Western diet increases brain metabolism and adaptive immune responses in a mouse model of amyloidosis.

Diet-induced increase in body weight is a growing health concern worldwide. Often accompanied by a low-grade metabolic inflammation that changes systemic functions, diet-induced alterations may contribute to neurodegenerative disorder progression as well. This study aims to non-invasively investigate diet-induced metabolic and inflammatory effects in the brain of an APPPS1 mouse model of Alzheimer's disease. [18F]FDG, [18F]FTHA, and [18F]GE-180 were used for in vivo PET imaging in wild-type and APPPS1 mice. Ex vivo flow cytometry and histology in brains complemented the in vivo findings. 1H- magnetic resonance spectroscopy in the liver, plasma metabolomics and flow cytometry of the white adipose tissue were used to confirm metaflammatory condition in the periphery. We found disrupted glucose and fatty acid metabolism after Western diet consumption, with only small regional changes in glial-dependent neuroinflammation in the brains of APPPS1 mice. Further ex vivo investigations revealed cytotoxic T cell involvement in the brains of Western diet-fed mice and a disrupted plasma metabolome. 1H-magentic resonance spectroscopy and immunological results revealed diet-dependent inflammatory-like misbalance in livers and fatty tissue. Our multimodal imaging study highlights the role of the brain-liver-fat axis and the adaptive immune system in the disruption of brain homeostasis in amyloid models of Alzheimer's disease.

[18F]pFBC, a Covalent CLIP-Tag Radiotracer for Detection of Viral Reporter Gene Transfer in the Murine Brain.

Preclinical models of neurological diseases and gene therapy are essential for neurobiological research. However, the evaluation of such models lacks reliable reporter systems for use with noninvasive imaging methods. Here, we report the development of a reporter system based on the CLIP-tag enzyme and [18F]pFBC, an 18F-labeled covalent CLIP-tag-ligand synthesized via a DoE-optimized and fully automated process. We demonstrated its specificity using a subcutaneous xenograft model and a model of viral vector-mediated brain gene transfer by engineering HEK293 cells and striatal neurons to express membrane-tethered CLIP-tag protein. After in vitro characterization of the reporter, mice carrying either CLIP-tag expressing or control subcutaneous xenografts underwent dynamic [18F]pFBC PET imaging. The CLIP-tag expressing xenografts showed a significantly higher uptake than control xenografts (tumor-to-muscle ratio 5.0 vs 1.7, p = 0.0379). In vivo, metabolite analysis by radio-HPLC from plasma and brain homogenates showed only one radio-metabolite in plasma and none in the brain. In addition, [18F]pFBC showed fast uptake and rapid clearance from the brain in animals injected with adeno-associated virus (AAV)-CLIP in the right striatum but no right-to-left (R-L) uptake difference in the striata in the acquired PET data. In contrast, autoradiography showed a clear accumulation of radioactivity in the AAV-CLIP-injected right striatum compared to the sham-injected left striatum control. CLIP-tag expression and brain integrity were verified by immunofluorescence and light sheet microscopy. In conclusion, we established a novel reporter gene system for PET imaging of gene expression in the brain and periphery and demonstrated its potential for a wide range of applications, particularly for neurobiological research and gene therapy with viral vectors.

A Fluorescent Probe as a Lead Compound for a Selective α-Synuclein PET Tracer: Development of a Library of 2-Styrylbenzothiazoles and Biological Evaluation of [18F]PFSB and [18F]MFSB.

