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Transient ischemic attack (TIA) initiates an ischemic cascade without resulting in frank infarction and, as such, represents a novel model to study the effects of this ischemic cascade and secondary neurodegeneration in humans.Patients with suspected TIA underwent acute brain perfusion imaging, and those with acute ischemia were enrolled into a prospective observational study. We collected baseline and 90-day magnetic resonance imaging, including MP-RAGE (high-resolution T1 sequence) and cognitive assessment with the Montreal Cognitive Assessment. Brain morphometry and within patient statistical analysis were performed to identify changes between baseline and 90-day imaging and clinical assessments.Fifty patients with TIA with acute perfusion lesions were studied. All patients experienced a decrease in global cortical gray matter (P=0.005). Patients with anterior circulation TIA (n=31) also had a significant reduction in the volume of the pons (P<0.001), ipsilesional parietal lobe (P<0.001), occipital lobe (P=0.002), frontal lobe (P<0.001), temporal lobe (P=0.003), and thalamus (P=0.016). Patients with an anterior perfusion lesion on acute imaging also had a significant decrease in Montreal Cognitive Assessment between baseline and day 90 (P=0.027), which may be related to the volume of thalamic atrophy (R2=0.28; P=0.009).In a prospective observational study, patients with TIA confirmed by acute perfusion imaging experienced a significant reduction in global gray matter and focal structural atrophy related to the area of acute ischemia. The atrophy also resulted in a proportional decreased cognitive performance on the Montreal Cognitive Assessment. Further studies are required to identify the mechanisms of this atrophy.