Performed Positron Emission Tomography Research Articles

Vivianne Tawfik, M.D., Ph.D., a Recipient of the 2022 James E. Cottrell, M.D., Presidential Scholar Award

Vivianne Tawfik, M.D., Ph.D., a Recipient of the 2022 James E. Cottrell, M.D., Presidential Scholar Award

Impact of P-gp and BCRP on pulmonary drug disposition assessed by PET imaging in rats.

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two efflux transporters which are expressed in the apical (i.e. airway lumen-facing) membranes of lung epithelial cells. To assess the influence of P-gp and BCRP on the pulmonary disposition of inhaled drugs, we performed positron emission tomography (PET) imaging in rats after intratracheal aerosolization of two model P-gp/BCRP substrate radiotracers (i.e. [11C]erlotinib and [11C]tariquidar). We studied rat groups in which both transporters were active (i.e. wild-type rats), either of the two transporters was inactive (Abcb1a/b(-/-) and Abcg2(-/-) rats) or both transporters were inactive (Abcg2(-/-) rats in which pulmonary P-gp activity was inhibited by treatment with unlabeled tariquidar). PET-measured lung distribution data were compared with brain-to-plasma radioactivity concentration ratios measured in a gamma counter at the end of the PET scan. For [11C]erlotinib, lung exposure (AUClungs) was moderately but not significantly increased in Abcb1a/b(-/-) rats (1.6-fold) and Abcg2(-/-) rats (1.5-fold), and markedly (3.6-fold, p<0.0001) increased in tariquidar-treated Abcg2(-/-) rats, compared to wild-type rats. Similarly, the brain uptake of [11C]erlotinib was substantially (4.5-fold, p<0.0001) increased when both P-gp and BCRP activities were impaired. For [11C]tariquidar, differences in AUClungs between groups pointed into a similar direction as for [11C]erlotinib, but were less pronounced and lacked statistical significance. Our study demonstrates functional P-gp and BCRP activity in vivo in the lungs and further suggests functional redundancy between P-gp and BCRP in limiting the pulmonary uptake of a model P-gp/BCRP substrate, analogous to the blood-brain barrier. Our results suggest that pulmonary efflux transporters are important for the efficacy and safety of inhaled drugs and that their modulation may be exploited in order to improve the pharmacokinetic and pharmacodynamic performance of pulmonary delivered drugs.

Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease.

Although the epigenetic regulatory protein histone deacetylase 6 (HDAC6) has been recently implicated in the etiology of Alzheimer's disease (AD), little is known about the role of HDAC6 in the etiopathogenesis of AD and whether HDAC6 can be a potential therapeutic target for AD. Here, we performed positron emission tomography (PET) imaging in combination with histopathological analysis to better understand the underlying pathomechanisms of HDAC6 in AD. We first developed [18F]PB118 which was demonstrated as a valid HDAC6 radioligand with excellent brain penetration and high specificity to HDAC6. PET studies of [18F]PB118 in 5xFAD mice showed significantly increased radioactivity in the brain compared to WT animals, with more pronounced changes identified in the cortex and hippocampus. The translatability of this radiotracer for AD in a potential human use was supported by additional studies, including similar uptake profiles in non-human primates, an increase of HDAC6 in AD-related human postmortem hippocampal tissues by Western blotting protein analysis, and our ex vivo histopathological analysis of HDAC6 in postmortem brain tissues of our animals. Collectively, our findings show that HDAC6 may lead to AD by mechanisms that tend to affect brain regions particularly susceptible to AD through an association with amyloid pathology.

Circadian disruption in mice through chronic jet lag-like conditions modulates molecular profiles of cancer in nucleus accumbens and prefrontal cortex.

