Charakterystyka zmian funkcji poznawczych w zależności od wieku u pacjentów z zespołem metabolicznym

Vladyslav V. Bezrukov1, Natalia Yu. Bachinskaya1, Oksana O. Kopchak1,2, Victor O. Kholin1, Oleksandr R. Pulyk3

1Department of Age Physiology and Pathology of the Nervous System, D.F. Chebotarev Institute of Gerontology of National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine

2Department of Neurology, Kyiv Medical University, Kyiv, Ukraine

3Department of Neurorehabilitation, Uzhhorod National University, Uzhhorod, Ukraine

Abstract

Introduction: According to World Health Organization (WHO) forecasts, by 2050 the number of people suffering from dementia will constitute about 150 millions in the world. Nowadays, Alzheimer’s disease plays the leading role in dementia emergence; it is the cause of age related dementia in 60% of cases.

The aim: This study aimed to assess the age related cognitive changes in patients with metabolic syndrome (MetS).

Materials and methods: 503 patients aged 45 to 89 years with chronic cerebral ischemia were included into the study. All the patients were divided into two groups: group 1 – without MetS (n = 198), group 2 – with MetS (n = 305). Patients of both groups were divided into 3 age subgroups: 1st – 45-59, 2nd – 60-74, 3rd – 75-89 years old.The MetS was defined according to the criteria of the American Heart Association, the World Heart Federation, the International Atherosclerosis Society, and the International Association for the Study of Obesity. To evaluate patients’ cognitive functions wide range of neuropsychological tests were used.

Results: Patients of both groups had significant age related cognitive deficit. MetS patients of all age subgroups with mild cognitive impairment syndrome revealed a significant decline of immediate and delayed memory on the verbal stimuli (especially in patients of elderly and senior age groups), the rate of sensorimotor reactions, mental capacity, and the active attention amount in comparison to the patients without MetS. MetS patients with dementia of the middle age had significantly lower parameters of immediate and delayed memory on the verbal stimuli, the rate of sensorimotor reactions, mental capacity, and the active attention amount in comparison to the patients without MetS but with dementia.

Conclusions:The presence of MetS was associated with more pronounced cognitive decline in the patients, concerning different aspects of memory, attention and executive functions.

Key words: cognitive impairment, age, metabolic syndrome

Wiad Lek 2018, 71, 8, -1523

Introduction

The past century was characterized by significant demographic shifts and by the increase of older age groups proportion among the population. Cognitive decline and dementia are significant health issues given the aging of the world population [1]. The nature of structural and functional, metabolic, neurotransmitter, biochemical and hemodynamic changes of the central nervous system during aging is the background for the development of a number of age related diseases, which are accompanied by the impairment of higher mental functions of varying degrees. According to World Health Organization (WHO) forecasts, by 2050 the number of people suffering from dementia will constitute about 150 millions in the world. Nowadays, Alzheimer’s disease plays the leading role in dementia emergence; it is the cause of age related dementia in 60% of cases [2,3]. In a number of countries, the cerebrovascular disease is the second recorded cause of dementia after Alzheimer’s disease in people of the elderly and senior age [2,3,4]. Cerebrovascular disease can lead to the development of significant cognitive impairment (CI) even in the absence of dementia [5]. The term ‘vascular cognitive impairment’ (VCI) was suggested for the indication of CI associated with vascular risk factors [6,7]. Clinically, VCI syndrome includes a wide range of cognitive and behavioral disorders, ranging from mild cognitive impairment (MCI) to vascular dementia [8].

It is clear that individual cardiovascular events and risk factors are associated with lowered cognition and dementia; and a growing research literature suggests that multiple vascular risk factors may have an additive adverse effect on cognition, resulting in increased risk for dementia [9]. The problem of MetS is of concern partly because it represents a cluster of risk factors for morbidity and mortality [10] and partly because these risk factors may interact in a synergic manner to influence cognition in a negative way. MetS has been defined as a cluster of the following risk factors: central obesity, elevated blood pressure, dyslipidemia (elevated triglycerides and lowered high-density lipoprotein cholesterol), and insulin resistance [11]. Detection of MetS is based on the presence of obesity (body mass index > 30 kg/m2 or waist circumference -94 cm for Europeans, Sub-Saharan African, Eastern Mediterranean or Middle East males and-80 cm for European, Sub-Saharan African, Eastern Mediterranean or Middle East females; 90 cm for South Asian, Central or South American or Chinese males and 80 cm for South Asian, Central or South American or Chinese females; 85 cm for Japanese males and 90 cm for Japanese females) and 2 or more of the following: (1) increased plasma triglyceride level (150mg/dL) or medication therapy for this condition; (2) reduced HDL level (<40 mg/dl in males and <50 mg/dL in females) or specific drug treatment; (3) high blood pressure (130×85 mmHg) or medication treatment and (4) raised fasting plasma glucose (100 mg/dL) [12]. Obesity, hypertension, dyslipidemia, and insulin resistance have been associated with an increased risk of cognitive impairment or dementia [13,14,15]. A promising area of preventive strategies for CI is the modification of cardiovascular risk factors – such as hypertension, hyperlipidemia, obesity, diabetes mellitus, carbohydrates intolerance, which play a key role in the development of cognitive deficits [16,17].

