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Prefrontal and Striatal Dopamine Release Are Inversely Correlated in Schizophrenia

Frankle, W Gordon; Himes, Michael; Mason, N Scott; Mathis, Chester A; Narendran, Rajesh
BACKGROUND:The dopamine (DA) hypothesis postulates hyperactivity of subcortical DA transmission and hypoactivity of cortical DA in schizophrenia (SCH). Positron emission tomography provides the ability to assess this hypothesis in humans. However, no studies have examined the relationship between cortical DA and striatal DA in this illness. METHODS:C]NPA was also measured in these subjects. RESULTS:in the dorsal caudate (r = -0.71, p = .005). CONCLUSIONS:Subjects with SCH demonstrated deficits of DA release in cortical brain regions relative to HC subjects. Examining both cortical and striatal DA release in the same subjects demonstrated an inverse relationship between cortical DA release and striatal DA release in SCH not present in HC subjects, providing support for the current DA hypothesis of SCH.
PMID: 35791965
ISSN: 1873-2402
CID: 5280342

Imaging Cortical Dopamine Transmission in Cocaine Dependence: A [11C]FLB 457-Amphetamine Positron Emission Tomography Study

Narendran, Rajesh; Mason, Neale Scott; Himes, Michael L; Frankle, W Gordon
BACKGROUND:receptors and dopamine release in CDSs. METHODS:after amphetamine. RESULTS:receptors and less dopamine release in CDSs were not associated with performance on working memory and attention tasks. CONCLUSIONS:transmission involve the cortex in cocaine dependence. Further studies to understand the clinical relevance of these findings are warranted.
PMID: 32507390
ISSN: 1873-2402
CID: 4481092

In-patient psychiatry management of COVID-19: rates of asymptomatic infection and on-unit transmission

Zhang, Emily; LeQuesne, Elizabeth; Fichtel, Katherine; Ginsberg, David; Frankle, W Gordon
BACKGROUND:New York City's first case of SARS-associated coronavirus (SARS-CoV-2) disease 2019 (COVID-19) was identified on 1 March 2020, prompting rapid restructuring of hospital-based services to accommodate the increasing numbers of medical admissions. Non-essential services were eliminated but in-patient treatment of psychiatric illnesses was necessarily maintained. AIMS/OBJECTIVE:To detail the response of the NYU Langone Health in-patient psychiatric services to the COVID-19 outbreak from 1 March to 1 May 2020. METHOD/METHODS:Process improvement/quality improvement study. RESULTS:Over this time period, our two in-patient psychiatric units (57 total beds) treated 238 patients, including COVID-19-positive and -negative individuals. Testing for COVID-19 was initially limited to symptomatic patients but expanded over the 62-day time frame. In total, 122 SARS-CoV-2 polymerase chain reaction (PCR) tests were performed in 98 patients. We observed an overall rate of COVID-19 infection of 15.6% in the patients who were tested, with an asymptomatic positive rate of 13.7%. Although phased roll-out of testing impaired the ability to fully track on-unit transmission of COVID-19, 3% of cases were clearly identified as results of on-unit transmission. CONCLUSIONS:Our experience indicates that, with appropriate precautions, patients in need of in-patient psychiatric admission who have COVID-19 can be safely managed. We provide suggested guidelines for COVID-19 management on in-patient psychiatric units which incorporate our own experiences as well as published recommendations.
PMCID:7463133
PMID: 32867874
ISSN: 2056-4724
CID: 4582932

Distinguishing Schizophrenia Subtypes: Can Dopamine Imaging Improve the Signal-to-Noise Ratio?

