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Mitochondrial dysfunction has been implicated in the pathophysiology of autism spectrum disorder (ASD) in previous studies of postmortem brain or peripheral samples. The authors investigated whether and where mitochondrial dysfunction occurs in the living brains of individuals with ASD and to identify the clinical correlates of detected mitochondrial dysfunction.This case-control study used positron emission tomography (PET) with 2-Among the brain regions in which mitochondrial dysfunction has been reported in postmortem studies of autistic brains, participants with ASD had significantly decreased [This study provides direct evidence to link in vivo brain mitochondrial dysfunction with ASD pathophysiology and its communicational deficits. The findings support the possibility that mitochondrial electron transport chain complex I is a novel therapeutic target for ASD core symptoms.

[Background] Lewy body diseases (LBDs), which are pathologically defined as the presence of intraneuronal α-synuclein (α-Syn) inclusions called Lewy bodies, encompass Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies. Autopsy studies have shown that the olfactory bulb (OB) is one of the regions where Lewy pathology develops and initiates its spread in the brain. [Objective] This study aims to clarify how Lewy pathology spreads from the OB and affects brain functions using nonhuman primates. [Methods] We inoculated α-Syn preformed fibrils into the unilateral OBs of common marmosets (Callithrix jacchus) and performed pathological analyses, manganese-enhanced magnetic resonance imaging, and 18F-fluoro-2-deoxy-d-glucose positron emission tomography up to 6 months postinoculation. [Results] Severe α-Syn pathology was observed within the olfactory pathway and limbic system, while mild α-Syn pathology was seen in a wide range of brain regions, including the substantia nigra pars compacta, locus coeruleus, and even dorsal motor nucleus of the vagus nerve. The brain imaging analyses showed reduction in volume of the OB and progressive glucose hypometabolism in widespread brain regions, including the occipital lobe, and extended beyond the pathologically affected regions. [Conclusions] We generated a novel nonhuman primate LBD model with α-Syn propagation from the OB. This model suggests that α-Syn propagation from the OB is related to OB atrophy and cerebral glucose hypometabolism in LBDs., パーキンソン病の認知機能障害は鼻からはじまる？ --レヴィ小体病における嗅覚系伝播経路の解明--. 京都大学プレスリリース. 2022-08-23.

The antitumor drug paclitaxel has low water solubility, and its bioavailability is limited by the dissolution rate. To overcome this low water solubility, the currently marketed drug, Taxol, is formulated in a vehicle including Cremophor EL and ethanol mixture (1/1, v/v). However, Cremophor EL has been shown to have serious adverse side effects, such as hypersensitivity reactions and neurotoxicity. Improving the solubility of paclitaxel makes it possible to reduce side effects and enhance drug efficacy during antitumor therapy. One way to improve the solubility of poorly soluble drugs is to decrease their particle size to the nano-range to increase the surface area and dissolution rate. In the present study, we aimed to develop a new method for paclitaxel nanoparticle production. Polymeric nanoparticles of paclitaxel were prepared by laser irradiation at 1064 nm, which is the wavelength in the near-IR region. The prepared nanoparticles had a mean size of 57.9 nm and were spherical in shape. X-ray powder diffraction analysis showed that paclitaxel in the nanoparticles was in an amorphous state. These results demonstrate that the preparation of nanoparticles by laser irradiation is effective in improving the solubility of paclitaxel. Furthermore, the nanoparticles had an equivalent efficacy to Taxol in cell growth inhibition against breast cancer MCF-7 cells and drug efficacy in MCF-7 tumor-bearing mice as determined using positron emission tomography. Our method for preparing paclitaxel nanoparticles may be more effective in treating tumors with fewer adverse side effects than conventional Taxol.

Abnormal mitochondrial metabolism has been described in the Alzheimer's disease (AD) brain. However, the relationship between AD pathophysiology and key mitochondrial processes remains elusive. The purpose of this study was to investigate whether mitochondrial complex I dysfunction is associated with amyloid aggregation or glucose metabolism and brain atrophy in patients with mild AD using positron emission tomography (PET).Amyloid- and tau-positive symptomatic AD patients with clinical dementia rating 0.5 or 1 (N = 30; mean age ± standard deviation: 71.8 ± 7.6 years) underwent magnetic resonance imaging and PET scans with [[In symptomatic cases, although mitochondrial complex I reduction is linked to a wide range of downstream neurodegenerative processes such as hypometabolism, atrophy, and cognitive decline, a link to amyloid was not observable. The data presented here support [

