028), and putaminal 18 F-DOPA uptake (Ki; −0·0023, −0·0009 to −0·0037; p=0·0013). No between-group differences were detected between idiopathic REM sleep behaviour disorder and Parkinson's disease groups with respect to 11 C-donepezil (p=0·39), 123 I-MIBG (p>0·99), neuromelanin-sensitive MRI (p=0·96), and 11 C-MeNER (p=0·56). By contrast, 15 (71%) of 21 patients with idiopathic REM sleep behaviour disorder had 18 F-DOPA Ki values within normal limits, whereas all patients with Parkinson's disease had significantly decreased 18 F-DOPA Ki values when compared with patients with idiopathic REM sleep behaviour disorder (p<0·0001). Interpretation Patients with idiopathic REM sleep behaviour disorder had fully developed pathology in the peripheral autonomic nervous system and the locus coeruleus, equal to that in diagnosed Parkinson's disease. These patients also showed noradrenergic thalamic denervation, but most had normal putaminal dopaminergic storage capacity. This caudorostral gradient of dysfunction supports the hypothesis that α-synuclein pathology in Parkinson's disease initially targets peripheral autonomic nerves and then spreads rostrally to the brainstem. Funding Lundbeck Foundation, Jascha Foundation, and the Swiss National Foundation. [ABSTRACT FROM AUTHOR]

Background and Objectives: Parkinson's disease (PD) patients experience several non-motor symptoms from the gastrointestinal tract that may partly be caused by parasympathetic deficiency. The pancreas is densely innervated by the vagus nerve, which mediates early meal-induced secretion of pancreatic polypeptide (PP). Early secretion after sham feeding has been validated as a marker of vagal integrity. Thus, the aim was to evaluate the ratio of increased PP plasma levels after sham feeding in PD and correlate findings with gastrointestinal transit time (GITT). Methods: Twenty-five PD patients and 17 controls were included. PP, insulin, and blood glucose levels were measured before, during, and after sham feeding with white bread and chocolate spread. GITT was measured using radiopaque markers. Furthermore, faeces samples were analyzed for pancreatic elastase enzyme as a marker of exocrine pancreatic function. Results: PD patients showed significantly lower PP ratio levels after sham feeding, whichwas most pronounced at 10 minutes. No significant association was seen between attenuated PP response and GITT in PD patients. No between-group differences were seen in glucose or insulin levels over time, but PD patients showed generally lower insulin levels compared to controls. No difference was found in faeces pancreatic elastase. Conclusions: Early-to-moderate stage PD patients demonstrated significantly decreased PP response after sham feeding suggestive of vagal denervation. [ABSTRACT FROM AUTHOR]

Background: Symptoms from the gastrointestinal tract are highly prevalent in Parkinson's disease (PD), but knowledge of the underlying pathology is incomplete and valid objective markers on regional gastrointestinal function are limited. Objective: The aims were to evaluate gastrointestinal transit time and motility in PD patients and controls. Methods: Twenty-two PD patients and 15 controls were included. Gastric-, small intestinal-, and caecum-ascending colonic transit times as well as colonic motility, defined as mass- and fastmovements, were performed using the ambulatory 3D-Transit system. Gastrointestinal transit time with radio opaque markers, gastric emptying scintigraphy, and subjective non-motor symptoms were also evaluated. Results: Using the 3D-Transit system, the patient group displayed significantly longer small intestinal- and caecum-ascending transit times (p = 0.030 and p = 0.0063). No between-group difference was seen in gastric transit time (p = 0.91). Time to first mass- and fast colonic movement were significantly increased in PD (p = 0.023 and p = 0.006). Radio opaque marker gastrointestinal transit time was significantly increased in the patient group (p < 0.0001), whereas no difference was seen in scintigraphic gastric emptying time (p = 0.68). Prevalence of constipation symptoms on the NMSQuest was 41% in PD and 7% in controls. Conclusions: Significantly increased small intestinal- and caecum-ascending 3D-Transit times were detected in PD patients. Also, time to first propagating colonic movement was increased. Radio opaque marker gastrointestinal transit time was significantly delayed, but no difference was seen in gastric transit time and gastric emptying time. The present findings highlight widespread intestinal involvement in PD increasing throughout the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal function has received increased interest in the context of Parkinson's disease (PD). Constipation is among the most frequent non-motor symptoms, but our understanding of the underlying pathology is limited. Subjective constipation correlates poorly with objective markers. Objective: The aims were to evaluate colonic transit time and volume in PD and to correlate these measures with subjective symptoms and gastric emptying. Methods: Thirty-two PD patients and 26 controls were included. Colonic transit time, computed tomography-based volume estimation, and gastric emptying were performed as objective markers of gastrointestinal function. Subjective gastrointestinal symptoms were evaluated by three different questionnaires. Results: Seventy-nine percent of PD patients displayed prolonged colonic transit time (p < 0.0001) and 66% of patients had significantly increased colonic volume (p = 0.0002). Particularly the transverse and rectosigmoid segments were affected. There was no difference in gastric emptying time between groups. The prevalence of subjective constipation in PD patients was significantly lower and ranged from 3% to 38% depending on the type of questionnaire. Conclusions: Significantly delayed colonic transit time and increased volume were frequent findings in PD patients, and objective dysfunction was considerably more prevalent than subjective constipation symptoms. Also, the prevalence of subjective constipation varied widely depending upon which questionnaire was employed. These findings highlight the need for more research on how to define constipation in PD and also the need for improved understanding of the relationship between subjective symptoms and objective dysfunction. [ABSTRACT FROM AUTHOR]

