Previous Positron Emission Tomography Studies Research Articles

Striatal dopamine D2 receptor availability as a predictor of subsequent alcohol use in social drinkers.

Whereas striatal dopamine D2 receptor (D2R) availability has shown to be altered in individuals with alcohol use disorder (AUD) and in healthy individuals with a family history of AUD, the role of D2R in the development of AUD is unknown. In this positron emission tomography (PET) study, we measured whether D2R availability is associated with subsequent alcohol use and alcohol-related factors, at a follow-up 8 to 16 years post-PET scan, in social drinkers. Longitudinal study investigating the association between PET data and later self-report measures in healthy individuals. Academic research imaging centre in Stockholm, Sweden. There were 71 individuals (68 of whom had evaluable PET data, 5 females, 42.0 years mean age) from a series of previous PET studies. One PET examination with the D2R antagonist radioligand [11 C]raclopride at baseline and self-report measures assessing alcohol use, drug use, impulsivity, reward sensitivity and family history of alcohol or substance use disorder at follow-up. We found no evidence for an association between D2R availability and later alcohol use (B = -0.019, B 95% CI = -0.043 to -0.006, P = 0.147) nor for the majority of the alcohol-related factors (B 95% CI = -0.034 to 0.004, P = 0.273-0.288). A negative association with a small effect size was found between D2R availability and later impulsivity (B = -0.017, B 95% CI = -0.034 to -0.001, P = 0.046). Low striatal dopamine D2 receptor availability may not be a strong predictor in the development of alcohol use disorder.

Positron emission tomography studies in adult patients with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, motor hyperactivity, impulsivity, and psychosocial as well as cognitive dysfunction. Although characteristic clinical manifestations have been described, no definitive biomarkers to diagnose ADHD have been established. In this review article, we summarize positron emission tomography (PET) studies conducted in adult patients with ADHD. We found that, although, disturbances of dopamine, serotonin, and norepinephrine functions have been implicated in ADHD, no characteristic findings have been identified from PET studies in patients with ADHD. Several previous PET studies on the central dopaminergic transmission-related ligands in patients with ADHD have shown altered binding of dopamine markers in the basal ganglia. However, no consistent results were observed in the binding characteristics for dopamine transporters and receptors. Findings from PET studies with ligands related to serotonin and norepinephrine pathways showed either unclear clinical significance or low replicability. Therefore, whether alterations of monoamine function may be involved in the pathophysiological mechanism remains to be clarified. The limitations of previous PET studies include their small sample sizes, focus on several kinds of existing ligands, and a questionable validity of the diagnosis (lack of biological diagnostic criteria). To determine the characteristic findings for diagnosing ADHD, further research is needed, and particularly, studies that evaluate new active ligands with specific binding to monoamine pathways should be undertaken.

Methylphenidate Differentially Affects Intrinsic Functional Connectivity of the Salience Network in Adult ADHD Treatment Responders and Non-Responders.

