A Prospective Cohort Study Exploring the Associations Between Chronic Postsurgical Pain and Postoperative Cognitive Dysfunction After Elective Knee or Hip Arthroplasty
Conditions: Postoperative Cognitive Dysfunction, Chronic Post Operative Pain, Satisfaction, Patient, Coping Behavior
Sponsor: McMaster University

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Chronic Post-surgical Pain, Postoperative Cognitive Dysfunction and 
Resilience in older people undergoing elective knee or hip surgery: a 
mixed method project to explore associations and underlying 
mechanisms.  The ArthroCaP study 
 
 
Short title (max 25 characters): CPSP, POCD and Resilience 
 
 
Protocol Version 3.0 
July 25, 2022 
 
 
 
 

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Table of Contents 
1. BACKGROUND AND RATIONALE ................................................................................................. 3 
2. OBJECTIVES ........................................................................................................................................ 4 
3. METHODS ........................................................................................................................................... 5 
3.1 Study design .............................................................................................................................................. 5 
3.2 Eligibility criteria ..................................................................................................................................... 6 
3.3 Recruitment and procedures .............................................................................................................. 6 
3.4 Measurements .......................................................................................................................................... 7 
3.4.1 Cognitive/neuropsychological assessment .............................................................................................. 8 
3.4.2 Biomarkers study ................................................................................................................................................. 9 
3.5 Sample size .............................................................................................................................................. 11 
3.6 Statistical analyses ................................................................................................................................ 11 
4. IMPORTANCE OF THE STUDY .................................................................................................... 12 
APPENDIX I. Study timeline, measurements, and data collection ..................................... 13 
REFERENCES ........................................................................................................................................ 15 
 
 
 

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1. BACKGROUND AND RATIONALE 
Surgery has been associated with short and long-term changes in cognition 
(postoperative cognitive dysfunction, POCD).1 2 The literature shows that most often patients 
show POCD during the first 1-3 months after surgery, and then recover.3 However, in the recently 
published NeuroVISION study, up to 30% of 65 years old or older people undergoing different 
types of noncardiac surgery presented a decline of ≥2 points in their Montreal Cognitive 
Assessment (MoCA) score at 1 year after surgery compared to prior to surgery.4 A ≥2 points in 
MoCA score has been shown to correspond to cognitive decline based on formal 
neuropsychological testing and to be of clinical significance.5 6 The risk factors and determinants 
of POCD are poorly understood.7  
Chronic pain has been associated with cognitive dysfunction, in particular memory and 
concentration deficits.8 The existing literature on chronic pain in general supports the hypothesis 
of a bidirectional interaction between pain and cognitive processing.8 However, in a longitudinal 
community-based study, a history of persistent pain (of any origin) at baseline was associated 
with memory decline, and even dementia, over 10 years of follow-up.9 We hypothesize that a 
similar association might exist between post-surgical pain, and in particular chronic post-surgical 
pain (CPSP) and POCD (objective 1). A surgical population including older ages and with an 
expected high prevalence of CPSP, like patients undergoing total knee and hip replacement,10 
seems a suitable population to evaluate this association. In this population, up to 23% of hip 
replacement and 34% of knee replacement surgery patients experience long term pain after 
surgery.11 The long-term need of analgesic therapy, and in particular, the chronic use of opioids 
in patients with CPSP, could also play an independent role in mediating the association between 
CPSP and cognitive changes. Overall, the existing literature on the association between CPSP and 
POCD, including the role of long-term opioid use, is very scanty and controversial.11-13 
The presence of pain, and in particular joint pain, can significantly interfere with mobility, 
and an impaired physical performance can eventually affect the cognitive performance.14 The 
Self-Administered Patient Satisfaction (SAPS) Scale is used as a more comprehensive measure of 
patient recovery after surgery, since it includes the overall satisfaction with surgery, self-reported 
extent of pain relief, and ability to perform home or yard work, and recreational activities.15 
Therefore it is also plausible to hypothesize an association of patient satisfaction (as measured 
by the SAPS) after surgery with long-term cognitive changes (objective 1). 
Mechanisms with which postoperative pain and satisfaction could affect postoperative 
cognitive changes are unclear. One interesting hypothesis is that pain and satisfaction might 
interact with cognitive abilities through neurogenesis interference (objective 2.a).8  This would 
be similar to what is observed in depression.16 17 Numerous studies in animals have linked 
depression with hippocampal-reduced neurogenesis. In rodents, reduced neurogenesis is both a 
consequence of chronic stress exposure, and a vulnerability that predisposes animals to develop 
depressive symptoms when later subjected to stress.18 In the absence of a non-invasive measure 
of neurogenesis in humans, correlational evidence in human studies has identified several high 
interference memory tests (like the Mnemonic Similarity Test [MST]) as putatively neurogenesis-
sensitive, because they are similarly impacted by factors that alter neurogenesis levels in 
rodents.19 20 In humans, deficits on the MST are associated with elevated scores on scales of 

