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10.1371/journal.pone.0309765
PONE-D-24-07185
Research Article
Biology and Life Sciences
Neuroscience
Cognitive Science
Cognitive Neuroscience
Cognitive Neurology
Cognitive Impairment
Biology and Life Sciences
Neuroscience
Cognitive Neuroscience
Cognitive Neurology
Cognitive Impairment
Medicine and Health Sciences
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Cognitive Neurology
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People and Places
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Biology and Life Sciences
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Body Weight
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Saudi Arabia
Medicine and Health Sciences
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Geriatric Care
Comorbidities, medications, depression, and physical performance measures associated with severe cognitive impairments in community-dwelling adults
Associated factors with severe cognitive impairment
Almutairi Gamar R. Conceptualization Formal analysis 1
Almegbas Noura R. Conceptualization Data curation 1
Alosaimi Rawan M. Conceptualization Formal analysis 1
Alqahtani Maha A. Data curation 2
Batook Saleh G. Writing – review & editing 3
Alfageh Ibrahim A. Conceptualization 4
Alshehri Mohammed M. Conceptualization Writing – review & editing 5
Alanazi Shuruq F. Conceptualization Data curation 6
https://orcid.org/0000-0002-2936-7581
Alhowimel Ahmed S. Supervision Writing – original draft 1
Alqahtani Bader A. Conceptualization Formal analysis 1
Alhwoaimel Norah A. Methodology Writing – original draft Writing – review & editing 1
https://orcid.org/0000-0002-2641-8339
Alenazi Aqeel M. Supervision Writing – original draft Writing – review & editing 1 *
1 Department of Health and Rehabilitation Sciences, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia
2 Department of Research and Innovation, King Abdullah International Medical Research Centre, Riyadh, Saudi Arabia
3 East Jeddah General Hospital, Western Region, Jeddah, Saudi Arabia
4 Abu Arish General Hospital, Jazan, Saudi Arabia
5 Department of Physical Therapy, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
6 Primary Health Care, Ministry of Health, Riyadh, Saudi Arabia
Sakurai Ryota Editor
Tokyo Metropolitan Institute of Geriatrics and Gerontology, JAPAN
Competing Interests: The authors have declared that no competing interests exist.

* E-mail: aqeelalenazi.pt@gmail.com, aqeel.alanazi@psau.edu.sa
19 9 2024
2024
19 9 e030976514 3 2024
17 8 2024
© 2024 Almutairi et al
2024
Almutairi et al
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Cognitive impairment negatively impacts health, psychological, social, and economic domains. Cognitive impairment commonly affects physical functions in older adults, whereas these are deteriorated. However, the prevalence and associated factors of cognitive impairment among community-dwelling adults in Saudi Arabia have not been investigated yet. This study aimed to examine the prevalence of severe cognitive impairment and its associated factors in community-dwelling older adults in Saudi Arabia. This cross-sectional study involved adults aged ≥50 years. Demographic data and clinical data, including number of medications and body mass index (BMI), were collected. Cognitive impairment and depressive symptoms were measured using Arabic versions of the Montreal Cognitive Assessment (MoCA) and Patient Health Questionnaire-9 (PHQ-9), respectively. The participants were divided into severe cognitive impairment and mild cognitive impairment or normal cognitive function groups based on a score of <20 or ≥20, respectively, using the MoCA. Physical measures included dynamic gait index (DGI) scores, timed up-and-go (TUG), 5 times sit-to-stand (5XSST), functional reach test, and 6-minute walk test. A total of 206 participants (female: n = 96) were included. The prevalence of severe cognitive impairment in the community-dwelling older adults was 12.6%. The number of chronic conditions (odds ratio [OR]: 2.31, p<0.001), number of medications (OR: 1.36, p = 0.003), and depressive symptoms using PHQ-9 (OR: 1.11, p = 0.009) were significantly associated with severe cognitive impairment after adjustment for other covariates, including age, sex, and BMI. Based on the physical function measures, only the scores for DGI (OR: 0.86, p = 0.003), TUG (OR: 1.16, p = 0.035) and 5XSST (OR: 1.25, p <0.001) were significantly associated with severe cognitive impairment. This study revealed a high prevalence of severe cognitive impairment among community-dwelling adults in Saudi Arabia. Its major risk factors include depressive symptoms, number of chronic conditions and medications, and physical measures, including DGI, TUG, and 5XSST.

http://dx.doi.org/10.13039/100009392 Prince Sattam bin Abdulaziz University PSAU/2024/R/1445 https://orcid.org/0000-0002-2641-8339
Alenazi Aqeel M. This study was supported via funding from Prince Sattam Bin Abdulaziz University project number (PSAU/2024/R/1445). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityData cannot be shared publicly because of ethical restrictions; the data contain potentially identifying and sensitive patient information that prevented us from sharing. Data are available from the Institutional Data Access / Ethics Committee of Sattam bin Abdulaziz University (contact via IRB-sciences@psau.net) for researchers who meet the criteria for access to confidential data.
Data Availability

Data cannot be shared publicly because of ethical restrictions; the data contain potentially identifying and sensitive patient information that prevented us from sharing. Data are available from the Institutional Data Access / Ethics Committee of Sattam bin Abdulaziz University (contact via IRB-sciences@psau.net) for researchers who meet the criteria for access to confidential data.
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pmcIntroduction

The life expectancy in Saudi Arabia has increased over several recent decades, resulting in a rapid increase in the proportion of older people. The General Authority for Statistics in Saudi Arabia estimated the percentage of persons aged ≥65 years accounts for 2.4% of the total population in 2019 [1]. By 2050, the elderly are predicted to account for 18.4% of the total population [2]. Consequently, age-related conditions require close monitoring and continuous care. Aging is associated with functional deterioration affecting various body systems, including musculoskeletal, cardiovascular, and cognition systems [3–6]. Cognitive decline is more prevalent with age, affecting well-being and bodily functions necessary to maintain total independence, self-care, and autonomy [7, 8].

Cognitive impairment is defined as a state of impaired cognition involving different domains, including memory, executive functions, attention, language, and visuospatial skills. The stages of cognitive impairment are very mild, mild, moderate, moderately severe, severe (middle dementia) and very severe (severe dementia). Mild cognitive impairment (MCI) is a stage of cognitive decline that is not sufficiently severe to require help with everyday tasks [9].

