Positron Emission Tomography Neuroimaging Research Articles

Synthesis and evaluation of TSPO-targeting radioligand [18F]F-TFQC for PET neuroimaging in epileptic rats

The translocator protein (TSPO) positron emission tomography (PET) can noninvasively detect neuroinflammation associated with epileptogenesis and epilepsy. This study explored the role of the TSPO-targeting radioligand [18F]F-TFQC, an m-trifluoromethyl ER176 analog, in the PET neuroimaging of epileptic rats. Initially, [18F]F-TFQC was synthesized with a radiochemical yield of 8%–10% (EOS), a radiochemical purity of over 99%, and a specific activity of 38.21 ± 1.73 MBq/nmol (EOS). After determining that [18F]F-TFQC exhibited good biochemical properties, [18F]F-TFQC PET neuroimaging was performed in epileptic rats at multiple time points in various stages of disease progression. PET imaging showed specific [18F]F-TFQC uptake in the right hippocampus (KA-injected site, i.e., epileptogenic zone), which was most pronounced at 1 week (T/NT 1.63 ± 0.21) and 1 month (T/NT 1.66 ± 0.20). The PET results were further validated using autoradiography and pathological analysis. Thus, [18F]F-TFQC can reflect the TSPO levels and localize the epileptogenic zone, thereby offering the potential for monitoring neuroinflammation and guiding anti-inflammatory treatment in patients with epilepsy.

A Fast-Binding, Functionally Reversible, COX-2 Radiotracer for CNS PET Imaging.

Cyclooxygenase-2 (COX-2) is an enzyme that plays a pivotal role in peripheral inflammation and pain via the prostaglandin pathway. In the central nervous system (CNS), COX-2 is implicated in neurodegenerative and psychiatric disorders as a potential therapeutic target and biomarker. However, clinical studies with COX-2 have yielded inconsistent results, partly due to limited mechanistic understanding of how COX-2 activity relates to CNS pathology. Therefore, developing COX-2 positron emission tomography (PET) radiotracers for human neuroimaging is of interest. This study introduces [11C]BRD1158, which is a potent and uniquely fast-binding, selective COX-2 PET radiotracer. [11C]BRD1158 was developed by prioritizing potency at COX-2, isoform selectivity over COX-1, fast binding kinetics, and free fraction in the brain. Evaluated through in vivo PET neuroimaging in rodent models with human COX-2 overexpression, [11C]BRD1158 demonstrated high brain uptake, fast target-engagement, functional reversibility, and excellent specific binding, which is advantageous for human imaging applications. Lastly, post-mortem samples from Huntington's disease (HD) patients and preclinical HD mouse models showed that COX-2 levels were elevated specifically in disease-affected brain regions, primarily from increased expression in microglia. These findings indicate that COX-2 holds promise as a novel clinical marker of HD onset and progression, one of many potential applications of [11C]BRD1158 human PET.

Differences in neuroinflammation in people who started antiretroviral treatment during primary versus chronic HIV infection: an 18kDa Translocator protein (TSPO) positron emission tomography (PET) study

Persistent inflammation is described in people with HIV (PWH) on antiretroviral treatment (ART). Early ART initiation is associated with reduced inflammation. We aimed to evaluate neuroinflammation, using translocator protein (TSPO) [11C]PBR28 PET neuroimaging in PWH who initiated ART during acute HIV (aPWH) versus chronic HIV infection (cPWH) versus a control population. This was a cross-sectional, observational study. All participants underwent [11C]PBR28 PET-CT neuroimaging. Using a two-tissue compartment model, total volume of distribution (VT) and distribution volume ratios (DVR) using cortical grey matter as a pseudo-reference region at 20 regions of interest (ROIs) were calculated. Differences in VT and DVR were compared between groups using the Kruskall-Wallis test. Seventeen neuro-asymptomatic male PWH on ART (9 aPWH, 8 cPWH) and 8 male control participants (CPs) were included. Median (interquartile range, IQR) age was 40 (30, 46), 44 (41, 47) and 21 (20, 25) years in aPWH, cPWH and CPs, respectively. Median (IQR) CD4 (cells/µL) and CD4:CD8 were 687 (652, 1014) and 1.37 (1.24, 1.42), and 700 (500, 720) and 0.67 (0.64, 0.82) in aPWH and cPWH, respectively. Overall, no significant difference in VT and DVR were observed between the three groups at any ROIs. cPWH demonstrated a trend towards higher mean VT compared with aPWH and CPs at most ROIs. No significant differences in neuroinflammation, using [11C]PBR28 binding as a proxy, were identified between cPWH, aPWH and CPs. A trend towards lower absolute [11C]PBR28 binding was seen amongst aPWH and CPs, suggesting early ART may mitigate neuroinflammation.

