Publications by authors named "Karoline Knudsen"

34 Publications

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

Parkinsonism Relat Disord 2021 Apr 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2021.04.027DOI Listing
April 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/sleep/zsab040DOI Listing
February 2021

Gastrointestinal Dysfunction in Parkinson's Disease.

J Clin Med 2021 Jan 31;10(3). Epub 2021 Jan 31.

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

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10030493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866791PMC
January 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

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

Skin Temperature in Parkinson's Disease Measured by Infrared Thermography.

Parkinsons Dis 2020 25;2020:2349469. Epub 2020 Jul 25.

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

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%,  = 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 3 and 5 phalanx and body mass index (BMI) ( = 0.661,  = 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/2349469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397449PMC
July 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

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

Normative values for gastric motility assessed with the 3D-transit electromagnetic tracking system.

Neurogastroenterol Motil 2020 06 10;32(6):e13829. Epub 2020 Mar 10.

Neurogastroenterology Unit, Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/nmo.13829DOI Listing
June 2020

In vivo positron emission tomography imaging of decreased parasympathetic innervation in the gut of vagotomized patients.

Neurogastroenterol Motil 2020 03 12;32(3):e13759. Epub 2019 Nov 12.

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

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 C-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 C-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 C-donepezil signal in the intestine of vagotomized patients, supporting that C-donepezil PET is a valid measure of intestinal parasympathetic denervation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/nmo.13759DOI Listing
March 2020

Enteric cholinergic neuropathy in patients with diabetes: Non-invasive assessment with positron emission tomography.

Neurogastroenterol Motil 2020 01 8;32(1):e13731. Epub 2019 Oct 8.

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

Background: C-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: C-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 cm [interquartile range [IQR] 446-697] vs HC median: 448 cm [IQR; 341-518; P < .01]), and the C 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 cm [IQR; 882-1312] vs HC: median 939 cm [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 cm [IQR; 41-69] vs HC: median 98 cm [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 C-Donepezil PET/CT, patients with DM and severe bowel symptoms have reduced cholinergic innervation of the gut indicative of parasympathetic denervation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/nmo.13731DOI Listing
January 2020

Normative values for region-specific colonic and gastrointestinal transit times in 111 healthy volunteers using the 3D-Transit electromagnet tracking system: Influence of age, gender, and body mass index.

Neurogastroenterol Motil 2020 02 29;32(2):e13734. Epub 2019 Sep 29.

GI Physiology Unit, Barts and the London School of Medicine and Dentistry, The Blizard Institute, Queen Mary University of London, London, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/nmo.13734DOI Listing
February 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1074248419838509DOI Listing
July 2019

Imaging the Autonomic Nervous System in Parkinson's Disease.

Curr Neurol Neurosci Rep 2018 09 19;18(11):79. Epub 2018 Sep 19.

Department of Nuclear Medicine and PET Centre Aarhus University Hospital, Institute of Clinical Medicine Aarhus University, Norrebrogade 44, Building 10, 8000, Aarhus C, Denmark.

Purpose Of Review: Patients with Parkinson's disease (PD) often display gastrointestinal and genitourinary autonomic symptoms years or even decades prior to diagnosis. These symptoms are thought to be caused in part by pathological α-synuclein inclusions in the peripheral autonomic and enteric nervous systems. It has been proposed that the initial α-synuclein aggregation may in some PD patients originate in peripheral nerve terminals and then spread centripetally to the spinal cord and brainstem. In vivo imaging methods can directly quantify the degeneration of the autonomic nervous system as well as the functional consequences such as perturbed motility. Here, we review the methodological principles of these imaging techniques and the major findings in patients with PD and atypical parkinsonism.

Recent Findings: Loss of sympathetic and parasympathetic nerve terminals in PD can be visualized using radiotracer imaging, including I-MIBG scintigraphy, and F-dopamine and C-donepezil PET. Recently, ultrasonographical studies disclosed reduced diameter of the vagal nerves in PD patients. Radiological and radioisotope techniques have demonstrated dysmotility and prolonged transit time throughout all subdivisions of the gastrointestinal tract in PD. The prevalence of objective dysfunction as measured with these imaging methods is often considerably higher compared to the prevalence of subjective symptoms experienced by the patients. Degeneration of the autonomic nervous system may play a key role in the pathogenesis of PD. In vivo imaging techniques provide powerful and noninvasive tools to quantify the degree and extent of this degeneration and its functional consequences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11910-018-0889-4DOI Listing
September 2018

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.
View Article and Find Full Text PDF

Download full-text PDF

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

Gastrointestinal transit time and heart rate variability in patients with mild acquired brain injury.

PeerJ 2018 6;6:e4912. Epub 2018 Jun 6.

Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.

Background: Constipation is suspected to occur frequently after acquired brain injury (ABI). In patients with ABI, heart rate variability (HRV) is reduced suggesting autonomic dysfunction. Autonomic dysfunction may be associated with prolonged gastrointestinal transit time (GITT). The primary aim of this study was to investigate if GITT is prolonged in patients with ABI. Secondarily, HRV and its correlation with GITT was investigated.

Methods: We included 25 patients with ABI (18 men, median age: 61.3 years, range [30.7-74.5]). GITT was assessed using radio-opaque markers and HRV was calculated from 24-hour electrocardiograms. Medical records were reviewed for important covariates, including primary diagnosis, time since injury, functional independence measure, and use of medication. The GITT assessed in patients was compared to a control group of 25 healthy subjects (18 men, median age: 61.5 years, range [34.0-70.9]).

Results: In ABI patients, the mean GITT was significantly longer than in healthy controls (2.68 days, 95% CI [2.16-3.19] versus (1.92 days, 95% CI [1.62-2.22],  = 0.011)). No correlation was found between HRV and GITT.

Conclusion: Patients with mild to moderate ABI have prolonged GITT unrelated to the HRV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7717/peerj.4912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994161PMC
June 2018

Gastric emptying in Parkinson's disease - A mini-review.

Parkinsonism Relat Disord 2018 10 6;55:18-25. Epub 2018 Jun 6.

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

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 C-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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2018.06.003DOI Listing
October 2018

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41531-017-0017-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460119PMC
April 2017

Reply to the letter to the Editor: Comment to Barichella and colleagues.

Mov Disord 2017 04 4;32(4):631. Epub 2017 Apr 4.

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.26991DOI Listing
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000003633DOI Listing
February 2017

Constipation in parkinson's disease: Subjective symptoms, objective markers, and new perspectives.

Mov Disord 2017 01 22;32(1):94-105. Epub 2016 Nov 22.

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

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.26866DOI Listing
January 2017

Cholinergic PET imaging in infections and inflammation using C-donepezil and F-FEOBV.

Eur J Nucl Med Mol Imaging 2017 Mar 26;44(3):449-458. Epub 2016 Oct 26.

Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Noerrebrogade 44, bygn. 10G, kaelderen, DK-8000, Aarhus C, Denmark.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00259-016-3555-6DOI Listing
March 2017