Magnetic resonance imaging shows delayed ischemic striatal neurodegeneration

Abstract

Brief focal ischemia leading to temporary neurological deficits induces delayed hyperintensity on T1-weighted magnetic resonance imaging (MRI) in the striatum of humans and rats. The T1 hyperintensity may stem from biochemical alterations including manganese (Mn) accumulation after ischemia. To clarify the significance of this MRI modification, we investigated the changes in the dorsolateral striatum of rats from 4 hours through 16 weeks after a 15-minute period of middle cerebral artery occlusion (MCAO), for MRI changes, Mn concentration, neuronal number, reactivities of astrocytes and microglia/macrophages, mitochondrial Mn-superoxide dismutase (Mn-SOD), glutamine synthetase (GS), and amyloid precursor protein. The cognitive and behavioral studies were performed in patients and rats and compared with striatal T1 hyperintensity to show whether alteration in brain function correlated with MRI and histological changes. The T1-weighted MRI signal intensity of the dorsolateral striatum increased from 5 days to 4 weeks after 15-minute MCAO, and subsequently decreased until 16 weeks. The Mn concentration of the dorsolateral striatum increased after ischemia in concert with induction of Mn-SOD and GS in reactive astrocytes. The neuronal survival ratio in the dorsolateral striatum decreased significantly from 4 hours through 16 weeks, accompanied by extracellular amyloid precursor protein accumulation and chronic glial/inflammatory responses. The patients and rats with neuroradiological striatal degeneration had late-onset cognitive and/or behavioral declines after brief focal ischemia. This study suggests that (1) the hyperintensity on T1-weighted MRI after mild ischemia may involve tissue Mn accumulation accompanied by Mn-SOD and GS induction in reactive astrocytes, (2) the MRI changes correspond to striatal neurodegeneration with a chronic inflammatory response and signs of oxidative stress, and (3) the subjects with these MRI changes are at risk for showing a late impairment of brain function even though the transient ischemia is followed by total neurological recovery.

Temporal profile of T2-Weighted MRI Distinguishes between Pannecrosis and Selective Neuronal Death after Transient Focal Cerebral Ischemia in the Rat

“…Even though morphologically similar to those of Fujioka et al (2003), the subcortical lesions described in our study had a different appearance on follow-up MRI. Since it involved the same brain structure, region-specific differences in lesion evolution are not a plausible explanation for this difference.…”

“…In mild transient ischemia of 30 mins and less, MRI changes have been shown to take a different course (Fujioka et al, 2003; van Lookeren Campagne et al, 1999). After a 15-mins vascular occlusion, Fujioka et al (2003) showed a delayed hyperintensity on T 1 -w images that was accompanied by a hypointensity on T 2 -w images between 5 days and 16 weeks after MCAO. These relaxation time changes were attributed to manganese accumulation in the striatum in concert with neurodegeneration and an inflammatory response that led to delayed impairment in cognitive function.…”

Selective Neuronal Loss in Ischemic Stroke and Cerebrovascular Disease

“…These changes affected the caudoputamen and cortex, appeared around 1 week after the stroke and disappeared in the following weeks to months together with progressive tissue atrophy ( Figure 3A). These authors subsequently reported 59 six additional clinical cases who, despite full neurological recovery, showed a decline in global cognitive functions at 12 months of follow-up. They replicated these MR findings in two experimental studies in Wistar rats subjected to 15-minute proximal MCAo, 35,59 where a striatal T2W hypointense signal appeared at day 5 to 7 but was preceded by transient hyperintensity at day 1, indicating vasogenic edema, whereas the T1W hyperintensity peaked at B4 weeks and then subsided slowly over months ( Figure 3B).…”

“…These authors subsequently reported 59 six additional clinical cases who, despite full neurological recovery, showed a decline in global cognitive functions at 12 months of follow-up. They replicated these MR findings in two experimental studies in Wistar rats subjected to 15-minute proximal MCAo, 35,59 where a striatal T2W hypointense signal appeared at day 5 to 7 but was preceded by transient hyperintensity at day 1, indicating vasogenic edema, whereas the T1W hyperintensity peaked at B4 weeks and then subsided slowly over months ( Figure 3B). Histology showed a severe and progressive SNL affecting the striatum, evolving from a mean of B20% of surviving neurons at 4 hours and day 3 down to only 3% at 16 weeks, together with marked and sustained astrocytosis and MA, yet not fulfilling criteria for pannecrosis.…”

“…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.…”