THE AIM

So far, the link between the MetS and the CI has not been sufficiently studied in aging; there are contradictory data in the literature on the impact of MetS on the CI severity [18,19,20,21,22,23,24,25,26]. Therefore, the objective of the study is to find out the age related characteristics of the cognitive changes in patients with MetS.

MaterialS and methods

Five hundred and three patients aged 45 to 89 years old with chronic cerebral ischemia were examined. The patients were divided into two groups: group1 – without MetS (n = 198), group 2 – with MetS (n = 305), comparable according to age, sex and education level. MetS was defined according to the National Heart, Lung and Blood Institute criteria, the American Heart Association, the World Heart Federation, the International Atherosclerosis Society, and the International Association for the Study of Obesity in the presence of three or more of the following factors in the patient: arterial hypertension (BP> 130/85 mm Hg) or hypotensive drugs use, obesity (waist circumference> 94 cm in men,> 80 cm in women) and dyslipidemia (increased serum triglyceride levels ≥ 1.7 mmol / L or normal triglyceride level under appropriate treatment; lowering the level of high density lipoproteins (HDL) <1 mmol / L for men and <1.3 mmol / L for women or normal HDL under appropriate treatment), increased blood glucose levels ≥5.6 mmol / L or hyperglycaemia therapy [11].

Patients in both clinical groups were also divided into 3 age subgroups: 45-59 – middle aged, 60-74 of elderly age, and 75-89 years old –senior patients. In the group of patients without MetS, there were 76 middle-aged, 84 elderly patients and 38 senior patients. The age composition of patients’ group with MetS was as follows: 108 middle-aged patients, 165 patients of the elderly age, 32 patients of senior age.

General clinical, neurological, laboratory and instrumental examinations were done, including anthropometric examination (body mass index – BMI, waist circumference), determination of blood lipid profile (lipidogram) and concentration of the thyroid gland hormones in the blood, magnetic resonance imaging of the brain. To evaluate patients’ cognitive functions the MMSE/ Mini Mental State Examination Scale (assessing patient’s ability in time and place orientation, short-term, long-term memory status, speech function, gnosis, praxis) [27]; the method of 10 words learning (studying the processes of memorizing, storing and reproducing information); the PALT/The Paired Associates Learning Test (learning the immediate and delayed recognition memory on the verbal stimuli [28]; the Schulte tables (determining the rate of sensorimotor reactions, mental performance and attention) were used. According to MMSE, scores of 29-30 were considered as the absence of cognitive impairment, scores of 28-27 – pre-mild cognitive impairment (pre-MCI), 25-26 – mild cognitive impairment (MCI), scores of ≤24 points – dementia.

While processing the statistical data of the obtained results, the validity of the difference between the average quantitative values of the two samples was determined according to the Student’s t-test. The characteristics of the study sample were compared using χ2 tests for dichotomous variables. The Pearson’s correlation coefficient (r) was used to determine the nature and extent of the association between the different data. A value of p<0,05 was considered statistically significant.

Ethical approval (Protocol No.11 from 23 of September 2016) was obtained from the Bioethics Commission of the D.F. Chebotarev Institute of Gerontology of National Academy of Medical Sciences of Ukraine. All study participants or their proxies signed informed consent forms.

Results

Patients in both clinical groups reported a decline of memory and attention to recent events, current events, names, dates, and so on. Patients with MetS and without MetS complained of increased irritability, general weakness and increased fatigue, decreased physical and mental performance, mood swings. Sleep disorders were more common among the patients with MetS and consisted of difficulty falling asleep, superficial and intermittent sleep, and early awakening, short sleep, obstructive sleep apnea syndrome. In addition, patients noted postsomnic disorders – low quality of wake-up time after sleep onset, unrefreshing sleep, increased wake-up time after sleep onset and lack of energy, increased drowsiness during the daytime shift work. Patients with MetS were significantly more likely to complain of numbness of the limbs in comparison to the patients without MetS (P <0.001).

