Andrew T. Higgins

The effects of normal aging on amyloid-β deposition in nondemented adults with Down syndrome as imaged by carbon 11-labeled Pittsburgh compound B.

In Down syndrome (DS), the overproduction of amyloid precursor protein is hypothesized to predispose young adults to early expression of Alzheimer‐like neuropathology.

Mind-body interactions in the regulation of airway inflammation in asthma: A PET study of acute and chronic stress.

BACKGROUND Psychological stress has long been recognized as a contributing factor to asthma symptom expression and disease progression. Yet, the neural mechanisms that underlie this relationship have been largely unexplored in research addressing the pathophysiology and management of asthma. Studies that have examined the mechanisms of this relationship in the periphery suggest that it is the superimposition of acute stress on top of chronic stress that is of greatest concern for airway inflammation. METHODS We compared asthmatic individuals with high and low levels of chronic life stress in their neural and peripheral physiological responses to the Trier Social Stress Test and a matched control task. We used FDG-PET to measure neural activity during performance of the two tasks. We used both circulating and airway-specific markers of asthma-related inflammation to assess the impact of acute stress in these two groups. RESULTS Asthmatics under chronic stress had a larger HPA-axis response to an acute stressor, which failed to show the suppressive effects on inflammatory markers observed in those with low chronic stress. Moreover, our PET data suggest that greater activity in the anterior insula during acute stress may reflect regulation of the effect of stress on inflammation. In contrast, greater activity in the mid-insula and perigenual anterior cingulate seems to reflect greater reactivity and was associated with greater airway inflammation, a more robust alpha amylase response, and a greater stress-induced increase in proinflammatory cytokine mRNA expression in airway cells. CONCLUSIONS Acute stress is associated with increases in markers of airway inflammation in asthmatics under chronic stress. This relationship may be mediated by interactions between the insula and anterior cingulate cortex, that determine the salience of environmental cues, as well as descending regulatory influence of inflammatory pathways in the periphery.

First-in-Human Evaluation of 18F-Mefway, a PET Radioligand Specific to Serotonin-1A Receptors

The serotonin-1A (5-HT1A; 5-HT is 5-hydroxytryptamine) receptor is implicated in an array of neurologic and psychiatric disorders. Current PET radioligands targeting 5-HT1A receptors have limitations hindering widespread PET studies of this receptor system. The 5-HT1A–specific antagonist radioligand N-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(trans-4-18F-fluoromethylcyclohexane)carboxamide (18F-mefway) exhibited promising in vivo properties in rhesus monkeys. The goal of this work was to examine the in vivo cerebral binding profile and metabolism of 18F-mefway in humans. Methods: Dynamic 18F-mefway PET data were acquired for 6 healthy volunteers (4 women, 2 men; age, 22–38 y). Scans were initiated with the injection of 192–204 MBq of radiotracer, and data were acquired for 2 h. Venous blood samples were collected and assayed to examine the in vivo metabolism profile of 18F-mefway. To examine the test–retest variability of 18F-mefway, a second PET scan was acquired at least 2 wk later for 4 subjects. Regional binding potentials (BPNDs) were calculated with the multilinear reference tissue model, and voxelwise BPND maps were calculated with Logan graphical analysis. Regions surrounding the brain were carefully inspected for uptake of radiolabeled species in bone. Results: 18F-mefway uptake in the brain occurred quickly, with a peak standardized uptake value (SUV) of 1.7. Rapid washout in the cerebellum resulted in SUVs of 0.2 at 120 min, whereas regions with specific 5-HT1A binding exhibited retention of radioligand, yielding SUVs of 0.4–0.9 at 120 min. Rapid metabolism of 18F-mefway was observed, with no detected 18F-fluoride ions in plasma. BPND values of 2.4 were measured in the mesial temporal lobe, with values of 1.6 in the insular cortex and 0.7–1.0 in other cortical regions. Stable BPND estimates were obtained using 90 min of dynamic data. Average test–retest variability was 8%. No evidence of radioactivity uptake in bone was observed. Conclusion: 18F-mefway exhibits favorable in vivo properties for serotonin 5-HT1A receptor measurements in humans. The simple radiosynthesis, high specific binding profile, and absence of PET signal in bone make 18F-mefway an attractive radiotracer for PET experiments examining the 5-HT1A receptor in neuropsychiatric disorders and drug intervention.

PET imaging of acetylcholinesterase inhibitor‐induced effects on α4β2 nicotinic acetylcholine receptor binding

Acetylcholinesterase inhibitors (AChEIs) are drugs that increase synaptic acetylcholine (ACh) concentrations and are under investigation as treatments for symptoms accompanying Alzheimers disease. The goal of this work was to use PET imaging to evaluate alterations of in vivo α4β2 nicotinic acetylcholine receptor (nAChR) binding induced by the AChEIs physostigmine (PHY) and galanthamine (GAL). The α4β2 nAChR‐specific radioligand [18F]nifene was used to examine the effects of 0.1–0.2 mg/kg PHY, 5 mg/kg GAL, and saline in three separate experiments all performed on each of two rat subjects. A 60‐min bolus‐infusion protocol was used with drug administered after 30 min. Data from the thalamus and cortex were analyzed with a graphical model accounting for neurotransmitter activation using the cerebellum as a reference region to test for transient competition with bound [18F]nifene. Significant [18F]nifene displacement was detected in both regions during one PHY and both GAL studies, while no significant competition was observed in both saline studies. This preliminary work indicates the viability of [18F]nifene in detecting increases in synaptic ACh induced by AChEIs. Synapse 67:882–886, 2013.