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stress, depression and binge drinking, and with increased age, while several weeks of high 
intensity exercise improve MST scores.21 22 Even if 30% of the NeuroVISION participants 
presented a decline of ≥2 points in their Montreal Cognitive Assessment (MoCA) score at 1 year, 
many participants experienced no changes or an improvement in their MoCA scores. To assess 
the role of neurogenesis in the association between CPSP and POCD, we can assess the 
correlation between changes in pain scores (and incidence of CPSP) with the MST, and separately 
with other cognitive/neuropsychological testing. According to the neurogenesis theory, as 
demonstrated in depressed patients recovering from their depressive state,17 we might see 
improved MST scores in patients who experience a postoperative improvement in their pain 
while still showing a postoperative decline in other cognitive domains/tests; and vice versa, 
patients with CPSP might show worsened MST scores, without showing significant changes in 
other cognitive tests/domains. Neurotrophic factors support the survival and function of 
hippocampal cells. Neurotrophic like the brain-derived neurotrophic factor (BDNF) and the 
insulin-like growth factor-1 (IGF-1) have been shown to enhance the association between higher 
aerobic fitness and better memory performance.23 Conversely, a reduction in neurotrophic 
factors might mediate the interaction of pain, reduced mobility and satisfaction, with cognition 
(objective 2.b). 
The Somatic Preoccupation and Coping (SPOC) questionnaire has been developed to 
measure postoperative patients’ coping abilities and recovery expectations in trauma orthopedic 
surgery.24 The SPOC has been showed to predict 1-year pain persistence and functional recovery, 
in patients after extremity fractures, independently of age.25 It is possible that coping abilities 
and expectation are also playing a role in recovery from elective orthopedic surgery. However, 
this has been never confirmed in the TKA context. Moreover, the SPOC has been validated and 
tested in overall younger populations. A possible decline in cognitive performance the first 
months after surgery, that especially older surgical populations might experience, has never been 
taken into account in previous studies measuring SPOC 4-6 weeks after surgery. In fact, coping 
strategies and expectations might also be affected by cognitive abilities, and vice versa (objective 
3). Although potentially very useful in clinical practice for a quantitative measurement of patient 
coping abilities and expectations, the SPOC can give only a partial understanding of patient 
resilience, i.e. how people live the experience of surgery, how and why they make choices about, 
and engage (or not) in, a surgical treatment for their condition, across different ages and 
comorbidities, in particular when suffering from a condition that interfere with their function 
(objective 4).  
With this as background and rationale, we propose to undertake the ArthroCaP study, 
i.e., a mixed-method study with the following objectives. 
 
2. OBJECTIVES 
The overarching objective of the ArthroCaP study is to explore the interplay between 
postoperative pain and self-reported recovery (i.e. satisfaction), coping abilities/expectations 
about surgery, and postoperative COGNITIVE trajectories in ≥50 years old people undergoing 
elective total knee arthroplasty (TKA) or total hip arthroplasty (THA). 
The specific objectives of the ArthroCaP study are: 

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1. to explore the association of CPSP, long-term opioid use, and a multi-domain 
measure of patient satisfaction, with POCD, measured as changes over time of the 
performance at the Montreal Cognitive Assessment (MoCA) score, and at additional 
neuropsychological testing. 
2. to explore whether postoperative cognitive changes are associated with changes in 
neurogenesis correlates (a) and in neurotrophic factors levels (b), and whether this 
association is mediated by changes in pain, mobility, and satisfaction 
3. to explore the association between coping strategies/expectations before and after 
surgery, as measured by the SPOC questionnaire, and cognitive changes after 
surgery; and to explore the correlation between changes in SPOC and cognitive 
changes from preoperative to 4-6 weeks after surgery. 
4. to qualitatively explore lived experiences of pain, mobility and aging, including 
resilience, expectations and satisfaction with surgery, in patients undergoing TKA or 
THA across different ages and comorbidities. 
 
The current protocol and ethics submission describes methods and seek ethics approval for 
specific objectives 1-3. Objective 4 will be covered in a separate protocol and ethics application. 
 
3. METHODS 
3.1 Study design and design modification 
The ArthroCaP study includes a quantitative component, represented by a nested 
prospective cohort study (objectives 1-3), and a qualitative component, represented by a series 
of semi-structured interviews (objective 4). The current protocol describes the quantitative 
component. 
The ArthroCaP study was initially designed as a sub-study of the ongoing “Determinants 
of Long-term Outcomes after Knee Arthroplasty: A Prospective Multicentre Cohort Study, also 
known as SPOC study. The SPOC study, approved by the Hamilton Integrated Research Ethics 
Board on March 11, 2019 (Project Number 5740), planned to enrol 388 ≥50 years old patients 
undergoing elective TKA in Hamilton (St Joseph’s Hospital and Juravinski Hospital). Maintaining 
the same prospective cohort design of the main study, the ArthroCaP sub-study was designed 
to add 1) baseline and longitudinal cognitive/neuropsychological assessments, and 2) baseline 
and longitudinal blood collections for the measurement of specific biomarkers and the 
development of a biobank for the future evaluation of additional biomarkers as suggested by 
new evidence and hypotheses (overall referred to as “Biomarkers study”, see 3.4.2).  
After the initial approval of ArthroCaP, the recruitment in the main SPOC study has 
experienced a significant slow-down due to the cancellation or deferral of elective surgeries 
during the COVID pandemic. This has affected the ability to recruit also in the ArthroCaP sub-
study and reduced the potential to reach the planned sample size before the termination of the 
SPOC study. Due to these circumstances, a decision was made by the ArthroCaP investigators to 
extend the recruitment in the ArthroCaP study beyond the termination of the SPOC study, and 
to include not only patients undergoing elective TKA (as in the SPOC study) but also those 
undergoing THA. The ArthroCaP study will maintain the same objectives and timeline. However, 
due to the extension beyond the termination of and population included in the SPOC study, 

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participants recruited not as part of the SPOC study will sign a new consent for participation in 
the ArthroCaP study, which includes those assessments that are necessary to answer the 
ArthroCaP research questions but that were initially performed as part of the SPOC study.  
The following sections are described to reflect the most updated study methods.” 
 
3.2 Eligibility criteria 
Patients are eligible to participate in ArthroCaP if they are:  
1. aged 50 years or older, 
2. scheduled for elective TKA for osteoarthritis and enrolled in the SPOC study*, or 
scheduled for THA for osteoarthritis 
3. able to provide informed consent. 
*After termination of the SPOC study, the enrolment in the SPOC study will no longer 
represent an inclusion criterion. 
 
