TSPO-PET Reveals Higher Inflammation in White Matter Disrupted by Paramagnetic Rim Lesions in Multiple Sclerosis.

Objective: To explore whether the inflammatory activity is higher in white matter (WM) tracts disrupted by paramagnetic rim lesions (PRLs) and if inflammation in PRL-disrupted WM tracts is associated with disability in people with multiple sclerosis (MS).

Methods: Forty-four MS patients and 16 healthy controls were included. 18 kDa-translocator protein positron emission tomography (TSPO-PET) with the C-PK11195 radioligand was used to measure the neuroinflammatory activity.

Brain Fluid Clearance After Traumatic Brain Injury Measured Using Dynamic Positron Emission Tomography.

Brain fluid clearance by pathways including the recently described paravascular glymphatic system is a critical homeostatic mechanism by which metabolic products, toxins, and other wastes are removed from the brain. Brain fluid clearance may be especially important after traumatic brain injury (TBI), when blood, neuronal debris, inflammatory cells, and other substances can be released and/or deposited. Using a non-invasive dynamic positron emission tomography (PET) method that models the rate at which an intravenously injected radiolabeled molecule (in this case C-flumazenil) is cleared from ventricular cerebrospinal fluid (CSF), we estimated the overall efficiency of brain fluid clearance in humans who had experienced complicated-mild or moderate TBI 3-6 months before neuroimaging ( = 7) as compared to healthy controls ( = 9).

Chemokine Receptor 2 Is A Theranostic Biomarker for Abdominal Aortic Aneurysms.

Abdominal aortic aneurysm (AAA) is a degenerative vascular disease impacting aging populations with a high mortality upon rupture. There are no effective medical therapies to prevent AAA expansion and rupture. We previously demonstrated the role of the monocyte chemoattractant protein-1 (MCP-1) / C-C chemokine receptor type 2 (CCR2) axis in rodent AAA pathogenesis via positron emission tomography/computed tomography (PET/CT) using CCR2 targeted radiotracer Cu-DOTA-ECL1i.

Naloxone's dose-dependent displacement of [C]carfentanil and duration of receptor occupancy in the rat brain.

The continuous rise in opioid overdoses in the United States is predominantly driven by very potent synthetic opioids, mostly fentanyl and its derivatives (fentanyls). Although naloxone (NLX) has been shown to effectively reverse overdoses by conventional opioids, there may be a need for higher or repeated doses of NLX to revert overdoses from highly potent fentanyls. Here, we used positron emission tomography (PET) to assess NLX's dose-dependence on both its rate of displacement of [C]carfentanil ([C]CFN) binding and its duration of mu opioid receptor (MOR) occupancy in the male rat brain.

A Baboon Brain Atlas for Magnetic Resonance Imaging and Positron Emission Tomography Image Analysis.

The olive baboon () is phylogenetically proximal to humans. Investigation into the baboon brain has shed light on the function and organization of the human brain, as well as on the mechanistic insights of neurological disorders such as Alzheimer's and Parkinson's. Non-invasive brain imaging, including positron emission tomography (PET) and magnetic resonance imaging (MRI), are the primary outcome measures frequently used in baboon studies.

Discovery of Highly Potent Adenosine A Receptor Agonists: Targeting Positron Emission Tomography Probes.

Adenosine receptor (AR) radiotracers for positron emission tomography (PET) have provided knowledge on the biodistribution of ARs in the central nervous system (CNS), which is of therapeutic interest for various neuropsychiatric disorders. Additionally, radioligands that can image changes in endogenous adenosine levels in different physiological and pathological conditions are still lacking. The binding of known antagonist adenosine A receptor (AR) radiotracer, [C]MDPX, failed to be inhibited by elevated endogenous adenosine in a rodent PET study.

Longitudinal change in TSPO PET imaging in progressive multiple sclerosis.

The objective of this pilot study was to assess a 2-year change in innate immune burden in 15 progressive multiple sclerosis (MS) patients using PK11195-PET. Sixteen age-matched healthy controls (HC) were included for baseline comparison. PK11195 uptake was higher in MS patients compared to HC within normal-appearing white matter (NAWM) and multiple gray matter regions.

A Multi-Ligand Imaging Study Exploring GABAergic Receptor Expression and Inflammation in Multiple Sclerosis.

Purpose: The γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter and essential for normal brain function. The GABAergic system has been shown to have immunomodulatory effects and respond adaptively to excitatory toxicity. The association of the GABAergic system and inflammation in patients with multiple sclerosis (MS) remains unknown.

Neurophysiological Biomarkers of Parkinson's Disease.

Background: There is a need for reliable and robust Parkinson's disease biomarkers that reflect severity and are sensitive to disease modifying investigational therapeutics.

Objective: To demonstrate the utility of EEG as a reliable, quantitative biomarker with potential as a pharmacodynamic endpoint for use in clinical assessments of neuroprotective therapeutics for Parkison's disease.

Methods: A multi modal study was performed including aquisition of resting state EEG data and dopamine transporter PET imaging from Parkinson's disease patients off medication and compared against age-matched controls.

Risk structured model of cholera infections in Cameroon.

Since 1991, Cameroon, a cholera endemic African country, has been experiencing large cholera outbreaks and cholera related deaths. In this paper, we use a "fitted" demographic equation (disease-free equation) to capture the total population of Cameroon, and then use a fitted low-high risk structured cholera differential equation model to study reported cholera cases in Cameroon from 1987 to 2004. For simplicity, our model has no spatial structure.

