James P O'Neil

University of California, Berkeley, Berkeley, California, United States

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Publications (75)302.67 Total impact

  • No preview · Article · Jul 2015

  • No preview · Article · Jul 2015

  • No preview · Article · Jul 2015
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    ABSTRACT: Determining the relative contribution of amyloid plaques and neurofibrillary tangles to brain dysfunction in Alzheimer disease is critical for therapeutic approaches, but until recently could only be assessed at autopsy. We report a patient with posterior cortical atrophy (visual variant of Alzheimer disease) who was studied using the novel tau tracer [(18) F]AV-1451 in conjunction with [(11) C]Pittsburgh compound B (PIB; amyloid) and [(18) F]fluorodeoxyglucose (FDG) positron emission tomography. Whereas [(11) C]PIB bound throughout association neocortex, [(18) F]AV-1451 was selectively retained in posterior brain regions that were affected clinically and showed markedly reduced [(18) F]FDG uptake. This provides preliminary in vivo evidence that tau is more closely linked to hypometabolism and symptomatology than amyloid. Ann Neurol 2014. © 2014 American Neurological Association.
    Full-text · Article · Feb 2015 · Annals of Neurology
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    ABSTRACT: Beta-amyloid (Aβ) deposition is one of the hallmarks of Alzheimer's disease (AD). However, it is also present in some cognitively normal elderly adults and may represent a preclinical disease state. While AD patients exhibit disrupted functional connectivity (FC) both within and between resting-state networks, studies of preclinical cases have focused primarily on the default mode network (DMN). The extent to which Aβ-related effects occur outside of the DMN and between networks remains unclear. In the present study, we examine how within- and between-network FC are related to both global and regional Aβ deposition as measured by [(11)C]PIB-PET in 92 cognitively normal older people. We found that within-network FC changes occurred in multiple networks, including the DMN. Changes of between-network FC were also apparent, suggesting that regions maintaining connections to multiple networks may be particularly susceptible to Aβ-induced alterations. Cortical regions showing altered FC clustered in parietal and temporal cortex, areas known to be susceptible to AD pathology. These results likely represent a mix of local network disruption, compensatory reorganization, and impaired control network function. They indicate the presence of Aβ-related dysfunction of neural systems in cognitively normal people well before these areas become hypometabolic with the onset of cognitive decline. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    No preview · Article · Nov 2014 · Cerebral Cortex
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    ABSTRACT: Recruitment of extra neural resources may allow people to maintain normal cognition despite amyloid-β (Aβ) plaques. Previous fMRI studies have reported such hyperactivation, but it is unclear whether increases represent compensation or aberrant overexcitation. We found that older adults with Aβ deposition had reduced deactivations in task-negative regions, but increased activation in task-positive regions related to more detailed memory encoding. The association between higher activity and more detailed memories suggests that Aβ-related hyperactivation is compensatory.
    No preview · Article · Sep 2014 · Nature Neuroscience
  • Nicholas T Vandehey · James P O'Neil
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    ABSTRACT: We present a simple method for trapping [(11)C]CO2 gas and releasing it into a buffered solution using an ion-exchange cartridge. Sodium hydroxide cartridges captured >99% of [(11)C]CO2 following NaOH activation. A sodium bicarbonate solution eluted >99% of trapped radioactivity. Trapping [(11)C]CO2 directly in small volumes of several solutions was less effective than cartridge methods. The recommended methods allow for fast and simple production of highly concentrated carbon-11 containing aqueous solutions for use in filling phantoms, calibrating detectors, or (bio)geochemical experiments.
    No preview · Article · Mar 2014 · Applied radiation and isotopes: including data, instrumentation and methods for use in agriculture, industry and medicine
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    ABSTRACT: To evaluate the effect of amyloid imaging on clinical decision making. We conducted a retrospective analysis of 140 cognitively impaired patients (mean age 65.0 years, 46% primary β-amyloid (Aβ) diagnosis, mean Mini-Mental State Examination 22.3) who underwent amyloid (Pittsburgh compound B [PiB]) PET as part of observational research studies and were evaluated clinically before and after the scan. One hundred thirty-four concurrently underwent fluorodeoxyglucose (FDG)-PET. We assessed for changes between the pre- and post-PET clinical diagnosis (from Aβ to non-Aβ diagnosis or vice versa) and Alzheimer disease treatment plan. The association between PiB/FDG results and changes in management was evaluated using χ(2) and multivariate logistic regression. Postmortem diagnosis was available for 24 patients (17%). Concordance between scan results and baseline diagnosis was high (PiB 84%, FDG 82%). The primary diagnosis changed after PET in 13/140 patients (9%) overall but in 5/13 (38%) patients considered pre-PET diagnostic dilemmas. When examined independently, discordant PiB and discordant FDG were both associated with diagnostic change (unadjusted p < 0.0001). However, when examined together in a multivariate logistic regression, only discordant PiB remained significant (adjusted p = 0.00013). Changes in treatment were associated with discordant PiB in patients with non-Aβ diagnoses (adjusted p = 0.028), while FDG had no effect on therapy. Both PiB (96%) and FDG (91%) showed high agreement with autopsy diagnosis. PET had a moderate effect on clinical outcomes. Discordant PiB had a greater effect than discordant FDG, and influence on diagnosis was greater than on treatment. Prospective studies are needed to better characterize the clinical role of amyloid PET.