 Patients will be excluded if any of the following exclusion criteria are met: 
1. known history of dementia, 
2. unavailability of tablet or computer with an internet connection for remote 
assessment, 
3. patient unable to interact with a tablet or computer due to language, visual, or 
hearing impairment, or any severely limited mobility of the upper limb joints, OR 
4. patient unable to understand spoken or written English.  
3.3 Recruitment and procedures  
While the SPOC study is still actively recruiting, the process of recruitment of eligible 
patients for the ArthroCaP study will coincide with that of the primary study, as described in the 
main SPOC protocol. Participants consenting to the “Determinants of Long-term Outcomes after 
Knee Arthroplasty: A Prospective Multicentre Cohort Study”, and meeting the eligibility criteria 
for this sub-study, will be explained and asked to consent to the specific procedures for the sub-
study. We will seek a specific patient consent to the additional baseline and longitudinal 
cognitive/neuropsychological assessments, and to the biomarker study, separately. In addition, 
for the biomarker study, a sub-study informed consent form will specifically and separately ask 
for consent to the storage of the blood sampling and to genetic analyses (see 3.4.2). Recruitment 
of patients after the termination of the SPOC study will follow similar procedures, however, the 
ArthroCaP study will be presented to the potential participants as one entity with all the 
assessments conducted by the sub-study team. 
Eligible patients will be approached for the first time in person, between 1 month and 1 
week before surgery, during the preoperative assessment visit or during a group exercise session 
(‘knee class’ or ‘hip class’). Some of them are fully informed about the study and provide consent 
at the first approach; some of them opt to be emailed the informed consent form and are called 
to follow up on their decision to participate in the study. For patients who are emailed the 
consent form and explained the study during a phone call, an initially verbal consent will be 
sought in order to allow for the remote baseline preoperative assessments. A signed written 
consent form will be then obtained when the patients are admitted to the hospital. Once the 

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patient consents to the sub-study, the sub-study-specific assessments will be done in addition to 
and separately (i.e., on a separate virtual or in-person visit) from the main study assessments. 
APPENDIX I summarizes the timeline, measurements, and data collection for the 
ArthroCaP study. The baseline and longitudinal assessments will occur in compliance with the 
local restrictions to research due to the COVID-19 pandemic and based on patient acceptance. 
Patient surveys will be completed over the phone or via videoconference. For 
cognitive/neuropsychological testing, the study will employ tools that are validated for remote 
administration, including online/electronic versions or versions adapted for administration 
through videoconference by trained personnel. For the baseline and every postoperative 
longitudinal assessment, patients will be invited to schedule a videoconference with the research 
personnel who will administer the tests or supervise the self-administration of the tests, 
depending on the specific test as described in 3.4.1. In case of change of the regulation currently 
in force, in-person assessments following the same timeline will be considered and offered to the 
participants as an option. Likewise, whenever the participant is due for clinical reasons for an in-
person visit, which is occurring in agreement with the study timeline, the option of performing 
the study assessments during the in-clinic visit will be offered to the participant. If necessary, the 
participants will be allowed to involve in the study a next of kin or support person who can help 
facilitate the access to an electronic device with an internet connection which will be used for 
the study videoconferences and for the administration of the online web-based 
neuropsychological tests. The videoconference-based assessments will be conducted using any 
of the following software options which allow screen sharing, i.e., McMaster Zoom, Microsoft 
Teams or Webex, based on availability and participant discretion. We expect each study 
videoconference/visit for the cognitive/neuropsychological assessment to last between 45 and 
60 minutes.  
Blood drawing will occur based on the study timeline (APPENDIX I) and in agreement with 
research restrictions in force (see 3.4.2). 
We will seek patient confirmation of consent to participate in the study at every in-person 
or virtual visit throughout the study.  
3.4 Measurements 
Patients who agree to participate in the ArthroCaP sub-study while the recruitment in 
SPOC is ongoing will undergo all the procedures and measurements outlined in the protocol for 
the main study. In particular, participants are assessed at baseline for their socio-demographics 
data, comorbidities, Physical Frailty Phenotype, health-related quality of life (EQ-5D), anxiety and 
depression (Hospital Anxiety and Depression Scale [HADS], pain, and pain medication. Pain scores 
(based on a numerical pain scale) and pain medications are assessed at baseline, and then 4-6 
weeks, 3 months, 6 months and 12 months after surgery. The SPOC instrument is administered 
at baseline and repeated at 4-6 weeks after surgery. The presence and severity of CPSP and 
satisfaction (SAPS) are measured at 3, 6, and 12 months. Changes in health-related quality of life 
and clinical complications are also monitored and collected over time. For TKA and THA patients 
approached after the termination of the recruitment in SPOC, these measurements will be 
described in the ArthroCaP informed consent form and conducted by the ArthroCaP study team 

