[11 C]arachidonic acid incorporation measurement in human brain: Optimization for clinical use.

Arachidonic acid (AA) is involved in signal transduction, neuroinflammation, and production of eicosanoid metabolites. The AA brain incorporation coefficient (K*) is quantifiable in vivo using [11 C]AA positron emission tomography, although repeatability remains undetermined. We evaluated K* estimates obtained with population-based metabolite correction (PBMC) and image-derived input function (IDIF) in comparison to arterial blood-based estimates, and compared repeatability. Eleven healthy volunteers underwent a [11 C]AA scan; five repeated the scan 6 weeks later, simulating a pre- and post-treatment study design. For all scans, arterial blood was sampled to measure [11 C]AA plasma radioactivity. Plasma [11 C]AA parent fraction was measured in 5 scans. K* was quantified using both blood data and IDIF, corrected for [11 C]AA parent fraction using both PBMC (from published values) and individually measured values (when available). K* repeatability was calculated in the test-retest subset. K* estimates based on blood and individual metabolites were highly correlated with estimates using PBMC with arterial input function (r = 0.943) or IDIF (r = 0.918) in the subset with measured metabolites. In the total dataset, using PBMC, IDIF-based estimates were moderately correlated with arterial input function-based estimates (r = 0.712). PBMC and IDIF-based K* estimates were ∼6.4% to ∼11.9% higher, on average, than blood-based estimates. Average K* test-retest absolute percent difference values obtained using blood data or IDIF, assuming PBMC for both, were between 6.7% and 13.9%, comparable to other radiotracers. Our results support the possibility of simplified [11 C]AA data acquisition through eliminating arterial blood sampling and metabolite analysis, while retaining comparable repeatability and validity.

Reduction in Constitutively Activated Auditory Brainstem Microglia in Aging and Alzheimer's Disease.

Background: Alzheimer's disease (AD) pathology is considered to begin in the brainstem, and cerebral microglia are known to play a critical role in AD pathogenesis, yet little is known about brainstem microglia in AD. Translocator protein (TSPO) PET, sensitive to activated microglia, shows high signal in dorsal brainstem in humans, but the precise location and clinical correlates of this signal are unknown. Objective: To define age and AD associations of brainstem TSPO PET signal in humans. Methods: We applied new probabilistic maps of brainstem nuclei to quantify PET-measured TSPO expression over the whole brain including brainstem in 71 subjects (43 controls scanned using 11C-PK11195; 20 controls and 8 AD subjects scanned using 11C-PBR28). We focused on inferior colliculi (IC) because of visually-obvious high signal in this region, and potential relevance to auditory dysfunction in AD. We also assessed bilateral cortex. Results: TSPO expression was normally high in IC and other brainstem regions. IC TSPO was decreased with aging (p = 0.001) and in AD subjects versus controls (p = 0.004). In cortex, TSPO expression was increased with aging (p = 0.030) and AD (p = 0.033). Conclusions: Decreased IC TSPO expression with aging and AD-an opposite pattern than in cortex-highlights underappreciated regional heterogeneity in microglia phenotype, and implicates IC in a biological explanation for strong links between hearing loss and AD. Unlike in cerebrum, where TSPO expression is considered pathological, activated microglia in IC and other brainstem nuclei may play a beneficial, homeostatic role. Additional study of brainstem microglia in aging and AD is needed.

[1-11C]-Butanol Positron Emission Tomography reveals an impaired brain to nasal turbinates pathway in aging amyloid positive subjects.

BACKGROUND: Reduced clearance of cerebrospinal fluid (CSF) has been suggested as a pathological feature of Alzheimer's disease (AD). With extensive documentation in non-human mammals and contradictory human neuroimaging data it remains unknown whether the nasal mucosa is a CSF drainage site in humans. Here, we used dynamic PET with [1-11C]-Butanol, a highly permeable radiotracer with no appreciable brain binding, to test the hypothesis that tracer drainage from the nasal pathway reflects CSF drainage from brain. As a test of the hypothesis, we examined whether brain and nasal fluid drainage times were correlated and affected by brain amyloid. METHODS: 24 cognitively normal subjects (≥ 65 years) were dynamically PET imaged for 60 min. using [1-11C]-Butanol. Imaging with either [11C]-PiB or [18F]-FBB identified 8 amyloid PET positive (Aß+) and 16 Aß- subjects. MRI-determined regions of interest (ROI) included: the carotid artery, the lateral orbitofrontal (LOF) brain, the cribriform plate, and an All-turbinate region comprised of the superior, middle, and inferior turbinates. The bilateral temporalis muscle and jugular veins served as control regions. Regional time-activity were used to model tracer influx, egress, and AUC. RESULTS: LOF and All-turbinate 60 min AUC were positively associated, thus suggesting a connection between the brain and the nose. Further, the Aß+ subgroup demonstrated impaired tracer kinetics, marked by reduced tracer influx and slower egress. CONCLUSION: The data show that tracer kinetics for brain and nasal turbinates are related to each other and both reflect the amyloid status of the brain. As such, these data add to evidence that the nasal pathway is a potential CSF drainage site in humans. These data warrant further investigation of brain and nasal contributions to protein clearance in neurodegenerative disease.

