Psychiatry and Clinical Neurosciences 2015; 69: 620–629
doi:10.1111/pcn.12296
Regular Article
Executive dysfunction assessed by Clock-Drawing Test in older non-demented subjects with metabolic syndrome is not mediated by white matter lesions Giovanni Viscogliosi, MD,1,3* Iulia Maria Chiriac, Evaristo Ettorre, MD, PhD1
MD,2
Paola Andreozzi,
MD1
and
1 Division of Gerontology, Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, Sapienza University, 2Division of Geriatrics, Casa di Cura Merry House, and 3Department of Epidemiology, Surveillance and Promotion of Health, National Institute of Health, Rome, Italy
Aims: Metabolic syndrome (MetS) has been associated with greater occurrence of white matter hyperintensities (WMH). It remains uncertain whether MetS as a construct is associated with poorer cognitive performances. This study explores whether MetS is associated with poorer performances in global and domain-specific cognitive tests in older nondemented subjects independently of its individual components, WMH severity and other variables. Methods: MetS was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III definition. Brain magnetic resonance studies (1.5T) were performed. Deep and periventricular WMH were graded using the Fazekas scale. Subjects underwent the Mini-Mental State Examination, the Babcock Short Story Recall test and the Clock-Drawing Test (CDT). Results: Eighty community-dwellers aged 67–91 years were studied. Subjects with MetS (n = 35) had more severe WMH, and poorer performances on the
URING RECENT YEARS, great efforts have been made in studying the pre-clinical phases of cognitive decline,1,2 with the major goal to define what the early clinical signs of an approaching dementia
D
*Correspondence: Giovanni Viscogliosi, MD, Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, Sapienza University, Viale Del Policlinico 155, 00100 Rome, Italy. Email: [email protected] Received 9 January 2015; revised 25 February 2015; accepted 13 March 2015.
620
CDT (P = 0.003) and the Babcock Short Story Recall test (P = 0.027). After multiple adjustment, MetS was inversely associated with CDT scores (B = −1.285; 95% confidence interval = −1.996–−0.575; P = 0.001) but not with episodic memory. Results were not affected by WMH severity. Interestingly, none of the individual components of MetS predicted poorer cognitive performances.
Conclusions: Impairment in executive functions assessed by CDT may represent an early and specific sign of cognitive decline in older individuals with MetS. Future longitudinal studies are needed to better establish the predictive role of MetS on dementia and to demonstrate the possibility of dementia prevention by targeting MetS. Key words: Clock-Drawing Test, executive dysfunction, metabolic syndrome, prevention, white matter hyperintensities.
are. Authors have indicated that deficits in executive functions may be detected earlier than those in memory tasks,3–6 irrespective of whether subjects report cognitive complaints. Executive functions are the ability to plan, judge, reason, solve problems and organize; and attention, abstraction and mental flexibility play pivotal roles in executive control.5,7 Impairment in executive function predicts Alzheimer’s disease and vascular dementia.3,5,7 Executive dysfunction is so frequently associated with cardiovascular (CV) risk factors and with sub-
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2015; 69: 620–629
Metabolic syndrome, executive functions 621
cortical vascular damage, that it may represent an early and specific marker of cognitive impairment in subjects with higher CV risk.2,4–6,8–10 Metabolic syndrome (MetS) is a constellation of multiple risk factors, including hypertension, atherogenic dyslipidemia, impaired glucose homeostasis and abdominal obesity.11 MetS is risky for the aging brain, as it has been associated with greater occurrence of subcortical white matter hyperintensities (WMH), which are associated with cognitive decline, late-onset depression and functional disability.2,4,11,12 Each MetS trait may potentially exert a negative influence on cognitive function.12 There are inconsistent results about whether MetS as a whole influences cognitive function and dementia risk, and whether the risk associated with MetS is greater than that conferred by the sum of its parts.13–17 Non-demented adults with MetS have poorer executive functioning when compared with controls.18–22 This study explored whether older non-demented individuals with MetS have poorer performances in cognitive tests that screen global cognition, executive functions and episodic memory; and whether such an association was independent of the individual components of MetS, WMH severity and other variables. The potential confounding role of depressive symptoms was also explored.