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using ArthroCaP-specific case report forms (CRFs), as done for the cognitive/neuropsychological 
assessment. 
3.4.1 Cognitive/neuropsychological assessment  
The baseline and cognitive/neuropsychological assessment will include the following 
(APPENDIX I): 
1) The Montreal Cognitive Assessment (MoCA) 
The MoCA (MoCA, https://www.mocatest.org)is a sensitive global cognitive screening tool, which 
evaluates multiple cognitive domains, including orientation, memory, language, attention, 
calculation, constructions/visuospatial skills, executive function, and abstraction.26  Time to 
administer the MoCA is approximately 10-15 minutes. The total possible score is 30 points and is 
calculated as a sum of the sub-scores for each sub-task. The final score is adjusted for the 
influence of education, by adding one point for an individual who has 12 years or fewer of formal 
education. For the remote assessment we will use the validated Full MoCA version for 
administration through audio-visual conference (https://www.mocatest.org/remote-moca-
testing/).  
2) The Mnemonic Similarity Task (MST) 
The classic MST consists of a series of 192 color photographs of everyday objects on a white 
background.27 There are typically two phases: an incidental encoding phase, when participants 
engaged in an indoor/outdoor judgment for each picture (based on their opinion with no right or 
wrong answer); and a subsequent recognition test with a three-choice response. The objects 
include three stimulus types (each representing one third of the objects): exact repetitions of 
earlier items, lures that are similar but not identical to earlier items, and novel foils. During the 
test, participants are asked to identify each item as “Old,” “Similar,” or “New”. The recognition 
memory score is calculated as the difference between the rate of “Old” responses given to repeat 
items minus “Old” responses given to foils. The lure discrimination index (which measures 
mnemonic discrimination) is calculated as the difference between the rate of “Similar” responses 
given to the lure items minus “Similar” responses given to the foils. Typically, ‘normal’ aging is 
associated with a decline in mnemonic discrimination (i.e. (identifying lure objects that are similar 
to memory set objects as “similar”) with preserved recognition memory (identifying repeated 
memory set objects as “old”).28 The traditional MST as here described has been used also in older 
people.29 30 It is available in a format for online administration. We are working with the task 
developers (http://faculty.sites.uci.edu/starklab/mnemonic-similarity-task-mst/) to have a 
validated modified online version of MST ready for use by the launch of our study; the modified 
version is adapted to increase the efficiency of the test (i.e. to obtain the same information but 
with a shorter test) and therefore its acceptability with older participants.29  
3) Additional neuropsychological testing 
The following neuropsychological testing (available in electronic versions for online 
administration) will be additionally performed:  
• the Visual Paired Associates Learning (PAL) test, designed after the Cambridge 
Neuropsychological Test Automated Battery (CANTAB) – PAL test, which measures 
hippocampal-dependent visuo-spatial memory by testing participant’s memory for 
object location pairs. For this test (expected time requirement 10 minutes), boxes are 

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displayed on the screen and are opened in a randomized order. One or more of them 
will contain a pattern. The patterns are then displayed in the middle of the screen, one 
at a time, and the participant must touch the box where the pattern was originally 
located. If the participant makes an error, the patterns are re-presented to remind the 
participant of their locations. The difficulty level increases through the test; 
• the Rapid serial Visual Presentation (RVP) test (designed after the CANTAB-RVP test), 
which assesses executive function (working memory and sustained attention). For this 
test (expected time requirement 7-10 minutes), a white box is shown in the centre of 
the screen, inside which digits from 2 to 9 appear in a pseudo-random order, at the rate 
of 100 digits per minute. Participants are requested to detect target sequences of digits 
(for example, 2-4-6, 3-5-7, 4-6-8). When the participant sees the target sequence they 
must respond by selecting the button in the centre of the screen as quickly as possible. 
The level of difficulty varies with either one- or three-target sequences that the 
participant must watch for at the same time. 
• the N-back test, which assesses visual working memory. For this task (expected time 
requirement 7-10 minutes), participants are shown a series of numbers on the screen, 
and are occasionally asked to enter the number they saw 2 numbers ago; AND  
• the Stroop word colour interference task, which assesses inhibitory control. For this test 
(expected time requirement 5-10 minutes), participants will be tested on their ability to 
identify the color of the word, not what the word actually states. This acts as a test of 
attention by tapping the ability to suppress a habitual response in favor of a less familiar 
one, and provides additional indices of simple attention like word reading and color 
identification. 
4) Subjective Memory Complaints (SMC) 
We will also assess Subjective Memory Complaints (SMC).31 Participants will be asked the 
following 4 questions: i) “Do you have any difficulty with your memory?” ii) “Do you forget where 
you have left things more than you used to?” iii) “Do you forget the names of close friends or 
relatives?” and iv) “Do other people find you forgetful?”. A positive response to any of these 
questions will indicate SMC.32 33 
3.4.2 Biomarkers study  
Participants who consent to the biomarker study will have their blood drawn when they 
are admitted to the hospital on the morning of surgery, before surgery. For the postoperative 
time points we will take into account the current changes in the modality of hospital admission 
for elective TKA due to the pandemic. A larger number of elective TKA are currently booked as 
same day procedures, with the patients being discharged on the same day of surgery. Therefore, 
every study participant, regardless of the type of hospital admission and actual length of stay, 
will have their blood for the biomarker study drawn 2-4 hours after surgery. Participants who 
stay at least one night in the hospital after surgery will also have their blood drawn daily from 
postoperative 1 to postoperative day 3, or to the day of discharge (whichever comes first), with 
the blood being preferentially drawn in the morning and with fasting. Tentatively, blood will be 
also collected at 4-6 weeks after surgery when patients who underwent TKA typically have their 
surgical follow-up. Currently, during the pandemic, ≥50% of participants are having an in-clinic 
visit. We expect that for ≥80% of the participants we will be able to have blood samples at 12 