Several risk factors can be used to predict cognitive decline in elderly populations. Alkhunizan et al. states that age, educational level, smoking, overweight, diabetes, high blood pressure, and hyperlipidemia are related to MCI and dementia [10]. The prevalence of MCI was 15–20% in people aged ≥60 years, making it a frequent disorder encountered by physicians. However, MCI is a transitional stage to dementia[10, 11].

Cognitive decline was associated with depressive symptoms among Chinese community-dwelling older adults [12]. Furthermore, cognitive decline was associated with depressive symptoms in Saudi community-dwelling adults [13]. However, this study relate the depressive symptoms with severe cognitive impairments. Therefore, using depressive symptom cutoff scores with severe cognitive impairment is crucial for screening and to establish interventional approaches in this population.

Cognitive functioning is associated with physical functioning. Among older adults, physical functions, including gait, balance, and mobility, are affected; however, these functions are more frequently deteriorated in the elderly with cognitive impairment [14–17]. A cross-sectional study investigating the relationship between mental impairment and each component of activity in daily living (ADL) in elderly populations showed that cognitive status can be a predictive factor for ADL in the elderly [18].

Cognitive impairment can negatively impact health, psychological, social, and economic domains. Individuals with cognitive impairment have a poor quality of life, a high risk of falls, and an increased rate of disability and functional limitations [19]. Progression of cognitive impairment increases dependency levels, affecting the amount of caregiving required. In addition, people with cognitive impairment have an increased risk of death, a lower quality of life, poor quality of mental health, and longer hospital stays [8].

The World Health Organization (WHO) considers severe cognitive impairment to be the seventh-leading cause of death involving all diseases [20]. Caregivers spend an average of 6.7 h on informal care for people with dementia [21]. The annual costs of dementia are estimated at US$ 818 billion and are predicted to increase to US$ 2 trillion by 2030 [22]. Nevertheless, the prevalence of and factors associated with severe cognitive impairment among community-dwelling adults in Saudi Arabia have not been investigated yet. Therefore, this study aimed to examine the prevalence of severe cognitive impairment and its associated factors in community-dwelling adults in Saudi Arabia. The findings of this study would provide a reliable basis for preventive community measures to decrease severe cognitive impairment among older adults in Saudi Arabia.

Methods

Study design and participants

This was a cross-sectional study performed in Saudi Arabia between February 2, 2022, and April 30, 2022, using convenience sampling. The inclusion criteria was as follows: age ≥50 years, being able to perform functional tests safely, being able to read and write in the Arabic language, and being a Saudi citizen. Non-Saudi adults, age <50 years, and an inability to read and write in Arabic, were considered as exclusion criteria since some outcome measures that were self-reported were validated in Arabic. Participants were recruited from different geographical regions across Saudi Arabia (Riyadh, Alkharj, Jazan, Jeddah, Arar, Hail, and Tabuk). The data was collected by trained physical therapists who recruited participants from different communities (mosques, malls, clinics, and other social-gathering locations). A total of 418 participants were approached, and 212 participants were included in the current study (inclusion rate, 50.7%). The reasons for refusal to participate were lack of time and transportation. The included participants signed written consent following the mandates of the Declaration of Helsinki. This study was approved by the Research Ethics Committee of the Prince Sattam Bin Abdulaziz University (No. RHPT/021/017)

Demographics and anthropometric data

Data were collected using a standardized questionnaire and all the interviewers were well-trained to mitigate information bias [23]. Data collection commenced with demographic data, including age, gender, and body mass index (BMI). Age was recorded in years and categorized into six groups (i.e., 50–54, 55–59, 60–64, 65–69, 70–74, and > 74 years). Gender was reported as male or female. Weight and height were measured in kg and cm, respectively. BMI was calculated by dividing weight in kg by squared height in m2 and categorized into three groups (i.e. normal weight [BMI < 25], overweight [25 < BMI <30] and obese [BMI ≥ 30]). Marital status was dichotomized as married or divorced/widowed.

Outcome measures

Cognitive function was assessed using the Arabic version of the Montreal Cognitive Assessment (MoCA) [24]. The MoCA comprises 7 parts, including visuospatial (maximum score, 5/5), animal name identification (3/3), attention (6/6), language (3/3), abstraction (2/2), delayed recall (5/5), orientation (6/6), and education (1/1). The total score ranged from 0 to 31 with a higher score indicating better cognitive functions. Participants were classified into severe cognitive impairment and MCI/normal cognitive function groups based on a score of < 20 and ≥ 20, respectively [25–27].

Exposure factors

Chronic diseases have been evaluated with different definitions and numbers in previous research. One of the definitions used chronic non-communicable diseases involved 10 conditions [28]. We used a similar definition with some revisions related to the prevalence of diseases in Saudi Arabia. Major chronic diseases, including hypertension, diabetes, cardiovascular disease, cancer, pulmonary disease, dyslipidemia, neurological diseases, osteoporosis, arthritis, and low back pain, were recorded via self-reported diagnoses. The total number of chronic diseases and currently used medications were also recorded. Self-reported chronic diseases had adequate validity with good agreement to well-known chronic conditions, such as diabetes, hypertension, and cardiovascular diseases [29, 30]. The number of currently used medications was reviewed by the research team and then recorded.

Depressive symptoms were measured using the Arabic version of Patient Health Questionnaire 9 (PHQ-9), which is considered as valid and reliable [31, 32]. PHQ-9 includes nine self-reported questions related to depressive symptoms, including anhedonia, depressed mood, sleep troubles, fatigue, change in appetite, decreased self-esteem, concentration disturbance, psychomotor disorder, and suicidal thoughts [33]. The participants reported the impact of symptoms through questions, such as ‘How difficult have these problems made it for you to do your work, take care of things at home or get along with other people?.’ The answers employed a four-point scale (0–3): ‘not at all = 0’, ‘several days = 1’, ‘more than half the days = 2,’ and nearly every day = 3’. The total score ranges from 0 to 27, with greater scores indicating more depressive symptoms.

Gait and balance while walking was assessed using the Arabic version of the dynamic gait index (DGI), which was previously translated and validated [34–36]. DGI evaluates the participants’ ability to walk steadily and modify their gait in response to challenging tasks. The participants’ walk performance was evaluated via the following gait tasks: steady-state walking, walking with changing speeds (fast/comfortable/slow), walking with head turned up and down, walking while stepping around and over obstacles, spinning while walking, and stair climbing. The scores were based on a 4-point scale, as follows: ‘3 = no gait dysfunction’, ‘2 = minimal impairment’, ‘1 = moderate impairment,’ and ‘0 = severe impairment’. The highest score possible was 24 points, indicating superior performance.