Simple SummaryMethylphenidate is frequently used to treat attention-deficit/hyperactivity disorder (ADHD). It has been reported to correct (aberrant) connectivity between brain regions. However, previous neuroimaging research has not provided a coherent picture. One possible reason is that methylphenidate may not necessarily result in a satisfactory clinical treatment response of every patient. This suggests that neuroimaging research about methylphenidate’s mode of action could benefit from subdividing patients into groups of treatment “Responders” and “Non-Responders”. However, previous research has not applied this idea so far. Here, we used machine learning techniques to discern Responders from Non-Responders based on clinical symptoms. Fifty-three stimulant-naïve adult ADHD patients underwent functional magnetic resonance imaging to determine functional connectivity at rest. Measurements were repeated after 6 weeks’ treatment with methylphenidate. We found that, prior to treatment, a specific part of the so-called salience network was hypo-connected with the bilateral putamen in the patient sample as a whole, compared with 50 healthy controls. After methylphenidate treatment, this aberrant connectivity was restored to almost “normal” levels in Responders, but not in Non-Responders. Involvement of the putamen is reminiscent of early positron emission tomography findings, already suggesting modulation of dopaminergic brain regions for the successful treatment of ADHD with methylphenidate.Positron emission tomography (PET) studies have shown involvement of the striatum when treating adult attention-deficit/hyperactivity disorder (ADHD) with methylphenidate (MPH). Results from resting-state functional magnetic resonance imaging (rs-fMRI) for the same issue were less unequivocal. Here, a new analytical framework was set up to investigate medication effects using seed-based rs-fMRI analysis to infer brain regions with alterations in intrinsic functional connectivity (IFC) corresponding with ADHD symptom reduction. In a within-subjects study design, 53 stimulant-naïve adult ADHD patients were investigated before and after 6 weeks of MPH treatment, using two major clinical symptom scales and rs-fMRI. The same data were acquired in a sample of 50 age- and sex-matched healthy controls at baseline. A consensual atlas provided seeds for five predefined major resting-state networks. In order to avoid biasing of medication effects due to putative treatment failure, the entire ADHD sample was first categorized into treatment Responders (N = 36) and Non-Responders (N = 17) using machine learning-based classification with the clinical scales as primary data. Imaging data revealed medication effects only in Responders. In that group, IFC of bilateral putamen changed significantly with medication and approached almost normal levels of IFC. Present results align well with results from previous PET studies, with seed-based rs-fMRI as an entirely different neuroimaging method.

Dissecting Motor and Cognitive Component Processes of a Finger-Tapping Task With Hybrid Dopamine Positron Emission Tomography and Functional Magnetic Resonance Imaging.

Striatal dopamine is involved in facilitation of motor action as well as various cognitive and emotional functions. Positron emission tomography (PET) is the primary imaging method used to investigate dopamine function in humans. Previous PET studies have shown striatal dopamine release during simple finger tapping in both the putamen and the caudate. It is likely that dopamine release in the putamen is related to motor processes while dopamine release in the caudate could signal sustained cognitive component processes of the task, but the poor temporal resolution of PET has hindered firm conclusions. In this study we simultaneously collected [11C]Raclopride PET and functional Magnetic Resonance Imaging (fMRI) data while participants performed finger tapping, with fMRI being able to isolate activations related to individual tapping events. The results revealed fMRI-PET overlap in the bilateral putamen, which is consistent with a motor component process. Selective PET responses in the caudate, ventral striatum, and right posterior putamen, were also observed but did not overlap with fMRI responses to tapping events, suggesting that these reflect non-motor component processes of finger tapping. Our findings suggest an interplay between motor and non-motor-related dopamine release during simple finger tapping and illustrate the potential of hybrid PET-fMRI in revealing distinct component processes of cognitive functions.

A positron emission tomography study of the serotonin1B receptor effect of electroconvulsive therapy for severe major depressive episodes

BackgroundElectroconvulsive therapy (ECT) is an effective treatment for depressive disorders, although its molecular mechanism of action is unknown. The serotonin 1B (5-HT1B) receptor is a potential target for treatment of depression and low 5-HT1B receptor binding in limbic regions has been reported in previous positron emission tomography (PET) studies of depression. MethodsThe objective of this longitudinal PET study was to examine the effect of ECT for depression on 5-HT1B receptor binding. Fifteen hospitalized patients with major depressive episodes were examined with PET and the 5-HT1B receptor selective radioligand [11C]AZ10419369, before and after ECT. Fifteen controls matched for age and sex were examined. Limbic regions with previously reported low 5-HT1B receptor binding in depression and a dorsal brain stem region were selected. ResultsThirteen patients completed the study according to protocol. Eleven out of thirteen patients responded to ECT. 5-HT1B receptor binding in hippocampus increased with 30 % after ECT (p=0.021). Using linear mixed effects modelling, we observed increases in 5-HT1B receptor binding following ECT with a moderate to large effect size, which did not differ significantly between regions. In an exploratory analysis, strong correlations between changes in 5-HT1B receptor binding and agitation scores on the Hamilton Depression Rating Scale after ECT were observed. LimitationsAlbeit representative of a PET study, the sample size is still small and there are potential confounding effects of medication. ConclusionsIncreased 5-HT1B receptor binding was observed following ECT for depression, corresponding to previous findings of increased 5-HT1B receptor binding in hippocampus after rapid acting ketamine for treatment resistant depression.