The RSNA QIBA Profile for Amyloid PET as an Imaging Biomarker for Cerebral Amyloid Quantification.

A standardized approach to acquiring amyloid PET images increases their value as disease and drug response biomarkers. Most 18F PET amyloid brain scans often are assessed only visually (per regulatory labels), with a binary decision indicating the presence or absence of Alzheimer disease amyloid pathology. Minimizing technical variance allows precise, quantitative SUV ratios (SUVRs) for early detection of ß-amyloid plaques and allows the effectiveness of antiamyloid treatments to be assessed with serial studies. Methods: The Quantitative Imaging Biomarkers Alliance amyloid PET biomarker committee developed and validated a profile to characterize and reduce the variability of SUVRs, increasing statistical power for these assessments. Results: On achieving conformance, sites can justify a claim that brain amyloid burden reflected by the SUVR is measurable to a within-subject coefficient of variation of no more than 1.94% when the same radiopharmaceutical, scanner, acquisition, and analysis protocols are used. Conclusion: This overview explains the claim, requirements, barriers, and potential future developments of the profile to achieve precision in clinical and research amyloid PET imaging.

Decreased CSF clearance and increased brain amyloid in Alzheimer's disease.

BACKGROUND: In sporadic Alzheimer's disease (AD), brain amyloid-beta (Aß) deposition is believed to be a consequence of impaired Aß clearance, but this relationship is not well established in living humans. CSF clearance, a major feature of brain glymphatic clearance (BGC), has been shown to be abnormal in AD murine models. MRI phase contrast and intrathecally delivered contrast studies have reported reduced CSF flow in AD. Using PET and tau tracer 18F-THK5117, we previously reported that the ventricular CSF clearance of the PET tracer was reduced in AD and associated with elevated brain Aß levels. METHODS: In the present study, we use two PET tracers, 18F-THK5351 and 11C-PiB to estimate CSF clearance calculated from early dynamic PET frames in 9 normal controls and 15 AD participants. RESULTS: we observed that the ventricular CSF clearance measures were correlated (r = 0.66, p < 0.01), with reductions in AD of 18 and 27%, respectively. We also replicated a significant relationship between ventricular CSF clearance (18F-THK5351) and brain Aß load (r = - 0.64, n = 24, p < 0.01). With a larger sample size, we extended our observations to show that reduced CSF clearance is associated with reductions in cortical thickness and cognitive performance. CONCLUSIONS: Overall, the findings support the hypothesis that failed CSF clearance is a feature of AD that is related to Aß deposition and to the pathology of AD. Longitudinal studies are needed to determine whether failed CSF clearance is a predictor of progressive amyloidosis or its consequence.

Positron Emission Tomography reveals age-associated hypothalamic microglial activation in women.

In rodents, hypothalamic inflammation plays a critical role in aging and age-related diseases. Hypothalamic inflammation has not previously been assessed in vivo in humans. We used Positron Emission Tomography (PET) with a radiotracer sensitive to the translocator protein (TSPO) expressed by activated microglia, to assess correlations between age and regional brain TSPO in a group of healthy subjects (n = 43, 19 female, aged 23-78), focusing on hypothalamus. We found robust age-correlated TSPO expression in thalamus but not hypothalamus in the combined group of women and men. This pattern differs from what has been described in rodents. Prominent age-correlated TSPO expression in thalamus in humans, but in hypothalamus in rodents, could reflect evolutionary changes in size and function of thalamus versus hypothalamus, and may be relevant to the appropriateness of using rodents to model human aging. When examining TSPO PET results in women and men separately, we found that only women showed age-correlated hypothalamic TSPO expression. We suggest this novel result is relevant to understanding a stark sex difference in human aging: that only women undergo loss of fertility-menopause-at mid-life. Our finding of age-correlated hypothalamic inflammation in women could have implications for understanding and perhaps altering reproductive aging in women.