Timed up-and-go (TUG) was used to measure balance, mobility, ability to walk, and risk of fall [37]. The examiner tasked the participant to stand up, walk for 3 meters, turn around, walk back, and sit down on a chair. Greater scores in seconds indicated poorer performance in balance and mobility and a greater risk of falling.

Dynamic balance and stability were measured using the functional reach test (FRT) [38]. The participants were instructed to extend forward their dominant arm to the greatest extent possible. An examiner measured the distance between the starting and ending points of the third metacarpal bone in cm. A lower distance indicates poor balance and a high risk of falling.

Endurance and aerobic capacity were assessed using the 6-minute walk test (6-MWT), following a standardized protocol [39]. 6-MWT examines the distance walked by participants over a period of 6 minutes. A greater distance (in m) indicates better endurance and performance.

The 5 times sit-to-stand test (5XSST) was used to measure functional lower extremity strength [40]. 5XSST measures the time required to complete five repetitions of the sit-to-stand position on a chair without using the hands. The shorter the time to complete the test, the better the outcome.

Statistical analysis

Descriptive statistics are used to define categorical variables and means, and standard deviations for continuous variables for each group. The two groups (severe cognitive impairment and MCI groups) were compared based on demographics and clinical variables using the Chi-squared or Fisher’s exact test for categorical variables and independent Student’s t-test for continuous variables.

Multiple binary logistic regression, odds ratio (OR), and 95% confidence interval (95% CI) were used to assess the potential associations between the risk factors and physical function measures of severe cognitive impairment. The variables included in the regression model were selected based on their relevance and potential association with cognitive impairment. The following two models were developed based on adjustments: model 1 was unadjusted, and model 2 was adjusted for age, sex, and BMI to control the key factors that have been shown to influence cognitive outcome. Previous studies employed unadjusted models [10, 41]. Missing variables were handled using case-wise deletion.

Receiver operating characteristic (ROC) curves were constructed to determine the cut-off scores for significant risk factors for severe cognitive impairment. The area under the ROC curve (AUC) indicates the overall accuracy of the model in detecting the presence or absence of the outcome, such as severe cognitive impairment. The maximum AUC is the best cut-off score, measured by the largest Youden’s index (sensitivity + [1 − specificity]). Sensitivity and specificity were calculated to determine true positives and true negatives, respectively. AUC values were interpreted according to an arbitrary guideline, no (AUC < 0.5), poor (0.5 ≤ AUC < 0.7), acceptable (0.7 ≤ AUC < 0.8), excellent (0.8 ≤ AUC < 0.9), and outstanding (AUC > 0.9) discriminant ability [42].

Finally, a sensitivity analysis was conducted using multiple imputation method to compare the results after five multiple imputations for missing observations using age, gender, and BMI as predicators with the results from the original dataset using case wise deletion. An alpha level of 0.05 was used for all analyses. All analyses were performed using IBM SPSS for Mac v.25.0 (SPSS Inc. Chicago, IL, USA).

Results

Our final analysis included 206 participants. Table 1 presents the demographics and clinical characteristics of participants with and without severe cognitive impairment. The prevalence of severe cognitive impairment among community-dwelling adults was 12.6% (n = 26); this was higher in women than that in men and in the 60–64-year age compared with that in the other age categories. Most of the variables, including age, sex, number of chronic conditions, number of medications, and depressive symptoms, differed significantly between the severe cognitive impairment and MCI or normal groups, determined using the PHQ-9, DGI score, TUG, 5XSST, FRT, and 6MWT results.

10.1371/journal.pone.0309765.t001 Table 1 Demographic, anthropometric and clinical factors of the participants.

Factors	Severe cognitive impairment (n = 26)	MCI/normal cognitive function (n = 180)	p-value*	
Age category			0.018	
50–54 years, n (%)	5 (19.2)	54 (30.0)		
55–59 years, n (%)	4 (15.4)	47 (26.1)		
60–64 years, n (%)	8 (30.8)	50 (27.8)		
65–69 years, n (%)	2 (7.7)	18 (10.0)		
70–74 years, n (%)	3 (11.5)	4 (2.2)		
375 years, n (%)	4 (15.4)	7 (3.9)		
Sex male/female	4/22	92/88	0.001	
Marital status			0.003	
    Married, n (%)	17 (65.4)	161 (89.4)		
    Divorced/widowed, n (%)	9 (34.6)	19 (10.6)		
BMI category	29.8±5	28.5±5	0.41	
Normal BMI (< 25), n (%)	4 (15.4)	50 (27.8)		
Overweight (25–29.9), n (%)	11 (42.3)	66 (36.7)		
Obese (330), n (%)	11 (42.3)	64 (35.6)		
Number of chronic conditions (mean±SD)	3.30±1.6	1.39±1.28	< 0.001	
Number of medications (mean±SD)	2.96±2.7	1.22.66±1.6	0.004	
PHQ-9 (mean±SD)	8.62±5.66	4.66±4.77	< 0.001	
DGI (mean±SD)	16.12±6.18	20.40±3.77	0.002	
TUG, sec (mean±SD)	12.58±3.4	10.52±2.9	0.001	
5XSST, sec (mean±SD)	19.32±8.7	13.44±3.47	0.002	
FRT, cm (mean±SD)	24.23±6,2	27.10±8.16	0.047	
6MWT, m (mean±SD)	377±89	428±106	0.026	
Notes: *p-value was based on Chi-square or Fisher’s Exact test and independent t-test for categorical and continuous variables, respectively.

MCI: mild cognitive impairment, BMI: body mass index, PHQ-9: Patient Health Questionnaire-9, DGI: dynamic gait index, TUG: timed up and go, 5XSST: 5 times sit-to-stand, FRT: functional reach test, 6MWT: 6-minute walk test

Table 2 shows the results of multiple binary logistic regression examining the associated risk factors of severe cognitive impairments, with OR and 95% CI. The number of chronic conditions (OR: 2.31, 95% CI [1.57, 3.41], p < 0.001), number of medications (OR: 1.36, 95% CI [1.11, 1.67], p = 0.003). and depressive symptoms determined using the PHQ-9 (OR: 1.11, 95% CI [1.03, 1.21], p = 0.009) were significantly associated with severe cognitive impairment after adjustment for other covariates, including age, sex, and BMI. Physical function measures showed that the DGI (OR: 0.86, 95% CI [0.77, 0.94], p = 0.003), TUG (OR: 1.16, 95% CI [1.01, 1.34], p = 0.035) and 5XSST (OR: 1.25, 95% CI [1.11, 1.39], p < 0.001) scores were significantly associated with severe cognitive impairment after adjustment for other covariates, including age, sex, and BMI.

