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Mild Cognitive Impairment among Type II Diabetes Mellitus Patients Attending University Teaching Hospital

BACKGROUND: Type II diabetes mellitus (TIIDM) has been associated with structural and functional changes in the brain. TIIDM is commonly associated with obesity, insulin resistance, hypertension, and dyslipidemia, all of which can have negative impact on brain. AIM: The aim of the study was to study the risk of mild cognitive impairment (MCI) among both diabetics and nondiabetics and to identify risk factors to MCI among both groups. METHODS: Two comparative cross-sectional studies were carried out enrolling 100 diabetics and 100 age, sex, and education matching non-diabetics. Cognitive function was assessed using Montreal Cognitive Assessment (MoCA) test and risk factors for MCI were assessed. RESULTS: The subjective complaint of memory impairment among diabetics was significantly higher (34%) compared to non-diabetics (13.0%), p < 0.05. The mean of objective MoCA score was significantly lower among diabetics (25.9 ± 2.5) compared to non-diabetics (27.4 ± 2.4), p < 0.001. The rate of MCI was significantly higher among TIIDM patients (22%) compared to non-diabetics (9%), p < 0.01 and odds ratio (OR) 2.8 (95% confidence interval 1.2–6.5). Among the two studied groups, the rate of MCI was significantly higher among those aged over 50 years compared to younger age as well as among hypertensive compared to non-hypertensive persons, (p < 0.05). Among diabetics, the MCI was significantly higher among those with secondary education, having heart diseases, longer duration of DM, or repeated hypoglycemia attack, p < 0.05. A healthy diet, brain training, and social activities were found to be significantly associated with normal cognition. Logistic analysis revealed that diabetics aged above 50 was the only significant predicting factor for MCI with an OR 2.9 (95% CI: 3.8–123.3), p < 0.001. CONCLUSION: TIIDM is significantly associated with 3-times increasing risk of having MCI compared to nondiabetics. The age, hypertension, cardiovascular diseases, duration of diabetes, and frequency of hypoglycemic episodes are risk factors for cognitive impairment. A healthy diet, brain training, and social activities were associated with better cognitive function.


Introduction
Cognition is a collective word for a range of higher brain functions containing language, memory, reasoning, and perception. Mild cognitive impairment (MCI) is an intermediate state between normal ageing and dementia including Alzheimer's disease (AD). MCI is a syndrome characteristic of early stages of many neurodegenerative diseases [1], [2]. Cognitive decline and dementia are among the most feared and most common illnesses of old age, making the identification of changeable risk factors for them, a crucial public health importance [3]. Diabetic patients may be susceptible to develop mental health problems because diabetes is counted as one of the most behaviorally and psychologically serious chronic medical illnesses [4].
The worldwide number of diabetic patients is expected to increase from 171 million in 2000 to 366 million by 2030. The prevalence was highest in the Eastern Mediterranean Region increasing from 5.9% (6 million) in 1980 to 13.7% (43 million) in 2014. The prevalence of diabetes in adults in Middle East and North Africa in 2019, 2030, and 2045 is 12.2%, 13.3%, and 13.9%, respectively. Regarding diabetes-related deaths, 43% occurred before the age of 70, with the highest proportion occurring in low-and middle-income countries [5], [6]. The International Diabetes Federation listed Egypt among the world top ten countries in the number of diabetic patients. It is alarming that the DM prevalence in Egypt has increased quickly within a short period from approximately 4.4 million in 2007 to 8.9 million in 2019 and it is expected to jump to 11.9 million by 2030 and 16.9 million by 2045 [6], [7].
The risk of cognitive dysfunction in Type II diabetes mellitus (TIIDM) may be affected by glycemic control, inflammation, hypoglycemia, macro/ microvascular pathology, and depression. The increasing effect of these conditions on the vascular etiology may decrease the threshold of cognition affection by other neurological conditions in the aging brain [8]. https://www.id-press.eu/mjms/index For diabetic patients, managerial functions are particularly important as when patients are asked to do complex tasks such as matching treatment dose with carbohydrate content, expecting the effect of physical activity on blood glucose, or identifying, and treating hypoglycemia correctly [9].
The aim of the study is to detect MCI among both diabetics and non-diabetics and to identify risk factors related to MCI among both groups.

