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Surgical specimens from patients with mesial temporal lobe epilepsy (MTLE) show abnormalities in tissue concentrations of metabotropic glutamate receptor type 5 (mGluR5). To clarify whether these abnormalities are specific to the epileptogenic zone (EZ), we characterized in vivo whole-brain mGluR5 availability in MTLE patients using positron emission tomography (PET) and [Thirty-one unilateral MTLE patients and 30 healthy controls underwent [[[

Study objectives The present study assessed brain perfusion patterns with single-photon emission computed tomography (SPECT) during sleepwalkers' post-sleep deprivation slow-wave sleep (SWS) and resting-state wakefulness. Methods Following a 24 hr period of sleep deprivation, 10 sleepwalkers and 10 sex- and age-matched controls were scanned with a high-resolution SPECT scanner. Participants were injected with 99mTc-ethylene cysteinate dimer after 2 min of stable SWS within their first sleep cycle as well as during resting-state wakefulness, both after a subsequent 24 hr period of sleep deprivation. Results When compared with controls' brain perfusion patterns during both SWS and resting-state wakefulness, sleepwalkers showed reduced regional cerebral perfusion in several bilateral frontal regions, including the superior frontal, middle frontal, and medial frontal gyri. Moreover, reduced regional cerebral perfusion was also found in sleepwalkers' left postcentral gyrus, insula, and superior temporal gyrus during SWS compared with controls. During resting-state wakefulness compared with controls, reduced cerebral perfusion was also found in parietal and temporal regions of sleepwalkers' left hemisphere, whereas the right parahippocampal gyrus showed increased regional cerebral perfusion. Conclusions Our results reveal patterns of reduced regional cerebral perfusion in sleepwalkers' frontal and parietal areas when compared with controls, regions previously associated with SWS generation and episode occurrence. Additionally, reduced perfusion in the dorsolateral prefrontal cortex and insula during recovery SWS is consistent with the clinical features of somnambulistic episodes, including impaired awareness and reduced pain perception. Altered regional cerebral perfusion patterns during sleepwalkers' resting-state wakefulness may be related to daytime functional anomalies in this population.

Metabotropic glutamate receptor type 5 (mGluR5) is a G protein-coupled receptor that has been implicated in several psychiatric and neurological diseases. The radiopharmaceutical [(11)C]ABP688 allows for in vivo quantification of mGluR5 availability using positron emission tomography (PET). In this study, we aimed to detail the regional distribution of [(11)C]ABP688 binding potential (BPND) and the existence of age/sex effects in healthy individuals.Thirty-one healthy individuals aged 20 to 77 years (men, n = 18, 45.3 ± 18.2 years; females, n = 13, 41.5 ± 19.6 years) underwent imaging with [(11)C]ABP688 using the high-resolution research tomograph (HRRT). We developed an advanced partial volume correction (PVC) method using surface-based analysis in order to accurately estimate the regional variation of radioactivity. BPND was calculated using the simplified reference tissue model, with the cerebellum as the reference region. Surface-based and volume-based analyses were performed for 39 cortical and subcortical regions of interest per hemisphere.We found the highest [(11)C]ABP688 BPND in the lateral prefrontal and anterior cingulate cortices. The lowest [(11)C]ABP688 BPND was observed in the pre- and post-central gyri as well as the occipital lobes and the thalami. No sex effect was observed. Associations between age and [(11)C]ABP688 BPND without PVC were observed in the right amygdala and left putamen, but were not significant after multiple comparisons correction.The present results highlight complexities underlying brain adaptations during the aging process, and support the notion that certain aspects of neurotransmission remain stable during the adult life span.