10.1371/journal.pone.0309765.t002 Table 2 Binary logistic regression for severe cognitive impairment versus risk factors.

	Unadjusted model
n = 206	Adjusted model
n = 206	
Factors	OR (95% CI)	p-value	OR (95% CI)	p-value	
Number of chronic conditions	2.35 (1.69, 3.28)	< 0.001	2.31 (1.57, 3.41)	< 0.001	
Number of medications	1.44 (1.19, 1.73)	< 0.001	1.36 (1.11, 1.67)	0.003	
PHQ-9	1.13 (1.06, 1.22)	0.001	1.11 (1.03, 1.21)	0.009	
DGI	0.83 (0.77, 0.90)	< 0.001	0.86 (0.77, 0.94)	0.003	
TUG	1.20 (1.07, 1.36)	0.003	1.16 (1.01, 1.34)	0.035	
5XSST	1.24 (1.13, 1.38)	< 0.001	1.25 (1.11, 1.39)	< 0.001	
FRT	0.96 (0.90, 1.01)	0.09	0.94 (0.88, 1.01)	0.08	
6MWT	0.99 (0.99, 0.99)	0.02	0.99 (0.99, 1.00)	0.27	
Notes: The adjusted model included age, gender, and BMI.

OR: odds ratio, BMI: body mass index, PHQ-9: Patient Health Questionnaire-9, DGI: dynamic gait index, TUG: timed up and go, 5XSST: 5 times sit-to-stand, FRT: functional reach test, 6MWT: 6-minute walk test

Table 3 summarizes the results of the ROC curve analysis, including AUC and identified cut-off scores for each risk factor (number of chronic conditions, number of medications, PHQ-9, DGI, TUG, 5XSST) associated with severe cognitive impairment, along with their sensitivity and specificity. Regarding the number of chronic conditions, having ≥ 2.5 chronic conditions demonstrated an excellent discriminant ability in predicting severe cognitive impairment (Fig 1). A cut-off score of 2.5 for the number of medications had an acceptable ability to detect the presence of severe cognitive impairment in older adults (Fig 2). The cut-off score for PHQ-9 associated with severe cognitive impairment was ≥6.5 (Fig 3), whereas that for the physical function measures DGI (Fig 4), TUG (Fig 5), and 5XSST (Fig 6) associated with severe cognitive impairment were ≤ 21, ≥ 11.77 s, and ≥ 15.60 s, respectively.

10.1371/journal.pone.0309765.g001 Fig 1 ROC curves for the number of chronic conditions associated with severe cognitive impairment.

10.1371/journal.pone.0309765.g002 Fig 2 ROC curves for the number of medications associated with severe cognitive impairment.

10.1371/journal.pone.0309765.g003 Fig 3 ROC curves for the PHQ-9 score associated with severe cognitive impairment.

10.1371/journal.pone.0309765.g004 Fig 4 ROC curves for the DGI score associated with severe cognitive impairment.

10.1371/journal.pone.0309765.g005 Fig 5 ROC curves for the TUG score associated with severe cognitive impairment.

10.1371/journal.pone.0309765.g006 Fig 6 ROC curves for the 5XSST score associated with severe cognitive impairment.

10.1371/journal.pone.0309765.t003 Table 3 ROC curve and cut-off scores for the significant risk factors of severe cognitive impairment.

Variables	AUC (95% CI)	Cut-off score (sensitivity, specificity)	
Number of chronic conditions	0.82 (0.74, 0.91)	2.5 (0.69, 0.80)	
Number of medications	0.71 (0.59, 0.82)	2.5 (0.50, 0.83)	
PHQ-9	0.73 (0.62, 0.83)	6.5 (0.65, 0.74)	
DGI	0.73 (0.63, 0.83)	21.5 (0.50, 0.89)	
TUG	0.69 (0.58, 0.79)	11.77 (0.58, 0.74)	
5XSST	0.77 (0.66, 0.87)	15.60 (0.62, 0.82)	
PHQ-9: Patient Health Questionnaire-9, DGI: Dynamic Gait Index, TUG: Timed Up and Go, 5XSST: 5 times sit-to-stand.

Notes: AUC < 0.5 and 0.5 ≤ AUC < 0.7 denote no and acceptable discriminant ability, respectively

The results for the sensitivity analysis showed similar results with the original dataset without imputation except for TUG (OR: 1.16, 95% CI [1.01, 1.34], p = 0.035) that became significant predictors for severe cognitive impairment.

Discussion

This study determined the prevalence and associated risk factors of severe cognitive impairment in community-dwelling older adults in Saudi Arabia using the MoCA scale. The associated risk factors for severe cognitive impairment were the number of major chronic diseases, number of medications, and depressive symptoms. Other physical functions associated with severe cognitive impairment included decreased scores for the DGI and increased times for the TUG and 5XSST. These cut-off scores for the risk factors and physical functions measures of severe cognitive impairment in community-dwelling adults may be useful for future clinical practice.

Severe cognitive impairment was higher in women and the 60–64-year age group. These findings disagree with a recent study performed on older adults in Norway, which showed that women were associated with a higher score on MoCA evaluations [43]. However, another study investigating cognitive impairment among older adults in Greece concluded that age or gender does not affect the MoCA score [44]. In contrast, a recent meta-analysis and systematic review of 41 studies found that the prevalence of MCI in community-dwelling Chinese older adults increases with age [45]. These differences in cognitive impairment prevalence are likely due to diversity involving screening tools and diagnostic criteria.