Quantitative imaging test approval and biomarker qualification: interrelated but distinct activities.

UNLABELLED: Quantitative imaging biomarkers could speed the development of new treatments for unmet medical needs and improve routine clinical care. However, it is not clear how the various regulatory and nonregulatory (eg, reimbursement) processes (often referred to as pathways) relate, nor is it clear which data need to be collected to support these different pathways most efficiently, given the time- and cost-intensive nature of doing so. The purpose of this article is to describe current thinking regarding these pathways emerging from diverse stakeholders interested and active in the definition, validation, and qualification of quantitative imaging biomarkers and to propose processes to facilitate the development and use of quantitative imaging biomarkers. A flexible framework is described that may be adapted for each imaging application, providing mechanisms that can be used to develop, assess, and evaluate relevant biomarkers. From this framework, processes can be mapped that would be applicable to both imaging product development and to quantitative imaging biomarker development aimed at increasing the effectiveness and availability of quantitative imaging. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100800/-/DC1.

Population-based input function for TSPO quantification and kinetic modeling with [11C]-DPA-713.

INTRODUCTION: Quantitative positron emission tomography (PET) studies of neurodegenerative diseases typically require the measurement of arterial input functions (AIF), an invasive and risky procedure. This study aims to assess the reproducibility of [11C]DPA-713 PET kinetic analysis using population-based input function (PBIF). The final goal is to possibly eliminate the need for AIF. MATERIALS AND METHODS: Eighteen subjects including six healthy volunteers (HV) and twelve Parkinson disease (PD) subjects from two [11C]-DPA-713 PET studies were included. Each subject underwent 90 min of dynamic PET imaging. Five healthy volunteers underwent a test-retest scan within the same day to assess the repeatability of the kinetic parameters. Kinetic modeling was carried out using the Logan total volume of distribution (VT) model. For each data set, kinetic analysis was performed using a patient-specific AIF (PSAIF, ground-truth standard) and then repeated using the PBIF. PBIF was generated using the leave-one-out method for each subject from the remaining 17 subjects and after normalizing the PSAIFs by 3 techniques: (a) Weightsubject×DoseInjected, (b) area under AIF curve (AUC), and (c) Weightsubject×AUC. The variability in the VT measured with PSAIF, in the test-retest study, was determined for selected brain regions (white matter, cerebellum, thalamus, caudate, putamen, pallidum, brainstem, hippocampus, and amygdala) using the Bland-Altman analysis and for each of the 3 normalization techniques. Similarly, for all subjects, the variabilities due to the use of PBIF were assessed. RESULTS: Bland-Altman analysis showed systematic bias between test and retest studies. The corresponding mean bias and 95% limits of agreement (LOA) for the studied brain regions were 30% and ± 70%. Comparing PBIF- and PSAIF-based VT estimate for all subjects and all brain regions, a significant difference between the results generated by the three normalization techniques existed for all brain structures except for the brainstem (P-value = 0.095). The mean % difference and 95% LOA is -10% and ±45% for Weightsubject×DoseInjected; +8% and ±50% for AUC; and +2% and ± 38% for Weightsubject×AUC. In all cases, normalizing by Weightsubject×AUC yielded the smallest % bias and variability (% bias = ±2%; LOA = ±38% for all brain regions). Estimating the reproducibility of PBIF-kinetics to PSAIF based on disease groups (HV/PD) and genotype (MAB/HAB), the average VT values for all regions obtained from PBIF is insignificantly higher than PSAIF (%difference = 4.53%, P-value = 0.73 for HAB; and %difference = 0.73%, P-value = 0.96 for MAB). PBIF also tends to overestimate the difference between PD and HV for HAB (% difference = 32.33% versus 13.28%) and underestimate it in MAB (%difference = 6.84% versus 20.92%). CONCLUSIONS: PSAIF kinetic results are reproducible with PBIF, with variability in VT within that obtained for the test-retest studies. Therefore, VT assessed using PBIF-based kinetic modeling is clinically feasible and can be an alternative to PSAIF.