    Full-text · Article · Dec 2013 · Neurology
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    ABSTRACT: Myocardial metabolic and perfusion imaging is a vital tool for understanding the physiologic consequences of heart failure. We used PET imaging to examine the longitudinal kinetics of (18)F-FDG and 14(R,S)-(18)F-fluoro-6-thia-heptadecanoic acid ((18)F-FTHA) as analogs of glucose and fatty acid (FA) to quantify metabolic substrate shifts with the spontaneously hypertensive rat (SHR) as a model of left ventricular hypertrophy (LVH) and failure. Myocardial perfusion and left ventricular function were also investigated using a newly developed radiotracer (18)F-fluorodihydrorotenol ((18)F-FDHROL). Longitudinal dynamic electrocardiogram-gated microPET/CT studies were performed with 8 SHR and 8 normotensive Wistar-Kyoto (WKY) rats over their life cycle. We determined the myocardial influx rate constant for (18)F-FDG and (18)F-FTHA (Ki(FDG) and Ki(FTHA), respectively) and the wash-in rate constant for (18)F-FDHROL (K1(FDHROL)). (18)F-FDHROL data were also used to quantify left ventricular ejection fraction (LVEF) and end-diastolic volume (EDV). Blood samples were drawn to independently measure plasma concentrations of glucose, insulin, and free fatty acids (FFAs). Ki(FDG) and Ki(FTHA) were higher in SHRs than WKY rats (P < 3 × 10(-8) and 0.005, respectively) independent of age. A decrease in Ki(FDG) with age was evident when models were combined (P = 0.034). The SHR exhibited higher K1(FDHROL) (P < 5 × 10(-6)) than the control, with no age-dependent trends in either model (P = 0.058). Glucose plasma concentrations were lower in SHRs than controls (P < 6 × 10(-12)), with an age-dependent rise for WKY rats (P < 2 × 10(-5)). Insulin plasma concentrations were higher in SHRs than controls (P < 3 × 10(-3)), with an age-dependent decrease when models were combined (P = 0.046). FFA levels were similar between models (P = 0.374), but an increase with age was evident only in SHR (P < 7 × 10(-6)). The SHR exhibited alterations in myocardial substrate use at 8 mo characterized by increased glucose and FA utilizations. At 20 mo, the SHR had LVH characterized by decreased LVEF and increased EDV, while simultaneously sustaining higher glucose and similar FA utilizations (compared with WKY rats), which indicates maladaptation of energy substrates in the failing heart. Elevated K1(FDHROL) in the SHR may reflect elevated oxygen consumption and decreased capillary density in the hypertrophied heart. From our findings, metabolic changes appear to precede mechanical changes of LVH progression in the SHR model.
    Full-text · Article · Oct 2013 · Journal of Nuclear Medicine
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    ABSTRACT: Impulsivity, a risk factor for substance abuse disorders, is modulated by the Val158 variant of the catechol-O-methyltransferase (COMT) gene. Rodent studies have shown that opioids enhance impulsivity. Furthermore, alcohol consumption leads to endogenous opioid release in the cortex and nucleus accumbens (NAc), and this opioid release is correlated with greater positive hedonic effect. Using the selective mu opioid receptor radioligand [(11) C] carfentanil, we find that, following alcohol consumption, individuals with the COMT Val158 allele have greater opioid release in the right NAc but less release in medial orbital frontal cortex (OFC). These data suggest that genetic regulation of dopamine levels can affect alcohol consumption in part by modulating endogenous opioid release in specific brain regions implicated in reward, which in turn promotes impulsive choice.