Corrigendum to “Mind-body interactions in the regulation of airway inflammation in asthma: A PET study of acute and chronic stress” [Brain Behav. Immun. 58 (2016) 18–30]

Please cite this article in press as: Rosenkranz, M.A., et al. Corrigendum to ‘‘Mind-body interactions in the regulation of airway inflammation in ast PET study of acute and chronic stress” [Brain Behav. Immun. 58 (2016) 18–30]. Brain Behav. Immun. (2017), http://dx.doi.org/10.1016/j.bbi.2017 Melissa A. Rosenkranz a,⇑, Stephane Esnault , Bradley T. Christian , Gina Crisafi , Lauren K. Gresham , Andrew T. Higgins , Mollie N. Moore , Sarah M. Moore , Helen Y. Weng , Rachel H. Salk , William W. Busse , Richard J. Davidson a,d,g

Tau and amyloid imaging in presymptomatic and symptomatic Alzheimer’s disease with [F-18]THK5117 and [C-11]PiB: A multimodal imaging study

neurodegenerative disease. Pathological tau deposition has been classified post mortem into six Braak stages. Initial cognitive impairment is typically detected in subjects in the limbic stages (III/IV), with more severe deterioration and dementia in subjects in the isocortical (V/VI) Braak stages. Methods: Sixteen healthy elderly (Table 1) underwent 18F-AV1451 tau PET (80-100 min tissue ratio, cerebellar gray reference) and 11C-PIB Ab PET (0-90 min DVR, cerebellar gray reference) examinations. Structural MR images were co-registered to the respective PET images, and regions of interest (ROIs) corresponding anatomically to the transentorhinal (I/II), limbic (III/IV), and isocortical (V/VI) Braak stages of tau deposition were created using FreeSurfer v5.1. A global cortical PIB DVR index was calculated. All study subjects had been cognitively examined at two or more time points over the course of 35 6 16.7 months prior to tau PET scans. Factor scores and slopes of decline were calculated for each subject on global cognition, working memory, episodic memory, and processing speed domains. Slopes were adjusted using mixed effects modeling with a larger population of healthy elderly. Partial Spearman rank correlations adjusted for age and education were performed on the resulting slopes and the Braak stage ROIs. Additional voxel-wise Spearman correlations were performed for each slope and the smoothed, MNI-template warped, gray-matter masked, and averaged 18F-AV1451 images. Results: Slopes of decline for the global cognition and working memory domains were highly correlated with 18F-AV1451 uptake in the ROI corresponding to Braak stage III/IV (Figure 1). Subsequent voxel-wise correlation for these domains yielded significant clusters mainly in inferior temporal lobe (Figure 2). No correlations were observed between the slopes for episodic memory or processing speed domains and 18F-AV1451 uptake in the Braak ROIs. However, slopes for processing speed were associated with increased 18F-AV1451 uptake in prefrontal and premotor cortical clusters (Figure 3). Global cortical PIB uptake showed no relation with any of the slopes Conclusions: Tau PET imaging enables the in vivo detection of tau pathology underlying early cognitive decline independent of Ab pathology.

78. Increased glucose metabolism during acute stress in emotional neural circuitry, assessed with FDG-PET, predicts airway inflammation and psychological symptoms in asthma

Although psychological stress contributes to frequency, severity, and burden of asthma symptoms, the role of the brain in the pathophysiology and treatment of this disease is unknown. To examine the neural mechanisms through which stress contributes to airway inflammation, asthmatic subjects high or low in chronic life stress underwent an acute stressor. [18F]Fluoro-deoxyglucose positron emission tomography (FDG-PET) was used to identify neural circuits active during performance of a social stress task or a matched control condition. Sputum was collected to assess markers of airway inflammation, including expression of genes in the IL-17 pathway, products of which can contribute to both inflammation and depression. Preliminary results indicate that, during an acute stressor, activation in the anterior and mid-cingulate cortex, as well as the inferior frontal gyrus is greater in those with high vs. low chronic stress. These increases in regional glucose metabolism also predicted increased gene expression in the IL-17 pathway, as well as symptoms of anxiety and depression. Moreover, those subjects high in chronic stress showed increased gene expression in the IL-17 pathway following an acute stressor, as well as increased symptoms of anxiety and depression, relative to those with low chronic stress levels. These data suggest potential neural pathways through which psychological stress may influence airway inflammation, thus leading to an increase in asthma symptoms, disease severity, and uncovering novel targets for future treatment.