(Chapter 5) was a randomised controlled trial of CPAP’s effect on brain structure in older

people with OSA. This is the first time the combined effects of OSA and aging on brain structure have been reported. MRI brain images were collected at baseline and 6 months after randomisation to

112 either CPAP or BSC. These were analysed using FreeSurfer, this time focusing specifically on hippocampal subfields, as I had already shown hippocampal hypertrophy in younger patients in study 1 and the hippocampus is known to be a site of neurogeneration in ischaemic preconditioning in animal models. I found fimbial hypotrophy after 6 months of CPAP in older patients with OSA but no hippocampal hypertrophy. This may be because aging leads to a reduction in neurogenerative capabilities inhibiting the protective effects of ischaemic preconditioning. Alternatively older OSA patients, who are less sleepy than younger patients, have actually had undiagnosed OSA for a long period, and prolonged exposure to IH has resulted in cessation of neurogeneration, as it has been shown to do in animal models.

6.2. FUTURE RESEARCH

Further work is needed to investigate the effects of intermittent hypoxia on brain structure and function in humans, as well as the protective role of ischaemic preconditioning. There is a subset of patients with moderate and severe OSA who are not symptomatically sleepy. Current guidelines state that these patients do not need to be offered CPAP. However these patients are still exposed to IH and sleep fragmentation. If either of these stimuli cause neural hypotrophy and cognitive dysfunction then these guidelines may have to be reviewed. This would be especially important if, as my thesis suggest, the hypotrophy and memory impairment are reversible in younger people, but not in older people, who may have been exposed to the stimuli for a prolonged period.

We have shown an association between cognitive function and brain structure in OSA. It would be very difficult to prove a cause and effect mechanism, but more studies investigating both brain structure and cognitive function in large numbers of patients would provide strong circumstantial evidence. In order to achieve the required sample size, collaboration among multiple research teams would be required. This might lead to the development of a standard battery of cognitive tests, sensitive to the deficits seen in OSA patients, which would aid the comparison of results between groups and allow meta-analyses to be carried out.

Driving ability is one of the most important complex cognitive tasks known to be impaired in OSA. This has a high cost, both economic and in terms of mortality. Current guidelines suggest that OSA patients can continue to drive if they are not excessively sleepy. IH may be linked to brain hypotrophy and impaired driving ability in non-sleepy OSA patients. I have shown that some patients do not develop brain hypertrophy after CPAP treatment but in fact develop further hypotrophy. Further research is required to investigate if brain hypotrophy in these patients is associated with impaired driving performance. If it is then the guidelines would need to be reviewed.

113 In order to further explore the relative roles of intermittent hypoxia and sleep fragmentation on brain structure, cognitive function and driving ability in OSA patients, I would propose a three armed randomised controlled trial. The first arm would be allocated to best supportive care and would therefore be exposed to both IH and sleep fragmentation. The second arm would be allocated to CPAP therapy and would therefore be exposed to neither IH nor sleep fragmentation. The third arm would be allocated to nocturnal oxygen therapy. This would not prevent airway obstruction and sleep fragmentation, but would remove the intermittent hypoxia. I would obtain MR brain images and measure cognitive function and driving simulator performance at baseline and again after 3 months of treatment. I would also study matched healthy controls at baseline and at three months.

It would be intriguing to study brain structure and cognitive function in subjects with restless leg syndrome, whose sleep is fragmented but who are not exposed to intermittent hypoxia. However it would not be possible to determine whether any changes in brain structure in these subjects were the result of sleep fragmentation or whether they were caused by frequent leg movements, or were even the cause of the restless leg syndrome The effects of pure sleep fragmentation could also be studied by using external interruptions to provoke frequent arousals from sleep in healthy controls over a prolonged period. However this approach would be difficult both practically and ethically.

The effects of intermittent hypoxia during sleep could be studied by manipulating the atmospheric oxygen concentration while healthy controls slept. Again, to mimic OSA, this would need to be done over prolonged period and this would be difficult practically and ethically. However this approach could be used in animal models to determine at what point IH stops being beneficial.

New automated techniques for the analysis of brain imaging are being developed constantly. Studies are needed to ensure that these techniques are validated in human brains, perhaps in post-mortem studies. Once they are proven to be valid they should be used to analyse as much data as possible. Automated analysis allows for rapid and relatively inexpensive analysis of large volumes of data. It is imperative that it used effectively and to its full potential.

Poor CPAP compliance means that this treatment, which is highly efficacious at preventing apnoeic events if worn, cannot be considered the panacea of OSA treatment. Potential new techniques for preventing apnoeas may include nerve stimulation or less invasive devices to maintain airway patency. If the sequelae of OSA are mediated by IH then enriching inspired air with oxygen may be beneficial. Pharmacological cures must continue to be explored. Above all, preventative measures in the field of public health must succeed to prevent an epidemic of OSA and all the health problems it causes.

6.3 CONCLUSION

114 The overall conclusion of the studied presented in this Thesis is that OSA leads to brain hypotrophy and cognitive impairment. However ischaemic preconditioning by IH may also be protective and lead to increased connectivity through dendritic sprouting. In younger patients ongoing dendritic sprouting leads to restoration of functional cognitive neural pathways after treatment. Future work should focus on preventing brain hypotrophy and ensuring effective treatment of OSA before neurogeneration switches off.

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