During neurological examination focal neurologic deficits ranged from 9 to 61%, and included hyperreflexia, ataxia, disorders of sensitivity in patients with MetS. Sensitivity disturbances were significantly more frequent (P <0.001) in patients with MetS (60.7%) in comparison to patients without MetS (25.3%) and manifested mainly as paresthesias in the distal limb parts in the form of creeps, light face and limbs numbness.

There was analyzed the CI frequency of different severity in patients without and with MetS, depending on their age. In particular, pre-MCI syndrome was significantly more common in middle-aged patients without MetS as compared to the elderly patients’group (χ2 = 18.0, P <0.001). MCI syndrome was significantly more frequent (χ2 = 9.1, P <0.01) in the elderly patients in comparison to middle-aged patients without MetS. When comparing patients of senior and middle-aged groups without MetS, MCI (χ2 = 8.5, P <0.01) and dementia (χ2 = 12,6, P <0,001) were significantly more common in patients of senior age, whereas pre-MCI cases were predominant in middle-aged patients (χ2 = 33,2, P <0,001).While comparing senior and elderly patients’ groups without MetS, pre-MCI (χ2 = 10.1, P <0.01) was more commonly found in elderly people, dementia was significantly higher in senior patients (χ2 = 4.7, P <0.05). There was no significant difference in the MCI frequency (χ2 = 0,3, P> 0,05) in patients of elderly and senior age groups without MetS (Fig. 1).

Patients with MetS of middle age were significantly more likely to have pre-MCI as compared to the elderly patients (χ2 = 4.8, P <0.05). There was no significant difference in the frequency of MCI (χ2 = 1.1, P> 0.05) in patients with MetS of middle and elderly age. Dementia was significantly more likely to be detected (χ2 = 10.9, P <0.001) among elderly patients with MetS as compared to the middle-aged ones. When comparing the senior and middle-aged patients with MetS, middle aged patients were more likely to have pre-MCI (χ2 = 10.4, P < 0.01), the dementia was significantly more common in the senior ones (χ2 = 18.7, P <0.001. There was no significant difference in the frequency of MCI in the senior and middle-aged patients with MetS (χ2 = 0.8, P> 0.05). When comparing senior and elderly patients with MetS, patients of the elderly age had significantly more common pre-MCI (χ2 = 5.6, P <0.05), whereas dementia was significantly more common in patients of senior age (χ2 = 3.9, P <0.05). There was no significant difference in the frequency of MCI in elderly and senior patients with MetS (χ2 = 0.1, P> 0.05) (see Fig. 1).

In both groups of patients with MetS and without it, there was established a statistically significant (P <0.001) negative correlation between patient’s age and MMSE score, parameters of short-term verbal and semantic memory and attention; the immediate and delayed memory amount on verbal stimuli, a score on the clock drawing test. Also, a reliable (P <0.001) positive correlation was found out between patients’ age and time indicators, which was evaluated when performing a special neuropsychological task with the use of Schulte tables (Fig. 2). Consequently, there was found significant influence of age on the cognitive functions of patients with and without MetS.

Some difference was found between groups of patients with MetS and without it but with MCI by means of a number of MMSE subtests (time orientation, space orientation, three words memorising, attention and counting, three words reproduction). Based on the analysis of MMSE subtests parameters, we found out that the subgroup of middle-aged patients with MetS had significantly lower parameters of short-term memory (χ2 = 32.7, P <0.001) as compared to patients without MetS, according to such subtest as three words memorizing (χ2 = 4.14, P <0.05), evaluation of attention and counting, reproduction of the verbal material (χ2 = 15.1, P <0.001). In the subgroup of elderly patients with MetS in comparison to the patients without MetS, there were determined significantly lower parameters of short-term memory (χ2 = 6.2, P <0.01) according to two subtests: three words memorizing subtest and reproducing the verbal material when refocusing (χ2 = 7,4, P <0,01) and the subtest of three words reproduction. Among patients of senior age with MetS, as compared to patients without MetS, there was found out a significant deterioration according to 2 subtests such as orientation in time (χ2 = 5.2, P <0.05), reduction of short-term memory (χ2 = 14.7, P <0.001) with the help of three words memorizing subtest. There was no significant difference in parameters between the senior patients’with MetS and without MetS according to the other MMSE subtests (P> 0.05).

