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In Parkinson disease (PD), pathological processes and neurodegeneration begin long before the cardinal motor symptoms develop and enable clinical diagnosis. In this prodromal phase, risk and prodromal markers can be used to identify individuals who are likely to develop PD, as in the recently updated International Parkinson and Movement Disorders Society research criteria for prodromal PD. However, increasing evidence suggests that clinical and prodromal PD are heterogeneous, and can be classified into subtypes with different clinical manifestations, pathomechanisms and patterns of spatial and temporal progression in the CNS and PNS. Genetic, pathological and imaging markers, as well as motor and non-motor symptoms, might define prodromal subtypes of PD. Moreover, concomitant pathology or other factors, including amyloid-β and tau pathology, age and environmental factors, can cause variability in prodromal PD. Patients with REM sleep behaviour disorder (RBD) exhibit distinct patterns of α-synuclein pathology propagation and might indicate a body-first subtype rather than a brain-first subtype. Identification of prodromal PD subtypes and a full understanding of variability at this stage of the disease is crucial for early and accurate diagnosis and for targeting of neuroprotective interventions to ensure efficacy.

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 T+ ) or without (PD T- ) rest tremor had 11 C-methylreboxetine( 11 C-MeNER) positron emission tomography (PET) to test the hypothesis that noradrenaline terminal function was relatively preserved in PD T+ compared to PD T- ., Methods: Sixty-five PD patients and 28 healthy controls (HC) were scanned with 11 C-MeNER PET. Patients were categorized as PD T+ if subscores in UPDRS-III item 3 or MDS-UPDRS-III item 17 was ≥2; remaining were categorized as PD T- . Simplified reference tissue model 2 distribution volume ratios (DVR) for 11 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 11 C-MeNER DVR compared to PD T- in LC and thalamus. The PD T+ mean LC DVR was similar to that of HC. PD T+ mean 11 C-MeNER DVRs were significantly lower than HC in the dorsal raphe while the PD T- group showed significantly lower mean 11 C-MeNER DVR across all regions compared to HC., Conclusion: While both PD T+ and PD T- groups showed a significant loss of noradrenaline terminal function compared to controls, noradrenergic neurons were relatively preserved in PD T+ in LC and thalamus. The greater loss of noradrenergic transporters in PD T- in LC and thalamus compared with PD T+ is in line with earlier in-vitro studies and could potentially contribute to their tremor negative phenotype., (Copyright © 2021. Published by Elsevier Inc.)

Brain death is the complete, irreversible cessation of brain function, including the capacity for brainstem, respiratory, and vegetative activities. It is a clinical diagnosis that can be supplemented with brain perfusion imaging. Absent cerebral blood flow can be visualized with CT angiography or perfusion scintigraphy. F-FDG PET/CT, visualizing glucose uptake, is another approach that has been shown to indicate brain death in small case series. We here present a case with unsuspected absent F-FDG uptake and thus no metabolic activity, in the brain. The patient was declared brain dead later the same day.

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., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Purpose: Cholinergic dysfunction appears to play a role in the cognitive impairment observed in Parkinson's disease and dementia with Lewy bodies. The occurrence of cholinergic dysfunction in the early stages of these conditions, however, has not been investigated. The objective of this study was to investigate cholinergic function in patients with idiopathic rapid eye movement sleep behaviour disorder (iRBD), a disorder recognized to be an early stage of both Parkinson's disease and dementia with Lewy bodies., Methods: A total of 21 patients with polysomnography-confirmed iRBD with no evidence of parkinsonism and cognitive impairment and 10 controls underwent positron emission tomography (PET) to assess brain acetylcholinesterase levels ( 11 C-donepezil PET) and nigrostriatal dopaminergic function ( 18 F-DOPA PET). Clinical examination included the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III, Mini Mental State Examination and Montreal Cognitive Assessment., Results: The 11 C-donepezil PET was successfully performed in 17 patients with iRBD and nine controls. Compared with controls, patients with iRBD showed a mean 7.65% reduction in neocortical 11 C-donepezil levels (P = 0.005). Bilateral superior temporal cortex, occipital cortex, cingulate cortex and dorsolateral prefrontal cortex showed the most significant reductions at voxel level., Conclusion: Reduced neocortical 11 C-donepezil binding in our patients indicates cholinergic denervation and suggests that the projections from the nucleus basalis of Meynert, which supplies cholinergic innervation to the neocortex, are dysfunctional in iRBD. Longitudinal studies will clarify if these changes are predictive of future cognitive impairment in these patients., (© 2019 European Academy of Neurology.)

