Sleep-Disordered Breathing in Vietnam Veterans with Posttraumatic Stress Disorder

REGULAR RESEARCH ARTICLES

Sleep-Disordered Breathing inVietnam Veterans with Posttraumatic

Stress Disorder

Jerome A. Yesavage, M.D., Lisa M. Kinoshita, Ph.D.,Timothy Kimball, Ph.D., Jamie Zeitzer, Ph.D., Leah Friedman, Ph.D.,

Art Noda, M.S., Renaud David, M.D., Beatriz Hernandez, B.A.,Tina Lee, M.D., Jauhtai Cheng, M.D., Ph.D., Ruth O’Hara, Ph.D.

Objective: To study the prevalence of sleep-disordered breathing (SDB) in Vietnam-era veterans. Methods: This was an observational study of Vietnam-era veteransusing unattended, overnight polysomnography, cognitive testing, and genetic mea-sures. Results: A sample of 105 Vietnam-era veterans with posttraumatic stress disor-der: 69% had an Apnea Hypopnea Index >10. Their mean body mass index was 31,“obese” by Centers for Disease Control and Prevention criteria, and body mass indexwas significantly associated with Apnea Hypopnea Index (Spearman r = 0.41, N = 97,p < 0.0001). No significant effects of sleep-disordered breathing or apolipoprotein sta-tus were found on an extensive battery of cognitive tests. Conclusion: There is arelatively high prevalence of SDB in these patients which raises the question of towhat degree excess cognitive loss in older PTSD patients may be due to a high preva-lence of SDB. (Am J Geriatr Psychiatry 2012; 20:199–204)

Key Words: Sleep-disordered breathing, Vietnam veterans, PTSD, apolipoprotein ε4

T he National Vietnam Veterans ReadjustmentStudy1 estimates that approximately 15% of

Vietnam veterans currently suffer from posttraumaticstress disorder (PTSD) while approximately 30%have suffered from PTSD at some time since their de-ployment to Vietnam. These veterans are now enter-ing an age range in which they are at risk for develop-ing cognitive decline and dementia, joining cohortsof World War II and Korean War veterans. A numberof studies report greater cognitive deficits in subjects

Received September 30, 2009; revised February 5, 2010; accepted February 23, 2010. From the Department of Veterans Affairs Health Care System(JAY, LMK, TK, JZ, TL, JC, ROH), Palo Alto, CA; Department of Psychiatry and Behavioral Sciences (JAY, LMK, TK, JZ, LF, AN, BH, TL, JC, ROH),Stanford University School of Medicine, Palo Alto, CA; and Memory Center (RD), CMRR – CHU, University of Nice Sophia, Antipolis, France.Send correspondence and reprint requests to Jerome Yesavage, M.D., Palo Alto VA Health Care System Psychiatry Services (151Y), 3801 MirandaAvenue, Palo Alto, CA 94304. e-mail: [email protected]

c© 2012 American Association for Geriatric PsychiatryDOI: 10.1097/JGP.0b013e3181e446ea

with PTSD compared with age-matched controls,especially in the areas of memory and attention.2–5

A recent meta-analysis of 28 studies found an effectsize of 0.82 of verbal memory impairment in PTSDversus control groups.6 The prevalence of sleep-disordered breathing (SDB) increases with age, andresearch indicates that SDB can also impair daytimecognitive function.7–10 Furthermore, apolipoprotein(APOE)-ε4 carrier status in individuals with SDBhas been found to impact cognitive function in an

Copyright © American Association for Geriatric Psychiatry. Unauthorized reproduction of thisarticle is prohibited.

Am J Geriatr Psychiatry 20:3, March 2012 199

Sleep-Disordered Breathing in Vietnam Veterans

additive manner.11,12 APOE is involved in lipopro-tein metabolism, and ε4 carrier status has been no-tably associated with increased risk of late-onsetAlzheimer disease.13–15 The purpose of this study isto assess the prevalence of SDB in Vietnam veteranswith PTSD and to examine the impact of SDB andthe APOE-ε4 allele on cognitive impairment in thesepatients.

