Kenneth Spicer

Effectiveness of prolonged fasting 18f-FDG PET-CT in the detection of cardiac sarcoidosis

BackgroundThe Japanese Ministry of Health and Welfare guidelines (JMHWG) are currently the standard used to diagnose cardiac sarcoidosis. JMHWG incorporate 67Gallium scintigraphy as a minor criterion, while fasting 18fluorine-2-fluro-2-deoxy-d-glucose (FDG) PET is not included. As there is no published data comparing the accuracy of prolonged fasting FDG PET-CT (PF-PET) and Gallium scintigraphy for detecting active cardiac sarcoidosis, we sought to compare these two modalities.Methods and ResultsWe retrospectively reviewed medical records and nuclear images of 76 patients with suspected cardiac sarcoid who had either PF-PET or Gallium scintigraphy between January 2004 and August 2008. Eleven patients were excluded due to inadequate fasting for PF-PET, incomplete records or diagnosis other than sarcoid. Cardiac catheterizations, electrocardiogram interpretations, echocardiography reports, pathology reports, therapeutic interventions, and follow-up findings were correlated to PF-PET and Gallium scintigraphy results. Nuclear images of all patients including controls were reviewed independently by two experienced nuclear physicians blinded to results. Using JMHWG as reference standard, sensitivity, specificity, and accuracy of PF-PET were 85%, 90%, and 86.7% and for Gallium scintigraphy were 15%, 80%, and 42.8%.ConclusionsRelative to Gallium scintigraphy, PF-PET appears to provide greater accuracy for detecting cardiac sarcoidosis. Our findings also highlight the importance of revising JMHWG to incorporate PF-PET and the importance of adequate prolonged fasting prior to FDG PET imaging.

Initial experience in the treatment of inherited mitochondrial disease with EPI-743.

Inherited mitochondrial respiratory chain disorders are progressive, life-threatening conditions for which there are limited supportive treatment options and no approved drugs. Because of this unmet medical need, as well as the implication of mitochondrial dysfunction as a contributor to more common age-related and neurodegenerative disorders, mitochondrial diseases represent an important therapeutic target. Thirteen children and one adult with genetically-confirmed mitochondrial disease (polymerase γ deficiency, n=4; Leigh syndrome, n=4; MELAS, n=3; mtDNA deletion syndrome, n=2; Friedreich ataxia, n=1) at risk for progressing to end-of-life care within 90 days were treated with EPI-743, a novel para-benzoquinone therapeutic, in a subject controlled, open-label study. Serial measures of safety and efficacy were obtained that included biochemical, neurological, quality-of-life, and brain redox assessments using technetium-99m-hexamethylpropyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) radionuclide imaging. Twelve patients treated with EPI-743 have survived; one polymerase γ deficiency patient died after developing pneumonia and one patient with Surf-1 deficiency died after completion of the protocol. Of the 12 survivors, 11 demonstrated clinical improvement, with 3 showing partial relapse, and 10 of the survivors also had an improvement in quality-of-life scores at the end of the 13-week emergency treatment protocol. HMPAO SPECT scans correlated with clinical response; increased regional and whole brain HMPAO uptake was noted in the clinical responders and the one subject who did not respond clinically had decreased regional and whole brain HMPAO uptake. EPI-743 has modified disease progression in >90% of patients in this open-label study as assessed by clinical, quality-of-life, and non-invasive brain imaging parameters. Data obtained herein suggest that EPI-743 may represent a new drug for the treatment of inherited mitochondrial respiratory chain disorders. Prospective controlled trials will be undertaken to substantiate these initial promising observations. Furthermore, HMPAO SPECT imaging may be a valuable tool for the detection of central nervous system redox defects and for monitoring response to treatments directed at modulating abnormal redox.

Prefrontal repetitive transcranial magnetic stimulation (rTMS) changes relative perfusion locally and remotely