Increased glial activation in 'Long-COVID' detected by positron emission tomography (PET) neuroimaging

Increased glial activation in 'Long-COVID' detected by positron emission tomography (PET) neuroimaging

The Sigma Receptors in Alzheimer's Disease: New Potential Targets for Diagnosis and Therapy.

Sigma (σ) receptors are a class of unique proteins with two subtypes: the sigma-1 (σ1) receptor which is situated at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), and the sigma-2 (σ2) receptor, located in the ER-resident membrane. Increasing evidence indicates the involvement of both σ1 and σ2 receptors in the pathogenesis of Alzheimer's disease (AD), and thus these receptors represent two potentially effective biomarkers for emerging AD therapies. The availability of optimal radioligands for positron emission tomography (PET) neuroimaging of the σ1 and σ2 receptors in humans will provide tools to monitor AD progression and treatment outcomes. In this review, we first summarize the significance of both receptors in the pathophysiology of AD and highlight AD therapeutic strategies related to the σ1 and σ2 receptors. We then survey the potential PET radioligands, with an emphasis on the requirements of optimal radioligands for imaging the σ1 or σ2 receptors in humans. Finally, we discuss current challenges in the development of PET radioligands for the σ1 or σ2 receptors, and the opportunities for neuroimaging to elucidate the σ1 and σ2 receptors as novel biomarkers for early AD diagnosis, and for monitoring of disease progression and AD drug efficacy.

Alzheimer's disease

Alzheimer’s disease (AD) is the most common cause of dementia associated with a progressive neurodegenerative disorder, with a prevalence of 44 million people throughout the world in 2015, and this figure is estimated to double by 2050. This disease is characterized by blood-brain barrier disruption, oxidative stress, mitochondrial impairment, neuroinflammation, and hypometabolism; it is related to amyloid-β peptide accumulation and tau hyperphosphorylation as well as a decrease in acetylcholine levels and a reduction of cerebral blood flow. Studies of potential disease-modifying therapy have generally been undertaken in patients with clinically detectable disease, yet evidence suggests that the pathological changes associated with AD begin several years before this. It is possible that pharmacological therapy may be beneficial in this pre-clinical stage before the neurodegenerative process is established. Techniques providing earlier diagnosis, such as cerebrospinal fluid biomarkers and amyloid positron emission tomography neuroimaging, are key to testing this theory in clinical trials. Recent results from trials of agents such as aducanumab are encouraging but must also be interpreted with caution. Such medicines could potentially delay the onset of dementia and would therefore markedly reduce its prevalence.

Menopause Status Moderates Sex Differences in Tau Burden: A Framingham PET Study.