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months after surgery. The opportunity to collect blood at 6 months in at least a subset of 
participants will depend on the evolution of the pandemic and the ability to have in-person 
research visits. APPENDIX I summarizes the timeline for blood collection. 
For the biomarkers study, patients will be asked consent separately for each of the three 
following research activities: 1) consent to have their blood drawn for measurement on plasma 
of specific biomarkers, i.e. neurotrophic factors and N-terminal pro–B-type natriuretic peptide 
(NT-proBNP); 2) consent to have their blood drawn and stored for future tests (biobank); and 3) 
consent to have their blood drawn (and stored) for current and future testing on genetic material.  
We will measure longitudinally the levels of neurotrophic factors that have showed 
promising results as possible mediators of the effect of physical performance (and, we 
hypothesize, pain and satisfaction), on neuroplasticity (and possibly cognitive performance), i.e. 
the brain-derived neurotrophic factor (BDNF) and the insulin-like growth factor-1 (IGF-1).23 We 
will include the measurement of the nerve growth factor (NGF), another neurotrophic factor that 
has been associated with neuron survival and cognitive performance.34 We will also measure NT-
proBNP. Preoperative NT-proBNP levels have been demonstrated to be a strong independent 
predictor of major postoperative outcomes after non-cardiac surgery.35 However, the role of NT-
proBNP in predicting postoperative cognitive outcomes has been not assessed. Moreover, NT-
proBNP is usually measured preoperatively whereas the dynamic changes of its perioperative 
and postoperative levels, and their correlation with postoperative outcomes, have never been 
evaluated. Interestingly, NT-proBNP has been shown to correlate with measures of physical 
performance and tolerance (like peak oxygen consumption, VO2 peak) which could be affected 
by persistent pain and could affect satisfaction. We will explore how the changes on NT-proBNP 
also correlate with changes in pain and satisfaction, as well as with changes in neurotrophic 
factors levels. 
We will measure the plasma levels of neurotrophic factors but also their RNA expression 
in blood leukocytes. For participants who agree to have their blood samples stored in the biobank 
and also to have their genetic material tested, we will explore other mechanistic hypotheses and 
other possible biomarkers in the field of CPSP and POCD from plasma but also RNA expression 
and DNA. 
At each time point, we will collect venous blood into EDTA tubes (from which to obtain 
both plasma and whole blood for DNA measurements) and RNA PAXGene tubes for blood RNA 
analysis. At each time point, we will collect overall (i.e. for specific biomarkers measurements 
and for the biobank) 10 ml of blood in EDTA and 10 ml of blood in RNA PAXGene tubes. If a patient 
does not consent to genetic testing, no RNA PAXGene tube will be collected and the EDTA blood 
will be used only for analyses on plasma and not for DNA testing. If a patient does not consent to 
biobanking but does consent to genetic testing, we will collect only half of the amount of blood 
into the 2 different types of tubes. Samples will be collected at the participating hospitals into 
pre-prepared study kits, and processed and aliquoted on site based on standard procedures as 
defined in a specific study manual. In particular, blood samples will be incubated in the RNA 
PAXgene tubes for a minimum of 2 hours at room temperature to completely lyse blood cells; 
they will be then frozen first at -20ºC for 24 hours, then transferred to -80ºC, upright in a wire 
rack. Samples will be batched, and transported to the Clinical Research Laboratory and Biobank 
(CRLB) - Genetic and Molecular Epidemiology Laboratory (GMEL) at the Hamilton Health 
Sciences, General Hospital Site. Part of the samples will be remain at the CRLB-GMEL and used 

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for NT-proBNP testing and for biobanking. From the CRLB-GMEL, part of the aliquots will be 
transported to Prof. Fahnestock’s laboratory at the McMaster University Health Sciences Centre 
for neurotrophic biomarkers measurement.  
3.5 Sample size  
The ArthroCaP study has been designed as a proof-of-concept study, hypothesis-
generating, with exploratory objectives. Based on the original recruitment rate in the main SPOC 
study, we expected to be able recruit in the sub-study ≥150 of the planned 388 SPOC participants. 
Although exploratory, enrolling ≥150 participants would give us a power of ≥80% to detect an 
association between moderate-severe CPSP at 6 months and ≥2 point decline in MoCA at 1 year, 
with an Odds Ratio of 2.5-3.0 when we consider some residual correlation between independent 
variables (i.e., R2£0.3 even after removing collinear covariates. This was based on the 
assumptions that 20% of the study participants will experience ≥2 point decline in MoCA at 1 year 
(considering the possibly younger age and different surgery representation in our study 
compared to NeuroVISION-1), and that 30% will present moderate-severe CPSP at 6 months (see 
sample size calculation for the main SPOC study).  
Due to the disruptions to recruitment secondary to the pandemic, we modified our target 
sample size to 100 patients, aware that the study will provide preliminary nondefinitive data to 
inform future research. This is consistent with the intent of the catalyst grant that supports the 
study. 
3.6 Statistical analyses  
Baseline characteristics will be summarized through descriptive statistics, i.e. mean 
(standard deviation), median (interquartile range [IQR]), or number (%) as appropriate. 
Objective 1. We will first evaluate the primary study objective modeling longitudinal 
changes in pain scores (independent variable) and changes in cognitive/neuropsychological 
scores (dependent variable) over time (4 weeks, and 3, 6, and 12 months after surgery) using 
multilevel (mixed effects) regression models, considering time points nested within patients.36 
Secondarily, in mixed effects models, we will specifically look at whether experiencing moderate-
severe persistent pain at 3 months after surgery (or at 6 months after surgery) predicts 
subsequent decline in cognitive performance (i.e. at 6 and 12 months, or at 12 months).9 Models 
will be adjusted for relevant covariates, including baseline characteristics (at the patient level, 
e.g. age, sex, comorbidity index, and anxiety/depression level) and pain medications as time-
varying variables. We will adopt a parsimonious approach in covariates selection, based on 
clinical relevance and removing collinear covariates (i.e., variance inflation factor >2.5) according 
to pre-specified priorities. We will use the same statistical approach to look at the association 
between satisfaction (measured with the SAPS instrument) and cognitive performance.  
Objectives 2. We will explore our objective 2a, analyzing separately change in MST scores 
and changes in other cognitive performance measures. Bonferroni correction of alpha values will 
be adopted to adjust for multiple comparisons. For the biomarker study (objective 2b), we will 
similarly model mixed effects regression models to evaluate how the biomarker levels change 
over time and how these changes correlate with changes in pain, satisfaction, and cognitive 
performance. We will also analyze whether biomarkers levels at baseline (before surgery), and 

