Contribution of cerebrovascular and Alzheimer-type pathology in the aetiology of neurocognitive disorders

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Copyright: Liu, Yue
Alzheimer’s disease (AD) and cerebrovascular disease (CVD) are the two most prevalent causes of dementia. However, the molecular basis of AD and Vascular dementia (VaD) remains incompletely understood, and effective treatments are still not available. In the last three decades, the interaction(s) between CVD and AD have attracted considerable interest. Mixed AD/CVD pathology is commonly seen in patients with clinically diagnosed AD dementia. Combined vascular and AD pathology is the leading cause of dementia in the very old, and there is a debate on whether this is due to an additive effect of both pathologies on cognitive impairment, and whether it represents an interaction between the two pathologies. This thesis explored the association and interaction between cerebrovascular disease and AD pathology/dementia from the perspectives of plasma lipid profiles, imaging biomarkers, post-mortem pathology, and animal models. In addition, studies on plasma biomarkers of AD and VaD and their independent contribution to dementia and cognitive decline were interpreted. In chapter 2, a systematic review and meta-analyses of several cerebral small vessel disease (CSVD) imaging biomarkers and AD found that CSVDs alone were not able to predict AD incidence but were associated with AD dementia and AD pathology. The strength of relationship increased with the presence of Apolipoprotein E (APOE ε4) genotype. Periventricular and parietal white matter hyperintensities (WMHs) and cortical microbleeds (CMBs) had stronger association with AD than CSVDs in other regions. Microinfarcts were less well studied in related imaging studies. We also further explored CSVDs and other cerebral vascular injuries in the aspect of neuropathology. In chapter 3, a cross-sectional study of autopsy brain pathology from National Alzheimer’s Coordinating Center (NACC) showed that CVD pathology had an additive effect with AD pathology in the development and progression of Alzheimer’s dementia. The relationship between the plasma lipidome and VaD and AD has received little attention. In chapter 4, liquid chromatography mass spectrometry was used to demonstrate that plasma ceramides and cholesterol-esters had the highest accuracy for the classification of VaD from controls, while in chapter 5, I showed that AD could be best discriminated by plasma cholesterols esters, sphingomyelins and triglycerides. The results obtained from clinical samples were supported by my preclinical animal model work which involved the induction of cerebral vascular lesions in AD transgenic mice. These mice were double transgenic rodents containing a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9), both directed to neurons. In chapter 6, neuroinflammation and cognitive deficits were significantly worse in APP/PS1 mice injected with endothelin-1 – a neuropeptide and vasoconstrictor – in the internal capsule compared to APP/PS1 controls. Finally, the neuroprotective effects of the glutathione precursor against biomarkers of oxidative stress, inflammation, Aβ pathology and ferroptosis, and its outcome on spatial memory in APP/PS1 mice were reported in chapter 7. Our findings on imaging and neuropathological biomarkers of cerebral vascular lesions collectively suggested that vascular lesions had a potentially additive effect on AD pathology in Alzheimer’s dementia. The result was supported by our animal study on interaction of induced brain infarcts and AD-like pathological hallmarks in transgenic mice. The two pathologies might have distinct profiles, especially at the lipid level. Strategies aimed at replenishing GSH levels using GGC may have beneficial effects in AD and other neurodegenerative diseases as well as on the ageing brain.
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Liu, Yue
Nady, Braidy
Sachdev, Perminder
Poljak, Anne
Wen, Wei
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PhD Doctorate
UNSW Faculty
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