Patients with damage to the primary visual cortex (V1) lose visual awareness, yet retain the ability to perform visuomotor tasks, which is called “blindsight.” To understand the neural mechanisms underlying this residual visuomotor function, we studied a non-human primate model of blindsight with a unilateral lesion of V1 using various oculomotor tasks. Functional brain imaging by positron emission tomography showed a significant change after V1 lesion in saccade-related visuomotor activity in the intraparietal sulcus area in the ipsi- and contralesional posterior parietal cortex. Single unit recordings in the lateral bank of the intraparietal sulcus (lbIPS) showed visual responses to targets in the contralateral visual field on both hemispheres. Injection of muscimol into the ipsi- or contralesional lbIPSs significantly impaired saccades to targets in the V1 lesion-affected visual field, differently from previous reports in intact animals. These results indicate that the bilateral lbIPSs contribute to visuomotor function in blindsight., Rikako Kato et al. use PET imaging to examine altered brain activity in blindsight macaques that lack visual awareness yet can still perform visuomotor tasks. They report that blindsight macaques exhibit a significant change in activity of the lateral bank of the intraparietal sulcus (lbIPS) bilaterally, and injection of muscimol into this region impairs visuomotor performance. These results suggest a role for the bilateral lbIPS in visuomotor function in blindsight conditions.

Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer’s disease (AD). In this study, we quantified the in vivo expression of the endoplasmic reticulum stress marker, sigma 1 receptor (S1R), using [ 11 C]SA4503 positron emission tomography (PET), the mitochondrial complex I (MC1) with [ 18 F]BCPP-EF, and the presynaptic vesicular protein SV2A with [ 11 C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and cerebral blood flow (CBF) measured with magnetic resonance imaging arterial spin labeling. Eight patients with AD were followed longitudinally to estimate the rate of change of the physiological and structural pathology markers with disease progression. The patients showed widespread increases in S1R (≤ 27%) and regional reduction in MC1 (≥ −28%) and SV2A (≥ −25%) radioligand binding, brain volume (≥ −23%), and CBF (≥ −26%). [ 18 F]BCPP-EF PET MC1 binding (≥ −12%) and brain volumes (≥ −5%) showed progressive reductions over 12 to 18 months, suggesting that they both could be used as pharmacodynamic indicators in early-stage therapeutics trials. Associations of reduced MC1 and SV2A and increased S1R radioligand binding with reduced cognitive performance in AD, although exploratory, suggested a loss of metabolic functional reserve with disease. Our study thus provides in vivo evidence for widespread, clinically relevant cellular stress and bioenergetic abnormalities in early AD.

(R)-[(11)C]verapamil is a radiotracer widely used for the evaluation of the P-glycoprotein (P-gp) function at the blood-brain barrier (BBB). Several studies have evaluated the pharmacokinetics of (R)-[(11)C]verapamil in rats and humans under different conditions. However, to the best of our knowledge, the pharmacokinetics of (R)-[(11)C]verapamil have not yet been evaluated in nonhuman primates. Our study aims to establish (R)-[(11)C]verapamil as a reference P-gp tracer for comparison of a newly developed P-gp positron emission tomography (PET) tracer in a species close to humans. Therefore, the study assesses the kinetics of (R)-[(11)C]verapamil and evaluates the effect of scan duration and P-gp inhibition on estimated pharmacokinetic parameters. Three nonhuman primates underwent two dynamic 91 min PET scans with arterial blood sampling, one at baseline and another after inhibition of the P-gp function. The (R)-[(11)C]verapamil data were analyzed using 1-tissue compartment model (1-TCM) and 2-tissue compartment model fits using plasma-corrected for polar radio-metabolites or non-corrected for radio-metabolites as an input function and with various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (SE %) of the estimated parameters. 1-TCM was selected as the model of choice to analyze the (R)-[(11)C]verapamil data at baseline and after inhibition and for all scan durations tested. The volume of distribution (V(T)) and the efflux constant k(2) estimations were affected by the evaluated scan durations, whereas the influx constant K(1) estimations remained relatively constant. After P-gp inhibition (tariquidar, 8 mg/kg), in a 91 min scan duration, the whole-brain V(T) increased significantly up to 208% (p < 0.001) and K(1) up to 159% (p < 0.001) compared with baseline scans. The k(2) values decreased significantly after P-gp inhibition in all the scan durations except for the 91 min scans. This study suggests the use of K(1), calculated with 1-TCM and using short PET scans (10 to 30 min), as a suitable parameter to measure the P-gp function at the BBB of nonhuman primates