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right after surgery (or at 4-6 weeks after surgery) predict cognitive changes/decline at 6 and 12 
months. 
Objective 3. To evaluate the role of coping abilities and expectations, as measured by the 
SPOC questionnaire, we will first analyze the association between baseline SPOC and baseline 
cognitive performance in a traditional multivariable linear regression analysis; similarly, we will 
analyze the association between early postoperative (4-6 weeks) SPOC and cognitive 
performance, after adjusting for baseline measurements. Then we will analyze whether 
preoperative and postoperative SPOC predict cognitive decline at 6 and 12 months using linear 
and logistic (i.e. with ≥2 point decline in MoCA as binary outcome) regression models. 
All the analyses for all the objectives will be first conducted in the overall sample of study 
participants. As additional analysis, we will explore whether there is a signal for any subgroup 
effect based on the type of surgery performed, i.e., knee versus hip arthroplasty. We will 
undertake such exploratory subgroup analyses as long as both subpopulations reach at least 30% 
of representation. 
 
4. IMPORTANCE OF THE STUDY 
“My father hasn’t been quite the same since his surgery…” As doctors, and as children, 
many of us have had and reported such experience. Anesthetic-related mortality has decreased 
100-fold over the last 100 years. However, when asked about their fears related to undergoing 
major surgery with general anesthesia, people, across different ages, indicate ‘brain damage’ and 
‘memory loss’ as main concerns, much more frequently than perioperative death.37 Moreover, 
the literature shows that, even with only a partial understanding of the concept of likelihood, 
most older people would not choose a treatment when the expected outcome is survival, if 
associated with cognitive and functional impairment.38 39 CPSP is highly prevalent in older people 
undergoing surgery, and in particular major orthopedic surgery; in the older surgical populations, 
also persistent postoperative cognitive dysfunction is highly prevalent. Both these conditions are 
associated with reduced autonomy and increased burden to patients, caregivers, and healthcare 
systems. 
On the other side, the existing literature shows a decrease in quality of life in people with 
chronic pain waiting for >6 months for assessment;40 and that people waiting for their major joint 
surgery tend to report that their waiting time is contributing significantly to the deterioration of 
their health.41 Likewise, the current experience with COVID and the deferral of elective surgeries 
is bringing to our attention what holding such treatment might mean to older people with chronic 
conditions. Our study will provide preliminary data on the role of chronic pain, and chronic pain 
medications, in the impact of surgery on older people’s cognitive abilities, and on the underlying 
mechanisms. It will inform larger confirmatory studies, and finally the design of interventions to 
enhance the benefits of surgery.

Version 3.0 July 25, 2022 - Page 13 of 18 
 
APPENDIX I. Study timeline, measurements, and data collection  
 
Before surgery 
 
After surgery 
Measurement 
Day -28 to -1 
Day of surgery 
Day of surgery 
(2-4 hours after 
surgery) 
+4-6 weeks 
 
+3 mo 
+6 mo 
+12 mo 
 
Online - Videoconference 
with research team 
or in person 
In person 
In person 
 
Online - Videoconference with research team 
or In person 
Socio-demographics 
x 
 
 
 
 
 
 
Comorbidities/ 
Medical History 
X 
 
 
 
 
 
 
Surgical 
characteristics 
 
 
 
x 
 
 
 
Pain Medication 
Usage 
x 
 
 
x 
x 
x 
x 
The Somatic 
Preoccupation and 
Coping (SPOC) 
Questionnaire 
x 
 
 
x 
 
 
 
FRAIL Scale (Frailty 
assessment) 
X 
 
 
 
 
 
 
Hospital Anxiety and 
Depression Scale 
(HADS) 
X 
 
 
 
 
 
 
Pain Assessment 
x 
 
 
x 
x 
x 
x 
Self-Administered 
Patient Satisfaction 
(SAPS) Scale 
 
 
 
 
 
x 
x 
x 
Complications 
 
 
 
x 
x 
x 
x 
Cognitive/ 
neuropsychological 
assessment  
- MoCA 
- MST 
x 
 
 
x 
 
x 
x 

Version 3.0 July 25, 2022 - Page 14 of 18 
 
- Other 
neuropsychological 
testing 
- SMC 
Blood drawing for 
biomarker study 
 
x 
x* 
x** 
 
x** 
x** 
*the subset of patients that stay in hospital at least one night after surgery will have blood collected also every morning on postoperative day 1-3, or until 
discharge (whichever comes first) 
**whenever an in person study visit is feasible depending on restrictions in place due to the pandemic and patient compliance  
MoCA, Montreal Cognitive Assessment; MST, Mnemonic Similarity Task; SMC, Subjective Memory Complaints