ObjectiveWomen have a higher lifetime risk of Alzheimer's disease (AD) than men. Among cognitively normal (CN) older adults, women exhibit elevated tau positron emission tomography (PET) signal compared with men. We explored whether menopause exacerbates sex differences in tau deposition in middle‐aged adults.Methods328 CN participants from the Framingham Study (mean age = 57 years (±10 years), 161 women, of whom, 104 were post‐menopausal) underwent tau and β‐amyloid (Aβ)‐PET neuroimaging. We examined global Aβ‐PET, and tau‐PET signal in 5 regions identified a priori as demonstrating significant sex differences in older adults (in temporal, inferior parietal, middle frontal, and lateral occipital regions). We examined sex and menopause status‐related differences in each region‐of‐interest, using linear regressions, as well as interactions with Aβ and APOEε4 genotype.ResultsWomen exhibited higher tau‐PET signal (p < 0.002), and global Aβ‐PET (p = 0.010), than men in inferior parietal, rostral middle frontal, and lateral occipital regions. Compared with age‐matched men, post‐menopausal women showed significantly higher tau‐PET signal in parieto‐occipital regions (p < 0.0001). By contrast, no differences in tau‐PET signal existed between pre‐menopausal women and men. Aβ‐PET was not associated with menopausal status or age. Neither Aβ‐PET nor APOEε4 status moderated sex or menopause associations with tau‐PET.InterpretationClear divergence in tauopathy between the sexes are apparent approximately 20 years earlier than previously reported. Menopause status moderated sex differences in Aβ and tau‐PET burden, with tau first appearing post‐menopause. Sex and menopause differences consistently appeared in middle frontal and parieto‐occipital regions but were not moderated by Aβ burden or APOEε4, suggesting that menopause‐related tau vulnerability may be independent of AD‐related pathways. ANN NEUROL 2022;92:11–22

Simultaneous multifactor Bayesian analysis (SiMBA) of PET time activity curve data

Positron emission tomography (PET) is an in vivo imaging method essential for studying the neurochemical pathophysiology of psychiatric and neurological disease. However, its high cost and exposure of participants to radiation make it unfeasible to employ large sample sizes. The major shortcoming of PET imaging is therefore its lack of power for studying clinically-relevant research questions. Here, we introduce a new method for performing PET quantification and analysis called SiMBA, which helps to alleviate these issues by improving the efficiency of PET analysis by exploiting similarities between both individuals and regions within individuals. In simulated [11C]WAY100635 data, SiMBA greatly improves both statistical power and the consistency of effect size estimation without affecting the false positive rate. This approach makes use of hierarchical, multifactor, multivariate Bayesian modelling to effectively borrow strength across the whole dataset to improve stability and robustness to measurement error. In so doing, parameter identifiability and estimation are improved, without sacrificing model interpretability. This comes at the cost of increased computational overhead, however this is practically negligible relative to the time taken to collect PET data. This method has the potential to make it possible to test clinically-relevant hypotheses which could never be studied before given the practical constraints. Furthermore, because this method does not require any additional information over and above that required for traditional analysis, it makes it possible to re-examine data which has already previously been collected at great expense. In the absence of dramatic advancements in PET image data quality, radiotracer development, or data sharing, PET imaging has been fundamentally limited in the scope of research hypotheses which could be studied. This method, especially combined with the recent steps taken by the PET imaging community to embrace data sharing, will make it possible to greatly improve the research possibilities and clinical relevance of PET neuroimaging.

Increased retention of tau PET ligand [18F]-AV1451 in Alzheimer\u2019s Disease Psychosis

Psychosis in Alzheimer’s disease (AD) represents a distinct disease subtype with a more rapid progression of illness evidenced by an increased velocity of cognitive decline and a hastened mortality. Previous biomarker and post-mortem studies have implicated tau neuropathology as a possible mediator of the accelerated decline in AD psychosis. Tau positron emission tomography (PET) neuroimaging provides the opportunity to evaluate tau pathology in-vivo, so that clinical symptomatology can be correlated with disease pathology. [18F]-AV1451 (Flortaucipir) is a PET ligand with high affinity for insoluble paired-helical filaments (PHFs) of hyperphosphorylated tau. In order to determine whether the development of psychosis and worsened prognosis in AD is associated with an increased burden of tau pathology that can be identified with tau imaging, we identified subjects within the Alzheimer’s disease neuroimaging initiative (ADNI) who had [18F]-AV1451 imaging at baseline and became psychotic over the course of the study (N = 17) and matched them 1:3 for gender, age, and education to subjects who had [18F]-AV1451 imaging at baseline and did not become psychotic (N = 50). We compared baseline [18F]-AV1451 retention, in addition to cognitive and functional baseline and longitudinal change, in those who became psychotic over the course of participation in ADNI with those who did not. Results suggest that increases in tau pathology in frontal, medial temporal, and occipital cortices, visualized with [18F]-AV1451 binding, are associated with psychosis and a more rapid cognitive and functional decline.