The number of chronic conditions, number of medications, and depressive symptoms were associated with severe cognitive impairment in the current study. The association between health status, as measured by the presence of chronic diseases and cognitive function among older adults (n = 130) in Saudi Arabia, showed a non-significant correlation between the two [46]. Furthermore, a recent study in the US involving 17,899 older adults found that the presence of stroke, high blood pressure, diabetes, heart problems, and disease comorbidity were associated with lower cognition levels [47]. They explained that the effects of chronic diseases on cognition level was partially mediated through depressive symptoms (19–54%) [47]. A national survey of 3,101 older adults reported that depressive symptoms, measured using PHQ-9, are associated with lower cognitive function [48]. Older adults who are at risk of depression are more likely to present with MCI [14]. The cause of depression (e.g. health-related diseases, social factors, or a combination of both) should be observed to explain the impact of chronic diseases and social factors on the development of depression and cognitive impairment.

Physical functions, including DGI, TUG, and 5XSST, exhibited an association with severe cognitive impairment, indicating a contribution to low cognitive function among older adults. Participants with severe cognitive impairment had lower DGI scores, and a cut-off score of ≤ 21 was associated with severe cognitive impairment. The relationship between cognitive functioning and gait performance, as measured using DGI, has been reported in a previous study, which revealed a strong relationship between cognition and gait performance in older adults (> 65 years old) undergoing physical therapy interventions at home [17]. One possible explanation is that walking speed can be a sign of brain injury (white matter disease) associated with cognitive deterioration [16]. Cognitive functions are necessary for gait performance during ageing, with significant relationships between yaw amplitude during turns and attention or visual–spatial ability [15, 35]. In our cohort, participants with severe cognitive impairment took a considerable amount of time to complete the TUG tests. A cut-off score of ≥ 11.77 s in TUG performance was associated with severe cognitive impairment. A prolonged time to plan a movement during TUG test performance is associated with MCI in older adults [49]. This finding can be explained by the contribution of visual-spatial processing during turning to enable clear directional movement [15].

The time taken to complete the 5XSST was also higher in the severe cognitive impairment group. A cut-off score of ≥ 15.60 s was associated with severe cognitive impairment. This result is consistent with a previous study that included 7,421 community-dwelling older adults; 15 s in 5XSST was a sensitive value to predict moderate cognitive impairment [50]. A recent logistic regression analysis showed that 5XSST is associated with cognitive functional decline in older adults [51]. Overall, the association between physical functions and cognitive impairment in our study reinforced the hypothesis that motor function is associated with cognitive function, as planning and decision-making are required for successful task completion.

In the current study, FRT and 6MWT were not associated with severe cognitive impairment. FRT was significantly associated with severe cognitive impairment in an unadjusted model with an odds ratio of 0.99. This indicated that a decreased in FRT distance increased the risk of severe cognitive impairment among the community-dwelling adults. However, after adjusting the model for potential covariates, this association did not reach a statistical significance, indicating a potential mediation of covariates involved in the association between FRT and severe cognitive impairment. 6MWT was not significantly associated with severe cognitive impairment in the community-dwelling adults, as evidenced using regression analysis. However, a significant difference was observed in the 6MWT between those with severe cognitive impairments and those with MCI or normal cognitive function using an independent Student’s t-test. This indicates potential confounding by other factors that were adjusted for in the regression model. Future research should examine this association with a larger sample size with consideration of other measures of mobility and balance.

We examined the cut-off scores for the number of chronic conditions using AUC and ROC. A cut-off score of approximately 2–3 number of chronic conditions was associated with severe cognitive impairment with an AUC of 82%. Although this AUC is considered to have excellent accuracy and discriminant ability (0.8 ≤ AUC < 0.9) [42]. These statistics provide valuable information (AUC = 82%) regarding the ability of our model to discriminate between cases and non-cases, and they are also commonly used in clinical and epidemiological research. Using ROC and AUC allowed us to examine the ability of each measure to discern severe cognitive impairment among the community-dwelling adults aged ≥50 years. However, the absence of a gold standard for the evaluation can limit the interpretability of the current results. AUC values for each functional measure may not reflect the true diagnostic accuracy for detecting severe cognitive impairment in this population. Therefore, the usefulness of these measures in clinical practice warrants future studies in similar populations. We believe that our findings may provide insights into the potential utility of functional measures, including the number of chronic diseases, number of medications, PHQ-9, DGI, TUG, and 5XSST, in the detection of severe cognitive impairment.

This study had several major strengths. First, this cross-sectional study employed a large sample of community-dwelling older adults in Saudi Arabia recruited through convenient sampling. The data collection focused on the risk factors. However, this study also had certain limitations, including lack of sufficient data to account for the underlying reasons for the factors involved and a limited number of participants from different regions. This study included only adults who were able to read and write in Arabic, which may have affected the representation of the elderly population because the illiteracy rate in Saudi Arabia for older adults is 59.29% [52]. Further research using larger sample sizes to examine and compare these findings in aged populations warranted. The study was cross-sectional; therefore, any significant association between cognitive impairment and risk factors cannot be definitively determined from the results, rather reverse causation stands as a possibility in the observational study design. Another limitation was the instruments used in the current study may have affected the validity and reliability of the results. We used a comprehensive battery of instruments to examine the factors associated, including functional performance, with severe cognitive impairment. Using a multidimensional approach may provide a more complete understanding of the relationship between these constructs and severe cognitive impairment. However, using multiple instruments may introduce measurement bias and impact the results regarding the prevalence of severe cognitive impairment in this population. To decrease the risk of measurement bias, we applied a rigorous instrument selection process based on established psychometric properties, reliability, validity, and clinical relevance, and ensured that all the instruments were administered and scored consistently across participants. Sensitivity analyses were conducted to assess the robustness of our findings against potential measurement errors. The results for imputations were similar to the results of the original dataset except for TUG that became a significant risk factor for severe cognitive impairment. This may indicate that an increase in the time for performing TUG was associated with severe cognitive impairment. It also indicates that the missing data affected the original results due to a lack of reaching significance level. In addition, using the self-reported data on chronic conditions, may be associated with recall bias. However, efforts were made to minimize bias as the data were collected using a standardized questionnaire and all the interviewers were well trained in mitigating information bias [23]. Objective measures for chronic conditions were not feasible in our study due to resource constraints and logistical limitations and recruitment feasibility from the community. Thus, a rigorous data validation process was used to minimize the impact of the self-reported data on our findings. This process included assessing the robustness of the data via data cleaning, consistency checks, sensitivity analyses, and double validation from research assistants. Finally, this study used convenience sample, rather than random sampling. This can raise another form of selection bias that might affect the results. Future research should examine chronic diseases using physician diagnoses and diagnostic codes for health records. Another limitation was that the participants may have been fatigued due to the multiple assessments. Although efforts were made to divide the assessments between two sessions, the potential impact of fatigue should be considered in future research in order to minimize its impact on the test outcomes.

