Publications by authors named "Tatyana D Fedorova"

18 Publications

  • Page 1 of 1

Fasting gallbladder volume is increased in patients with Parkinson's disease.

Parkinsonism Relat Disord 2021 Jun 30;87:56-60. Epub 2021 Apr 30.

Department of Nuclear Medicine and PET, Aarhus University Hospital, Palle Juul-Jensens Boulevard 165, J220, 8200, Aarhus N, Denmark.

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.
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http://dx.doi.org/10.1016/j.parkreldis.2021.04.027DOI Listing
June 2021

Microsleep disturbances are associated with noradrenergic dysfunction in Parkinson's disease.

Sleep 2021 Feb 20. Epub 2021 Feb 20.

Department of Neurology, University Hospital Cologne, Faculty of Medicine, University of Cologne, Köln, Germany.

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 analysed 27 PD patients and 13 healthy control (HC) subjects who underwent over-night 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.
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http://dx.doi.org/10.1093/sleep/zsab040DOI Listing
February 2021

Preserved noradrenergic function in Parkinson's disease patients with rest tremor.

Neurobiol Dis 2021 May 5;152:105295. Epub 2021 Feb 5.

Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, 8200 Aarhus N, Denmark; Department of Neurology, Restorative Parkinson Unit, Universitetssjukhuset, 22184 Lund, Sweden.

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 (PD) or without (PD) rest tremor had C-methylreboxetine(C-MeNER) positron emission tomography (PET) to test the hypothesis that noradrenaline terminal function was relatively preserved in PD compared to PD.

Methods: Sixty-five PD patients and 28 healthy controls (HC) were scanned with C-MeNER PET. Patients were categorized as PD if subscores in UPDRS-III item 3 or MDS-UPDRS-III item 17 was ≥2; remaining were categorized as PD. Simplified reference tissue model 2 distribution volume ratios (DVR) for C-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.

Results: Tremor positive PD patients had a significantly higher mean C-MeNER DVR compared to PD in LC and thalamus. The PD mean LC DVR was similar to that of HC. PD mean C-MeNER DVRs were significantly lower than HC in the dorsal raphe while the PD group showed significantly lower mean C-MeNER DVR across all regions compared to HC.

Conclusion: While both PD and PD groups showed a significant loss of noradrenaline terminal function compared to controls, noradrenergic neurons were relatively preserved in PD in LC and thalamus. The greater loss of noradrenergic transporters in PD in LC and thalamus compared with PD is in line with earlier in-vitro studies and could potentially contribute to their tremor negative phenotype.
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http://dx.doi.org/10.1016/j.nbd.2021.105295DOI Listing
May 2021

Brain-first versus body-first Parkinson's disease: a multimodal imaging case-control study.

Brain 2020 10;143(10):3077-3088

Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark.

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.
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http://dx.doi.org/10.1093/brain/awaa238DOI Listing
October 2020

Altered sensorimotor cortex noradrenergic function in idiopathic REM sleep behaviour disorder - A PET study.

Parkinsonism Relat Disord 2020 06 19;75:63-69. Epub 2020 May 19.

Aarhus University Hospital, Department of Nuclear Medicine and PET Centre, Aarhus, Denmark.

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 C-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 C-MeNER PET, we investigated whether iRBD patients showed similar NART binding reductions in M1S1 cortex as PD patients. Additionally, we investigated whether C-MeNER binding and loss of nigrostriatal dopamine storage capacity measured with F-DOPA PET were correlated.

Methods: 17 iRBD patients, 16 PD patients with (PD) and 14 without RBD (PD), and 25 control subjects underwent C-MeNER PET. iRBD patients also had F-DOPA PET. Volume-of-interest analyses and voxel-level statistical parametric mapping were performed.

Results: Partial-volume corrected C-MeNER binding potential (BP) values in M1S1 differed across the groups (P = 0.022) with the iRBD and PD groups showing significant reductions (controls vs. iRBD P = 0.007; control vs. PDP = 0.008). Voxel-wise comparisons confirmed reductions of M1S1 C-MeNER binding in PD and iRBD patients. Significant correlation was seen between putaminal F-DOPA uptake and thalamic C-MeNER binding in iRBD patients (r = 0.343, P = 0.013).