Version 3.0 July 25, 2022 - Page 15 of 18 
 
REFERENCES 
 
1. Evered LA, Silbert BS. Postoperative Cognitive Dysfunction and Noncardiac 
Surgery. 
Anesth 
Analg 
2018;127(2):496-505. 
doi: 
10.1213/ANE.0000000000003514 
2. Evered L, Silbert B, Knopman DS, et al. Recommendations for the nomenclature of 
cognitive change associated with anaesthesia and surgery-2018. Can J Anaesth 
2018;65(11):1248-57. doi: 10.1007/s12630-018-1216-x 
3. Newman S, Stygall J, Hirani S, et al. Postoperative cognitive dysfunction after 
noncardiac surgery: a systematic review. Anesthesiology 2007;106(3):572-90. 
doi: 00000542-200703000-00023 [pii] [published Online First: 2007/02/28] 
4. Neuro VI. Perioperative covert stroke in patients undergoing non-cardiac surgery 
(NeuroVISION): a prospective cohort study. Lancet 2019;394(10203):1022-
29. doi: 10.1016/S0140-6736(19)31795-7 
5. Krishnan K, Rossetti H, Hynan LS, et al. Changes in Montreal Cognitive Assessment 
Scores 
Over 
Time. 
Assessment 
2017;24(6):772-77. 
doi: 
10.1177/1073191116654217 
6. Tan HH, Xu J, Teoh HL, et al. Decline in changing Montreal Cognitive Assessment 
(MoCA) scores is associated with post-stroke cognitive decline determined by 
a formal neuropsychological evaluation. PLoS One 2017;12(3):e0173291. doi: 
10.1371/journal.pone.0173291 
7. Berger M, Nadler JW, Browndyke J, et al. Postoperative Cognitive Dysfunction: 
Minding the Gaps in Our Knowledge of a Common Postoperative Complication 
in 
the 
Elderly. 
Anesthesiol 
Clin 
2015;33(3):517-50. 
doi: 
10.1016/j.anclin.2015.05.008 
8. Mazza S, Frot M, Rey AE. A comprehensive literature review of chronic pain and 
memory. Prog Neuropsychopharmacol Biol Psychiatry 2018;87(Pt B):183-92. 
doi: 10.1016/j.pnpbp.2017.08.006 [published Online First: 2017/08/12] 
9. Whitlock EL, Diaz-Ramirez LG, Glymour MM, et al. Association Between Persistent 
Pain and Memory Decline and Dementia in a Longitudinal Cohort of Elders. 
JAMA 
Intern 
Med 
2017;177(8):1146-53. 
doi: 
10.1001/jamainternmed.2017.1622 [published Online First: 2017/06/07] 
10. Rice DA, Kluger MT, McNair PJ, et al. Persistent postoperative pain after total knee 
arthroplasty: a prospective cohort study of potential risk factors. Br J Anaesth 
2018;121(4):804-12. doi: 10.1016/j.bja.2018.05.070 [published Online First: 
2018/09/22] 
11. Fong HK, Sands LP, Leung JM. The role of postoperative analgesia in delirium and 
cognitive decline in elderly patients: a systematic review. Anesth Analg 
2006;102(4):1255-66. 
doi: 
10.1213/01.ane.0000198602.29716.53 
[published Online First: 2006/03/23] 
12. Laigaard J, Bache N, Stottmeier S, et al. Cognitive Function During Opioid Tapering 
in Patients with Chronic Pain: A Prospective Cohort Study. J Pain Res 
2020;13:3385-94. doi: 10.2147/JPR.S273025 [published Online First: 
2020/12/29] 
13. Els C, Jackson TD, Kunyk D, et al. Adverse events associated with medium- and 
long-term use of opioids for chronic non-cancer pain: an overview of Cochrane 

Version 3.0 July 25, 2022 - Page 16 of 18 
 
Reviews. 
Cochrane 
Database 
Syst 
Rev 
2017;10:CD012509. 
doi: 
10.1002/14651858.CD012509.pub2 [published Online First: 2017/10/31] 
14. Wu YH, Liu LK, Chen WT, et al. Cognitive Function in Individuals With Physical 
Frailty but Without Dementia or Cognitive Complaints: Results From the I-Lan 
Longitudinal Aging Study. J Am Med Dir Assoc 2015;16(10):899 e9-16. doi: 
10.1016/j.jamda.2015.07.013 [published Online First: 2015/09/01] 
15. Mahomed N, Gandhi R, Daltroy L, et al. The self-administered patient satisfaction 
scale for primary hip and knee arthroplasty. Arthritis 2011;2011:591253. doi: 
10.1155/2011/591253 [published Online First: 2011/11/03] 
16. Becker S, Wojtowicz JM. A model of hippocampal neurogenesis in memory and 
mood 
disorders. 
Trends 
Cogn 
Sci 
2007;11(2):70-6. 
doi: 
10.1016/j.tics.2006.10.013 [published Online First: 2006/12/19] 
17. Han X, Wu Y, Zhong Y, et al. Recovery of High Interference Memory in Spite of 
Lingering Cognitive Deficits in a Longitudinal Pilot Study of Hospitalized 
Depressed 
Patients. 
Front 
Psychiatry 
2020;11:736. 
doi: 
10.3389/fpsyt.2020.00736 [published Online First: 2020/08/28] 
18. Snyder JS, Soumier A, Brewer M, et al. Adult hippocampal neurogenesis buffers 
stress responses and depressive behaviour. Nature 2011;476(7361):458-61. 
doi: 10.1038/nature10287 [published Online First: 2011/08/05] 
19. Gandy K, Kim S, Sharp C, et al. Pattern Separation: A Potential Marker of Impaired 
Hippocampal Adult Neurogenesis in Major Depressive Disorder. Front 
Neurosci 2017;11:571. doi: 10.3389/fnins.2017.00571 [published Online 
First: 2017/11/11] 
20. Stark SM, Kirwan CB, Stark CEL. Mnemonic Similarity Task: A Tool for Assessing 
Hippocampal 
Integrity. 
Trends 
Cogn 
Sci 
2019;23(11):938-51. 
doi: 
10.1016/j.tics.2019.08.003 [published Online First: 2019/10/11] 
21. Camfield DA, Fontana R, Wesnes KA, et al. Effects of aging and depression on 
mnemonic discrimination ability. Neuropsychol Dev Cogn B Aging 
Neuropsychol 
Cogn 
2018;25(3):464-83. 
doi: 
10.1080/13825585.2017.1325827 [published Online First: 2017/05/17] 
22. Dery N, Pilgrim M, Gibala M, et al. Adult hippocampal neurogenesis reduces 
memory interference in humans: opposing effects of aerobic exercise and 
depression. Front Neurosci 2013;7:66. doi: 10.3389/fnins.2013.00066 
[published Online First: 2013/05/04] 
23. Heisz JJ, Clark IB, Bonin K, et al. The Effects of Physical Exercise and Cognitive 
Training on Memory and Neurotrophic Factors. J Cogn Neurosci 
2017;29(11):1895-907. doi: 10.1162/jocn_a_01164 [published Online First: 
2017/07/13] 
24. Busse JW, Bhandari M, Guyatt GH, et al. Development and validation of an 
instrument to predict functional recovery in tibial fracture patients: the 
Somatic Pre-Occupation and Coping (SPOC) questionnaire. J Orthop Trauma 
2012;26(6):370-8. doi: 10.1097/BOT.0b013e31822421e2 [published Online 
First: 2011/10/21] 
25. Khan JS, Devereaux PJ, LeManach Y, et al. Patient coping and expectations about 
recovery predict the development of chronic post-surgical pain after 