Conclusion

The prevalence of severe cognitive impairment was moderate among community-dwelling adults in Saudi Arabia. Several risk factors were significantly associated with decline in cognitive function. Individuals with chronic conditions, a higher number of medications, and a score of ≥ 6.5 in the PHQ-9 were more likely to have severe cognitive impairment. Deterioration in the DGI, TUG, and 5XSST test performance was associated with the development of severe cognitive impairment in community-dwelling adults. Further research is required to develop multimodal risk reduction approaches and examine their effectiveness in community-dwelling adults.

Supporting information

S1 Checklist STROBE check list is available in the supporting information.

(DOCX)

10.1371/journal.pone.0309765.r001
Decision Letter 0
Khan Mohammad (Md) Jobair Academic Editor
© 2024 Mohammad (Md) Jobair Khan
2024
Mohammad (Md) Jobair Khan
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version0
4 Apr 2024

PONE-D-24-07185Comorbidities, medications, depression, and physical performance measures are associated with severe cognitive impairments in community-dwelling adultsPLOS ONE

Dear Dr. Alenazi,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Mohammad (Md) Jobair Khan, BSPT, MPH

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors of this study have presented information concerning the associations between certain measurements and severe cognitive impairments in community-dwelling adults. Overall, the study is well-designed and drafted. However, there are opportunities for improvement in the draft before publication, as outlined in the comments and suggestions provided below.

1. General:

The language and grammar use need major enhancement.

2. Abstract:

A: Begin by formulating a concise main idea for your objective, followed by its elaboration. Consider incorporating one background sentence emphasizing the importance of aging and related impairments, akin to the approach taken in your introduction (it is clearly indicated in introduction).

B: Please consider refining the method to enhance clarity and ensure grammatical correctness.

3. Introduction:

A: Use simple past tense ('reached 2.4%') when referring to the previous statistic, as mentioned.

B: Depressive symptoms measurement was mentioned in the abstract, it wasn't specifically addressed in the introduction. Consider incorporating this aspect briefly into the introduction for clarity and coherence.

4. Discussion:

Insufficient discussion has been provided regarding the two physical measures, namely the Functional Reach Test and the 6-minute walk test. Please include this aspect in your discussion.

Reviewer #2: This manuscript reports on a cross-sectional study that examines the prevalence of severe cognitive impairment among community-dwelling older adults in Saudi Arabia and its association with comorbidities, medication use, depressive symptoms, and physical performance measures. The topic is of significant importance, aiming to fill a crucial gap in the literature by providing insights into factors associated with severe cognitive impairment. The attempt to conduct this initial stage of epidemiological investigation is commendable. However, to enhance the clarity and impact of the findings, there are several areas where improvements are recommended. Publication is advised after addressing the outlined major and minor issues.

Major issues:

1. Sampling Framework and Process:

The manuscript requires more detail regarding the sampling framework and process, including the number of individuals approached and the success rate. This information is vital for assessing the study's representativeness and potential selection bias.

2. Exclusion Criteria and Generalisability:

Given the exclusion criteria for the ability to read and write in Arabic, a discussion on the literacy rate among the elderly in Saudi Arabia is necessary. This will help evaluate the generalisability of the study results to the target population.

3. Data Collection and Chronic Disease Assessment:

The manuscript should clarify whether the clinical data collection included physical examinations or was solely based on verbal communication asking about chronic diseases. Furthermore, the approach to evaluating chronic diseases, given the variability in definitions and numbers in prior research, needs greater transparency. If the diagnosis is self-reported, the manuscript should address potential biases, such as recall and social desirability bias, and question the validity of referring to these as "clinical variables".

4. Participant Fatigue:

The potential for participant fatigue due to undergoing multiple assessments should be considered. The manuscript should describe any efforts made to prevent fatigue bias or discuss this potential bias in the discussion section if such measures were not taken.

5. Depressive Symptoms as Exposure:

The manuscript describes the measurement of depressive symptoms as part of the outcome measures, yet the study's aim suggests it as an exposure factor. This needs clarification for consistency and accuracy in the study's presentation.

6. Accuracy of Exposure Measures:

The manuscript's utilisation of self-reported data for comorbidities (not objectively measured) brings into question the accuracy of these exposure measures. This issue is crucial as it directly impacts the validity of the findings, including the reported odds ratios of severe cognitive impairment and risk factors. The reliance on ROC and AUC for inference, despite their potential to be significantly affected by biases, warrants a critical evaluation. It is imperative that the authors devote a substantial portion of the discussion to addressing and mitigating potential biases, including measurement and selection biases. This focus is essential to align the study with its objectives and enhance its relevance and credibility. An in-depth evaluation of these more fundamental aspects, such as the nature and impact of biases on the study's conclusions, would provide a more solid foundation for the research findings than the technical details provided by ROC and AUC analyses alone.

Minor issues:

1. Instrument Use and Measurement Bias:

The use of several instruments to measure outcomes raises questions about the study's inference regarding the prevalence of cognitive impairment and whether it may be affected by measurement bias. The authors should address the choice of instruments and their impact on study conclusions.

2. ROC and AUC Inference:

The use of ROC and AUC for several inferences, without a gold standard for evaluation, warrants a discussion on how this information contributes to future studies and the study's coherence.

The manuscript tackles a pivotal research area with significant implications for understanding cognitive impairment among the elderly. However, concerns regarding sampling, data collection, and potential biases necessitate careful consideration before publication. The study's strengths lie in its attempt to explore under-investigated associations within a specific population. Ensuring the clarity, consistency, and accuracy of the methodology and findings will greatly enhance the manuscript's contribution to the field.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

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10.1371/journal.pone.0309765.r002
Author response to Decision Letter 0
Submission Version1
26 May 2024

Response to reviewers PLOS ONE

Dear Editor and reviewers,

Thank you for your constructive feedback and comments that help us in improving our manuscript. All comments were considered with track changes and highlighted in yellow across the manuscript.

Reviewer #1: The authors of this study have presented information concerning the associations between certain measurements and severe cognitive impairments in community-dwelling adults. Overall, the study is well-designed and drafted. However, there are opportunities for improvement in the draft before publication, as outlined in the comments and suggestions provided below.

