Arterial Spin Labeling MR Perfusion Acetazolamide Challenge for Assessing Cerebrovascular Reserve in Moya-Moya Andrew Sung, David Shin, Eric Wong, Thomas Liu, Roland Lee, James Chen University of California, San Diego Medical Center Presentation Number: EE-07

Disclosures None.

Cerebrovascular Reserve (CVR) Measure of the ability for the brain to increase blood flow by autoregulatory vasodilation. Evaluation of CVR is particularly useful for Evaluating the risk of future ischemic events Therapeutic interventions Patient selection Intervention planning

Acetazolamide (ACZ) Challenge Acetazolamide (ACZ) is a vasodilator Mechanism of action: carbonic anhydrase inhibitor, crosses blood-brain-barrier and causes cerebral acidosis  vasodilation  increased cerebral blood flow (CBF). Systemic BP, HR, RR, arterial pH, arterial CO2, CMRO2 are unaffected. By measuring pre and post ACZ CBF, can calculate the cerebrovascular reactivity:

Measuring Cerebral Blood Flow (CBF) Imaging techniques: Xe-CT Perfusion CT (iodinated contrast) MR perfusion Contrast (Gd)– DSC Non-contrast – ASL PET (15O2, C15O2, H215O) SPECT (Tc99m-HMPAO/ ECD) Advantages of ASL No radiation (vs. CT perfusion, Xe-CT, PET, SPECT) No contrast (vs. CT perfusion, MR DSC perfusion) Greater availability (vs. Xe- CT, PET)

ASL Cerebrovascular Reserve Protocol Baseline ASL brain perfusion Post-labeling delay (PLD): 2 sec Labeling Duration (LD): 1.5 sec Administration of acetazolamide 1g IV. Wait 15-20 minutes. Post-acetazolamide ASL brain perfusion.

Case Report 29 year-old female with a history of Moya-Moya status-post left encephaloduroarteriosynangiosis (EDAS), presents with headaches, right-sided hemiparesis, and gait instability.

Imaging Findings Magnetic resonance angiography (MRA) shows an occluded proximal left MCA (red arrow), with a left encephaloduroarteriosynangiosis (EDAS) (blue arrow).

Case Report Unclear whether patient’s symptoms were from inadequate function of the EDAS versus other etiology. Evaluation of cerebrovascular reserve was requested to assess need for further revascularization.

Results ASL maps show appropriate response to acetazolamide administration with globally increased cerebral blood flow. Subtraction images better demonstrate the relative difference in increased CBF following administration of acetazolamide. Although there was relative less increase in CBF in the EDAS territory, no steal phenomenon was demonstrated. Top row: CBF (Pre-ACZ) Middle row: CBF (Post-ACZ) Bottom row: Subtraction maps

Results Absence of steal phenomenon suggests adequate function of the EDAS, and thus no further revascularization indicated. Patient’s symptoms likely attributable to migraines.

Potential Pitfall Transit Delay Labeling Duration ASL Signal Post-labeling delay* Time Key assumption in ASL: post- labeling delay is longer than the longest physiologic transit time. This allows the entire tagged bolus to reach the voxel before imaging. * Conventionally, post-labeling delay accounts for the time after labeling and before imaging. For illustration purposes, post-labeling delay is shown to include the labeling time.

Potential Pitfall Transit Delay Labeling Duration ASL Signal Post-labeling delay Time Long transit delays, as seen in collateral flow states, may underestimate ASL estimated CBF if the post-labeling delay is not long enough. This is due to the fact that the image is acquired before the entire tagged bolus reaches the voxel.

Post-Labeling Delay (PLD) Transit Delay Labeling Duration ASL Signal Post-labeling delay Time Thus, an appropriate PLD will allow for the entire tagged bolus to reach the target voxel before imaging. Note, a PLD that is too long will allow the ASL signal to decay too much, resulting in decreased signal-to-noise (SNR).

Effect of Acetazolamide Pre-ACZ ASL Signal Post-labeling delay In long-transit states, such as in collateral flow, the pre-ACZ CBF measurement may be underestimated. With acetazolamide administration, there is both a global increase in blood flow and decrease in transit delays. This allows more accurate estimation of blood flow in the post- ACZ measurement. Results in overestimation of the magnitude of delta-CBF, although, the direction of flow increase/decrease will remain the same. Post-labeling delay Post-ACZ

Choosing the PLD Rule-of-thumb: set the PLD longer than the longest transit time. 2 seconds is adequate in most clinical patients. Longer transit times (2-3 s) in elderly patients, collateral flow, stroke. Troubleshooting: Curvilinear high signal (arterial transit artifact – ATA), reflects ASL tag within the arterial vasculature, and may indicate an inadequate PLD. Arterial Transit Artifact (ATA) in Moya-Moya Patient Zaharchuk G, et al. Stroke 2014.

Summary ASL perfusion acetazolamide challenge can assess whole-brain cerebrovascular reactivity (CVR) without radiation or intravenous contrast. This technique is particularly useful in any patients who may require multiple and frequent surveillance scans. Particularly treated Moya-Moya

Summary ASL acetazolamide challenge benefits Avoids repeated gadolinium contrast administration – a potential benefit given the current concern of linear gadolinium agents depositing in the brain with repeated administration. Avoids repeated CT radiation dose and repeated iodinated contrast administration. Has greater availability than Xe-CT or PET. Can be easier to interpret - pre and post acetazolamide scans are performed in one scan session, allowing easy subtraction and interpretation. This is in contrast to the labor-intensive process of manual ROIs placement.

References Zaharchuk G, Do HM, Marks MP, et al. Arterial Spin-labeling MRI can identify the presence and intensity of collateral perfusion in patients with Moyamoya disease. Stroke 2011; 42:2485-91. Yun TJ, Paeng JC, Sohn C, et al. Monitoring cerebrovascular reactivity through the use of arterial spin labeling in patients with Moyamoya Disease. Radiology 2016; 278(1): 205-13. Inoue Y, Tanaka Y, Hata H, et al. Arterial spin-labeling evaluation of cerebrovascular reactivity to acetazolamide in healthy subjects. AJNR Am J Neuroradiol 2014; 35: 1111-6. Vagal AS, Leach JL, Fernandez-Ulloa F, et al. The Acetazolamide Challenge: Techniques and Applications in the Evaluation of Chronic Cerebral Ischemia. AJNR 2009; 30:876-84.