[18F]MC225 has been developed as a weak substrate of P-glycoprotein (P-gp) aimed to measure changes in the P-gp function at the blood-brain barrier with positron emission tomography. This study evaluates [18F]MC225 kinetics in non-human primates and investigates the effect of both scan duration and P-gp inhibition. Three rhesus monkeys underwent two 91-min dynamic scans with blood sampling at baseline and after P-gp inhibition (8 mg/kg tariquidar). Data were analyzed using the 1-tissue compartment model (1-TCM) and 2-tissue compartment model (2-TCM) fits using metabolite-corrected plasma as the input function and for various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (%) of the estimated parameters. For the 91-min scan duration, the influx constant K1 increased by 40.7% and the volume of distribution (VT) by 30.4% after P-gp inhibition, while the efflux constant k2 did not change significantly. Similar changes were found for all evaluated scan durations. K1 did not depend on scan duration (10 min - K1 = 0.2191 vs 91 min - K1 = 0.2258), while VT and k2 did. A scan duration of 10 min seems sufficient to properly evaluate the P-gp function using K1 obtained with 1-TCM. For the 91-min scan, VT and K1 can be estimated with a 2-TCM, and both parameters can be used to assess P-gp function.

Mitochondrial dysfunction plays a critical role in the pathogenesis of kidney diseases via ATP depletion and reactive oxygen species overproduction. Nonetheless, few studies have reported the renal mitochondrial status clinical settings, partly due to a paucity of methodologies. Recently, a positron emission tomography probe, 18F-BCPP-BF, was developed to non-invasively visualize and quantitate the renal mitochondrial status in vivo. Here, 18F-BCPP-BF positron emission tomography was applied to three mechanistic kidney disease models in rats: kidney ischemia-reperfusion, 5/6 nephrectomy and anti-glomerular basement membrane glomerulonephritis. In rats with ischemia-reperfusion, a slight decrease in the kidney uptake of 18F-BCPP-BF was accompanied by morphological abnormality of the mitochondria in the proximal tubular cells after three hours of reperfusion, when the kidney function was slightly declined. In 5/6 nephrectomy and rats with anti-glomerular basement membrane glomerulonephritis, the kidney uptake of 18F-BCPP-BF cumulatively decreased with impairment of the kidney function, which was accompanied by a reduction of mitochondrial protein and a pathological tubulointerstitial exacerbation rather than glomerular injury. The 18F-BCPP-BF uptake in the injured kidney was suggested to represent the volume of healthy tubular epithelial cells with normally functioning mitochondria. Thus, this positron emission tomography probe can be a powerful tool for studying the pathophysiological meanings of the mitochondrial status in kidney disease.

Mitochondrial complex I (MC-I) is an essential regulator of brain bioenergetics and can be quantified in the brain using PET radioligand 18F-BCPP-EF. Here we evaluate the test–retest reproducibility of 18F-BCPP-EF in humans, and assess the use of a non-invasive quantification method (standardised uptake value ratio – SUVR). Thirty healthy volunteers had a 90-min dynamic 18F-BCPP-EF scan with arterial blood sampling, five of which received a second scan to be included in the test–retest analysis. Time-activity curves (TAC) were analysed using multilinear analysis 1 (MA1) and the two-tissue compartment model (2TC) to estimate volumes of distribution (VT). Regional SUVR-1 values were calculated from the 70 to 90-min TAC data using the centrum semiovale as a pseudo reference region, and compared to kinetic analysis-derived outcome measures. The mean absolute test–retest variability of VT ranged from 12% to 18% across regions. Both DVR-1and SUVR-1 had improved test–retest variability in the range 2%–7%. SUVR-1 was highly correlated with DVR-1 (r2 = 0.97, n = 30). In conclusion, 18F-BCPP-EF has suitable test–retest reproducibility and can be used to quantify MC-I in clinical studies.

ObjectiveIn vivo glycolysis-related glucose metabolism and electron transport chain-related mitochondrial activity may be different regionally in the brains of patients with Alzheimer disease (AD). To test this hypothesis regarding AD pathophysiology, we measured the availability of mitochondrial complex-I (MC-I) with the novel PET probe [18F]2-tert- butyl-4-chloro-5–2H- pyridazin-3-one ([18F]BCPP-EF), which binds to MC-I, and compared [18F]BCPP-EF uptake with 18F-fluorodeoxyglucose ([18F]FDG) uptake in the living AD brain.MethodsFirst, the total distribution volume (VT) of [18F]BCPP-EF from 10 normal controls (NCs) was quantified using arterial blood samples and then tested to observe whether VT could substitute for the standard uptake value relative to the global count (SUVRg). Eighteen NCs and 14 different NCs underwent PET with [18F]BCPP-EF or [18F]FDG, respectively. Second, 32 patients with AD were scanned semiquantitatively with double PET tracers. Interparticipant and intraparticipant comparisons of the levels of MC-I activity ([18F]BCPP-EF) and glucose metabolism ([18F]FDG) were performed.ResultsThe [18F]BCPP-EF VT was positively correlated with the [18F]BCPP-EF SUVRg, indicating that the use of the SUVRg was sufficient for semiquantitative evaluation. The [18F]BCPP-EF SUVRg, but not the [18F]FDG SUVRg, was significantly lower in the parahippocampus in patients with AD, highlighting the prominence of oxidative metabolic failure in the medial temporal cortex. Robust positive correlations between the [18F]BCPP-EF SUVRg and [18F]FDG SUVRg were observed in several brain regions, except the parahippocampus, in early-stage AD.ConclusionsMitochondrial dysfunction in the parahippocampus was shown in early-stage AD. Mitochondria-related energy failure may precede glycolysis-related hypometabolism in regions with pathologically confirmed early neurodegeneration in AD.