On Improved 3D-CNN-Based Binary and Multiclass Classification of Alzheimer's Disease Using Neuroimaging Modalities and Data Augmentation Methods.

Alzheimer's disease (AD) is an irreversible illness of the brain impacting the functional and daily activities of elderly population worldwide. Neuroimaging sensory systems such as Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) measure the pathological changes in the brain associated with this disorder especially in its early stages. Deep learning (DL) architectures such as Convolutional Neural Networks (CNNs) are successfully used in recognition, classification, segmentation, detection, and other domains for data interpretation. Data augmentation schemes work alongside DL techniques and may impact the final task performance positively or negatively. In this work, we have studied and compared the impact of three data augmentation techniques on the final performances of CNN architectures in the 3D domain for the early diagnosis of AD. We have studied both binary and multiclass classification problems using MRI and PET neuroimaging modalities. We have found the performance of random zoomed in/out augmentation to be the best among all the augmentation methods. It is also observed that combining different augmentation methods may result in deteriorating performances on the classification tasks. Furthermore, we have seen that architecture engineering has less impact on the final classification performance in comparison to the data manipulation schemes. We have also observed that deeper architectures may not provide performance advantages in comparison to their shallower counterparts. We have further observed that these augmentation schemes do not alleviate the class imbalance issue.

3D convolutional neural networks-based multiclass classification of Alzheimer\u2019s and Parkinson\u2019s diseases using PET and SPECT neuroimaging modalities

BackgroundAlzheimer’s disease (AD) is a neurodegenerative brain pathology formed due to piling up of amyloid proteins, development of plaques and disappearance of neurons. Another common subtype of dementia like AD, Parkinson’s disease (PD) is determined by the disappearance of dopaminergic neurons in the region known as substantia nigra pars compacta located in the midbrain. Both AD and PD target aged population worldwide forming a major chunk of healthcare costs. Hence, there is a need for methods that help in the early diagnosis of these diseases. PD subjects especially those who have confirmed postmortem plaque are a strong candidate for a second AD diagnosis. Modalities such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) can be combined with deep learning methods to diagnose these two diseases for the benefit of clinicians.ResultIn this work, we deployed a 3D Convolutional Neural Network (CNN) to extract features for multiclass classification of both AD and PD in the frequency and spatial domains using PET and SPECT neuroimaging modalities to differentiate between AD, PD and Normal Control (NC) classes. Discrete Cosine Transform has been deployed as a frequency domain learning method along with random weak Gaussian blurring and random zooming in/out augmentation methods in both frequency and spatial domains. To select the hyperparameters of the 3D-CNN model, we deployed both 5- and 10-fold cross-validation (CV) approaches. The best performing model was found to be AD/NC(SPECT)/PD classification with random weak Gaussian blurred augmentation in the spatial domain using fivefold CV approach while the worst performing model happens to be AD/NC(PET)/PD classification without augmentation in the frequency domain using tenfold CV approach. We also found that spatial domain methods tend to perform better than their frequency domain counterparts.ConclusionThe proposed model provides a good performance in discriminating AD and PD subjects due to minimal correlation between these two dementia types on the clinicopathological continuum between AD and PD subjects from a neuroimaging perspective.

