Acute thalamic damage as a prognostic biomarker for post-traumatic epileptogenesis.

OBJECTIVE: To identify magnetic resonance imaging (MRI) biomarkers for post-traumatic epilepsy. METHODS: The EPITARGET (Targets and biomarkers for antiepileptogenesis, epitarget.eu) animal cohort completing T2 relaxation and diffusion tensor MRI follow-up and 1-month-long video-electroencephalography monitoring included 98 male Sprague-Dawley rats with traumatic brain injury and 18 controls. T2 imaging was performed on day (D) 2, D7, and D21 and diffusion tensor imaging (DTI) on D7 and D21 using a 7-Tesla Bruker PharmaScan MRI scanner. The mean and standard deviation (SD) of the T2 relaxation rate, multiple diffusivity measures, and diffusion anisotropy at each time-point within the ventroposterolateral and ventroposteromedial thalamus were used as predictor variables in multi-variable logistic regression models to distinguish rats with and without epilepsy. RESULTS: Twenty-nine percent (28/98) of the rats with traumatic brain injury (TBI) developed epilepsy. The best-performing logistic regression model utilized the D2 and D7 T2 relaxation time as well as the D7 diffusion tensor data. The model distinguished rats with and without epilepsy (Bonferroni-corrected p-value < .001) with a cross-validated concordance statistic of 0.74 (95% confidence interval [CI] 0.60-0.84). In a cross-validated classification test, the model exhibited 54% sensitivity and 91% specificity, enriching the epilepsy rate within the study population from the expected 29% to 71%. A model using the D2 T2 data only resulted in a 73% enriched epilepsy rate (regression p-value .007, cross-validated concordance 0.70, 95% CI 0.56-0.80, sensitivity 29%, specificity 96%). SIGNIFICANCE: An MRI parameter set reporting on acute and subacute neuropathologic changes common to experimental and human TBI presents a diagnostic biomarker for post-traumatic epileptogenesis. Significant enrichment of the study population was achieved even when using a single time-point measurement, producing an expected epilepsy rate of 73%.

Docetaxel chemotherapy response in PC3 prostate cancer mouse model detected by rotating frame relaxations and water diffusion.

MRI is a common method of prostate cancer diagnosis. Several MRI-derived markers, including the apparent diffusion coefficient (ADC) based on diffusion-weighted imaging, have been shown to provide values for prostate cancer detection and characterization. The hypothesis of the study was that docetaxel chemotherapy response could be picked up earlier with rotating frame relaxation times TRAFF2 and TRAFF4 than with the continuous wave T1ρ , adiabatic T1ρ , adiabatic T2ρ , T1 , T2 or water ADC. Human PC3 prostate cancer cells expressing a red fluorescent protein were implanted in 21 male mice. Docetaxel chemotherapy was given once a week starting 1 week after cell implantation for 10 randomly selected mice, while the rest served as a control group (n = 11). The MRI consisted of relaxation along a fictitious field (RAFF) in the second (RAFF2) and fourth (RAFF4) rotating frames, T1 and T2 , continuous wave T1ρ , adiabatic T1ρ and adiabatic T2ρ relaxation time measurements and water ADC. MRI was conducted at 7 T, once a week up to 4 weeks from cell implantation. The tumor volume was monitored using T2 -weighted MRI and optical imaging. The histology was evaluated after the last imaging time point. Significantly reduced RAFFn, T1ρ, T2ρ and conventional relaxation times 4 weeks after tumor implantation were observed in the treated tumors compared with the controls. The clearest short- and long-term responses were obtained with T1 , while no clear improvement in response to treatment was detected with novel methods compared with conventional methods or with RAFFn compared with all others. The tumor volume decreased after a two-week time point for the treated group and increased significantly in the control group, which was supported by increasing red fluorescent light emission in the control tumors. Decreased relaxation times were associated with successful chemotherapy outcomes. The results indicate altered relaxation mechanisms compared with higher dose chemotherapies previously published.

Nuclei-specific deposits of iron and calcium in the rat thalamus after status epilepticus revealed with quantitative susceptibility mapping (QSM).

PURPOSE: To investigate pathological changes in the rat brain after pilocarpine-induced status epilepticus using quantitative susceptibility mapping (QSM). MATERIALS AND METHODS: 3D multiecho gradient-echo (GRE) data were acquired from ex vivo brains of pilocarpine-injected and age-matched control rats at 11.7T. Maps of R2* and quantitative susceptibility were calculated from the acquired 3D GRE magnitude and phase data, respectively. QSM and R2* maps were compared with Perls' (iron) and Alizarin-red-S (calcium) stainings in the same brains to investigate the pathophysiological basis of susceptibility contrast. RESULTS: Bilaterally symmetric lesions were detected in reproducible thalamic regions of pilocarpine-treated rats, characterized by hyperintensity in R2* maps. In comparison, quantitative susceptibility maps demonstrated heterogeneous contrast within the lesions, with distinct hyperintense (paramagnetic) and hypointense (diamagnetic) areas. Comparison with histological assessment revealed localized deposits of iron- and calcium-positive granules in thalamic nuclei corresponding to paramagnetic and diamagnetic areas delineated in the susceptibility maps, respectively. Pronounced differences were observed in the lesions between background-corrected phase images and reconstructed susceptibility maps, indicating unreliable differentiation of iron and calcium deposits in phase maps. Multiple linear regression showed a significant association between susceptibility values and measured optical densities (ODs) of iron and calcium in the lesions (R2 = 0.42, P < 0.001), with a positive dependence on OD of iron and negative dependence on OD of calcium. CONCLUSION: QSM can detect and differentiate pathological iron and calcium deposits with high sensitivity and improved spatial accuracy compared to R2* or GRE phase images, rendering it a promising technique for diagnosing thalamic lesions after status epilepticus. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:554-564.

