Cohort Study of Risk Factors for Postoperative Cognitive Decline

Adults 65 years and older represent the fastest-growing age group in the United States, and
account for one third of all surgical patients. These older adults are at the highest risk
for deleterious postoperative neurocognitive outcomes. Postoperative cognitive dysfunction
(POCD) occurs in up to 40% of older adults after major non-cardiac surgery. POCD is a
syndrome characterized by a decrease in performance on neuropsychological test battery from
before to after surgery. Neuropsychological testing for POCD typically spans cognitive
domains including memory, attention, concentration, and/or executive function. There is an
increasing body of literature suggesting that exposure to surgery and anesthesia increases
the risk of Alzheimer's disease (AD). Surgery and anesthesia enhance neuropathologic changes
known to underlie AD including amyloid beta accumulation and aggregation, neuroinflammation,
increased levels of tau and tau phosphorylation, and memory decline. However, not everyone
with a history of surgery and anesthesia develops POCD, suggesting biological risk factors
are involved. It is well established that the gene most strongly associated with AD is
apolipoprotein E (APOE), with the APOE4 allele conferring an increased risk of AD in a
sex-dependent manner. Our recent retrospective longitudinal cohort study found that an APOE4
allele was associated with an accelerated rate of cognitive and functional status decline
following surgery. Another gene polymorphism of interest is the PLA2-allele of the gene
encoding platelet glycoprotein IIIa. A recent investigation of cardiac surgery patients found
that PLA2-allele was present in a significantly higher percentage among subjects that had
POCD when compared to those without cognitive decline. Although the mechanisms of POCD remain
unclear, our preliminary data suggest that the PLA2 and APOE4 alleles contribute to POCD in
older adults in a sex-dependent manner. Presently, the role of either genetic factors or
biological sex in the development of POCD is unknown. There is, therefore, a critical need to
determine which individuals are at high-risk for developing POCD by virtue of biological sex
or genetic predisposition. The knowledge gained in the proposed research has the potential to
shed light on mechanistic pathways, a necessary next step in order to ultimately identify
therapeutic strategies.

Innovation Sex Differences: Though half of the US surgical population is comprised of women,
basic and clinical perioperative research studies have either excluded women or have matched
cases-controls by sex to avoid confounding. We will be the first to determine effects of sex
in POCD in a prospective, clinical cohort. Multi-disciplinary Approach: One barrier to
progress in this field is the lack of a multi-disciplinary, collaborative approach. Few
perioperative physicians are well versed in aging/dementia research or neuropsychological
testing. This proposal describes collaboration among experts in neurology, anesthesiology,
geriatrics, dementia, and perioperative medicine. Study population: Because age and
pre-existing cognitive impairment are the most well known risk factors for POCD, we will
enrich our study population by including only subjects ≥65 years. Unlike prior studies, we
will not exclude participants with mild cognitive impairment. Study Outcomes: We will include
functional status outcomes (i.e. IADLs), which are absent from most POCD studies. Genetic
variables: This will be the first study to investigate the role of PLA2 in POCD following
non-cardiac surgery.

Preliminary Studies APOE4 increases the risk of postoperative cognitive dysfunction: We
performed a retrospective cohort analysis of several Oregon Alzheimer's disease Center (OADC)
longitudinal cohort studies: the Oregon Brain Aging Study (OBAS), the Intelligent Systems for
Assessing Aging Changes (ISAAC),14 the Klamath Exceptional Aging project (KEAP), and the
African American Dementia and Aging Project (AADAPt). We compared the rate of change over
time in various cognitive and functional status measures. Out of a total of 1,052 subjects,
247 subjects had surgery/anesthesia after study enrollment. Subjects underwent cognitive and
functional test batteries once/year. The mean follow-up after study enrollment was 7 years
(SD=4.6). After controlling for age, level of education, and Cumulative Illness Rating Scale
(CIRS) score, we found that the surgical group experienced a more rapid rate of deterioration
compared with the nonsurgical group in multiple cognitive and functional measures.
Furthermore, when compared with APOE- subjects, subjects with an APOE4 allele had an
accelerated rate of cognitive and functional decline after surgical exposure.

Older men with APOE4 are at higher risk of postoperative cognitive dysfunction: Next, we
divided the above cohort by sex and repeated the analyses comparing men and women who were
exposed to surgery/anesthesia. When controlling for the presence of an APOE4 allele, we did
not find any sex differences in cognitive outcomes after surgery. (Data not shown) However,
when we compared men vs. women APOE4 carriers, we found that men with at least one copy of
the APOE4 allele who were exposed to surgery/anesthesia had a more rapid rate of decline in
several measures of cognition.

Inclusion Criteria:

- Scheduled for an in-patient, elective spine surgery where subject will receive general
anesthesia

- Presenting to spine clinic and undergoing conservative, non-surgical management of
spine disorder

- Subjects must have sufficient vision and hearing to complete neuropsychological
testing

- Proficient in spoken and written English language

Exclusion Criteria:

- Diagnosed dementia or dementia-related treatment (i.e. donepezil prescription, or
memory-care facility residence)

- Significant disease of the central nervous system (CNS) (i.e. Parkinson's disease)

- History of stroke or traumatic brain injury

- Major psychiatric disorder (i.e. schizophrenia)

- Alcohol or drug abuse according to DSM-V within the last 2 years

- Need for urgent/emergent surgery

- Surgery/anesthesia within prior 12 months

- Refusal of consent