The conversion of endogenous alpha-synuclein (asyn) to pathological asyn-enriched aggregates is a hallmark of Parkinson's disease (PD). These inclusions can be detected in the central and enteric nervous system (ENS). Moreover, gastrointestinal symptoms can appear up to 20 years before the diagnosis of PD. The dual-hit hypothesis posits that pathological asyn aggregation starts in the ENS, and retrogradely spreads to the brain. In this study, we tested this hypothesis by directly injecting preformed asyn fibrils into the duodenum wall of wild-type rats and transgenic rats with excess levels of human asyn. We provide a meticulous characterization of the bacterial artificial chromosome (BAC) transgenic rat model with respect to initial propagation of pathological asyn along the parasympathetic and sympathetic pathways to the brainstem, by performing immunohistochemistry at early time points post-injection. Induced pathology was observed in all key structures along the sympathetic and parasympathetic pathways (ENS, autonomic ganglia, intermediolateral nucleus of the spinal cord (IML), heart, dorsal motor nucleus of the vagus, and locus coeruleus (LC)) and persisted for at least 4 months post-injection. In contrast, asyn propagation was not detected in wild-type rats, nor in vehicle-injected BAC rats. The presence of pathology in the IML, LC, and heart indicate trans-synaptic spread of the pathology. Additionally, the observed asyn inclusions in the stomach and heart may indicate secondary anterograde propagation after initial retrograde spreading. In summary, trans-synaptic propagation of asyn in the BAC rat model is fully compatible with the "body-first hypothesis" of PD etiopathogenesis. To our knowledge, this is the first animal model evidence of asyn propagation to the heart, and the first indication of bidirectional asyn propagation via the vagus nerve, i.e., duodenum-to-brainstem-to-stomach. The BAC rat model could be very valuable for detailed mechanistic studies of the dual-hit hypothesis, and for studies of disease modifying therapies targeting early pathology in the gastrointestinal tract.

Cerebral metabolic rate of oxygen consumption (CMRO(2)), cerebral blood flow (CBF), and oxygen extraction fraction (OEF) are important indices of healthy aging of the brain. Although a frequent topic of study, changes of CBF and CMRO(2) during normal aging are still controversial, as some authors find decreases of both CBF and CMRO(2) but increased OEF, while others find no change, and yet other find divergent changes. In this reanalysis of previously published results from positron emission tomography of healthy volunteers, we determined CMRO(2) and CBF in 66 healthy volunteers aged 21 to 81 years. The magnitudes of CMRO(2) and CBF declined in large parts of the cerebral cortex, including association areas, but the primary motor and sensory areas were relatively spared. We found significant increases of OEF in frontal and parietal cortices, excluding primary motor and somatosensory regions, and in the temporal cortex. Because of the inverse relation between OEF and capillary oxygen tension, increased OEF can compromise oxygen delivery to neurons, with possible perturbation of energy turnover. The results establish a possible mechanism of progression from healthy to unhealthy brain aging, as the regions most affected by age are the areas that are most vulnerable to neurodegeneration.

Objectives: Evidence from experimental animal models of Parkinson's disease (PD) suggests a characteristic pattern of metabolic perturbation in discrete, very small basal ganglia structures. These structures are generally too small to allow valid investigation by conventional positron emission tomography (PET) cameras. However, the high-resolution research tomograph (HRRT) PET system has a resolution of 2 mm, sufficient for the investigation of important structures such as the pallidum and thalamic subnuclei., Materials and Methods: Using the HRRT, we performed [(18)F]-fluorodeoxyglucose (FDG) scans on 21 patients with PD and 11 age-matched controls. We employed three types of normalization: white matter, global mean, and data-driven normalization. We performed volume-of-interest analyses of small subcortical gray matter structures. Voxel-based comparisons were performed to investigate the extent of cortical hypometabolism., Results: The most significant level of relative subcortical hypermetabolism was detected in the external pallidum (GPe), irrespective of normalization strategy. Hypermetabolism was suggested also in the internal pallidum, thalamic subnuclei, and the putamen. Widespread cortical hypometabolism was seen in a pattern very similar to previously reported patterns in patients with PD., Conclusion: The presence and extent of subcortical hypermetabolism in PD is dependent on type of normalization. However, the present findings suggest that PD, in addition to widespread cortical hypometabolism, is probably characterized by true hypermetabolism in the GPe. This finding was predicted by the animal 2-deoxyglucose autoradiography literature, in which high-magnitude hypermetabolism was also most robustly detected in the GPe., (© 2011 John Wiley & Sons A/S.)