Magnetization transfer SWIFT MRI consistently detects histologically verified myelin loss in the thalamocortical pathway after a traumatic brain injury in rat.

Traumatic brain injury (TBI) is associated with various neurocognitive deficits, and rapid assessment of the damage is potentially important for the prevention and treatment of these deficits. Imaging assessment of mild or moderate damage outside the primary lesion area after TBI, however, remains challenging. Magnetization transfer (MT) has clearly been underutilized in imaging the damage caused by TBI. Here, we applied the MT ratio (MTR) using sweep imaging with Fourier transformation (SWIFT) to study microstructural tissue damage in the thalamocortical pathway outside the primary lesion in a lateral fluid percussion injury rat model of TBI, 5 months after injury. MTR was decreased in layers VIb-IV of the barrel cortex and related subcortical areas, mainly indicating demyelination, which was verified by histology. The largest MTR change in the cortex was in layer VIb (-8.2%, pFDR  = 0.01), and the largest MTR change in the subcortical areas was in the caudal-most portion of the internal capsule (-11.0%, pFDR  < 0.005). These areas exhibited the greatest demyelination and substantial cellularity attributed to gliosis. Correlation analysis of group-averaged results from the subcortical areas revealed an excellent correlation of MTR with myelin (r2  = 0.94, p < 0.001), but no correlation with increased cellularity as detected by Nissl staining. Thus, MTR using SWIFT can be a valuable tool for the assessment of subtle changes after TBI in both cortical and subcortical areas.

Glioma cell density in a rat gene therapy model gauged by water relaxation rate along a fictitious magnetic field.

Longitudinal and transverse rotating-frame relaxation time constants, T(1) (ρ) and T(2) (ρ) , have previously been successfully applied to detect gene therapy responses and acute stroke in animal models. Those experiments were performed with continuous-wave irradiation or with frequency-modulated pulses operating in an adiabatic regime. The technique called Relaxation Along a Fictitious Field (RAFF) is a recent extension of frequency-modulated rotating-frame relaxation methods. In RAFF, spin locking takes place along a fictitious magnetic field, and the decay rate is a function of both T(1ρ) and T(2ρ) processes. In this work, the time constant characterizing water relaxation with RAFF (T(RAFF) ) was evaluated for its utility as a marker of response to gene therapy in a rat glioma model. To investigate the sensitivity to early treatment response, we measured several rotating-frame and free-precession relaxation time constants and the water apparent diffusion coefficients, and these were compared with histological cell counts in 8 days of treated and control groups of animals. T(RAFF) was the only parameter exhibiting significant association with cell density in three different tumor regions (border, intermediate, and core tissues). These results indicate that T(RAFF) may provide a marker to identify tumors responding to treatment.

Low spin-lock field T1 relaxation in the rotating frame as a sensitive MR imaging marker for gene therapy treatment response in rat glioma.

PURPOSE: To prospectively assess the effectiveness of T1 relaxation in the rotating frame (T1 rho) dispersion and the low spin-lock radiofrequency field (B(1)) T1 rho magnetic resonance (MR) imaging relaxation time in noninvasive monitoring of gene therapy response in BT4C glioma in rats. MATERIALS AND METHODS: All animal studies were approved by the ethical committee of the National Laboratory Animal Center. Rats with BT4C gliomas (n=9) were treated with herpes simplex virus thymidine kinase gene therapy and were compared with untreated rats (n=5). Absolute T1 rho at a B(1) range of 2.0 x 10(-6) to 1.4 x 10(-4) T, T1, T2, and apparent diffusion constant were measured at 4.7 T during treatment. Statistical significance was tested by using repeated-measures analysis of variance. RESULTS: A significant (P<.05) lengthening of T1 rho was observed beginning on the 4th day of treatment, and T1 rho values increased to be approximately 80% higher than values observed before treatment. These changes preceded T1 and T2 changes and resembled those of water diffusion. The T1 rho was associated with a treatment-induced decrease in cell density; this was the only measured MR imaging property that provided significant (P<.05) Pearson correlation with cell density in the tumor border. T1 rho relaxation dispersion, however, did not offer additional benefits over those offered in one B(1) experiment in the early phase of treatment. CONCLUSION: T1 rho with low B(1) is an excellent MR imaging marker of early gene therapy response in gliomas. The low B(1) approach is not limited by specific absorption rate restrictions; this finding suggests that spin-lock methods could be applicable in clinical settings. (