Radiolabeled peptides for tumor imaging with PET that can be produced with kits are currently in the spotlight of radiopharmacy and nuclear medicine. The diagnosis of neuroendocrine tumors in particular has been a prime example for the usefulness of peptides labeled with a variety of different radionuclides. Among those, 68Ga and 18F stand out because of the ease of radionuclide introduction (e.g., 68Ga isotope) or optimal nuclide properties for PET imaging (slightly favoring the 18F isotope). The in vivo properties of good manufacturing practice–compliant, newly developed kitlike-producible 18F-SiFA– and 18F-SiFAlin– (SiFA = silicon-fluoride acceptor) modified TATE derivatives were compared with the current clinical gold standard 68Ga-DOTATATE for high-quality imaging of somatostatin receptor–bearing tumors. Methods: SiFA- and SiFAlin-derivatized somatostatin analogs were synthesized and radiolabeled using cartridge-based dried 18F and purified via a C18 cartridge (radiochemical yield 49.8% ± 5.9% within 20–25 min) without high-performance liquid chromatography purification. Tracer lipophilicity and stability in human serum were tested in vitro. Competitive receptor binding affinity studies were performed using AR42J cells. The most promising tracers were evaluated in vivo in an AR42J xenograft mouse model by ex vivo biodistribution and in vivo PET/CT imaging studies for evaluation of their pharmacokinetic profiles, and the results were compared with those of the current clinical gold standard 68Ga-DOTATATE. Results: Synthetically easily accessible 18F-labeled silicon-fluoride acceptor–modified somatostatin analogs were developed. They exhibited high binding affinities to somatostatin receptor–positive tumor cells (1.88–14.82 nM). The most potent compound demonstrated comparable pharmacokinetics and an even slightly higher absolute tumor accumulation level in ex vivo biodistribution studies as well as higher tumor standardized uptake values in PET/CT imaging than 68Ga-DOTATATE in vivo. The radioactivity uptake in nontumor tissue was higher than for 68Ga-DOTATATE. Conclusion: The introduction of the novel SiFA building block SiFAlin and of hydrophilic auxiliaries enables a favorable in vivo biodistribution profile of the modified TATE peptides, resulting in high tumor-to-background ratios although lower than those observed with 68Ga-DOTATATE. As further advantage, the SiFA methodology enables a kitlike labeling procedure for 18F-labeled peptides advantageous for routine clinical application.

Molecular imaging offers unprecedented opportunities for investigating dynamic changes underlying neuropsychiatric conditions. Here, we evaluated whether [11C]ABP688, a positron emission tomography (PET) ligand that binds to the allosteric site of the metabotropic glutamate receptor type 5 (mGluR5), is sensitive to glutamate fluctuations after a pharmacological challenge. For this, we used ceftriaxone (CEF) administration in rats, an activator of the GLT-1 transporter (EAAT2), which is known to decrease extracellular levels of glutamate. MicroPET [11C]ABP688 dynamic acquisitions were conducted in rats after a venous injection of either saline (baseline) or CEF 200 mg/kg (challenge). Binding potentials (BPND) were obtained using the simplified reference tissue method. Between-condition statistical parametric maps indicating brain regions showing the highest CEF effects guided placement of microdialysis probes for subsequent assessment of extracellular levels of glutamate. The CEF administration increased [11C]ABP688 BPND in the thalamic ventral anterior (VA) nucleus bilaterally. Subsequent microdialysis assessment revealed declines in extracellular glutamate concentrations in the VA. The present results support the concept that availability of mGluR5 allosteric binding sites is sensitive to extracellular concentrations of glutamate. This interesting property of mGluR5 allosteric binding sites has potential applications for assessing the role of glutamate in the pathogenesis of neuropsychiatric conditions.

