A study on cognitive decline with respect to metabolic syndrome and inflammation in elderly Indians
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.162037
Source of Support: None, Conflict of Interest: None
Background: This study was undertaken to find out if metabolic syndrome (MetS) in the elderly was associated with cognitive decline and also if this association was modified by the presence of inflammation.
Keywords: Cognitive decline; elderly; high sensitivity C-reactive protein; metabolic syndrome
As modern management of diseases has improved with a greater understanding of the disease processes, the number of people living beyond the age of 60 years has also increased rapidly. Besides ageing, the high prevalence of obesity and the related co-morbidities, particularly affecting the elderly population, are considered as major health care problems.  Insulin resistance, as the main underlying disorder of obesity-related diseases, is more pronounced in overweight and obese individuals. The degree of insulin resistance increases with increasing age, and the elderly are, therefore, at a higher risk of developing the cardiometabolic risk factors summarized as metabolic syndrome (MetS). , It is widely accepted that cardiovascular risk factors play a role in the development of Alzheimer's diseases and vascular dementia.  In elderly patients, the diagnosis of MetS may be further related to a more pronounced cognitive decline and disability.  The identification and treatment of patients with MetS would, therefore, be an important approach to reduce morbidity and impairment in the elderly population.
Ageing is associated with increased inflammatory activity.  Serum C-reactive protein (CRP) is a sensitive marker for systemic low-grade inflammation and is an important predictor of the underlying presence of type 2 diabetes mellitus and of cardiovascular diseases.  Indeed, the level of inflammation in the setting of MetS may help to identify those at high risk of developing an adverse outcome.
This study was undertaken to investigate if MetS was associated with cognitive decline and also if the outcome was further modified by the level of inflammation.
This was an observational, prospective cross-sectional study conducted over a period of 18 months at a tertiary care hospital in eastern India. Fifty consecutive patients of age more than 60 years having MetS were selected in one group (group 1); and, another 50 consecutive patients of age more than 60 years without MetS were selected in another group (group 2), both after ensuring that the exclusion criteria had been compiled with. A total of 109 subjects were finally evaluated as 6 patients from group 1 and 3 patients from group 2 had to be excluded for failing to meet the inclusion criteria.
Metabolic syndrome was diagnosed in these patients according to the International Diabetes Federation (IDF) criteria  that is,
1. Waist circumference ≥90 cm for men and ≥80 cm for women
With two or more of the following:
2. Fasting triglycerides >150 mg/dl or on specific medication
3. High-density lipoprotein (HDL) cholesterol <40 mg/dl for men or <50 mg/dl for women
4. Blood pressure >130 mm of Hg systolic and >85 mm of Hg diastolic or previously diagnosed hypertension or on specific medication for hypertension
5. Fasting plasma glucose >100 mg/dl or previously diagnosed type-2 diabetes mellitus
Patients with known preexisting neurological or psychological diseases were excluded from the study. Those with conditions which can alter the cognitive functions or lipid profile like sepsis, chronic liver/kidney disease, malignancy, dyselectrolytemia, hypothyroidism, collagen vascular disease, congestive cardiac failure; and, seriously ill patients were also excluded from study.
A detailed clinical history and examination were undertaken that included examination of the blood pressure and height and weight measurement. The body mass index (BMI) was calculated by the standard equation: BMI = weight (in kg)/height (in m 2 ). Waist circumference was measured by a nonstretchable measuring tape snugly fitting at the midpoint between the lowest rib and the iliac crest in fasting state at the end of expiration. Modified Mini-Mental Score (3MS) Examination of Teng was used for assessment of cognitive impairment.  It is a brief general cognitive battery with components of orientation, concentration, language, praxis, immediate and delayed memory with a maximum (best) score of 100. Cognitive impairment was defined as a decline of 5 or more on 3MS. Among the laboratory investigations, complete hemogram, fasting and postprandial blood sugar, glycosylated hemoglobin, liver function test, thyroid stimulating hormone, serum sodium and potassium, urea and creatinine and fasting lipid profile values were recorded. Routine urine examination, chest X-ray and electrocardiogram were also done to evaluate the conditions of the exclusion criteria. Serum high sensitivity CRP (hs-CRP) was measured by a highly sensitive nephelometric assay. A level of >3 mg/dl was considered as 'high inflammation,' whereas a level <3 mg/dl was considered as 'low inflammation.'
