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Open Access Publications from the University of California

Scholarly Works (7 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2013)

Positron emission tomography (PET) is a unique and powerful imaging technique that is used to visualize and quantify various biological processes in living subjects in health and disease. PET imaging can also provide biological information for the assessment of therapies. In this dissertation, we will cover three projects that utilize the quantitative capability of PET for studying two neurological disorders: Alzheimer's disease and brain tumors.

One of the goals in PET imaging is to produce an image volume that accurately describes the true distribution of the injected radioactivity. The correction factor that has the most significant impact on the quantitative aspects of a PET image is attenuation correction. Without it, the reconstructed images will give a distorted view of the true activity distribution. Head movement during a PET scan (especially a dynamic scan) can also lead to a loss in the information content contained in a PET image. This is especially true when scanning patients with dementia or movement disorders. The transmission scan, which is typically acquired at the start of a PET study, corrects for photon attenuation in each of the serial emission scans that are acquired afterwards.

In the first project of this dissertation, we developed a retrospective image-based movement correction (MC) method and evaluated its implementation on dynamic 18F-FDDNP PET images of cognitively intact control subjects and patients with Alzheimer's disease (AD), each with varying degrees of head movement. 18F-FDDNP is a PET probe that binds to beta-amyloid plaques and neurofibrillary tangles, the neuropathological hallmarks of AD. The MC method corrected for transmission-emission misalignments as well as for emission-emission misalignments that might have been present in the dynamic PET scan. The image quality, tracer kinetics, and diagnostic accuracy of the 18F-FDDNP PET images were significantly improved after applying the MC method.

In the second project of this dissertation, we investigated whether changes in 18F-FLT kinetic parameters, taken early after the start of therapy, could predict overall survival and progression-free survival in patients with recurrent malignant glioma undergoing treatment with bevacizumab (an angiogenesis inhibitor) and irinotecan (a chemotherapeutic agent). 18F-FLT is a radiotracer used in PET to measure cellular proliferation. We found that when a group of optimal kinetic parameter changes are incorporated into a linear discriminant function, one could accurately classify patients into their known survival groups. This method is advantageous because by reliably identifying short- and long-term survivors early during therapy, clinicians can discontinue ineffective treatment strategies and switch to more advanced treatment regimens that could improve patient outcome.

Our third project expanded on what we did in our second project in that we acquired longitudinal 18F-FDOPA PET scans in addition to 18F-FLT PET scans. We also tried to predict overall survival as a continuous outcome variable using multiple linear regression (as opposed to a dichotomous categorical variable with discriminant analysis from before). In brain tumors, 18F-FDOPA is used to image amino acid transport. We found that in patients with recurrent malignant glioma, kinetic information from 18F-FLT alone was more predictive than using information from 18F-FDOPA alone. Using both probes combined provided comparable results to using 18F-FLT alone, suggesting that a single tracer may provide sufficient information for predicting OS with reasonable accuracy.

The studies reported in this dissertation have demonstrated in three examples that the utility of kinetic quantification can significantly improve the value of PET for imaging biological functions in brain tissues in vivo. The developed methodologies in these examples are also expected to be useful in other quantitative brain PET imaging studies – for other applications or using other tracers.

  • 2 supplemental videos
Cover page: Brain Imaging with Positron Emission Tomography: Quantification and Biomedical Applications in Alzheimer's Disease and Brain Tumors
  • Article
  • Peer Reviewed
UCLA Previously Published Works (2010)
Subcortical white matter is known to be relatively unaffected by amyloid deposition in Alzheimer’s disease (AD). We investigated the use of subcortical white matter as a reference region to quantify [18F]FDDNP binding in the human brain. Dynamic [18F]FDDNP PET studies were performed on 7 control subjects and 12 AD patients. Population efflux rate constants ( $$ {k\prime_2} $$ ) from subcortical white matter (centrum semiovale) and cerebellar cortex were derived by a simplified reference tissue modeling approach incorporating physiological constraints. Regional distribution volume ratio (DVR) estimates were derived using Logan and simplified reference tissue approaches, with either subcortical white matter or cerebellum as reference input. Discriminant analysis with cross-validation was performed to classify control subjects and AD patients. The population estimates of $$ {k\prime_2} $$ in subcortical white matter did not differ significantly between control subjects and AD patients but the variability of individual estimates of $$ {k\prime_2} $$ determined in white matter was lower than that in cerebellum. Logan DVR showed dependence on the efflux rate constant in white matter. The DVR estimates in the frontal, parietal, posterior cingulate, and temporal cortices were significantly higher in the AD group (p<0.01). Incorporating all these regional DVR estimates as predictor variables in discriminant analysis yielded accurate classification of control subjects and AD patients with high sensitivity and specificity, and the results agreed well with those using the cerebellum as the reference region. Subcortical white matter can be used as a reference region for quantitative analysis of [18F]FDDNP with the Logan method which allows more accurate and less biased binding estimates, but a population efflux rate constant has to be determined a priori.
    Cover page: Quantitative analysis of [18F]FDDNP PET using subcortical white matter as reference region
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2014)
    Head movement during a dynamic brain PET/CT imaging results in mismatch between CT and dynamic PET images. It can cause artifacts in CT-based attenuation corrected PET images, thus affecting both the qualitative and quantitative aspects of the dynamic PET images and the derived parametric images. In this study, we developed an automated retrospective image-based movement correction (MC) procedure. The MC method first registered the CT image to each dynamic PET frames, then re-reconstructed the PET frames with CT-based attenuation correction, and finally re-aligned all the PET frames to the same position. We evaluated the MC method's performance on the Hoffman phantom and dynamic FDDNP and FDG PET/CT images of patients with neurodegenerative disease or with poor compliance. Dynamic FDDNP PET/CT images (65 min) were obtained from 12 patients and dynamic FDG PET/CT images (60 min) were obtained from 6 patients. Logan analysis with cerebellum as the reference region was used to generate regional distribution volume ratio (DVR) for FDDNP scan before and after MC. For FDG studies, the image derived input function was used to generate parametric image of FDG uptake constant (Ki) before and after MC. Phantom study showed high accuracy of registration between PET and CT and improved PET images after MC. In patient study, head movement was observed in all subjects, especially in late PET frames with an average displacement of 6.92 mm. The z-direction translation (average maximum = 5.32 mm) and x-axis rotation (average maximum = 5.19 degrees) occurred most frequently. Image artifacts were significantly diminished after MC. There were significant differences (P<0.05) in the FDDNP DVR and FDG Ki values in the parietal and temporal regions after MC. In conclusion, MC applied to dynamic brain FDDNP and FDG PET/CT scans could improve the qualitative and quantitative aspects of images of both tracers.
      Cover page: Automated Movement Correction for Dynamic PET/CT Images: Evaluation with Phantom and Patient Data
      • Article
      • Peer Reviewed
      UC Riverside Previously Published Works (2020)