1. General:

The language and grammar use need major enhancement.

RESPONSE: Thank you for your comment, we sent the manuscript for proofreading service (EDITAGE). We attached the certificate with the supplementary materials.

2. Abstract:

A: Begin by formulating a concise main idea for your objective, followed by its elaboration. Consider incorporating one background sentence emphasizing the importance of aging and related impairments, akin to the approach taken in your introduction (it is clearly indicated in introduction).

RESPONSE: Thank you for your comment, we revised this accordingly.

B: Please consider refining the method to enhance clarity and ensure grammatical correctness.

RESPONSE: Thank you for your comment, we sent the manuscript for proofreading service (EDITAGE). We attached the certificate with the supplementary materials.

3. Introduction:

A: Use simple past tense ('reached 2.4%') when referring to the previous statistic, as mentioned.

RESPONSE: we revised the manuscript and sent it for a proofreading service.

B: Depressive symptoms measurement was mentioned in the abstract, it wasn't specifically addressed in the introduction. Consider incorporating this aspect briefly into the introduction for clarity and coherence.

RESPONSE: Thank you for your comment, we added a paragraph related to depressive symptoms.

4. Discussion:

Insufficient discussion has been provided regarding the two physical measures, namely the Functional Reach Test and the 6-minute walk test. Please include this aspect in your discussion.

RESPONSE: thank you for your comment, we added a paragraph in the discussion related to FRT and 6MWT.

Reviewer #2: This manuscript reports on a cross-sectional study that examines the prevalence of severe cognitive impairment among community-dwelling older adults in Saudi Arabia and its association with comorbidities, medication use, depressive symptoms, and physical performance measures. The topic is of significant importance, aiming to fill a crucial gap in the literature by providing insights into factors associated with severe cognitive impairment. The attempt to conduct this initial stage of epidemiological investigation is commendable. However, to enhance the clarity and impact of the findings, there are several areas where improvements are recommended. Publication is advised after addressing the outlined major and minor issues.

RESPONSE: Thank you for your comments. We revised according to your suggestions.

Major issues:

1. Sampling Framework and Process:

The manuscript requires more detail regarding the sampling framework and process, including the number of individuals approached and the success rate. This information is vital for assessing the study's representativeness and potential selection bias.

RESPONSE: Thank you for your comment, we revised and added more details to the methods section regarding the sampling method and recruitment.

2. Exclusion Criteria and Generalisability:

Given the exclusion criteria for the ability to read and write in Arabic, a discussion on the literacy rate among the elderly in Saudi Arabia is necessary. This will help evaluate the generalisability of the study results to the target population.

RESPONSE: we included this in the limitation section with the percentage of illiteracy among older adults.

3. Data Collection and Chronic Disease Assessment:

The manuscript should clarify whether the clinical data collection included physical examinations or was solely based on verbal communication asking about chronic diseases. Furthermore, the approach to evaluating chronic diseases, given the variability in definitions and numbers in prior research, needs greater transparency. If the diagnosis is self-reported, the manuscript should address potential biases, such as recall and social desirability bias, and question the validity of referring to these as "clinical variables".

RESPONSE: Thank you for your comment, we included the validity and reliability of self-reported chronic diseases to the methods, and we added this to the limitation section.

4. Participant Fatigue:

The potential for participant fatigue due to undergoing multiple assessments should be considered. The manuscript should describe any efforts made to prevent fatigue bias or discuss this potential bias in the discussion section if such measures were not taken.

RESPONSE: Thank you for your comment and suggestion. We discussed this in the limitation section and future directions.

5. Depressive Symptoms as Exposure:

The manuscript describes the measurement of depressive symptoms as part of the outcome measures, yet the study's aim suggests it as an exposure factor. This needs clarification for consistency and accuracy in the study's presentation.

RESPONSE: Thank you for your comment. We agree with you depression was considered as an exposure factor and we revised accordingly.

6. Accuracy of Exposure Measures:

The manuscript's utilisation of self-reported data for comorbidities (not objectively measured) brings into question the accuracy of these exposure measures. This issue is crucial as it directly impacts the validity of the findings, including the reported odds ratios of severe cognitive impairment and risk factors. The reliance on ROC and AUC for inference, despite their potential to be significantly affected by biases, warrants a critical evaluation. It is imperative that the authors devote a substantial portion of the discussion to addressing and mitigating potential biases, including measurement and selection biases. This focus is essential to align the study with its objectives and enhance its relevance and credibility. An in-depth evaluation of these more fundamental aspects, such as the nature and impact of biases on the study's conclusions, would provide a more solid foundation for the research findings than the technical details provided by ROC and AUC analyses alone.

RESPONSE: thank you for bringing this up and we agree with you regarding the accuracy of exposure measures. We added a paragraph discussing the potential bias and the efforts made. We added this to the discussion section.

Minor issues:

1. Instrument Use and Measurement Bias:

The use of several instruments to measure outcomes raises questions about the study's inference regarding the prevalence of cognitive impairment and whether it may be affected by measurement bias. The authors should address the choice of instruments and their impact on study conclusions.

RESPONSE: Thank you for your comment. We added a paragraph in the discussion section discussing the selection of instruments and measurement bias.

2. ROC and AUC Inference:

The use of ROC and AUC for several inferences, without a gold standard for evaluation, warrants a discussion on how this information contributes to future studies and the study's coherence.

RESPONSE: Thank you for your comment. We added a paragraph in the discussion related to the concerns associated with ROC and AUC.

The manuscript tackles a pivotal research area with significant implications for understanding cognitive impairment among the elderly. However, concerns regarding sampling, data collection, and potential biases necessitate careful consideration before publication. The study's strengths lie in its attempt to explore under-investigated associations within a specific population. Ensuring the clarity, consistency, and accuracy of the methodology and findings will greatly enhance the manuscript's contribution to the field.

RESPONSE: thank you for your comment. We addressed all comments and suggestions in this manuscript to improve the manuscript.

10.1371/journal.pone.0309765.r003
Decision Letter 1
Sakurai Ryota Academic Editor
© 2024 Ryota Sakurai
2024
Ryota Sakurai
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version1
14 Jun 2024

PONE-D-24-07185R1Comorbidities, medications, depression, and physical performance measures are associated with severe cognitive impairments in community-dwelling adultsPLOS ONE

Dear Dr. Alenazi,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Thank you for your effort to improve the manuscript. The reviewer additionally made minor comments. Please revise the manuscript following the comments.