A method to detect and quantify aggregated α-synuclein (αSYN) fibrils in vivo would drastically impact the current understanding of multiple neurodegenerative diseases, revolutionizing their diagnosis and treatment. Several efforts have produced promising scaffolds, but a notable challenge has hampered the establishment of a clinically successful αSYN positron emission tomography (PET) tracer: the requirement of high selectivity over the other misfolded proteins amyloid ß (Aß) and tau. By designing and screening a library of 2-styrylbenzothiazoles based on the selective fluorescent probe RB1, this study aimed at developing a selective αSYN PET tracer. [3H]PiB competition binding assays identified PFSB (Ki = 25.4 ± 2.3 nM) and its less lipophilic analogue MFSB, which exhibited enhanced affinity to αSYN (Ki = 10.3 ± 4.7 nM) and preserved selectivity over Aß. The two lead compounds were labeled with fluorine-18 and evaluated using in vitro autoradiography on human brain slices, where they demonstrated up to 4-fold increased specific binding in MSA cases compared to the corresponding control, reasonably reflecting selective binding to αSYN pathology. In vivo PET imaging showed [18F]MFSB successfully crosses the blood-brain barrier (BBB) and is taken up in the brain (SUV = 1.79 ± 0.02). Although its pharmacokinetic profile raises the need for additional structural optimization, [18F]MFSB represents a critical step forward in the development of a successful αSYN PET tracer by overcoming the major challenge of αSYN/Aß selectivity.

The Structural Combination of SIL and MODAG Scaffolds Fails to Enhance Binding to α-Synuclein but Reveals Promising Affinity to Amyloid ß.

A technique to image α-synuclein (αSYN) fibrils in vivo is an unmet scientific and clinical need that would represent a transformative tool in the understanding, diagnosis, and treatment of various neurodegenerative diseases. Several classes of compounds have shown promising results as potential PET tracers, but no candidate has yet exhibited the affinity and selectivity required to reach clinical application. We hypothesized that the application of the rational drug design technique of molecular hybridization to two promising lead scaffolds could enhance the binding to αSYN up to the fulfillment of those requirements. By combining the structures of SIL and MODAG tracers, we developed a library of diarylpyrazoles (DAPs). In vitro evaluation through competition assays against [3H]SIL26 and [3H]MODAG-001 showed the novel hybrid scaffold to have preferential binding affinity for amyloid ß (Aß) over αSYN fibrils. A ring-opening modification on the phenothiazine building block to produce analogs with increased three-dimensional flexibility did not result in an improved αSYN binding but a complete loss of competition, as well as a significant reduction in Aß affinity. The combination of the phenothiazine and the 3,5-diphenylpyrazole scaffolds into DAP hybrids did not generate an enhanced αSYN PET tracer lead compound. Instead, these efforts identified a scaffold for promising Aß ligands that may be relevant to the treatment and monitoring of Alzheimer's disease (AD).

Repurposing the mucolytic agent ambroxol for treatment of sub-acute and chronic ischaemic stroke.

Ambroxol is a well-known mucolytic expectorant, which has gained much attention in amyotrophic lateral sclerosis, Parkinson's and Gaucher's disease. A specific focus has been placed on ambroxol's glucocerebrosidase-stimulating activity, on grounds that the point mutation of the gba1 gene, which codes for this enzyme, is a risk factor for developing Parkinson's disease. However, ambroxol has been attributed other characteristics, such as the potent inhibition of sodium channels, modification of calcium homeostasis, anti-inflammatory effects and modifications of oxygen radical scavengers. We hypothesized that ambroxol could have a direct impact on neuronal rescue if administered directly after ischaemic stroke induction. We longitudinally evaluated 53 rats using magnetic resonance imaging to examine stroke volume, oedema, white matter integrity, resting state functional MRI and behaviour for 1 month after ischemic stroke onset. For closer mechanistic insights, we evaluated tissue metabolomics of different brain regions in a subgroup of animals using ex vivo nuclear magnetic resonance spectroscopy. Ambroxol-treated animals presented reduced stroke volumes, reduced cytotoxic oedema, reduced white matter degeneration, reduced necrosis, improved behavioural outcomes and complex changes in functional brain connectivity. Nuclear magnetic resonance spectroscopy tissue metabolomic data at 24 h post-stroke proposes several metabolites that are capable of minimizing post-ischaemic damage and that presented prominent shifts during ambroxol treatment in comparison to controls. Taking everything together, we propose that ambroxol catalyzes recovery in energy metabolism, cellular homeostasis, membrane repair mechanisms and redox balance. One week of ambroxol administration following stroke onset reduced ischaemic stroke severity and improved functional outcome in the subacute phase followed by reduced necrosis in the chronic stroke phase.