Cerebral glucose metabolism in bipolar disorder: A voxel-based meta-analysis of positron emission tomography studies.

BackgroundPrevious positron emission tomography studies have reported the changes of cerebral glucose metabolism in bipolar disorder. However, the findings across studies remain controversial, containing differing results.MethodsA systematic literature search of the PubMed, Embase, Cochrane Library, and Web of Science databases was conducted. We conducted a voxel‐wide meta‐analysis of cerebral glucose metabolism studies, using the seed‐based mapping approach, in patients with bipolar disorder (BD).ResultsWe identified 7 studies suitable for inclusion, which included a total of 126 individuals with BD and 160 healthy controls. The most consistent and robust findings were an increase in cerebral glucose metabolism in the right precentral gyrus and a decrease in the left superior temporal gyrus, left middle temporal gyrus, and cerebellum. Additionally, the sex distribution and illness duration had significant moderating effects on cerebral glucose metabolism alterations.ConclusionsCerebral glucose metabolism alterations in these brain regions are likely to reflect the disease‐related functional abnormalities such as emotion and cognition. These findings contribute to a better understanding of the neurobiological underpinnings of bipolar disorder.Limitations.This study was done at a study level and cannot be addressed at the patient level. Subgroup analysis of BD I and BD II is not possible due to limited literature data.

18 F]FDG PET may differentiate cerebral amyloid angiopathy from Alzheimer's disease.

Cerebral amyloid angiopathy (CAA) is a frequent cause of both intracerebral hemorrhage (ICH) and cognitive impairment in the elderly. Diagnosis relies on the Boston criteria, which use magnetic resonance imaging markers including ≥2 exclusively lobar cerebral microbleeds (lCMBs). Although amyloid positron emission tomography (PET) may provide molecular diagnosis, its specificity relative to Alzheimer's disease (AD) is limited due to the prevalence of positive amyloid PET in cognitively normal elderly. Using early-phase 11 C-Pittsburgh compound B as surrogate for tissue perfusion, a significantly lower occipital/posterior cingulate (O/PC) tracer uptake ratio in probable CAA relative to AD was recently reported, consistent with histopathological lesion distribution. We tested whether this finding could be reproduced using [18 F]fluorodeoxyglucose (FDG)-PET, a widely available modality that correlates well with early-phase amyloid PET in both healthy subjects and AD. From a large memory clinic database, we retrospectively included 14 patients with probable CAA (Boston criteria) and 21 patients with no lCMB fulfilling AD criteria including cerebrospinal fluid biomarkers. In all, [18 F]FDG-PET/computed tomography (CT) was available as part of routine care. No subject had a clinical history of ICH. Regional standardized [18 F]FDG uptake values normalized to the pons (standard uptake value ratio [SUVr]) were obtained, and the O/PC ratio was calculated. The SUVr O/PC ratio was significantly lower in CAA versus AD (1.02±0.14 vs. 1.19±0.18, respectively; p=0.024). Despite the small sample, our findings are consistent with the previous early-phase amyloid PET study. Thus, [18 F]FDG-PET may help differentiate CAA from AD, particularly in cases of amyloid PET positivity. Larger prospective studies, including in CAA-related ICH, are however warranted.

