Brain p3-Alcβ peptide restores neuronal viability impaired by Alzheimer's amyloid β-peptide.

We propose a new therapeutic strategy for Alzheimer's disease (AD). Brain peptide p3-Alcβ37 is generated from the neuronal protein alcadein β through cleavage of γ-secretase, similar to the generation of amyloid β (Aβ) derived from Aβ-protein precursor/APP. Neurotoxicity by Aβ oligomers (Aβo) is the prime cause prior to the loss of brain function in AD.

Early distribution of F-labeled AAV9 vectors in the cerebrospinal fluid after intracerebroventricular or intracisternal magna infusion in non-human primates.

Background: The delivery of adeno-associated virus (AAV) vectors via the cerebrospinal fluid (CSF) has emerged as a valuable method for widespread transduction in the central nervous system. Although infusion into the cerebral ventricles is a common protocol in preclinical studies of small animals, the cisterna magna has been recognized as an alternative target for clinical studies because it can be reached in a less invasive manner using an intrathecal catheter via the subarachnoid space from a lumbar puncture.

Methods: We evaluated the early distribution of fluorine-18-labeled AAV9 vectors infused into the lateral ventricle or cisterna magna of four non-human primates using positron emission tomography.

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 (F-BCPP-EF) and β-amyloid (Aβ) deposition (C-PiB) 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.

Methods: Five- to 25-week-old SAMP10 and control SAMR1 mice, were used in the experiments.

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 F-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.

Anatomical-guided attention enhances unsupervised PET image denoising performance.

Although supervised convolutional neural networks (CNNs) often outperform conventional alternatives for denoising positron emission tomography (PET) images, they require many low- and high-quality reference PET image pairs. Herein, we propose an unsupervised 3D PET image denoising method based on an anatomical information-guided attention mechanism. The proposed magnetic resonance-guided deep decoder (MR-GDD) utilizes the spatial details and semantic features of MR-guidance image more effectively by introducing encoder-decoder and deep decoder subnetworks.

Head-to-head comparison of (R)-[C]verapamil and [F]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)-[C]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 [F]MC225.

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

()-[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 ()-[C]verapamil in rats and humans under different conditions. However, to the best of our knowledge, the pharmacokinetics of ()-[C]verapamil have not yet been evaluated in 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.

Synthesis and evaluation of N-isopropyl-p-[C]methylamphetamine as a novel cerebral blood flow tracer for positron emission tomography.

Introduction: Increases in fasting plasma glucose (PG) levels lead to a decrease in 2-deoxy-2-[F]fluoro-D-glucose ([F]FDG) uptake in the normal brain, especially in the precuneus, resulting in an Alzheimer's disease (AD)-like uptake pattern. Therefore, patients with higher PG levels, such as those with diabetes, can be erroneously diagnosed with AD when positron emission tomography (PET) imaging is done using [F]FDG, due to reduced uptake of [F]FDG in the precuneus. To help avoid an erroneous diagnosis of AD due to differences in glucose metabolism, evaluating cerebral blood flow (CBF) in the brain is useful.

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

[F]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 [F]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).

Positron emission tomography imaging of renal mitochondria is a powerful tool in the study of acute and progressive kidney disease models.

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, F-BCPP-BF, was developed to non-invasively visualize and quantitate the renal mitochondrial status in vivo.

Imaging mitochondrial complex I activation during a vibrotactile stimulation: A PET study using [F]BCPP-EF in the conscious monkey brain.

In order to evaluate the capability of 2--butyl-4-chloro-5-{6-[2-(2-[F]fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([F]BCPP-EF), a novel positron emission tomography (PET) probe for mitochondrial complex I (MC-I) activity, to assess neuronal activation, an activation PET study was conducted in the conscious monkey brain with a continuous unilateral vibrotactile stimulation. PET scans with [O]HO, [F]BCPP-EF, or 2-deoxy-2-[F]fluoroglucose ([F]FDG) were conducted under: (1) resting conditions; (2) a continuous vibration stimulation; (3) a continuous vibration stimulation after 15-min pre-vibration; and (4) a continuous vibration stimulation after 30-min pre-vibration. The contralateral/ipsilateral ratio (CIR) in the somatosensory cortex showed significant increases in the uptake of [O]HO, [F]BCPP-EF, and [F]FDG with the vibration stimulation.