Neurovascular Uncoupling: Multimodal Imaging Delineates the Acute Effects of 3,4-Methylenedioxymethamphetamine.

Psychedelic compounds such as 3,4-methylenedioxymethamphetamine (MDMA) have attracted increasing interest in recent years because of their therapeutic potential in psychiatric disorders. To understand the acute effects of psychedelic drugs in vivo, blood-oxygenation-level-dependent (BOLD) functional MRI (fMRI) has been widely used. In particular, fMRI studies have suggested that MDMA leads to inhibition of brain activity, challenging previous hypotheses indicating mainly excitatory effects based, among others, on increased metabolism shown by 18F-FDG functional PET (fPET). However, interpretation of hemodynamic changes induced by psychedelics is difficult because of their potent vascular effects. Methods: We aimed to delineate the acute effects of MDMA using simultaneous PET/fMRI in rats. For this purpose, hemodynamic changes measured by BOLD fMRI were related to alterations in glucose utilization and serotonin transporter (SERT) occupancy using 18F-FDG fPET/fMRI and 11C-DASB PET/fMRI. Results: We show that MDMA induces localized increases in glucose metabolism in limbic projection areas involved in emotional processing. The increased glucose metabolism was accompanied by global cerebral and extracerebral hemodynamic decreases. We further demonstrated a strong correlation between SERT occupancies and regional BOLD reductions after acute MDMA administration. Conclusion: Our data indicate that hemodynamic decreases after acute MDMA administration are of a nonneuronal nature and initiate peripherally. Within the brain, MDMA triggers neuronal activation in limbic projection areas, whereas increased serotonin levels induced by SERT blockage cause neurovascular uncoupling through direct vascular effects. Correct understanding of the in vivo mechanism of MDMA not only supports ongoing research but also warrants a reassessment of previous studies on neuronal effects of psychedelics relying on neurovascular coupling and recommends 18F-FDG fPET as a potentially more robust measure for pharmacologic research.

Combining CRISPR-Cas9 and brain imaging to study the link from genes to molecules to networks.

Receptors, transporters, and ion channels are important targets for therapy development in neurological diseases, but their mechanistic role in pathogenesis is often poorly understood. Gene editing and in vivo imaging approaches will help to identify the molecular and functional role of these targets and the consequence of their regional dysfunction on the whole-brain level. We combine CRISPR-Cas9 gene editing with in vivo positron emission tomography (PET) and functional MRI (fMRI) to investigate the direct link between genes, molecules, and the brain connectome. The extensive knowledge of the Slc18a2 gene encoding the vesicular monoamine transporter (VMAT2), involved in the storage and release of dopamine, makes it an excellent target for studying the gene network relationships while structurally preserving neuronal integrity and function. We edited the Slc18a2 in the substantia nigra pars compacta of adult rats and used in vivo molecular imaging besides behavioral, histological, and biochemical assessments to characterize the CRISPR-Cas9-mediated VMAT2 knockdown. Simultaneous PET/fMRI was performed to investigate molecular and functional brain alterations. We found that stage-specific adaptations of brain functional connectivity follow the selective impairment of presynaptic dopamine storage and release. Our study reveals that recruiting different brain networks is an early response to the dopaminergic dysfunction preceding neuronal cell loss. Our combinatorial approach is a tool to investigate the impact of specific genes on brain molecular and functional dynamics, which will help to develop tailored therapies for normalizing brain function.

Roux-En-Y Gastric Bypass (RYGB) Surgery during High Liquid Sucrose Diet Leads to Gut Microbiota-Related Systematic Alterations.