      Background

      H2 15 O-positron emission tomography (PET) is considered the reference standard for absolute cerebral blood flow (CBF). However, this technique requires an arterial input function measured through continuous sampling of arterial blood, which is invasive and has limitations with tracer delay and dispersion.

      Purpose

      To demonstrate a new noninvasive method to quantify absolute CBF with a PET/MRI hybrid scanner. This blood-free approach, called PC-PET, takes the spatial CBF distribution from a static H2 15 O-PET scan, and scales it to the whole-brain average CBF value measured by simultaneous phase-contrast MRI.

      Study type

      Observational.

      Subjects

      Twelve healthy controls (HC) and 13 patients with Moyamoya disease (MM) as a model of chronic ischemic disease.

      Field strength/sequences

      3T/2D cardiac-gated phase-contrast MRI and H2 15 O-PET.

      Assessment

      PC-PET CBF values from whole brain (WB), gray matter (GM), and white matter (WM) in HCs were compared with literature values since 2000. CBF and cerebrovascular reactivity (CVR), which is defined as the percent CBF change between baseline and post-acetazolamide (vasodilator) scans, were measured by PC-PET in MM patients and HCs within cortical regions corresponding to major vascular territories. Statistical Tests: Linear, mixed effects models were created to compare CBF and CVR, respectively, between patients and controls, and between different degrees of stenosis.

      Results

      The mean CBF values in WB, GM, and WM in HC were 42 ± 7 ml/100 g/min, 50 ± 7 ml/100 g/min, and 23 ± 3 ml/100 g/min, respectively, which agree well with literature values. Compared with normal regions (57 ± 23%), patients showed significantly decreased CVR in areas with mild/moderate stenosis (47 ± 17%, P = 0.011) and in severe/occluded areas (40 ± 16%, P = 0.016). Data Conclusion: PC-PET identifies differences in cerebrovascular reactivity between healthy controls and cerebrovascular patients. PC-PET is suitable for CBF measurement when arterial blood sampling is not accessible, and warrants comparison to fully quantitative H2 15 O-PET in future studies.