Biodistribution and radiation dosimetry of a positron emission tomographic ligand, 18F-SP203, to image metabotropic glutamate subtype 5 receptors in humans.

PURPOSE: A new PET ligand, 3-fluoro-5-(2-(2-(18)F-(fluoromethyl)-thiazol-4-yl)ethynyl)benzonitrile ((18)F-SP203), is a positron emission tomographic radioligand selective for metabotropic glutamate subtype 5 receptors. The purposes of this study were to estimate the radiation-absorbed doses of (18)F-SP203 in humans and to determine from the distribution of radioactivity in bone structures with various proportions of bone and red marrow whether (18)F-SP203 undergoes defluorination. METHODS: Whole-body images were acquired for 5 h after injecting (18)F-SP203 in seven healthy humans. Urine was collected at various time points. Radiation-absorbed doses were estimated by the Medical Internal Radiation Dose scheme. RESULTS: After injecting (18)F-SP203, the two organs with highest radiation exposure were urinary bladder wall and gallbladder wall, consistent with both urinary and fecal excretion. In the skeleton, most of the radioactivity was in bone structures that contain red marrow and not in those without red marrow. Although the dose to red marrow (30.9 microSv/MBq) was unusually high, the effective dose (17.8 microSv/MBq) of (18)F-SP203 was typical of that of other (18)F radiotracers. CONCLUSION: (18)F-SP203 causes an effective dose in humans typical of several other (18)F radioligands and undergoes little defluorination.

Intrathecal 99mTc-DTPA imaging of molecular passage from lumbar cerebrospinal fluid to brain and periphery in humans.

INTRODUCTION: Cerebrospinal fluid (CSF) molecular exchange with brain interstitial fluid (ISF) and periphery is implicated in neurological disorders but needs better quantitative clinical assessment approaches. METHODS: Following intrathecal (ITH) dosing via lumbar puncture, Technetium-99 m (99mTc-) diethylenetriaminepentaacetic acid (DTPA) imaging was used to quantify neuraxial spread, CSF-brain molecular exchange, and CSF-peripheral clearance in 15 normal human volunteers. The effect of experimental convection manipulation on these processes was also assessed. RESULTS: Rostral cranial 99mTc-DTPA exposures were influenced by the volume of artificial CSF in the formulation. Signal translocation to the cranial cisterns and the brain parenchyma was observable by 3 hours. 99mTc-DTPA penetrated cortical ISF but showed lower signal in deeper structures. Urinary 99mTc-DTPA signal elimination was accelerated by higher formulation volumes and mechanical convection. DISCUSSION: Widely used for detecting CSF leaks, ITH 99mTc-DTPA imaging can also become a useful clinical biomarker for measuring molecular exchange physiology between the CSF, brain, and periphery.

Neurophysiological Biomarkers of Parkinson's Disease.

BACKGROUND: There is a need for reliable and robust Parkinson's disease biomarkers that reflect severity and are sensitive to disease modifying investigational therapeutics. OBJECTIVE: To demonstrate the utility of EEG as a reliable, quantitative biomarker with potential as a pharmacodynamic endpoint for use in clinical assessments of neuroprotective therapeutics for Parkison's disease. METHODS: A multi modal study was performed including aquisition of resting state EEG data and dopamine transporter PET imaging from Parkinson's disease patients off medication and compared against age-matched controls. RESULTS: Qualitative and test/retest analysis of the EEG data demonstrated the reliability of the methods. Source localization using low resolution brain electromagnetic tomography identified significant differences in Parkinson's patients versus control subjects in the anterior cingulate and temporal lobe, areas with established association to Parkinson's disease pathology. Changes in cortico-cortical and cortico-thalamic coupling were observed as excessive EEG beta coherence in Parkinson's disease patients, and correlated with UPDRS scores and dopamine transporter activity, supporting the potential for cortical EEG coherence to serve as a reliable measure of disease severity. Using machine learning approaches, an EEG discriminant function analysis classifier was identified that parallels the loss of dopamine synapses as measured by dopamine transporter PET. CONCLUSION: Our results support the utility of EEG in characterizing alterations in neurophysiological oscillatory activity associated with Parkinson's disease and highlight potential as a reliable method for monitoring disease progression and as a pharmacodynamic endpoint for Parkinson's disease modification therapy.

Statistical Considerations for Planning Clinical Trials with Quantitative Imaging Biomarkers.

