Perfusion Imaging Grand Rounds January 18, 2017 Gloria J. Guzmán Pérez-Carrillo, MD, MSc Neuroradiology Section, Department of Medical Imaging

Nothing to disclose

Overview Clinical uses of perfusion imaging, in particular stroke and tumor evaluation CT perfusion MR perfusion Dynamic Contrast-Enhanced (DCE) Dynamic Susceptibility Contrast (DSC) Arterial Spin Labeling (ASL) Intravoxel Incoherent Motion (IVIM) Summary of MR perfusion

Learning objectives To define the different types of perfusion techniques To understand their clinical applications in stroke and tumor evaluation To define their technical limitations 

Perfusion modalities and clinical uses Stroke work-up CT Perfusion MR Dynamic Susceptibility Contrast (DSC) Tumor imaging MR Dynamic Contrast-Enhanced (DCE) Dynamic Susceptibility Contrast (DSC) Arterial Spin Labeling (ASL) Intravoxel Incoherent Motion (IVIM) Multiple other clinical indications: Vasospasm, Moya Moya, etc. Briefly

CT Perfusion

CT perfusion, how to perform? Arterial input function (AIF)-A2 and venous output function (VOF)-superior sagittal sinus after contrast

CT perfusion, how to perform? Arterial input function (AIF)-A2 and venous output function (VOF)-superior sagittal sinus

CT perfusion parameters Cerebral blood flow (CBF): Measured in units of milliliters of blood per 100 g of brain tissue per minute and is defined as the volume of flowing blood moving through a given volume of brain in a specific amount of time Cerebral blood volume (CBV): Measured in units of milliliters of blood per 100 g of brain and is defined as the volume of flowing blood for a given volume of brain Mean transit time (MTT): Measured in seconds and defined as the average amount of time it takes blood to transit through the given volume of brain Time to peak (TTP): Measured in seconds as the time it takes for the bolus to reach the highest HU CBF= CBV/MTT

CT perfusion parameters

Tmax Tmax is theoretically the arrival delay between the AIF and [contrast]  Used either as an independent measure or equivalent to MTT Multiple factors can affect its calculation (deconvolution method,bolus delay, bolus dispersion, etc.)

CT perfusion penumbra CBF= CBV/MTT rCBF CBF= CBV/MTT Thus, when there is increased MTT, there is decreased CBF Decreased CBF may or may not be associated with decreased CBV. If mismatched = PENUMBRA rCBV MTT

CT perfusion, quantitative? In the clinical setting, for now only qualitative due to differences between vendors and post-processing software Quantitative MTT increase > 145% CBF < 25 mL x 100 g-1 min-1 CBV < 2 mL x 100 g-1 TTP > 6 seconds

CT perfusion pearls In normal patients, cortex ALWAYS has higher CBV and CBF as compared to white matter TTP is not a reliable measurement due to hemodynamic variability MTT is the most sensitive parameter Posterior circulation ischemia harder to image due to prolonged time of bolus arrival Only a few levels acquired, not entire brain volume, be aware perfusion defects could be missed

CT perfusion, pitfalls of acquisition Suboptimal contrast bolus Cardiac arrhythmia Severe intracranial vascular narrowing Multiple intracranial emboli Lack of adequate flow within the vessels of the circle of Willis Inappropriate ROI over vessels

MR Perfusion

Why perfusion in tumors Differentiation between tumor recurrence and post-treatment change. Seminal article Sugahara et al., AJNR 2000

Why perfusion in tumors Predictive of survival: Seminal article Meng Law et al., Radiology 2008

Dynamic Contrast-Enhanced (DCE)

DCE, what is it? “Permeability” MRI Takes advantage of increased T1 relaxivity of Gd Based on a two-compartmental (plasma space and extravascular-extracellular space) pharmacokinetic model Resulting signal intensity–time curve reflects a composite of tissue perfusion, vessel permeability, and extravascular-extracellular space Depicts the wash-in, plateau, and washout contrast kinetics of the tissue

DCE, why it works Increase in the rate of T 1 relaxation is proportional to the concentration of the contrast agent. Relate signal enhancement in T 1 -weighted images to the tissue contrast agent concentration.  Extracellular contrast media diffuse from the blood into the EES of tissue at a rate determined by tissue perfusion and permeability of the capillaries and their surface area.

