Extracellular acidosis differentiates pancreatitis and pancreatic cancer in mouse models using acidoCEST MRI.

Differentiating pancreatitis from pancreatic cancer would improve diagnostic specificity, and prognosticating pancreatitis that progresses to pancreatic cancer would also improve diagnoses of pancreas pathology. The high glycolytic metabolism of pancreatic cancer can cause tumor acidosis, and different levels of pancreatitis may also have different levels of acidosis, so that extracellular acidosis may be a diagnostic biomarker for these pathologies. AcidoCEST MRI can noninvasively measure extracellular pH (pHe) in the pancreas and pancreatic tissue. We used acidoCEST MRI to measure pHe in a KC model treated with caerulein, which causes pancreatitis followed by development of pancreatic cancer. We also evaluated the KC model treated with PBS, and wild-type mice treated with caerulein or PBS as controls. The caerulein-treated KC cohort had lower pHe of 6.85-6.92 before and during the first 48 h after initiating treatment, relative to a pHe of 6.92 to 7.05 pHe units for the other cohorts. The pHe of the caerulein-treated KC cohort decreased to 6.79 units at 5 weeks when pancreatic tumors were detected with anatomical MRI, and sustained a pHe of 6.75 units at the 8-week time point. Histopathology was used to evaluate and validate the presence of tumors and inflammation in each cohort. These results showed that acidoCEST MRI can differentiate pancreatic cancer from pancreatitis in this mouse model, but does not appear to differentiate pancreatitis that progresses to pancreatic cancer vs. pancreatitis that does not progress to cancer.

Molecular imaging detects impairment in the retrograde axonal transport mechanism after radiation-induced spinal cord injury.

PURPOSE: The goal of this study was to determine whether molecular imaging of retrograde axonal transport is a suitable technique to detect changes in the spinal cord in response to radiation injury. PROCEDURES: The lower thoracic spinal cords of adult female BALB/c mice were irradiated with single doses of 2, 10, or 80 Gy. An optical imaging method was used to observe the migration of the fluorescently labeled nontoxic C-fragment of tetanus toxin (TTc) from an injection site in the calf muscles to the spinal cord. Changes in migration patterns compared with baseline and controls allowed assessment of radiation-induced alterations in the retrograde neuronal axonal transport mechanism. Subsequently, tissues were harvested and histological examination of the spinal cords performed. RESULTS: Transport of TTc in the thoracic spinal cord was impaired in a dose-dependent manner. Transport was significantly decreased by 16 days in animals exposed to either 10 or 80 Gy, while animals exposed to 2 Gy were affected only minimally. Further, animals exposed to the highest dose also experienced significant weight loss by 9 days and developed posterior paralysis by 45 days. Marked histological changes including vacuolization, and white matter necrosis were observed in radiated cords after 30 days for mice exposed to 80 Gy. CONCLUSION: Radiation of the spinal cord induces dose-dependent changes in retrograde axonal transport, which can be monitored by molecular imaging. This approach suggests a novel diagnostic modality to assess nerve injury and monitor therapeutic interventions.

Impairment of retrograde neuronal transport in oxaliplatin-induced neuropathy demonstrated by molecular imaging.

BACKGROUND AND PURPOSE: The purpose of our study was to utilize a molecular imaging technology based on the retrograde axonal transport mechanism (neurography), to determine if oxaliplatin-induced neurotoxicity affects retrograde axonal transport in an animal model. MATERIALS AND METHODS: Mice (n = 8/group) were injected with a cumulative dose of 30 mg/kg oxaliplatin (sufficient to induce neurotoxicity) or dextrose control injections. Intramuscular injections of Tetanus Toxin C-fragment (TTc) labeled with Alexa 790 fluorescent dye were done (15 ug/20 uL) in the left calf muscles, and in vivo fluorescent imaging performed (0-60 min) at baseline, and then weekly for 5 weeks, followed by 2-weekly imaging out to 9 weeks. Tissues were harvested for immunohistochemical analysis. RESULTS: With sham treatment, TTc transport causes fluorescent signal intensity over the thoracic spine to increase from 0 to 60 minutes after injection. On average, fluorescence signal increased 722%+/-117% (Mean+/-SD) from 0 to 60 minutes. Oxaliplatin treated animals had comparable transport at baseline (787%+/-140%), but transport rapidly decreased through the course of the study, falling to 363%+/-88%, 269%+/-96%, 191%+/-58%, 121%+/-39%, 75%+/-21% with each successive week and stabilizing around 57% (+/-15%) at 7 weeks. Statistically significant divergence occurred at approximately 3 weeks (p≤0.05, linear mixed-effects regression model). Quantitative immuno-fluorescence histology with a constant cutoff threshold showed reduced TTc in the spinal cord at 7 weeks for treated animals versus controls (5.2 Arbitrary Units +/-0.52 vs 7.1 AU +/-1.38, p<0.0004, T-test). There was no significant difference in neural cell mass between the two groups as shown with NeuN staining (10.2+/-1.21 vs 10.5 AU +/-1.53, p>0.56, T-test). CONCLUSION: We show-for the first time to our knowledge-that neurographic in vivo molecular imaging can demonstrate imaging changes in a model of oxaliplatin-induced neuropathy. Impaired retrograde neural transport is suggested to be an important part of the pathophysiology of oxaliplatin-induced neuropathy.