Mitochondrial complex I density is associated with IQ and cognition in cognitively healthy adults: an in vivo [18F]BCPP-EF PET study.

BACKGROUND: Mitochondrial function plays a key role in regulating neurotransmission and may contribute to general intelligence. Mitochondrial complex I (MC-I) is the largest enzyme of the respiratory chain. Recently, it has become possible to measure MC-I distribution in vivo, using a novel positron emission tomography tracer [18F]BCPP-EF, thus, we set out to investigate the association between MC-I distribution and measures of cognitive function in the living healthy brain. RESULTS: Analyses were performed in a voxel-wise manner and identified significant associations between [18F]BCPP-EF DVRCS-1 in the precentral gyrus and parietal lobes and WAIS-IV predicted IQ, WAIS-IV arithmetic and WAIS-IV symbol-digit substitution scores (voxel-wise Pearson's correlation coefficients transformed to Z-scores, thresholded at Z = 2.3 family-wise cluster correction at p < 0.05, n = 16). Arithmetic scores were associated with middle frontal and post-central gyri tracer uptake, symbol-digit substitution scores were associated with precentral gyrus tracer uptake. RAVLT recognition scores were associated with [18F]BCPP-EF DVRCS-1 in the middle frontal gyrus, post-central gyrus, occipital and parietal regions (n = 20). CONCLUSIONS: Taken together, our findings support the theory that mitochondrial function may contribute to general intelligence and indicate that interindividual differences in MC-I should be a key consideration for research into mitochondrial dysfunction in conditions with cognitive impairment.

Brown adipose tissue evaluation using water and triglyceride as indices by diffuse reflectance spectroscopy.

Brown adipose tissue (BAT) is related to lipid and glucose metabolism, and BAT evaluation is expected to contribute to disease prevention and treatment. We aimed to establish a BAT evaluation method using simple and non-invasive diffuse reflectance spectroscopy (DRS). We acquired diffuse reflectance spectra of BAT using DRS from rats with cold stimulation and analyzed the second-derivative spectra. To predict the amount of triglyceride in BAT from the second-derivative spectra, partial least-squares regression analysis was performed, and we examined whether BAT weight can be predicted from the amount of triglyceride by single regression analysis. By focusing on changes in the amount of triglyceride in BAT with cold stimulation, it was suggested that this amount could be predicted spectroscopically, and the predicted amount of triglyceride could be used to estimate the BAT weight with cold stimulation. If these results can be translated into humans, they may contribute to preventing metabolic disorders.

Brain p3-Alcß peptide restores neuronal viability impaired by Alzheimer's amyloid ß-peptide.

We propose a new therapeutic strategy for Alzheimer's disease (AD). Brain peptide p3-Alcß37 is generated from the neuronal protein alcadein ß through cleavage of γ-secretase, similar to the generation of amyloid ß (Aß) derived from Aß-protein precursor/APP. Neurotoxicity by Aß oligomers (Aßo) is the prime cause prior to the loss of brain function in AD. We found that p3-Alcß37 and its shorter peptide p3-Alcß9-19 enhanced the mitochondrial activity of neurons and protected neurons against Aßo-induced toxicity. This is due to the suppression of the Aßo-mediated excessive Ca2+ influx into neurons by p3-Alcß. Successful transfer of p3-Alcß9-19 into the brain following peripheral administration improved the mitochondrial viability in the brain of AD mice model, in which the mitochondrial activity is attenuated by increasing the neurotoxic human Aß42 burden, as revealed through brain PET imaging to monitor mitochondrial function. Because mitochondrial dysfunction is common in the brain of AD patients alongside increased Aß and reduced p3-Alcß37 levels, the administration of p3-Alcß9-19 may be a promising treatment for restoring, protecting, and promoting brain functions in patients with AD.

Lower Availability of Mitochondrial Complex I in Anterior Cingulate Cortex in Autism: A Positron Emission Tomography Study.