Aim: Decreased activity of the mitochondrial electron transport chain (ETC) has been implicated in the pathogenesis of Parkinson's disease (PD). This model would most likely predict a decrease in the rate of cerebral oxygen consumption (CMRO(2)). To test this hypothesis, we compared CMRO(2) and cerebral blood flow (CBF) PET scans from PD patients and healthy controls., Materials and Methods: Nine early-stage PD patients and 15 healthy age-matched controls underwent PET scans for quantitative mapping of CMRO(2) and CBF. Between-group differences were evaluated for absolute data and intensity-normalized values., Results: No group differences were detected in regional magnitudes of CMRO(2) or CBF. Upon normalization using the reference cluster method, significant relative CMRO(2) decreases were evident in widespread prefrontal, parieto-occipital, and lateral temporal regions. Sensory-motor and subcortical regions, brainstem, and the cerebellum were spared. A similar pattern was evident in normalized CBF data, as described previously., Conclusion: While the data did not reveal substantially altered absolute CMRO(2) in brain of PD patients, employing data-driven intensity normalization revealed widespread relative CMRO(2) decreases in cerebral cortex. The detected pattern was very similar to that reported in earlier CBF and CMRglc studies of PD, and in the CBF images from the same subjects. Thus, the present results are consistent with the occurrence of parallel declines in CMRO(2), CBF, and CMRglc in spatially contiguous cortical regions in early PD, and support the hypothesis that ETC dysfunction could be a primary pathogenic mechanism in early PD., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The main motor symptoms of Parkinson's disease (PD) are linked to degeneration of the nigrostriatal dopamine (DA) fibers, especially those innervating the putamen. This degeneration can be assessed in molecular imaging studies with presynaptic tracers such as [(18)F]-fluoro-L-DOPA (FDOPA) and ligands for DA transporter ligands. However, the pathologies of PD are by no means limited to nigrostriatal loss. Results of post mortem and molecular imaging studies reveal parallel degenerations of cortical noradrenaline (NA) and serotonin (5-HT) innervations, which may contribute to affective and cognitive changes of PD. Especially in advanced PD, cognitive impairment can come to resemble that seen in Alzheimer's dementia, as can the degeneration of acetylcholine innervations arising in the basal forebrain. The density of striatal DA D(2) receptors increases in early untreated PD, consistent with denervation upregulation, but there is an accelerated rate of DA receptor loss as the disease advances. Animal studies and post mortem investigations reveal changes in brain opioid peptide systems, but these are poorly documented in imaging studies of PD. Relatively minor changes in the binding sites for GABA are reported in cortex and striatum of PD patients. There remains some controversy about the expression of the 18 kDa translocator protein (TSPO) in activated microglia as an indicator of an active inflammatory component of neurodegeneration in PD. A wide variety of autonomic disturbances contribute to the clinical syndrome of PD; the degeneration of myocardial sympathetic innervation can be revealed in SPECT studies of PD patients with autonomic failure. Considerable emphasis has been placed on investigations of cerebral blood flow and energy metabolism in PD. Due to the high variance of these physiological estimates, researchers have often employed normalization procedures for the sensitive detection of perturbations in relatively small patient groups. However, a widely used normalization to the global mean must be used with caution, as it can result in spurious findings of relative hypermetabolic changes in subcortical structures. A meta-analysis of the quantitative studies to date shows that there is in fact widespread hypometabolism and cerebral blood flow in the cerebral cortex, especially in frontal cortex and parietal association areas. These changes can bias the use of global mean normalization, and probably represent the pathophysiological basis of the cognitive impairment of PD.

The distribution of brain oxidative metabolism values among healthy humans is astoundingly wide for a measure that reflects normal brain function and is known to change very little with most changes of brain function. It is possible that the part of the oxygen consumption rate that is coupled to ATP turnover is the same in all healthy human brains, with different degrees of uncoupling explaining the variability of total oxygen consumption among people. To test the hypothesis that about 75% of the average total oxygen consumption of human brains is common to all individuals, we determined the variability in a large group of normal healthy adults. To establish the degree of variability in different regions of the brain, we measured the regional cerebral metabolic rate for oxygen in 50 healthy volunteers aged 21-66 and projected the values to a common age of 25.Within each subject and region, we normalized the metabolic rate to the population average of that region. Coefficients of variation ranged from 10 to 15% in the different regions of the human brain and the normalized regional metabolic rates ranged from 70% to 140% of the population average for each region, equal to a two-fold variation. Thus the hypothetical threshold of oxygen metabolism coupled to ATP turnover in all subjects is no more than 70% of the average oxygen consumption of that population.