Constipation is among the first nonmotor symptoms to develop in the prodromal phase of PD. Pathological alpha-synuclein deposition is present throughout the gastrointestinal tract up to 20 years preceding diagnosis. Nevertheless, constipation in the context of PD remains ill defined and poorly understood. In this review, we summarize current knowledge of subjective symptoms and objective measures of constipation in PD. More than 10 different definitions of constipation have been used in the PD literature, making generalizations difficult. When pooling results from the most homogeneous studies in PD, a median constipation prevalence of 40% to 50% emerges, but with large variation across individual studies. Also, constipation prevalence tends to increase with disease progression. A similar prevalence is observed among patients with idiopathic rapid eye movement sleep behavior disorder. Interestingly, we detected a correlation between constipation prevalence in PD patients and healthy control groups in individual studies, raising concerns about how various constipation questionnaires are implemented across study populations. More than 80% of PD patients exhibit prolonged colonic transit time, and the same is probably true for de novo PD patients. Thus, the prevalence of objective colonic dysfunction exceeds the prevalence of subjective constipation. Colonic transit time measures are simple, widely available, and hold promise as a useful biomarker in manifest PD. More research is needed to elucidate the role of gastrointestinal dysfunction in disease progression of PD. Moreover, colonic transit measures may have utility as a more accurate risk factor for predicting PD in the prodromal phase. © 2016 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The tau tangle ligand (18)F-AV-1451 ((18)F-T807) binds to neuromelanin in the midbrain, and may therefore be a measure of the pigmented dopaminergic neuronal count in the substantia nigra. Parkinson's disease is characterized by progressive loss of dopaminergic neurons. Extrapolation of post-mortem data predicts that a ∼30% decline of nigral dopamine neurons is necessary to cause motor symptoms in Parkinson's disease. Putamen dopamine terminal loss at disease onset most likely exceeds that of the nigral cell bodies and has been estimated to be of the order of 50-70%. We investigated the utility of (18)F-AV-1451 positron emission tomography to visualize the concentration of nigral neuromelanin in Parkinson's disease and correlated the findings to dopamine transporter density, measured by (123)I-FP-CIT single photon emission computed tomography. A total of 17 patients with idiopathic Parkinson's disease and 16 age- and sex-matched control subjects had (18)F-AV-1451 positron emission tomography using a Siemens high-resolution research tomograph. Twelve patients with Parkinson's disease also received a standardized (123)I-FP-CIT single photon emission computed tomography scan at our imaging facility. Many of the patients with Parkinson's disease displayed visually apparent decreased (18)F-AV-1451 signal in the midbrain. On quantitation, patients showed a 30% mean decrease in total nigral (18)F-AV-1451 volume of distribution compared with controls (P = 0.004), but there was an overlap of the individual ranges. We saw no significant correlation between symptom dominant side and contralateral nigral volume of distribution. There was no correlation between nigral (18)F-AV-1451 volume of distribution and age or time since diagnosis. In the subset of 12 patients, who also had a (123)I-FP-CIT scan, the mean total striatal dopamine transporter signal was decreased by 45% and the mean total (18)F-AV-1451 substantia nigra volume of distribution was decreased by 33% after median disease duration of 4.7 years (0.5-12.4 years). (18)F-AV-1451 positron emission tomography may be the first radiotracer to reflect the loss of pigmented neurons in the substantia nigra of parkinsonian patients. The magnitude of the nigral signal loss was smaller than the decrease in striatal dopamine transporter signal measured by dopamine transporter single photon emission computed tomography. These findings suggest a more severe loss of striatal nerve terminal function compared with neuronal cell bodies, in accordance with the post-mortem literature. [ABSTRACT FROM AUTHOR]

Braak's hypothesis has been extremely influential over the last two decades. However, neuropathological and clinical evidence suggest that the model does not conform to all patients with Parkinson's disease (PD). To resolve this controversy, a new model was recently proposed; in brain-first PD , the initial α-synuclein pathology arise inside the central nervous system, likely rostral to the substantia nigra pars compacta, and spread via interconnected structures – eventually affecting the autonomic nervous system; in body-first PD , the initial pathological α-synuclein originates in the enteric nervous system with subsequent caudo-rostral propagation to the autonomic and central nervous system. By using REM-sleep behavior disorder (RBD) as a clinical identifier to distinguish between body-first PD (RBD-positive at motor symptom onset) and brain-first PD (RBD-negative at motor symptom onset), we explored the literature to evaluate clinical and imaging differences between these proposed subtypes. Body-first PD patients display: 1) a larger burden of autonomic symptoms - in particular orthostatic hypotension and constipation, 2) more frequent pathological α-synuclein in peripheral tissues, 3) more brainstem and autonomic nervous system involvement in imaging studies, 4) more symmetric striatal dopaminergic loss and motor symptoms, and 5) slightly more olfactory dysfunction. In contrast, only minor cortical metabolic alterations emerge before motor symptoms in body-first. Brain-first PD is characterized by the opposite clinical and imaging patterns. Patients with pathological LRRK2 genetic variants mostly resemble a brain-first PD profile whereas patients with GBA variants typically conform to a body-first profile. SNCA-variant carriers are equally distributed between both subtypes. Overall, the literature indicates that body-first and brain-first PD might be two distinguishable entities on some clinical and imaging markers. [ABSTRACT FROM AUTHOR]

The average human lifespan has increased dramatically over the past century. However, molecular and physiological alterations of the healthy brain during aging remain incompletely understood. Generalized synaptic restructuring may contribute to healthy aging and the reduced metabolism observed in the aged brain. The aim of this study was to assess healthy brain aging using [18F]FDG as a measure of cerebral glucose consumption and [11C]UCB-J PET as an indicator of synaptic density. Using in vivo PET imaging and the novel synaptic-vesicle-glycoprotein 2A (SV2A) radioligand [11C]UCB-J alongside with the fluorodeoxyglucose radioligand [18F]FDG, we obtained SUVR-1 values for 14 pre-defined volume-of-interest brain regions defined on MRI T1 scans. Regional differences in relative [18F]FDG and [11C]UCB-J uptake were investigated using a voxel-wise approach. Finally, correlations between [11C]UCB-J, [18F]FDG PET, and age were examined. We found widespread cortical reduction of synaptic density in a cohort of older HC subjects (N = 15) compared with young HC subjects (N = 11). However, no reduction persisted after partial volume correction and corrections for multiple comparison. Our study confirms previously reported synaptic stability during aging. Regional differences in relative [18F]FDG and [11C]UCB-J uptake were observed with up to 20 % higher [11C]UCB-J uptake in the amygdala and temporal lobe and up to 34 % higher glucose metabolism in thalamus, striatum, occipital, parietal and frontal cortex. In vivo PET using [11C]UCB-J does not support declining synaptic density levels during aging. Thus, loss of synaptic density may be unrelated to aging and does not seem to be a sufficient explanation for the recognized reduction in brain metabolism during aging. Our study also demonstrates that the relationship between glucose consumption and synaptic density is not uniform throughout the human brain with implications for our understanding of neuroenergetics. [Display omitted] • Widespread reduction of [11C]UCB-J binding suggest a declining number of synapses in brain aging. • No significant reduction of synapses persisted after PVC and correction for multiple comparisons. • Synaptic loss does not seem to be a major contributor to reduction in brain metabolism during aging. • Some cerebral regions have a higher glucose consumption per synapse than others. • The glucose consumption per synapse may be changed with aging, particularly in the frontal lobes. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most common neurodegenerative disease. Patients show deposits of pathological, aggregated α-synuclein not only in the brain but throughout almost the entire length of the digestive tract. This gives rise to non-motor symptoms particularly within the gastrointestinal tract and patients experience a wide range of frequent and burdensome symptoms such as dysphagia, bloating, and constipation. Recent evidence suggests that progressive accumulation of gastrointestinal pathology is underway several years before a clinical diagnosis of PD. Notably, constipation has been shown to increase the risk of developing PD and in contrast, truncal vagotomy seems to decrease the risk of PD. Animal models have demonstrated gut-to-brain spreading of pathological α-synuclein and it is currently being intensely studied whether PD begins in the gut of some patients. Gastrointestinal symptoms in PD have been investigated by the use of several different questionnaires. However, there is limited correspondence between subjective gastrointestinal symptoms and objective dysfunction along the gastrointestinal tract, and often the magnitude of dysfunction is underestimated by the use of questionnaires. Therefore, objective measures are important tools to clarify the degree of dysfunction in future studies of PD. Here, we summarize the types and prevalence of subjective gastrointestinal symptoms and objective dysfunction in PD. The potential importance of the gastrointestinal tract in the etiopathogenesis of PD is briefly discussed. [ABSTRACT FROM AUTHOR]