Browning of white adipose tissue (WAT) into beige adipocytes has been proposed as a strategy to tackle the ongoing obesity epidemic. Thermogenic stimuli have been investigated with the aim of converting existing white adipose tissue, primarily used for energy storage, into beige adipocytes capable of dissipating energy; however, evaluation is complicated by the dearth of noninvasive methodologies to quantify

Browning of white adipose tissue (WAT) into beige adipocytes has been proposed as a strategy to tackle the ongoing obesity epidemic. Thermogenic stimuli have been investigated with the aim of converting existing white adipose tissue, primarily used for energy storage, into beige adipocytes capable of dissipating energy; however, evaluation is complicated by the dearth of noninvasive methodologies to quantify de novo beige adipocytes in WAT. Imaging with [18F]FDG is commonly used to measure brown adipose tissue (BAT) and beige adipocytes but the relationship between beige adipocytes, thermogenesis and [18F]FDG uptake is unclear. [18F]BCPP-EF, a tracer for mitochondrial complex-I (MC-I), acts as a marker of oxidative metabolism and may be useful for the detection of newly formed beige adipocytes. Mice received doses of the β3-adrenergic agonist CL-316,243 subchronically for 7 days to induce formation of beige adipocytes in inguinal white fat. PET imaging was performed longitudinally with both [18F]FDG (a marker of glycolysis) and [18F]BCPP-EF (an MC-I marker) to assess the effect of thermogenic stimulation on uptake in browning inguinal WAT and interscapular BAT. Treatment with CL-316,243 led to significant increases in both [18F]FDG and [18F]BCPP-EF in inguinal WAT. The uptake of [18F]BCPP-EF in inguinal WAT was significantly increased above control levels after 3 days of stimulation, whereas [18F]FDG only showed a significant increase after 7 days. The uptake of [18F]BCPP-EF in newly formed beige adipocytes was blocked by pretreatment with an adrenoceptor antagonist suggesting that beige adipocyte formation may be associated with the activation of MC-I. However, in BAT, uptake of [18F]BCPP-EF was unaffected by β3-adrenergic stimulation, potentially due to the high expression of MC-I. [18F]BCPP-EF can detect newly formed beige adipocytes in WAT generated after subchronic treatment with the β3-adrenergic agonist CL-316,243 and displays both higher inguinal WAT uptake and earlier detection than [18F]FDG. The MC-I tracer may be a useful tool in the evaluation of new therapeutic strategies targeting metabolic adipose tissues to tackle obesity and metabolic diseases.

Purpose P-glycoprotein (P-gp) function is altered in several brain disorders; thus, it is of interest to monitor the P-gp function in vivo using PET. (R)-[11C]verapamil is considered the gold standard tracer to measure the P-gp function; however, it presents some drawbacks that limit its use. New P-gp tracers have been developed with improved properties, such as [18F]MC225. This study compares the characteristics of (R)-[11C]verapamil and [18F]MC225 in the same subjects. Methods Three non-human primates underwent 4 PET scans: 2 with (R)-[11C]verapamil and 2 with [18F]MC225, at baseline and after P-gp inhibition. The 30-min PET data were analyzed using 1-Tissue Compartment Model (1-TCM) and metabolite-corrected plasma as input function. Tracer kinetic parameters at baseline and after inhibition were compared. Regional differences and simplified methods to quantify the P-gp function were also assessed. Results At baseline, [18F]MC225 VT values were higher, and k2 values were lower than those of (R)-[11C]verapamil, whereas K1 values were not significantly different. After inhibition, VT values of the 2 tracers were similar; however, (R)-[11C]verapamil K1 and k2 values were higher than those of [18F]MC225. Significant regional differences between tracers were found at baseline, which disappeared after inhibition. The positive slope of the SUV-TAC was positively correlated to the K1 and VT of both tracers. Conclusion [18F]MC225 and (R)-[11C]verapamil show comparable sensitivity to measure the P-gp function in non-human primates. Moreover, this study highlights the 30-min VT as the best parameter to measure decreases in the P-gp function with both tracers. [18F]MC225 may become the first radiofluorinated tracer able to measure decreases and increases in the P-gp function due to its higher baseline VT.