Conventional indices of the utilization of FDOPA in living human brain have not consistently revealed important declines in dopamine function with normal aging. However, most methods of kinetic analysis have assumed irreversible trapping of decarboxylated FDOPA metabolites in brain, an assumption that is violated even in PET recordings of short duration. Therefore, we have developed methods for the calculation of steady-state storage of FDOPA together with its decarboxylated metabolites (V(d), mlg(-1)), based upon improved kinetic analysis of 120-min emission recordings. In a group of 28 normal male subjects, of age ranging from 23 to 73 years, the magnitude of V(d) in the striatum and in extrastriatal regions declined by approximately 10% with each decade. The utilization of FDOPA was also calculated by several conventional methods assuming irreversible trapping, i.e. the net blood brain clearance (K(in)(app), mlg(-1)min(-1)), the DOPA decarboxylase activity relative to a reference tissue input (k(3)(S), min(-1)), and relative to the arterial input (k(3)(D), min(-1)). None of these methods revealed an age-related decline in FDOPA utilization in the extended striatum, although the magnitude of K(in)(app) did decline in cerebral cortex. Thus, the capacity to synthesize [(18)F]fluorodopamine remained largely intact in striatum of the elderly subjects, but in the presence of a substantially increased rate of washout (k(loss)), which was evident in all brain regions examined. Consequently, the magnitude of V(d) declined with healthy aging, possibly reflecting impaired vesicular storage capacity, resulting in enhanced exposure of cytosolic [(18)F]fluorodopamine to monoamine oxidase., (Copyright 2008 Elsevier Inc. All rights reserved.)

Background and Purpose: Previous volumetric magnetic resonance imaging (MRI) studies of Parkinson's disease (PD) utilized primarily voxel-based morphometry (VBM), and investigated mostly patients with moderate- to late-stage disease. We now use deformation-based morphometry (DBM), a method purported to be more sensitive than VBM, to test for atrophy in patients with early-stage PD., Methods: T1-weighted MRI images from 24 early-stage PD patients and 26 age-matched normal control subjects were compared using DBM. Two separate studies were conducted, where two minimally-biased nonlinear intensity-average were created; one for all subjects and another for just the PD patients. The DBM technique creates an average population-based MRI-average in an iterative hierarchical fashion. The nonlinear transformations estimated to match each subject to the MRI-average were then analysed., Results: The DBM comparison between patients and controls revealed significant contraction in the left cerebellum, and non-significant trends towards frontal, temporal and cingulate sulcal expansions with frontal and temporal white matter contractions. Within the patient group, the unified PD rating scores were highly correlated with local expansions in or near sulci bordering on frontal and temporal cortex., Conclusion: Our results suggest that DBM could be a sensitive method for detecting morphological changes in early-stage PD.

In a recent issue of NeuroImage, we presented evidence that biased global mean (GM) normalization of brain PET data can generate the appearance of subcortical foci with relative hypermetabolism in patients with Parkinson's disease (PD), and other degenerative disorders. In a commentary to our article, Ma and colleagues presented a study seeking to establish that a pattern of widespread hypermetabolism, known as the Parkinson's disease related pattern (PDRP) is a genuine metabolic feature of PD. In the present paper, we respond to the arguments presented by Ma et al., and we provide a critical reappraisal of the evidence for the existence of the PDRP. To this end, we present new analyses of PET data sets, which demonstrate that very similar patterns of relative subcortical increases are seen in PD, Alzheimer's disease, hepatic encephalopathy, healthy aging, and simulation data. Furthermore, longitudinal studies of PD previously reported relative hypermetabolism in very small anatomical structures such as the subthalamic nucleus. We now demonstrate how focal hypermetabolism attributed to small nuclei can similarly arise as a consequence of GM normalization. Finally, we give a comprehensive summary of the entire deoxyglucose autoradiography literature on acquired parkinsonism in experimental animals. Based on this evidence, we conclude that (1) there is no quantitative evidence for widespread subcortical hypermetabolism in PD, (2) very similar patterns of subcortical hyperactivity are evident in various other brain disorders whenever GM normalization is utilized, and (3) the PDRP is not evident in animal models of PD. In the absence of quantitative evidence for the PDRP, our alternative interpretation of normalization bias seems the more parsimonious explanation for the reports of relative hypermetabolism in PD.

