Volume 31 Number 4

Introduction

Diabetes is considered one of the most significant health challenges of the 21st century¹. Diabetes-related foot ulcers (DFUs) have been identified as a top-10 leading cause of the global disability burden^2,3. DFUs are defined as “foot ulcers in people with diagnosed diabetes mellitus and are usually accompanied by neuropathy (PN) and/or peripheral artery disease (PAD) in the lower extremity”⁴. Globally, around 20 million people have a DFU at any one time² and will have poorer quality of life and increased risks of hospitalisation, amputation and mortality compared to those without DFUs^2,5,6. Moreover, recent evidence also suggests that diabetes and DFUs may be associated with detrimental cognitive changes^7–9.

Cognition is defined as the “brain’s ability to acquire, process, store, and retrieve information”¹⁰. For people with diabetes with diabetes-related complications, the cognitive domains reported to be affected include executive function, psychomotor speed, memory, attention, concentration, verbal fluency and reaction time^9,11. These cognitive changes are believed to be caused by multiple factors, including defects in insulin signalling, autonomic function, neuroinflammatory pathways, mitochondrial metabolism, increased inflammatory and oxidative stress pathways, and vascular deficits^7,12–14. In turn, these cognitive changes can detrimentally influence self-care management in people with diabetes^15,16.

However, studies to date in those with DFU report conflicting findings related to cognition, likely due to the different study designs, populations, outcomes and follow-up periods used^17,18. Therefore, it is still unclear whether cognitive changes in people with diabetes are worsened by the presence of DFU or by other diabetes-related complications that are risk factors for DFU such as PN or PAD.

The primary aim of this study is to investigate cognition in people with type 2 diabetes with a DFU (cases), compared to those who do not have a foot ulcer but do have diagnosed type 2 diabetes and are accompanied by other diabetes-related lower extremity complications (DRLECs) such as PN and/or PAD (controls). Secondary aims include investigating changes in cognition over time (12 weeks) in people with diabetes with a DFU and in subgroups of people with a DFU who heal compared to those who do not heal. Therefore, it is hypothesised that cognitive changes in people with diabetes are further influenced by the presence of DFU or DRLECs. Therefore, cases are defined as people who have a foot ulcer with diagnosed type 2 diabetes (DFU) and are accompanied by PN and/or PAD in the lower extremity⁴, while controls are defined as people who do not have a foot ulcer but do have diagnosed type 2 diabetes and are accompanied by PN and/or PAD in the lower extremity (DRLECs). The findings of this study will provide new evidence on whether cognition is further influenced in people with diabetes by a DFU or by other diabetes-related complications that are risk factors for a DFU.

Methods

Study design

The study design for the project combines a case control study nested in a 12-week prospective longitudinal study. The case control study will investigate cognition in people with type 2 diabetes with DFUs (cases), compared to those with DRLECs (controls). A prospective longitudinal study will then further investigate changes in cognition over 12 weeks of follow-up for those people with type 2 diabetes with a DFU (cases).

Settings

The study setting will be outpatient diabetic foot services (eight facilities), including hospitals and community health services in Australia.

Participants

Eligible participants will be those aged 18 years and over who are diagnosed with type 2 diabetes with DFUs (cases), and people with type 2 diabetes with DRLECs (controls). Figure 1 displays the definitions of the terms for participants’ selection^4,19. Exclusion criteria will be those previously diagnosed with cognitive impairment (mild, moderate or severe), dementia, cerebrovascular accident, neurodegenerative diseases or those who are pregnant. Participants will be allocated to one of two groups: those with DFUs (cases); and those with DRLECs (controls). The International Working Group of the Diabetic Foot (IWGDF) risk classification system²⁰ (Table 1) will be used to assign controls to the categories of moderate (category 2) or high (category 3) ulcer risk. The control group will be matched in age and sex with the case group during recruitment.