Taking into consideration the MMSE subtest profile, patients with MetS and MCI of different age groups had significantly worse short-term memory parameters than the patients without MetS. The middle-aged and elderly patients had identical changes in the cognitive profile, whereas it varies in the patients with MetS of senior age due to the increased deteriorations in time orientation in addition to the short- memory decline.

Based on the results of wide range of neuropsychological tests in the MCI patients it was found out that the parameters of immediate and delayed memory according to PALT were not significantly different in the subgroup of middle-aged patients with and without MetS. Patients of the elderly and senior age with MetS and MCI had significantly (P <0.001) worse parameters of immediate and delayed memory according to PALT as compared to patients without MetS (Fig. 3).

The patients with MetS and MCI syndrome from all three age groups, required significantly more (P<0.001) time to perform a special neuropsychological task according to Schulte tables as compared to the patients without MetS but with MCI syndrome (Fig. 3), indicating a decrease of psychomotor reactions rate and attention.

Considering the significant negative impact of cognitive decline and especially of dementia on the patients’ life quality, we analyzed cognitive functions in patients with dementia, depending on age and the presence of MetS. In the middle age subgroup of patients with dementia the mean MMSE score was 22,1+0,9 in patients without MetS and 21,8+2,1 in those with MetS (p>0,05). In the subgroup of elderly patients with dementia mean MMSE score depending on the presence of MetS was 21,3+2,0 (without MetS) and 21,6+1,9 (with MetS) (p>0,05). In the senior aged patients with dementia there was no significant difference concerning the mean MMSE score depending on the presence of MetS: 21,1+1,6 (in patients without MetS) and 21,5+1,9 (patients with MetS) (p>0,05). In evaluation of the MMSE subtest profile, we found out that the middle-aged patients with MetS and dementia as compared to the patients without MetS of the same age were significantly more time-disoriented (χ2 = 6.93, P <0.01). There was no significant difference in the results of other MMSE subtests performed by middle-aged patients with dementia associated with MetS. While studying the MMSE subtest profile of the elderly patients with dementia, depending on the presence of MetS, it was found out that the patients with MetS in comparison to those ones without MetS, had significantly decresed time-orientation score(χ2 = 5.38, P <0.05), and showed lower results in copying the picture test (χ2 = 5.87, P <0.05). When evaluating the profile of MMSE subtest perfomed by the senior patients with dementia, depending on the presence of MetS, it was found out that the patients with MetS as compared to those without MetS, were significantly worse in the subtests of simple sentence writing (χ2 = 4.04, P <0.05) and copying the picture (χ2 = 4.37, P <0.05).

Taking into consideration the MMSE data, age related changes in the cognitive profile were of different character. In particular, the middle-aged patients with MetS and dementia had significantly declined ability in time-orientation as compared to those ones without MetS; the elderly patients with MetS and dementia as compared to patients without MetS were more time-disoriented and had a declined ability of constructional praxis. The senior patients with MetS in the presence of dementia performed significantly worse subtests on writing a simple sentence and copying the picture as compared to patients without MetS. Consequently, according to MMSE data elderly and senior patients’ executive functions with MetS and dementia were more affected.

According to the results of neuropsychological tests of the patients with dementia, it was found out that in the subgroups of the elderly and senior patients with MetS and without MetS, the parameters of immediate and delayed memory according to PALT data did not differ significantly. The middle-aged patients with MetS in the presence of dementia revealed a significant decline (P<0.05) of immediate and delayed memory according to PALT data as compared to the patients without MetS (Fig. 4). Patients of the middle-aged subgroup with MetS in the presence of dementia needed significantly more time to perform a special neuropsychological task according to Schulte tables and had significantly lower parameters of the sensorimotor reactions rate (P <0.001), as compared to the patients without MetS with dementia (see Fig. 4). At the same time, patients of elderly and senior age with MetS and without MetS in the presence of dementia showed no significant difference according to the above-mentioned neuropsychological tests.

Patients with MetS as compared to the patients without MetS in the presence of MCI syndrome demonstrated a significant decline of the following cognitive functions: immediate and delayed associative recognition memory for verbal stimuli (especially in the elderly and senior age), the sensorimotor reactions rate, attention amount, mental activity in all age subgroups. At the same time, only middle-aged patients with MetS in the presence of dementia revealed a significant decline of immediate and delayed associative memory on verbal stimuli, the rate of sensorimotor responses, mental performance, and attention as compared to the patients without MetS but with dementia. In the elderly and senior age patients with MetS and without MetS in the presence of dementia we found equally decreased parameters of immediate and delayed recognition associative memory on verbal stimuli, rate of sensorimotor reactions, mental performance and attention.