Positron emission tomography imaging of novel AAV capsids maps rapid brain accumulation

Adeno-associated viruses (AAVs) are typically single-stranded deoxyribonucleic acid (ssDNA) encapsulated within 25-nm protein capsids. Recently, tissue-specific AAV capsids (e.g. PHP.eB) have been shown to enhance brain delivery in rodents via the LY6A receptor on brain endothelial cells. Here, we create a non-invasive positron emission tomography (PET) methodology to track viruses. To provide the sensitivity required to track AAVs injected at picomolar levels, a unique multichelator construct labeled with a positron emitter (Cu-64, t1/2 = 12.7 h) is coupled to the viral capsid. We find that brain accumulation of the PHP.eB capsid 1) exceeds that reported in any previous PET study of brain uptake of targeted therapies and 2) is correlated with optical reporter gene transduction of the brain. The PHP.eB capsid brain endothelial receptor affinity is nearly 20-fold greater than that of AAV9. The results suggest that novel PET imaging techniques can be applied to inform and optimize capsid design.

Pathophysiological interrelated deactivation/activation processes in the exhausted brain after whiplash injury.

In this paper pathophysiological interrelated deactivation/activation phenomena are set out in the example of whiplash injury. These phenomena could have been underestimated in previous positron emission tomography studies as their focus was on hypoperfusion rather than hyperperfusion. In addition, statistical parametric mapping analysis of cerebral studies is normally not fine-tuned to special interesting areas rather than to obvious clusters of difference.

Imaging Microglial Activation in Individuals at Clinical High Risk for Psychosis: an In Vivo PET Study with [18F]FEPPA.

Several lines of evidence implicate microglial activation and abnormal immune response in the etiology of psychosis. Previous positron emission tomography (PET) neuroimaging studies of the translocator protein 18 kDa, TSPO, were limited by low affinity of the first-generation radioligand, low-resolution scanners, and small sample sizes. Moreover, there is a dearth of literature on microglial activation in individuals at clinical high risk (CHR) for psychosis. We used a novel second-generation TSPO radioligand, [18F]FEPPA, to examine whether microglial activation is elevated in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of antipsychotic-naive CHR. Twenty-four CHR (antipsychotic-naive n=22) and 23 healthy volunteers (HV) completed a high resolution [18F]FEPPA PET scan and MRI. The PET data were analyzed using the validated two-tissue compartment model with arterial plasma input function with total volume of distribution (VT) as outcome measure. All analyses were controlled for the TSPO rs6971 polymorphism. We did not observe any significant differences in microglial activation, as indexed by [18F]FEPPA VT, between CHR and HV in either the DLPFC (F(1, 44)=0.41, p=0.52) or the hippocampus (F(1, 44)=2.78, p=0.10). Exploratory associations show that in CHR, [18F]FEPPA VT was positively correlated with apathy (DLPFC: r=0.55, p=0.008; hippocampus: r=0.52, p=0.013) and state anxiety (DLPFC: r=0.60, p=0.003; hippocampus: r=0.48, p=0.024). The lack of significant group differences in [18F]FEPPA VT suggests that microglial activation is not significantly elevated in the clinical high risk state that precedes psychosis.

Automated voxel classification used with atlas-guided diffuse optical tomography for assessment of functional brain networks in young and older adults.

Atlas-guided diffuse optical tomography (atlas-DOT) is a computational means to image changes in cortical hemodynamic signals during human brain activities. Graph theory analysis (GTA) is a network analysis tool commonly used in functional neuroimaging to study brain networks. Atlas-DOT has not been analyzed with GTA to derive large-scale brain connectivity/networks based on near-infrared spectroscopy (NIRS) measurements. We introduced an automated voxel classification (AVC) method that facilitated the use of GTA with atlas-DOT images by grouping unequal-sized finite element voxels into anatomically meaningful regions of interest within the human brain. The overall approach included volume segmentation, AVC, and cross-correlation. To demonstrate the usefulness of AVC, we applied reproducibility analysis to resting-state functional connectivity measurements conducted from 15 young adults in a two-week period. We also quantified and compared changes in several brain network metrics between young and older adults, which were in agreement with those reported by a previous positron emission tomography study. Overall, this study demonstrated that AVC is a useful means for facilitating integration or combination of atlas-DOT with GTA and thus for quantifying NIRS-based, voxel-wise resting-state functional brain networks.