DCE, parameters Transfer constant (k-trans) Fractional volume of the extravascular-extracellular space (ve) Rate constant (kep, where kep = k trans /ve) Fractional volume of the plasma space (vp)

DCE, parameters Transfer constant (k-trans) Fractional volume of the extravascular-extracellular space (ve) Rate constant (kep, where kep = k trans /ve) Fractional volume of the plasma space (vp)

DCE, parameters Transfer constant (k-trans) Fractional volume of the extravascular-extracellular space (ve) Rate constant (kep, where kep = k trans /ve) Fractional volume of the plasma space (vp)

DCE, K-trans K-trans most commonly used. Due to BBB, normally there is very low permeability (i.e. leakiness) in the cerebral blood vessels. Thus, any increased in permeability is due to increase in number of abnormal BV’s due tumor angiogenesis (VGEF pathway) Tumor vessels are further characterized by the absence of muscularis propria, widened interendothelial junctions, and a widely discontinuous or absent basement membrane, results in increased permeability Increased abnormal BV’s are usually insufficient to feed tumor, thus regional area of necrosis and hypoxia

DCE, how to perform? Perform baseline T1 mapping Acquire DCE MR perfusion images Convert signal intensity data to gadolinium concentration, determine the vascular input function, and perform pharmacokinetic modeling

DCE, baseline T1 mapping Assumed that the change in T 1 is directly proportional to the tissue contrast agent concentration, however, this is not always true Baseline mapping of T 1 and equilibrium magnetization as a preliminary step in DCE-MR imaging analysis needed to correct for the nonlinear relationship between signal intensity on dynamically acquired DCE-MR imaging images and underlying gadolinium-based contrast agent concentration In our case, we do variable angle technique

DCE, dynamic imaging Done with spoiled GRE to correct for high T2 component of GRE alone, with SNR trade-off We use three-dimensional time-resolved imaging of contrast kinetics and time-resolved angiography with stochastic trajectories are K-space subsampling techniques that (in contrast to older rapid imaging techniques such as keyhole imaging) sample both the center and periphery of K-space during the dynamic image acquisition, allowing for higher spatial resolution

DCE, how to perform?

DCE, how to interpret Qualitative: higher leak on K-trans maps on affected side vs. contralateral tissue Quantitative: K-trans: high-grade tumors (median 0.89, 25th to 75th quartiles 0.46 –2.67) vs. low-grade tumors (median 0.09, 25th to 75th quartiles 0.04 –0.13). Kep: high-grade tumors (median 6.76, 25th to 75th quartiles 3.77–16.88) vs. low-grade tumors (median 0.66, 25th to 75th quartiles 0.29 –1.04). Ve: high-grade tumors (median 0.12, 25th to 75th quartiles 0.11–0.15) vs. low-grade tumors (median 0.23, 25th to 75th quartiles 0.19 –0.26).

DCE, how to interpret Dynamic curves, akin to breast cancer MR studies

DCE, pitfalls If there is a lot of underlying tissue damage from surgery/treatment, there will be a lot of “leakiness” and K-trans might be spuriously elevated Complexity in image acquisition and pharmacokinetic model post-processing, user-dependence, and lack of widely available and easy-to-use post-processing software are all drawbacks Lower temporal and spatial resolution compared to DSC

Dynamic Susceptibility Contrast (DSC)

DSC, what is it? First pass of a bolus of gadolinium-based contrast agent through brain tissue is monitored by a series of T2*-weighted MR images Susceptibility effect of the paramagnetic contrast agent leads to a signal loss in the signal intensity– time curve, which is converted into a concentration-time curve on a pixel-by-pixel basis

DSC for stroke, similar to CT rCBF rCBV MTT TTP

ADC Flair rCBV T1Gd DSC, how to perform

DSC, how to measure Use rCBV, do ROI over lesion (A) and mirrored on contralateral side (B) and do a ratio (A/B)

DSC for tumor vs. radiation necrosis Threshold for radiation necrosis rCBV <1.5, with median <1.0 Threshold for tumor rCBV>1.5 to 2.0 (sens vs. spec) AJNR February 2009 30: 367-372

DSC for tumor vs. radiation necrosis Threshold for radiation necrosis rCBV <1.5, with median <1.0 J Neurooncol (2010) 99: 81-88

DSC, pitfalls Inappropriate bolus: evaluate time-concentration curve rCBV of up to 2.4 has been reported in radiation necrosis, although rare DSC MR perfusion does not allow a robust absolute quantification, mainly because of the lack of a direct linear relationship between contrast concentration and signal changes Susceptibility artifacts affect signal, thus always correlate with SWI/GRE images

DSC, pitfalls In area of susceptibility, you have no T2* signal, thus it will show up as a black hole in DSC

DSC, pitfalls Partial volume effect from low spatial resolution Stenosis will rate-limit contrast and result in underestimation of CBF and overestimation of MTT, must always check graph Non-uniform T2* relaxivity of tissues

Arterial Spin Labeling (ASL)

ASL, what is it? Uses magnetically labeled blood as an endogenous tracer, without need to use Gd Two main types of ASL technique: continuous ASL and pulsed ASL Continuous: prolonged radiofrequency pulse that continuously labels arterial blood water below the imaging slab until a steady state of tissue magnetization is reached Pulsed: short radiofrequency pulse is used to label a thick slab of arterial blood at a single point in time and imaging is performed after a period of time to allow distribution in the tissue of interest

In tagged images, magnetization is inverted ASL, how is it done?