drugs; and contraindications for brain magnetic resonance examination. Written informed consent to the study was obtained from all participants. Sociodemographic features, medical history and general habits of the subjects were collected by trained operators using standardized questionnaires. Blood samples were drawn in the early morning after an overnight fast and analyzed within 30 min from collection. Triglycerides, fasting blood glucose (FBG) and high-density lipoprotein (HDL) cholesterol concentrations were determined using standard laboratory techniques. High-sensitivity C-reactive protein (HsCRP) concentrations were determined using commercially available enzyme-linked immunosorbent assay kits. Waist circumference (WC) was measured at the level of the iliac crest with patients standing, at the end of a normal expiration. Blood pressure was measured twice from the right arm with subjects in the sitting position, after a rest of 10 min, using a mercury sphygmomanometer. Systolic (SBP) and diastolic (DBP) blood pressure levels were defined as first and fifth Korotkoff phases. Average values were considered. According to the National Cholesterol Education Program Adult Treatment Panel-III definition, MetS was defined as alteration in three or more of the following five criteria: (i) WC > 102 cm in men and >88 cm in women; (ii) FBG ≥ 110 mg/dL; (iii) plasma triglycerides ≥ 150 mg/dL; (iv) HDL cholesterol < 40 mg/dL in men and < 50 mg/dL in women; and (v) SBP ≥ 130 mmHg and/or DBP ≥ 85 mmHg and/or antihypertensive treatment.25 Magnetic resonance imaging (MRI) studies (1.5 Tesla, GE-Horizon device, GE Healthcare, Milan, Italy) were performed in basal conditions, using a head coil. MRI protocol included proton density, and T1 and T2-weighted sequences. Axial slices were 5–6 mm thick, with an inter-slice gap of 1.0–1.2 mm. Hard copies of the scans were evaluated by the same operator, blinded to the clinical features of the subjects. All scans were read for periventricular and deep WMH. WMH were focal hyperintensities on proton density and T2-weighted images. Periventricular WMH were lesions abutting the lateral ventricles, at the level of frontal and occipital horns and laterally to ventricles. Deep WMH were hyperintense lesions separated from the lateral ventricles. Infarcts were focal lesions with defined contours, that appeared
METHODS Community-dwelling older subjects, referred to the ambulatory care center of our department for a comprehensive geriatric assessment during June– October 2014, were considered for this study. Inclusion criteria were: age ≥ 65 years; ability to complete all elements of the study assessment; and absence of dementia. Dementia was defined according to the DSM-IV23 criteria and/or whether the subjects scored > 0.5 on the Clinical Dementia Rating Scale.24 Participants were grouped according to the presence of MetS. Subjects were consecutively enrolled if they did not possess any of the following features: mood disorders with onset before age 50 and other neurological and psychiatric diagnoses; clinical CV diseases, defined as history or evidence of acute myocardial infarction, symptomatic or silent stroke, and peripheral artery disease; diabetes mellitus and/or current antidiabetic treatment; malignancies; current smoking; conditions of acute or chronic pain and/or current treatment with analgesic/anti-inflammatory
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
622 G. Viscogliosi et al.
isointense to cerebrospinal fluid with a diameter of > 3 mm. WMH were graded on a severity-scale according to the semi-quantitative method of Fazekas and colleagues.26 Deep WMH were graded as absent (score = 0), punctate (score = 1), nearly coalescent (score = 2) and confluent (score = 3). Periventricular WMH were graded as absent (score = 0), pencil-thin lines (score = 1), caps or bands (score = 2) and confluent (score = 3) (see Fig. 1 for examples). WMH degree was classified as absent/slight (score = 0–1), moderate (score = 2), or severe (score = 3). Neuropsychological tests were administered by experienced geriatricians blinded to the clinical and neuroradiological features of the subjects. Global cognitive function was assessed with Folstein’s Mini-Mental State Examination (MMSE),27 the best-validated instrument to evaluate cognitive function in older persons. Total score ranges are from 0 to 30; the higher the score the better the cognitive performance. Results were adjusted for age and educational level, according to standard procedures. Executive functions were evaluated using the Clock-Drawing Test (CDT). Each subject was given a pre-drawn circle and asked to insert numbers. Then, subjects were asked to place the clock hands to read ‘10 past 11’. In this study, the method by Sunderland and colleagues was adopted to score CDT performances.28 This is a 10-point scoring system: 1 denotes very poor and 10 the best performance. Five points are given for numbers placed in the correct position; the remaining points are given for accuracy of hands denoting the time 11:10. By convention, a score < 6 indicates relevant impairment. Episodic memory was assessed by administering the Babcock Short Story Recall Test, whose details are described elsewhere.29 This is a 21-unit story measuring immediate and delayed (10-min) recall. The total score, obtained by summing scores in immediate and delayed recall sections, ranges from 0 to 16; the higher the score the higher the level of episodic memory. Depressive symptoms were investigated through the 15-item Geriatric Depression Scale (GDS), a wellvalidated screening tool for depression in older people; the higher the score the greater the depressive symptoms.30 By convention, scores ≥ 10 indicate subjects with high probability of having some form of depression. The GDS question, ‘Do you feel you have more problems with memory than most?’ was used to identify subjects with complaints of memory loss.