Dementia with Lewy bodies is characterized by a high burden of autonomic dysfunction and Lewy pathology in peripheral organs and components of the sympathetic and parasympathetic nervous system. Parasympathetic terminals may be quantified with 18F-fluoroetoxybenzovesamicol, a PET tracer that binds to the vesicular acetylcholine transporter in cholinergic presynaptic terminals. Parasympathetic imaging may be useful for diagnostics, improving our understanding of autonomic dysfunction and for clarifying the spatiotemporal relationship of neuronal degeneration in prodromal disease. Therefore, we aimed to investigate the cholinergic parasympathetic integrity in peripheral organs and central autonomic regions of subjects with dementia with Lewy bodies and its association with subjective and objective measures of autonomic dysfunction. We hypothesized that organs with known parasympathetic innervation, especially the pancreas and colon, would have impaired cholinergic integrity. To achieve these aims, we conducted a cross-sectional comparison study including 23 newly diagnosed non-diabetic subjects with dementia with Lewy bodies (74 ± 6 years, 83% male) and 21 elderly control subjects (74 ± 6 years, 67% male). We obtained whole-body images to quantify PET uptake in peripheral organs and brain images to quantify PET uptake in regions of the brainstem and hypothalamus. Autonomic dysfunction was assessed with questionnaires and measurements of orthostatic blood pressure. Subjects with dementia with Lewy bodies displayed reduced cholinergic tracer uptake in the pancreas (32% reduction, P = 0.0003) and colon (19% reduction, P = 0.0048), but not in organs with little or no parasympathetic innervation. Tracer uptake in a region of the medulla oblongata overlapping the dorsal motor nucleus of the vagus correlated with autonomic symptoms (rs = −0.54, P = 0.0077) and changes in orthostatic blood pressure (rs = 0.76, P < 0.0001). Tracer uptake in the pedunculopontine region correlated with autonomic symptoms (rs = −0.52, P = 0.0104) and a measure of non-motor symptoms (rs = −0.47, P = 0.0230). In conclusion, our findings provide the first imaging-based evidence of impaired cholinergic integrity of the pancreas and colon in dementia with Lewy bodies. The observed changes may reflect parasympathetic denervation, implying that this process is initiated well before the point of diagnosis. The findings also support that cholinergic denervation in the brainstem contributes to dysautonomia. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence suggests that α-synuclein aggregates-a defining pathology of Parkinson's disease-display cell-to-cell transmission. α-synuclein aggregation is hypothesised to start in autonomic nerve terminals years before the appearance of motor symptoms, and subsequently spread via autonomic nerves to the spinal cord and brainstem. To assess this hypothesis, we investigated sympathetic, parasympathetic, noradrenergic, and dopaminergic innervation in patients with idiopathic rapid eye movement (REM) sleep behaviour disorder, a prodromal phenotype of Parkinson's disease.Methods: In this prospective, case-control study, we recruited patients with idiopathic REM sleep behaviour disorder, confirmed by polysomnography, without clinical signs of parkinsonism or dementia, via advertisement and through sleep clinics in Denmark. We used 11C-donepezil PET and CT to assess cholinergic (parasympathetic) gut innervation, 123I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure integrity of pigmented neurons of the locus coeruleus, 11C-methylreboxetine (MeNER) PET to assess noradrenergic nerve terminals originating in the locus coeruleus, and 18F-dihydroxyphenylalanine (DOPA) PET to assess nigrostriatal dopamine storage capacity. For each imaging modality, we compared patients with idiopathic REM sleep behaviour disorder with previously published reference data of controls without neurological disorders or cognitive impairment and with symptomatic patients with Parkinson's disease. We assessed imaging data using one-way ANOVA corrected for multiple comparisons.Findings: Between June 3, 2016, and Dec 19, 2017, we recruited 22 consecutive patients with idiopathic REM sleep behaviour disorder to the study. Compared with controls, patients with idiopathic REM sleep behaviour disorder had decreased colonic 11C-donepezil uptake (-0·322, 95% CI -0·112 to -0·531; p=0·0020), 123I-MIBG heart:mediastinum ratio (-0·508, -0·353 to -0·664; p<0·0001), neuromelanin-sensitive MRI locus coeruleus:pons ratio (-0·059, -0·019 to -0·099; p=0·0028), and putaminal 18F-DOPA uptake (Ki; -0·0023, -0·0009 to -0·0037; p=0·0013). No between-group differences were detected between idiopathic REM sleep behaviour disorder and Parkinson's disease groups with respect to 11C-donepezil (p=0·39), 123I-MIBG (p>0·99), neuromelanin-sensitive MRI (p=0·96), and 11C-MeNER (p=0·56). By contrast, 15 (71%) of 21 patients with idiopathic REM sleep behaviour disorder had 18F-DOPA Ki values within normal limits, whereas all patients with Parkinson's disease had significantly decreased 18F-DOPA Ki values when compared with patients with idiopathic REM sleep behaviour disorder (p<0·0001).Interpretation: Patients with idiopathic REM sleep behaviour disorder had fully developed pathology in the peripheral autonomic nervous system and the locus coeruleus, equal to that in diagnosed Parkinson's disease. These patients also showed noradrenergic thalamic denervation, but most had normal putaminal dopaminergic storage capacity. This caudorostral gradient of dysfunction supports the hypothesis that α-synuclein pathology in Parkinson's disease initially targets peripheral autonomic nerves and then spreads rostrally to the brainstem.Funding: Lundbeck Foundation, Jascha Foundation, and the Swiss National Foundation. [ABSTRACT FROM AUTHOR]