Conclusions: This study found altered noradrenergic neurotransmission in the M1S1 cortex of iRBD patients. The observed reduction of M1S1 C-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 C-MeNER binding and putaminal F-DOPA binding suggests that these neurotransmitter systems degenerate in parallel in the iRBD phenotype of prodromal PD.
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http://dx.doi.org/10.1016/j.parkreldis.2020.05.013DOI Listing
June 2020

A Screening-Based Method for Identifying Patients with REM Sleep Behaviour Disorder in a Danish Community Setting.

J Parkinsons Dis 2020 ;10(3):1249-1253

Aarhus University Hospital, Department of Nuclear Medicine and PET Centre, Aarhus, Denmark.

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.
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http://dx.doi.org/10.3233/JPD-202020DOI Listing
January 2020

Cardiac C-Donepezil Binding Increases With Age in Healthy Humans: Potentially Signifying Sigma-1 Receptor Upregulation.

J Cardiovasc Pharmacol Ther 2019 07 26;24(4):365-370. Epub 2019 Mar 26.

1 Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Aarhus, Denmark.

Background: Donepezil may have cardioprotective properties, but the mechanism is unclear. Using positron-emission tomography (PET), we explored C-donepezil uptake in the heart of humans in relation to age. The results are discussed in the context of the cardioprotective property of donepezil.

Methods: We included data from 57 patients with cardiac C-donepezil PET scans. Linear regression analyses were performed to explore the correlation between cardiac C-donepezil standardized uptake value (SUV) and age. Subgroup analyses were performed for healthy controls, patients with prodromal or diagnosed Parkinson disease (PD), males, and females.

Results: In the total group of 57 patients, linear regression analysis revealed a significant positive correlation between cardiac C-donepezil uptake and age ( r = .63, P < .0001). The average increase was ≈1.25 SUV per decade and a 2-fold increase in SUV from age 30 to 65 years. Subgroup analyses also showed significant correlations: healthy control patients alone (n = 28, r = .73, P < .0001), prodromal or diagnosed PD (n = 29, r = .28, P = .03), male patients (n = 34, r = .49, P < .0001), and female patients (n = 23, r = .82, P < .0001). No other organs showed increased C-donepezil binding with age.

Conclusions: C-donepezil SUV increases robustly with age in the normal human heart. We speculate that the increased donepezil binding is caused primarily by sigma-1 receptor upregulation. If our interpretation is correct, it shows that sigma-1 receptors are dynamically regulated and may represent an overlooked target for pharmacological intervention studies.
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http://dx.doi.org/10.1177/1074248419838509DOI Listing
July 2019

Objective intestinal function in patients with idiopathic REM sleep behavior disorder.

Parkinsonism Relat Disord 2019 01 18;58:28-34. Epub 2018 Aug 18.

Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark.

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.
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http://dx.doi.org/10.1016/j.parkreldis.2018.08.011DOI Listing
January 2019

In-vivo staging of pathology in REM sleep behaviour disorder: a multimodality imaging case-control study.

Lancet Neurol 2018 07 1;17(7):618-628. Epub 2018 Jun 1.

Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark. Electronic address:

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 C-donepezil PET and CT to assess cholinergic (parasympathetic) gut innervation, I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure integrity of pigmented neurons of the locus coeruleus, C-methylreboxetine (MeNER) PET to assess noradrenergic nerve terminals originating in the locus coeruleus, and 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 C-donepezil uptake (-0·322, 95% CI -0·112 to -0·531; p=0·0020), 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 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 C-donepezil (p=0·39), I-MIBG (p>0·99), neuromelanin-sensitive MRI (p=0·96), and C-MeNER (p=0·56). By contrast, 15 (71%) of 21 patients with idiopathic REM sleep behaviour disorder had F-DOPA Ki values within normal limits, whereas all patients with Parkinson's disease had significantly decreased 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.
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http://dx.doi.org/10.1016/S1474-4422(18)30162-5DOI Listing
July 2018

Decreased noradrenaline transporter density in the motor cortex of Parkinson's disease patients.

Mov Disord 2018 07 24;33(6):1006-1010. Epub 2018 May 24.

Aarhus University Hospital, Department of Nuclear Medicine and PET Centre, Aarhus, Denmark.

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 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 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 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 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.
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http://dx.doi.org/10.1002/mds.27411DOI Listing
July 2018

Observations on muscle activity in REM sleep behavior disorder assessed with a semi-automated scoring algorithm.

Clin Neurophysiol 2018 03 28;129(3):541-547. Epub 2017 Dec 28.

Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark; Department of Neurology, University Hospital Cologne, Cologne, Germany.