Psychiatry and Clinical Neurosciences 2015; 69: 620–629
Statistical analysis All analyses were performed via SPSS 17.0 for Windows. Characteristics of participants are presented according to the presence of MetS. Ordinal variables are presented as mean ± SD, nominal variables as frequencies. The Student’s unpaired t-test and χ2 statistic were used to compare continuous and dichotomous variables, respectively, according to the presence of MetS. Linear bivariate regression analyses with calculation of Pearson’s correlation coefficients were performed to identify interrelationships between cognitive function, depressive symptoms, WMH severity, MetS and its individual components. Logistic regression analyses were performed to identify variables independently associated with cognitive performances. Variables showing significant associations in bivariate analyses were tested as explanatory variables in multiple regression models. With the exception of HsCRP values, all variables were normally distributed. Due to their skewed distribution, HsCRP values were log10-transformed. Statistical significance was set for two-sided P-values ≤ 0.05.
RESULTS Eighty subjects were studied (58.6% women), mean age 80.4 ± 5.3 years (67–91), median 79 years. Thirty-five subjects with MetS and 45 without were included in this study. As expected, subjects with MetS were more likely to have abdominal obesity, higher FBG, more severe deep (P < 0.001) and periventricular WMH (P = 0.013) and higher inflammatory levels than controls, and they were more likely to use lipid-lowering drugs (Table 1). None of the subjects had silent brain infarcts. MetS was significantly accompanied by poorer performances in CDT (P = 0.003) and Babcock Short Story Recall (P = 0.027). Twenty-seven percent of subjects with MetS and 5.0% of controls (P = 0.007) exhibited relevant deficits in executive functions (CDT < 6). Although in both groups mean GDS scores fell in the subclinical range (
doi:10.1111/pcn.12296
Regular Article
Executive dysfunction assessed by Clock-Drawing Test in older non-demented subjects with metabolic syndrome is not mediated by white matter lesions Giovanni Viscogliosi, MD,1,3* Iulia Maria Chiriac, Evaristo Ettorre, MD, PhD1
MD,2
Paola Andreozzi,
MD1
and
1 Division of Gerontology, Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, Sapienza University, 2Division of Geriatrics, Casa di Cura Merry House, and 3Department of Epidemiology, Surveillance and Promotion of Health, National Institute of Health, Rome, Italy
Aims: Metabolic syndrome (MetS) has been associated with greater occurrence of white matter hyperintensities (WMH). It remains uncertain whether MetS as a construct is associated with poorer cognitive performances. This study explores whether MetS is associated with poorer performances in global and domain-specific cognitive tests in older nondemented subjects independently of its individual components, WMH severity and other variables. Methods: MetS was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III definition. Brain magnetic resonance studies (1.5T) were performed. Deep and periventricular WMH were graded using the Fazekas scale. Subjects underwent the Mini-Mental State Examination, the Babcock Short Story Recall test and the Clock-Drawing Test (CDT). Results: Eighty community-dwellers aged 67–91 years were studied. Subjects with MetS (n = 35) had more severe WMH, and poorer performances on the
URING RECENT YEARS, great efforts have been made in studying the pre-clinical phases of cognitive decline,1,2 with the major goal to define what the early clinical signs of an approaching dementia
D
*Correspondence: Giovanni Viscogliosi, MD, Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, Sapienza University, Viale Del Policlinico 155, 00100 Rome, Italy. Email: [email protected] Received 9 January 2015; revised 25 February 2015; accepted 13 March 2015.
620
CDT (P = 0.003) and the Babcock Short Story Recall test (P = 0.027). After multiple adjustment, MetS was inversely associated with CDT scores (B = −1.285; 95% confidence interval = −1.996–−0.575; P = 0.001) but not with episodic memory. Results were not affected by WMH severity. Interestingly, none of the individual components of MetS predicted poorer cognitive performances.