      Level of evidence

      3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019. J. Magn. Reson. Imaging 2020;51:183-194.
        Cover page: Simultaneous phase‐contrast MRI and PET for noninvasive quantification of cerebral blood flow and reactivity in healthy subjects and patients with cerebrovascular disease
        • Article
        • Peer Reviewed
        Research Grants Program Office (RGPO) Funded Publications (2021)
        Human pluripotent stem cells (PSCs), which are composed of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), provide an opportunity to advance cardiac cell therapy-based clinical trials. However, an important hurdle that must be overcome is the risk of teratoma formation after cell transplantation due to the proliferative capacity of residual undifferentiated PSCs in differentiation batches. To tackle this problem, we propose the use of a minimal noncardiotoxic doxorubicin dose as a purifying agent to selectively target rapidly proliferating stem cells for cell death, which will provide a purer population of terminally differentiated cardiomyocytes before cell transplantation. In this study, we determined an appropriate in vitro doxorubicin dose that (a) eliminates residual undifferentiated stem cells before cell injection to prevent teratoma formation after cell transplantation and (b) does not cause cardiotoxicity in ESC-derived cardiomyocytes (CMs) as demonstrated through contractility analysis, electrophysiology, topoisomerase activity assay, and quantification of reactive oxygen species generation. This study establishes a potentially novel method for tumorigenic-free cell therapy studies aimed at clinical applications of cardiac cell transplantation.
          Cover page: Method for selective ablation of undifferentiated human pluripotent stem cell populations for cell-based therapies
          • Article
          • Peer Reviewed
          UC Riverside Previously Published Works (2019)
          Background and Purpose- Noninvasive imaging of brain perfusion has the potential to elucidate pathophysiological mechanisms underlying Moyamoya disease and enable clinical imaging of cerebral blood flow (CBF) to select revascularization therapies for patients. We used hybrid positron emission tomography (PET)/magnetic resonance imaging (MRI) technology to characterize the distribution of hypoperfusion in Moyamoya disease and its relationship to vessel stenosis severity, through comparisons with a normative perfusion database of healthy controls. Methods- To image CBF, we acquired [15O]-water PET as a reference and simultaneously acquired arterial spin labeling (ASL) MRI scans in 20 Moyamoya patients and 15 age-matched, healthy controls on a PET/MRI scanner. The ASL MRI scans included a standard single-delay ASL scan with postlabel delay of 2.0 s and a multidelay scan with 5 postlabel delays (0.7-3.0s) to estimate and account for arterial transit time in CBF quantification. The percent volume of hypoperfusion in patients (determined as the fifth percentile of CBF values in the healthy control database) was the outcome measure in a logistic regression model that included stenosis grade and location. Results- Logistic regression showed that anterior ( P<0.0001) and middle cerebral artery territory regions ( P=0.003) in Moyamoya patients were susceptible to hypoperfusion, whereas posterior regions were not. Cortical regions supplied by arteries with stenosis on MR angiography showed more hypoperfusion than normal arteries ( P=0.001), but the extent of hypoperfusion was not different between mild-moderate versus severe stenosis. Multidelay ASL did not perform differently from [15O]-water PET in detecting perfusion abnormalities, but standard ASL overestimated the extent of hypoperfusion in patients ( P=0.003). Conclusions- This simultaneous PET/MRI study supports the use of multidelay ASL MRI in clinical evaluation of Moyamoya disease in settings where nuclear medicine imaging is not available and application of a normative perfusion database to automatically identify abnormal CBF in patients.
            Cover page: Identifying Hypoperfusion in Moyamoya Disease With Arterial Spin Labeling and an [15O]-Water Positron Emission Tomography/Magnetic Resonance Imaging Normative Database
            • Article
            • Peer Reviewed
            UC Davis Previously Published Works (2022)
            Background The PET tracer (4S)-4-(3-[18F]fluoropropyl)-l-glutamate (18F-FSPG) targets the system xC- cotransporter, which is overexpressed in various tumors. Purpose To assess the role of 18F-FSPG PET/CT in intracranial malignancies. Materials and Methods Twenty-six patients (mean age, 54 years ± 12; 17 men; 48 total lesions) with primary brain tumors (n = 17) or brain metastases (n = 9) were enrolled in this prospective, single-center study (ClinicalTrials.gov identifier: NCT02370563) between November 2014 and March 2016. A 30-minute dynamic brain 18F-FSPG PET/CT scan and a static whole-body (WB) 18F-FSPG PET/CT scan at 60-75 minutes were acquired. Moreover, all participants underwent MRI, and four participants underwent fluorine 18 (18F) fluorodeoxyglucose (FDG) PET imaging. PET parameters and their relative changes were obtained for all lesions. Kinetic modeling was used to estimate the 18F-FSPG tumor rate constants using the dynamic and dynamic plus WB PET data. Imaging parameters were correlated to lesion outcomes, as determined with follow-up MRI and/or pathologic examination. The Mann-Whitney U test or Student t test was used for group mean comparisons. Receiver operating characteristic curve analysis was used for performance comparison of different decision measures. Results 18F-FSPG PET/CT helped identify all 48 brain lesions. The mean tumor-to-background ratio (TBR) on the whole-brain PET images at the WB time point was 26.6 ± 24.9 (range: 2.6-150.3). When 18F-FDG PET was performed, 18F-FSPG permitted visualization of non-18F-FDG-avid lesions or allowed better lesion differentiation from surrounding tissues. In participants with primary brain tumors, the predictive accuracy of the relative changes in influx rate constant Ki and maximum standardized uptake value to discriminate between poor and good lesion outcomes were 89% and 81%, respectively. There were significant differences in the 18F-FSPG uptake curves of lesions with good versus poor outcomes in the primary brain tumor group (P < .05) but not in the brain metastases group. Conclusion PET/CT imaging with (4S)-4-(3-[18F]fluoropropyl)-l-glutamate (18F-FSPG) helped detect primary brain tumors and brain metastases with a high tumor-to-background ratio. Relative changes in 18F-FSPG uptake with multi-time-point PET appear to be helpful in predicting lesion outcomes. Clinical trial registration no. NCT02370563 © RSNA, 2022 Online supplemental material is available for this article.
              Cover page: 18F-FSPG PET/CT Imaging of System xC- Transporter Activity in Patients with Primary and Metastatic Brain Tumors.
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