As imaging technologies and treatment options continue to advance, imaging outcome measures are becoming increasingly utilized as the basis of making major decisions in new drug development and clinical practice. Quantitative imaging biomarkers (QIBs) are now commonly used for subject selection, response assessment, and safety monitoring. Although quantitative measurements can have many advantages compared with subjective, qualitative endpoints, it is important to recognize that QIBs are measured with error. This study uses Monte Carlo simulation to examine the impact of measurement error on a variety of clinical trial designs as well as to test proposed adjustments for measurement error. The focus is on some of the QIBs currently being studied by the Quantitative Imaging Biomarkers Alliance. The results show that the ability of QIBs to discriminate between health states and predict patient outcome is attenuated by measurement error; however, the known technical performance characteristics of QIBs can be used to adjust study sample size, control the misinterpretation rate of imaging findings, and establish statistically valid decision thresholds. We conclude that estimates of the precision and bias of a QIB are important for properly designing clinical trials and establishing the level of imaging standardization required.

18F-FPEB PET/CT Shows mGluR5 Upregulation in Parkinson's Disease.

BACKGROUND AND PURPOSE: Dopamine and glutamate reciprocally regulate each other in some of the neurocircuits affected by Parkinson's disease (PD). The objective of this pilot study was to explore relationships between these neurotransmitter systems with positron emission tomography. METHODS: The sample consisted of nine patients with PD and eight healthy volunteers (HVs). Dynamic images of the brain were acquired after the IV administration of ∼370 MBq (10 mCi) of [11 C]PE2i, a dopamine transporter (DaT) imaging agent, and ∼185 MBq (∼5 mCi) of [18 F]FPEB, a selective metabotropic glutamate receptor 5 (mGluR5) antagonist. Multiple volumes of interest were semiautomatically placed on contemporaneously acquired MRI scans. Nondisplaceable binding potentials (BPND ) were calculated with the Logan reference tissue model using cerebellar white matter as the reference region. RESULTS: The findings showed that average [18 F]FPEB BPND values were slightly more than 20% higher in PD than HVs in several mesocortical regions, including the bilateral putamen (P = .01), hippocampus (P = .02), and amygdala (P = .05). Average [11 C]PE2i BPND was significantly reduced by about half or more in patients with PD in the bilateral caudate (P < .001) and putamen (P < .001). CONCLUSIONS: mGluR5 seems upregulated in strategic dopaminergic brain regions adversely affected by PD. The findings seem to confirm that DaT tracers are better discriminatory biomarkers for diagnosing PD; however, mGluR5 tracers might deserve further exploration as potential biomarkers of response in clinical trials.

Noninvasive PK11195-PET Image Analysis Techniques Can Detect Abnormal Cerebral Microglial Activation in Parkinson's Disease.

BACKGROUND AND PURPOSE: Neuroinflammation has been implicated in the pathophysiology of Parkinson's disease (PD), which might be influenced by successful neuroprotective drugs. The uptake of [11 C](R)-PK11195 (PK) is often considered to be a proxy for neuroinflammation, and can be quantified using the Logan graphical method with an image-derived blood input function, or the Logan reference tissue model using automated reference region extraction. The purposes of this study were (1) to assess whether these noninvasive image analysis methods can discriminate between patients with PD and healthy volunteers (HVs), and (2) to establish the effect size that would be required to distinguish true drug-induced changes from system variance in longitudinal trials. METHODS: The sample consisted of 20 participants with PD and 19 HVs. Two independent teams analyzed the data to compare the volume of distribution calculated using image-derived input functions (IDIFs), and binding potentials calculated using the Logan reference region model. RESULTS: With all methods, the higher signal-to-background in patients resulted in lower variability and better repeatability than in controls. We were able to use noninvasive techniques showing significantly increased uptake of PK in multiple brain regions of participants with PD compared to HVs. CONCLUSION: Although not necessarily reflecting absolute values, these noninvasive image analysis methods can discriminate between PD patients and HVs. We see a difference of 24% in the substantia nigra between PD and HV with a repeatability coefficient of 13%, showing that it will be possible to estimate responses in longitudinal, within subject trials of novel neuroprotective drugs.

Human biodistribution and radiation dosimetry of the tachykinin NK1 antagonist radioligand [18F]SPA-RQ: comparison of thin-slice, bisected, and 2-dimensional planar image analysis.