Biological rhythms regulate physiological activities. Shiftwork disrupts normal circadian rhythms and may increase the risk of cancer through unknown mechanisms. To mimic environmental light/dark changes encountered by shift workers, a protocol called 'chronic jet lag (CJL)' induced by repeatedly shifting light-dark cycles has been used. Here, we subjected mice to CJL by advancing light-dark cycle by 6 h every 2 days, and conducted RNA sequencing to analyze the expression profile and molecular signature in the brain areas of prefrontal cortex and nucleus accumbens. We also performed positron emission tomography (PET) imaging to monitor changes related to glucose metabolism in brain. Our results reveal systematic reprogramming of gene expression associated with cancer-related pathways and metabolic pathways in prefrontal cortex and nucleus accumbens. PET imaging indicates that glucose uptake level was significantly reduced in whole brain as well as the individual brain regions. Moreover, qPCR analysis describes that the expression levels of cancer-related genes were altered in prefrontal cortex and nucleus accumbens. Overall, these results suggest a molecular and metabolic link with CJL-mediated cancer risk, and generate hypotheses on how CJL increases the susceptibility to cancer.

Assessment of bone marrow status in diffuse B-cell large cell lymphoma: PET/CT capabilities

The aim of this work was to present the results of a retrospective study of 35 patients with morphologically diagnosed diffuse B-cell large cell lymphoma with bone marrow damage from 22 to 82 years old, median 63 years. There were 27 men and 8 women. After histological confirmation, all patients performed positron emission tomography combined with computed tomography with 18F-fluorodeoxyglucose (FDG PET/CT) followed by bone marrow trepanobiopsy. Specific bone marrow lesions were detected in 100% of cases with PET/CT and in 68.6% of cases with trepanobiopsy. Diffuse bone marrow damage was detected in 24 (68.6%) cases, focal – in 10 (28.6%) patients and in 1 (2.8%) patient – a mixed variant. The data obtained indicate the predominance of diffuse damage to the bone marrow. The statistical analysis established the value of the standardized maximum absorption coefficient of FDG SUVmax for bone marrow damage equal more than 3.58. Sensitivity was at 90% and a specificity was at 92%. The sensitivity of the PET/CT method is higher with focal lesions of the bone marrow than with diffuse. SUVmax was 10.26 ± 1.67 and 2.86 ± 0.09, respectively. The differences between them are significant (p &lt; 0.0001). PET/CT is a non-invasive method of metabolic imaging allows you to assess the condition of the bone marrow and other extranodal symptoms of the disease at the stage of diagnosis, treatment and follow-up. It can replace the traditional method of bone marrow biopsy with diffuse B-cell large cell lymphoma.

Brain activity and transcriptional profiling in mice under chronic jet lag

Shift work is known to be associated with an increased risk of neurological and psychiatric diseases, but how it contributes to the development of these diseases remains unclear. Chronic jet lag (CJL) induced by shifting light-dark cycles repeatedly is a commonly used protocol to mimic the environmental light/dark changes encountered by shift workers. Here we subjected wildtype mice to CJL and performed positron emission tomography imaging of glucose metabolism to monitor brain activities. We also conducted RNA sequencing using prefrontal cortex and nucleus accumbens tissues from these animals, which are brain regions strongly implicated in the pathology of various neurological and psychiatric conditions. Our results reveal the alterations of brain activities and systematic reprogramming of gene expression in brain tissues under CJL, building hypothesis for how CJL increases the susceptibility to neurological and psychiatric diseases.

Brain pharmacokinetics and biodistribution of 11C-labeled isoproterenol in rodents