Please submit your revised manuscript by Jul 29 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Ryota Sakurai, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: I can see much improvement from the previous manuscript. Here are additional comments for the authors to consider:

BMI is not demographic data, but it is listed under the heading of demographics. I suggest changing the headline title to reflect the content better.

Marital status was mentioned in the method section but it was not included in Table 1. Please include this information for completeness.

In the introduction, the authors stated that the study aimed to examine the prevalence of severe cognitive impairment and its associated factors, later referred to as exposures. Since this is a cross-sectional study, these factors may be subject to reverse causality. It is crucial to acknowledge that the relationships identified could be due to reverse causality and should not be used definitively to determine the risk of severe cognitive impairment.

Please clarify if there is any specific reason behind the variable choices in including the adjusted model.

There is a missing period at line 227. Please correct this punctuation error.

In line 264, the steps taken to decrease measurement bias are not clearly stated. The author later describes the data validation process in lines 303 to 305, which includes data cleaning, consistency checks, sensitivity analysis, and double validation from the research assistant. In lines 363 to 365, the author discusses efforts to minimise information bias. To maintain consistency and improve the flow of the text, consider reorganising the discussion section, particularly the parts that address the limitation of measurement bias and the efforts made in the study.

In line 267, the authors mentioned conducting sensitivity analysis. Could you specify what type of sensitivity analysis was conducted? If possible, include this information in the supplemental analysis.

The authors mentioned subgroup results in the discussion section at line 269 (Severe cognitive impairment was higher in women and the 60–64-year age group.) However, the result was not confirmed in any tables or the results section. Please ensure all findings are included and clearly presented.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

10.1371/journal.pone.0309765.r004
Author response to Decision Letter 1
Submission Version2
22 Jul 2024

Response to reviewers

Dear Editor and reviewers, thank you for your valuable feedback on our manuscript that helps us in improving the paper. We responded to each comment and provide responses with boldface across the manuscript.

Reviewer #2: I can see much improvement from the previous manuscript. Here are additional comments for the authors to consider:

1. Comment: BMI is not demographic data, but it is listed under the heading of demographics. I suggest changing the headline title to reflect the content better.

Response: ‘anthropometric’ has been added to the headline title and table 1

2. Comment: Marital status was mentioned in the method section, but it was not included in Table 1. Please include this information for completeness.

Response: the following sentence has been added to table 1

Marital status was dichotomized as married or divorced/widowed. We also included this in the table1.

3. Comment: In the introduction, the authors stated that the study aimed to examine the prevalence of severe cognitive impairment and its associated factors, later referred to as exposures. Since this is a cross-sectional study, these factors may be subject to reverse causality. It is crucial to acknowledge that the relationships identified could be due to reverse causality and should not be used definitively to determine the risk of severe cognitive impairment.

Response: The following sentence has been added to the limitation of study:

The study was cross-sectional; therefore, any significant association between cognitive impairment and risk factors cannot be definitively determined from the results, rather reverse causation stands as a possibility in the observational study design.

4. Comment: Please clarify if there is any specific reason behind the variable choices in including the adjusted model.

5. Response: Thank you for your comment. The variables included in the adjusted model were selected based on their relevance in the literature and their potential association with cognitive impairment as mentioned in the introduction (line 88-99). The adjusted model for age, gender and BMI aimed to control for key factors that have been previously shown to influence cognitive outcome. To clarify this point, the second paragraph of the statistical analysis section has been amended to read as following:

Multiple binary logistic regression, odds ratio (OR), and 95% confidence interval (95% CI) were used to assess the potential associations between the risk factors and physical function measures of severe cognitive impairment. The variables included in the regression model were selected based on their relevance and potential association with cognitive impairment. The following two models were developed based on adjustments: model 1 was unadjusted, and model 2 was adjusted for age, sex, and BMI to control the key factors that have been shown to influence cognitive outcome. Previous studies employed unadjusted models [10, 41]. Missing variables were handled using case-wise deletion.

6. Comment: There is a missing period at line 227. Please correct this punctuation error.

Response: Corrected

7. Comment: In line 264, the steps taken to decrease measurement bias are not clearly stated. The author later describes the data validation process in lines 303 to 305, which includes data cleaning, consistency checks, sensitivity analysis, and double validation from the research assistant. In lines 363 to 365, the author discusses efforts to minimise information bias. To maintain consistency and improve the flow of the text, consider reorganising the discussion section, particularly the parts that address the limitation of measurement bias and the efforts made in the study.

Response: The discussion section reorganized.

8. Comment: In line 267, the authors mentioned conducting sensitivity analysis. Could you specify what type of sensitivity analysis was conducted? If possible, include this information in the supplemental analysis.

Response: Thank you for your comment. The dataset has some missing observations for some of the key predictor variables. We performed multiple imputations and compared the results. The results for the sensitivity analysis showed similar results with the original dataset without imputation except for TUG (OR: 1.16, 95% CI [1.01, 1.34], p=0.035) that became significant predictors for severe cognitive impairment. We added the sensitivity analysis to the methods and its results to the results section for clarification. We also added to the discussion this clarification.

9. Comment: The authors mentioned subgroup results in the discussion section at line 269 (Severe cognitive impairment was higher in women and the 60–64-year age group.) However, the result was not confirmed in any tables or the results section. Please ensure all findings are included and clearly presented.

Response: This point mentioned in the results:

“The prevalence of severe cognitive impairment among community-dwelling adults was 12.6% (n = 26); this was higher in women than that in men and in the 60–64-year age compared with that in the other age categories”

A clarification of the number of men/women has been added to table 1.

Attachment Submitted filename: Response to reviewers - NA.docx

10.1371/journal.pone.0309765.r005
Decision Letter 2
Sakurai Ryota Academic Editor
© 2024 Ryota Sakurai
2024
Ryota Sakurai
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version2
19 Aug 2024

Comorbidities, medications, depression, and physical performance measures are associated with severe cognitive impairments in community-dwelling adults

PONE-D-24-07185R2

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10.1371/journal.pone.0309765.r006
Acceptance letter
Sakurai Ryota Academic Editor
© 2024 Ryota Sakurai
2024
Ryota Sakurai
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
10 Sep 2024

PONE-D-24-07185R2

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