Kevin Berger

Noninvasive Detection and Localization of Vulnerable Plaque and Arterial Thrombosis With Computed Tomography Angiography/Positron Emission Tomography

Background— It has been shown that plaque uptake of fluorodeoxyglucose is proportional to macrophage density. We tested the hypothesis that arterial thrombosis occurs in areas with high fluorodeoxyglucose uptake and that computed tomography angiography (CTA) can detect thrombi in vessels. Methods and Results— Twenty New Zealand White rabbits were studied before and after atherosclerosis induction through de-endothelialization and a high-cholesterol diet; 14 were then thrombus triggered. CTA/positron emission tomography scans were performed before cholesterol diet, at the middle diet feeding, at the end of diet feeding, and after triggering. Serum inflammatory markers were measured. Maximal standardized uptake value was measured over the thoracic and upper and lower abdominal aortas and correlated with thrombosis and macrophage density on sections from the same sites. Aortic diameters averaged 2.84±1.16 mm. The sensitivity, specificity, and accuracy of CTA for detecting thrombi were 92%, 89%, and 90%, respectively. Plasminogen activator inhibitor-1 and C-reactive protein levels increased with atherosclerosis and thrombosis triggering. Maximal standardized uptake value at baseline was 0.62±0.13, 0.96±0.33 at the middle of feeding, and 1.06±0.38 at the end of feeding. Segments that developed thrombosis had the highest maximal standardized uptake value of 1.32±0.69 (113% increase; P=0.002) and had a 129% increase in macrophage density compared with segments without thrombi (P=0.01). Conclusions— Fluorodeoxyglucose uptake was proportional to the duration of cholesterol feeding and peaked with plaque disruption and thrombosis. CTA was highly accurate in detecting thrombi. Our findings in this animal model of atherosclerotic plaques with high macrophage density showed that CTA/positron emission tomography can be used to identify and localize inflamed plaques and thrombosis. With the currently available technology and nuclear tracers, however, many challenges remain before clinical applications are possible.

Disruption of limbic white matter pathways in mild cognitive impairment and Alzheimer's disease: A DTI/FDG-PET Study†

Background: Alzheimers disease (AD) and mild cognitive impairment (MCI) affect the limbic system, causing medial temporal lobe (MTL) atrophy and posterior cingulate cortex (PCC) hypometabolism. Additionally, diffusion tensor imaging (DTI) studies have demonstrated that MCI and AD involve alterations in cerebral white matter (WM) integrity. Objectives: To test if (1) patients with MCI and AD exhibit decreases in the integrity of limbic WM pathways; (2) disconnection between PCC and MTL, manifested as disruption of the cingulum bundle, contributes to PCC hypometabolism during incipient AD. Methods: We measured fractional anisotropy (FA) and volume of the fornix and cingulum using DTI in 23 individuals with MCI, 21 with mild‐to‐moderate AD, and 16 normal control (NC) subjects. We also measured PCC metabolism using 18F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) in AD and MCI patients. Results: Fornix FA and volume were reduced in MCI and AD to a similar extent. Descending cingulum FA was reduced in AD while volume was reduced in MCI and even more so in AD. Both FA and volume of the fornix and descending cingulum reliably discriminated between NC and AD. Fornix FA and descending cingulum volume also reliably discriminated between NC and MCI. Only descending cingulum volume reliably discriminated between MCI and AD. In the combined MCI‐AD cohort, PCC metabolism directly correlated with both FA and volume of the descending cingulum. Conclusions: Disruption of limbic WM pathways is evident during both MCI and AD. Disconnection of the PCC from MTL at the cingulum bundle contributes to PCC hypometabolism during incipient AD. Hum Brain Mapp, 2012.

Asymmetry of Subinsular Anisotropy by in vivo Diffusion Tensor Imaging

The cortical regions specialized in speech–language exhibit a left–right asymmetry, e.g., a larger cortical size in the left auditory cortex and Wernickes area. The possibility of developmental asymmetry in axonal fibers interconnecting speech–language cortical areas can be investigated by in vivo diffusion tensor imaging. Fifteen right‐handed native English speakers showed a markedly significant asymmetry (P < 0. 0005) in the relative anisotropy of water diffusion in the subinsular white matter, greater on the left. Additionally, the first principal diffusivity was greater and the second and third principal diffusivities were smaller on the left than right side. These results suggest the subinsular axonal structures developed differently between the left and right sides. A possible association between the hemispheric specialization in language and speech and the subinsular axonal fiber development is discussed. Hum. Brain Mapp. 20:82–90, 2003.

Alzheimer's disease and amnestic mild cognitive impairment weaken connections within the default-mode network: a multi-modal imaging study.