Discussion

Consequently, based on the obtained results, patients with MetS had more affected cognitive functions comparing with patients without MetS, but with chronic cerebral ischemia. There was revealed a significant influence of age on the severity of cognitive impairments – patients of both clinical groups revealed increased cognitive deficit severity. Our findings concerning cognitive decline can be associated with aging changes of the brain, deterioration of the blood supply to the brain, enhancement of neurodegenerative processes on the background of metabolic disorders with involvement of the structures responsible for cognitive functioning. Different data have been presented to explain association between metabolic syndrome and cognitive impairment. Some evidences have emphasized a combination of neuroanatomical and neuroendocrine changes resulting in cognitive deficit [29,30]. In some studies, based on imaging techniques, in those with metabolic syndrome, volume losses- neurodegeneration in the hippocampus and frontal lobes have been clearly discovered leading cognitive problems in affected ones. In fact, in metabolic syndrome, both brain structure and brain lipid metabolism may be affected leading to cognitive impairment [31].

The results of a number of studies correspond to the data obtained by us. In particular, Ashrafi et al. [32] showed a direct association between metabolic syndrome and cognitive impairment, after being adjusted for gender and age. According to the results of Yaffe et al. [33], increased risk for cognitive disorder was directly associated with the number of the components of metabolic syndrome. Chang et al. [34] on Taiwanese older adults revealed that metabolic syndrome remained a major predictor for cognitive impairment by adjusting sex, age, education level, marital status and even apolipoprotein genotype. In a systematic review by Collins et al. [35], the presence of metabolic syndrome was associated with executive cognitive dysfunction and memory deficits for both men and women younger than 75 years, but contradictory results were achieved for the people older than 75 years. In another study by Parnowski et al. [36], dementia was significantly correlated with metabolic syndrome and its components of low HDL cholesterol, and hyperglycemia. In the study of Rubens et al. [37] metabolic syndrome was associated with impaired reading, working memory, and attention among adolescents. According to the data of Harrison et al. [38], the association between MetS and cognitive decline, which has been described in younger populations (<75), was not apparent in the population of individuals aged 85 and older at baseline.

Conclusions

The presence of metabolic syndrome was related to more pronounced cognitive decline in the patients, especially impairing different aspects of memory, attention and executive functions. The most significant negative impact of MetS on the cognitive functions was found in the middle age subgroup of patients with dementia, concerning deterioration of short-term, immediate and delayed associative memory and parameters of the sensorimotor reactions. Taking into consideration these results more attention should be paid to the MetS risk factors especially in this age group of patients to prevent further deterioration of their cognitive functions.

Other clinical trials should be undertaken to determine if addressing MetS and metabolic-based risk factors through lifestyle modification gives the possibility of slowing down or ameliorating the cognitive aging process itself.

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Authors’ contributions:

According to the order of the Authorship.

Conflict of interest:

The Authors declare no conflict of interest.

CORRESPONDING AUTHOR

Oleksandr Pulyk

Department of Neurorehabilitation,

Uzhhorod National University, Uzhhorod, Ukraine

e-mail: apulyk@gmail.com

Received: 25.08.2018

Accepted: 12.11.2018

*- P <0.05, ** – P <0.001 in comparison to the corresponding subgroup of middle-aged patients within each clinical group,

# – P <0,05 in comparison to the corresponding subgroup of the elderly patients within each clinical group,

α – P <0,05, αα – P <0,001 in comparison to the appropriate subgroup of patients without MetS

Fig. 1. Frequency of pre-MCI (light columns), of MCI syndrome (shadow columns) and dementia (dark columns) in patients with and without MetS.

І – MMSE score;

II – 10 words learning test (words);

ІІI- PALT immediate memory (words);

IV – PALT delayed memory (words);

V- the Schulte tables (time indicators, which were evaluated when performing a special neuropsychological task)

Fig. 2. Correlation coefficient between age of patients without (light columns), with (shadow columns) MetS and the parameters of the neuropsychological tests.

* – P <0,05 in comparison to the results of patients without MetS

Fig. 3. Results of the neuropsychological tests obtained in different age groups of patients with MCI syndrome without (light columns) and with (shadow columns) MetS.

* – P <0,05 as compared to the patients without MS.

Fig. 4. Results of the neuropsychological tests obtained in different age groups of patients with MCI syndrome without MetS (light columns) and with (shadow columns) MetS.