Background: Global mean (GM) normalization is one of the most commonly used methods of normalization in PET and SPECT group comparison studies of neurodegenerative disorders. It requires that no between-group GM difference is present, which may be strongly violated in neurodegenerative disorders. Importantly, such GM differences often elude detection due to the large intrinsic variance in absolute values of cerebral blood flow or glucose consumption. Alternative methods of normalization are needed for this type of data., Materials and Methods: Two types of simulation were performed using CBF images from 49 controls. Two homogeneous groups of 20 subjects were sampled repeatedly. In one group, cortical CBF was artificially decreased moderately (simulation I) or slightly (simulation II). The other group served as controls. Ratio normalization was performed using five reference regions: (1) Global mean; (2) An unbiased VOI; (3) Data-driven region extraction (Andersson); (4-5) Reference cluster methods (Yakushev et al.). Using voxel-based statistics, it was determined how much of the original signal was detected following each type of normalization., Results: For both simulations, global mean normalization performed poorly, with only a few percent of the original signal recovered. Global mean normalization moreover created artificial increases. In contrast, the data-driven reference cluster method detected 65-95% of the original signal., Conclusion: In the present simulation, the reference cluster method was superior to GM normalization. We conclude that the reference cluster method will likely yield more accurate results in the study of patients with early to moderate stage neurodegenerative disorders.

Aim: Recent studies of Parkinson's disease (PD) report subcortical increases of cerebral blood flow (CBF) or cerebral metabolic rate of glucose (CMRglc), after conventional normalization to the global mean. However, if the global mean CBF or CMRglc is decreased in the PD group, this normalization necessarily generates artificial relative increases in regions unaffected by the disease. This potential bias may explain the reported subcortical increases in PD. To test this hypothesis, we performed simulations with manipulation and subsequently analysis of sets of quantitative CBF maps by voxel-based statistics., Materials and Methods: CBF images from 49 healthy volunteers were randomly assigned to four sets of two groups of 20 subjects. For each set, CBF images in one group were manipulated, while the other group served as controls. In the first simulation, an isolated cortical decrease was simulated. In the second simulation, focal increases in the globus pallidus and thalamus motor nuclei were simulated in addition to cortical decreases, thus emulating the putative metabolic pattern in PD. The data were analyzed with both the SSM method and a univariate statistical approach with normalization to either the global mean or to the white matter mean., Results: In Simulation I, global normalization robustly created artefactual subcortical increases, irrespective of analysis methodology. Simulation II demonstrated that an increased signal from the small subcortical structures involved in PD can probably not be detected with present instrumentation and typically-used sample sizes., Conclusion: Imposing focal decreases on cortical CBF in conjunction with global mean normalization gives rise to spurious relative CBF increases in all of the regions reported to be hyperactive in PD. Since no PET study has reported absolute increases of CBF or CMRglc in any subcortical region in PD, we conclude that the relative increases reported in some studies most likely arise from biased normalization to the global mean.

Hyperoxic therapy for cerebral ischemia is suspected to reduce cerebral blood flow (CBF), due to the vasoconstrictive effect of oxygen on cerebral arterioles. We hypothesized that vasodilation predominates when 5% CO(2) is added to the inhaled oxygen (carbogen). Therefore, we used positron emission tomography (PET) to measure CBF and cerebral metabolic rate of oxygen (CMRO(2)) during inhalation of test gases (O(2), CO(2), carbogen and atmospheric air) in 10 healthy volunteers. Arterial blood gases were recorded during administration of each gas. The data were analyzed with volume-of-interest and voxel-based statistical methods. Inhalation of CO(2) or carbogen significantly increased global CBF, whereas pure oxygen decreased global CBF. The CMRO(2) generally remained unchanged, except in white matter during oxygen inhalation relative to condition of atmospheric air inhalation. The volume-of-interest results were confirmed by statistical cluster analysis. Oxygen and carbogen were equally potent in increasing oxygen saturation of arterial blood (Sa(O2)). The present data demonstrate that inhalation of carbogen increases both CBF and Sa(O2) in healthy adults. In conclusion we speculate that carbogen inhalation is sufficient for optimal oxygenation of healthy brain tissue, whereas carbogen induces concomitant increases of CBF and Sa(O2).

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.