1.ABSTRACTBackgroundSynaptic loss and neurite dystrophy are early events in Alzheimer’s Disease (AD). We aimed to characterise early synaptic microstructural changes in vivo.MethodsMRI neurite orientation dispersion and density imaging (NODDI) and diffusion tensor imaging (DTI) were used to image cortical microstructure in both sporadic, late onset, amyloid PET positive AD patients and healthy controls (total n = 28). We derived NODDI measures of grey matter extracellular free water (FISO), neurite density (NDI) and orientation dispersion (ODI), which provides an index of neurite branching and orientation, as well as more conventional DTI measures of fractional anisotropy (FA), mean/axial/radial diffusivity (MD, AD, RD, respectively). We also performed [11C]UCB-J PET, which provides a specific measure of the density of pre-synaptic vesicular protein SV2A. Both sets of measures were compared to regional brain volumes.ResultsThe AD patients showed expected relative decreases in regional brain volumes (range, -6 to - 23%) and regional [11C]UCB-J densities (range, -2 to -25%). Differences between AD and controls were greatest in the hippocampus. NODDI microstructural measures showed greater FISO (range, +26 to +44%) in AD, with little difference in NDI (range, -1 to +7%) and mild focal changes in ODI (range, -4 to +3%). Regionally greater FISO and lower [11C]UCB-J binding were correlated across grey matter in patients (most strongly in the caudate, r2 = 0.37, p = 0.001). FISO and DTI RD were strongly positively associated, particularly in the hippocampus (r2 = 0.98, p < 7.4 × 10−9). After 12-18 months we found a 5% increase in FISO in the temporal lobe, but little change across all ROIs in NDI and ODI. An exploratory analysis showed higher parietal lobe FISO was associated with lower language scores in people with AD.ConclusionsWe interpreted the increased extracellular free water as a possible consequence of glial activation. The dynamic range of disease-associated differences and the feasibility of measuring FISO on commercially available imaging systems makes it a potential surrogate for pathology related to synapse loss that could be used to support early-stage evaluations of novel therapeutics for AD.

Dihydromethidine (DHM) labeled with 18F at the para position of the peripheral benzene ring was designed as a positron emission tomography (PET) radiotracer for non-invasive imaging of reactive oxygen species (ROS). This compound readily crosses the blood-brain barrier and is oxidized by ROS, and the oxidation product is retained intracellularly. PET imaging of ROS-producing rat brain microinfused with sodium nitroprusside identified specific brain regions with high ROS concentrations. This tracer should be useful for studies of the pathophysiological roles of ROS, and in the diagnosis of neurodegenerative diseases.

In a recent study, we demonstrated that the ventral striatum (VSt) controls finger movements directly during the early recovery stage after spinal cord injury (SCI), implying that the VSt may be a part of neural substrates responsible for the recovery of dexterous finger movements. The VSt is accepted widely as a key node for motivation, but is not thought to be involved in the direct control of limb movements. Therefore, whether a causal relationship exists between the VSt and motor recovery after SCI is unknown, and the role of the VSt in the recovery of dexterous finger movements orfinger movements in general after SCI remains unclear. In the present study, functional brain imaging in a macaque model of SCI revealed a strengthened functional connectivity between motor-related areas and the VSt during the recovery process for precision grip, but not whole finger grip after SCI. Furthermore, permanent lesion of the VSt impeded the recoveryof precision grip, but not coarse grip. Thus, the VSt was needed specifically for functional recovery of dexterous finger movements. These results suggest that the VSt is the key node of the cortical reorganization required for functional recovery of finger dexterity.

BCPP compounds have been developed as PET imaging probes for neurodegenerative diseases in the living brain. 18F-BCPP-EF identifies damaged neuronal areas based on the lack of MC-I; however, its underlying mechanisms of action and specificity for MC-I remain unclear. We herein report the effects of BCPP-BF, -EF, -EM on MC-I in respiratory chain complexes using cardiomyocyte SMP. BCPP compounds inhibited the binding of 3H-dihydrorotenone to MC-I and the proton pumping activity of MC-I in a concentration-dependent manner in vitro. These results suggest that BCPP compounds are MC-I selective inhibitors, and, thus, these radiolabeled compounds are useful for the quantitative imaging of MC-I using PET.

Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer’s disease (AD). We quantified the in vivo density of the endoplasmic reticulum stress marker, the sigma 1 receptor (S1R) using [11C]SA4503 PET, as well as that of mitochondrial complex I (MC1) with [18F]BCPP-EF and the pre-synaptic vesicular protein SV2A with [11C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and brain perfusion (CBF) measured with MRI arterial spin labelling. 8 AD patients were followed longitudinally to estimate rates of change with disease progression over 12-18 months. The AD patients showed widespread increases in S1R (≤ 27%) and regional decreases in MC1 (≥ -28%), SV2A (≥ -25%), brain volume (≥ -23%), and CBF (≥ -26%). [18F]BCPP-EF PET MC1 density (≥ -12%) and brain volumes (≥ -5%) were further reduced at follow up in brain regions consistent with the differences between AD patients and controls at baseline. Exploratory analyses showing associations of MC1, SV2A and S1R density with cognitive changes at baseline and longitudinally with AD, but not in controls, suggested a loss of metabolic functional reserve with disease. Our study thus provides novel in vivo evidence for widespread cellular stress and bioenergetic abnormalities in early AD and that they may be clinically meaningful.

Purpose P-glycoprotein (P-gp) function is altered in several brain disorders; thus, it is of interest to monitor the P-gp function in vivo using PET. (R)-[11C]verapamil is considered as the gold standard tracer to measure the P-gp function, however, it presents some drawbacks that limit its use. New P-gp tracers have been developed with improved properties, such as [18F]MC225. This study compares the characteristics of (R)-[11C]verapamil and [18F]MC225 in the same subjects. Methods Three non-human primates underwent 4 PET scans: 2 with (R)-[11C]verapamil and 2 with [18F]MC225, at baseline and after P-gp inhibition. The 30-min PET data were analyzed using 1-TCM and metabolite-corrected-plasma as input function. Tracer kinetic parameters at baseline and after-inhibition were compared. Regional differences and simplified methods to quantify the P-gp function were also assessed. Results At baseline, [18F]MC225 VT values were higher and k2 values were lower than those of (R)-[11C]verapamil, whereas K1 values were not significantly different. After-inhibition, VT values of the 2 tracers were similar, however, (R)-[11C]verapamil K1 and k2 values were higher than those of [18F]MC225. Significant regional differences between tracers were found at baseline, which disappeared after inhibition. The positive slope of the SUV-TAC was positively correlated to the K1 and VT of both tracers. Conclusion [18F]MC225 and (R)-[11C]verapamil show comparable sensitivity to measure the P-gp function in non-human primates. Moreover, this study highlights the 30-min VT as the best parameter to measure decreases in the P-gp function with both tracers. [18F]MC225 may become the first radiofluorinated tracer able to measure decreases and increases in the P-gp function due to its higher baseline VT.

(R)-[11C]verapamil is a radiotracer widely used for the evaluation of the P-glycoprotein (P-gp) function at the blood–brain barrier (BBB). Several studies have evaluated the pharmacokinetics of (R)-[11C]verapamil in rats and humans under different conditions. However, to the best of our knowledge, the pharmacokinetics of (R)-[11C]verapamil have not yet been evaluated in nonhuman primates. Our study aims to establish (R)-[11C]verapamil as a reference P-gp tracer for comparison of a newly developed P-gp positron emission tomography (PET) tracer in a species close to humans. Therefore, the study assesses the kinetics of (R)-[11C]verapamil and evaluates the effect of scan duration and P-gp inhibition on estimated pharmacokinetic parameters. Three nonhuman primates underwent two dynamic 91 min PET scans with arterial blood sampling, one at baseline and another after inhibition of the P-gp function. The (R)-[11C]verapamil data were analyzed using 1-tissue compartment model (1-TCM) and 2-tissue compartment model fits using plasma-corrected for polar radio-metabolites or non-corrected for radio-metabolites as an input function and with various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (SE %) of the estimated parameters. 1-TCM was selected as the model of choice to analyze the (R)-[11C]verapamil data at baseline and after inhibition and for all scan durations tested. The volume of distribution (VT) and the efflux constant k2 estimations were affected by the evaluated scan durations, whereas the influx constant K1 estimations remained relatively constant. After P-gp inhibition (tariquidar, 8 mg/kg), in a 91 min scan duration, the whole-brain VT increased significantly up to 208% (p < 0.001) and K1 up to 159% (p < 0.001) compared with baseline scans. The k2 values decreased significantly after P-gp inhibition in all the scan durations except for the 91 min scans. This study suggests the use of K1, calculated with 1-TCM and using short PET scans (10 to 30 min), as a suitable parameter to measure the P-gp function at the BBB of nonhuman primates.