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.
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http://dx.doi.org/10.1016/j.clinph.2017.12.029DOI Listing
March 2018

Evaluation of the noradrenergic system in Parkinson's disease: an 11C-MeNER PET and neuromelanin MRI study.

Brain 2018 02;141(2):496-504

Aarhus University Hospital, Department of Nuclear Medicine and PET Centre, Aarhus, Denmark.

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.
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http://dx.doi.org/10.1093/brain/awx348DOI Listing
February 2018

Pancreatic Polypeptide in Parkinson's Disease: A Potential Marker of Parasympathetic Denervation.

J Parkinsons Dis 2017 ;7(4):645-652

Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark.

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, which was 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.
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http://dx.doi.org/10.3233/JPD-171189DOI Listing
June 2018

Gastrointestinal Transit Time in Parkinson's Disease Using a Magnetic Tracking System.

J Parkinsons Dis 2017 ;7(3):471-479

Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark.

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 fast movements, 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.
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http://dx.doi.org/10.3233/JPD-171131DOI Listing
April 2018

Imaging Parkinson's disease below the neck.

NPJ Parkinsons Dis 2017 25;3:15. Epub 2017 Apr 25.

Department of Nuclear Medicine & PET Centre, Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Parkinson's disease is a systemic disorder with widespread and early -synuclein pathology in the autonomic and enteric nervous systems, which is present throughout the gastrointestinal canal prior to diagnosis. Gastrointestinal and genitourinary autonomic symptoms often predate clinical diagnosis by several years. It has been hypothesized that progressive -synuclein aggregation is initiated in hyperbranched, non-myelinated neuron terminals, and may subsequently spread via retrograde axonal transport. This would explain why autonomic nerves are so prone to formation of -synuclein pathology. However, the hypothesis remains unproven and in vivo imaging methods of peripheral organs may be essential to study this important research field. The loss of sympathetic and parasympathetic nerve terminal function in Parkinson's disease has been demonstrated using radiotracers such as I-meta-iodobenzylguanidin, F-dopamine, and C-donepezil. Other radiotracer and radiological imaging methods have shown highly prevalent dysfunction of pharyngeal and esophageal motility, gastric emptying, colonic transit time, and anorectal function. Here, we summarize the methodology and main findings of radio-isotope and radiological modalities for imaging peripheral pathology in Parkinson's disease.
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http://dx.doi.org/10.1038/s41531-017-0017-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460119PMC
April 2017

In Vivo cortical tau in Parkinson's disease using 18F-AV-1451 positron emission tomography.

Mov Disord 2017 06 3;32(6):922-927. Epub 2017 Mar 3.

Dept of Nuclear Medicine & PET Centre, Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.

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.
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http://dx.doi.org/10.1002/mds.26961DOI Listing
June 2017

Objective Colonic Dysfunction is Far more Prevalent than Subjective Constipation in Parkinson's Disease: A Colon Transit and Volume Study.

J Parkinsons Dis 2017 ;7(2):359-367

Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark.

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.
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http://dx.doi.org/10.3233/JPD-161050DOI Listing
January 2018

Decreased intestinal acetylcholinesterase in early Parkinson disease: An C-donepezil PET study.

Neurology 2017 Feb 18;88(8):775-781. Epub 2017 Jan 18.

From the Department of Nuclear Medicine and PET-Centre (T.D.F., L.B.S., K.K., A.C.S., N.P., D.J.B., P.B.) and Department of Neurology (J.G.), Aarhus University Hospital, Denmark.

Objective: To investigate systemic levels of acetylcholinesterase in early Parkinson disease (PD) with C-donepezil PET, a potential marker of parasympathetic innervation.

Methods: This was a cross-sectional study with 19 patients with early-stage PD (disease duration 1.5 ± 0.6 years) and 16 age-matched controls who had clinical assessments, olfaction tests, and C-donepezil PET to measure acetylcholinesterase density in peripheral organs.

Results: The patients with PD showed significantly reduced C-donepezil uptake in the small intestine (-14%, = 0.018), colon (-22%, < 0.001), and kidneys (-14%, = 0.028). No difference in myocardial or pancreatic acetylcholinesterase levels was seen.

Conclusion: We found significantly decreased C-donepezil signal in the intestine and kidneys of patients with early PD, suggesting that parasympathetic denervation is present early in the disease course.
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http://dx.doi.org/10.1212/WNL.0000000000003633DOI Listing
February 2017