Subjects and Methods
The study is a comparative cross-sectional study. It was done at Zagazig University outpatient clinics, Sharkya Governorate. These clinics serve the city and most of the nearby villages. Method for sampling of TIIDM patients was a convenient non probability sampling, where all TIIDM patients attended to the clinic during the period of study were selected from the medical records. It included 100 TIIDM patients with an age which ranges from 40 to 60 years old. The second group composed of 100 non-diabetic subjects with age, sex, and education matched to the diabetic group. They were patients attending the outpatient clinics with mild symptoms (not serious health problem such as abdominal cramps, cough, viral infections, and mild fever) and their fasting blood sugar was below 100 mg/dL. Written consent was obtained from all participants after ensuring their full understanding of the research. The approval of head of diabetes unit at Zagazig University Hospitals before starting the research was taken.
A questionnaire was designed and pilot study was done before implementation. A face to face interview was carried out with studied participants to fulfill the questionnaire. It was used to collect data on general demographics (age, sex, and education), smoking habit (smoking or not), and medical history (memory complaints and its effect on his job and social life, cardiovascular problems, hypertension, and family history of dementia). Diabetic history of TIIDM patients (duration of diabetes, regular treatment or not, and hypoglycemic episodes) was also assessed. Dietary habits were also assessed in the questionnaire regarding (fast food, balanced main meal, canned tuna, eggs, beans, vegetables, fruits, unroasted nuts, dark chocolate, and dairy products). Social activities (going to clubs and mosques), intellectual activities (reading, listening to the radio, using the internet, and playing mental games), and physical activities were also assessed in the questionnaire. Anthropometric measurements (weight and length) and waist/hip ratio, and systolic and diastolic blood pressure were assessed.
The case definition of MCI was based on the recommendations of the National Institute on Aging-Alzheimer's Association [10], depending on subjective complaint, objective detection using cognitive test, and normal daily activities using 36 short form quality of life. Subjective Concern regarding a change in cognition: There should be evidence of concern about a change in cognition, in comparison with the person's previous level. We measured subjective cognitive concerns through two questions according to Lara et al. (2016): "How would you best describe your memory at present?," with answer options being very good, good, moderate, bad or very bad, and "Compared to 12 months ago, would you say your memory is now better, the same or worse than it was then?" Participants were considered to have memory complaints if they answered "bad" or "very bad" to the former question and/or "worse" to the latter [11].
Objective impairment in one or more cognitive domains: The current study is planned to detect MCI among both diabetics and non-diabetics, using the Arabic version of the Montreal Cognitive Assessment (MoCA) test after having permission for use. It assesses visuospatial abilities using a clock-drawing task and a three-dimensional cube copy. Short-term memory recall that contains two learning trials of five nouns and delayed recall after approximately 5 min is assessed. Attention, concentration, and working memory are evaluated using a sustained attention task, a serial subtraction task, and digits forward and backwards. Orientation to time and place is evaluated. Multiple aspects of executive functions are assessed using an alternation task adapted from the trail making B task, a phonemic fluency task, and a two-item verbal abstraction task. Finally, language is assessed using a three-item confrontation naming task with low-familiarity animals, repetition of two syntactically complex sentences, and the aforementioned fluency task [12], [13]. The maximum score is 30 points, any score greater than or equal to 26 points indicates a normal cognition. It has high sensitivity (90%) and specificity (87%) for detecting individuals with MCI [13], [14].

Data management and analysis
The collected data were revised, coded, entered, and verified with proofreading data, where one researcher checked the data entered against the original document. Data analysis was done using Statistical Package for the Social Sciences 18 for windows. Qualitative data were presented in frequencies and percentages. Chi-squared test was used for measuring differences meanwhile odds ratio (OR) and 95% confidence interval (CI) were computed to assess the degree of association. Mean, standard deviation, and t-test were used for quantitative data, when comparing between two means. When data are not normally distributed, non-parametric Mann-Whitney test was used. Multivariate logistic analysis was done to predict risk factors significantly associated with MCI. p < 0.05 was considered significant and p < 0.01 was considered highly significant.