Although convolutional neural networks (CNNs) demonstrate the superior performance in denoising positron emission tomography (PET) images, a supervised training of the CNN requires a pair of large, high-quality PET image datasets. As an unsupervised learning method, a deep image prior (DIP) has recently been proposed; it can perform denoising with only the target image. In this study, we propose an innovative procedure for the DIP approach with a four-dimensional (4D) branch CNN architecture in end-to-end training to denoise dynamic PET images. Our proposed 4D CNN architecture can be applied to end-to-end dynamic PET image denoising by introducing a feature extractor and a reconstruction branch for each time frame of the dynamic PET image. In the proposed DIP method, it is not necessary to prepare high-quality and large patient-related PET images. Instead, a subject’s own static PET image is used as additional information, dynamic PET images are treated as training labels, and denoised dynamic PET images are obtained from the CNN outputs. Both simulation with [18F]fluoro-2-deoxy-D-glucose (FDG) and preclinical data with [18F]FDG and [11C]raclopride were used to evaluate the proposed framework. The results showed that our 4D DIP framework quantitatively and qualitatively outperformed 3D DIP and other unsupervised denoising methods. The proposed 4D DIP framework thus provides a promising procedure for dynamic PET image denoising.

Mitochondrial complex I (MC-I) is an essential regulator of brain bioenergetics and can be quantified in the brain using PET radioligand (18)F-BCPP-EF. Here we evaluate the test–retest reproducibility of (18)F-BCPP-EF in humans, and assess the use of a non-invasive quantification method (standardised uptake value ratio – SUVR). Thirty healthy volunteers had a 90-min dynamic (18)F-BCPP-EF scan with arterial blood sampling, five of which received a second scan to be included in the test–retest analysis. Time-activity curves (TAC) were analysed using multilinear analysis 1 (MA1) and the two-tissue compartment model (2TC) to estimate volumes of distribution (V(T)). Regional SUVR-1 values were calculated from the 70 to 90-min TAC data using the centrum semiovale as a pseudo reference region, and compared to kinetic analysis-derived outcome measures. The mean absolute test–retest variability of V(T) ranged from 12% to 18% across regions. Both DVR-1and SUVR-1 had improved test–retest variability in the range 2%–7%. SUVR-1 was highly correlated with DVR-1 (r(2) = 0.97, n = 30). In conclusion, (18)F-BCPP-EF has suitable test–retest reproducibility and can be used to quantify MC-I in clinical studies.

Background: While marked reductions in neural activity and mitochondrial function have been reported in Alzheimer’s disease (AD), the degree of mitochondrial activity in mild cognitive impairment (MCI) or early-stage AD remains unexplored. Here, we used positron emission tomography (PET) to examine the direct relationship between mitochondrial activity (18F-BCPP-EF) and β-amyloid (Aβ) deposition (11C-PiB), followed by immunohistochemistry for ATPB (an ATP synthase on the mitochondrial inner membrane), in the same brains of senescence-accelerated mouse prone 10 (SAMP10) mice, an Aβ-developing neuroinflammatory animal model showing accelerated senescence with deterioration in cognitive functioning similar to that in MCI.Results: The SUVRs of 18F-BCPP-EF and 11C-PiB were significantly higher in the 15-week-old SAMP10 mice than in the control and 5-week-old SAMP10 mice. The two parameters were found to negatively correlate with each other. Consistent with these binding results, the immunohistochemical analysis demonstrated upregulation of ATPB in neurons, astrocytes, and microglia, but not in pericytes, in the 15-week-old SAMP10 mice. Conclusions: The present results provide in vivo evidence of an increase in mitochondrial energy production and amyloid burden at an early stage in SAMP10 mice. The inverse correlation between these two phenomena suggests a concurrent compensatory increase in neuronal energy production and Aβ-induced elevation of neuroinflammatory responses in glial cells, as confirmed immunohistochemically. The combination of PET and immunohistochemistry allowed in vivo evaluation of altered mitochondrial activity during neuropathological processes, including Aβ accumulation, in an animal model of AD spectrum disorder.

