Association of the ASCO Classification with the Executive Function Subscores of the Montreal Cognitive Assessment in Patients with Postischemic Stroke Kazuo Washida, MD, PhD,* Masafumi Ihara, MD, PhD,† Hisatsugu Tachibana, MD,* Kenji Sekiguchi, MD, PhD,* Hisatomo Kowa, MD, PhD,* Fumio Kanda, MD, PhD,* and Tatsushi Toda, MD, PhD*
Background: The ASCO classification can evaluate the etiology and mechanisms of ischemic stroke more comprehensively and systematically than conventional stroke classification systems such as Trial of Org 10172 in Acute Stroke Treatment (TOAST). Simultaneously, risk factors for cognitive impairment such as arterial sclerosis, leukoaraiosis, and atrial fibrillation can also be gathered and graded using the ASCO classification. Methods: Sixty patients with postischemic stroke underwent cognitive testing, including testing by the Japanese version of the Montreal cognitive assessment (MoCA-J) and the mini-mental state examination (MMSE). Ischemic strokes were categorized and graded by the ASCO classification. In this phenotype-based classification, every patient is characterized by the A-S-C-O system (A for Atherosclerosis, S for Small vessel disease, C for Cardiac source, and O for Other cause). Each of the 4 phenotypes is graded 0, 1, 2, or 3, according to severity. The conventional TOAST classification was also applied. Correlations between individual MoCA-J/MMSE scores and the ASCO scores were assessed. Results: The total score of the ASCO classification significantly correlated with the total scores of MoCA-J and MMSE. This correlation was more apparent in MoCAJ than in MMSE, because MoCA-J scores were normally distributed, whereas MMSE scores were skewed toward the higher end of the range (ceiling effect). Results for individual subtests of MoCA-J and MMSE indicated that cognitive function for visuoexecutive, calculation, abstraction, and remote recall significantly correlated with ASCO score. Conclusions: These results suggest that the ASCO phenotypic classification of stroke is useful not only for assessing the etiology of ischemic stroke but also for predicting cognitive decline after ischemic stroke. Key Words: ASCO phenotypic classification—poststroke cognitive impairment—Montreal cognitive assessment—mini-mental state examination. Ó 2014 by National Stroke Association
The burden of stroke stemming from its effect on cognition has been underestimated for a long time. Ischemic stroke is a major cause of adult chronic disability and represents an important cause of cognitive decline and
dementia. Poststroke cognitive impairment (PSCI) appears in about one third of patients with stroke.1 The prevalence of cognitive impairment among patients with a history of stroke is similar to that of subjects
From the *Division of Neurology, Graduate School of Medicine, Kobe University, Kobe; and †Department of Neurology, The National Cerebral and Cardiovascular Center, Suita, Osaka, Japan. Received March 25, 2014; accepted April 3, 2014. This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Japanese Ministry of Education, Science and Culture (to T.T.).