OBJECTIVE: 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. METHODS: This case-control study used positron emission tomography (PET) with 2-tert-butyl-4-chloro-5-{6-[2-(2-[18F]fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([18F]BCPP-EF), a radioligand that binds to the mitochondrial electron transport chain complex I, to examine the topographical distribution of mitochondrial dysfunction in living brains of individuals with ASD. Twenty-three adult males with high-functioning ASD, with no psychiatric comorbidities and free of psychotropic medication, and 24 typically developed males with no psychiatric diagnoses, matched with the ASD group on age, parental socioeconomic background, and IQ, underwent [18F]BCPP-EF PET measurements. Individuals with mitochondrial disease were excluded by clinical evaluation and blood tests for abnormalities in lactate and pyruvate levels. RESULTS: Among the brain regions in which mitochondrial dysfunction has been reported in postmortem studies of autistic brains, participants with ASD had significantly decreased [18F]BCPP-EF availability specifically in the anterior cingulate cortex compared with typically developed participants. The regional specificity was revealed by a significant interaction between diagnosis and brain regions. Moreover, the lower [18F]BCPP-EF availability in the anterior cingulate cortex was significantly correlated with the more severe ASD core symptom of social communication deficits. CONCLUSIONS: 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.

Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer's disease.

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 [11C]SA4503 positron emission tomography (PET), the mitochondrial complex I (MC1) with [18F]BCPP-EF, and the presynaptic 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 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%). [18F]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.

Lewy Body Disease Primate Model with α-Synuclein Propagation from the Olfactory Bulb.

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 18 F-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. © 2022 International Parkinson and Movement Disorder Society.

Imaging Adipose Tissue Browning using Mitochondrial Complex-I Tracer [18F]BCPP-EF.

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 ß3-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 ß3-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 ß3-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.

Characterization of Novel Paclitaxel Nanoparticles Prepared by Laser Irradiation.

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.

Mitochondrial complex I abnormalities underlie neurodegeneration and cognitive decline in Alzheimer's disease.

BACKGROUND AND PURPOSE: 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). METHODS: 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 [18 F]2-tert-butyl-4-chloro-5-2H-pyridazin-3-one (BCPP-EF), [11 C]Pittsburgh Compound-B (PiB) and [18 F]fluorodeoxyglucose (FDG) to assess brain atrophy, mitochondrial complex I dysfunction, amyloid deposition, and glucose metabolism, respectively. Local cortical associations among these biomarkers and gray matter volume were evaluated with voxel-based regressions models. RESULTS: [18 F]BCPP-EF standardized uptake value ratio (SUVR) was positively correlated with [18 F]FDG SUVR in the widespread brain area, while its associations with gray matter volume were restricted to the parahippocampal gyrus. Reductions in [18 F]BCPP-EF SUVR were associated with domain-specific cognitive performance. We did not observe regional associations between mitochondrial dysfunction and amyloid burden. CONCLUSIONS: 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 [18 F]BCPP-EF as an excellent imaging tool to investigate mitochondrial dysfunction in AD.

In vivo alterations of mitochondrial activity and amyloidosis in early-stage senescence-accelerated mice: a positron emission tomography study.

PURPOSE: 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 ß-amyloid (Aß) deposition (11C-PiB) in the same brains of senescence-accelerated mouse prone 10 (SAMP10) mice, an Aß-developing neuroinflammatory animal model showing accelerated senescence with deterioration in cognitive functioning similar to that in MCI. METHODS: Five- to 25-week-old SAMP10 and control SAMR1 mice, were used in the experiments. PET was used to measure the binding levels (standard uptake value ratios; SUVRs) of [18F]2-tert-butyl-4-chloro-5-2H-pyridazin-3-one (18F-BCPP-EF) for mitochondrial complex 1 availability, and 11C-PiB for Aß deposition, in the same animals, and immunohistochemistry for ATPB (an ATP synthase on the mitochondrial inner membrane) was also performed, to determine changes in mitochondrial activity in relation to amyloid burden during the early stage of cognitive impairment. RESULTS: The SUVR of 18F-BCPP-EF was significantly lower and that of 11C-PiB was 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. The immunohistochemical analysis demonstrated temporal upregulation of ATPB levels at 15-week-old, but decreased at 25 week-old SAMP10 mice. CONCLUSION: The present results provide in vivo evidence of a decrease in mitochondrial energy production and elevated amyloidosis at an early stage in SAMP10 mice. The inverse correlation between these two phenomena suggests a concurrent change in neuronal energy failure by Aß-induced elevation of neuroinflammatory responses. Comparison of PET data with histological findings suggests that temporal increase of ATPB level may not be neurofunctionally implicated during neuropathological processes, including Aß pathology, in an animal model of early-phase AD spectrum disorder.