Deep learning has attracted growing interest for application to medical imaging, such as positron emission tomography (PET), due to its excellent performance. Convolutional neural networks (CNNs), a facet of deep learning requires large training-image datasets. This presents a challenge in a clinical setting because it is difficult to prepare large, high-quality patient-related datasets. Recently, the deep image prior (DIP) approach has been devised, based on the fact that CNN structures have the intrinsic ability to solve inverse problems such as denoising without pre-training and do not require the preparation of training datasets. Herein, we proposed the dynamic PET image denoising using a DIP approach, with the PET data itself being used to reduce the statistical image noise. Static PET data were acquired for input to the network, with the dynamic PET images being handled as training labels, while the denoised dynamic PET images were represented by the network output. We applied the proposed DIP method to computer simulations and also to real data acquired from a living monkey brain with 18F-fluoro-2-deoxy-D-glucose (18F-FDG). As a simulation result, our DIP method produced less noisy and more accurate dynamic images than the other algorithms. Moreover, using real data, the DIP method was found to perform better than other types of post-denoising method in terms of contrast-to-noise ratio, and also maintain the contrast-to-noise ratio when resampling the list data to 1/5 and 1/10 of the original size, demonstrating that the DIP method could be applied to low-dose PET imaging. These results indicated that the proposed DIP method provides a promising means of post-denoising for dynamic PET images.

C-11-preladenant was developed as a novel PET ligand for the adenosine A(2A) receptors (A(2A)Rs). The present study aimed to evaluate the suitability of C-11-preladenant PET for the quantification of striatal A(2A)Rs and the assessment of A(2A)R occupancy in the conscious monkey brain. Methods: C-11-preladenant was intravenously injected into conscious monkeys (n = 4, 18 PET scans), and a 91-min dynamic scan was started. Arterial blood samples in combination with metabolite analysis were obtained during the scan to provide the input function for kinetic modeling. The distribution volume (VT) was obtained by kinetic modeling with a 2-tissue-compartment model. The simplified reference tissue model (SRTM) with selected reference regions (cerebellum, cingulate, parietal cortex, and occipital cortex) was tested to estimate the binding potential (BPND) in kAR-rich regions. BPND obtained from the SRTM was compared with distribution volume ratio (DVR)-1. The effects of blood volume, blood delay, and scan duration on BPND and DVR-1 were investigated. VT and BPND were also obtained after preblocking with unlabeled preladenant (1 mg/kg), A(2A)R-selective KW-6002 (0.5-1 mg/kg), and nonselective adenosine receptor antagonist caffeine (2.5-10 mg/kg). A(2A)R occupancy was studied with caffeine blockade. Results: Regional uptake of 11 c_preladenant was consistent with the distribution of A(2A)Rs in the monkey brain, with the highest uptake in the putamen, followed by the caudate, and the lowest uptake in the cerebellum. Tracer kinetics were well described by the 2-tissue-compartment model with a lower constraint on k4 to stabilize fits. The highest VT was observed in A2AR-rich regions (-5.8-7.4) and lowest value in the cerebellum (-1.3). BPND values estimated from the SRTM with different scan durations were comparable and were in agreement with DVR-1 (-4.3-5.3 in A(2A)R-rich regions). preladenant preinjection decreased the tracer uptake in A(2A)R-rich regions to the level of the reference regions. Caffeine pretreatment reduced the tracer up take in the striatum in a dose-dependent manner. Conclusion: C-11-preladenant PET is suitable for noninvasive quantification of A(2A)Rs and assessment of A(2A)R occupancy in A(2A)R-rich regions in the monkey brain. SRTM using the cerebellum as the reference tissue is the applicable model for A(2A)R quantification.

We tested a hypothesis that liposome-encapsulated hemoglobin (LEH) with high oxygen (O2 ) affinity (h-LEH, P50 O2 = 10 mm Hg) may work better than LEH with low O2 affinity (l-LEH, P50 O2 = 40 mm Hg) in cerebral ischemia and reperfusion injury using positron emission tomography (PET) in primates undergoing middle cerebral artery (MCA) occlusion and reperfusion. Cerebral blood flow (CBF), O2 extract fraction (OEF), and cerebral metabolic rate of O2 (CMRO2 ) were successively determined by PET before ischemia, at 2 h of ischemia, immediately after reperfusion, and 3 h after reperfusion. Five minutes after MCA occlusion, 10 mL/kg of h-LEH (n = 6) was intravenously infused and compared with the results from previous data of monkeys treated with l-LEH (n = 6), empty liposome (n = 4), or saline (n = 8) as control. After the series of PET studies, the integrated area of cerebral infarction was determined histologically in 12 coronal brain slices. There was no significant difference in CBF, OEF, or CMRO2 up to 2 h of ischemia. A high CBF with a low OEF tended to be suppressed after reperfusion in LEH-treated monkeys. Three hours after reperfusion, the area of mild CMRO2 reduction (down to -30%) decreased (P