    Full-text · Article · Oct 2013 · Clinical and Translational Science
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    ABSTRACT: Apolipoprotein E ε4 (ApoE4) has been associated with an increased risk of Alzheimer's disease (AD), amyloid deposition and hypometabolism. ApoE4 is less prevalent in non-amnestic AD variants suggesting a direct effect on the clinical phenotype. However, the impact of ApoE4 on amyloid burden and glucose metabolism across different clinical AD syndromes is not well understood. We aimed to assess the relationship between amyloid deposition, glucose metabolism and ApoE4 genotype in a clinically heterogeneous population of AD patients. 52 patients with probable AD (National Institute on Aging-Alzheimer's Association) underwent [(11)C]Pittsburgh compound B (PIB) and [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) scans. All patients had positive PIB-PET scans. 23 were ApoE4 positive (ApoE4+) (14 heterozygous and 9 homozygous) and 29 were ApoE4 negative (ApoE4-). Groups consisted of language-variant AD, visual-variant AD and AD patients with amnestic and dysexecutive deficits. 52 healthy controls were included for comparison. FDG and PIB uptake was compared between groups on a voxel-wise basis and in regions of interest. While PIB patterns were diffuse in both patient groups, ApoE4- patients showed higher PIB uptake than ApoE4+ patients across the cortex. Higher PIB uptake in ApoE4- patients was particularly significant in right lateral frontotemporal regions. In contrast, similar patterns of hypometabolism relative to controls were found in both patient groups, mainly involving lateral temporoparietal cortex, precuneus, posterior cingulate cortex and middle frontal gyrus. Comparing patient groups, ApoE4+ subjects showed greater hypometabolism in bilateral medial temporal and right lateral temporal regions, and ApoE4- patients showed greater hypometabolism in cortical areas, including supplementary motor cortex and superior frontal gyrus. ApoE4+ AD patients showed lower global amyloid burden and greater medial temporal hypometabolism compared with matched ApoE4- patients. These findings suggest that ApoE4 may increase susceptibility to molecular pathology and modulate the anatomic pattern of neurodegeneration in AD.
    No preview · Article · Aug 2013 · Journal of neurology, neurosurgery, and psychiatry
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    ABSTRACT: The performance of a SPECT imaging system for imaging vertically oriented glass columns (10 cm diameter x 30 cm long) has been evaluated in terms of spatial resolution, image uniformity, and linearity. This imaging system was developed to support research in environmental geosciences by determining flow patterns in heterogeneous porous media (e.g., sediment) through simultaneous monitoring of sediment chemistry and flow parameters. Using a Derenzo-like hot-rod phantom, rods down to 7.9 mm diameter were resolved. Flood images had an integral uniformity of 8.5% and differential uniformity of 6.2% in the center of the field of view. The ratio of total detected counts to the mean image reconstructed value was within 2% of linear over a range of greater than two orders of magnitude of counts.
    No preview · Article · Apr 2013 · IEEE Transactions on Nuclear Science
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    ABSTRACT: ABSTRACT The fields of nanotechnology and medicine have merged in the development of new imaging and drug delivery agents based on nanoparticle platforms. As one example, a mutant of bacteriophage MS2 can be differentially modified on the exterior and interior surfaces for the concurrent display of targeting functionalities and payloads, respectively. In order to realize their potential for use in in vivo applications, the biodistribution and circulation properties of this class of agents must first be investigated. A means of modulating and potentially improving the characteristics of nanoparticle agents is the appendage of PEG chains. Both MS2 and MS2-PEG capsids possessing interior DOTA chelators were labeled with 64Cu and injected intravenously into mice possessing tumor xenografts. Dynamic imaging of the agents was performed using PET-CT on a single animal per sample, and the biodistribution at the terminal time-point (24 h) was assessed by gamma counting of the organs ex vivo for 3 animals per agent. Compared to other viral capsids of similar size, the MS2 agents showed longer circulation times. Both MS2 and MS2-PEG bacteriophage behaved similarly, although the latter agent showed significantly less uptake in the spleen. This effect may be attributed to the ability of the PEG chains to mask the capsid charge. Although the tumor uptake of the agents may result from the enhanced permeation and retention (EPR) effect, selective tumor imaging may be acheived in the future by using exterior targeting groups.
    No preview · Article · Dec 2012 · Molecular Pharmaceutics
  • M. Janabi · B. C. Childs · N. T. Vandehey · J. P. O'Neil
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    ABSTRACT: In an effort to more quickly evaluate the conditioning of our 18F-fluorine target and determine the amount of F2 that is released with each unload, a simple spectrophotometer was fabricated that aids in quantifying the I2 produced as a result of bubbling F2 gas into a solution of potassium iodide. A narrow range LED (470 +/- 10 nm), combined with a wide range photodiode (320-1100 nm) were used to construct the simple spectrophotometer device. We were able to use this device to quantitate the amount of F2 released and obtained a good correlation (R2>0.991) with the values obtained by the ``traditional'' titration method.