Parkinson's disease is characterized by the presence of abnormal, intraneuronal α-synuclein aggregates, which may propagate from cell-to-cell in a prion-like manner. However, it remains uncertain where the initial α-synuclein aggregates originate. We have hypothesized that Parkinson's disease comprises two subtypes. A brain-first (top-down) type, where α-synuclein pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system; and a body-first (bottom-up) type, where the pathology originates in the enteric or peripheral autonomic nervous system and then spreads to the brain. We also hypothesized that isolated REM sleep behaviour disorder (iRBD) is a prodromal phenotype for the body-first type. Using multimodal imaging, we tested the hypothesis by quantifying neuronal dysfunction in structures corresponding to Braak stages I, II and III involvement in three distinct patient groups. We included 37 consecutive de novo patients with Parkinson's disease into this case-control PET study. Patients with Parkinson's disease were divided into 24 RBD-negative (PDRBD-) and 13 RBD-positive cases (PDRBD+) and a comparator group of 22 iRBD patients. We used 11C-donepezil PET/CT to assess cholinergic (parasympathetic) innervation, 123I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure the integrity of locus coeruleus pigmented neurons, and 18F-dihydroxyphenylalanine (FDOPA) PET to assess putaminal dopamine storage capacity. Colon volume and transit times were assessed with CT scans and radiopaque markers. Imaging data from the three groups were interrogated with ANOVA and Kruskal-Wallis tests corrected for multiple comparisons. The PDRBD- and PDRBD+ groups showed similar marked reductions in putaminal FDOPA-specific uptake, whereas two-thirds of iRBD patients had normal scans (P < 10-13, ANOVA). When compared to the PDRBD- patients, the PDRBD+ and iRBD patients showed reduced mean MIBG heart:mediastinum ratios (P < 10-5, ANOVA) and colon 11C-donepezil standard uptake values (P = 0.008, ANOVA). The PDRBD+ group trended towards a reduced mean MRI locus coeruleus: pons ratio compared to PDRBD- (P = 0.07, t-test). In comparison to the other groups, the PDRBD+ group also had enlarged colon volumes (P < 0.001, ANOVA) and delayed colonic transit times (P = 0.01, Kruskal-Wallis). The combined iRBD and PDRBD+ patient data were compatible with a body-first trajectory, characterized by initial loss of cardiac MIBG signal and 11C-colonic donepezil signal followed by loss of putaminal FDOPA uptake. In contrast, the PDRBD- data were compatible with a brain-first trajectory, characterized by primary loss of putaminal FDOPA uptake followed by a secondary loss of cardiac MIBG signal and 11C-donepezil signal. These findings support the existence of brain-first and body-first subtypes of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Cholinergic changes play a fundamental role in the natural history of dementia with Lewy bodies and Lewy body disease in general. Despite important achievements in the field of cholinergic research, significant challenges remain. We conducted a study with four main objectives: (i) to examine the integrity of cholinergic terminals in newly diagnosed dementia with Lewy bodies; (ii) to disentangle the cholinergic contribution to dementia by comparing cholinergic changes in Lewy body patients with and without dementia; (iii) to investigate the in vivo relationship between cholinergic terminal loss and atrophy of cholinergic cell clusters in the basal forebrain at different stages of Lewy body disease; and (iv) to test whether any asymmetrical degeneration in cholinergic terminals would correlate with motor dysfunction and hypometabolism. To achieve these objectives, we conducted a comparative cross-sectional study of 25 newly diagnosed dementia with Lewy bodies patients (age 74 ± 5 years, 84% male), 15 healthy control subjects (age 75 ± 6 years, 67% male) and 15 Parkinson's disease patients without dementia (age 70 ± 7 years, 60% male). All participants underwent 18F-fluoroetoxybenzovesamicol PET and high-resolution structural MRI. In addition, we collected clinical 18F-fluorodeoxyglucose PET images. Brain images were normalized to standard space and regional tracer uptake and volumetric indices of basal forebrain degeneration were extracted. Patients with dementia showed spatially distinct reductions in cholinergic terminals across the cerebral cortex, limbic system, thalamus and brainstem. Also, cholinergic terminal binding in cortical and limbic regions correlated quantitatively and spatially with atrophy of the basal forebrain. In contrast, patients without dementia showed decreased cholinergic terminal binding in the cerebral cortex despite preserved basal forebrain volumes. In patients with dementia, cholinergic terminal reductions were most severe in limbic regions and least severe in occipital regions compared to those without dementia. Interhemispheric asymmetry of cholinergic terminals correlated with asymmetry of brain metabolism and lateralized motor function. In conclusion, this study provides robust evidence for severe cholinergic terminal loss in newly diagnosed dementia with Lewy bodies, which correlates with structural imaging measures of cholinergic basal forebrain degeneration. In patients without dementia, our findings suggest that loss of cholinergic terminal function occurs 'before' neuronal cell degeneration. Moreover, the study supports that degeneration of the cholinergic system is important for brain metabolism and may be linked with degeneration in other transmitter systems. Our findings have implications for understanding how cholinergic system pathology contributes to the clinical features of Lewy body disease, changes in brain metabolism and disease progression patterns. [ABSTRACT FROM AUTHOR]

Isolated rapid eye movement sleep behaviour disorder (iRBD) is a sleep disorder characterized by the loss of rapid eye movement sleep muscle atonia and the appearance of abnormal movements and vocalizations during rapid eye movement sleep. It is a strong marker of incipient synucleinopathy such as dementia with Lewy bodies and Parkinson's disease. Patients with iRBD already show brain changes that are reminiscent of manifest synucleinopathies including brain atrophy. However, the mechanisms underlying the development of this atrophy remain poorly understood. In this study, we performed cutting-edge imaging transcriptomics and comprehensive spatial mapping analyses in a multicentric cohort of 171 polysomnography-confirmed iRBD patients [67.7 ± 6.6 (49–87) years; 83% men] and 238 healthy controls [66.6 ± 7.9 (41–88) years; 77% men] with T1-weighted MRI to investigate the gene expression and connectivity patterns associated with changes in cortical thickness and surface area in iRBD. Partial least squares regression was performed to identify the gene expression patterns underlying cortical changes in iRBD. Gene set enrichment analysis and virtual histology were then done to assess the biological processes, cellular components, human disease gene terms, and cell types enriched in these gene expression patterns. We then used structural and functional neighbourhood analyses to assess whether the atrophy patterns in iRBD were constrained by the brain's structural and functional connectome. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems, functional networks, cytoarchitectonic classes, and cognitive brain systems associated with cortical changes in iRBD. All comparisons were tested against null models that preserved spatial autocorrelation between brain regions and compared to Alzheimer's disease to assess the specificity of findings to synucleinopathies. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the cortical thinning occurring in iRBD. Moreover, we demonstrated that cortical thinning was constrained by the brain's structural and functional connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with cortical thickness, changes in cortical surface area were related to distinct genes, namely genes involved in the inflammatory response, and to different spatial mapping patterns. The gene expression and connectivity patterns associated with iRBD were all distinct from those observed in Alzheimer's disease. In summary, this study demonstrates that the development of brain atrophy in synucleinopathies is constrained by specific genes and networks. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: The peripheral autonomic nervous system may be involved years before onset of motor symptoms in some patients with Parkinson's disease (PD). Specific imaging techniques to quantify the cholinergic nervous system in peripheral organs are an unmet need. We tested the hypothesis that patients with PD display decreased [18F]FEOBV uptake in peripheral organs - a sign of parasympathetic denervation.Methods: We included 15 PD patients and 15 age- and sex matched healthy controls for a 70 min whole-body dynamic positron emission tomography (PET) acquisition. Compartmental modelling was used for tracer kinetic analyses of adrenal gland, pancreas, myocardium, spleen, renal cortex, muscle and colon. Standard uptake values (SUV) at 60-70 min post injection were also extracted for these organs. Additionally, SUVs were also determined in the total colon, prostate, parotid and submandibular glands.Results: We found no statistically significant difference of [18F]FEOBV binding parameters in any organs between patients with PD and healthy controls, although trends were observed. The pancreas SUV showed a 14% reduction in patients (P = 0.021, not statistically significant after multiple comparison correction). We observed a trend towards lower SUVs in the pancreas, colon, adrenal gland, and myocardium of PD patients with versus without probable REM sleep behavior disorder.Conclusion: [18F]FEOBV PET may not be a sensitive marker for parasympathetic degeneration in patients with PD. [ABSTRACT FROM AUTHOR]