PATIENTS AND METHODS

Subjects

Community-dwelling veterans 55 years or olderwith PTSD of any race or ethnicity were recruitedthrough media advertisement, local veteran agencies,clinician referral from the outpatient clinics of the VAPalo Alto Health Care System, geriatric clinics, andthe National Center for PTSD branch at the MenloPark Division of VA Palo Alto Health Care System.From these sources, 157 male subjects residingprimarily in the San Francisco Bay Area received aninitial screening, 123 were found eligible for furtherevaluation and, of these, 105 were found eligiblefor study participation (Table 1). The presence ofPTSD was determined by the Clinician AdministeredPTSD Scale,16 with the entry criteria of a ClinicianAdministered PTSD Scale current or lifetime score≥40. Additional scales used to assess the history oftrauma in our subjects included the Trauma HistoryQuestionnaire17 and Life Stressor Checklist revised.18

Subjects were excluded if they 1) had a current orlifetime history of any other psychiatric disorder withprimary psychotic features or symptoms that metDiagnostic and Statistical Manual, Fourth Edition(DSM-IV) criteria for Bipolar Disorder (Struc-tured Clinical Interview for DSM-IV, Non-PatientEdition)19; 2) had a current or recent exposure totrauma in the past 3 months (chart review, inter-view); 3) met DSM-IV criteria for drug or alcoholabuse or dependence (except nicotine) within the last30 days (Structured Clinical Interview for DSM-IV,Non-Patient Edition with an additional measureof alcohol use: Lifetime Drinking History20–22); 4)were alcohol intoxicated (by breathalyzer), in alcoholwithdrawal (by examination) during testing orexhibited toxicology evidence of illicit substanceuse before examination (72-hr metabolite toxicologyscreen); 5) showed evidence of probable or possible

TABLE 1. Demographics of 105 Subjects

Age (yr) 59.9 ± 3.1Education (yr) 14.3 ± 2.4Years with PTSD 31.8 ± 11.1CAPS lifetime Score 81.3 ± 20.9Body mass index 31.1 ± 6.1 (n = 97)

22.8 ± 19.8 (n = 99)(69% with AHI ≥ 10)

Apnea Hypopnea Index (46% with AHI ≥ 20)APOE ε4-carriers 26% ε4-carriersRace (%)

White 70Black/African American 8Am. Indian/Alaska Native 2Asian 1Native Hawaii/Pacific Islander 3More than one race 11Unknown 5

Ethnicity (%)Hispanic or Latino 11Not Hispanic or Latino 80Unknown 9

dementia (Mini-Mental State Examination23 score<23); 6) reported a history of seizure or other neu-rologic disorder or system illness affecting centralnervous system function (chart review, interview);7) had an acute illness or unstable chronic illness(chart review, interview, basic blood chemistries);8) suffered a head injury within 1 year or had ahistory of loss of consciousness >24 hours; or 9) usedsystemic steroid medication (with the exception ofestrogen replacement therapy). Subjects were notrecruited on the basis of presence or absence of sleepor sleep-disordered breathing complaints.

Evaluations

Cognitive status was examined in our subjects us-ing a variety of tests. Our primary outcome mea-sure was the Rey Auditory Verbal Learning Test(RAVLT).24 The RAVLT is a reliable and a valid mea-sure of verbal learning and memory (see Ref. 25for reviews).26 Studies have observed deficits on thismeasure in both PTSD and samples of older individ-uals.27,28 A broad battery of secondary measures(Table 2) was also used, as PTSD seems to beassociated with impairments in memory, atten-tion, concentration, and deficits in speed of mentalprocessing, verbal fluency, and executive function.4

In addition to the Mini-Mental State Examination, thesecondary measures included the following: 1) sub-tests from the Wechsler Adult Intelligence Scale-III,29


200 Am J Geriatr Psychiatry 20:3, March 2012

Yesavage et al.

TABLE 2. Secondary Neuropsychological Measures

Performance: All Subjects

Z-ScoreMeasure Construct Measured n Mean ± SD mean ± SDb

Digit span Attention/concentrationa 105 9.44 ± 2.50 −0.19 ± 0.83Digit symbol Processing speeda 105 9.05 ± 2.70 −0.32 ± 0.90Letter-number sequencing Working memorya 104 10.20 ± 3.20 0.07 ± 1.07Block design Visuospatial abilitya 105 9.98 ± 2.84 −0.01 ± 0.95Rey-Osterrieth complex figure Visual memory, visuospatial Copy 105 31.41 ± 4.24 0.11 ± 1.06

ability, constructions Immediate 105 18.45 ± 7.28 0.29 ± 1.03Recall 105 18.07 ± 7.07 0.49 ± 0.97

Benton Visual Retention Test— Constructions, visual memory Copy 105 9.23 ± 1.07 n/amemory and copy for designs Memory 105 5.72 ± 1.67 −0.85 ± 1.07

Visual Form Discrimination Visual recognition memory, Recognition 105 25.78 ± 4.28 n/aTest—recognition and matching visual perception Matching 105 29.54 ± 2.97 n/a