Pearson's correlation, odd's ratio (OR), Chi-square test and linear and logistic regression were used to assess the associations of the variables at appropriate points. Descriptive statistics have been presented with mean, range, and standard deviation of the variables. All the data were analyzed using SPSS statistical software version 17.0 (published by SPSS Inc., IBM, Chicago).
The patients were divided into 2 groups: Group 1 (cases) and group 2 (controls). The descriptive statistics of group 1 and 2 are shown in [Table 1] and [Table 2], respectively. The mean age in the group 1 was 69.52 ± 6.69 years (maximum = 86 years, minimum = 61 years). The mean age in the group 2 was 69.04 ± 6.76 years (maximum = 82 years, minimum = 60 years). Thus, both the groups had a similar age profile, and they were age matched. In the group 1, 40% (n = 20) were female and 60% (n = 30) were male subjects. In the group 2, 48% (n = 24) were female and 52% (n = 26) were male subjects. Thus, the two groups were sex-matched. The mean BMI of the patients in group 1 was 27.66 ± 2.28 kg/m 2 , while that in the patients in group 2 was 23.91 ± 1.27 kg/m 2 . Thus, most of the diabetic patients were overweight. The mean waist circumference of the patients with MetS was 97.46 ± 7.21 cm, while that in the patients without MetS was 80.44 ± 4.02 cm.
In group 1, it was found that among the components of MetS, increased fasting glucose was the most common component. It was present in 60% (n = 30) patients of MetS. Hypertension was present in 56% (n = 28) patients. Hypertriglyceridemia was present in 54% (n = 27) patients. Low HDL cholesterol was present in 52% (n = 26) patients; whereas in group 2, increased fasting glucose was present in 28% (n = 14) patients. Hypertension was present in 32% (n = 16) patients. Hypertriglyceridemia was present in 20% (n = 10) and low HDL cholesterol was present in 24% (n = 12) patients.
The mean serum hs-CRP in patients with MetS was 6.56 ± 9.72 mg/dl while that in patients without MetS was 1.95 ± 1.93 mg/dl. In group-1, 40% (n = 20) were having high inflammation, while in group-2, 24% (n = 12) were having high inflammation. In the former group, 16% (n = 8) patients were male and 24% (n = 12) were female. In the latter group, male and female subjects were 12% (n = 6) and 12% (n = 6), respectively.
The mean 3MS in the patients with MetS was 92.30 ± 6.97 while that in the patients without MetS was 94.66 ± 5.08. In group-1, 36% (n = 18) patients were having a decreased 3MS, while in group 2, 22% (n = 11) were having a decreased 3MS. In the former group, 18% (n = 9) were males and 18% (n = 9) were females. In the latter group, the male and female patients were 12% (n = 6) and 10% (n = 5), respectively.
The OR was calculated for the risk of development of dementia in MetS. An increased risk of dementia was found in patients of MetS with an OR of 1.994 with 95% confidence interval of 0.824-4.827. The hs-CRP values correlated strongly with reduction in 3MS both in patients with MetS (Pearson's correlation: −0.782, P < 0.001) and without MetS (Pearson's correlation: −0.548, P < 0.001). The Chi-square test was performed to assess for an association between raised hs-CRP values and the presence of dementia in patients with and without MetS. It revealed an association between elevated hs-CRP and dementia in patients with MetS (Pearson's Chi-square: 5.22, P < 0.05, phi coefficient: 0.323, P < 0.05). However, no significant association was seen in patients without MetS (P value: 0.774).
[Figure 1] and [Figure 2] show the regression pattern (linear and logistic) of hs-CRP and 3MS in patients belonging to group 1 and group 2, respectively. Adjusted R 2 values for group 1 patients are 62.7% as compared to 28.6% for group 2, thus emphasizing that more than 60% variance in the 3MS score can be accounted for by the raised hs-CRP in MetS as compared to <30% in the non-MetS group. The ANOVA showed statistical significance of the regression model in both the groups (P < 0.05). The standardized β for logistic regression was 2.219 for group 1 and 1.741 for group 2 P < 0.001 on both the occasions.