Isolated REM sleep behaviour disorder (iRBD) is a synucleinopathy characterized by abnormal behaviours and vocalizations during REM sleep. Most iRBD patients develop dementia with Lewy bodies, Parkinson's disease, or multiple system atrophy over time. Patients with iRBD exhibit brain atrophy patterns that are reminiscent of those observed in overt synucleinopathies. However, the mechanisms linking brain atrophy to the underlying alpha-synuclein pathophysiology are poorly understood. Our objective was to investigate how the prion-like and regional vulnerability hypotheses of alpha-synuclein might explain brain atrophy in iRBD. Using a multicentric cohort of 182 polysomnography-confirmed iRBD patients who underwent T1-weighted MRI, we performed vertex-based cortical surface and deformation-based morphometry analyses to quantify brain atrophy in patients (67.8 years, 84% men) and 261 healthy controls (66.2 years, 75%) and investigated the morphological correlates of motor and cognitive functioning in iRBD. Next, we applied the agent-based Susceptible-Infected-Removed model (i.e., a computational model that simulates in silico the spread of pathologic alpha-synuclein based on structural connectivity and gene expression) and tested if it recreated atrophy in iRBD by statistically comparing simulated regional brain atrophy to the atrophy observed in patients. The impact of SNCA and GBA gene expression and brain connectivity was then evaluated by comparing the model fit to the one obtained in null models where either gene expression or connectivity was randomized. The results showed that iRBD patients present with cortical thinning and tissue deformation, which correlated with motor and cognitive functioning. Next, we found that the computational model recreated cortical thinning (r = 0.51, p = 0.0007) and tissue deformation (r = 0.52, p = 0.0005) in patients, and that the connectome's architecture along with SNCA and GBA gene expression contributed to shaping atrophy in iRBD. We further demonstrated that the full agent-based model performed better than network measures or gene expression alone in recreating the atrophy pattern in iRBD. In summary, atrophy in iRBD is extensive, correlates with motor and cognitive function, and can be recreated using the dynamics of agent-based modelling, structural connectivity, and gene expression. These findings support the concepts that both prion-like spread and regional susceptibility account for the atrophy observed in prodromal synucleinopathies. Therefore, the agent-based Susceptible-Infected-Removed model may be a useful tool for testing hypotheses underlying neurodegenerative diseases and new therapies aimed at slowing or stopping the spread of alpha-synuclein pathology. [ABSTRACT FROM AUTHOR]

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-[(11)C]-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-[(11)C]-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 (11)C-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 (11)C-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 (11)C-donepezil binding may, therefore, represent a marker of parasympathetic denervation of internal organs, but further validation studies are needed. [ABSTRACT FROM AUTHOR]

To assess the agreement between clinical cardiovascular adrenergic function and cardiac adrenergic innervation in type 2 diabetes patients (T2D). Thirty-three patients with T2D were investigated bimodally through (1) a standardized clinical cardiovascular adrenergic assessment, evaluating adequacy of blood pressure responses to the Valsalva maneuver and (2) 123I-meta-iodobenzylguanidine (MIBG) scintigraphy assessing myocardial adrenergic innervation measured as early and delayed heart heart/mediastinum (H/M) ratio, and washout rate (WR). T2D patients had significantly lower early and delayed H/M-ratios, and lower WR, compared to laboratory specific reference values. Thirteen patients had an abnormal adrenergic composite autonomic severity score (CASS > 0). Patients with abnormal CASS scores had significantly higher early H/M ratios (1.76 [1.66–1.88] vs. 1.57 [1.49–1.63], p < 0.001), higher delayed H/M ratios (1.64 [1.51:1.73] vs. 1.51 [1.40:1.61] (p = 0.02)), and lower WR (−0.13(0.10) vs −0.05(0.07), p = 0.01). Lower Total Recovery and shorter Pressure Recovery Time responses from the Valsalva maneuver was significantly correlated to lower H/M early (r = 0.55, p = 0.001 and r = 0.5, p = 0.003, respectively) and lower WR for Total Recovery (r = −0.44, p = 0.01). The present study found impairment of sympathetic innervation in T2D patients based on parameters derived from MIBG cardiac scintigraphy (low early H/M, delayed H/M, and WR). These results confirm prior studies. We found a mechanistically inverted relationship with favourable adrenergic cardiovascular responses being significantly associated unfavourable MIBG indices for H/M early and delayed. This paradoxical relationship needs to be further explored but could indicate adrenergic hypersensitivity in cardiac sympathetic denervated T2D patients. • Patients with type 2 diabetes have impaired cardiac sympathetic innervation. • Preserved cardiovascular reflex response is associated with sympathetic denervation. • MIBG scintigraphy allows for assessment of cardiac autonomic innervation integrity. [ABSTRACT FROM AUTHOR]