Results
The mean age among diabetic group was 50.7 ± 6.6 years and 56% of them were females and 85% were married. While the mean age among non-diabetics was 50.4 ± 6.4 years and 59% of them were females and 90% were married. The education level in the two groups was more or less comparable and around half of both groups had university education level. About 40% of the both groups had professional jobs. Table 1 presents subjective complaint of memory impairment among all participants. The percentages of diabetics complained of frequent forgetfulness, bad/good memory, those who family and friends complained from their memory or complained that their memory affected their daily work were significantly higher compared to non-diabetic group (p < 0.05).
Depending on subjective complaint, objective cognitive impairment and normal daily activities, 22 diabetics were suffered from MCI (22%) compared to nine non-diabetics individuals (9%), p = 0.01 and OR 2.8 (95 % CI 1.2-6.5). The mean MoCA score test was significantly lower among diabetics or non-diabetics with MCI (23.2 ± 1.3 and 23.6 ± 1.3, respectively) compared to those with normal cognition in both groups (26.8 ± 2.2 and 27.7 ± 2.1, respectively), p<0.001. Table 3 presents the socio-demographic, medical, and physical history among diabetics and non-diabetics in relation to MCI. Among diabetics, the prevalence of MCI was significantly higher among those aged >50, those with secondary education, hypertensive patients, those with heart diseases, having longer duration of DM, or repeated hypoglycemia, p<0.05. Among non-diabetics, the prevalence of MCI was significantly higher among those aged >50 and hypertensive patients, p<0.05.
The mean monthly intake of fast food, dairy products, eggs, and nuts was significantly lower among diabetics with MCI than among those with normal cognition, p < 0.05. The mean monthly intake of fast food, balanced main meal, eggs, canned tuna, and unroasted nuts was significantly lower among non-diabetics with MCI compared to those with normal cognition (p < 0.05). Diabetics with normal cognition had higher monthly social activities than those with MCI, p < 0.05. While, non-diabetics with normal cognition spent more hours in praying at mosques and playing mental games compared to those with MCI, (p < 0.001) ( Table 4).
Logistic regression analysis for predicting the risk of MCI among diabetics was carried out using age, sex, education, smoking, body mass index (BMI), hypertension, heart disease, regular treatment, and history of hypoglycemia in the model. It revealed that diabetics aged above 50 and those with hypertension were the only significant predicting factors for MCI, p < 0.01 ( Table 5).