P.1.i.030 - Effect of electroconvulsive therapy on interregional serotonin-1A receptor binding correlations in depressed patients

Results from studies in serotonin-1A (5-HT1A) knockout mice and previous positron emission tomography (PET) studies in humans imply a role for 5-HT1A receptors in normal state anxiety as well as in certain anxiety disorders. The objective of this study was to investigate 5-HT1A receptor binding potential (BP) in social anxiety disorder (SAD).Using PET and [carbonyl-11C]WAY-100635, we compared a homogeneous group of 12 unmedicated, male SAD patients with 18 healthy control subjects (HC). A multivariate ANOVA with all regional BP values as dependent variables, age and four radiochemical variables as covariates was performed.We found a significantly lower 5-HT1A BP in several limbic and paralimbic areas but not in the hippocampus (p = .234) of SAD patients. The difference in 5-HT1A binding was most significant in the amygdala (−21.4%; p = .003). There was also a more than 20% lower 5-HT1A BP of SAD patients in the anterior cingulate cortex (p = .004), insula (p = .003), and dorsal raphe nuclei (p = .030).The lower 5-HT1A binding in the amygdala and mesiofrontal areas of SAD patients is consistent with 1) preclinical findings of elevated anxiety in 5-HT1A knockout mice, 2) a previous PET study in healthy volunteers showing an inverse correlation between 5-HT1A BP and state anxiety, and 3) another human PET study in patients with panic disorder showing reduced 5-HT1A binding, thus corroborating the potential validity of 5-HT1A receptors as targets in the treatment of human anxiety disorders.

Corticostriatal and Dopaminergic Response to Beer Flavor with Both fMRI and [(11) C]raclopride Positron Emission Tomography.

Cue-evoked drug-seeking behavior likely depends on interactions between frontal activity and ventral striatal (VST) dopamine (DA) transmission. Using [(11) C]raclopride (RAC) positron emission tomography (PET), we previously demonstrated that beer flavor (absent intoxication) elicited VST DA release in beer drinkers, inferred by RAC displacement. Here, a subset of subjects from this previous RAC-PET study underwent a similar paradigm during functional magnetic resonance imaging (fMRI) to test how orbitofrontal cortex (OFC) and VST blood oxygenation level-dependent (BOLD) responses to beer flavor are related to VST DA release and motivation to drink. Male beer drinkers (n=28, age=24±2, drinks/wk=16±10) from our previous PET study participated in a similar fMRI paradigm wherein subjects tasted their most frequently consumed brand of beer and Gatorade(®) (appetitive control). We tested for correlations between BOLD activation in fMRI and VST DA responses in PET, and drinking-related variables. Compared to Gatorade, beer flavor increased wanting and desire to drink, and induced BOLD responses in bilateral OFC and right VST. Wanting and desire to drink correlated with both right VST and medial OFC BOLD activation to beer flavor. Like the BOLD findings, beer flavor (relative to Gatorade) again induced right VST DA release in this fMRI subject subset, but there was no correlation between DA release and the magnitude of BOLD responses in frontal regions of interest. Both imaging modalities showed a right-lateralized VST response (BOLD and DA release) to a drug-paired conditioned stimulus, whereas fMRI BOLD responses in the VST and medial OFC also reflected wanting and desire to drink. The data suggest the possibility that responses to drug-paired cues may be rightward biased in the VST (at least in right-handed males) and that VST and OFC responses in this gustatory paradigm reflect stimulus wanting.

Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status.

In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are nonselective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N-[(11) C]methyl)benperidol ([(11) C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in two independent samples. Sample 1 (n = 39) was composed of obese and nonobese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5 to 12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1-), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10-14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1- was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R-selective [(11) C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states.

