A Pilot Study of Biomarkers in Obstructive Sleep Apnea

It is being increasingly understood that OSA represents an inflammatory state, with multiple
studies showing increased levels of circulating cytokines, possibly providing the link
between OSA and cardiovascular/pulmonary morbidity (Nadeem et al., 2013). In support of this,
use of CPAP therapy is associated with a reduction in the levels of circulating cytokines in
patients with OSA (Baessler et al, 2013). Despite these data, to our knowledge, there are no
studies that specifically examine the association between the presence of cytokines and
surgical complications. The present investigation may be helpful for future studies looking
at this relationship. Inflammation has recently been emphasized as a component of the CNS
manifestations of OSA as well, including generalized cognitive deficits and post-operative
delirium (Flink et al., 2012; Lal et al., 2012). It is possible that intermittent hypoxia
leads to CNS inflammation/activation of microglia (as has been shown in in vitro studies;
Yang et al., 2013), which, together with blood-brain barrier (BBB) breakdown (recently shown
to be involved in OSA; Lim & Pack, 2014), results in elevated circulating peripheral levels
of cytokines. Alternatively (or additionally), there could be direct peripheral activation of
systemic macrophages as a consequence No Title Page 6 of 36
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4/15/16 of sleep deprivation and the cortisol/stress response to this condition. In any
event, to date, there are no studies exploring the presence or levels of cytokines in the CSF
of patients with OSA. In addition to the release of inflammatory cytokines, activation of
microglia causes the release of neuroprotective neurotrophins (Nakajima & Kohsaka, 2004).
Alterations in levels of several neurotrophins have been implicated in multiple CNS diseases.
For example, in Parkinson's disease, there is a known elevation in cytokines with reduced
circulating levels of CSF neurotrophins (BDNF and NGF) and this balance has been posited to
underlie some of the symptoms and progression of the disease (Nagatsu et al., 2000). BDNF has
recently been shown to protect against the development of Alzheimer's disease and dementia,
as well as to increase with caloric restriction and physical activity (Aisen, 2014).
Considering OSA is associated with obesity, it is possible that low BDNF may (at least in
part) mediate some of the cognitive deficits seen in OSA. Additionally, low BDNF is
associated with postoperative delirium in clinical studies (Grandi et al., 2011). Currently,
the role of neurotrophins in OSA remains underinvestigated. Of all the known neurotrophins,
only BDNF has been studied in OSA patients, and the results are conflicting, with some
studies suggesting reduced levels of serum BDNF (Wang et al., 2012) and others showing no
differences compared to control patients (Panaree et al., 2011). This may in part be due to
the detection methods employed or small sample sizes, and to date, no one has investigated
CSF levels of neurotrophins in this patient population. Here we hypothesize that the
detrimental effects of circulating cytokines in OSA may be balanced in some patients by
beneficial effects exerted by neurotrophins, and that this differential balance may
represent: 1) a tool for identifying which patients are at risk for post-operative
complications in future studies, i.e., a useful biomarker for stratifying operative risk; 2)
a new understanding of the pathophysiology of OSA; and 3) a role for neuroprotective
strategies in the management of OSA.

Inclusion Criteria:

- Patients between the ages of 50 and 84

- Treated and Untreated OSA Patients: Known OSA, diagnosed by polysomnography

- Treated OSA Patients: Known CPAP prescription, dose used nightly, and compliance
status

- Controls: No suspicion for OSA, based on STOP-BANG screening score (<3)

- Any patient presenting for knee replacement surgery with prior consent for spinal or
combined spinal-epidural anesthesia

Exclusion Criteria:

- Presence of dementia

- Presence of cognitive disease

- Presence of depression, anxiety, or other mood disorder(s)

- Recent oral steroid therapy (within prior 6 months)

- Requirement of stress-dose steroids pre-operatively

- Autoimmune disease

- Neurologic disease

- Controls: Suspected OSA, either disclosed by patient, or by clinical suspicion based
on STOP-BANG questionnaire (score ≥ 3)

- Chronic renal disease

- Chronic liver disease

- Traumatic spinal or spinal-epidural placement (i.e., blood-contaminated CSF)

- Alcohol abuse - defined as being diagnosed with alcohol abuse or consuming more than 2
drinks per night, on average

- Use of NSAIDs within 7 days prior to surgery

- Chronic benzodiazepine use (for more than one month)