Although transcranial magnetic stimulation has been used as a stand‐alone brain mapping tool, relatively few studies have attempted to couple TMS with functional brain imaging to understand the neurobiological effects of TMS. Technical problems of placing a TMS coil in a PET or MRI scanner have hampered previous efforts at imaging the immediate effects of TMS. Perfusion SPECT offers the advantage of tracer injection away from the camera, with later image development. We wondered if perfusion SPECT could be used to visualize brain changes during rTMS over the left prefrontal cortex—a region where rTMS has been shown to cause changes in mood or working memory. Eight healthy adult subjects were scanned with brain SPECT scintigraphy using 30 mCi (1110 MBq) Neurolite® (DuPont Pharma) on a triple‐headed Picker camera. Each subject had three scans: (1) baseline, (2) bolus tracer injection during seconds 10–20 of a train of 2 min of left prefrontal rTMS (10 Hz; 60% motor threshold (MT); 10 s on/off, 600 stimuli) (2MIN), and (3) exactly as in the 2MIN, but immediately after subjects had received 18 min of high frequency stimulation (20 Hz; 80% MT; 2 s on/28 s off, 1440+600=2040 total stimuli) (20MIN). Scans were linearly transformed into Talairach space using SPM96b and compared across conditions (p<0·05 for display). Contrary to our prestudy hypothesis, there was no relative increase at the coil site during the 2 min or the 20 min scan compared to baseline. In fact, at the 20 min comparison perfusion was relatively decreased in the right prefrontal cortex, bilateral anterior cingulate, and anterior temporal cortex. Also, relative perfusion was significantly increased in the orbitofrontal cortex (L>R) and hypothalamus at 20 min and at 2 min, with thalamic increases occurring at the 20 min scan compared to baseline. There was an apparent TMS dose effect with twice as many decreases at 20 min than 2 min. Directly comparing the 20 min to the 2 min scans demonstrated opposite hemisphere decreases and relative increases in the ipsilateral (left) hemisphere as a function of more TMS stimuli. Full interpretation of these results is hampered by incomplete knowledge of the effect of the relative amount of stimulation to rest during tracer uptake, pharmacokinetics of tracer uptake, and depth and intensity of the magnetic field. Nevertheless, coupling rTMS with split‐dose perfusion SPECT appears to be a promising method for understanding the brain changes associated with rTMS, and for directly visualizing neural circuits. We have demonstrated that prefrontal rTMS at high frequencies has both local and remote effects. These imaging results may help explain the cognitive and behavioural effects demonstrated in other prefrontal rTMS studies involving mood and working memory. Copyright

Vascular permeability in experimental spinal cord injury

Following spinal cord injury in rats there was a time-dependent change of vascular permeability as reflected by extravasation of 125I-labelled serum albumin. The change of vascular permeability correlated with tissue calcium and water accumulation suggesting that cord exposure to plasma calcium as a consequence of vascular injury may contribute to the progressive post-traumatic cord necrosis.

Autonomic Dysfunction and Gastroparesis in Cirrhosis

Background Patients with cirrhosis of the liver frequently present with many gastrointestinal complaints that are most likely due to abnormal gastrointestinal motility. The cause of these motility disorders in cirrhotics is unknown, however, underlying autonomic dysfunction may play a role. Objective To determine the association between autonomic dysfunction and delayed gastric emptying in cirrhotic patients. Methods We prospectively studied 20 patients with cirrhosis of the liver and postprandial abdominal pain, nausea, and vomiting and 10 asymptomatic patients with Hepatitis C (HCV) and no evidence of cirrhosis. All patients underwent 5 standardized cardiovascular tests to assess autonomic function. Each test was scored on a continuum from 0 (normal) to 5 (severe disease), thus producing a composite score of 0 to 5 for each subject. A composite score of greater than 1.5 was considered abnormal, with 5 representing severe autonomic involvement. A solid phase gastric emptying study was performed in each patient and a gastric retention of greater than 50% at 100 minutes was considered abnormal. Results The mean percent retention at 100 minutes was 70.7% in the cirrhotic group vs. 26.1% (P < 0.001) in the patients with HCV and no evidence of cirrhosis (controls). The composite autonomic score for the cirrhotic group was 3.4 vs. 1.2 (P < 0.001) in the controls. Conclusions Our results suggest that gastroparesis is common in patients with cirrhosis of the liver, and may account for gastrointestinal symptoms of postprandial abdominal pain, nausea, and vomiting. The presence of autonomic dysfunction correlates positively with underlying motility disorders, such as delayed gastric emptying.

Temporal profile of thromboxane-prostacyclin imbalance in experimental spinal cord injury

Thromboxane-prostacyclin imbalance may be an important determinant of platelet-vessel wall interactions that are vital in circulatory homeostasis. In experimental spinal cord injury, the vascular damage contributes substantially to the process of progressive secondary injury culminating in post-traumatic myelopathy. In this study, we found a time-dependent alteration of thromboxane-prostacyclin balance in the injured spinal cord with thromboxane dominance during the first 2 h: a time when maximal vascular injury is reflected by extravasation of 125I-labelled serum albumin. The thromboxane-prostacyclin imbalance reverted to favor prostacyclin by 18 h post-injury. This time-dependent alteration of thromboxane-prostacyclin balance should be considered in the planning of therapeutic attempts to prevent secondary injury by pharmacological modulation of platelet-vessel wall interaction.