Exploring the relationship between social attachment and dopamine D2/3 receptor availability in the brains of healthy humans using [11C]-(+)-PHNO

ABSTRACTDifferences in striatal dopamine (DA) function may be related to differences in the degree of social attachment to others. Using positron emission tomography (PET), socially detached persons demonstrate reduced DA D2/3 receptor (D2/3R) availability in the striatum. However, previous PET studies have only used antagonist radiotracers for D2/3R and have not specifically examined regions of interest (ROIs) such as the ventral striatum (VS). In 32 healthy persons, we investigated the relationship between self-reported attachment and DA D2/3R availability in striatal and extrastriatal ROIs as measured using the agonist radiotracer [11C]-(+)-PHNO. Surprisingly, more social attachment—as measured by the attachment subscale of the temperament and character inventory—was related to less [11C]-(+)-PHNO binding in the VS (r(30) = −.43, p = .01). This relationship held in a subsample who also completed the detachment subscale of the Karolinska Scales of Personality (r(10) = .62, p = .03). However, no relationships were observed with BPND in the dorsal striatum or D3R-specific ROIs. One potential explanation for these findings is that persons who are more socially detached have less endogenous DA occupying D2/3R in the VS. This interpretation warrants investigation by future research. These findings may help us better understand the neurochemical basis of attachment.

Abstract P5-01-07: Radiotherapy may induce enhanced uptake on 18F-fluoroestradiol PET scans

Abstract Introduction: Whole body imaging of 18F-fluoroestradiol (FES) uptake combined with positron emission tomography (PET) has been applied for diagnosis and prediction of therapy response in estrogen receptor (ER) positive breast cancer patients. A maximal standardized uptake value (SUVmax) of 1.5 has previously been defined as the optimal threshold for FES uptake to differentiate between ER-positive and negative tumor lesions. FES uptake in healthy tissue differs per anatomic site and can be influenced by extrinsic factors. Previous FES PET studies have suggested that radiotherapy (RTx) may cause heterogeneous enhanced uptake in lungs. The cause of this uptake has not been elucidated yet. This is an exploratory study to evaluate whether patients with RTx prior to FES PET show enhanced FES uptake in tissues in the irradiation field. Methods: Our FES PET database was screened between 2009 and June 2015 for patients who had RTx ≤6 months before FES PET, independent of location of RTx. Irradiation fields were reconstructed and fused with the FES PET scan. The main outcome was the presence of enhanced FES uptake, defined as visually increased FES uptake above background with a SUVmax >1.5 in the irradiation field in the absence of an oncologic substrate on the concordant (contrast enhanced) CT scan. Results: A total of 133 patients were identified in the database; 29 were eligible for the study. Mean age at the first FES PET scan was 57 (SD 9) years. 28/29 patients had breast cancer, 2/28 had a concurrent other malignancy. Seventeen patients (59%) showed enhanced uptake in the RTx field. 15/17 patients were irradiated in the thoracic area, and 2/17 at the hip. Enhanced uptake was mostly located at the dorsomedial side of the lungs, or subcutaneously after thoracic- or hip RTx, respectively. Patients with normal FES uptake in the radiation field were irradiated in the pelvic/lumbal spine area (n=5), hip (n=3) or thorax (n=4). Time range between RTx and FES PET did not differ between patients with and without enhanced FES uptake (mean 50.9 days [range 0-156] vs. mean 56.8 days [range 0-178]). Systemic treatment at the time of FES PET did not differ between the patients with and without enhanced uptake. Radiation dosage in gray (Gy) was related to enhanced FES uptake, after RTx in the thoracic area or at the hip. Conclusion: RTx can induce enhanced uptake in the irradiation field on the FES PET scan in part of the patients. Irradiation-induced FES uptake most frequently occurs in lung tissue. Therefore, physicians should keep the possibility of radiation-induced aspecific enhanced tracer uptake in mind, when interpreting FES PET scan of patients that have recently received RTx. Citation Format: Venema CM, van der Veen SJ, Glaudemans AWJM, Schröder CP, de Vries EFJ, Hospers GAP. Radiotherapy may induce enhanced uptake on 18F-fluoroestradiol PET scans. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-01-07.