UNLABELLED: (18)F-Labeled substance P antagonist-receptor quantifier ([(18)F]SPA-RQ) [2-fluoromethoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-[(2S,3S)-2-phenyl-piperidin-3-yl)amine] is a selective radioligand for in vivo quantification of tachykinin NK(1) receptors with PET. The aims of this study were to estimate the radiation safety profile and relative risks of [(18)F]SPA-RQ with 3 different methods of image analysis. METHODS: Whole-body PET images were acquired in 7 healthy subjects after injection of 192 +/- 7 MBq (5.2 +/- 0.2 mCi) [(18)F]SPA-RQ. Emission images were serially acquired at multiple time-points from 0 to 120 min and approximately 180-240 min after injection. Urine samples were collected after each imaging session and for 24 h after the last scan to measure excreted radioactivity. Horizontal tomographic images were compressed to varying degrees in the anteroposterior direction to create 3 datasets: thin-slice, bisected, and 2-dimensional (2D) planar images. Regions of interest were drawn around visually identifiable source organs to generate time-activity curves for each dataset. Residence times were determined from these curves, and doses to individual organs and the body as a whole were calculated using OLINDA/EXM 1.0. RESULTS: The lungs, upper large intestine wall, small intestine, urinary bladder wall, kidneys, and thyroid had the highest radiation-absorbed doses. Biexponential fitting of mean bladder and urine activity showed that about 41% of injected activity was excreted via urine. Assuming a 2.4-h urine voiding interval, the calculated effective doses from thin-slice, bisected, and 2D planar images were 29.5, 29.3, and 32.3 microSv/MBq (109, 108, and 120 mrem/mCi), respectively. CONCLUSION: Insofar as effective dose is an accurate measure of radiation risk, all 3 methods of analysis provided quite similar estimates of risk to human subjects. The radiation dose was moderate and would potentially allow subjects to receive multiple PET scans in a single year. Individual organ exposures varied among the 3 methods, especially for structures asymmetrically located in an anterior or posterior position. Bisected and 2D planar images almost always provided higher organ dose estimates than thin-slice images. Thus, either the bisected or 2D planar method of analysis appears acceptable for quantifying human radiation burden, at least for radioligands with a relatively broad distribution in the body and not concentrated in a small number of radiation sensitive organs.

Dopamine transporter binding in smokers and nonsmokers.

PURPOSE: Regional brain concentrations of dopamine transporters have been examined to elucidate the neurochemical substrates of neurologic and psychiatric conditions. Many of these conditions are associated with increased (or decreased) cigarette smoking prevalence; therefore, current smoking may confound the results of these investigations. This study determined whether healthy current smokers and nonsmokers exhibit differences in dopamine transporter (DAT) binding measured by Tc-99m TRODAT SPECT. MATERIALS AND METHODS: Tc-99m TRODAT SPECT brain scans were retrospectively evaluated in 46 nonsmokers and 8 current smokers, all of whom had been recruited and screened as healthy controls for previous imaging studies. The scans were acquired approximately 3 hours after the intravenous administration of 740 MBq (20 mCi) of Tc-99m TRODAT and were reconstructed with a simple bandpass filter. Regions of interest (ROIs) were placed manually on subregions of the right and left basal ganglia and distribution volume ratios (DVRs) were compared for the smoker and nonsmoker groups. RESULTS: There were significant decreases in DAT binding in current smokers compared with nonsmokers in the caudate nuclei bilaterally, the right anterior putamen and the left posterior putamen. CONCLUSION: Reduced DAT binding in ROIs relevant to movement disorders as well as other neuropsychiatric conditions may have important implications for evaluating scans in these patient populations.

Three-Dimensional Dosimetry for Radiation Safety Estimates from Intrathecal Administration.