Version 3.0 July 25, 2022 - Page 17 of 18 
 
traumatic tibial fracture repair. Br J Anaesth 2016;117(3):365-70. doi: 
10.1093/bja/aew225 [published Online First: 2016/08/21] 
26. Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, 
MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 
2005;53(4):695-9. doi: 10.1111/j.1532-5415.2005.53221.x 
27. Yassa MA, Stark CE. Pattern separation in the hippocampus. Trends Neurosci 
2011;34(10):515-25. doi: 10.1016/j.tins.2011.06.006 [published Online First: 
2011/07/27] 
28. Stark SM, Yassa MA, Lacy JW, et al. A task to assess behavioral pattern separation 
(BPS) in humans: Data from healthy aging and mild cognitive impairment. 
Neuropsychologia 
2013;51(12):2442-9. 
doi: 
10.1016/j.neuropsychologia.2012.12.014 
[published 
Online 
First: 
2013/01/15] 
29. Stark SM, Stevenson R, Wu C, et al. Stability of age-related deficits in the mnemonic 
similarity task across task variations. Behav Neurosci 2015;129(3):257-68. 
doi: 10.1037/bne0000055 [published Online First: 2015/06/02] 
30. Bennett IJ, Stark SM, Stark CEL. Recognition Memory Dysfunction Relates to 
Hippocampal Subfield Volume: A Study of Cognitively Normal and Mildly 
Impaired Older Adults. J Gerontol B Psychol Sci Soc Sci 2019;74(7):1132-41. 
doi: 10.1093/geronb/gbx181 [published Online First: 2018/02/06] 
31. Mitchell AJ, Beaumont H, Ferguson D, et al. Risk of dementia and mild cognitive 
impairment in older people with subjective memory complaints: meta-
analysis. Acta Psychiatr Scand 2014;130(6):439-51. doi: 10.1111/acps.12336 
[published Online First: 2014/09/16] 
32. Tsutsumimoto K, Makizako H, Doi T, et al. Subjective Memory Complaints are 
Associated with Incident Dementia in Cognitively Intact Older People, but Not 
in Those with Cognitive Impairment: A 24-Month Prospective Cohort Study. 
Am J Geriatr Psychiatry 2017;25(6):607-16. doi: 10.1016/j.jagp.2016.12.008 
[published Online First: 2017/02/22] 
33. Schmand B, Jonker C, Hooijer C, et al. Subjective memory complaints may 
announce dementia. Neurology 1996;46(1):121-5. doi: 10.1212/wnl.46.1.121 
[published Online First: 1996/01/01] 
34. Fahnestock M, Shekari A. ProNGF and Neurodegeneration in Alzheimer's Disease. 
Front Neurosci 2019;13:129. doi: 10.3389/fnins.2019.00129 [published 
Online First: 2019/03/12] 
35. Duceppe E, Parlow J, MacDonald P, et al. Canadian Cardiovascular Society 
Guidelines on Perioperative Cardiac Risk Assessment and Management for 
Patients Who Undergo Noncardiac Surgery. Can J Cardiol 2017;33(1):17-32. 
doi: 10.1016/j.cjca.2016.09.008 [published Online First: 2016/11/21] 
36. Austin PC, Goel V, van Walraven C. An introduction to multilevel regression 
models. Can J Public Health 2001;92(2):150-4. [published Online First: 
2001/05/08] 
37. Matthey P, Finucane BT, Finegan BA. The attitude of the general public towards 
preoperative assessment and risks associated with general anesthesia. Can J 
Anaesth 2001;48(4):333-9. doi: 10.1007/BF03014959 

Version 3.0 July 25, 2022 - Page 18 of 18 
 
38. Fried TR, McGraw S, Agostini JV, et al. Views of older persons with multiple 
morbidities on competing outcomes and clinical decision-making. J Am Geriatr 
Soc 2008;56(10):1839-44. doi: 10.1111/j.1532-5415.2008.01923.x 
39. Fried TR, Bradley EH, Towle VR, et al. Understanding the treatment preferences 
of seriously ill patients. N Engl J Med 2002;346(14):1061-6. doi: 
10.1056/NEJMsa012528 
40. Lynch ME, Campbell F, Clark AJ, et al. A systematic review of the effect of waiting 
for 
treatment 
for 
chronic 
pain. 
Pain 
2008;136(1-2):97-116. 
doi: 
10.1016/j.pain.2007.06.018 [published Online First: 2007/08/21] 
41. Snider MG, MacDonald SJ, Pototschnik R. Waiting times and patient perspectives 
for total hip and knee arthroplasty in rural and urban Ontario. Can J Surg 
2005;48(5):355-60. [published Online First: 2005/10/27]