IntroductionIsoproterenol is a non-selective β receptor agonist, which is a drug approved for bradycardia and bronchial asthma in many countries. Recently, isoproterenol has been reported to have the potential as a drug for the treatment of Alzheimer's disease by inhibiting the aggregation of tau protein. Isoproterenol is a highly potent drug causing increases in heart rates even when its plasma concentration is very low. Thus, it is critical to know if potentially effective therapeutic levels of isoproterenol can be achieved, maintaining safe plasma levels without any untoward pharmacological effects. The purpose of the study is to investigate the brain pharmacokinetics and biodistribution of 11C-labeled isoproterenol in rodents. MethodsWe performed positron emission tomography (PET) brain imaging and biodistribution studies of [11C]isoproterenol. 120-min scans with arterial blood sampling were performed in rats. Additionally, plasma and brain homogenates were analyzed with radio-HPLC to characterize its metabolite profiles. As a measure of [11C]isoproterenol brain uptake, total distribution volumes were determined by a pharmacokinetic compartment model. Biodistribution of [11C]isoproterenol was investigated in mice at six-time points from 1-min to 90-min after injection. ResultsWe found a modest brain uptake of [11C]isoproterenol. Its brain pharmacokinetics showed that the concentration of isoproterenol in the brain at equilibrium was about two-fold higher than in the plasma (total distribution volumes 2.0 ± 0.2 cm3/mL). Only unmetabolized isoproterenol was detected in the brain at 30 min after injection, although isoproterenol was rapidly metabolized in plasma. The biodistribution study showed that isoproterenol and its metabolite are excreted mainly via the urinary system. Conclusions, advances in knowledge and implications for patient careIn this study, we have shown that rat brain concentrations of isoproterenol are only two-fold of that in plasma at equilibrium. If the brain pharmacokinetics are similar in the human brain, it may be difficult to achieve potentially therapeutic levels of this drug safely in humans. Further studies appear warranted to investigate the brain pharmacokinetics in humans with PET using [11C]isoproterenol.

Hemiparkinsonism or Hemidystonia With Hemiatrophy Syndrome: A Case Series With Follow-Up

Hemiparkinsonism-hemiatrophy syndrome (HPHA) and hemidystonia-hemiatrophy syndrome (HDHA) are rare movement disorders composed of hemidystonia or hemiparkinsonism that present with unilateral limb, face, trunk, or cerebral hemiatrophy and mostly occur following head trauma or postanoxic events. However, relatively little is known about the pathogenesis of these conditions. In our case series, we present three HPHA patients and one HDHA patient who underwent detailed neuropsychological, radiological, motor, and non-motor functional assessments with a mean follow-up of 2 years. We followed two patients who showed differences in their progression for more than 2 years: one barely progressed with no treatment, and the other exhibited levodopa-induce dyskinesia (LID) and definitive progression while receiving multiple adjunctive therapies. In addition, we performed positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) and 18F-dihydroxyphenylalanine (DOPA) in one HPHA patient who showed bilaterally symmetrical uptake of FDG with no significant increase or decrease in the cerebral hemispheres, including the striatum, but exhibited a significant reduction in the uptake of 18F-DOPA in the contralateral posterior striatum. In this study, we followed HPHA patients who showed different disease courses to explore the clinical characteristics and pathogenesis of HPHA and HDHA and illustrate the clinical heterogeneity of these diseases.

Measurement of Hepatic ABCB1 and ABCG2 Transport Activity with [11C]Tariquidar and PET in Humans and Mice.

P-Glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) in the canalicular membrane of hepatocytes mediate the biliary excretion of drugs and drug metabolites. To measure hepatic ABCB1 and ABCG2 activity, we performed positron emission tomography (PET) scans with the ABCB1/ABCG2 substrate [11C]tariquidar in healthy volunteers and wild-type, Abcb1a/b(-/-), Abcg2(-/-), and Abcb1a/b(-/-)Abcg2(-/-) mice without and with coadministration of unlabeled tariquidar. PET data were analyzed with a three-compartment pharmacokinetic model. [11C]Tariquidar underwent hepatobiliary excretion in both humans and mice, and tariquidar coadministration caused a significant reduction in the rate constant for the transfer of radioactivity from the liver into bile (by -74% in humans and by -62% in wild-type mice), suggesting inhibition of canalicular efflux transporter activity. Radio-thin-layer chromatography analysis revealed that the majority of radioactivity (>87%) in the mouse liver and bile was composed of unmetabolized [11C]tariquidar. PET data in transporter knockout mice revealed that both ABCB1 and ABCG2 mediated biliary excretion of [11C]tariquidar. In vitro experiments indicated that tariquidar is not a substrate of major hepatic basolateral uptake transporters (SLCO1B1, SLCO1B3, SLCO2B1, SLC22A1, and SLC22A3). Our data suggest that [11C]tariquidar can be used to measure hepatic canalicular ABCB1/ABCG2 transport activity without a confounding effect of uptake transporters.