ASL for tumor ASL DSC

ASL for tumor Measures CBF Ratio of tumor vs. normal contralateral site is performed For high-grade tumors a 3-4 ratio is used as a cutoff, but there is a wide range, thus it not used clinically

ASL, pitfalls Significantly lower SNR and spatial/temporal resolution compared to DSC Labeling techniques / Continuous technique: Increases magnetization transfer effect. If the magnetization transfer effects are present only during the labeling scheme, perfusion may be overestimated because the saturation effect of the macromolecular pool will result in reduced signal of the free water pool from the tissue of interest Complex mathematical kinetic modeling Arterial transit time varies significantly across BV, ASL uses only a single time point to decrease acquisition time Partial volume errors similar to DSC

Intravoxel Incoherent Motion (IVIM)

IVIM, what is it? Diffusion-based perfusion Fast diffusion in intravascular component (f) and fast decay (D*)*

IVIM, how to perform? Acquire multiple b values between b0-b100 Between 3-5 values, typically b0, 10,20,40, 80 No Gd used, use endogenous diffusivity of perfusion

IVIM, how to perform? Derive f, or the perfusion fraction

IVIM, how to measure Measure f, or the perfusion fraction  American Journal of Neuroradiology 35.2 (2014): 256-262

IVIM, pitfalls Relatively new, not enough data Since based on diffusion values, results vary by machine and vendor Vendor platforms are available, but not a lot of clinical experience with them Complex mathematical modeling, has not yet been determined whether Gaussian, Bayesian, Kurtosis, Skweness is best

Not all black or white with tumors Important to recognize that treated tumors are dynamic and heterogeneous Both radiation necrosis/treatment change and tumor are often present Multi-parametric tools that include physiological and molecular markers hold promise as complementary tools to anatomic and perfusion imaging for tumor evaluation

In summary Korean J Radiol 2014;15(5):554-577

In summary Clinical perfusion CT and MR are mainly performed for stroke and tumor evaluation MR DSC is the workhorse of tumor evaluation, except in the setting of susceptibility artifacts DCE is a powerful perfusion tool, but technically challenging ASL and IVIM are alternatives in patients that have contraindications to Gd studies Further work needs to be done to refine the techniques

In summary We have reviewed: The different types of perfusion techniques The clinical application of perfusion in stroke and tumor evaluation The technical limitations of perfusion imaging

Korean J Radiol 2014;15(5):554-577

References Barajas, R. F., et al. "Distinguishing recurrent intra-axial metastatic tumor from radiation necrosis following gamma knife radiosurgery using dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging." American Journal of Neuroradiology 30.2 (2009): 367-372. Essig, Marco, et al. "Perfusion MRI: the five most frequently asked technical questions." AJR. American journal of roentgenology 200.1 (2013): 24. Federau, Christian, et al. "Perfusion measurement in brain gliomas with intravoxel incoherent motion MRI." American Journal of Neuroradiology 35.2 (2014): 256-262. Jahng, Geon-Ho, et al. "Perfusion magnetic resonance imaging: a comprehensive update on principles and techniques." Korean journal of radiology 15.5 (2014): 554-577. Law, Meng, et al. "Gliomas: predicting time to progression or survival with cerebral blood volume measurements at dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging 1." Radiology 247.2 (2008): 490-498. Mitsuya, Koichi, et al. "Perfusion weighted magnetic resonance imaging to distinguish the recurrence of metastatic brain tumors from radiation necrosis after stereotactic radiosurgery." Journal of neuro-oncology 99.1 (2010): 81-88. Niesten, Joris M., et al. "Optimisation of vascular input and output functions in CT-perfusion imaging using 256 (or more)-slice multidetector CT." European radiology 23.5 (2013): 1242-1249. Stroke CTP Vanderbilt Protocol and Workflow Manual. http://www.mc.vanderbilt.edu/documents/NeuroICU/files/Stroke%20CTP.pdf Sugahara, Takeshi, et al. "Posttherapeutic intraaxial brain tumor: the value of perfusion-sensitive contrast-enhanced MR imaging for differentiating tumor recurrence from nonneoplastic contrast-enhancing tissue." American Journal of Neuroradiology 21.5 (2000): 901-909. Tofts, Paul S., et al. "Estimating kinetic parameters from dynamic contrast-enhanced T 1-weighted MRI of a diffusable tracer: standardized quantities and symbols." Journal of Magnetic Resonance Imaging 10.3 (1999): 223-232.

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