 

Figure 1. Definitions of the terms for participants’ selection

 

Table 1. IWGDF 2019 risk classification²⁰

Sample size calculation

The primary hypothesis is that there is a significant difference in cognition in people with type 2 diabetes with DFUs compared to people with type 2 diabetes with DRLECs. This primary hypothesis was used to calculate the sample size for this study. A search of the literature was unable to locate any similar previous case controlled studies with similar comparison groups to estimate the sample size by using exposed and unexposed percentages, odds ratio, risk/prevalence ratio or risk/ prevalence differences. Therefore, a medium level of effect size was assumed to estimate the sample size (d=0.5). The cases to control allocation ratio were taken as 1:1. G*Power (ver. 3.1.9.4) was used to calculate the sample size²¹ and the calculated sample size for a one-tail test is 57 for each group by using the independent sample t-test with 80% power and an overall significance of 0.05. As there is a number of hypotheses, including a prospective longitudinal follow-up, we inflated the sample size by 20% to account for the likely attrition rate during the 12-week follow-up. Hence, the sample size recruited for each group will be 68 participants.

Variables of interest

Baseline variables of demographic information (age, gender, ethnicity, marital status and education level), weight and height, and data related to diabetes and DFUs (comorbidities and foot-related conditions) will be obtained (see Figure 2 for variable definitions). Clinical examination records will be utilised to collect medical history related to comorbidities and foot-related conditions. The foot-related conditions include the presence/absence of a previous foot ulcer, previous amputation, PN, PAD, acute Charcot foot, depth of ulcer, infection and ulcer size. All participants will be weighed using an electronic portable scale while height will be measured using a stadiometer, ensuring that participants are barefoot with the heels, hips and shoulders touching the vertical scale bar, the chin straight and the inion touching the back of the vertical scale. The horizontal sliding measure will be lowered to the highest point of the head to lightly touch the top of the head. Weight and height will be used to calculate the body mass index (BMI) by dividing the body mass (kg) by the square of the height (m²) of each participant.

 

Figure 2. Descriptions of demographic data

 

Covariates

Cognition is influenced by several confounders such as demographics (gender, age and education level^22,23), cardiovascular factors (blood pressure, cholesterol level, presence of carotid plaque)^24–26, depression²⁷ and physical activity and sedentary lifestyle²⁸. Therefore, data will be collected on these items. The level of depression and physical activity will be assessed through the Patient Health Questionnaire-Depression (PHQ-9)^29,30 and the Yale Physical Activity Survey (YPAS)³¹ respectively in both baseline and follow-up data collection periods. The effect of demographic and cardiovascular factors on cognition will be controlled as covariates during the analysis.

The self-administered PHQ-9 survey is a validated nine-item depression survey widely used for assisting primary care clinicians in diagnosing depression and monitoring treatment^29–30. It is widely used among healthcare professionals caring for people with diabetes for screening for depression^32,33. The survey is scored from 0 to 27, with a higher score indicating a higher probability of depression²⁹. Furthermore, based on the raw PHQ-9 score, the level of depression is categorised into mild depression, moderate depression, moderately severe depression, and severe depression, by ranging PHQ-9 scores from 5 to 9, 10 to 14, 15 to 19, and 20–27 respectively²⁹.

The self-administered YPAS was developed to determine the type, amount and patterning of physical activity/exercise which may influence cognition in older adults³¹. The tool is composed of two sections – “the amount of physical activity/exercise performed during a typical week in the past month” and “activities performed in the past month” – to estimate weekly energy expenditure³¹. Furthermore, the total time spent on those activities in a week is converted to weekly energy expenditure (kcal·wk-¹) and total time index per week (h·wk-¹) for measuring the level of physical activity³⁴. The YPAS has shown acceptable validity³⁵ and reliability^36,37. Furthermore, the YPAS has also been previously used and found reliable in chronic wound research in Australian settings³⁸.