Quantitative susceptibility mapping identifies inflammation in a subset of chronic multiple sclerosis lesions.

Chronic active multiple sclerosis lesions, characterized by a hyperintense rim of iron-enriched, activated microglia and macrophages, have been linked to greater tissue damage. Post-mortem studies have determined that chronic active lesions are primarily related to the later stages of multiple sclerosis; however, the occurrence of these lesions, and their relationship to earlier disease stages may be greatly underestimated. Detection of chronic active lesions across the patient spectrum of multiple sclerosis requires a validated imaging tool to accurately identify lesions with persistent inflammation.

18F-FPEB PET/CT Shows mGluR5 Upregulation in Parkinson's Disease.

Background And Purpose: Dopamine and glutamate reciprocally regulate each other in some of the neurocircuits affected by Parkinson's disease (PD). The objective of this pilot study was to explore relationships between these neurotransmitter systems with positron emission tomography.

Methods: The sample consisted of nine patients with PD and eight healthy volunteers (HVs).

Comparison of two different methods of image analysis for the assessment of microglial activation in patients with multiple sclerosis using (R)-[N-methyl-carbon-11]PK11195.

Chronic active multiple sclerosis (MS) lesions have a rim of activated microglia/macrophages (m/M) leading to ongoing tissue damage, and thus represent a potential treatment target. Activation of this innate immune response in MS has been visualized and quantified using PET imaging with [11C]-(R)-PK11195 (PK). Accurate identification of m/M activation in chronic MS lesions requires the sensitivity to detect lower levels of activity within a small tissue volume.

Noninvasive PK11195-PET Image Analysis Techniques Can Detect Abnormal Cerebral Microglial Activation in Parkinson's Disease.

Background And Purpose: Neuroinflammation has been implicated in the pathophysiology of Parkinson's disease (PD), which might be influenced by successful neuroprotective drugs. The uptake of [ C](R)-PK11195 (PK) is often considered to be a proxy for neuroinflammation, and can be quantified using the Logan graphical method with an image-derived blood input function, or the Logan reference tissue model using automated reference region extraction. The purposes of this study were (1) to assess whether these noninvasive image analysis methods can discriminate between patients with PD and healthy volunteers (HVs), and (2) to establish the effect size that would be required to distinguish true drug-induced changes from system variance in longitudinal trials.

[ C]arachidonic acid incorporation measurement in human brain: Optimization for clinical use.

Arachidonic acid (AA) is involved in signal transduction, neuroinflammation, and production of eicosanoid metabolites. The AA brain incorporation coefficient (K*) is quantifiable in vivo using [ C]AA positron emission tomography, although repeatability remains undetermined. We evaluated K* estimates obtained with population-based metabolite correction (PBMC) and image-derived input function (IDIF) in comparison to arterial blood-based estimates, and compared repeatability.

Reduction of PK11195 uptake observed in multiple sclerosis lesions after natalizumab initiation.

Objective: The objective of this study is to longitudinally analyze the uptake of [C]PK11195-PET in multiple sclerosis patients after 3 and 6 months of natalizumab treatment.

Methods: Eighteen MS patients, starting treatment with monocloncal anti-VLA-4, were enrolled in a longitudinal PK-PET study. PK uptake was quantified by volume of distribution (VT) calculation using image-derived input function at baseline, 3 and 6 months.

Transient and chronic seizure-induced inflammation in human focal epilepsy.

In animal models, inflammation is both a cause and consequence of seizures. Less is known about the role of inflammation in human epilepsy. We performed positron emission tomography (PET) using a radiotracer sensitive to brain inflammation in a patient with frontal epilepsy ~36 h after a seizure as well as during a seizure-free period.

Image-guided synthesis reveals potent blood-brain barrier permeable histone deacetylase inhibitors.

Recent studies have revealed that several histone deacetylase (HDAC) inhibitors, which are used to study/treat brain diseases, show low blood-brain barrier (BBB) penetration. In addition to low HDAC potency and selectivity observed, poor brain penetrance may account for the high doses needed to achieve therapeutic efficacy. Here we report the development and evaluation of highly potent and blood-brain barrier permeable HDAC inhibitors for CNS applications based on an image-guided approach involving the parallel synthesis and radiolabeling of a series of compounds based on the benzamide HDAC inhibitor, MS-275 as a template.

Therapeutic doses of buspirone block D3 receptors in the living primate brain.

Dopamine D3 receptor (D3R) antagonists may be effective medications for multiple substance use disorders (SUDs). However, no selective D3R antagonists are currently available for clinical testing. Buspirone, originally characterized as a 5-HT1A partial agonist and used as an anxiolytic, also binds to D3R and D4R with high affinity, with lower affinity to D2R, and interferes with cocaine reward.

Radionuclide labeling and evaluation of candidate radioligands for PET imaging of histone deacetylase in the brain.

Histone deacetylases (HDACs) regulate gene expression by inducing conformational changes in chromatin. Ever since the discovery of a naturally occurring HDAC inhibitor, trichostatin A (TSA) stimulated the recent development of suberoylanilide (SAHA, Zolinza®), HDAC has become an important molecular target for drug development. This has created the need to develop specific in vivo radioligands to study epigenetic regulation and HDAC engagement for drug development for diseases including cancer and psychiatric disorders.

An alternative approach to protein folding.

A diffusion theory-based, all-physical ab initio protein folding simulation is described and applied. The model is based upon the drift and diffusion of protein substructures relative to one another in the multiple energy fields present. Without templates or statistical inputs, the simulations were run at physiologic and ambient temperatures (including pH).