Roux-en-Y gastric bypass (RYGB) surgery has been proven successful in weight loss and improvement of co-morbidities associated with obesity. Chronic complications such as malabsorption of micronutrients in up to 50% of patients underline the need for additional therapeutic approaches. We investigated systemic RYGB surgery effects in a liquid sucrose diet-induced rat obesity model. After consuming a diet supplemented with high liquid sucrose for eight weeks, rats underwent RYGB or control sham surgery. RYGB, sham pair-fed, and sham ad libitum-fed groups further continued on the diet after recovery. Notable alterations were revealed in microbiota composition, inflammatory markers, feces, liver, and plasma metabolites, as well as in brain neuronal activity post-surgery. Higher fecal 4-aminobutyrate (GABA) correlated with higher Bacteroidota and Enterococcus abundances in RYGB animals, pointing towards the altered enteric nervous system (ENS) and gut signaling. Favorable C-reactive protein (CRP), serine, glycine, and 3-hydroxybutyrate plasma profiles in RYGB rats were suggestive of reverted obesity risk. The impact of liquid sucrose diet and caloric restriction mainly manifested in fatty acid changes in the liver. Our multi-modal approach reveals complex systemic changes after RYGB surgery and points towards potential therapeutic targets in the gut-brain system to mimic the surgery mode of action.

Alpha-Synuclein PET Tracer Development-An Overview about Current Efforts.

Neurodegenerative diseases such as Parkinson's disease (PD) are manifested by inclusion bodies of alpha-synuclein (α-syn) also called α-synucleinopathies. Detection of these inclusions is thus far only possible by histological examination of postmortem brain tissue. The possibility of non-invasively detecting α-syn will therefore provide valuable insights into the disease progression of α-synucleinopathies. In particular, α-syn imaging can quantify changes in monomeric, oligomeric, and fibrillic α-syn over time and improve early diagnosis of various α-synucleinopathies or monitor treatment progress. Positron emission tomography (PET) is a non-invasive in vivo imaging technique that can quantify target expression and drug occupancies when a suitable tracer exists. As such, novel α-syn PET tracers are highly sought after. The development of an α-syn PET tracer faces several challenges. For example, the low abundance of α-syn within the brain necessitates the development of a high-affinity ligand. Moreover, α-syn depositions are, in contrast to amyloid proteins, predominantly localized intracellularly, limiting their accessibility. Furthermore, another challenge is the ligand selectivity over structurally similar amyloids such as amyloid-beta or tau, which are often co-localized with α-syn pathology. The lack of a defined crystal structure of α-syn has also hindered rational drug and tracer design efforts. Our objective for this review is to provide a comprehensive overview of current efforts in the development of selective α-syn PET tracers.

Striatal and prefrontal D2R and SERT distributions contrastingly correlate with default-mode connectivity.

Although brain research has taken important strides in recent decades, the interaction and coupling of its different physiological levels is still not elucidated. Specifically, the molecular substrates of resting-state functional connectivity (rs-FC) remain poorly understood. The aim of this study was elucidating interactions between dopamine D2 receptors (D2R) and serotonin transporter (SERT) availabilities in the striatum (CPu) and medial prefrontal cortex (mPFC), two of the main dopaminergic and serotonergic projection areas, and the default-mode network. Additionally, we delineated its interaction with two other prominent resting-state networks (RSNs), the salience network (SN) and the sensorimotor network (SMN). To this extent, we performed simultaneous PET/fMRI scans in a total of 59 healthy rats using [11C]raclopride and [11C]DASB, two tracers used to image quantify D2R and SERT respectively. Edge, node and network-level rs-FC metrics were calculated for each subject and potential correlations with binding potentials (BPND) in the CPu and mPFC were evaluated. We found widespread negative associations between CPu D2R availability and all the RSNs investigated, consistent with the postulated role of the indirect basal ganglia pathway. Correlations between D2Rs in the mPFC were weaker and largely restricted to DMN connectivity. Strikingly, medial prefrontal SERT correlated both positively with anterior DMN rs-FC and negatively with rs-FC between and within the SN, SMN and the posterior DMN, underlining the complex role of serotonergic neurotransmission in this region. Here we show direct relationships between rs-FC and molecular properties of the brain as assessed by simultaneous PET/fMRI in healthy rodents. The findings in the present study contribute to the basic understanding of rs-FC by revealing associations between inter-subject variances of rs-FC and receptor and transporter availabilities. Additionally, since current therapeutic strategies typically target neurotransmitter systems with the aim of normalizing brain function, delineating associations between molecular and network-level brain properties is essential and may enhance the understanding of neuropathologies and support future drug development.