    No preview · Article · Dec 2012
  • N. T. Vandehey · J. P. O'Neil
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    ABSTRACT: This paper describes the modifications made to a BioRad EM-1 UV detector for use in a radioactive material handling hot cell. A 5m cable has been built to allow the control unit to remain outside of the hot cell while the optics unit resides inside the hot cell. A USB data acquisition and control device has also been added to the control unit, allowing for PC control of the instrument and reading UV signals without the need to choose a pre-determined absorbance range, maximizing the dynamic range of measured absorbance.
    No preview · Article · Dec 2012
  • Linh C Dang · James P O'Neil · William J Jagust
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    ABSTRACT: Claims of gene-behavior associations are complex and sometimes difficult to replicate because these relationships involve many downstream endogenous and environmental processes that mediate genetic effects. Knowing these mediating processes is critical to understanding the links between genes and behavior and how these factors differ between people. We identified and characterized the effects of a gene on neurochemistry and neural networks to elucidate the mechanism, at the systems level, whereby genes influence cognition. Catechol-O-methyltransferase (COMT) degrades dopamine in the prefrontal cortex (PFC) and is polymorphic with alleles differing in enzymatic activity. We found that COMT genotype determined dopamine synthesis, such that individuals with greater COMT activity synthesized more dopamine. Dopamine synthesis in the midbrain and ventral striatum affected functional connectivity in the default mode network, likely through the mesocorticolimbic pathway, in an inverted-U pattern with greater functional connectivity in medial PFC associated with intermediate levels of COMT activity and dopamine. Greater functional connectivity correlated with greater deactivation during performance of a set-shifting task that engaged the PFC. Greater deactivation was in turn associated with better performance. The integration of these results yields a model whereby COMT affects prefrontal function by a mechanism involving dopaminergic modulation of the default mode network. The model features the well-known inverted-U function between dopamine and performance and supports the hypothesis that dopamine and the default mode network shift attentional resources to influence prefrontal cognition.
    No preview · Article · Nov 2012 · NeuroImage
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    ABSTRACT: We demonstrate the utility of nuclear medical imaging technologies and a readily available radiotracer, [99mTc]TcO4-, for the non-invasive monitoring of Fe(II) production in acetate-stimulated sediments from Old Rifle, CO, USA. Microcosms consisting of sediment in artificial groundwater media amended with acetate were probed by repeated injection of radiotracer over three weeks. Gamma camera imaging was used to non-invasively quantify the rate and extent of [99mTc]TcO4- partitioning from solution to sediment. Aqueous Fe(II) and sediment-associated Fe(II) were also measured and correlated with the observed tracer behavior. For each injection of tracer, curves of 99mTc concentration in solution vs. time were fitted to an analytic function that accounts for both the observed rate of sedimentation as well as the rate of 99mTc association with the sediment. The rate and extent of 99mTc association with the biostimulated sediment correlated well with the production of Fe(II) and a mechanism of [99mTc]TcO4- reduction via reaction with surface bound Fe(II) to form an immobile Tc(IV) species was inferred. After three weeks of bioreduction, a subset of microcosms was aerated in order to reoxidize the Fe(II) to Fe(III), which also destroyed the affinity of the [99mTc]TcO4- for the sediments. However, within 3 days post oxidation, the rate of Tc(VII) reduction was faster than immediately before oxidation implying a rapid return to more extensive bioreduction. Furthermore, aeration soon after a tracer injection showed that sediment-bound Tc(IV) is rapidly resolubilized to Tc(VII). In contrast to the 99mTcO4-, a second commercially available tracer, 99mTc-DTPA (diethylenetriaminepentaacetic acid), had minimal association with sediment in both controls and biostimulated sediments. These experiments show the promise of [99mTc]TcO4- and 99mTc-DTPA as non-invasive imaging probes for a redox sensitive radiotracer and a conservative flow tracer, respectively.
    No preview · Article · Oct 2012 · Environmental Science & Technology
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    Linh C Dang · James P O'Neil · William J Jagust
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    ABSTRACT: Attentional processing has been associated with the dorsal attention, default mode, and frontoparietal control networks. The dorsal attention network is involved in externally focused attention whereas the default mode network is involved in internally directed attention. The frontoparietal control network has been proposed to mediate the transition between external and internal attention by coupling its activity to either the dorsal attention network or the default mode network, depending on the attentional demand. Dopamine is hypothesized to modulate attention and has been linked to the integrity of these three attention-related networks. We used PET with 6-[(18)F]fluoro-L-m-tyrosine to quantify dopamine synthesis capacity in vivo and fMRI to acquire stimulus-independent brain activity in cognitively healthy human subjects. We found that in the resting state where internal cognition dominates, dopamine enhances the coupling between the frontoparietal control network and the default mode network while reducing the coupling between the frontoparietal control network and the dorsal attention network. These results add a neurochemical perspective to the role of network interaction in modulating attention.