PURPOSE Operculoinsular epilepsy (OIE) can be challenging to diagnose. While the value of SPECT cerebral blood flow and PET F-FDG studies for presurgical evaluation of patients with medial temporal lobe epilepsy (MTLE) is well established, it remains unclear whether they can help identify an operculoinsular epileptic focus. This study assesses the value of interictal/ictal regional cerebral blood flow (rCBF) SPECT and FDG PET for OIE diagnosis. METHODS Eighteen patients with proven OIE who underwent interictal/ictal rCBF SPECT and/or FDG-PET prior to epilepsy surgery were identified from our clinical database and were compared with a group of 18 patients who underwent MTLE surgery. Regional cerebral blood flow SPECT and FDG PET images were reevaluated visually by an expert reader blind to clinical data. RESULTS Interictal/ictal rCBF SPECT correctly identified an operculoinsular focus in 11 (65%) of 17 OIE patients and was misleading in 3 cases (18%). Secondary activation in areas connected to the insula was often observed. In the MTLE group, the area of maximal increased perfusion was congruent in 12 (75%) of 16 patients and extended to the ipsilateral insula in 1 patient. FDG PET findings were concordant with the epileptic focus in 8 (47%) of 17 OIE patients and were misleading in 4 (24%), whereas they were concordant in all MTLE patients. CONCLUSIONS Interictal/ictal rCBF SPECT can identify a concordant operculoinsular focus in a significant proportion of OIE patients and offers a valuable diagnostic tool in nonlesional cases. By contrast, the value of interictal FDG PET in this population is more equivocal.

Molecular imaging techniques using 18 F-fluorodeoxyglucose, amyloid tracers, and, more recently, tau ligands have taken dementia research by storm and undoubtedly improved our understanding of neurodegenerative diseases. The ability to image in vivo the pathological substrates of degenerative diseases and visualize their downstream impact has led to improved models of pathogenesis, better differential diagnosis of atypical conditions, as well as focused subject selection and monitoring of treatment in clinical trials aimed at delaying or preventing the symptomatic phase of Alzheimer's disease. In this article, we present the main molecular imaging techniques used in research and practice. We further summarize the key findings brought about by each technique individually and more recently, as adjuncts to each other. Specific limitations of each imaging modality are discussed, as well as recommendations to overcome them. A nonvalidated clinical algorithm is proposed for earlier and more accurate identification of complex/atypical neurodegenerative diseases.

Cholinergic neurons of the pedunculopontine tegmental nucleus (PPTg) are thought to be involved in cognitive functions such as sustained attention, and lesions of these cells have been documented in patients showing fluctuations of attention such as in Parkinson's disease or dementia with Lewy Body. Animal studies have been conducted to support the role of these cells in attention, but the lesions induced in these animals were not specific to the cholinergic PPTg system, and were assessed by post-mortem methods remotely performed from the in vivo behavioral assessments. Moreover, sustained attention have not been directly assessed in these studies, but rather deduced from indirect measurements. In the present study, rats were assessed on the 5-Choice Serial Reaction Time Task (5-CSRTT), and a specific measure of variability in response latency was created. Animals were observed both before and after selective lesion of the PPTg cholinergic neurons. Brain cholinergic denervation was assessed both in vivo and ex vivo, using PET imaging with [(18)F]fluoroethoxybenzovesamicol ([(18)F]FEOBV) and immunocytochemistry respectively. Results showed that the number of correct responses and variability in response latency in the 5-CSRTT were the only behavioral measures affected following the lesions. These measures were found to correlate significantly with the number of PPTg cholinergic cells, as measured with both [(18)F]FEOBV and immunocytochemistry. This suggests the primary role of the PPTg cholinergic cells in sustained attention. It also allows to reliably use the PET imaging with [(18)F]FEOBV for the purpose of assessing the relationship between behavior and cholinergic innervation in living animals.

Brain imaging has evolved to facilitate our understanding of structural and functional correlates of emotional, behavioral, and cognitive disorder we face in the clinical practice of geriatric psychiatry. The application of brain imaging techniques as diagnostic or therapeutic monitoring tools is still evolving. Today, brain imaging is both a clinical and research tool. Some imaging modalities have current clinical indications, mainly in ruling out treatable or modifiable illnesses that present with behavioral and/or cognitive symptoms in old age, and some require further validation to improve their predictive value. Clinicians need to use brain imaging tools wisely and in the broader context of various clinical data sources (e.g., history, examination, laboratory studies) to more focally define, explain, and, ultimately, manage clinical syndromes. In this chapter, we will provide an overview of currently available neuroimaging modalities, orient clinicians to structural and functional neuroanatomy, provide case examples on how neuroimaging can support the clinical diagnostic process, and offer suggestion on how to use neuroimaging optimally in geriatric psychiatry clinics.