Elucidating the complementarity of resting-state networks derived from dynamic [18F]FDG and hemodynamic fluctuations using simultaneous small-animal PET/MRI.

Functional connectivity (FC) and resting-state network (RSN) analyses using functional magnetic resonance imaging (fMRI) have evolved into a growing field of research and have provided useful biomarkers for the assessment of brain function in neurological disorders. However, the underlying mechanisms of the blood oxygen level-dependant (BOLD) signal are not fully resolved due to its inherent complexity. In contrast, [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) has been shown to provide a more direct measure of local synaptic activity and may have additional value for the readout and interpretation of brain connectivity. We performed an RSN analysis from simultaneously acquired PET/fMRI data on a single-subject level to directly compare fMRI and [18F]FDG-PET-derived networks during the resting state. Simultaneous [18F]FDG-PET/fMRI scans were performed in 30 rats. Pairwise correlation analysis, as well as independent component analysis (ICA), were used to compare the readouts of both methods. We identified three RSNs with a high degree of similarity between PET and fMRI-derived readouts: the default-mode-like network (DMN), the basal ganglia network and the cerebellar-midbrain network. Overall, [18F]FDG connectivity indicated increased integration between different, often distant, brain areas compared to the results indicated by the more segregated fMRI-derived FC. Additionally, several networks exclusive to either modality were observed using ICA. These networks included mainly bilateral cortical networks of a limited spatial extent for fMRI and more spatially widespread networks for [18F]FDG-PET, often involving several subcortical areas. This is the first study using simultaneous PET/fMRI to report RSNs subject-wise from dynamic [18F]FDG tracer delivery and BOLD fluctuations with both independent component analysis (ICA) and pairwise correlation analysis in small animals. Our findings support previous studies, which show a close link between local synaptic glucose consumption and BOLD-fMRI-derived FC. However, several brain regions were exclusively attributed to either [18F]FDG or BOLD-derived networks underlining the complementarity of this hybrid imaging approach, which may contribute to the understanding of brain functional organization and could be of interest for future clinical applications.

[11C]MODAG-001-towards a PET tracer targeting α-synuclein aggregates.

PURPOSE: Deposition of misfolded alpha-synuclein (αSYN) aggregates in the human brain is one of the major hallmarks of synucleinopathies. However, a target-specific tracer to detect pathological aggregates of αSYN remains lacking. Here, we report the development of a positron emission tomography (PET) tracer based on anle138b, a compound shown to have therapeutic activity in animal models of neurodegenerative diseases. METHODS: Specificity and selectivity of [3H]MODAG-001 were tested in in vitro binding assays using recombinant fibrils. After carbon-11 radiolabeling, the pharmacokinetic and metabolic profile was determined in mice. Specific binding was quantified in rats, inoculated with αSYN fibrils and using in vitro autoradiography in human brain sections of Lewy body dementia (LBD) cases provided by the Neurobiobank Munich (NBM). RESULTS: [3H]MODAG-001 revealed a very high affinity towards pure αSYN fibrils (Kd = 0.6 ± 0.1 nM) and only a moderate affinity to hTau46 fibrils (Kd = 19 ± 6.4 nM) as well as amyloid-ß1-42 fibrils (Kd = 20 ± 10 nM). [11C]MODAG-001 showed an excellent ability to penetrate the mouse brain. Metabolic degradation was present, but the stability of the parent compound improved after selective deuteration of the precursor. (d3)-[11C]MODAG-001 binding was confirmed in fibril-inoculated rat striata using in vivo PET imaging. In vitro autoradiography showed no detectable binding to aggregated αSYN in human brain sections of LBD cases, most likely, because of the low abundance of aggregated αSYN against background protein. CONCLUSION: MODAG-001 provides a promising lead structure for future compound development as it combines a high affinity and good selectivity in fibril-binding assays with suitable pharmacokinetics and biodistribution properties.