Biodistribution and radioimmunopharmacokinetics of 131I-Ama monoclonal antibody in atherosclerotic rabbits

Monoclonal antibodies have been raised against Ama isolated from human and experimental atherosclerotic plaque. 131I-Ama-MoAb in the whole antibody form was injected into normal NZW rabbits and Watanabe hyperlipidemic rabbits. Biodistribution studies showed that atheromatous aortas had a significantly higher (5-7X) uptake of 131I-Ama-MoAb than that of normal aortas. However, 131I-Ama-MoAb was cleared very slowly from atherosclerotic rabbits. As a result, atheromas could not be identified by imaging because of the low target to non-target ratios.

Perfusion Network Shift during Seizures in Medial Temporal Lobe Epilepsy

Background Medial temporal lobe epilepsy (MTLE) is associated with limbic atrophy involving the hippocampus, peri-hippocampal and extra-temporal structures. While MTLE is related to static structural limbic compromise, it is unknown whether the limbic system undergoes dynamic regional perfusion network alterations during seizures. In this study, we aimed to investigate state specific (i.e. ictal versus interictal) perfusional limbic networks in patients with MTLE. Methods We studied clinical information and single photon emission computed tomography (SPECT) images obtained with intravenous infusion of the radioactive tracer Technetium- Tc 99 m Hexamethylpropyleneamine Oxime (Tc-99 m HMPAO) during ictal and interictal state confirmed by video-electroencephalography (VEEG) in 20 patients with unilateral MTLE (12 left and 8 right MTLE). Pair-wise voxel-based analyses were used to define global changes in tracer between states. Regional tracer uptake was calculated and state specific adjacency matrices were constructed based on regional correlation of uptake across subjects. Graph theoretical measures were applied to investigate global and regional state specific network reconfigurations. Results A significant increase in tracer uptake was observed during the ictal state in the medial temporal region, cerebellum, thalamus, insula and putamen. From network analyses, we observed a relative decreased correlation between the epileptogenic temporal region and remaining cortex during the interictal state, followed by a surge of cross-correlated perfusion in epileptogenic temporal-limbic structures during a seizure, corresponding to local network integration. Conclusions These results suggest that MTLE is associated with a state specific perfusion and possibly functional organization consisting of a surge of limbic cross-correlated tracer uptake during a seizure, with a relative disconnection of the epileptogenic temporal lobe in the interictal period. This pattern of state specific shift in metabolic networks in MTLE may improve the understanding of epileptogenesis and neuropsychological impairments associated with MTLE.

Brain uptake of Tc99m-HMPAO correlates with clinical response to the novel redox modulating agent EPI-743 in patients with mitochondrial disease.

While decreased ATP production and redox imbalance are central to mitochondrial disease pathogenesis, efforts to develop effective treatments have been hampered by the lack of imaging markers of oxidative stress. In this study we wished to determine if Tc99m-HMPAO, a SPECT imaging marker of cerebral blood flow and glutathione/protein thiol content, could be used to monitor the effect(s) of EPI-743, an oral redox modulating, para-benzoquinone based therapeutic for mitochondrial disease. We hypothesized that treatment changes in HMPAO uptake would be inversely proportional to changes in oxidative stress within the brain and directly correlate to clinical response to EPI-743 therapy. Twenty-two patients with mitochondrial disease were treated with EPI-743. Each underwent baseline and 3-month Tc99m-HMPAO SPECT scanning along with clinical/neurologic evaluations. Diseases treated were: Leigh syndrome (n=7), polymerase γ deficiency (n=5), MELAS (n=5), Friedreich ataxia (n=2), Kearns-Sayre syndrome, Pearson syndrome, and mtDNA depletion syndrome. Neuro-anatomic uptake analyses of HMPAO were performed with NeuroGam™ (Segami Corp.) statistical software and clinical response was assessed by the Newcastle Paediatric Mitochondrial Disease Scale or Newcastle Mitochondrial Disease Adult Scale depending on patient age. For all 22 patients there was a significant linear correlation between the change in cerebellar uptake of HMPAO and the improvement in Newcastle score (r=0.623, **p=0.00161). The MELAS subgroup showed a significant relationship of whole brain uptake (n=5, r=0.917, *p=0.028) to improvement in Newcastle score. We conclude that Tc99m-HMPAO SPECT scanning has promise as a general marker of the oxidative state of the brain and its response to redox modulating therapies. Further studies will be needed to confirm these findings in a more homogenous study population.

Magnetic resonance chemical shift microimaging of aging human skin in vivo: initial findings

Background/aims: In recent decades, interest has increased in the chronological and environmental factors governing the aging of skin. Various methods have been used for determining water and lipid content of human skin as a function of subject age. Magnetic resonance chemical shift imaging (CSI) offers a noninvasive technique for observing detailed distributions of water, lipids and other chemicals in the skin, and thus may be useful in dermatogerontology.