Assessment of brain delivery of a model ABCB1/ABCG2 substrate in patients with non-contrast-enhancing brain tumors with positron emission tomography

BackgroundP-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are two efflux transporters expressed at the blood–brain barrier which effectively restrict the brain distribution of the majority of currently known anticancer drugs. High-grade brain tumors often possess a disrupted blood–brain tumor barrier (BBTB) leading to enhanced accumulation of magnetic resonance imaging contrast agents, and possibly anticancer drugs, as compared to normal brain. In contrast to high-grade brain tumors, considerably less information is available with respect to BBTB integrity in lower grade brain tumors.Materials and methodsWe performed positron emission tomography imaging with the radiolabeled ABCB1 inhibitor [11C]tariquidar, a prototypical ABCB1/ABCG2 substrate, in seven patients with non-contrast -enhancing brain tumors (WHO grades I–III). In addition, ABCB1 and ABCG2 levels were determined in surgically resected tumor tissue of four patients using quantitative targeted absolute proteomics.ResultsBrain distribution of [11C]tariquidar was found to be very low across the whole brain and not significantly different between tumor and tumor-free brain tissue. Only one patient showed a small area of enhanced [11C]tariquidar uptake within the brain tumor. ABCG2/ABCB1 ratios in surgically resected tumor tissue (1.4 ± 0.2) were comparable to previously reported ABCG2/ABCB1 ratios in isolated human micro-vessels (1.3), which suggested that no overexpression of ABCB1 or ABCG2 occurred in the investigated tumors.ConclusionsOur data suggest that the investigated brain tumors had an intact BBTB, which is impermeable to anticancer drugs, which are dual ABCB1/ABCG2 substrates. Therefore, effective drugs for antitumor treatment should have high passive permeability and lack ABCB1/ABCG2 substrate affinity.Trial registrationEuropean Union Drug Regulating Authorities Clinical Trials Database (EUDRACT), 2011-004189-13. Registered on 23 February 2012, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2011-004189-13.

PET Neuroimaging Reveals Serotonergic and Metabolic Dysfunctions in the Hippocampal Electrical Kindling Model of Epileptogenesis

Glucose metabolism and serotonergic neurotransmission have been reported to play an important role in epileptogenesis. We therefore aimed to use neuroimaging to evaluate potential alterations in serotonin 5-HT1A receptor and glucose metabolism during epileptogenesis in the rat electrical kindling model.To achieve this goal, we performed positron emission tomography (PET) imaging in a rat epileptogenesis model triggered by electrical stimulation of the hippocampus using 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG), a radiolabeled analog of glucose, and 2′-methoxyphenyl-(N-2′-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine (18F-MPPF), a radiolabeled 5-HT1A receptor ligand, to evaluate brain metabolism and 5-HT1A receptor functionality. Since the 5-HT1A receptor is also highly expressed in astrocytes, glial fibrillary acidic protein (GFAP) immunofluorescence was performed to detect astrogliosis arising from the kindling procedure once the study was finalized. Lastly, in vitro18F-MPPF autoradiography was performed to evaluate changes in 5HT1A receptor expression.18F-FDG PET showed reduction of glucose uptake in cortical structures, whereas 18F-MPPF PET revealed an enhancement of tracer binding potential (BPND) in key areas rich in 5-HT1A receptor involved in epilepsy, including septum, hippocampus and entorhinal cortex of kindled animals compared to controls. However, in vitro 5-HT1A receptor autoradiography showed no changes in densitometric signal in any brain region, suggesting that the augmentation in BPND found by PET could be caused by reduction of synaptic serotonin. Importantly, astroglial activation was detected in the hippocampus of kindled rats.Overall, electrical kindling induced hypometabolism, astrogliosis and serotonergic alterations in epilepsy-related regions. Furthermore, the present findings point to 5-HT1A receptor as a valuable epileptogenesis biomarker candidate and a potential therapeutic target.