Outcomes of interest

The primary outcome (global cognition) will be measured using the Montreal Cognitive Assessment tool (MoCA)³⁹. The MoCA is a widely used validated screening test for assessing global cognition that is composed of 30 questions (score range 0–30)^39,40. The MoCA has several categories based on the level of cognition; 26–30 is considered normal cognition, 18–25 mild cognitive impairment (MCI), 10–17 moderate cognitive impairment and 0–10 severe cognitive impairment^39,40. The MoCA is recommended for use to assess cognitive changes in clinical settings^41,42. Furthermore, the internal consistency of the MoCA is good, with a Cronbach’s alpha of 0.83³⁹. Moreover, sensitivity and specificity to identifying MCI of MoCA among people with type 2 diabetes have been noted to be 67% and 93%⁴³.

Study procedures

Participants who fulfil the inclusion criteria will be recruited from the participating diabetic foot services as a convenience sample. Figure 3 displays a summary of the study procedures.

 

Figure 3. Summary of the study processes

 

Prerequisite eligibility criteria

All eligible consenting participants will be initially screened to ensure they are free from acute signs and symptoms of hypoglycaemia (clinical signs and symptoms) and moderate to severe foot infection (from medical records and clinical signs and symptoms) at their baseline study visit as these conditions are known to confound cognitive changes^44,45. If a participant has any signs or symptoms of these conditions, they will not have baseline measurements performed and instead be invited to return for a future baseline visit.

Baseline measurements

Baseline measurements will be gathered from both cases and controls that include demographic information, comorbidities, foot-related conditions, BMI, MoCA, PHQ-9 and YPAS.

Follow-up measurements

The case group will be followed up 12 weeks after baseline data has been collected. At week 12, comorbidities, foot-related conditions, MoCA, PHQ-9 and YPAS will be collected from cases. The study process is depicted in Figure 3.

Statistical analyses

The data will be analysed using the Statistical Package for Social Sciences (SPSS) (version 29). The descriptive categorical data will be presented as counts and frequencies while descriptive continuous data will be presented as mean (SD) or median (IQR). All primary and secondary outcome variables will first be assessed graphically using scatter and boxplots and mean/median analyses to look at the between-group differences in data. Explanatory continuous variables will be compared between case and control groups using independent t-tests (parametric test) or Mann-Whitney U tests (non-parametric test) based on the test results of Shapiro-Wilk (normality test). Furthermore, a regression analysis will be performed to investigate the outcome of cognition among cases and controls, adjusting for the covariates (e.g., duration of diabetes, education, depression, physical activity, obesity and cardiovascular factors [presence/absence of hypertension, dyslipidaemia, cardiovascular diseases]).

During follow-up, the difference in cognition changes over time for cases will be analysed using generalised linear mixed models, utilising time as the primary independent variable, and controlling for covariates (e.g., duration of diabetes, education, depression, physical activity, obesity and cardiovascular factors) to assess changes in cognition. Furthermore, logistic regression, adjusted for duration of diabetes, education, depression, physical activity, obesity and cardiovascular factors, will be performed to assess any difference in cognition among cases who have healed compared to those not healed during the follow-up period of 12 weeks.

Ethical considerations

This protocol has been approved by two human research ethics committees – participating hospitals and health services (Hospital HREC/89344) and university ethics committees (University HREC Administration approval – 6859). Furthermore, governance approval has been received from each of the diabetes foot services for granting permission for data collection.

Discussion

The relationships between cognition and people with type 2 diabetes and DFUs are unclear due to the few relevant empirical studies reporting inconsistent findings. Therefore, it is still unclear if DFUs influence cognition among people with diabetes and how ulcer healing may influence cognition over time. Therefore, this case control study nested in a prospective longitudinal study is planned to address this existing evidence gap.

