Utility of (11)C-methionine and (11)C-donepezil for imaging of Staphylococcus aureus induced osteomyelitis in a juvenile porcine model:comparison to autologous (111)In-labelled leukocytes, (99m) Tc-DPD, and (18)F-FDG

The aim of this study was to compare (11)C-methionine and (11)C-donepezil positron emission tomography (PET) with (111)In-labeled leukocyte and (99m)Tc-DPD (Tc-99m 3,3-diphosphono-1,2-propanedicarboxylic acid) single-photon emission computed tomography (SPECT), and (18)F-fluorodeoxyglucose ((18)F-FDG) PET to improve detection of osteomyelitis. The tracers’ diagnostic utility where tested in a juvenile porcine hematogenously induced osteomyelitis model comparable to osteomyelitis in children. Five 8-9 weeks old female domestic pigs were scanned seven days after intra-arterial inoculation in the right femoral artery with a porcine strain of Staphylococcus aureus. The sequential scan protocol included Computed Tomography, (11)C-methionine and (11)C-donepezil PET, (99m)Tc-DPD and (111)In-labelled leukocytes scintigraphy, and (18)F-FDG PET. This was followed by necropsy of the pigs and gross pathology, histopathology, and microbial examination. The pigs developed a total of 24 osteomyelitic lesions, 4 lesions characterized as contiguous abscesses and pulmonary abscesses (in two pigs). By comparing the 24 osteomyelitic lesions, (18)F-FDG accumulated in 100%, (111)In-leukocytes in 79%, (11)C-methionine in 79%, (11)C-donepezil in 58%, and (99m)Tc-DPD in none. Overall, (18)F-FDG PET was superior to (111)In-leukocyte SPECT and (11)C-methionine in marking infectious lesions

Cholinergic system changes in Parkinson's disease: emerging therapeutic approaches

In patients with Parkinson's disease, heterogeneous cholinergic system changes can occur in different brain regions. These changes correlate with a range of clinical features, both motor and non-motor, that are refractory to dopaminergic therapy, and can be conceptualised within a systems-level framework in which nodal deficits can produce circuit dysfunctions. The topographies of cholinergic changes overlap with neural circuitries involved in sleep and cognitive, motor, visuo-auditory perceptual, and autonomic functions. Cholinergic deficits within cognition network hubs predict cognitive deficits better than do total brain cholinergic changes. Postural instability and gait difficulties are associated with cholinergic system changes in thalamic, caudate, limbic, neocortical, and cerebellar nodes. Cholinergic system deficits can involve also peripheral organs. Hypercholinergic activity of mesopontine cholinergic neurons in people with isolated rapid eye movement (REM) sleep behaviour disorder, as well as in the hippocampi of cognitively normal patients with Parkinson's disease, suggests early compensation during the prodromal and early stages of Parkinson's disease. Novel pharmacological and neurostimulation approaches could target the cholinergic system to treat motor and non-motor features of Parkinson's disease

Assessment of Gastrointestinal Autonomic Dysfunction:Present and Future Perspectives

The autonomic nervous system delicately regulates the function of several target organs, including the gastrointestinal tract. Thus, nerve lesions or other nerve pathologies may cause autonomic dysfunction (AD). Some of the most common causes of AD are diabetes mellitus and α-synucleinopathies such as Parkinson’s disease. Widespread dysmotility throughout the gastrointestinal tract is a common finding in AD, but no commercially available method exists for direct verification of enteric dysfunction. Thus, assessing segmental enteric physiological function is recommended to aid diagnostics and guide treatment. Several established assessment methods exist, but disadvantages such as lack of standardization, exposure to radiation, advanced data interpretation, or high cost, limit their utility. Emerging methods, including high-resolution colonic manometry, 3D-transit, advanced imaging methods, analysis of gut biopsies, and microbiota, may all assist in the evaluation of gastroenteropathy related to AD. This review provides an overview of established and emerging assessment methods of physiological function within the gut and assessment methods of autonomic neuropathy outside the gut, especially in regards to clinical performance, strengths, and limitations for each method

Gastric Emptying Time and Volume of the Small Intestine as Objective Markers in Patients With Symptoms of Diabetic Enteropathy

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

A postmortem study suggests a revision of the dual-hit hypothesis of Parkinson's disease

The dual-hit hypothesis of Parkinson's disease (PD) originally postulated that a neurotropic pathogen leads to formation of alpha-synuclein pathology in the olfactory bulb (OB) and dorsal motor nucleus of the vagus (DMV) and then invades the brain from these two entry points. Little work has been conducted to validate an important underlying premise for the dual-hit hypothesis, namely that the initial Lewy pathology does arise simultaneously in the OB and the enteric nervous system (ENS) plexuses and DMV at the earliest disease stage. We conducted a focused re-analysis of two postmortem datasets, which included large numbers of mild Lewy body disease (LBD) cases. We found that cases with alpha-synuclein pathology restricted to the peripheral autonomic nervous system and/or lower brainstem (early body-first LBD cases) very rarely had any OB pathology, suggesting that Lewy pathology commonly arises in the ENS without concomitant involvement of the OB. In contrast, cases with mild amygdala-predominant Lewy pathology (early brain-first LBD cases) nearly always showed OB pathology. This is compatible with the first pathology being triggered in the OB or amygdala followed by secondary spreading to connected structures, but without early involvement of the ENS or lower brainstem. These observations support that the pathologic process starts in either the olfactory bulb or the ENS, but rarely in the olfactory bulb and gut simultaneously. More studies on neuropathological datasets are warranted to reproduce these findings. The agreement between the revised single-hit hypothesis and the recently proposed brain-first vs. body-first model of LBD is discussed.Peer reviewe