Quantitative Rodent Brain Receptor Imaging.

Positron emission tomography (PET) is a non-invasive imaging technology employed to describe metabolic, physiological, and biochemical processes in vivo. These include receptor availability, metabolic changes, neurotransmitter release, and alterations of gene expression in the brain. Since the introduction of dedicated small-animal PET systems along with the development of many novel PET imaging probes, the number of PET studies using rats and mice in basic biomedical research tremendously increased over the last decade. This article reviews challenges and advances of quantitative rodent brain imaging to make the readers aware of its physical limitations, as well as to inspire them for its potential applications in preclinical research. In the first section, we briefly discuss the limitations of small-animal PET systems in terms of spatial resolution and sensitivity and point to possible improvements in detector development. In addition, different acquisition and post-processing methods used in rodent PET studies are summarized. We further discuss factors influencing the test-retest variability in small-animal PET studies, e.g., different receptor quantification methodologies which have been mainly translated from human to rodent receptor studies to determine the binding potential and changes of receptor availability and radioligand affinity. We further review different kinetic modeling approaches to obtain quantitative binding data in rodents and PET studies focusing on the quantification of endogenous neurotransmitter release using pharmacological interventions. While several studies have focused on the dopamine system due to the availability of several PET tracers which are sensitive to dopamine release, other neurotransmitter systems have become more and more into focus and are described in this review, as well. We further provide an overview of latest genome engineering technologies, including the CRISPR/Cas9 and DREADD systems that may advance our understanding of brain disorders and function and how imaging has been successfully applied to animal models of human brain disorders. Finally, we review the strengths and opportunities of simultaneous PET/magnetic resonance imaging systems to study drug-receptor interactions and challenges for the translation of PET results from bench to bedside.

Imaging SERT Availability in a Rat Model of L-DOPA-Induced Dyskinesia.

PURPOSE: The development of L-DOPA-induced dyskinesia (LID) is one of the most severe side effects of chronic L-DOPA treatment in Parkinson's disease patients. [11C]DASB positron emission tomography (PET) provides a prominent tool to visualize and quantify serotonin transporter (SERT) pathology in vivo in patients and in animal models. To evaluate the effect of chronic L-DOPA treatment on SERT availability in an animal model of LID, we performed a longitudinal PET study. PROCEDURES: Rats received a unilateral 6-hydroxydopamine (6-OHDA) lesion, and striatal and extrastriatal SERT expression levels were studied with [11C]DASB, a marker of SERT availability, before and after daily treatment with L-DOPA. Dyskinesias were evaluated at different time points over a period of 21 days. RESULTS: [11C]DASB binding was found to be decreased after 6-OHDA lesions in the striatum, cortex, and hippocampus 5 weeks after 6-OHDA injection in the lesioned hemisphere of the rat brain. Chronic L-DOPA priming resulted in a relative preservation of SERT availability in the lesioned and healthy hemisphere compared to baseline measurements. CONCLUSIONS: Our longitudinal PET data support a preservation of SERT availability after the induction of L-DOPA-induced dyskinesia, which is in line with previous reports in dyskinetic PD patients.

11 C Radiolabeling of anle253b: a Putative PET Tracer for Parkinson's Disease That Binds to α-Synuclein Fibrils in†vitro and Crosses the Blood-Brain Barrier.