Frankle, W Gordon; Narendran, Rajesh
PMID: 31908286
ISSN: 1873-2402
CID: 4257142

Failure to detect amphetamine-induced dopamine release in the cortex with [11 C]FLB 457 positron emission tomography (PET): Methodological considerations

Gertler, Joshua; Tollefson, Savannah; Jordan, Rehima; Himes, Michael; Mason, N Scott; Frankle, W Gordon; Narendran, Rajesh
Studies in nonhuman primates and humans have demonstrated that amphetamine-induced dopamine release in the cortex can be measured with [11 C]FLB 457 and PET imaging. This technique has been successfully used in recent clinical studies to show decreased dopamine transmission in the prefrontal cortex in schizophrenia and alcohol dependence. Here, we present data from a cohort of twelve healthy controls in whom an oral amphetamine challenge (0.5 mg kg-1 ) did not lead to a significant reduction in [11 C]FLB 457 BPND (i.e., binding potential relative to non-displaceable uptake). Two factors that likely contributed to the inability to displace [11 C]FLB 457 BPND in this cohort relative to successful cohorts are: (1) the acquisition of the baseline and post-amphetamine scans on different days as opposed to the same day and (2) the initiation of the post-amphetamine [11 C]FLB 457 scan at ∼ 5 hours as opposed to ∼ 3 hours following oral amphetamine. Furthermore, we show [11 C]FLB 457 reproducibility data from a legacy dataset to support greater variability in cortical BPND when the test and re-test scans are acquired on different days as compared to the same day. These results highlight the methodological challenges that continue to plague the field with respect to imaging dopamine release in the cortex.
PMID: 29876970
ISSN: 1098-2396
CID: 3144522

Amphetamine-Induced Striatal Dopamine Release Measured With an Agonist Radiotracer in Schizophrenia

Frankle, W Gordon; Paris, Jennifer; Himes, Michael; Mason, N Scott; Mathis, Chester A; Narendran, Rajesh
BACKGROUND:Receptor imaging studies have reported increased amphetamine-induced dopamine release in subjects with schizophrenia (SCH) relative to healthy control subjects (HCs). A limitation of these studies, performed with D2/3 antagonist radiotracers, is the failure to provide information about D2/3 receptors configured in a state of high affinity for the agonists (i.e., D2/3 receptors coupled to G proteins [D2/3 HIGH]). The endogenous agonist dopamine binds with preference to D2/3 HIGH receptors relative to D2/3 LOW receptors, making it critical to understand the status of D2/3 HIGH receptors in SCH. METHODS:D2/3 agonist positron emission tomography radiotracer [11C]N-propyl-norapomorphine ([11C]NPA) binding potential (BPND) was measured in 14 off-medication subjects with SCH and 14 matched HCs at baseline and after the administration of 0.5 mg kg-1 oral D-amphetamine. The amphetamine-induced change in BPND (ΔBPND) was calculated as the difference between BPND in the postamphetamine condition and BPND in the baseline condition and was expressed as a percentage of BPND at baseline. RESULTS:A trend-level increase was observed in comparing baseline [11C]NPA BPND (repeated-measures analysis of variance, F1,26 = 3.34, p = .08) between the SCH and HC groups. Amphetamine administration significantly decreased BPND in all striatal regions across all subjects in both groups. No differences were observed in [11C]NPA ΔBPND (repeated-measures analysis of variance, F1,26 = 1.9, p = .18) between HCs and subjects with SCH. Amphetamine significantly increased positive symptoms in subjects with SCH (19.5 ± 5.3 vs. 23.7 ± 4.1, paired t test, p < .0001); however, no correlations were noted with [11C]NPA BPND or ΔBPND. CONCLUSIONS:This study provides in vivo indication of a role for postsynaptic factors in amphetamine-induced psychosis in SCH.
PMCID:5862747
PMID: 29325847
ISSN: 1873-2402
CID: 2905042

An open-label positron emission tomography study to evaluate serotonin transporter occupancy following escalating dosing regimens of (R)-(-)-O-desmethylvenlafaxine and racemic O-desmethylvenlafaxine

