Obstructive Sleep Apnea Outcome Analysis

Overall Goal: This research plan will develop the candidate’s knowledge and skills in the diagnosis and treatment of obstructive sleep apnea, methodology and outcome analyses in longitudinal trials, and neuroimaging to provide expertise in cerebral microvascular contribution to cognitive deterioration and depressive symptoms in elderly patients with OSA.
Significance: Obstructive sleep apnea (OSA) is a major health problem, as more than 22 million adults in the U.S suffer from
OSA but estimates suggest that 85% of individuals with moderate to severe OSA remain undiagnosed.1 Patients with untreated moderate to severe OSA are at a greater risk for depression, mild cognitive impairment (MCI), and dementia compared to those without OSA. In OSA,
repetitive intracranial blood flow surges during apneic episodes cause disturbances in microvascular functions, resulting in hypoperfusion2-4 and poor cerebral vasomotor reactivity.5-7 Hypoxemia promotes the development of cerebral small vessel disease (C-SVD).8-11 A consequence of C-SVD is disruption of neuronal activity in regions involved in regulation of mood and cognition 9,12,13 and changes in prefrontal and frontal lobe vascular perfusion8,14-16 as demonstrated by imaging studies of OSA.
Also, hypoxia and reoxygenation cause oxidative stress,17,18 that alters blood-brain barrier functions, leading to the formation of C-SVD19-21 and cerebral amyloid angiopathy (CAA).22-25 Hypoperfusion causes an accumulation of toxic Aβ aggregates and a reduction of amyloid clearance.26 The progression of C-SVD has shown to be associated with new onset of depression,27 MCI, and a higher rate of conversion from MCI to dementia28-30 in elderly patients. Therefore, we hypothesize that C-SVD may mediate the associations between OSA and depression and cognitive impairment. The presence of multiple neuropsychiatric manifestations of OSA may represent mixed pathologies and indicate damage to various areas of the brain. In our pilot
MRI data in 19 elderly patients with both depression and MCI, compared to the non-OSA group (n=13), the OSA group (n=13) had greater baseline MRI signal hyperintensities in deep white matter (effect size=0.49, F=11.3, df=12, p=0.006), periventricular white matter (effect size=0.32, F=5.6, df=12, p=0.035), and subcortical gray matter reduction (effect size=0.40, F=8.0, df=12, p=0.015) after controlling for age, sex, education, intracranial volume, and bilateral hippocampal volume. Also, more patients in the OSA group had grade 2 to 3 deep white matter lesions (33% vs. 0%) and periventricular white matter lesions (83% vs. 46%) than in the non-OSA group, suggesting that OSA may contribute to the development or progression of C-SVD. Our pilot MRI data supports our hypothesis. The goals of this Mentored Patient-Oriented Research Career Development Award (K23) research plan are to test our hypothesis that OSA causes depression and MCI through damaging C-SVD by investigating whether the improvement of cognition and depression are correlated with the improvement of C-SVD with CPAP treatment.
Specific Aims: Patients (aged 65+ years) will be recruited from the Depression and Memory Disorder Clinics.
Patients meet the criteria for MCI (Logical Memory I or II ≤ 11) or a current episode of depression (DSM-V and 12 ≤ HRSD ≤ 30) and have a stop-Bang score of ≥ 3 will receive out of center OSA diagnostic test for 2 consecutive nights. Total 60 patients with OSA (AHI ≥15), including 30 with depression and 30 with MCI, will receive CPAP treatment. Cognitive measures include Verbal Memory (SRT), processing speed (Trial A and Digit Symbol), and executive function (Trial B and Digit Symbol); depression is measured with HRSD and BDI. After 3 months of CPAP treatment, if depressed patients do not respond to CPAP treatment for depression (≤ 50% reduction in HRSD) and patients have a new onset of depression (HRSD≥ 12), they will be treated with serotonergic antidepressants while continuing CPAP treatment. The rationale is that serotonergic antidepressants improve depression and may improve OSA by reducing upper airway collapsibility. MRI (WMHs and WMLs) and DTI (white matter integrity) are used to measure the microvascular burden in all patients at baseline and 6
months.
Aim 1: Determine the effects of CPAP on neurocognitive symptoms in elderly patients with OSA
Hypothesis 1a: Patients will show significant improvement in cognitive outcome measures
Hypothesis 1b: Depressed patients will show significant improvement in depressive symptom measures
Aim 2: Evaluate the effects of CPAP on the changes of volume of WMHs and the severity of WMLs.
Hypothesis 2a: Patients will show significant improvement in both WMHs and the severity of WMLs
Hypothesis 2b: Depressed patients will show significant improvement in DWMHs and DWMLs
Aim 3: Investigate the microvascular mechanisms underlying the associations between OSA and neurocognitive functions
Hypothesis 3a: At 6 months, the improvement of both WMHs and WMLs will be significantly correlated with the improvement of cognitive measures with CPAP treatment. Hypothesis 3b: At 6 months, the improvement of both WMHs and WMLs will be significantly correlated with the improvement of depressive symptoms with CPAP treatment.
Aim 4: Explore whether add-on medications to treat residual neurocognitive symptoms after 6 months adequate CPAP treatment are beneficial. Hypothesis 4a: Patients with residual depression (HRSD ≥ 7) will show further improvement with add-on antidepressant. Hypothesis 4b: Patients with residual MCI will show further improvement with Aricept.