Address correspondence to Kazuo Washida, MD, PhD, Division of Neurology, Kobe University, Graduate School of Medicine, Kusunokicho 7-5-2, Chuo-ku, Kobe 650-0017, Japan. E-mail: [email protected]
kobe-u.ac.jp. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.04.009
Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 9 (October), 2014: pp 2250-2255
RELATIONSHIP BETWEEN ASCO CLASSIFICATION AND MoCA-J SCORE
10 years older without a history of stroke. In addition, a recent study demonstrated that poststroke mild cognitive impairment (MCI) is progressive and develops into dementia in 24.4% of patients within 3 years, giving a mean conversion rate of approximately 8% per year.3 Patients with PSCI showed a much poorer prognosis. Thus, the concept of PSCI, including poststroke MCI, should be emphasized for early detection and treatment, even if the impairment is not severe enough to meet the criteria for dementia. The ASCO phenotypic classification is proposed as a new classification of stroke.4 The ASCO classification can evaluate the etiology and mechanisms of ischemic stroke more comprehensively and systematically than conventional stroke classification systems such as the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. Increasing knowledge about ischemic stroke mechanisms and the introduction of new diagnostic techniques have supported the promotion of the new ASCO phenotypic classification, which aims to characterize patients using different grades of evidence for ischemic stroke subtypes. With this new way of classifying patients, no information is neglected when the diagnosis is made, and treatment can be adapted to the observed phenotypes and the most likely etiology. Furthermore, risk factors for dementia such as atherosclerosis, small vessel disease, and atrial fibrillation can be summarized and graded using the ASCO classification. For the detection of cognitive impairment after ischemic stroke, the Montreal cognitive assessment (MoCA) is more sensitive than the mini-mental state examination (MMSE).5 The MoCA is a simple, standalone, cognitive screening test with a good sensitivity and specificity in detecting MCI and, unlike the MMSE, includes executive tasks.6 However, additional predictive methods for early detection of PSCI are urgently needed. For example, medial temporal atrophy has predictive value for cognitive decline after stroke but it seems to be less informative than the MoCA or MMSE. If the ASCO classification has a predictive value for PSCI, its clinical value will be enhanced. The main aim of this study was to evaluate the additive value of the ASCO phenotypic classification in assessing cognitive impairment of patients with postischemic stroke over the use of the Japanese version of the MoCA (MoCA-J) and MMSE. We found additional evidence that the ASCO classification can not only assess the etiology of ischemic stroke but also predict cognitive decline after ischemic stroke.
Materials and Methods
Figure 1. Example of the grading system (phenotyping) in a patient with an ipsilateral carotid stenosis .50% (atherosclerosis, grade 3), a single, deep branch artery stroke (small vessel disease, grade 2), atrial fibrillation (cardioembolism, grade 3), and a platelet count of 700,000/mm3 (other causes, grade 1). Stroke subtype is A3-S2-C3-O1.
and 2013. Patients taking part in the study gave informed consent as approved by the Committee of Medical Ethics within our faculty. All procedures were performed in accordance with the guidelines for clinical study from the Ethical Committee of Kobe University. Patients with infratentorial infarction or strategic single-infarct dementia were excluded. Patients with other dementing illnesses including Alzheimer disease and Lewy body dementia were not enrolled in this study to exclude the possibility of nonvascular causes of neurodegenerative cognitive impairment in the subjects.
Ischemic Stroke Assessment by the ASCO and TOAST Classifications Sixty consecutive patients with postischemic stroke were assessed by the ASCO classification of stroke. All ischemic strokes were confirmed by imaging studies. The ischemic stroke was categorized and graded by the ASCO phenotypic classification. In this phenotypebased classification, every patient is characterized by the A-S-C-O system (A for Atherosclerosis, S for Small vessel disease, C for Cardiac source, O for Other cause). Each of the 4 phenotypes is graded 0, 1, 2, or 3, according Table 1. The ASCO phenotypic classification of stroke A S C O 3 2 1
Subjects Sixty patients with first-ever ischemic stroke were enrolled in this study more than 3 months after admission to the Kobe University Neurology Clinic between 2012
Atherosclerosis Small vessel disease Cardiac disease Other causes Definitely a potential cause of the index stroke Causality uncertain Unlikely a direct cause of the index stroke (but disease is present) Disease not present Insufficient workup
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Table 2. Clinical features and demographics of patients Variable
Mean age, y (range) Gender (M:F) Modified Rankin Scale, mean 6 SD (range) NIHSS 6 SD (range) Hypertension, n (%) Diabetes mellitus, n (%) Dyslipidemia, n (%) Cigarette smoking, n (%) MoCA-J 6 SD (range) MMSE 6 SD (range)
68 6 13 (39-92) 40:20 1.65 6 .7 (0-4) 1.82 6 .6 (0-7) 45 (75) 23 (38.3) 28 (46.7) 25 (41.7) 19.6 6 4.8 (3-28) 24.3 6 4.6 (5-30)
including MoCA-J and MMSE more than 3 months after ischemic stroke. MoCA-J less than 24 and MMSE less than 24 were regarded as indicating cognitive decline in this study. Two neurologists were involved in the neuropsychologic assessment; if their assessments did not agree, patients were re-examined.