We applied a multi-modal imaging approach to examine structural and functional alterations in the default-mode network (DMN) that are associated with Alzheimers disease (AD) and amnestic mild cognitive impairment (aMCI), a transitional phase between healthy cognitive aging and dementia. Subjects included 10 patients with probable AD, 11 patients with aMCI, and 12 age- and education-matched normal controls (NC). Whole-brain resting-state functional, diffusion-weighted, and volumetric magnetic resonance imaging (MRI) data as well as 18F-fluorodeoxyglucose-based positron emission tomography (FDG-PET) data were acquired. We carried out resting-state functional MRI-based functional connectivity and diffusion MRI-based structural connectivity analyses using isthmus of the cingulate cortex (ICC) and the subjacent white matter as the seeds. Whole-brain group and region of interest-based analyses demonstrated that AD weakens the structural and functional connections between ICC and other regions within the DMN, consistent with regional reduction of metabolic activity and atrophy within the DMN. A progressive weakening trend of these connections was also observed from NC to aMCI and then AD, although significant differences between aMCI and the other two groups were not found. Overall, based on both FDG-PET and MRI results, the DMN appears to serve as a window to understanding structural and functional brain changes associated with AD and aMCI.

Plaque Rupture and Thrombosis Are Reduced by Lowering Cholesterol Levels and Crystallization With Ezetimibe and Are Correlated With Fluorodeoxyglucose Positron Emission Tomography

Objective— This study evaluated effects of lipid lowering with ezetimibe on plaque burden and associated cholesterol crystallization and inflammation in a rabbit model of plaque disruption and thrombosis. Methods and Results— Atherosclerotic rabbits (Group I, n=10 without; Group II, n=12 with ezetimibe, 1 mg/kg per day) were pharmacologically triggered for plaque disruption. Fluorodeoxyglucose positron emission tomography, RAM 11 macrophage staining, and serum inflammatory markers detected arterial inflammation. Serum and aortic wall cholesterol levels were measured, and thrombus area was planimetered. Cholesterol crystal density on aortic surface was scored (0 to +3) by scanning electron microscopy. Serum and aortic wall cholesterol, plaque area, and thrombosis area were significantly lower in Group II versus Group I (83.4±106.4 versus 608±386 mg/dL, P=0.002; 3.12±1.40 versus 9.39±5.60 mg/g, P=0.003; 10.84±1.6 versus 17.48±1.8 mm2, P<0.001; and 0.05±0.15 versus 0.72±0.58 mm2, P=0.01, respectively). There were significant correlations between crystal density and plaque area (r=0.75, P<0.003) and between crystal density and RAM 11 (r=0.82, P<0.001). Scanning electron microscopy demonstrated that there were fewer crystals in Group II versus Group I (+1.2±0.61 versus +2.4±0.63, P<0.001) and less inflammation detected by fluorodeoxyglucose positron emission tomography and RAM 11 (P<0.004 and P<0.04, respectively). Conclusion— Lowering cholesterol levels with ezetimibe reduced plaque burden, crystallization, and inflammation, preventing plaque disruption and thrombosis.

ACR Appropriateness Criteria Sinonasal Disease

Imaging of sinonasal pathology may occur for assessment of rhinosinusitis or mass lesions. Rhinosinusitis is prevalent in up to 16% of the US population with annual economic burdens estimated at 22 billion dollars. Rhinosinusitis is characterized as acute or chronic based on symptom duration; if four or more episodes occur annually, the term recurrent acute rhinosinusitis (RARS) is used. In acute uncomplicated rhinosinusitis when inflammatory change remains in the paranasal sinuses and nasal cavity, imaging may not be required. Distinction between viral or bacterial rhinosinusitis is a clinical diagnosis, and imaging should be interpreted in conjunction with clinical and endoscopic findings. Sinus CT imaging is appropriate per clinical judgment in associated complications including headache, facial pain, swelling, orbital proptosis, or cranial nerve palsies. In maxillary sinusitis, teeth may require assessment because 20% may be odontogenic in origin. MRI may be complementary in aggressive infections with intraocular/intracranial complications, invasive fungal sinusitis, or sinonasal masses. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Automated cardiac motion compensation in PET/CT for accurate reconstruction of PET myocardial perfusion images.