Evaluation of intracellular processes in quinolinic acid-induced brain damage by imaging reactive oxygen species generation and mitochondrial complex I activity.

PURPOSE: Our study aimed to elucidate the intracellular processes associated with quinolinic acid (QA)-induced brain injury by acquiring semiquantitative fluorescent images of reactive oxygen species (ROS) generation and positron emission tomography (PET) images of mitochondrial complex I (MC-I) activity. METHODS: Ex vivo fluorescent imaging with dihydroethidium (DHE) and PET scans with 18F-BCPP-EF were conducted at 3 h and 24 h after QA injection into the rat striatum. Immunohistochemical studies were performed 24 h after QA injection into the rat brain using monoclonal antibodies against neuronal nuclei (NeuN) and CD11b. RESULTS: A strong DHE-derived fluorescent signal was detected in a focal area within the QA-injected striatum 3 h after QA injection, and increased fluorescent signal spread throughout the striatum and parts of the cerebral cortex after 24 h. By contrast, 18F-BCPP-EF uptake in the QA-injected rat brain was unchanged after 3 h and markedly decreased after 24 h, not only in the striatum but also in the cerebral hemisphere. The fluorescent signal in the striatum 24 h after QA injection colocalised with microglial marker expression. CONCLUSIONS: We successfully obtained functional images of focal ROS generation during the early period of excitotoxic injury, and microglial ROS generation and mitochondrial dysfunction were observed during the progression of the inflammatory response. Both ex vivo DHE imaging and in vivo 18F-BCPP-EF-PET were sufficiently sensitive to detect the respective processes of QA-induced brain damage. Our study contributes to the functional imaging of multiple events during the pathological process.

Differences in in vitro microglial accumulation of the energy metabolism tracers [18F]FDG and [18F]BCPP-EF during LPS- and IL4 stimulation.

The positron emission tomography probes 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and 2-tert-butyl-4-chloro-5-{6-[2-(2-[18F]fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([18F]BCPP-EF) are designed to evaluate glycolysis and oxidative phosphorylation, respectively, and are both used to estimate neuronal activity. However, previous studies have shown a discrepancy in these probes' accumulation in the compromised region, possibly due to the presence of activated microglia acting like deleterious or neuroprotective phenotypes. Hence, we evaluated lipopolysaccharide (LPS)- and interleukin 4 (IL4)-stimulated microglial uptake of [14C]2DG and [18F]BCPP-EF to give a new insight into the hypothesis that different uptake of [18F]FDG and [18F]BCPP-EF can be ascribed to the different metabolic pathways activated during microglial activation. LPS or IL4 stimulation increased the proinflammatory or anti-inflammatory marker gene expression in microglial cells. In LPS-stimulated cells, [14C]2DG uptake and glycolysis related gene expression were elevated, and [18F]BCPP-EF uptake was reduced. In IL4-stimulated cells, [18F]BCPP-EF uptake was increased, and [14C]2DG uptake was decreased. The expression of genes involved in glycolysis and mitochondrial complex I subunits was not changed by IL4 stimulation. The uptake of [14C]2DG and [18F]BCPP-EF differs in LPS- and IL4-stimulated polarized microglial cells. The present results suggest that the in vivo accumulation of metabolic tracers [18F]FDG and [18F]BCPP-EF can be influenced by the different aspects of neuroinflammation.