Opposite alterations of 5\xadHT2A receptor brain density in subjects with schizophrenia: relevance of radiotracers pharmacological profile

The status of serotonin 5­HT2A receptors (5­HT2ARs) in schizophrenia has been controversial. In vivo positron emission tomography neuroimaging and in vitro post-mortem binding studies have reported conflicting results about 5­HT2AR density. Radiotracers bind different receptor conformations depending on their agonist, antagonist or inverse agonist properties. This study investigates 5­HT2AR density in the post-mortem prefrontal cortex from subjects with schizophrenia and controls using three radiotracers with a different pharmacological profile. The specific binding parameters of the inverse agonist [18F]altanserin, the agonist [3H]lysergic acid diethylamide (LSD) and the antagonist [3H]MDL100907 to brain cortex membranes from 20 subjects with schizophrenia and 20 individually matched controls were evaluated under similar methodological conditions. Ten schizophrenia subjects were antipsychotic-free at death. Saturation curve analyses were performed by non-linear regression to obtain a maximal density of binding sites (Bmax) and the affinity of the respective radiotracers (Kd). In schizophrenia subjects, 5-HT2AR density was decreased when quantified by [18F]altanserin binding, whereas increased when evaluated by [3H]LSD binding. However, [3H]MDL100907 binding was unaltered. A slight loss of affinity (higher Kd) was observed exclusively in [3H]LSD binding. The findings were more evident in antipsychotic-free subjects than in antipsychotic-treated subjects. In conclusion, a higher proportion of the 5-HT2AR-active functional conformation, which is rather identified by agonist radiotracers, was observed in schizophrenia patients. A consequent reduction of the inactive 5-HT2AR conformation, which is preferentially identified by inverse agonist radiotracers, was also obtained. Antagonist radiotracers do not distinguish between molecular conformations of the receptor, and accordingly, the absence of changes was shown. These results are compatible with the proposed increased functional activity of brain cortical 5-HT2ARs in schizophrenia.

PET neuroimaging reveals upregulation of dopamine D2 receptor contributes to amygdaloid dysfunction in rat acute restraint stress model

Acute stress relates to high prevalence of anxiety, depression or even sudden death. Although dopaminergic system in amygdala-medial prefrontal cortex (mPFC) circuit is hyper-responsive to stress-induced anxiety, the mechanisms that control anxiety still remains unanswered. Here, the acute restraint stress model(ARS) was established to develop anxiety-like behavior. The D2-dopamine receptor (D2R) availability in amygdala and mPFC was assessed using [18F]-fallypride positron emission tomography(PET) and immunohistochemical assay. We revealed that ARS paradigm was successfully established, as evidenced by elevated plus-maze test(EPM) and increased corticosterone release. Moreover, PET imaging displayed elevated D2R availability in the amygdala and mPFC in ARS as compared to that in the naives.PET imaging combined with immunohistochemical assay confirmed that amygdaloid D2R was significantly implicated in stress-induced anxiety. Our findings delivered valuable insights into neuromechanism of amygdaloid D2R underlying stress-induced anxiety and might have important implications for developing therapeutics for anxiety by targeting amygdaloid D2R.

PET Neuroimaging of Alzheimer's Disease: Radiotracers and Their Utility in Clinical Research.

Alzheimer's Disease (AD), the leading cause of senile dementia, is a progressive neurodegenerative disorder affecting millions of people worldwide and exerting tremendous socioeconomic burden on all societies. Although definitive diagnosis of AD is often made in the presence of clinical manifestations in late stages, it is now universally believed that AD is a continuum of disease commencing from the preclinical stage with typical neuropathological alterations appearing decades prior to its first symptom, to the prodromal stage with slight symptoms of amnesia (amnestic mild cognitive impairment, aMCI), and then to the terminal stage with extensive loss of basic cognitive functions, i.e., AD-dementia. Positron emission tomography (PET) radiotracers have been developed in a search to meet the increasing clinical need of early detection and treatment monitoring for AD, with reference to the pathophysiological targets in Alzheimer's brain. These include the pathological aggregations of misfolded proteins such as β-amyloid (Aβ) plagues and neurofibrillary tangles (NFTs), impaired neurotransmitter system, neuroinflammation, as well as deficient synaptic vesicles and glucose utilization. In this article we survey the various PET radiotracers available for AD imaging and discuss their clinical applications especially in terms of early detection and cognitive relevance.

Leveraging Open Science Drug Development for PET: Preliminary Neuroimaging of 11C-Labeled ALK2 Inhibitors.

