A fter a first-ever stroke, ≈10% of patients develop poststroke dementia, which is defined as dementia occurring after stroke in patients without dementia before stroke. 1 After recurrent stroke, the prevalence of poststroke dementia rises from 10% after a first-ever stroke to >30%, thus having coined the term multi-infarct dementia. 2 With a 1-year recurrent stroke rate of >10%, multi-infarct dementa has an unequivocally high contribution to the long-term disability of stroke patients. 3 But

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... spite of its high disease burden, there is no specific treatment for multi-infarct dementia. One reason for the lack of specific treatments is that the underlying pathophysiological mechanisms of multi-infarct dementia are unclear. The secondary gliosis in remote brain regions, which share synaptic connections with the lesion site, might play an important role in the pathophysiology of multi-infarct dementia. 4, 5 However, an appropriate animal model of multi-infarct dementia, which enables the investigation of its pathophysiological mechanisms and the preclincal evaluation of potential treatments, is lacking, to date. In the current work, we present a mouse model of recurrent photothrombotic stroke that leads to inreasing cognitive impairment and resembles the clinical features of human multi-infarct dementia. Methods Animals Our experiments were performed using adult male C57BL/6 mice. All experiments were conducted in accordance with animal welfare regulations, and experimental protocols were approved by the local ethics committee. All experiments were performed in a randomized and blinded design. Ischemia Model Focal cerebral ischemia was induced in the right parietal cortex of 25 adult male C57BL/6 mice by photothrombosis of cortical microvessels (detailed Methods are available in the online-only Data Supplement). 6 At an interval of 10 days, a second photothrombotic Background and Purpose-In spite of its high disease burden, there is no specific treatment for multi-infarct dementia. The preclinical evaluation of candidate drugs is limited because an appropriate animal model is lacking. Therefore, we aimed to evaluate whether a mouse model of recurrent photothrombotic stroke is suitable for the preclinical investigation of multi-infarct dementia. Methods-Recurrent photothrombotic cortical infarcts were induced in 25 adult C57BL/6 mice. Twenty-five sham-operated animals served as controls. The object recognition test and the Morris water maze test were performed >6 weeks to assess cognitive deficits. Afterward, histological analyses were performed to characterize histopathologic changes associated with recurrent photothrombotic infarcts. Results-After the first infarct, the object recognition test showed a trend toward an impaired formation of recognition memories (P=0.08), and the Morris Water Maze test revealed significantly impaired spatial learning and memory functions (P<0.05). After recurrent infarcts, the object recognition test showed significant recognition memory deficits (P<0.001) and the Morris water maze test demonstrated persisting spatial learning and memory deficits (P<0.05). Histological analyses revealed remote astrogliosis in the hippocampus. Conclusions-Our results show progressive cognitive deficits in a mouse model of recurrent photothrombotic stroke. The presented model resembles the clinical features of human multi-infarct dementia and enables the investigation of its pathophysiological mechanisms and the evaluation of treatment strategies.