Statistical Analysis Correlations of individual cognitive activity with the scores of MoCA-J and MMSE were assessed using the Pearson correlation analysis. Subtests of the MoCA-J and MMSE were evaluated by dividing the mean subtest score by its standard deviation. A lower Z-score indicates greater discrimination between subjects.
Abbreviations: M:F, male:female; MMSE, mini-mental state examination; MoCA-J, Montreal cognitive assessment-Japanese version; NIHSS, National Institute of Health Stroke Scale; SD, standard deviation.
to severity. The ASCO classification methods are illustrated in Figure 1 and Table 1. In this study, the original ASCO classification grading was modified as follows for quantitative evaluation: the original grade 1 was grade 3 in the revised version, and the original grade 3 was grade 1 in the revised version. The total ASCO score was 12 (A, 3; S, 3; C, 3; O, 3). The stroke subtype with the highest ASCO grade was regarded as the most likely etiology of the stroke (A, Atherosclerosis; S, Small vessel disease; C, Cardioembolism; O, Other causes). The ischemic strokes of the patients were also categorized by the conventional TOAST method.
Results Patient Demographic Data Clinical features and demographic data of patients are summarized in Table 2. All patients had at least 1 risk factor for ischemic cerebrovascular disease, such as hypertension, diabetes mellitus, dyslipidemia, or cigarette smoking. The mean modified Rankin Scale score was 1.65 (range, 0-4) and the mean National Institute of Health Stroke Scale (NIHSS) score was 1.82 (range, 0-7). These patients’ clinical histories and radiologic features excluded the possibility of coexisting strategic single-infarct dementia.
Stroke Subtyping Classification by ASCO and TOAST Neuropsychologic Examination All subjects underwent a general physical and neurologic examination, and a neuropsychologic assessment,
Ischemic strokes were categorized and graded by the ASCO phenotypic classification. The corresponding categorizations by the ASCO and TOAST classifications are
Table 3. ASCO and TOAST classifications in the present study
A S C O Undeterminded
23.33 30.00 30.00 6.67 –
21.67 35.00 26.67 6.67 10.00 TOAST
A, N 5 13
S, N 5 21
C, N 5 16
O, N 5 4
Undetermined, N 5 6
A S C O
13 11 3 0
18 21 4 0
13 15 16 0
2 3 0 4
5 6 4 0
Abbreviations: ASCO, A for Atherosclerosis, S for Small vessel disease, C for Cardiac source, O for Other cause; TOAST, Trial of Org 10172 in Acute Stroke Treatment. Comparison of ASCO results at evidence grade 3 with TOAST results, giving percentages of etiologies found with both classification systems. TOAST results (column) and the corresponding ASCO score distribution (rows) for evidence grades 1-3.
RELATIONSHIP BETWEEN ASCO CLASSIFICATION AND MoCA-J SCORE
were normally distributed, whereas MMSE scores were skewed toward the higher end of the range. Of the 37 patients with an impaired MoCA-J score (,24), only 20 (54%) had an impaired MMSE score (,24), whereas all 20 patients with an impaired MMSE score had an impaired MoCA-J score. Results for individual subtests of the MoCA-J and the MMSE are summarized in Table 4. Coefficients of variation .5 were found in 4 MMSE subtests (orientation, registration, naming, and language) but in no MoCA-J subtests.