An Optimized MicroPET Imaging Method for the Distribution and Synergies of Natural Products.

Purpose: Understanding the distribution and interaction of the Traditional Chinese Medicines (TCMs) is an integral source of herbal drug discovery. An optimized radio-labeled method was explored that could conduct in situ biodistribution studies in animals. We evaluated the feasibility of the method and applied glycyrrhetinic acid and platycodon (PG) polysaccharides as models.Procedures: [18F]-GA is a novel radiotracer which was performed positron emission tomography (PET) studies to assay the biodistribution of GA in mice. In addition, PG polysaccharide was used to intervene the biodistribution and dosimetry of GA. Scanning data were analyzed with professional software.Results: Record the time-activity curves for all organs then use the normalization method to calculate the area under the curve as a dosimetry for each organ. Moreover, the addition of PG polysaccharides can significantly improve the dosimetry of GA in the lungs, and its effect was related to the administration time.Conclusion: MicroPET imaging opens up a new avenue for the application of drug interactions between the TCMs.

Influence of OATPs on Hepatic Disposition of Erlotinib Measured With Positron Emission Tomography

To assess the hepatic disposition of erlotinib, we performed positron emission tomography (PET) scans with [11C]erlotinib in healthy volunteers without and with oral pretreatment with a therapeutic erlotinib dose (300 mg). Erlotinib pretreatment significantly decreased the liver exposure to [11C]erlotinib with a concomitant increase in blood exposure, pointing to the involvement of a carrier‐mediated hepatic uptake mechanism. Using cell lines overexpressing human organic anion‐transporting polypeptides (OATPs) 1B1, 1B3, or 2B1, we show that [11C]erlotinib is selectively transported by OATP2B1. Our data suggest that at PET microdoses hepatic uptake of [11C]erlotinib is mediated by OATP2B1, whereas at therapeutic doses OATP2B1 transport is saturated and hepatic uptake occurs mainly by passive diffusion. We propose that [11C]erlotinib may be used as a hepatic OATP2B1 probe substrate and erlotinib as an OATP2B1 inhibitor in clinical drug–drug interaction studies, allowing the contribution of OATP2B1 to the hepatic uptake of drugs to be revealed.

Neural correlates of apathy in late-life depression: a pilot [18 F]FDDNP positron emission tomography study.

Neurotoxicity associated with amyloid and tau protein aggregation could represent a pathophysiological cascade that, along with vascular compromise, may predispose individuals to late-life depression (LLD). In LLD, apathy is common, leads to worsening of functioning, and responds poorly to antidepressant treatment. Better understanding of the pathophysiological mechanisms of apathy in LLD would facilitate development of more effective diagnostic and treatment approaches. In this cross-sectional pilot study, we performed positron emission tomography scans after injection of 2-(1-{6-[(2-[18 F]fluoroethyl)(methyl)-amino]-2-naphthyl}ethylidene) malononitrile ([18 F]FDDNP), an in vivo amyloid and tau neuroimaging study, in patients with LLD to explore neural correlates of apathy. Sixteen depressed elderly volunteers received clinical assessments and [18 F]FDDNP positron emission tomography scans. The cross-sectional relationship of [18 F]FDDNP binding levels with depression (Hamilton Depression Rating Scale) and apathy (Apathy Evaluation Scale) were studied using Spearman's correlation analyses because of the relatively small sample size. Age, sex, and years of education were partialed out. Significance levels were set at P ≤ 0.05. [18 F]FDDNP binding in the anterior cingulate cortex was negatively associated with the Apathy Evaluation Scale total (r = -0.62, P = 0.02; where low Apathy Evaluation Scale score equals greater severity of apathy). This suggests that apathy in LLD is associated with higher amyloid and/or tau levels in the anterior cingulate cortex. None of the regional [18 F]FDDNP binding levels was significantly associated with the Hamilton Depression Rating Scale total. This pilot study suggests that increased apathy in subjects with LLD may be associated with greater amyloid and/or tau burden in certain brain regions. Future studies in larger samples would elucidate the generalizability of these results, which eventually could lead to improved diagnostic and treatment methods in LLD.