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 < 0.0001, P < 0.001; probabilistic map: P < 0.05), specifically on the clinically-defined most affected side (P < 0.05), and reduced locus coeruleus volume (P < 0.0001). Reduced MRI contrast was confined to the middle and caudal locus coeruleus (voxel approach, rostral: P = 0.48, middle: P < 0.0001, and caudal: P < 0.05; probabilistic map, rostral: P = 0.90, middle: P < 0.01, and caudal: P < 0.05). The noradrenaline transporter density was lower in patients with Parkinson's diseasein all examined regions (group effect P < 0.0001). No significant correlation was observed between locus coeruleus MRI contrast and noradrenaline transporter density. In contrast, the individual ratios of noradrenaline transporter density and locus coeruleus MRI contrast were lower in Parkinson's disease patients in all examined regions (group effect P < 0.001). Our multimodal imaging approach revealed pronounced noradrenergic terminal loss relative to cellular locus coeruleus degeneration in Parkinson's disease; the latter followed a distinct spatial pattern with the middle-caudal portion being more affected than the rostral part. 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. [ABSTRACT FROM AUTHOR]

Background/Aims Patients with diabetes mellitus (DM) often suffer from gastrointestinal (GI) symptoms, but these correlate poorly to established objective GI motility measures. Our aim is to perform a detailed evaluation of potential measures of gastric and small intestinal motility in patients with DM type 1 and severe GI symptoms. Methods Twenty patients with DM and 20 healthy controls (HCs) were included. GI motility was examined with a 3-dimensional-Transit capsule, while organ volumes were determined by CT scans. Results Patients with DM and HCs did not differ with regard to median gastric contraction frequency (DM: 3.0 contractions/minute [interquartile range {IQR}, 2.9-3.0]; HCs: 2.9 [IQR, 2.8-3.1]; P = 0.725), amplitude of gastric contractions (DM: 9 mm [IQR, 8-11]; HCs: 11 mm (IQR, 9-12); P = 0.151) or fasting volume of the stomach wall (DM: 149 cm3 [IQR, 112-187]; HCs: 132 cm3 [IQR, 107-154]; P = 0.121). Median gastric emptying time was prolonged in patients (DM: 3.3 hours [IQR, 2.6-4.6]; HCs: 2.4 hours [IQR, 1.8-2.7]; P = 0.002). No difference was found in small intestinal transit time (DM: 5 hours [IQR, 3.7-5.6]; HCs: 4.8 hours [IQR, 3.9-6.0]; P = 0.883). However, patients with DM had significantly larger volume of the small intestinal wall (DM: 623 cm3 [IQR, 487-766]; HCs: 478 cm3 [IQR, 393-589]; P = 0.003). Among patients, 13 (68%) had small intestinal wall volume and 9 (50%) had gastric emptying time above the upper 95% percentile of HCs. Conclusion In our study, gastric emptying time and volume of the small intestinal wall appeared to be the best objective measures in patients with DM type 1 and symptoms and gastroenteropathy. [ABSTRACT FROM AUTHOR]

Introduction: Autonomic denervation in patients with Parkinson's disease (PD) and isolated REM-sleep behavior disorder (iRBD) could impede gallbladder function leading to increased fasting gallbladder volume (fGBV) and higher risk of gallstones. We aimed to determine fGBV in patients with PD, iRBD, and healthy controls (HCs).Methods: We included 189 subjects; 100 patients with PD, 21 with iRBD, and 68 HCs. fGBV was determined from abdominal CT scans, and radiopaque gallstone frequency was evaluated.Results: Median fGBV was 35.7 ml in patients with PD, 31.8 ml in iRBD, and 27.8 ml in HCs (Kruskal-Wallis test: P = 0.0055). Post-tests adjusted for multiple comparison revealed a significant group difference between patients with PD and HCs (P = 0.0038). In the PD group, 23% had enlarged fGBV (cut-off at mean + 2 x standard deviation (SD) in the HC group). No difference in fGBV was observed between iRBD and the other two groups. The total prevalence of gallstones was 6.4% with no differences between the three groups.Conclusion: Almost a quarter of patients with PD in our cohort exhibited increased fGBV. This study illuminates a potentially overlooked topic in PD research and calls for more studies on biliary dysfunction. [ABSTRACT FROM AUTHOR]

Background: The Motilis 3D‐Transit system allows ambulatory description of transit patterns throughout the gastrointestinal tract and offers an alternative method for studying gastric motility. We aimed to establish normative values for gastric motility assessed with the method. Method: A total of 132 healthy volunteers ingested the 3D‐Transit capsule for assessment of gastrointestinal transit times. Recordings from 125 subjects were used for definition of normative values. Forty‐six subjects were studied on two consecutive days. Recordings were reanalyzed using newly developed software providing information on gastric emptying (GE) as well as contraction frequency and movement during gastric contractions. Results: The median GE time was 2.7 hours (range 0.1‐21.2). In 89% of subjects, the capsule passed the pylorus within a postingestion period of 6 hours. The median frequency of gastric contractions was 3.1 per minute (range 2.6‐3.8). The frequency was higher in women (3.2, range 2.7‐3.8) than in men (3.0, range 2.6‐3.5) and increased with age (0.004 per year) (P <.05). The median amplitudes were 35° (range 4‐85) when based on rotation of the capsule and 11 mm (range 6‐31) when based on capsule change in position. The rotation amplitude was higher in women and decreased with increasing BMI (P <.05). The position amplitude was also higher in women and increased with the amount of calories in the test meal, but decreased with increasing BMI and age (P <.05). Day‐to‐day variation (P >.05) was considerable while inter‐rater variability was small. Conclusion and Inferences: We have established normative values for gastric motility assessed with the 3D‐Transit system. [ABSTRACT FROM AUTHOR]