Implication for practice

This study will provide novel evidence on how cognitive changes may differ between those with DFUs compared to those with only DRLECs. Results should indicate which groups may, or may not, benefit from regular assessment of cognition to help clinicians in detecting early cognitive changes among people with diabetes with DFUs/DRLECs. Cognitive changes may affect self-care behaviour, including physical activity, healthy diet plans, self-monitoring of glucose levels, and adherence to treatment and medication⁴⁶. For those at increased risk of cognitive impairment with DRLECs/DFUs, interventions to provide additional support to both the person with DRLECs/DFUs and their carer to manage their chronic condition could be implemented as part of primary prevention to mitigate the impact on self-care behaviour and adherence to treatment processes among people with type 2 diabetes.

Strengths

A case control study nested in a prospective longitudinal study is designed to assess cognitive changes between those with DFUs and those with only DRLECs. The robust methodology will be used to overcome limitations of the previous studies^7–10 in areas of participant selection, data collection and controlling potential confounders as covariates during the analysis.

Limitations

The proposed 12-week follow-up time is based on the literature which suggests that around 50% of DFUs will be completely epithelialised within this time^47,48 and complete epithelialisation without any drainage of a previous foot ulcer site is defined as a healed foot ulcer⁴.

Furthermore, it is expected that the number of participants recruited in each follow-up subgroup (i.e., for each group n=20–30) should provide statistically significant differences⁴⁹. However, a limitation is that there is inadequate time to follow up with all patients until healing. Furthermore, there is no reliable evidence of a timeframe to repeat the MoCA assessment with meaningful cognitive changes. The proposed study has limited resources to look at differences between people with type 2 diabetes with and without DFU but does not consider other diabetes-related complications individually (i.e., PN, PAD). Foot-related conditions are assessed from medical records by following the clear guidance of the Queensland High Risk-Foot Form (QHRFF) which has been shown to have appropriate reliability and validity. QHRFF has also been recognised as a standardised instrument for collecting foot-related conditions data⁵⁰ and is used in other studies for research purposes^19,51. Additionally, the PN and PAD data from the QHRFF is captured by clinicians who have been trained to do these assessments at research standards (i.e., PN – 10-gram monofilament test and PAD – toe systolic pressure).

However, clinical data such as PN, PAD, ulcer characteristics and medical co-morbidities are not specifically collected for the purpose of this study which may affect the reliability of findings. Furthermore, the impact of certain medications (except hypoglycaemic drugs) on cognition is also not considered in this study. Nevertheless, as there is a lack of any evidence in this research field, the findings of this study will provide important evidence to inform larger studies investigating how cognition influences different diabetes-related complications that are risk factors for DFU.

Acknowledgments

The first author acknowledges the support of the Queensland University of Technology (QUT) as this study has been undertaken in partial fulfilment of a Doctor of Philosophy.

Conflict of interest

No conflicts of interest to report.

Ethics statement

This protocol has been approved by two human research ethics committees: participating hospital and health services (Hospital HREC/89344) and university ethics committees (University HREC Administration approval – 6859).

Funding

This publication was supported by QUT Postgraduate Research Award and QUT Higher Degree Research tuition fee scholarships.

Authors’ contributions

All authors conceived and designed the study. NK wrote the first draft of the manuscript while KF, PAL, CP and MM critically reviewed the manuscript.

Author(s)

Nimantha Karunathilaka*^1–3, Christina Parker^1,3, Peter A Lazzarini^1,4,5, Margaret MacAndrew^1,3, Kathleen Finlayson^1,3
1Centre for Healthcare Transformation, Queensland University of Technology, Brisbane, QLD, Australia
²Department of Nursing & Midwifery, Faculty of Allied Health Sciences, General Sir John Kotelawala Defence University, Ratmalana, Sri Lanka
³School of Nursing, Queensland University of Technology, Brisbane, QLD, Australia
⁴School of Public Health and Social Work, Queensland University of Technology, Brisbane, QLD, Australia
⁵Allied Health Research Collaborative, The Prince Charles Hospital, Brisbane, QLD, Australia

*Corresponding author email nimantha.durage@hdr.qut.edu.au

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