Logical Memory I and II—WMS-R Verbal memory Log Mem Ia 105 8.73 ± 3.76 −0.42 ± 1.25Log Mem IIa 105 9.08 ± 3.35 −0.31 ± 1.12Percent retention 105 80.88 ± 18.47 n/a

Boston Naming Test Confrontation naming 105 55.11 ± 4.10 0.02 ± 1.08Controlled Oral Word Phonemic fluency 105 36.95 ± 12.54 −0.33 ± 1.03

Association (FAS)Animal Naming Semantic fluency 105 18.77 ± 4.70 −0.22 ± 1.00Trail Making Test (Parts A and B) Set shifting, executive functioning Trails A (Secs) 105 39.19 ± 15.92 −0.55 ± 0.98

Trails B (Secs) 104 101.42 ± 52.20 −0.47 ± 1.08Delis Kaplan Executive Function Executive functioning (cognitive Inhibitiona 103 9.62 ± 3.14 −0.13 ± 1.05

System—Color-Word flexibility, inhibition) Inhibition/switchinga 103 10.28 ± 3.01 0.09 ± 1.00Interference Test

Mini Mental State Examination Global cognitive functioning 100 28.06 ± 1.70 −0.46 ± 1.18

aNormative data used to calculate z scores were based on samples with similar demographics to our sample (age 55 yr and older,education + 12 yrs).

bAge-adjusted scaled scores (mean: 10, SD: 3).

including Digit Span (attention, concentration), DigitSymbol (processing speed), Letter Number Sequenc-ing (working memory), and Block Design (visu-ospatial ability); 2) Rey-Osterrieth Complex Figure(visuospatial constructional ability, and visual learn-ing and memory)30; 3) Benton Visual Retention Test(constructions and visual memory)31; 4) VisualForm Discrimination Test (visuospatial memory)32;5) Logical Memory I and II from Wechsler MemoryScales-R (immediate and delayed narrative auditorymemory and recall)33; 6) Boston Naming Test (ver-bal confrontation naming)34,35; 7) Controlled OralWord Association (phonemic fluency)36; 8) AnimalNaming (semantic fluency); 9) Parts A and B ofthe Trail Making Test (set shifting and speed ofprocessing)37; and 10) Delis Kaplan Executive Func-tion System—Color Word interference test (process-ing executive functioning, cognitive flexibility, andinhibition).38

SDB was assessed in all subjects using unat-tended, overnight polysomnography (Safiro Ambu-latory PSG System; Compumedics, Charlotte, NC).

The standard clinical recording montage includedscalp electroencephalography (applied at positionsaccording to the International 10–20 System of Elec-trode Placement), chin and bilateral tibialis elec-tromyography, electro-oculography, electrocardiog-raphy, nasal and oral airflow (thermister), abdomi-nal and thoracic excursion (piezoelectric band), fingerpulse oximetry, snoring sounds (microphone), andbody position. All data were scored for sleep stagingand respiratory events by a registered polysomno-graphic technologist39 and were reviewed by a diplo-mat of the American Board of Sleep Medicine. Forthis study, a main outcome measure was the Apnea-Hypopnea Index (AHI), a descriptor of the severityof SDB. An apnea is defined as a “cessation or nearcomplete cessation (>70% reduction) of airflow fora minimum of 10 sec,” an hypopnea is “a greaterthan 30% reduction of amplitude in thoracoabdom-inal movement or airflow as compared to baselinewith a greater 4% oxygen desaturation” and AHIrepresents “the number of apneas and hypopneasdivided by the number of hours of sleep.”40(pp.283–284)




reformat last parenthesis to be superscript) All sub-jects with clinically significant SDB (AHI ≥10) agreedto have their primary medical doctors notified of thisfinding. Of the 68 subjects who had AHI ≥10 at base-line, 34 reported whether they used continuous pos-itive airway pressure (CPAP) at follow-up (Year 1).Of these 34 subjects, only seven reported CPAP use(21%) and 27 did not (79%).