Relationship between the ASCO Classification and Tests of Cognitive Function
Figure 2. Distribution of MoCA-J and MMSE scores of the patients after ischemic stroke. A significant relationship exists between MoCA-J and MMSE (R2 5 .79; P , .05; Pearson correlation analysis). MoCA-J scores are normally distributed, whereas MMSE scores are skewed toward the higher end of the range. Abbreviations: MMSE, mini-mental state examination; MoCA-J, Montreal cognitive assessment-Japanese version.
summarized in Table 3. Grade 3 ASCO evidence was found in 23% of the subjects for Atherosclerosis (A), 30% of the subjects for Small vessel disease (S), 30% of the subjects for Cardiac source (C), and 6.7% of the subjects for Other cause (O). Eighty-eight percent of the patients were classified into more than 1 category. All cases could be determined by the ASCO classification. On the other hand, using the TOAST classification, the distribution was 22% (Atherosclerosis), 35% (Lacunae), 27% (Cardioembolism), and 6.7% (Others). Specifically mentioned, 10% cases were diagnosed as undetermined because more than 2 causes existed. There was a high concordance for grade 3 etiologic classification between the ASCO and TOAST systems.
Relationship between MoCA-J and MMSE There was a significant relationship between MoCA-J and MMSE (R2 5 .79; P , .05; Fig 2). MoCA-J scores
In all patients with postischemic stroke, there was a significant correlation between the ASCO score and MoCA-J score (R2 5 .47; P ,.05; Fig 3A). There was also a significant correlation between the ASCO score and MMSE score (R2 5 .41; P , .05; Fig 3B). Compared with MoCA-J scores, MMSE scores were skewed toward the higher end of the range (ceiling effect) and MoCA-J was more sensitive to cognitive decline in patients with postischemic stroke than MMSE. Results for individual subtests of MoCA-J indicated that cognitive function tests for visuoexecutive, abstraction, and remote recall were correlated closely with the ASCO score. Results for individual subtests of MMSE indicated that cognitive function tests for calculation and remote recall were correlated closely with the ASCO score.
Discussion This study shows that the total score of the ASCO classification significantly correlates with the total scores of MoCA-J and MMSE. This correlation was more apparent in MoCA-J than in MMSE, because MoCA-J scores were normally distributed, whereas MMSE scores were skewed toward the higher end of the range (ceiling effect). Results for individual subtests of MoCA-J and MMSE indicated that cognitive function for visuoexecutive, calculation, abstraction, and remote recall function significantly correlated with the ASCO score in patients with PSCI.
Table 4. Cognitive test results: average subtest scores MoCA-J
Average (SD) Z-score
3.4 (1.4) 2.4
2.6 (.8) 3.4
4.6 (1.3) 3.6
1.4 (.7) 1.9
1.1 (.8) 1.3
1.2 (1.0) 1.1
5.2 (1.4) 3.8
Average (SD) Z-score
8.9 (1.8) 5.0
2.9 (.2) 12.5
2.8 (1.7) 1.6
1.1 (1.1) 1.0
2.0 (.3) 7.4
5.6 (.7) 8.6
.9 (.3) 3.0
Abbreviations: MMSE, mini-mental state examination; MoCA-J, Montreal cognitive assessment-Japanese version; SD, standard deviation.
Figure 3. Distribution of MoCA-J, MMSE, and ASCO scores of patients after ischemic stroke. A significant correlation exists between the ASCO phenotypic classification total score and MoCA-J (R2 5 .47; P , .05) (A). There is also a significant correlation between the ASCO phenotypic classification total score and the MMSE score (R2 5 .41; P , .05; Pearson correlation analysis) (B). Compared with MoCA-J scores, MMSE scores are skewed toward the higher end of the range (ceiling effect). Abbreviations: ASCO, A for Atherosclerosis, S for Small vessel disease, C for Cardiac source, O for Other cause; MMSE, mini-mental state examination; MoCA-J, Montreal cognitive assessment-Japanese version.
