Neuropathology of obstructive sleep apnoea.

Owen, J 2017, Neuropathology of obstructive sleep apnoea., Doctor of Philosophy (PhD), Health and Biomedical Sciences, RMIT University.

Document type: Thesis
Collection: Theses

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Title Neuropathology of obstructive sleep apnoea.
Author(s) Owen, J
Year 2017
Abstract Obstructive sleep apnoea (OSA) is a sleep disorder involving frequent cessations of breathing due to collapse of the upper airway, leading to sleep fragmentation and hypoxia in the brain. Neuroimaging studies have found evidence of atrophy and degenerative changes in the brains of untreated OSA patients as well as cognitive deficits. Continuous positive airway pressure (CPAP) is an effective treatment that restores airflow when used during sleep. The precise neuropathological changes occurring in the brains of OSA patients are currently unknown. Animal models of intermittent hypoxia (IH) have been utilised to investigate neuropathological changes that might be occurring in the human brain. Such studies have found that mice exposed to IH show brain atrophy, reduced myelination, reactive gliosis and increased phosphorylation of tau protein leading to neurofibrillary tangle (NFT) formation. Additionally, genetically modified mice that express phenotypic changes associated with Alzheimer’s disease (AD) and exposed to IH show an increase in a hallmark pathological marker of AD: beta amyloid (Aβ) plaques. Aβ plaques and NFTs are abnormal protein aggregates that accumulate in the brains of patients with AD, initially in the hippocampus. One study has previously investigated the neuropathological changes in OSA patients, however the hippocampus was not examined. The aim of the present thesis was to investigate neuropathological changes in post-mortem hippocampal tissue of OSA patients using immunohistochemistry. The study also compared the similarity of these changes to those observed in AD, as well as the effect of CPAP treatment and the effect of age. The study sample included brain tissue from 34 (18 female, 16 male) Icelandic OSA patients with a mean age of 67.0 ±11.1 years.

AD is typically diagnosed in late life, with age being the biggest risk factor, but neuropathological changes are thought to begin decades prior to clinical diagnosis. OSA is usually diagnosed in midlife. Since there is a higher prevalence of OSA among patients with dementia/AD than in the general elderly population, it seems possible that OSA may trigger the neuropathological changes associated with AD. In this thesis, the first project assessed the accumulation of Aβ plaques and NFTs in the brainstem and hippocampus of OSA patients. In the brainstem, no association was found between the presence of Aβ plaques or NFTs and severity of OSA. In the hippocampus, significant relationships were found between OSA severity and the burdens of NFTs (r2=0.166, p=0.017) and Aβ plaques (r2=0.134, p=0.033). The burdens of NFT and Aβ in the hippocampus increased with OSA severity, with both relationships being stronger in patients who did not use CPAP and weaker in those using CPAP (NFTs No CPAP vs CPAP, r2=0.315 vs 0.023; Aβ No CPAP vs CPAP, r2=0.360 vs 0.059). This result indicates that CPAP is protective against the accumulation of Aβ plaques and NFTs. Age was a factor in the relationship between OSA severity and NFTs (r2=0.314, p=0.001), but not for Aβ burden.

The second project investigated the relationship of OSA severity and reactive gliosis. Reactive gliosis is the response of glial cells to injury in the brain and is commonly seen after a variety of different brain injuries including AD. Reactive gliosis was assessed via counts of immunolabelled microglia and astrocytes and by measuring the intensity of immunoreactivity in five regions of the hippocampus: hilus, CA3, CA1, subiculum and entorhinal cortex. Evidence of reactive gliosis in relation to OSA severity was found in all regions except the CA1, with age influencing some relationships. Increasing OSA severity was associated with increased numbers of microglia in the hilus (r2=0.134, p=0.033) and subiculum (r2=0.197, p=0.010), and increased numbers of astrocytes in the subiculum (r2=0.132, p=0.038), increased intensity of immunolabelling of astrocytes in the entorhinal cortex (r2=0.178, p=0.028) and decreased intensity of immunolabelling of astrocytes in the CA3 (r2=0.123, p=0.042). These findings indicate that reactive gliosis is present in the hippocampus in severe OSA and it involves regional subpopulations of astrocytes. All significant relationships between glial markers and OSA severity were stronger among CPAP non-users and most were weaker among CPAP users, suggesting that CPAP may attenuate these changes.

The third project investigated the size of the hippocampus and degree of demyelination in relation to OSA severity. Severe hippocampal atrophy and demyelination are commonly seen in AD and neuroimaging studies suggest that similar changes may occur in OSA. Cortical cell layer thickness was measured in the CA1 and entorhinal cortex, and layer area was measured in the dentate gyrus. The intensity of myelin basic protein immunoreactivity was measured in the same regions to investigate demyelination. As OSA severity increased, decreases were seen in the thickness of cortical layers in CA1 (total depth, r2=0.135, p=0.039; layer 1, r2=0.157, p=0.025; layer 2, r2=0.255, p=0.003; layer 3, r2=0.185, p=0.014), the molecular layer of the dentate (r2=0.136, p=0.038) and to a lesser extent in entorhinal cortex (layer 1, r2=0.186, p=0.028). Cortical thickness in layer 2 of CA1 was influenced by age. As OSA severity increased, the extent of myelin diminished in the entorhinal cortex (layer 6, r2=0.282, p=0.006; deep white matter, r2=0.390, p=0.001), indicating that demyelination occurred in these regions. The extent of myelination was unaffected by age. Many of the hippocampal size relationships were stronger in CPAP non-users and weaker in CPAP users, suggesting that protection is afforded to CPAP users. Conversely, most of the demyelination relationships did not change with CPAP status, indicating that CPAP is ineffective at attenuating demyelination.

For the first time, AD-like neuropathology, reactive gliosis, cortical atrophy and demyelination have been observed in the hippocampus of OSA patients. Additionally, CPAP has been shown to reduce such neuropathological changes, providing strong incentives for patients to adhere to treatment. The spatiotemporal pattern of neuropathological changes in OSA is remarkably similar to that seen in early AD, suggesting that OSA may accelerate the pathogenesis of AD. The present thesis has limitations, including the relatively small sample size and the lack of a control group, and additional research will be needed to confirm and extend these findings. Nonetheless, this thesis has found that there are significant neuropathological changes associated with increasing OSA severity that can be attenuated with CPAP treatment, and it supports the interesting possibility that CPAP may have potential as a prophylactic treatment against AD.
Degree Doctor of Philosophy (PhD)
Institution RMIT University
School, Department or Centre Health and Biomedical Sciences
Subjects Neurology and Neuromuscular Diseases
Keyword(s) Obstructive sleep apnoea
Alzheimer's disease
Neurofibrillary tangle
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Created: Wed, 13 Dec 2017, 09:06:08 EST by Denise Paciocco
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