Delayed changes in T₁‐weighted signal intensity in a rat model of 15‐minute transient focal ischemia studied by magnetic resonance imaging/spectroscopy and synchrotron radiation X‐ray fluorescence

Abstract

Previous studies have found that rats subjected to 15-min transient middle cerebral artery occlusion (MCAO) show neurodegeneration in the dorsolateral striatum only, and the resulting striatal lesion is associated with increased T 1 -weighted (T 1 W) signal intensity (SI) and decreased T 2 -weighted (T 2 W) SI at 2-8 weeks after the initial ischemia. It has been shown that the delayed increase in T 1 W SI in the ischemic region is associated with deposition of paramagnetic manganese ions. However, it has been suggested that other mechanisms, such as tissue calcification and lipid accumulation, also contribute to the relaxation time changes. To clarify this issue, we measured changes in relaxation times, lipid accumulation, and elemental distributions in the brain of rats subjected to 15-min MCAO using MRI, in vivo The time course and outcome of brain lesion development after cerebral ischemia can be monitored and characterized by magnetic resonance imaging (MRI) (1-3). For example, it has been shown in numerous studies that T 2 of water protons in ischemic tissue increases significantly between 1-4 days after ischemia, followed by gradual recovery to its normal level and, in many cases, subsequent secondary changes (1-3). Relaxation time changes that occur during the acute/subacute phases of cerebral ischemia can be explained by such mechanisms as reductions in cerebral blood flow (CBF) and blood oxygenation, alterations in cerebral energy metabolism, tissue edema, and selective neuronal loss (1-3). In comparison, the metabolic and molecular events underlying the relaxation time changes during the chronic phase of ischemia are often more complex, and have been shown to depend on the duration and severity of the initial ischemia. For instance, transient focal ischemia with a duration of 15 min results exclusively in subcortical (CP) lesions, which show normal T 1 and elevated T 2 at 3 days, but have elevated T 1 -weighted (T 1 W) signal intensity (SI) and reduced T 2 -weighted (T 2 W) SI at 2 weeks after ischemia, likely due to simultaneous decreases in both T 1 and T 2 in the ischemic lesion (4,5). On the other hand, transient focal ischemia with a duration of 60 min induces brain lesions of two distinct types (CP lesions and cortico-subcortical (CP ϩ ) lesions), which develop and mature with different time courses reflecting different mechanisms of neurodegeneration (6,7). At 2 weeks after ischemia, CP lesions resulting from 60-min focal ischemia are characterized by normal T 1 and T 2 , while the CP ϩ lesions are frequently associated with elevated T 1 and T 2 (6).Delayed T 2 decreases observed in the chronic stage of cerebral ischemia have been attributed to iron deposition associated with hemorrhagic transformation, vascular degradation, or chronic inflammation (6,8 -10). Delayed increases in T 1 W SI observed in the 15-min transient focal ischemia model is associated with deposition of paramagnetic manganese ions (5). It has been proposed that other mechanisms, such as tissue calcification and lipid accumul...

Selective Neuronal Loss in Ischemic Stroke and Cerebrovascular Disease

“…These slowly evolving striatal changes were associated with increasingly impaired behavioral tests, and biochemical analyses showed high tissue amounts of manganese. This pattern of MR changes, which strikingly differs from known poststroke changes but is reminiscent of findings in anoxic or hypoglycemic coma (see above), has been replicated once regarding T1, 82 while transient day 1 striatal T2-hyperintense lesion, but no T1 changes, was observed in some rats in Wegener et al 39 60-minute proximal MCAo study , associated with very severe SNL and inflammation as in Fujioka's study. This MR pattern may reflect accumulation in tissues of agents that shorten T1 and T2 relaxation times, such as iron and manganese 59,82 or reactive oxygen species.…”

“…This pattern of MR changes, which strikingly differs from known poststroke changes but is reminiscent of findings in anoxic or hypoglycemic coma (see above), has been replicated once regarding T1, 82 while transient day 1 striatal T2-hyperintense lesion, but no T1 changes, was observed in some rats in Wegener et al 39 60-minute proximal MCAo study , associated with very severe SNL and inflammation as in Fujioka's study. This MR pattern may reflect accumulation in tissues of agents that shorten T1 and T2 relaxation times, such as iron and manganese 59,82 or reactive oxygen species. Why these changes have not been more regularly replicated so far is intriguing but may reflect differences in experimental protocol and possibly genetic factors in humans, as well as possibly magnetic field strength, which strongly influences signal.…”

“…In addition, although SNL can be detected in vivo using radionuclide imaging, the search for non-ionizing biomarkers such as MR-based spectroscopy (e.g. NAA 82 ) is an important goal. Similarly, whether SNL can be mitigated by neurogenesis is another important issue.…”

<i>In Vivo</i> Brain MR Imaging at Subnanoliter Resolution: Contrast and Histology

“…[72][73][74] Thus, the activated iron-rich astrocytes may survive an inflammation and become detectable by MR imaging. 72,75 Furthermore, the manganese-dependent enzymes glutamine synthetase and manganese superoxide dismutase (MnSOD) may be abundant in activated astrocytes. The glutamine synthetase [76][77][78] is a glia-specific enzymatic protein (astrocytes and oligodendrocytes) that contains 8 Mn 2+ ions and accounts for approximately 80% of total manganese in the brain.…”

“…82 Accordingly, focal ischemia induces delayed hyperintensity on T 1 W MR imaging of the human brain, [86][87][88][89] in agreement with intense MnSOD immunoreactivities 83 in reactive astrocytosis. 86,88 In rats, temporal occlusion of the middle cerebral artery induces delayed hyperintensity on fat-suppressed T 1 W (and delayed hypointensity on T 2 W) MR imaging in the striatum, 75,87 where the manganese concentration increases in proportion to the induced glutamine synthetase and MnSOD in reactive astrocytes. 75,83,87 The lack of fat signals in localized MR spectra of the rat brain 75 rules out microglial fat 90 as a source of MR imaging contrast.…”