Stroke and cognitive impairment pose major threats to elderly people. PSCI includes all forms of cognitive decline that develop after stroke, even if not severe enough to fit the criteria for dementia after stroke.7,8 The true cognitive burden of stroke is probably underestimated because cognitive impairment of stroke is 3 times more common than in stroke-free subjects.9 PSCI significantly worsens the survival rate of patients even compared with patients with Alzheimer disease.10 Nevertheless, little attention is usually paid to cognitive impairment after stroke. In the present situation, guidelines for care and rehabilitation of patients with stroke
K. WASHIDA ET AL.
neither clearly define the optimal timing nor the most appropriate instruments for cognitive evaluation after ischemic stroke. Recently, several effective treatments for PSCI have been reported. Administration of donepezil in the acute phase of ischemic stroke improved the MMSE score and prognosis of the patients.11 Early poststroke rehabilitation is associated with a reduction in dementia risk among patients with ischemic stroke.12 Furthermore, early treatment of poststroke depression by antidepressant drugs may improve cognitive ability and survival rate.13 In addition, the diagnostic concept ‘‘Cognitive Impairment No Dementia (CIND)’’, namely vascular mild cognitive impairment, predicts further cerebrovascular events in addition to cognitive decline.14 Thus, early detection and treatment of PSCI are essential not only to improve cognitive decline but also to prevent secondary ischemic stroke. Appropriate instruments to detect PSCI are urgently needed. Several batteries of neuropsychologic tests are available for predicting PSCI. The MoCA has been recommended for vascular cognitive impairment. For example, the MoCA score at acute phase after stroke has predictive value for PSCI.5 Several clinical studies have demonstrated that patients with PSCI often have impaired executive function and that MoCA is more sensitive than the MMSE for detection of cognitive decline after stroke.5 In this study, MMSE tended to overlook cognitive decline after stroke and MoCA-J could detect PSCI more sharply than MMSE. Compared with MoCA-J, MMSE scores were skewed toward the higher end of the range because of the easiness of the tasks (ceiling effect). To detect PSCI, MoCA-J should be used to assess the cognitive ability of patients with postischemic stroke. The ASCO classification of stroke is proposed by Amarenco et al.4 The concept is to introduce a complete ‘‘stroke phenotyping’’ classification as distinguished from past classifications that subtype strokes by characterizing only the most likely cause of stroke. In clinical practice, many ischemic strokes have complex etiologies and cannot be diagnosed as belonging to only 1 category by a conventional classification system such as TOAST.15 Simultaneously, the ASCO score reflects risk factors not only for ischemic stroke but also for cognitive impairment such as arterial stenosis,16 leukoaraiosis,17 and atrial fibrillation.18 Patients with arterial stenosis, leukoaraiosis, or atrial fibrillation tend to show more serious cognitive impairment. That was probably why the ASCO score was associated with PSCI as assessed by MoCA-J and MMSE in this study. In addition, subtest analyses demonstrated that MoCA-J and MMSE revealed cognitive impairment for visuoexecutive, calculation, abstraction, and remote recall function, and the executive functions are often impaired in vascular cognitive impairment syndromes including PSCI. In this study, the cognitive scores of patients with ASCO scores 4-6 seemed to have a large variance, and
RELATIONSHIP BETWEEN ASCO CLASSIFICATION AND MoCA-J SCORE
the ASCO score could not reveal subtle cognitive declines. We speculate that the grading (0, 1, 2, or 3) criteria of the ASCO classification are still inaccurate. For example, grade for small vessel disease (S) does not define the degree of leukoaraiosis or microbleeds.4 A strict and appropriate indication of the degree of leukoaraiosis should be given. In addition, under other causes (O), frequent causes of ischemic stroke such as vasculitis and paraneoplastic syndrome are not included in the present ASCO classification. Several rare, but important, causes of stroke should be added. There are several limitations of this study. For example, we did not follow the 60 patients long enough. The temporal profiles of cognitive function of patients with postischemic stroke should be explored. In addition, a recent study has demonstrated that there is substantial heritability for ischemic stroke and PSCI and this varies markedly for different stroke subtypes.19,20 In future, the cognitive ability of patients with PSCI should be explored in a perspective of genetic heritability. In conclusion, these results suggest that the ASCO phenotypic classification of stroke is useful not only for assessing the etiology of ischemic stroke but also for predicting cognitive decline after ischemic stroke. Acknowledgment: We are indebted to Ms Kodama for her excellent technical assistances.
