Role of Cerebral Ischemia in Cognitive Impairment: Clinical and Experimental Study

This dissertation, "Role of Cerebral Ischemia in Cognitive Impairment: Clinical and Experimental Study" by Liangyu, Zou, 鄒良玉, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Role of cerebral ischemia in cognitive impairment - clinical and experimental study Submitted by ZOU Liangyu for the degree of Doctor of Philosophy at the University of Hong Kong in October, 2005 Stroke and Alzheimer's disease (AD) are leading causes of death and disability worldwide. Both diseases share similar mechanisms of neuronal injury and death. Ischemic cerebral lesions are not uncommon among AD patients, which are thought to induce vascular cognitive impairment (VCI) and accelerate the progression of AD. Various risk factors have been studied among stroke patients to predict the occurrence of VCI. Our clinical study assessed 334 patients with ischemic stroke and found an incidence of 43.1% for cognitive impairment at baseline; risk factors were older age, female gender, being a widow or widower, poor self-support, bladder and bowel incontinence, impaired balance and mobility, lower functional independence measurement (FIM), and lower modified Barthel Index (BI). A follow up assessment was performed in 117 patients with normal mini-mental state examination (MMSE) score at baseline. The incidence of VCI at 6 months after stroke was 53.8%; older age, impaired visual acuity, and lower FIM were the independent risk factors. A predictive VCI score including these factors were devised with a sensitivity of 62.9% and specificity of 79.1%. Experimental studies were performed in mice transgenic for both human amyloid precursor protein (APP) and human presenilin-1 (PS1) genes or APP gene alone as well as in non-transgenic mice. Photothrombotic stroke was induced, and spatial memory was tested with Morris water maze task from day 3 to day 7 after stroke. On day 7 after stroke, infarct volume (IFV) was measured using 2,3,5- triphenyltetrazolium chloride (TTC) staining, amount of beta-amyloid (Aβ) 40 and Aβ42 was detected by Sandwich ELISAs, neurons in cortex and hippocampus were counted using Nissl staining, the expressions of APP, heat shock protein 70 (HSP70) and mitogen-activated kinases (MAPKs) were measured using western blotting method, and immunoreactivities for 6E10, synaptophysin and microtubule associated protein 2 (MAP-2) were measured using immunochemistry method. APP/PS1 mice were more susceptible to photothrombotic stroke than APP or non-transgenic mice with an increased IFV and post-stroke memory impairment. When the APP mice were artificially separated into two groups according to IFV, a larger IFV was not associated with memory impairment. Greater amounts of Aβ40 and Aβ42 were found in APP/PS1 mice than that in non-transgenic mice. Compared with the non-ischemic hemisphere, there was a greater loss of neurons and a possible greater loss of synapses (as indicated by MAP-2, a synaptic marker) in CA1, higher ratios of phosphorylated c-Jun N-terminal kinase (PJNK) to JNK and of phosphorylated p38 to p38 in the ischemic hemisphere of the APP/PS1 mice, and a greater expression of HSP70 in the ischemic hemisphere of non-transgenic mice. In summary, APP/PS1 mice are more susceptible to photothrombotic stroke with an increased IFV and post-stroke memory impairment. Nevertheless, the increased IFV alone does not induce the post-stroke memory impairment in APP/PS1 mice. In APP/PS1 mice, higher amounts of Aβ40 and Aβ42 may activate MAPKs pathways and/or inhibit HSP70 expression, which in turn, induce a greater loss of