Conclusions: Impairment in executive functions assessed by CDT may represent an early and specific sign of cognitive decline in older individuals with MetS. Future longitudinal studies are needed to better establish the predictive role of MetS on dementia and to demonstrate the possibility of dementia prevention by targeting MetS. Key words: Clock-Drawing Test, executive dysfunction, metabolic syndrome, prevention, white matter hyperintensities.
are. Authors have indicated that deficits in executive functions may be detected earlier than those in memory tasks,3–6 irrespective of whether subjects report cognitive complaints. Executive functions are the ability to plan, judge, reason, solve problems and organize; and attention, abstraction and mental flexibility play pivotal roles in executive control.5,7 Impairment in executive function predicts Alzheimer’s disease and vascular dementia.3,5,7 Executive dysfunction is so frequently associated with cardiovascular (CV) risk factors and with sub-
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2015; 69: 620–629
Metabolic syndrome, executive functions 621
cortical vascular damage, that it may represent an early and specific marker of cognitive impairment in subjects with higher CV risk.2,4–6,8–10 Metabolic syndrome (MetS) is a constellation of multiple risk factors, including hypertension, atherogenic dyslipidemia, impaired glucose homeostasis and abdominal obesity.11 MetS is risky for the aging brain, as it has been associated with greater occurrence of subcortical white matter hyperintensities (WMH), which are associated with cognitive decline, late-onset depression and functional disability.2,4,11,12 Each MetS trait may potentially exert a negative influence on cognitive function.12 There are inconsistent results about whether MetS as a whole influences cognitive function and dementia risk, and whether the risk associated with MetS is greater than that conferred by the sum of its parts.13–17 Non-demented adults with MetS have poorer executive functioning when compared with controls.18–22 This study explored whether older non-demented individuals with MetS have poorer performances in cognitive tests that screen global cognition, executive functions and episodic memory; and whether such an association was independent of the individual components of MetS, WMH severity and other variables. The potential confounding role of depressive symptoms was also explored.
drugs; and contraindications for brain magnetic resonance examination. Written informed consent to the study was obtained from all participants. Sociodemographic features, medical history and general habits of the subjects were collected by trained operators using standardized questionnaires. Blood samples were drawn in the early morning after an overnight fast and analyzed within 30 min from collection. Triglycerides, fasting blood glucose (FBG) and high-density lipoprotein (HDL) cholesterol concentrations were determined using standard laboratory techniques. High-sensitivity C-reactive protein (HsCRP) concentrations were determined using commercially available enzyme-linked immunosorbent assay kits. Waist circumference (WC) was measured at the level of the iliac crest with patients standing, at the end of a normal expiration. Blood pressure was measured twice from the right arm with subjects in the sitting position, after a rest of 10 min, using a mercury sphygmomanometer. Systolic (SBP) and diastolic (DBP) blood pressure levels were defined as first and fifth Korotkoff phases. Average values were considered. According to the National Cholesterol Education Program Adult Treatment Panel-III definition, MetS was defined as alteration in three or more of the following five criteria: (i) WC > 102 cm in men and >88 cm in women; (ii) FBG ≥ 110 mg/dL; (iii) plasma triglycerides ≥ 150 mg/dL; (iv) HDL cholesterol < 40 mg/dL in men and < 50 mg/dL in women; and (v) SBP ≥ 130 mmHg and/or DBP ≥ 85 mmHg and/or antihypertensive treatment.25 Magnetic resonance imaging (MRI) studies (1.5 Tesla, GE-Horizon device, GE Healthcare, Milan, Italy) were performed in basal conditions, using a head coil. MRI protocol included proton density, and T1 and T2-weighted sequences. Axial slices were 5–6 mm thick, with an inter-slice gap of 1.0–1.2 mm. Hard copies of the scans were evaluated by the same operator, blinded to the clinical features of the subjects. All scans were read for periventricular and deep WMH. WMH were focal hyperintensities on proton density and T2-weighted images. Periventricular WMH were lesions abutting the lateral ventricles, at the level of frontal and occipital horns and laterally to ventricles. Deep WMH were hyperintense lesions separated from the lateral ventricles. Infarcts were focal lesions with defined contours, that appeared
METHODS Community-dwelling older subjects, referred to the ambulatory care center of our department for a comprehensive geriatric assessment during June– October 2014, were considered for this study. Inclusion criteria were: age ≥ 65 years; ability to complete all elements of the study assessment; and absence of dementia. Dementia was defined according to the DSM-IV23 criteria and/or whether the subjects scored > 0.5 on the Clinical Dementia Rating Scale.24 Participants were grouped according to the presence of MetS. Subjects were consecutively enrolled if they did not possess any of the following features: mood disorders with onset before age 50 and other neurological and psychiatric diagnoses; clinical CV diseases, defined as history or evidence of acute myocardial infarction, symptomatic or silent stroke, and peripheral artery disease; diabetes mellitus and/or current antidiabetic treatment; malignancies; current smoking; conditions of acute or chronic pain and/or current treatment with analgesic/anti-inflammatory