There is an urgent clinical need for imaging of α-synuclein (αSyn) fibrils, the hallmark biomarker for Parkinson's disease, in neurodegenerative disorders. Despite immense efforts, promising tracer candidates for nuclear imaging of αSyn are rare. Diphenyl pyrazoles are known modulators of αSyn aggregation and thus bear potential for non-invasive detection of this biomarker in vivo. Here we demonstrate high-affinity binding of the family member anle253b to fibrillar αSyn and present a high-yielding site-selective radiosynthesis route for 11 C radiolabeling using in-situ generated [11 C]formaldehyde and reductive methylation. Radio-HPLC of the tracer after incubation with rat serum in vitro shows excellent stability of the molecule. Positron emission tomography in healthy animals is used to assess the pharmacokinetics and biodistribution of the tracer, showing good penetration of the blood-brain barrier and low background binding to the non-pathological brain.

PET/MRI Hybrid Systems.

Over the last decade, the combination of PET and MRI in one system has proven to be highly successful in basic preclinical research, as well as in clinical research. Nowadays, PET/MRI systems are well established in preclinical imaging and are progressing into clinical applications to provide further insights into specific diseases, therapeutic assessments, and biological pathways. Certain challenges in terms of hardware had to be resolved concurrently with the development of new techniques to be able to reach the full potential of both combined techniques. This review provides an overview of these challenges and describes the opportunities that simultaneous PET/MRI systems can exploit in comparison with stand-alone or other combined hybrid systems. New approaches were developed for simultaneous PET/MRI systems to correct for attenuation of 511 keV photons because MRI does not provide direct information on gamma photon attenuation properties. Furthermore, new algorithms to correct for motion were developed, because MRI can accurately detect motion with high temporal resolution. The additional information gained by the MRI can be employed to correct for partial volume effects as well. The development of new detector designs in combination with fast-decaying scintillator crystal materials enabled time-of-flight detection and incorporation in the reconstruction algorithms. Furthermore, this review lists the currently commercially available systems both for preclinical and clinical imaging and provides an overview of applications in both fields. In this regard, special emphasis has been placed on data analysis and the potential for both modalities to evolve with advanced image analysis tools, such as cluster analysis and machine learning.

Impact of the Arterial Input Function Recording Method on Kinetic Parameters in Small-Animal PET.

The goal of this study was to validate the use of an MR-compatible blood sampler (BS) with a detector system based on a lutetium oxyorthosilicate scintillator and avalanche photodiodes for small-animal PET. Methods: Five rats underwent a 60-min 18F-FDG study. For each animal, the arterial input function (AIF) was derived from the BS recording, from manual sampling (MS), and from the PET image. These AIFs were applied for kinetic modeling of the striatum using the irreversible 2-tissue-compartment model. The MS-based technique with a dispersion correction served as a reference approach, and the kinetic parameters that were estimated with the BS- and the image-derived AIFs were compared with the reference values. Additionally, the effect of applying a population-based activity ratio for plasma to whole blood (p/wb) and the dispersion correction was assessed. Results: The K1, k2, and k3 values estimated with the reference approach were 0.174 ± 0.037 mL/min/cm3, 0.342 ± 0.080 1/min, and 0.048 ± 0.009 1/min, respectively. The corresponding parameters obtained with the BS- and image-derived AIFs deviated from these values by 0.6%-18.8% and 16.7%-47.9%, respectively. To compensate for the error in the BS-based technique, data from one MS collected at the end of the experiment were combined with the data from the first 10 min of the BS recording. This approach reduced the deviation in the kinetic parameters to 1.8%-6.3%. Using p/wb led to a 1.7%-8.3% difference from the reference parameters. The sensitivity of the BS was 23%, the energy resolution for the 511-keV photopeak was 19%, and the timing resolution was 11.2 ns. Conclusion: Online recording of the blood activity level with the BS allows precise measurement of AIF, without loss of blood volume. Combining the BS data with one MS is the most accurate approach for the data analysis. The high sensitivity of the device may allow application of lower radioactivity doses.