    Full-text · Article · Jul 2012 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: Cognitive flexibility or the ability to change behavior in response to external cues is conceptualized as two processes: one for shifting between perceptual features of objects and another for shifting between the abstract rules governing the selection of these objects. Object and rule shifts are believed to engage distinct anatomical structures and functional processes. Dopamine activity has been associated with cognitive flexibility, but patients with dopaminergic deficits are not impaired on all tasks assessing cognitive flexibility, suggesting that dopamine may have different roles in the shifting of objects and rules. The goals of this study were to identify brain regions supporting object and rule shifts and to examine the role of dopamine in modulating these two forms of cognitive flexibility. Sixteen young, healthy volunteers underwent fMRI while performing a set-shift task designed to differentiate shifting between object features from shifting between abstract task rules. Participants also underwent PET with 6-[¹⁸F]-fluoro-l-m-tyrosine (FMT), a radiotracer measuring dopamine synthesis capacity. Shifts of abstract rules were not associated with activation in any brain region, and FMT uptake did not correlate with rule shift performance. Shifting between object features deactivated the medial PFC and the posterior cingulate and activated the lateral PFC, posterior parietal areas, and the striatum. FMT signal in the striatum correlated negatively with object shift performance and deactivation in the medial PFC, a component of the default mode network, suggesting that dopamine influences object shifts via modulation of activity in the default mode network.
    Full-text · Article · May 2012 · Journal of Cognitive Neuroscience
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    ABSTRACT: OBJECTIVE: To assess the association between lifestyle practices (cognitive and physical activity) and β-amyloid deposition, measured with positron emission tomography using carbon 11-labeled Pittsburgh Compound B ([(11)C]PiB), in healthy older individuals. DESIGN: Cross-sectional clinical study. SETTING: Berkeley, California. PARTICIPANTS: Volunteer sample of 65 healthy older individuals (mean age, 76.1 years), 10 patients with Alzheimer disease (AD) (mean age, 74.8 years), and 11 young controls (mean age, 24.5 years) were studied from October 31, 2005, to February 22, 2011. MAIN OUTCOME MEASURES: Cortical [(11)C]PiB average (frontal, parietal, lateral temporal, and cingulate regions) and retrospective, self-report scales assessing participation in cognitive activities (eg, reading, writing, and playing games) and physical exercise. RESULTS: Greater participation in cognitively stimulating activities across the lifespan, but particularly in early and middle life, was associated with reduced [(11)C]PiB uptake (P < .001, accounting for age, sex, and years of education). Older participants in the highest cognitive activity tertile had [(11)C]PiB uptake comparable to young controls, whereas those in the lowest cognitive activity tertile had [(11)C]PiB uptake comparable to patients with AD. Although greater cognitive activity was associated with greater physical exercise, exercise was not associated with [(11)C]PiB uptake. CONCLUSIONS: Individuals with greater early- and middle- life cognitive activity had lower [(11)C]PiB uptake. The tendency to participate in cognitively stimulating activities is likely related to engagement in a variety of lifestyle practices that have been implicated in other studies showing reduced risk of AD-related pathology. We report a direct association between cognitive activity and [(11)C]PiB uptake, suggesting that lifestyle factors found in individuals with high cognitive engagement may prevent or slow deposition of β-amyloid, perhaps influencing the onset and progression of AD.
    No preview · Article · Jan 2012 · Archives of neurology

Publication Stats

2k Citations
302.67 Total Impact Points


  • 1997-2015
    • University of California, Berkeley
      • Lawrence Berkeley Laboratory
      Berkeley, California, United States
  • 2000-2014
    • Lawrence Berkeley National Laboratory
      • • Life Sciences Division
      • • Center for Functional Imaging
      • • Nuclear Science Division
      Berkeley, CA, United States
  • 2010
    • University of California, San Francisco
      San Francisco, California, United States
  • 1996
    • Washington University in St. Louis
      • Department of Medicine
      San Luis, Missouri, United States
  • 1992-1994
    • University of Illinois, Urbana-Champaign
      • Department of Chemistry
      Urbana, IL, United States