Impact of aging on animal models of Parkinson's disease

Aging is the biggest risk factor for developing Parkinson's disease (PD), the second most common neurodegenerative disorder. Several animal models have been developed to explore the pathophysiology underlying neurodegeneration and the initiation and spread of alpha-synuclein-related PD pathology, and to investigate biomarkers and therapeutic strategies. However, bench-to-bedside translation of preclinical findings remains suboptimal and successful disease-modifying treatments remain to be discovered. Despite aging being the main risk factor for developing idiopathic PD, most studies employ young animals in their experimental set-up, hereby ignoring age-related cellular and molecular mechanisms at play. Consequently, studies in young animals may not be an accurate reflection of human PD, limiting translational outcomes. Recently, it has been shown that aged animals in PD research demonstrate a higher susceptibility to developing pathology and neurodegeneration, and present with a more disseminated and accelerated disease course, compared to young animals. Here we review recent advances in the investigation of the role of aging in preclinical PD research, including challenges related to aged animal models that are limiting widespread use. Overall, current findings indicate that the use of aged animals may be required to account for age-related interactions in PD pathophysiology. Thus, although the use of older animals has disadvantages, a model that better represents clinical disease within the elderly would be more beneficial in the long run, as it will increase translational value and minimize the risk of therapies failing during clinical studies. Furthermore, we provide recommendations to manage the challenges related to aged animal models

Kinetic Modelling of Infection Tracers [ 18

Introduction. Positron emission tomography (PET) is increasingly applied for infection imaging using [18F]FDG as tracer, but uptake is unspecific. The present study compares the kinetics of [18F]FDG and three other PET tracers with relevance for infection imaging. Methods. A juvenile porcine osteomyelitis model was used. Eleven pigs underwent PET/CT with 60-minute dynamic PET imaging of [18F]FDG, [68Ga]Ga-citrate, [11C]methionine, and/or [11C]donepezil, along with blood sampling. For infectious lesions, kinetic modelling with one- and two-tissue-compartment models was conducted for each tracer. Results. Irreversible uptake was found for [18F]FDG and [68Ga]Ga-citrate; reversible uptake was found for [11C]methionine (two-tissue model) and [11C]donepezil (one-tissue model). The uptake rate for [68Ga]Ga-citrate was slow and diffusion-limited. For the other tracers, the uptake rate was primarily determined by perfusion (flow-limited uptake). Net uptake rate for [18F]FDG and distribution volume for [11C]methionine were significantly higher for infectious lesions than for correspondingly noninfected tissue. For [11C]donepezil in pigs, labelled metabolite products appeared to be important for the analysis. Conclusions. The kinetics of the four studied tracers in infection was characterized. For clinical applications, [18F]FDG remains the first-choice PET tracer. [11C]methionine may have a potential for detecting soft tissue infections. [68Ga]Ga-citrate and [11C]donepezil were not found useful for imaging of osteomyelitis

Distribution of cholinergic nerve terminals in the aged human brain measured with [18F]FEOBV PET and its correlation with histological data

Introduction: [18F]fluoroetoxybenzovesamicol ([18F]FEOBV) is a positron emission topography (PET) tracer for the vesicular acetylcholine transporter (VAChT), a protein located predominantly in synaptic vesicles in cholinergic nerve terminals. We aimed to use [18F]FEOBV PET to study the cholinergic topography of the healthy human brain. Materials and methods: [18F]FEOBV PET brain data volumes of healthy elderly humans were normalized to standard space and intensity-normalized to the white matter. Stereotactic atlases of regions of interest were superimposed to describe and quantify tracer distribution. The spatial distribution of [18F]FEOBV PET uptake was compared with histological and gene expression data. Results: Twenty participants of both sexes and a mean age of 73.9 ± 6.0 years, age-range [64; 86], were recruited. Highest tracer binding was present in the striatum, some thalamic nuclei, and the basal forebrain. Intermediate binding was found in most nuclei of the brainstem, thalamus, and hypothalamus; the vermis and flocculonodular lobe; and the hippocampus, amygdala, insula, cingulate, olfactory cortex, and Heschl's gyrus. Lowest binding was present in most areas of the cerebral cortex, and in the cerebellar nuclei and hemispheres. The spatial distribution of tracer correlated with immunohistochemical post-mortem data, as well as with regional expression levels of SLC18A3, the VAChT coding gene. Discussion: Our in vivo findings confirm the regional cholinergic distribution in specific brain structures as described post-mortem. A positive spatial correlation between tracer distribution and regional gene expression levels further corroborates [18F]FEOBV PET as a validated tool for in vivo cholinergic imaging. The study represents an advancement in the continued efforts to delineate the spatial topography of the human cholinergic system in vivo