Error-free reconstruction of PET data with a registered CT attenuation map is essential for accurate quantification and interpretation of cardiac perfusion. Misalignment of the CT and PET data can produce an erroneous attenuation map that projects lung attenuation parameters onto the heart wall, thereby underestimating the attenuation and creating artifactual areas of hypoperfusion that can be misinterpreted as myocardial ischemia or infarction. The major causes of misregistration between CT and PET images are the respiratory motion, cardiac motion and gross physical motion of the patient. The misalignment artifact problem is overcome with automated cardiac registration software that minimizes the alignment error between the two modalities. Results show that the automated registration process works equally well for any respiratory phase in which the CT scan is acquired. Further evaluation of this procedure on 50 patients demonstrates that the automated registration software consistently aligns the two modalities, eliminating artifactual hypoperfusion in reconstructed PET images due to PET/CT misregistration. With this registration software, only one CT scan is required for PET/CT imaging, which reduces the radiation dose required for CT-based attenuation correction and improves the clinical workflow for PET/CT.

Do brain activation changes persist in athletes with a history of multiple concussions who are asymptomatic

Primary objective: To evaluate brain activation patterns of asymptomatic athletes with a history of two or more concussions. Research design: A paired case-control design was used to evaluate brain activation patterns during cognitive performance in 14 athletes with a history of two or more concussions and 14 age- and sex-matched controls with no previous concussion. Methods and procedures: Percentage Blood-Oxygen-Level-Dependent (BOLD) change during an N-back working memory task was assessed in all participants. Performance on the Trail-Making Test Form A and B, Symbol-Digit Modalities Test and the Immediate Post-concussion Assessment and Cognitive Test (ImPACT) was also compared between groups. Main results: As expected, brain regions activated during the performance of the N-back were equivalent between groups. The groups performed similarly on the neurocognitive measures. The history of concussion group was less accurate than controls on the 1-, 2- and 3-back conditions of the N-back. Conclusions: Following the complete resolution of symptoms, a history of two or more concussions is not associated with changes in regional brain activation during the performance of working memory task. Compensatory brain activation may only persist during the typically brief time athletes experience symptoms following concussion.

ACR Appropriateness Criteria Head Trauma

Neuroimaging plays an important role in the management of head trauma. Several guidelines have been published for identifying which patients can avoid neuroimaging. Noncontrast head CT is the most appropriate initial examination in patients with minor or mild acute closed head injury who require neuroimaging as well as patients with moderate to severe acute closed head injury. In short-term follow-up neuroimaging of acute traumatic brain injury, CT and MRI may have complementary roles. In subacute to chronic traumatic brain injury, MRI is the most appropriate initial examination, though CT may have a complementary role in select circumstances. Advanced neuroimaging techniques are areas of active research but are not considered routine clinical practice at this time. In suspected intracranial vascular injury, CT angiography or venography or MR angiography or venography is the most appropriate imaging study. In suspected posttraumatic cerebrospinal fluid leak, high-resolution noncontrast skull base CT is the most appropriate initial imaging study to identify the source, with cisternography reserved for problem solving. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Evaluation of hypoxia in a feline model of head and neck cancer using 64Cu-ATSM positron emission tomography/computed tomography

BackgroundHuman and feline head and neck squamous cell carcinoma (HNSCC) share histology, certain molecular features, as well as locally aggressive and highly recurrent clinical behavior. In human HNSCC, the presence of significant hypoxia within these tumors is considered an important factor in the development of a more aggressive phenotype and poor response to therapy. We hypothesized that feline head and neck tumors, particularly HNSCC, would exhibit hypoxia and that 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) positron emission tomography/computed tomography (PET/CT) would permit detection of intratumoral hypoxia.Methods12 cats with measureable head and neck tumors were given 64Cu-ATSM and iodinated contrast for PET/CT scan. The presence or absence of hypoxia was also assessed using an intratumoral fluorescent life-time probe to quantitate pO2 and pimonidazole immunohistochemical staining in biopsy specimens. In two cats, intratumoral O2 and 64Cu-ATSM uptake was measured before and after treatment with anti-angiogenic agents to determine the effect of these agents on hypoxia.ResultsEleven of twelve feline tumors demonstrated significant 64Cu-ATSM uptake, regardless of malignant or benign etiology. The presence (and absence) of hypoxia was confirmed using the fluorescent O2 detection probe in nine tumors, and using pimonidazole staining in three tumors. Squamous cell carcinomas (HNSCC) demonstrated the highest degree of hypoxia, with Tmax/M ratios ranging from 4.3 to 21.8. Additional non-neoplastic tissues exhibited 64Cu-ATSM uptake suggestive of hypoxia including reactive draining lymph nodes, non-malignant thyroid pathology, a tooth root abscess, and otitis media. In two cats with HNSCC that received anti-vascular agents, the pattern of 64Cu-ATSM uptake was altered after treatment, demonstrating the potential of the feline model to study the modulation of tumor oxygenation.ConclusionFeline HNSCC serves as a clinically relevant model for the investigation of intratumoral hypoxia including its measurement, modulation and targeting.