Acute blood–brain barrier opening in experimentally induced focal cerebral ischemia is preferentially identified by quantitative magnetization transfer imaging

Abstract

Pathologic changes in brain tissue during and after stroke may lead to injury of the blood-brain barrier (BBB) and subsequent hemorrhagic transformation (HT). In a rat model of HT, the apparent diffusion coefficient of water, cerebral blood flow, relaxation times, T 1 and T 2 , and magnetization transfer (MT) related parameters (T 1sat , K for and the MT ratio) were repetitively measured during 3 h of focal ischemia and 2 h of reperfusion (n ‫؍‬ 8). Areas of BBB opening were identified by sequential assay of the transcapillary influx of Gd-diethylenetriaminepentaacetic acid (Gd-DTPA) by MRI and 14 C-␣-aminoisobutyric acid (AIB) by quantitative autoradiography. Ischemia-injured regions of interest were identified from the MRI data and divided into those with and without BBB opening. Of the several MRI parameters measured, the T 1sat in the caudate-putamen and preoptic area during ischemia and the first 2 h of reperfusion correlated best with the regional pattern of BBB opening observed thereafter. These data suggest that an ipsilateral/ contralateral T 1sat ratio > 1.6 demarcates leakage of small molecules such as Gd-DTPA and AIB across the BBB. Key words: Gd-DTPA; hemorrhagic transformation; magnetization transfer; MRI; rt-PA; stroke Thrombolysis using recombinant tissue plasminogen activator (rt-PA) has proven to be an effective intervention for the treatment of acute ischemic stroke (1), but the risk of hemorrhagic transformation (HT) following such treatment remains an obstacle to widespread usage of thrombolytic agents. To illustrate this risk, the probability of symptomatic HT increases significantly during the first 36 h after stroke onset in patients receiving rt-PA (6.4% vs. 0.6% in placebo-treated patients), and 61% of the patients with symptomatic HT die within 3 months (1). Studies performed using animal stroke models show similar findings with increased risk of HT associated with thrombolytics (2-5). In view of these complications with thrombolytic therapy, it is important to develop diagnostic imaging techniques that reliably identify tissue regions that are prone to HT and to obtain such data when deciding on a treatment protocol.One of the possible imaging techniques is computed tomography (CT). The sensitivity of CT for detection of early ischemic damage remains controversial because a significant proportion of stroke patients show negative acute CT images but go on to develop large infarcts (6). Although it is the standard diagnostic test for extant cerebral bleeding, CT has a limited capacity to predict HT in ischemic stroke (7). An early report from the NINDS rt-PA Stroke Trial showed only a 57% efficiency for the prediction of symptomatic HT based on early CT findings (1). A more recent retrospective analysis of CT films from the trial adjusted the data for group imbalances in several baseline clinical features and found that early ischemic changes were not predictive of clinical deterioration at 24 h or of symptomatic intracerebral hemorrhage (i.e., death) at 90 days (8). It may be that high...

Acute Leakage Patterns of Fluorescent Plasma Flow Markers after Transient Focal Cerebral Ischemia Suggest Large Openings in Blood‐Brain Barrier

“…The sites and magnitude of lowered CBF and subsequent recovery of flow after cerebral ischemia have been documented for this model by four different studies and found to be fairly reproducible [6,7,17,18]. In the present instance, CBF was measured at times during occlusion and reperfusion in about one-third of the rats from each dextran group.…”

“…Opening of the blood-brain barrier (BBB), leakage of plasma proteins, resultant edema and subsequent hemorrhagic transformation (HT) after ischemic stroke and reperfusion are complicating factors in a cascade of events that often lead to permanent brain injury [4,5,18,32]. Three hours of reperfusion after 3 h of focal ischemia results in BBB opening, whereas 6 h of occlusion alone does not [37].…”

Quantitation and localization of blood‐to‐brain influx by magnetic resonance imaging and quantitative autoradiography in a model of transient focal ischemia

“…After reperfusion, the blood flow rates rebounded to varying degrees in the affected regions; CBF was, however, not statistically different among the regions at this time (Table 2). Additionally, measurements of multiparameter MRI data were obtained for the same ROIs from these animals and are reported in an accompanying paper (20).…”

A Longitudinal Magnetization Transfer Imaging Evaluation of Brain Injury in a Macaque Model of NeuroAIDS

“…15,20 MRI scans were performed on a Siemens 3T Trio scanner with the CP extremity coil (Siemens Medical Solutions, Malvern, PA) before SIV inoculation and in 2,4,8,12,16, and 20 weeks post-inoculation (WPI). Blood samples were collected from each animal for monitoring CD4 + and CD8 + T cells before each MRI scan.…”

“…1,2 The magnetization transfer ratio (MTR), derived from MT imaging, has been explored and used to evaluate brain injury in various brain diseases (such as multiple sclerosis, Alzheimer's disease, stroke, and epilepsy). [3][4][5][6][7][8] Also, a few studies in HIV patients have demonstrated that MT imaging might be a robust technique to assess neurodegeneration after HIV infection. [9][10][11][12][13] However, prior MT imaging studies in HIV patients did not provide the dynamic MTR changes during the course of infection and those results could be biased with unknown conditions such as time of infection, patient age, and treatment history.…”