Intrathecal administration is of growing interest for drug delivery, and its utility is being increasingly investigated through imaging. In this work, the 3-dimensional Voxel-Based Internal Dosimetry Application (VIDA) and 4D Extended Cardiac Torso Phantom (XCAT) were extended to provide radiation safety estimates specific to intrathecal administration. Methods: The 3-dimensional VIDA dosimetry application Monte Carlo simulation was run using a modified XCAT phantom with additional and edited cerebrospinal fluid (CSF) regions to produce voxel-level absorbed dose per unit cumulated activity maps for 9 selected source regions. Simulation validation was performed to compare absorbed dose estimates for common organs in a preexisting dosimetry tool (OLINDA/EXM). Dynamic planar imaging data were acquired in 6 healthy subjects using administered volumes of 5 or 15 mL (n = 3 each) of 185 MBq of 99mTc-diethylenetriaminepentaacetic acid. Absorbed dose was estimated for each subject using the intrathecal-specific dosimetry application. Results: Simulation results were within 6% of OLINDA estimates for common organs. Absorbed dose estimates were highest (0.3-0.8 mGy/MBq) in the lumbar CSF space. A whole-body effective dose estimate of 0.003 mSv/MBq was observed. An administered volume dependency was observed with a 15-mL volume, resulting in lower absorbed dose estimates for several intrathecal and nonintrathecal regions. Conclusion: The intrathecal-specific VIDA implementation enables tailored dosimetry estimation for regions most relevant in intrathecal administration. Absorbed doses are highly localized to CSF and spinal regions and should be taken into consideration when designing intrathecal imaging studies. A potentially interesting relationship was observed between absorbed dose and administered volume, which merits further investigation.

Reduction of PK11195 uptake observed in multiple sclerosis lesions after natalizumab initiation.

OBJECTIVE: The objective of this study is to longitudinally analyze the uptake of [11C]PK11195-PET in multiple sclerosis patients after 3 and 6 months of natalizumab treatment. METHODS: Eighteen MS patients, starting treatment with monocloncal anti-VLA-4, were enrolled in a longitudinal PK-PET study. PK uptake was quantified by volume of distribution (VT) calculation using image-derived input function at baseline, 3 and 6 months. Pharmacokinetic quantification was done using a segmented MRI, and selected areas included white matter, gadolinium enhancing lesions, non-enhancing lesions, cortical grey matter and thalamus. VTs of lesions were calculated in reference to each patient's white matter (VT ratio=VTr), to consider physiologic variability. RESULTS: Test-retest variability was stable for healthy control (HC). Quantification of PK uptake was completed in 18 patients, and baseline uptake was compared to 6-month uptake. After the start of natalizumab VTr significantly decreased in 13 individual enhancing lesions present within 5 patients (p=0.001). Moreover, VTr of the sum of non-enhancing lesions showed a moderate decrease (p=0.03). No longitudinal changes were detected in normal appearing white matter, the thalamus and cortical grey matter. CONCLUSION: A reduction in PK11195 uptake was observed in both enhancing and chronic lesions after the start of natalizumab. PK11195 PET can be used as tool to assess the longitudinal change in MS lesions.

Comparison of region-of-interest analysis and human observers in the diagnosis of Parkinson's disease using [99mTc]TRODAT-1 and SPECT.

This study determined the relative accuracy of diagnosis of Parkinson's disease (PD) using SPECT imaging data, comparing a semi-quantitative region-of-interest (ROI) approach and human observers. A set of patients with PD and normal healthy control subjects were studied using the dopamine transporter tracer [(99m)Tc]TRODAT-1 and SPECT. The sample comprised 81 patients (mean age +/- SD, 63.4 +/- 10.4 years; age range, 39.0-84.2 years) and 94 healthy controls (mean age +/- SD, 61.8 +/- 11.0 years; age range, 40.9-83.3 years). A standardized template containing six ROIs was transposed onto subregions of the brain, and the ratio of striatal to background ROI values was used as a semi-quantitative outcome measure. All images were used in a human observer study, with four experienced investigators. The data from the observer and ROI studies were analysed using a receiver operating characteristic (ROC) analysis, where the area under the ROC curve (AUC) indicated the diagnostic accuracy. ROI analysis and human observers gave similar diagnostic performance (mean observer AUC = 0.89, best ROI AUC = 0.90). This suggested that the human observers are visually acquiring similar information from the images that are contained in the semi-quantitative striatal uptake.

Yttrium-90 microsphere radioembolotherapy in a patient with spontaneously ruptured hepatocellular carcinoma.

Spontaneous rupture of hepatocellular carcinoma (HCC) is a potentially fatal presentation of the disease. Although many options for treatment exist, Yttrium-90 transcatheter arterial radioembolization has not previously been reported. We report a case of a 92-year-old woman found to have a ruptured HCC treated with radioembolization that showed no viable tumor and no extrahepatic disease at 2 years. While further studies are warranted, this patient's clinical course may suggest that radioembolization may be an additional palliative treatment option in these patients.