Introduction: Noradrenergic denervation is thought to aggravate motor dysfunction in Parkinson's disease (PD). In a previous PET study with the norepinephrine transporter (NART) ligand 11C-MeNER, we detected reduced NART binding in primary sensorimotor cortex (M1S1) of PD patients. Idiopathic rapid-eye-movement sleep behaviour disorder (iRBD) is a phenotype of prodromal PD. Using 11C-MeNER PET, we investigated whether iRBD patients showed similar NART binding reductions in M1S1 cortex as PD patients. Additionally, we investigated whether 11C-MeNER binding and loss of nigrostriatal dopamine storage capacity measured with 18F-DOPA PET were correlated.Methods: 17 iRBD patients, 16 PD patients with (PDRBD+) and 14 without RBD (PDRBD-), and 25 control subjects underwent 11C-MeNER PET. iRBD patients also had 18F-DOPA PET. Volume-of-interest analyses and voxel-level statistical parametric mapping were performed.Results: Partial-volume corrected 11C-MeNER binding potential (BPND) values in M1S1 differed across the groups (P = 0.022) with the iRBD and PDRBD+ groups showing significant reductions (controls vs. iRBD P = 0.007; control vs. PDRBD+P = 0.008). Voxel-wise comparisons confirmed reductions of M1S1 11C-MeNER binding in PD and iRBD patients. Significant correlation was seen between putaminal 18F-DOPA uptake and thalamic 11C-MeNER binding in iRBD patients (r2 = 0.343, P = 0.013).Conclusions: This study found altered noradrenergic neurotransmission in the M1S1 cortex of iRBD patients. The observed reduction of M1S1 11C-MeNER binding in iRBD may represent noradrenergic terminal degeneration or physiological down-regulation of NARTs in this prodromal phenotype of PD. The correlation between thalamic 11C-MeNER binding and putaminal 18F-DOPA binding suggests that these neurotransmitter systems degenerate in parallel in the iRBD phenotype of prodromal PD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease copathology is common in PD at autopsy. In non-PD subjects with mild cognitive impairment, tau depositions can be detected using 18F-AV-1451 PET. We hypothesized that 18F-AV-1451 PET would show tau aggregation in PD with mild cognitive impairment and correlate with cognitive dysfunction.Objectives: To describe tau aggregation in PD patients.Methods: Twenty-six PD patients and 23 controls had 18F-AV-1451 PET and neuropsychological assessment to detect mild cognitive impairment.Results: Nine PD patients (35%) were identified with mild cognitive impairment. Regional analyses showed no significant differences between groups. Voxel-wise analyses showed no correlation with cognitive domain z-scores within patients. One patient with mild cognitive impairment was estimated Braak tau stage 5; all other patients were stage 0.Conclusion: Our results indicate that tau pathology, as detected by 18F-AV-1451, is uncommon in PD with mild cognitive impairment and shows no significant correlation with cognitive dysfunction at this stage. © 2017 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Introduction: Immune cells utilize acetylcholine as a paracrine-signaling molecule. Many white blood cells express components of the cholinergic signaling pathway, and these are up-regulated when immune cells are activated. However, in vivo molecular imaging of cholinergic signaling in the context of inflammation has not previously been investigated. Methods: We performed positron emission tomography (PET) using the glucose analogue 18F-FDG, and 11C-donepezil and 18F-FEOBV, markers of acetylcholinesterase and the vesicular acetylcholine transporter, respectively. Mice were inoculated subcutaneously with Staphylococcus aureus, and PET scanned at 24, 72, 120, and 144 h post-inoculation. Four pigs with post-operative abscesses were also imaged. Finally, we present initial data from human patients with infections, inflammation, and renal and lung cancer. Results: In mice, the FDG uptake in abscesses peaked at 24 h and remained stable. The 11C-donepezil and 18F-FEOBV uptake displayed progressive increase, and at 120-144 h was nearly at the FDG level. Moderate 11C-donepezil and slightly lower 18F-FEOBV uptake were seen in pig abscesses. PCR analyses suggested that the 11C-donepezil signal in inflammatory cells is derived from both acetylcholinesterase and sigma-1 receptors. In humans, very high 11C-donepezil uptake was seen in a lobar pneumonia and in peri-tumoral inflammation surrounding a non-small cell lung carcinoma, markedly superseding the 18F-FDG uptake in the inflammation. In a renal clear cell carcinoma no 11C-donepezil uptake was seen. Discussion: The time course of cholinergic tracer accumulation in murine abscesses was considerably different from 18F-FDG, demonstrating in the 11C-donepezil and 18F-FEOBV image distinct aspects of immune modulation. Preliminary data in humans strongly suggest that 11C-donepezil can exhibit more intense accumulation than 18F-FDG at sites of chronic inflammation. Cholinergic PET imaging may therefore have potential applications for basic research into cholinergic mechanisms of immune modulation, but also clinical applications for diagnosing infections, inflammatory disorders, and cancer inflammation. [ABSTRACT FROM AUTHOR]

Noradrenergic neurotransmission may play an important role in tremor modulation through its innervation of key structures of the central tremor circuits. Here, Parkinson's disease (PD) patients with (PDT+) or without (PDT-) rest tremor had 11C-methylreboxetine(11C-MeNER) positron emission tomography (PET) to test the hypothesis that noradrenaline terminal function was relatively preserved in PDT+ compared to PDT-. Sixty-five PD patients and 28 healthy controls (HC) were scanned with 11C-MeNER PET. Patients were categorized as PDT+ if subscores in UPDRS-III item 3 or MDS-UPDRS-III item 17 was ≥2; remaining were categorized as PDT-. Simplified reference tissue model 2 distribution volume ratios (DVR) for 11C-MeNER were calculated for thalamus, dorsal and median raphe, locus coeruleus (LC) and red nucleus using time activity curves (TACs) obtained from volumes of interest (VOI). Data were statistically interrogated with a general linear mixed model using 'region', and 'group' as factors and the interaction of 'region x group' was examined. Tremor positive PD patients had a significantly higher mean 11C-MeNER DVR compared to PDT- in LC and thalamus. The PDT+ mean LC DVR was similar to that of HC. PDT+ mean 11C-MeNER DVRs were significantly lower than HC in the dorsal raphe while the PDT- group showed significantly lower mean 11C-MeNER DVR across all regions compared to HC. While both PD T+ and PD T- groups showed a significant loss of noradrenaline terminal function compared to controls, noradrenergic neurons were relatively preserved in PDT+ in LC and thalamus. The greater loss of noradrenergic transporters in PDT- in LC and thalamus compared with PDT+ is in line with earlier in-vitro studies and could potentially contribute to their tremor negative phenotype. • Noradrenaline is associated with rest tremor in Parkinson's disease. • Noradrenaline is preserved in tremor predominant Parkinson's Disease. • Patients without tremor show loss of noradrenaline in locus coeruleus and thalamus. [ABSTRACT FROM AUTHOR]

Background: The 3D‐Transit electromagnet tracking system (Motilis Medica, SA, Lausanne, Switzerland) is an emerging tool for the ambulatory assessment of gastrointestinal (GI) transit and motility. Using this tool, we aimed to derive normative values for region‐specific colonic and GI transit times and to assess the influence of age, gender, and body mass index (BMI). Methods: Regional and total colonic transit times (CTT), gastric emptying (GET), small intestinal (SITT), and whole gut (WGTT) transit times were extracted from 111 healthy volunteers from the United Kingdom and Denmark (58 female; median age: 40 years [range: 21‐88]). The effects of age, gender, and BMI were assessed using standard statistical methods. Key Results: The ascending, transverse, descending, and rectosigmoid colon transit times accounted for 32%, 34%, 17%, and 17% of total CTT in females, and 33%, 25%, 14%, and 28% of total CTT in males. CTT and WGTT were seen to cluster at intervals separated by approximately 24 hours, providing further evidence of the non‐continuous nature of these measurements. Increasing age was associated with longer CTT (P =.021), WGTT (P <.001) ascending (P =.004), transverse (P <.001), and total right (P <.001) colon transit times, but shorter rectosigmoid (P =.004) transit time. Female gender was significantly associated with longer transverse (P =.049) and descending (P <.001) colon transit times, but shorter rectosigmoid (P <.001) transit time. Increasing BMI was significantly associated with shorter WGTT (P =.012). Conclusions and Inferences: For the first time, normative reference values for region‐specific colonic transit have been presented. Age, gender, and BMI were seen to have an effect on transit times. [ABSTRACT FROM AUTHOR]