Head-to-head comparison of (R)-[11C]verapamil and [18F]MC225 in non-human primates, tracers for measuring P-glycoprotein function.

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.

Mitochondrial complex I abnormalities is associated with tau and clinical symptoms in mild Alzheimer's disease.

BACKGROUND: Mitochondrial electron transport chain abnormalities have been reported in postmortem pathological specimens of Alzheimer's disease (AD). However, it remains unclear how amyloid and tau are associated with mitochondrial dysfunction in vivo. The purpose of this study is to assess the local relationships between mitochondrial dysfunction and AD pathophysiology in mild AD using the novel mitochondrial complex I PET imaging agent [18F]BCPP-EF. METHODS: Thirty-two amyloid and tau positive mild stage AD dementia patients (mean age ± SD: 71.1 ± 8.3 years) underwent a series of PET measurements with [18F]BCPP-EF mitochondrial function, [11C]PBB3 for tau deposition, and [11C] PiB for amyloid deposition. Age-matched normal control subjects were also recruited. Inter and intrasubject comparisons of levels of mitochondrial complex I activity, amyloid and tau deposition were performed. RESULTS: The [18F]BCPP-EF uptake was significantly lower in the medial temporal area, highlighting the importance of the mitochondrial involvement in AD pathology. [11C]PBB3 uptake was greater in the temporo-parietal regions in AD. Region of interest analysis in the Braak stage I-II region showed significant negative correlation between [18F]BCPP-EF SUVR and [11C]PBB3 BPND (R = 0.2679, p = 0.04), but not [11C] PiB SUVR. CONCLUSIONS: Our results indicated that mitochondrial complex I is closely associated with tau load evaluated by [11C]PBB3, which might suffer in the presence of its off-target binding. The absence of association between mitochondrial complex I dysfunction with amyloid load suggests that mitochondrial dysfunction in the trans-entorhinal and entorhinal region is a reflection of neuronal injury occurring in the brain of mild AD.

The posterior parietal cortex contributes to visuomotor processing for saccades in blindsight macaques.

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.

Test-retest variability and reference region-based quantification of 18F-BCPP-EF for imaging mitochondrial complex I in the human brain.

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.

Pharmacokinetic Modeling of (R)-[11C]verapamil to Measure the P-Glycoprotein Function in Nonhuman Primates.

(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.

4D deep image prior: dynamic PET image denoising using an unsupervised four-dimensional branch convolutional neural network.

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.

Pharmacokinetic Modeling of [18F]MC225 for Quantification of the P-Glycoprotein Function at the Blood-Brain Barrier in Non-Human Primates with PET.

[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.

In vivo positron emission tomography imaging of mitochondrial abnormalities in a mouse model of tauopathy.

Damaged mitochondria may be one of the earliest manifestations of Alzheimer's disease. Because oxidative phosphorylation is a primary source of neuronal energy, unlike glycolysis-dependent energy production in inflamed glia, mitochondrial respiration could provide a selective biomarker of neuronal deterioration in Alzheimer's disease. Here we used a recently developed positron emission tomography (PET) probe targeting mitochondrial complex I (MC-I), 18F-BCPP-EF, to non-invasively visualize mitochondrial abnormalities in the brains of tau transgenic mice (rTg4510). Tauopathy and neuroinflammation were visualized by PET using a tau probe 11C-PBB3 and a translocator protein probe, 18F-FEBMP, respectively. A marked reduction in 18F-BCPP-EF uptake was observed in hippocampal and forebrain regions of tau transgenic mice, colocalizing with regions of tauopathy, neuronal damage, and neuroinflammation. MC-I signals were highly correlated with atrophy assayed by magnetic resonance imaging, but negatively associated with inflammatory signals, indicating that neuronal metabolic signals measured by MC-I PET were robust to inflammatory interference. MC-I may be a useful imaging biomarker to detect neuronal damage and metabolic changes with minimal interference from concomitant glial hypermetabolism.