Single-cell resolution mapping of neuronal damage in acute focal cerebral ischemia using thallium autometallography

Neuronal damage shortly after onset or after brief episodes of cerebral ischemia has remained difficult to assess with clinical and preclinical imaging techniques as well as with microscopical methods. We here show, in rodent models of middle cerebral artery occlusion (MCAO), that neuronal damage in acute focal cerebral ischemia can be mapped with single-cell resolution using thallium autometallography (TlAMG), a histochemical technique for the detection of the K⁺-probe thallium (Tl⁺) in the brain. We intravenously injected rats and mice with thallium diethyldithiocarbamate (TlDDC), a lipophilic chelate complex that releases Tl⁺ after crossing the blood-brain barrier. We found, within the territories of the affected arteries, areas of markedly reduced neuronal Tl⁺ uptake in all animals at all time points studied ranging from 15 minutes to 24 hours after MCAO. In large lesions at early time points, areas with neuronal and astrocytic Tl⁺ uptake below thresholds of detection were surrounded by putative penumbral zones with preserved but diminished Tl⁺ uptake. At 24 hours, the areas of reduced Tl⁺ uptake matched with areas delineated by established markers of neuronal damage. The results suggest the use of 201 TlDDC for preclinical and clinical single-photon emission computed tomography (SPECT) imaging of hyperacute alterations in brain K⁺ metabolism and prediction of tissue viability in cerebral ischemia.