Mutations in the gene encoding activin receptor-like kinase 2 (ALK2) are implicated in the pathophysiology of a pediatric brainstem cancer, diffuse intrinsic pontine glioma (DIPG). Inhibitors of ALK2 that cross the blood–brain barrier have been proposed as a method of treatment for DIPG. As part of an open science approach to radiopharmaceutical and drug discovery, we developed 11C-labeled radiotracers from potent and selective lead ALK2 inhibitors to investigate their brain permeability through positron emission tomography (PET) neuroimaging. Four radiotracers were synthesized by 11C-methylation and assessed by dynamic PET imaging in healthy Sprague–Dawley rats. One of the compounds, [11C]M4K2127, showed high initial brain uptake (SUV ∼ 2), including in the region of interest (pons). This data supports the use of this chemotype as a brain penetrant ALK2 inhibitor that permeates evenly into the pons with potential application for the treatment of DIPG.

Pet imaging of receptor occupancy

The discovery and development of drugs for treatment of brain disorders is an extremely challenging process requiring large resources, timelines, and associated costs. Positron Emission Tomography (PET) enables in vivo neuroimaging of various components of receptors, transporters, enzymatic activity and other types of proteins. PET also allows for studying the response to physiological or drug interventions in experimental medicine studies. Moreover, PET neuroimaging can assist to establish diagnoses in certain brain disorders and thereby improve patient selection and stratification for clinical trials. Over the past couple of decades, PET neuroimaging has thus become a central component of the evaluation of novel drugs for brain disorders, enabling decision-making in phase I studies, where early discharge of risk provides increased confidence to progress a candidate to a later phase testing at the right dose level or alternatively to kill a compound through failure to meet key criteria. The so called "3 pillars" of drug survival, namely; tissue exposure, target engagement, and pharmacologic activity, are particularly well suited for evaluation by PET imaging. Molecular neuroimaging has thus increasingly established itself as a unique tool that not only can demonstrate drug penetration and kinetics in the brain, but also identify pharmacodynamic effects, e.g., changes in glucose metabolism. It can also quantitate therapeutic action in vivo by determining, e.g., drug occupancy whereby the relevant dose ranges to be used in clinical efficacy trials can be determined.DisclosureNo significant relationships.

Radiofluorination of oxazole-carboxamides for preclinical PET neuroimaging of GSK-3

Glycogen synthase kinase 3 (GSK-3) is an enzyme that is dysregulated in oncology, neurodegeneration, neuroinflammation and several mental health illnesses. As such, GSK-3 is a long-sought after target for positron emission tomography (PET) imaging and therapeutic intervention. Herein, we report on the development and radiofluorination of two oxazole-4-carboxamides, including one bearing a non-activated aromatic ring. Both compounds demonstrated excellent selectivity in a kinase screen and inhibit GSK-3 with high affinity. [18F]OCM-49 was synthesized from [18F]fluoride using a copper-mediated reaction of an aryl boronic acid precursor, while [18F]OCM-50 used a trimethylammonium triflate precursor, and both radiotracers were translated for preclinical PET imaging in rodents. Due to superior radiochemical yields and brain uptake (peak standardized uptake value of ∼2.0), [18F]OCM-50 was further evaluated in non-human primate and also showed good brain uptake and rapid clearance. Further studies to consider clinical translation of both radiotracers are underway.

Imaging Kappa Opioid Receptors in the Living Brain with Positron Emission Tomography.