Upregulation of cannabinoid receptor type 2, but not TSPO, in senescence-accelerated neuroinflammation in mice: a positron emission tomography study.

Background: Microglial cells are activated in response to changes in brain homeostasis during aging, dementia, and stroke. Type 2 endocannabinoid receptors (CB2) and translocator protein 18 kD (TSPO) are considered to reflect distinct aspects of microglia-related neuroinflammatory responses in the brain. CB2 activation is considered to relate to the neuroprotective responses that may occur predominantly in the early stage of brain disorders such as Alzheimer's disease, while an increase in TSPO expression tends to occur later during neuroinflammation, in a proinflammatory fashion.

Sensitive and early detection of mitochondrial dysfunction in the liver of NASH model mice by PET imaging with F-BCPP-BF.

Background: Nonalcoholic fatty liver disease is a common disorder that progresses from simple fatty liver (steatosis) to nonalcoholic steatohepatitis (NASH). It is thought that mitochondrial dysfunction plays a critical role in the progression of NASH. In this study, we developed a non-invasive method for early diagnosis and staging of NASH that directly measures mitochondrial complex-I (MC-I) activity in the liver of NASH model mice by positron emission tomography (PET) imaging using the novel tracer 2-tert-butyl-4-chloro-5-[6-(4-[F]fluorobutoxy)-pyridin-3-ylmethoxy]-2H-pyridazin-3-one (F-BCPP-BF).

Effect of Oxygen Affinity of Liposome-Encapsulated Hemoglobin on Cerebral Ischemia and Reperfusion as Detected by Positron Emission Tomography in Nonhuman Primates.

We tested a hypothesis that liposome-encapsulated hemoglobin (LEH) with high oxygen (O ) affinity (h-LEH, P O  = 10 mm Hg) may work better than LEH with low O affinity (l-LEH, P O  = 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), O extract fraction (OEF), and cerebral metabolic rate of O (CMRO ) 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.

In vivo TSPO and cannabinoid receptor type 2 availability early in post-stroke neuroinflammation in rats: a positron emission tomography study.

Background: Upregulated levels of 18-kDa translocator proteins (TSPO) and type 2 endocannabinoid receptors (CB2) are considered to reflect different aspects of microglia-related neuroinflammatory responses in the brain. Relative to the increase in the TSPO expression that occurs slightly later during neuroinflammation in a proinflammatory fashion, CB2 activation is considered to relate to the neuroprotective responses that occurs predominantly at an early stage of brain disorders. These findings, however, were deduced from studies with different animal samples under different experimental settings.

Effect of MPTP on Serotonergic Neuronal Systems and Mitochondrial Complex I Activity in the Living Brain: A PET Study on Conscious Rhesus Monkeys.

The objective of the present PET study was to compare the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on serotonergic neuronal systems and mitochondrial complex I (MC-I) activity with that of dopamine in conscious rhesus monkeys (). A Parkinson disease monkey model was prepared by repeated administration of MPTP. For the PET measurements, normal and MPTP-treated conscious monkeys received an intravenous injection of C-DASB for serotonin transporter, F-MPPF for serotonin 1A receptor, C-PE2I for dopamine transporter, C-6MeTyr for dopamine synthesis, C-raclopride for dopamine D receptor, or F-BCPP-EF for MC-I.

In Vivo Evaluation of C-Preladenant for PET Imaging of Adenosine A Receptors in the Conscious Monkey.

C-preladenant was developed as a novel PET ligand for the adenosine A receptors (ARs). The present study aimed to evaluate the suitability of C-preladenant PET for the quantification of striatal ARs and the assessment of AR occupancy in the conscious monkey brain. C-preladenant was intravenously injected into conscious monkeys ( = 4, 18 PET scans), and a 91-min dynamic scan was started.