PET Imaging in Huntington's Disease.

To date, little is known about how neurodegeneration and neuroinflammation propagate in Huntington’s disease (HD). Unfortunately, no treatment is available to cure or reverse the progressive decline of function caused by the disease, thus considering HD a fatal disease. Mutation gene carriers typically remain asymptomatic for many years although alterations in the basal ganglia and cortex occur early on in mutant HD gene–carriers. Positron Emission Tomography (PET) is a functional imaging technique of nuclear medicine which enables in vivo visualization of numerous biological molecules expressed in several human tissues. Brain PET is most powerful to study in vivo neuronal and glial cells function as well as cerebral blood flow in a plethora of neurodegenerative disorders including Parkinson’s disease, Alzheimer’s and HD. In absence of HD–specific biomarkers for monitoring disease progression, previous PET studies in HD were merely focused on the study of dopaminergic terminals, cerebral blood flow and glucose metabolism in manifest and premanifest HD–gene carriers. More recently, research interest has been exploring novel PET targets in HD including the state of phosphodiesterse expression and the role of activated microglia. Hence, a better understanding of the HD pathogenesis mechanisms may lead to the development of targeted therapies. PET imaging follow–up studies with novel selective PET radiotracers such as 11C-IMA–107 and 11C-PBR28 may provide insight on disease progression and identify prognostic biomarkers, elucidate the underlying HD pathology and assess novel pharmaceutical agents and over time.

The role of the salience network in processing lexical and nonlexical stimuli in cochlear implant users: an ALE meta-analysis of PET studies.

Previous positron emission tomography (PET) studies have shown that various cortical areas are activated to process speech signal in cochlear implant (CI) users. Nonetheless, differences in task dimension among studies and low statistical power preclude from understanding sound processing mechanism in CI users. Hence, we performed activation likelihood estimation meta-analysis of PET studies in CI users and normal hearing (NH) controls to compare the two groups. Eight studies (58 CI subjects/92 peak coordinates; 45 NH subjects/40 peak coordinates) were included and analyzed, retrieving areas significantly activated by lexical and nonlexical stimuli. For lexical and nonlexical stimuli, both groups showed activations in the components of the dual-stream model such as bilateral superior temporal gyrus/sulcus, middle temporal gyrus, left posterior inferior frontal gyrus, and left insula. However, CI users displayed additional unique activation patterns by lexical and nonlexical stimuli. That is, for the lexical stimuli, significant activations were observed in areas comprising salience network (SN), also known as the intrinsic alertness network, such as the left dorsal anterior cingulate cortex (dACC), left insula, and right supplementary motor area in the CI user group. Also, for the nonlexical stimuli, CI users activated areas comprising SN such as the right insula and left dACC. Previous episodic observations on lexical stimuli processing using the dual auditory stream in CI users were reconfirmed in this study. However, this study also suggests that dual-stream auditory processing in CI users may need supports from the SN. In other words, CI users need to pay extra attention to cope with degraded auditory signal provided by the implant.