Kappa opioid receptor (KOR) neuroimaging using positron emission tomography (PET) has been immensely successful in all phases of discovery and validation in relation to radiotracer development from preclinical imaging to human imaging. There are now several KOR-specific PET radiotracers that can be utilized for neuroimaging, including agonist and antagonist ligands, as well as C-11 and F-18 variants. These technologies will increase KOR PET utilization by imaging centers around the world and have provided a foundation for future studies. In this chapter, I review the advances in KOR radiotracer discovery, focusing on ligands that have been translated into human imaging, and highlight key attributes unique to each KOR PET radiotracer. The utilization of these radiotracers in KOR PET neuroimaging can be subdivided into three major investigational classes: the first, measurement of KOR density; the second, measurement of KOR drug occupancy; the third, detecting changes in endogenous dynorphin following activation or deactivation. Given the involvement of the KOR/dynorphin system in a number of brain disorders including, but not limited to, pain, itch, mood disorders and addiction, measuring KOR density in the living brain will offer insight into the chronic effects of these disorders on KOR tone in humans. Notably, KOR PET has been successful at measuring drug occupancy in the human brain to guide dose selection for maximal therapeutic efficacy while avoiding harmful side effects. Lastly, we discuss the potential of KOR PET to detect changes in endogenous dynorphin in the human brain, to elucidate neural mechanisms and offer critical insight into disease-modifying therapeutics. We conclude with comments on other translational neuroimaging modalities such as MRI that could be used to study KOR-dynorphin tone in the living human brain.

Positron Emission Tomography Imaging of the Endocannabinoid System: Opportunities and Challenges in Radiotracer Development.

The endocannabinoid system (ECS) is involved in a wide range of biological functions and comprises cannabinoid receptors and enzymes responsible for endocannabinoid synthesis and degradation. Over the past 2 decades, significant advances toward developing drugs and positron emission tomography (PET) tracers targeting different components of the ECS have been made. Herein, we summarized the recent development of PET tracers for imaging cannabinoid receptors 1 (CB1R) and 2 (CB2R) as well as the key enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), particularly focusing on PET neuroimaging applications. State-of-the-art PET tracers for the ECS will be reviewed including their chemical design, pharmacological properties, radiolabeling, as well as preclinical and human PET imaging. In addition, this review addresses the current challenges for ECS PET biomarker development and highlights the important role of PET ligands to study disease pathophysiology as well as to facilitate drug discovery.

Proper names from story recall are associated with beta-amyloid in cognitively unimpaired adults at risk for Alzheimer's disease

Due to advances in the early detection of Alzheimer's disease (AD) biomarkers including beta-amyloid (Aβ), neuropsychological measures that are sensitive to concurrent, subtle changes in cognition are critically needed. Story recall tasks have shown sensitivity to early memory declines in persons with mild cognitive impairment (MCI) and early stage dementia, as well as in persons with autosomal dominantly inherited AD up to 10 years prior to a dementia diagnosis. However, the evidence is inconclusive regarding relationships between evidence of Aβ and story recall measures. Because story recall tasks require the encoding and delayed retrieval of several lexical-semantic categories, such as proper names, verbs, and numerical expressions, and because lexical categories have been shown to be differentially impaired in persons with MCI, we focused on item-level analyses of lexical-semantic retrieval from a quintessential story recall task, Logical Memory from the Wechsler Memory Scale-Revised. Our objective was to investigate whether delayed recall of lexical categories (proper names, verbs and/or numerical expressions), as well as the traditional total score measure, was associated with “preclinical AD,” or cognitively unimpaired adults with positive Aβ deposition on positron emission tomography (PET) neuroimaging using Pittsburgh Compound B (PiB). We developed an item-level scoring system, in which we parsed items into lexical categories and examined the immediate and delayed recall of these lexical categories from 217 cognitively unimpaired participants from the Wisconsin Registry for Alzheimer's Prevention (WRAP). We performed binary logistic regression models with story recall score as predictor and Aβ status (positive/negative) as the outcome. Using baseline Logical Memory data, proper names from delayed story recall were significantly associated with Aβ status, such that participants who recalled more proper names were less likely to be classified as PiB(+) (odds ratio = .58, p = .01). None of the other story recall variables, including total score, were associated with PiB status. Secondary analyses determined that immediate recall of proper names was not significantly associated with Aβ, suggesting a retrieval deficit rather than that of encoding. The present findings suggest that lexical semantic retrieval measures from existing story recall tasks may be sensitive to Aβ deposition, and may provide added utility to a widely-used, long-standing neuropsychological test for early detection of cognitive decline on the AD continuum.