Cholinergic PET imaging in infections and inflammation using 11C-donepezil and 18F-FEOBV.

Immune cells utilize acetylcholine as a paracrine-signaling molecule. Many white blood cells express components of the cholinergic signaling pathway, and these are up-regulated when immune cells are activated. However, in vivo molecular imaging of cholinergic signaling in the context of inflammation has not previously been investigated. We performed positron emission tomography (PET) using the glucose analogue 18F-FDG, and 11C-donepezil and 18F-FEOBV, markers of acetylcholinesterase and the vesicular acetylcholine transporter, respectively. Mice were inoculated subcutaneously with Staphylococcus aureus, and PET scanned at 24, 72, 120, and 144h post-inoculation. Four pigs with post-operative abscesses were also imaged. Finally, we present initial data from human patients with infections, inflammation, and renal and lung cancer. In mice, the FDG uptake in abscesses peaked at 24h and remained stable. The 11C-donepezil and 18F-FEOBV uptake displayed progressive increase, and at 120-144h was nearly at the FDG level. Moderate 11C-donepezil and slightly lower 18F-FEOBV uptake were seen in pig abscesses. PCR analyses suggested that the 11C-donepezil signal in inflammatory cells is derived from both acetylcholinesterase and sigma-1 receptors. In humans, very high 11C-donepezil uptake was seen in a lobar pneumonia and in peri-tumoral inflammation surrounding a non-small cell lung carcinoma, markedly superseding the 18F-FDG uptake in the inflammation. In a renal clear cell carcinoma no 11C-donepezil uptake was seen. The time course of cholinergic tracer accumulation in murine abscesses was considerably different from 18F-FDG, demonstrating in the 11C-donepezil and 18F-FEOBV image distinct aspects of immune modulation. Preliminary data in humans strongly suggest that 11C-donepezil can exhibit more intense accumulation than 18F-FDG at sites of chronic inflammation. Cholinergic PET imaging may therefore have potential applications for basic research into cholinergic mechanisms of immune modulation, but also clinical applications for diagnosing infections, inflammatory disorders, and cancer inflammation.

Visualization of drug translocation in the nasal cavity and pharmacokinetic analysis on nasal drug absorption using positron emission tomography in the rat

We performed positron emission tomography (PET) using 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) to evaluate the pharmacokinetics of nasal drug absorption in the rat. The dosing solution of [18F]FDG was varied in volume (ranging from 5 to 25μl) and viscosity (using 0% to 3% concentrations of hydroxypropylcellulose). We modeled the pharmacokinetic parameters regarding the nasal cavity and pharynx using mass balance equations, and evaluated the values that were obtained by fitting concentration–time profiles using WinNonlin® software. The regional nasal permeability was also estimated using the active surface area derived from the PET images. The translocation of [18F]FDG from the nasal cavity was visualized using PET. Analysis of the PET imaging data revealed that the pharmacokinetic parameters were independent of the dosing solution volume; however, the viscosity increased the absorption rate constant and decreased the mucociliary clearance rate constant. Nasal permeability was initially higher but subsequently decreased until the end of the study, indicating regional differences in permeability in the nasal cavity. We concluded that the visualization of drug translocation in the nasal cavity in the rat using PET enables quantitative analysis of nasal drug absorption, thereby facilitating the development of nasal formulations for human use.

The origin of nausea in migraine-a PET study.