Background: 11C‐Donepezil positron emission tomography (PET) allows non‐invasive assessment of cholinergic innervation of visceral organs. We aimed to compare cholinergic innervation in the gut in patients with diabetes mellitus (DM) and in healthy controls (HC). Methods: 11C‐Donepezil PET and computed tomography (CT) were performed in 19 patients with type 1 DM and gastrointestinal symptoms and in 19 age‐ and sex‐matched HC in a cross‐sectional design. Key Results: All patients had severe gastrointestinal symptoms when assessed by standard questionnaires. DM patients had significantly increased volume of the small intestinal wall (DM: median 557 cm3 [interquartile range [IQR] 446‐697] vs HC median: 448 cm3 [IQR; 341‐518; P <.01]), and the 11C Donepezil PET uptake was reduced in patients (DM: median 7.08 standardized uptake value [SUV] [IQR; 5.94‐8.43] vs HC: median 9.18 SUV [IQR; 8.57‐10.11; P <.01]). A similar pattern was found in colon (DM: median volume 1064 cm3 [IQR; 882‐1312] vs HC: median 939 cm3 [IQR; 785‐1081; P =.13] and DM: median 1.22 SUV (IQR; 1.08‐1.36) vs HC: median 1.42 SUV (IQR; 1.32‐1.53; P =.03). Furthermore, patients had significantly reduced pancreatic volume (DM: median 53 cm3 [IQR; 41‐69] vs HC: median 98 cm3 [IQR;82‐110; P <.01]) and reduced PET uptake of the pancreas (DM: median 13.14 SUV [IQR;9.58‐15.82] vs HC: median 21.46 SUV [IQR;18.97‐24.06; P <.01]) as well as the adrenal gland (DM: median 7.62 SUV [IQR;7.61;15.82] vs HC: median 15.51 SUV [IQR;12.22;19.49; P =.03]). Conclusion and Inferences: Assessed with 11C‐Donepezil PET/CT, patients with DM and severe bowel symptoms have reduced cholinergic innervation of the gut indicative of parasympathetic denervation. [ABSTRACT FROM AUTHOR]

Introduction 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. A computer program with an automated scoring algorithm would thus be a valuable asset for sleep professionals scoring RBD. Methods An electromyogram (EMG) computer algorithm for scoring ‘tonic’ (2× root mean square (RMS) of baseline EMG activity for > 15 s per 30 s epoch), ‘phasic’ (max amplitude > 4×RMS baseline (or 2× during concomitant ‘tonic’ activity), 3 s epochs) and ‘any’ (‘tonic’ and/or ‘phasic’) submental muscle activity during REM sleep was created using the criteria’s of McCarter et al. [1]. For validation of the computer algorithm, visual scoring of EMG activity done by two blinded board-certified sleep professionals was compared to scoring of the computer algorithm in the first consecutive 10 Parkinson’s disease (PD) patients with RBD (PD RBD+ ) and 10 PD patients without RBD (PD RBD− ) using regression analysis and Kappa statistics. Subsequently, 29 non-RBD subjects (14 PD RBD− and 15 healthy controls) and 23 RBD subjects (16 PD RBD+ and 7 idiopathic RBD subjects) were analyzed with the computer algorithm to test for discrimination power between RBD and non-RBD subjects. Results The computer algorithm showed high congruency with human ratings on single epoch level (using Kappa statistics: ‘tonic’ activity κ  = 0.74 & κ  = 0.78, ‘phasic’ activity κ  = 0.80 & κ  = 0.76, ‘any’ activity κ  = 0.83 & κ  = 0.82), which was similar to the κ values between the two human raters (‘tonic’ activity κ  = 0.64, ‘phasic’ activity κ  = 0.79, ‘any’ activity κ  = 0.82). In the discrimination analysis, all RBD subjects were correctly identified by excess of submental muscle activity, when artifacts were removed before analysis. At an individual patient level, cut-off values with full differentiation between non-RBD and RBD subjects were obtained for ‘phasic’ and ‘any’ activity (cut off values at > 10% of REM sleep; range of non-RBD subjects, 1.3–8.2% for ‘phasic’ and ‘any’; range of RBD subjects, 13.2–64.5% for ‘phasic’ and 13.3–77.4% for ‘any’, respectively). Conclusion Our proposed automated computer algorithm allows a fast quantitation of ‘tonic’, ‘phasic’, and ‘any’ EMG activity with good agreement to visual ratings and was able to detect and rate REM sleep without atonia. The computer algorithm seems a promising tool to be used in the clinical setting for supporting a diagnosis of RBD. [ABSTRACT FROM AUTHOR]

Objectives REM sleep without atonia (RSWA) is a key feature of REM sleep behavior disorder (RBD). However, detailed visual scoring of EMG on 30 and 3 s intervals is highly time demanding. A computer program with automated scoring algorithm would thus be a valuable asset for sleep professionals scoring RBD. Methods Criteria’s for tonic (2xRMS baseline for >15 s per 30 s epoch), phasic (max amplitude >4 × RMS baseline (or 2 × Tonic), 3 s epochs) and any (tonic and/or phasic) chin EMG activity were implemented in a software algorithm. Sleep stages, respiratory-, arousal- and artifact events were visually scored and imported into the software. Visual scoring of EMG activity done by a blinded board-certified sleep professional was compared to the software algorithm by regression analysis and Kappa statistics. A total of 31989 3 s epochs in 19 patients with Parkinson’s disease (PD) were evaluated (mean age 65.2 ± 9.7, 10 RBD+, 9 RBD−). Results Total percentages of tonic, phasic and any muscle activity correlated strongly between the software algorithm and visual scoring ( R 2 > 0.97 for all activities). Cohen’s Kappa indicated very high agreement on individual events (0.73 for tonic, 0.80 for phasic, 0.83 for any activity). A cut-off value of 10% of any activity separated both groups correctly. Bouts of phasic activity were longer in patients with RBD compared non-RBD (375.4 ± 61.1 versus 478.3 ± 88.9, p = 0.014). Conclusion/significance Our software reliably detects altered chin muscle activity in PD patients when excluding artifact corrupted epochs, providing a fast tool for detecting RBD patients and metrics for correlation analysis with clinical variables. [ABSTRACT FROM AUTHOR]