Microvascular alterations and Corpora Amylacea progression in the post-mortem hippocampus of patients with obstructive sleep apnoea

Xu, C 2019, Microvascular alterations and Corpora Amylacea progression in the post-mortem hippocampus of patients with obstructive sleep apnoea, Doctor of Philosophy (PhD), Health and Biomedical Sciences, RMIT University.

Document type: Thesis
Collection: Theses

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Title Microvascular alterations and Corpora Amylacea progression in the post-mortem hippocampus of patients with obstructive sleep apnoea
Author(s) Xu, C
Year 2019
Abstract Obstructive sleep apnoea (OSA) is a sleep disorder that involves frequent episodes of breathing cessation or significant decreases in airflow during sleep, leading to periods of blood oxygen desaturation. These episodes of intermittent hypoxia (IH) followed by reoxygenation are thought to induce oxidative stress and neuroinflammation. Patients with severe OSA exhibit neuropsychological deficits and impaired memory. Continuous positive airway pressure (CPAP) is the standard treatment for OSA patients, but not all cognitive symptoms can be reversed by this procedure, suggesting that severe OSA may permanently injure the brain. The CA1 region of the hippocampus is one of the first regions of the brain to suffer hypoxic injury. This vulnerability is supported by imaging studies showing that the volume of the hippocampus is reduced in people with severe OSA. Since it is not known why some parts of the hippocampus are selectively vulnerable to hypoxia, an investigation of the microvessels in these regions could provide new insights.

The first aim of the present study was to investigate the effects of OSA severity, regular CPAP use and advanced age on angiogenesis and microvascular remodelling in different regions of the hippocampus (Chapter 3). It was hypothesised that there would be significantly increased microvascular alterations in the high OSA group (oxygen desaturation index: ODI
≥ 20 events/h sleep) compared to the low OSA group (ODI < 20 events/h sleep). The hypothesis was tested by measuring capillaries that had been immunostained by either CD34, VWF, Claudin 5, GluT-1 or Collagen IV, in the fimbria, CA4, CA1, subiculum and collateral sulcus regions. Analyses were conducted on formalin-fixed, paraffin-embedded hippocampal tissues obtained at autopsy from 30 OSA patients. The results showed that angiogenesis did not occur in OSA; instead moderate-severe OSA was associated with a 10 - 25% increase in the mean diameters of capillaries in the fimbria and CA4 regions, suggesting that microvascular remodelling occurred in response to IH in OSA. These changes were not reversed by CPAP treatment. The lack of adaptive microvascular changes in the CA1 region might be a factor in the selective vulnerability of this region to hypoxia.

The second aim was to systematically investigate the presence of morphological abnormalities in the microvessels of the hippocampus of OSA patients (Chapter 4). It was hypothesised that if microvascular abnormalities are caused by oxidative stress, they would be more prevalent in the high OSA group and advanced age group, while regular CPAP users would display fewer abnormalities. The results showed there were increased numbers of abnormal microvessels in the high OSA group in the CA1 region, but not in other parts of the hippocampus. It is speculated that increased numbers of abnormal microvessels in the CA1 region enhances its vulnerability to hypoxic injury and causes permanent degenerative changes that limit the ability of CPAP to reverse memory impairments.

Corpora amylacea (CoA) are often regarded as correlates of the ageing process, and their numbers have been reported to increase steadily after the age of 50. Despite the fact that CoA were first identified in the central nervous system (CNS) over a century ago, little is known about their spatial distribution in the hippocampus of aged OSA patients. The third aim was to determine the distribution and progression pattern of CoA in the hippocampus, and to assess how the density and size of CoA change with advancing age (Chapter 5). It was hypothesised that CoA would be concentrated in periventricular and subpial regions, and that their density and size would increase with age. The results revealed that while the size of CoA increases with age, the packing density does not. A distinct distribution pattern of CoA was observed by low-magnification scanning photomicrographs that began at the fimbria and then progressively spread along the pial surface of the hippocampal formation to more distant regions. This progression pattern did not correlate with age. This spatiotemporal sequence has not been reported previously, and the reasons for this pattern of spread are unknown.

The fourth aim of the present study was to investigate factors that may be associated with CoA formation (Chapter 6). Since CoA contain oxidised lipids and proteins, it has been speculated that they are markers of oxidative stress or the consequence of neurodegenerative processes. It was hypothesised that increased OSA severity would be associated with larger and more numerous CoA. The results confirmed that OSA severity was significantly correlated with the spatiotemporal distribution of CoA, as well as increased CoA density. However, as these correlations did not diminish with regular CPAP use, a role for hypoxia or oxidative stress was not supported. Furthermore, CoA were rarely observed in the CA1 region, despite this region being thought to experience the highest levels of hypoxia and oxidative stress. The data also failed to support neurodegeneration as a cause of CoA, as no correlations were found between CoA burden (distribution, density or size), and the burden of Amyloid ß (Aß) plaques, Tau+ neurofibrillary tangles, neuropil loss or demyelination.

This study advances our understanding of regional differences in the capacity of the hippocampal microvasculature to remodel in response to increasing severity of OSA and to ageing, and offers a new explanation for the selective vulnerability of the CA1 to hypoxia. This study also advances our understanding of the factors that contribute to the formation of CoA, showing that OSA severity is correlated with the spatial extent and numbers of CoA in the hippocampus, while patient age is correlated with their size. In contrast, oxidative stress and neurodegeneration now appear unlikely to contribute to the formation of CoA in the human hippocampus. It is recommended that larger studies be conducted, that include patients without OSA, so that the present findings can be confirmed and extended.
Degree Doctor of Philosophy (PhD)
Institution RMIT University
School, Department or Centre Health and Biomedical Sciences
Subjects Central Nervous System
Keyword(s) Obstructive sleep apnoea
Chronic intermittent hypoxia
Oxidative stress
Continuous positive airway pressure
Vascular remodelling
Corpora amylacea
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Created: Mon, 30 Sep 2019, 14:43:50 EST by Adam Rivett
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