The allelic status of APOE was determined in allsubjects. Genomic DNA was extracted from frozenwhole blood samples using the method of Lahiri andNurnberger.41 DNA isolation from plasma was per-formed using the protocol of Fowke et al.42 All DNAextractions were performed in a different laboratoryat which polymerase chain reaction amplificationswere performed to avoid contamination with poly-merase chain reaction products. APOE genotypingwas performed according to the restriction isotypingprotocol of Hixson and Vernier.43

RESULTS

Our subjects were primarily from the San Fran-cisco Bay Area and of the expected demographicmake-up of Vietnam-era veterans living in this region(Table 1). APOE ε4 carrier status was at the expectedprevalence (26% of our sample). The incidence of SDBwas 69% using a criterion of AHI ≥10. As expected,body mass index (BMI) was significantly associatedwith AHI (Spearman r = 0.41, N = 97, p <0.0001).APOE ε4 carrier status was not associated with AHI≥10: mean (SD) AHI scores in APOE ε4 patients was22.9 (18.9) versus 22.6 (20.3) in non-APOE ε4 patients.We also performed a two-way analysis of varianceand found no significant effect of AHI ≥10 (F[1,94j =2.54, p = 0.11), APOE ε4 status (F[194] = 2.64, p = 0.11),or an interaction between the two (F[1,94] = 0.02,p = 0.88) on the RAVLT, our primary cognitive out-come measure, whether the effects of BMI were re-moved. No significant effects of sleep-disorderedbreathing or APOE status were found on an extensivebattery of cognitive tests (two-way analysis of vari-ance, F[1,94] ≤3.08, p ≥0.08; Tables 2 and 3).

DISCUSSION

Recently, a team of researchers44 found that PTSDwas associated with a nearly twofold risk of devel-

TABLE 3. Rey Auditory Verbal Learning Test (RAVLT) by APOEε4 Status, Mean ± SD (n)

All Non-ε4 Carriers ε4 Carriers

All 40.8 ± 9.2 (98) 41.7 ± 9.1 (73) 38.0 ± 9.1 (25)AHI < 10 43.1 ± 6.4 (31) 44.0 ± 6.5 (23) 40.6 ± 5.9 (8)AHI ≥ 10 39.7 ± 10.1 (67) 40.7 ± 10.0 (50) 36.7 ± 10.2 (17)

Notes: 105 evaluations completed but genetic and AHI resultsavailable on 98 for technical reasons.

oping dementia among older veterans such as veter-ans with PTSD had a 7-year cumulative incident de-mentia rate of 14.4%, whereas those without PTSDhad a rate of 8.1%. Using age as the time scale andadjusting for demographics, medical, and psychiatriccomorbidities, patients with PTSD were nearly twiceas likely to develop incident dementia (hazards ratio:1.93, 95% confidence interval: 1.86–2.00). SDB was notstudied by Yaffe et al.; however, a sample of olderveterans with PTSD who were similar to those inour study and possibly in the study by Yaffe et al.was found to have AHI levels higher than expected.45

These findings raise the question of to what degreeexcess cognitive loss in older patients with PTSD maybe due to a high prevalence of SDB.

The BMI of the patients with PTSD in this study av-eraged 31, which is “obese” (not just “overweight”)according to Centers for Disease Control andPrevention criteria (http://www.cdc.gov/healthyweight/). Another study of a similar sample founda BMI of 30 in 157 veterans with PTSD.46 Further,obesity is considered a risk factor for SDB with riskincreasing as BMI increases.47 The findings of a highprevalence of obesity in patients with PTSD suggeststhat it should be a concern not only for its impact onthe general health of the patient but also because itmay engender SDB, which in turn may explain someof the excess cognitive decline seen in these patientsas they grow older.48

Treating SDB coupled with obesity is likely to bea significant challenge in this population. It is wellknown that patient acceptance of CPAP is poor.49

Of particular note is that few in our cohort suc-cessfully followed up with CPAP treatment for SDB.Much current research on the effects of SDB oncognitive function now focuses on patients undertreatment.50 For example, the National Heart, Lungand Blood Institute, is funding the Apnea PositivePressure Long-term Efficacy Study, which includes



Yesavage et al.

neuropsychologic assessments and uses a longitu-dinal design to study the impact of CPAP on acommunity-based sample of SDB patients.51 Thisstudy suggests that even if research demonstratesthat CPAP will help prevent cognitive decline in olderadults, additional research may be needed to de-termine factors that will facilitate Vietnam-era vet-eran patients to seek treatment for both SDB andobesity.

The authors acknowledge the efforts of Emily Luther,Kader Ucar, and Claire Stewart for their assistance withstudy coordination and data collection.

This research was supported by the Sierra-PacificMental Illness Research, Education, and Clinical Center(MI- RECC) and the Medical Research Service of the De-partment of Veterans Affairs. Dr. David’s contribution wasalso supported by an Alzheimer disease Plan grant fromthe Conseil General des Alpes-Maritimes, Nice, France.

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Sleep-Disordered Breathing in Vietnam Veterans with Posttraumatic Stress Disorder