In our cross-sectional comparative study, we found that the prevalence of cognitive decline was more in patients with MetS. Among the patients having MetS, those having high hs-CRP values were found to have developed greater cognitive decline than the ones having low hs-CRP values. Similar studies from the western countries by Yaffe et al. and Dik et al. had also shown similar results. ,, On the other hand, when we compared cognitive impairment in the elderly patients with MetS and having high inflammation, with elderly patients without MetS, it was found that cognitive impairment was significantly more in the former group. MetS was found to increase the risk of cognitive decline. Regression analysis also suggested that the presence of a high hs-CRP especially in the MetS group can influence the development of cognitive decline. From these results, it can be concluded that cognitive impairment is significantly modifiable by the presence of high inflammation. In addition to this, it was found that increased fasting glucose was the most common component of MetS, followed by hypertension, increased triglyceride and decreased high density lipoproteins. Some other studies, however, had hypertension as the most common component. ,,,, Our study revealed poorer glycemic control in Indian patients. Hs-CRP level was significantly more in elderly patients with MetS and its prevalence was also more in the elderly patients with MetS than in those without MetS. This finding was similar to other studies reported in the medical literature.
The mechanism of cognitive decline in patients with MetS is not very clear. However, there are few plausible explanations. There is a possibility of increased cerebrovascular disease involving both micro and macrocirculation in these patients.  There is evidence of increased amount of brain atrophy in patients with obesity.  Aggregations of β amyloid in the brain and increased neurofibrillary tangles have been found in patients having insulin resistance and hypertension, respectively, even in the absence of cognitive decline. 
The presence of inflammation in MetS is well-described in medical literature. ,,0[,21] The link between MetS and inflammation might be an underlying atherosclerosis, and it might be this atherosclerosis or the combined effect of atherosclerosis and inflammation, which is giving rise to the cognitive decline. , Our study has shown that patients having both MetS and inflammation are doing worse than the ones not having MetS or inflammation, as far as the cognitive decline is concerned. Our study has also shown that both inflammation and MetS are accountable for by a significant variation in the cognitive scores. However, the cause-effect relationship between inflammation, MetS and cognitive decline is yet to be established and is controversial. Alternate theories indicating a genetic predisposition resulting in an increased inflammatory response and subsequent adverse outcomes including a cognitive decline have been proposed. 
To the best of our knowledge, our study is the first in the Indian population, which deals with cognitive decline, inflammation and MetS in the elderly. Our study will probably help in better understanding of MetS, especially in the geriatric population in India. As we have compared age and sex matched groups, the results obtained are less likely to be confounded. We have included hs-CRP as an indicator for inflammation, which is a very sensitive tool. CRP values measured by the highly sensitive methods have been found to be independent predictors of future cardiovascular morbidity and hence its measurement is recommended for cardiovascular risk assessment and management in apparently healthy individuals, as opposed to the standard CRP assays that are used for monitoring infections and other inflammatory conditions. , Furthermore, the 3MS is internationally accepted as a standard measure of global cognitive function. It includes 4 more items with a more graded scoring than the Mini Mental Score examination (MMSE). The 3MS has been demonstrated to have a greater sensitivity with enhanced validity and reliability to a broader variety of cognitive functions than the MMSE. 
Our study has some limitations. It was a cross-sectional study. A longitudinal study, which would record the cognitive and inflammatory changes over a period of time, would have been more suitable. A small sample size, measurement of a single inflammatory marker, the inclusion of only hospital-based population, and the insensitivity of 3MS to detect cognitive changes were some of the other limitations of our study. Furthermore, the effect of therapeutic agents used for dyslipidemia and diabetes were not taken into account, which could have modified the result.
This study shows that cognitive decline in elderly is associated with the presence of inflammation and MetS. An early identification of the high-risk groups may offer benefit by disease course modification and better caregiving.
[Figure 1], [Figure 2]
[Table 1], [Table 2]