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
622 G. Viscogliosi et al.
isointense to cerebrospinal fluid with a diameter of > 3 mm. WMH were graded on a severity-scale according to the semi-quantitative method of Fazekas and colleagues.26 Deep WMH were graded as absent (score = 0), punctate (score = 1), nearly coalescent (score = 2) and confluent (score = 3). Periventricular WMH were graded as absent (score = 0), pencil-thin lines (score = 1), caps or bands (score = 2) and confluent (score = 3) (see Fig. 1 for examples). WMH degree was classified as absent/slight (score = 0–1), moderate (score = 2), or severe (score = 3). Neuropsychological tests were administered by experienced geriatricians blinded to the clinical and neuroradiological features of the subjects. Global cognitive function was assessed with Folstein’s Mini-Mental State Examination (MMSE),27 the best-validated instrument to evaluate cognitive function in older persons. Total score ranges are from 0 to 30; the higher the score the better the cognitive performance. Results were adjusted for age and educational level, according to standard procedures. Executive functions were evaluated using the Clock-Drawing Test (CDT). Each subject was given a pre-drawn circle and asked to insert numbers. Then, subjects were asked to place the clock hands to read ‘10 past 11’. In this study, the method by Sunderland and colleagues was adopted to score CDT performances.28 This is a 10-point scoring system: 1 denotes very poor and 10 the best performance. Five points are given for numbers placed in the correct position; the remaining points are given for accuracy of hands denoting the time 11:10. By convention, a score < 6 indicates relevant impairment. Episodic memory was assessed by administering the Babcock Short Story Recall Test, whose details are described elsewhere.29 This is a 21-unit story measuring immediate and delayed (10-min) recall. The total score, obtained by summing scores in immediate and delayed recall sections, ranges from 0 to 16; the higher the score the higher the level of episodic memory. Depressive symptoms were investigated through the 15-item Geriatric Depression Scale (GDS), a wellvalidated screening tool for depression in older people; the higher the score the greater the depressive symptoms.30 By convention, scores ≥ 10 indicate subjects with high probability of having some form of depression. The GDS question, ‘Do you feel you have more problems with memory than most?’ was used to identify subjects with complaints of memory loss.
Psychiatry and Clinical Neurosciences 2015; 69: 620–629
Statistical analysis All analyses were performed via SPSS 17.0 for Windows. Characteristics of participants are presented according to the presence of MetS. Ordinal variables are presented as mean ± SD, nominal variables as frequencies. The Student’s unpaired t-test and χ2 statistic were used to compare continuous and dichotomous variables, respectively, according to the presence of MetS. Linear bivariate regression analyses with calculation of Pearson’s correlation coefficients were performed to identify interrelationships between cognitive function, depressive symptoms, WMH severity, MetS and its individual components. Logistic regression analyses were performed to identify variables independently associated with cognitive performances. Variables showing significant associations in bivariate analyses were tested as explanatory variables in multiple regression models. With the exception of HsCRP values, all variables were normally distributed. Due to their skewed distribution, HsCRP values were log10-transformed. Statistical significance was set for two-sided P-values ≤ 0.05.
RESULTS Eighty subjects were studied (58.6% women), mean age 80.4 ± 5.3 years (67–91), median 79 years. Thirty-five subjects with MetS and 45 without were included in this study. As expected, subjects with MetS were more likely to have abdominal obesity, higher FBG, more severe deep (P < 0.001) and periventricular WMH (P = 0.013) and higher inflammatory levels than controls, and they were more likely to use lipid-lowering drugs (Table 1). None of the subjects had silent brain infarcts. MetS was significantly accompanied by poorer performances in CDT (P = 0.003) and Babcock Short Story Recall (P = 0.027). Twenty-seven percent of subjects with MetS and 5.0% of controls (P = 0.007) exhibited relevant deficits in executive functions (CDT < 6). Although in both groups mean GDS scores fell in the subclinical range (