Frankle, W Gordon; Robertson, Brigitte; Maier, Gary; Paris, Jennifer; Asmonga, Deanna; May, Maureen; Himes, Michael L; Mason, N Scott; Mathis, Chester A; Narendran, Rajesh
SEP-227162 [R(-)-O-desmethylvenlafaxine] is an enantiomer of the venlafaxine metabolite O-desmethylvenlafaxine (ODV, Pristiq™, Wyeth). This study compared the serotonin transporter (SERT) occupancy achieved by SEP-227162 and ODV, at daily doses of 25, 50, 100, and 150 mg using [11 C]DASB positron emission tomography (PET). Sixteen healthy male subjects participated in one of four dose groups (N = 4 per group) during which they were administered two doses of the study drug (SEP-227162 or ODV). For each study drug, total daily doses of 25, 50, 100, and150 mg were studied. Subjects underwent three PET scans with [11 C]DASB. A baseline, off-medication, scan was performed prior to dosing and a [11 C]DASB PET scan was performed after 72 hr at each dose level. [11 C]DASB binding potential (BPND ) was calculated using the simplified reference tissue method. SERT occupancy was calculated as the change in BPND (ΔBPND ) from baseline scan to the on-medication scan relative to the baseline BPND value. SEP-227162 and ODV significantly reduced regional distribution volumes and region BPND values in a dose-dependent manner. Across all doses ODV produced significantly greater SERT occupancy than SEP-227162 (ANOVA F = 21.8, df = 1,23, p < .001). The total daily dose required to provide 50% SERT occupancy was 24.8 mg for SEP-227162 and 14.4 mg for ODV. In vitro data suggests a ratio of 3.3:1 for binding at human SERT for SEP-227162 relative to ODV. Our study suggests a ratio of 1.7:1, highlighting the value of in vivo imaging in the drug development process.
PMID: 29216407
ISSN: 1098-2396
CID: 2899832

Brain translocator protein occupancy by ONO-2952 in healthy adults: A Phase 1 PET study using [11 C]PBR28

Frankle, William G; Narendran, Rajesh; Wood, Andrew T; Suto, Fumitaka; Himes, Michael L; Kobayashi, Michiyoshi; Ohno, Tomoya; Yamauchi, Akinori; Mitsui, Katsukuni; Duffy, Kevin; Mark, Bruce
ONO-2952, a novel antagonist of translocator protein 18 kDa (TSPO), binds with high affinity to TSPO in rat brain and human tumor cell line membrane preparations. This study used the TSPO-specific PET radioligand [11 C]PBR28 to confirm binding of ONO-2952 to brain TSPO in human subjects, and evaluate brain TSPO occupancy and its relationship with ONO-2952 plasma concentration. Sixteen healthy subjects received a single oral dose of 200, 60, 20, or 6 mg ONO-2952 (n=4 per dose). Two PET scans with [11 C]PBR28 were conducted
PMID: 28245513
ISSN: 1098-2396
CID: 2471262

Comment on Analyses and Conclusions of "Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [(11)C]PBR28 PET Brain Imaging Study"

Narendran, Raj; Frankle, W Gordon
PMID: 27133410
ISSN: 1535-7228
CID: 2154442

Cortical Dopamine Transmission as Measured with the [11C]FLB 457 - Amphetamine PET Imaging Paradigm Is Not Influenced by COMT Genotype

Narendran, Rajesh; Tumuluru, Divya; May, Maureen A; Chowdari, Kodavali V; Himes, Michael L; Fasenmyer, Kelli; Frankle, W Gordon; Nimgaonkar, Vishwajit L
Basic investigations link a Val158Met polymorphism (rs4680) in the catechol-O-methyltransferase (COMT) gene to not only its enzymatic activity, but also to its dopaminergic tone in the prefrontal cortex. Previous PET studies have documented the relationship between COMT Val158Met polymorphism and D1 and D2/3 receptor binding potential (BP), and interpreted them in terms of dopaminergic tone. The use of baseline dopamine D1 and D2/3 receptor binding potential (BPND) as a proxy for dopaminergic tone is problematic because they reflect both endogenous dopamine levels (a change in radiotracer's apparent affinity) and receptor density. In this analysis of 31 healthy controls genotyped for the Val158Met polymorphism (Val/Val, Val/Met, and Met/Met), we used amphetamine-induced displacement of [11C]FLB 457 as a direct measure of dopamine release. Our analysis failed to show a relationship between COMT genotype status and prefrontal cortical dopamine release. COMT genotype was also not predictive of baseline dopamine D2/3 receptor BPND.
PMCID:4913897
PMID: 27322568
ISSN: 1932-6203
CID: 2154432