BackgroundNausea is a common and disabling symptom of migraine. The origin of nausea is not well understood although functional connections between trigeminal neurons and the nucleus tractus solitarius may explain occurrence of nausea with pain. However, nausea occurs as a premonitory symptom in about a quarter of patients, suggesting that a primary brain alteration unrelated to the experience of pain may be the reason for nausea.MethodsWe performed positron emission tomography scans with H215O PET in premonitory phase of nitroglycerin-induced migraine and compared patients with and without nausea.ResultsThe results showed activation in rostral dorsal medulla and periaqueductal grey (PAG) in the nausea group, which was absent in the no nausea group. The rostral dorsal medullary area included the nucleus tractus solitarius, dorsal motor nucleus of the vagus nerve and the nucleus ambiguus, all of which are thought to be involved in brain circuits mediating nausea.ConclusionsThe results demonstrate that nausea can occur as a premonitory symptom in migraine, independent of pain and trigeminal activation. This is associated with activation of brain structures known to be involved in nausea. We conclude that nausea is a centrally driven symptom in migraine.

A Marker for Treatment-Resistant Depression?

Most patients with major depression do not achieve remission with the first prescribed therapy. To try to find a biomarker for treatment resistance, investigators performed positron emission tomography (PET) and magnetic resonance imaging on 82 untreated patients with major depression and then randomized them to 12 weeks of treatment with either escitalopram (10–20 mg/day) or cognitive-behavioral therapy (CBT; 16 sessions). Of the …

Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks

Our aim was identify brain areas involved in the premonitory phase of migraine using functional neuroimaging. To this end, we performed positron emission tomography scans with H2(15)O to measure cerebral blood flow as a marker of neuronal activity. We conducted positron emission tomography scans at baseline, in the premonitory phase without pain and during migraine headache in eight patients. We used glyceryl trinitrate (nitroglycerin) to trigger premonitory symptoms and migraine headache in patients with episodic migraine without aura who habitually experienced premonitory symptoms during spontaneous attacks. The main outcome was comparing the first premonitory scans in all patients to baseline scans in all patients. We found activations in the posterolateral hypothalamus, midbrain tegmental area, periaqueductal grey, dorsal pons and various cortical areas including occipital, temporal and prefrontal cortex. Brain activations, in particular of the hypothalamus, seen in the premonitory phase of glyceryl trinitrate-triggered migraine attacks can explain many of the premonitory symptoms and may provide some insight into why migraine is commonly activated by a change in homeostasis.

Coronary Microvascular Dysfunction After ST-Segment–Elevation Myocardial Infarction

Variable degrees of coronary microvascular dysfunction occur at the time of ST-segment–elevation myocardial infarction (STEMI) correlating with infarct size and long-term prognosis. Angiographic methods for assessing microvascular dysfunction in the cardiac catheterization laboratory at the time of STEMI include thrombolysis in myocardial infarction flow grade, thrombolysis in myocardial infarction frame count, and thrombolysis in myocardial infarction myocardial perfusion grade.1 More recently, coronary wire-based methods measuring Doppler-derived parameters, such as the coronary flow velocity reserve (CFVR), or measuring thermodilution-derived parameters, such as the index of microcirculatory resistance, have been shown to be more powerful predictors of acute left ventricular dysfunction, myocardial viability, and subsequent adverse outcomes.2,3 Article see p 207 Although it is widely accepted that the degree of microvascular dysfunction occurring in the myocardium subtended by the infarct-related vessel correlates with infarct size and prognosis, there has been some debate on whether more global microvascular dysfunction, involving myocardial regions not supplied by the infarct-related vessel, is present at the time of STEMI. For example, Uren et al4 performed positron emission tomography imaging in 13 patients with STEMI and found a decreased coronary flow reserve in the noninfarct-related vessel, which improved at 6-month follow-up. However, Ntalianis et al5 measured fractional flow reserve in a nonculprit vessel at the time of STEMI in 75 patients and again 1 month later and found no significant difference in fractional flow reserve or in index of microcirculatory resistance, which was measured in a subgroup, suggesting that the microvascular dysfunction resulting from STEMI is limited to the territory supplied by the infarct-related artery. In this issue of Circulation: Cardiovascular Interventions , van de Hoef et al6 report long-term follow-up in 100 patients presenting with STEMI, in whom they measured Doppler wire-derived CFVR, diastolic deceleration time, and systolic flow reversal …