Background 18F-THK5351 is a quinoline-derived tau imaging agent with high affinity to paired helical filaments (PHF). However, high levels of 18F-THK5351 retention in brain regions thought to contain negligible concentrations of PHF raise questions about the interpretation of the positron emission tomography (PET) signals, particularly given previously described interactions between quinolone derivatives and monoamine oxidase B (MAO-B). Here, we tested the effects of MAO-B inhibition on 18F-THK5351 brain uptake using PET and autoradiography. Methods Eight participants (five mild cognitive impairment, two Alzheimer’s disease, and one progressive supranuclear palsy) had baseline 18F-AZD4694 and 18F-THK5351 scans in order to quantify brain amyloid and PHF load, respectively. A second 18F-THK5351 scan was conducted 1 week later, 1 h after a 10-mg oral dose of selegiline. Three out of eight patients also had a third 18F-THK5351 scan 9–28 days after the selegiline administration. The primary outcome measure was standardized uptake value (SUV), calculated using tissue radioactivity concentration from 50 to 70 min after 18F-THK5351 injection, normalizing for body weight and injected radioactivity. The SUV ratio (SUVR) was determined using the cerebellar cortex as the reference region. 18F-THK5351 competition autoradiography studies in postmortem tissue were conducted using 150 and 500 nM selegiline. Results At baseline, 18F-THK5351 SUVs were highest in the basal ganglia (0.64 ± 0.11) and thalamus (0.62 ± 0.14). In the post-selegiline scans, the regional SUVs were reduced on average by 36.7% to 51.8%, with the greatest reduction noted in the thalamus (51.8%) and basal ganglia (51.4%). MAO-B inhibition also reduced 18F-THK5351 SUVs in the cerebellar cortex (41.6%). The SUVs remained reduced in the three patients imaged at 9–28 days. Tissue autoradiography confirmed the effects of MAO-B inhibition on 18F-THK5351 uptake. Conclusions These results indicate that the interpretation of 18F-THK5351 PET images, with respect to tau, is confounded by the high MAO-B availability across the entire brain. In addition, the heterogeneous MAO-B availability across the cortex may limit the interpretation of 18F-THK5351 scans using reference region methods.

To determine whether the Parkinson disease-related covariance pattern (PDRP) expression is abnormally increased in idiopathic REM sleep behavior disorder (RBD) and whether increased baseline activity is associated with greater individual risk of subsequent phenoconversion.For this cohort study, we recruited 2 groups of RBD and control subjects. Cohort 1 comprised 10 subjects with RBD (63.5 ± 9.4 years old) and 10 healthy volunteers (62.7 ± 8.6 years old) who underwent resting-state metabolic brain imaging with (18)F-fluorodeoxyglucose PET. Cohort 2 comprised 17 subjects with RBD (68.9 ± 4.8 years old) and 17 healthy volunteers (66.6 ± 6.0 years old) who underwent resting brain perfusion imaging with ethylcysteinate dimer SPECT. The latter group was followed clinically for 4.6 ± 2.5 years by investigators blinded to the imaging results. PDRP expression was measured in both RBD groups and compared with corresponding control values.PDRP expression was elevated in both groups of subjects with RBD (cohort 1: p0.04; cohort 2: p0.005). Of the 17 subjects with long-term follow-up, 8 were diagnosed with Parkinson disease or dementia with Lewy bodies; the others did not phenoconvert. For individual subjects with RBD, final phenoconversion status was predicted using a logistical regression model based on PDRP expression and subject age at the time of imaging (r(2) = 0.64, p0.0001).Latent network abnormalities in subjects with idiopathic RBD are associated with a greater likelihood of subsequent phenoconversion to a progressive neurodegenerative syndrome.