Quantification of ONO-2952 Occupancy of 18-kDaTranslocator Protein in Conscious Monkey Brains using Positron Emission Tomography.

We have previously shown that ONO-2952, a novel 18-kDa translocator protein (TSPO) antagonist, inhibits stress-induced accumulation of neurosteroids and noradrenaline release in the rat brain and alleviates the subsequent symptomatic responses with a brain TSPO occupancy of 50% or more. In this study, we measured ONO-2952 brain TSPO occupancy in conscious rhesus monkeys using positron emission tomography (PET) with C-PBR28 as ligand for translational research to clinical application. PET scans were performed after single and repeated oral administration of ONO-2952 at several dose levels for each animal, with sequential arterial blood sampling.

Effects of acetaminophen on mitochondrial complex I activity in the rat liver and kidney: a PET study with F-BCPP-BF.

Background: In the present study, 2-tert-butyl-4-chloro-5-[6-(4-F-fluorobutoxy)-pyridin-3-ylmethoxy]-2H-pyridazin-3-one (F-BCPP-BF), a PET probe for mitochondrial complex I (MC-I), was used to validate whether MC-I is a useful biomarker for detecting acetaminophen-induced dysfunctions in the liver and kidney. The kinetic and distribution of F-BCPP-BF were assessed in rats using high-resolution animal PET in vivo. The binding specificity of F-BCPP-BF to MC-I in the liver and kidney was confirmed by the pre-administration of rotenone, a specific MC-I inhibitor.

Reduction of dopamine D receptor binding in the striatum after a single administration of esketamine, but not R-ketamine: a PET study in conscious monkeys.

R-ketamine appears to be a potent, long-lasting and safer antidepressant, relative to esketamine (S-ketamine), since it might be free of psychotomimetic side effects. Using [C]raclopride and positron emission tomography (PET), we investigated whether esketamine and R-ketamine can affect dopamine D receptor binding in the conscious monkey brain. A single infusion of esketamine (0.

PET Imaging of Mitochondrial Complex I with 18F-BCPP-EF in the Brains of MPTP-Treated Monkeys.

Unlabelled: (18)F-BCPP-EF was applied to assess mitochondrial complex I (MC-I) activity in the brains of Parkinson disease model monkeys prepared by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and also presynaptic dopamine parameters.

Methods: (11)C-β-CFT for the dopamine transporter; (11)C-3,4-dihydroxy-phenyl-L-alanine (β-(11)C-L-DOPA), L-6-(18)F-fluorodopa ((18)F-FDOPA), or 6-(11)C-methyl-m-tyrosine ((11)C-6MemTyr) for dopamine synthesis; or 2-tert-butyl-4-chrolo-5-{6-[2-(2-(18)F-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ((18)F-BCPP-EF) for MC-I was intravenously injected into normal and MPTP monkeys in order to analyze their uptake in the striatum.

Results: Significant reductions in presynaptic dopamine parameters and MC-I activity were detected in the striatum of MPTP monkeys.

Evaluation of 6-11C-Methyl-m-Tyrosine as a PET Probe for Presynaptic Dopaminergic Activity: A Comparison PET Study with β-11C-l-DOPA and 18F-FDOPA in Parkinson Disease Monkeys.

Unlabelled: We recently developed a novel PET probe, 6-(11)C-methyl-m-tyrosine ((11)C-6MemTyr), for quantitative imaging of presynaptic dopamine synthesis in the living brain. In the present study, (11)C-6MemTyr was compared with β-(11)C-l-DOPA and 6-(18)F-fluoro-l-dopa ((18)F-FDOPA) in the brains of normal and Parkinson disease (PD) model monkeys (Macaca fascicularis).

Methods: PD model monkeys were prepared by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, and (11)C-β-CFT was applied to assess neuronal damage as dopamine transporter (DAT) availability.