Discussion
With the growing interest in MCI, our study discussed two major observations: The first, the prevalence of MCI among both diabetics and nondiabetics, and second, risk factors for MCI among both groups.
The prevalence of diabetes and MCI is increasing worldwide partially due to the increase in the aging population and lifestyle choices [15]. In this study, the prevalence of MCI was 22% among the diabetic group and 9% among the non-diabetic group with almost 3 times increased risk of having Table 2 shows that the mean of total MoCA score was significantly lower among diabetics than nondiabetics (p < 0.001). The means of certain domains as verbal fluency, abstraction, and delayed recall also showed significant difference between both groups, (p < 0.05).  MCI, p < 0.01 and the mean of total MoCA score was significantly lower among diabetics than non-diabetics (p < 0.001) and this was also reported by Li et al.
(2019) using the MoCA, (p < 0.05) [16]. Several studies showed that the prevalence of MCI among studied Type II diabetic patients was higher than among nondiabetics [16], [17], [18]. Other studies as Salama et al. (2018) in Cairo and Ding et al. (2015) in China found that the prevalence of MCI was 14.2% and 20.1%, respectively, among healthy individuals [19], [20]. The variation in the prevalence of MCI has been due to the demographic characteristics of the source populations, implementation of MCI diagnostic criteria, differences in sampling procedures, the education level, and the age range of participants (especially the studies done in Cairo and Mansoura had age range ≥ 60 years and the dementia of normal aging may have played a role in this prevalence).
The present study aimed to find the risk factors for MCI among both diabetics and non-diabetics. In accordance to other studies [21], [22], and [23], the prevalence of MCI among both groups increased significantly with age with p < 0.01 and by making a logistic regression analysis, old age (above 50) was a significant predicting factor for MCI among diabetics, p < 0.001. In the current study, the prevalence of MCI    [20]. Mindy et al. (2017) also found that regarding diabetics 15.7% of diabetic males and 18.5% of diabetic females had MCI with p > 0.05. This difference may be due to that females live longer than males and a wider range of age of the mentioned studies [24]. The present study and Li et al. (2019) found that education was a protective factor (p < 0.01) [16].
TIIDM for more than 10 years' duration was found to be significantly associated with MCI (31.1% of patients) compared to 7.7% among TIIDM patients with duration <10 years with 5 times risk of having MCI, p < 0.01. Several studies proved that a longer duration of DM has been implicated in accelerated cognitive decline [18], [25], [26]. History of hypoglycemic episodes was associated with a higher rate of MCI (50.0%) compared to 17.4% among those who had not history (OR = 4.7, 95% CI 1.4-15.5), p < 0.05. Similarly, other studies demonstrated that history of hypoglycemia was significantly associated with cognitive impairment [27], [28].
In addition, the present study discussed other risk factors for MCI among both diabetics and nondiabetics. The rate of MCI among hypertensive diabetics (27.5%) and non-diabetics (20.6%) was significantly higher compared to non-hypertensive diabetics (9.7%) and non-diabetics (4.2%), p < 0.01. By making a logistic regression analysis, hypertension was a significant predicting factor for MCI among diabetics, p < 0.01. Among diabetics hypertensive Chen et al. (2012) denoted as well that the percent of hypertension among diabetics with MCI was 58.1% compared to 40.6% among nonhypertensive diabetics (p < 0.05) [29]. Amer et al. (2012) stated that the presence of hypertension significantly associated with MCI (39.1%) compared to 19.4% among non-hypertensive with MCI patients with p < 0.05 [22]. The current study showed that the rate of MCI among diabetics and non-diabetics with history of heart diseases was 43.7% and 12.5%, respectively, compared to 17.9% and 8.3% among those with no heart problems, respectively, (p > 0.05). Weinstein et al. (2018) reported that 19.3% of diabetics with ischemic heart diseases had MCI compared to 11.5% among those without heart diseases (p < 0.001) [30]. Other studies denoted as well that several cardiac problems were associated with subsequent cognitive decline [31], [32].
Several studies evaluated the contributions of specific foods and nutrients to cognitive function. The present study showed that the mean consumption of the certain food items such as eggs, balanced meal, canned tuna, unroasted nuts, and dairy products was significantly higher among both diabetics and nondiabetics with normal cognition compared to those with MCI. The present results were in line with Devore et al. (2010) and Ylilauri et al. (2017) who suggested that regular consumption of food such as eggs and nuts, could be related to more favorable cognitive outcomes [33], [34]. Moreover, Park and Fulgoni (2013) demonstrated associations between milk products and cheese with cognitive function [35]. Qin et al. (2014) supported a better role of canned tuna in slowing rate of cognitive decline among Chinese older adults [36].
Concerning social and mental activities among diabetics and non-diabetics, this study found that both groups with normal cognition were having more social activities (going to clubs, listening to the radio, and praying at mosques) and mental activities than those with MCI with p < 0.05. These were in agreement with other studies among TIIDM patients [37] and nondiabetic participants [38] who denoted that among both groups, loneliness and social isolation significantly associated with a decrease in all cognitive function measures (p < 0.001). Choi et al. (2016) and Fu et al. (2018) mentioned that participation in social activities was significantly associated with better cognitive performance [39], [40]. A study in China found that there were statistical differences (p < 0.05) in reading, listening to music, and suffering the internet among the TIIDM-MCI group and non-diabetics-MCI group [18]. Similar to the current study, other studies reported that increased participation in mental activities was associated with better performance on grammatical reasoning, spatial working memory, and episodic memory tasks [41], [42].
This study was done without funding, so it was carried out only on 100 diabetics and 100 non-diabetic participants. In the future, larger sample size studies are needed to confirm the results in the current study.

Conclusion
The study concluded that TIIDM is significantly associated with MCI and almost 3-time increasing risk of having MCI. Aging, hypertension, cardiovascular diseases, duration of disease, and frequency of hypoglycemic episodes are risk factors for cognitive impairment. A healthy diet, brain training, and social activities were associated with better cognitive function.

Ethics approval and consent to participate
Written consent was obtained from all participants after ensuring their full understanding of the research. Approval of Head of diabetes unit at Zagazig University Hospitals before starting the research was taken.