Introduction [ 18 F]fluoroethoxybenzovesamicol ([ 18 F]FEOBV) is a PET radiotracer with high selectivity and specificity to the vesicular acetylcholine transporter (VAChT). It has been shown to be a sensitive in vivo measurement of changes of cholinergic innervation densities following lesion of the nucleus basalis of Meynert (NBM) in rat. The current study used [ 18 F]FEOBV with PET imaging to detect the effect of a highly selective lesion of the pedunculopontine (PPTg) nucleus in rat. Methods After bilateral and selective lesions of the PPTg cholinergic neurons, rats were scanned using [ 18 F]FEOBV, then sacrificed, and their brain tissues collected for immunostaining and quantification of the VAChT. Results Comparisons with control rats revealed that cholinergic losses can be detected in the brainstem, lateral thalamus, and pallidum by using both in vivo imaging methods with [ 18 F]FEOBV, and ex vivo measurements. In the brainstem PPTg area, significant correlations were observed between in vivo and ex vivo measurements, while this was not the case in the thalamic and pallidal projection sites. Conclusions These findings support PET imaging with [ 18 F]FEOBV as a reliable in vivo method for the detection of neuronal terminal losses resulting from lesion of the PPTg. Useful applications can be found in the study of neurodegenerative diseases in human, such as Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, or dementia with Lewy bodies.

Rationale. Alzheimer’s Disease (AD) is a neurodegenerative condition characterized in part by deficits in cholinergic basalocortical and septohippocampal pathways. [18F]Fluoroethoxybenzovesamicol ([18F]FEOBV), a Positron Emission Tomography ligand for the vesicular acetylcholine transporter (VAChT), is a potential molecular agent to investigate brain diseases associated with presynaptic cholinergic losses. Purpose. To demonstrate this potential, we carried out an [18F]FEOBV autoradiography study to compare postmortem brain tissues from AD patients to those of age-matched controls. Methods. [18F]FEOBV autoradiography binding, defined as the ratio between regional grey and white matter, was estimated in the hippocampus (13 controls, 8 AD) and prefrontal cortex (13 controls, 11 AD). Results. [18F]FEOBV binding was decreased by 33% in prefrontal cortex, 25% in CA3, and 20% in CA1. No changes were detected in the dentate gyrus of the hippocampus, possibly because of sprouting or upregulation toward the resilient glutamatergic neurons of the dentate gyrus. Conclusion. This is the first demonstration of [18F]FEOBV focal binding changes in cholinergic projections to the cortex and hippocampus in AD. Such cholinergic synaptic (and more specifically VAChT) alterations, in line with the selective basalocortical and septohippocampal cholinergic losses documented in AD, indicate that [18F]FEOBV is indeed a promising ligand to explore cholinergic abnormalities in vivo.

This work evaluates a maximum likelihood parameter estimation method for regions-of-interest (ML-ROI) when incorporated in a direct 4D PET image reconstruction framework including the simplified reference tissue model with the basis function method (SRTM-BFM) tracer kinetic model. The ML-ROI algorithm has been evaluated for the usual task of estimating the radioactivity concentration for ROI spatial-bases compared to voxels. We therefore extend the application of this method to include the direct estimation of binding potential (BP) values on simulated 2D+time data sets (with use of [11C]raclopride time-activity curves (TACs) from real data). The performance of the proposed method is evaluated by comparing BP estimates with those obtained from a conventional post reconstruction approach, as well as the original ML-ROI method. It is shown that the use of ROIs as spatial basis functions leads to much lower %RMSE for BP regional estimates (%RMSE reduced by a factor of 2 or more), and furthermore using direct BP estimation in conjunction with ROI spatial basis functions reduces the still further. However, the major improvement is from the use of ROI spatial basis functions, rather than the use of direct kinetic parameter estimation. On the other hand, the considerable time gained (2 orders of magnitude) makes it a potential candidate for routine application.

Translation of carbon-11 labeled PET tracers to clinical settings is currently impeded by the technical difficulties associated with [