234 Kinetic analysis of dynamic 11C-verapamil PET study: Compartmental v adaptive mixture models comparison

Background: Temporal aspects of dynamic positron emission tomography (PET) generally rely on compartmental models (CM), with questionable assumptions to summarise functional kinetics of injected radio-tracers in living tissues. Material and Methods: The tracer signal time-course is a combination of vascular delivery and tissue retention effects which do not always satisfy the assumptions of tissue homogeneity and instant mixing within compartments required by the CM. This tissue activity time-course can typically be expressed as a convolution between the signal of the tracer in the arterial supply and the tissue residue function. The residue represents the amount of tracer remaining in the tissue and provides a description of the tracer kinetics measurable by the PET scan. Thus, in statistical terms, the residue can be thought of as a survival function for the residence of the tracer in the tissue which does not require the physiological constraints intrinsic in the exponential-like residue needed for CM. Accordingly more flexible novel approaches − nonparametric and later adaptive mixture models − to estimate the residue based on a piecewise linear form have been developed. The new approaches have been successfully probed on two of the most well-established PET radiotracers, O-H2O and F-fluorodeoxyglucose, used for perfusion and glucose metabolism respectively. This study shows the extension of the new approaches to the multiple-drug resistance transporter P-glycoprotein (P-gp) highly present at the blood–brain barrier (BBB) using C-Verapamil (Vp) in healthy humans before and after inhibition of the P-gp by Cyclosporine (CsA) infusion. Previous PET studies on measuring BBB activity by CsA infusion using Vp have revealed difficulties for the CM to recover metabolic information as they require a full understanding of the tracers metabolisation in the tissue, which is still not certain for Vp. This problem is especially latent when the inhibition of the P-gp allows the tracer through the BBB where it is retained once at the brain tissue level. Results: This work examines and evaluate adaptive mixture model as an alternative to conventional compartment techniques in recovering metabolic information from dynamic PET studies with less biological restrictions. Key bioparameters such as flux, flow, blood volume and volume of distribution from the two different approaches are compared. Cross-validation is used to make regional comparisons and evaluate the fit of the two different estimated residue functions to the tissue activity curves. Conclusions: The accuracy of the standard models for Vp PET studies can be questionable, likely because behaviour of Vp metabolites in tissue is still unclear. Significant statistical evidence in favour of the new adaptivemixture models has been found. Supported by Science Foundation Ireland under SFI-PI 11/27 and by the National Institute of Health (NCI) under PO1-CA-42045.

Quantification of opioid receptor availability following spontaneous epileptic seizures: Correction of [11C]diprenorphine PET data for the partial-volume effect

Previous positron emission tomography (PET) studies in refractory temporal lobe epilepsy (TLE) using the non-selective opioid receptor antagonist [(11)C]diprenorphine (DPN) did not detect any changes in mesial temporal structures, despite known involvement of the hippocampus in seizure generation. Normal binding in smaller hippocampi is suggestive of increased receptor concentration in the remaining grey matter. Correction for partial-volume effect (PVE) has not been used in previous DPN PET studies. Here, we present PVE-corrected DPN-PET data quantifying post-ictal and interictal opioid receptor availability in humans with mTLE. Eight paired datasets of post-ictal and interictal DPN PET scans and eleven test/retest control datasets were available from a previously published study on opioid receptor changes in TLE following seizures (Hammers et al., 2007a). Five of the eight participants with TLE had documented hippocampal sclerosis. Data were re-analyzed using regions of interest and a novel PVE correction method (structural functional synergistic-resolution recovery (SFS-RR); (Shidahara et al., 2012)). Data were denoised, followed by application of SFS-RR, with anatomical information derived via precise anatomical segmentation of the participants' MRI (MAPER; (Heckemann et al., 2010)). [(11)C]diprenorphine volume-of-distribution (VT) was quantified in six regions of interest. Post-ictal increases were observed in the ipsilateral fusiform gyri and lateral temporal pole. A novel finding was a post-ictal increase in [(11)C]DPN VT relative to the interictal state in the ipsilateral parahippocampal gyrus, not observed in uncorrected datasets. As for voxel-based (SPM) analyses, correction for global VT values was essential in order to demonstrate focal post-ictal increases in [(11)C]DPN VT. This study provides further direct human in vivo evidence for changes in opioid receptor availability in TLE following seizures, including changes that were not evident without PVE correction. Denoising, resolution recovery and precise anatomical segmentation can extract valuable information from PET studies that would be missed with conventional post-processing procedures.