References 1. Jin YP, Di Legge S, Ostbye T, et al. The reciprocal risks of stroke and cognitive impairment in an elderly population. Alzheimer’s Dement 2006;37:345-350. 2. De Ronchi D, Palmer K, Pioggiosi P, et al. The combined effect of age, education, and stroke on dementia and cognitive impairment no dementia in the elderly. Dement Geriat Cogn Disord 2007;24:266-273. 3. Sachdev PS, Chen X, Brodaty H, et al. The determinants and longitudinal course of post-stroke mild cognitive impairment. J Int Neuropsychol Soc 2009;15:915-923. 4. Amarenco P, Bogousslavsky J, Caplan LR, et al. New approach to stroke subtyping: the A-S-C-O (phenotypic) classification of stroke. Cerebrovasc Dis 2009;27:502-508. 5. Salvadori E, Pasi M, Poggesi A, et al. Predictive value of MoCA in the acute phase of stroke on the diagnosis of mid-term cognitive impairment. J Neurol 2013; 260:2220-2227. 6. Rossetti HC, Lacritz LH, Cullum CM, et al. Normative data for the Montreal Cognitive Assessment (MoCA) in a population-based sample. Neurology 2011;77:1272-1275.
7. Ihara M, Okamoto Y, Takahashi R. Suitability of the Montreal cognitive assessment versus the mini-mental state examination in detecting vascular cognitive impairment. J Stroke Cerebrovasc Dis 2013;22:737-741. 8. Ihara M, Okamoto Y, Hase Y, et al. Association of physical activity with the visuospatial/executive functions of the Montreal cognitive assessment in patients with vascular cognitive impairment. J Stroke and Cerebrovasc Dis 2013;22:e146-e151. 9. Pendlebury ST, Rothwell PM. Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis. Lancet Neurol 2009;8:1006-1018. 10. Carod-Atral FJ, Egido JA. Quality of life after stroke: the importance of a good recovery. Cerebrovasc Dis 2009; 27:204-214. 11. Barrett K, Brott TG, Brown RF Jr, et al. Enhancing recovery after acute ischemic stroke with donepezil as an adjuvant therapy to standard medical care: results of a phase IIA clinical trial. J Stroke Cerebrovasc dis 2011;20:177-182. 12. Chou YC, Liao CC, Su LT, et al. Stroke rehabilitation is associated with a reduction in dementia risk: a population-based retrospective cohort study. J Rehabil Med 2012;44:319-324. 13. Kimura M, Robinson RG, Kosier JT. Treatment of cognitive impairment after poststroke depression. Stroke 2000;31:1486. 14. Narasimhalu K, Ang S, De Silca DA, et al. The prognostic effects of poststroke cognitive impairment no dementia and domain-specific cognitive impairments in nondisabled ischemic stroke patients. Stroke 2011;42:883-888. 15. Adams HP, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24:35-41. 16. Romero JR, Beiser A, Seshadri S, et al. Carotid artery atherosclerosis, MRI indices of brain ischemia, aging, and cognitive impairment: the Framingham study. Stroke 2009;40:1590-1596. 17. Schulz UG, Gruter BE, Brilley D, et al. Leukoaraiosis and increased cerebral susceptibility to ischemia: lack of confounding by carotid disease. J Am Heart Assoc 2013; 2:e000261. 18. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012;33:1500-1510. 19. Bevan S, Traylor M, Adib-Samii P, et al. Genetic heritability of ischemic stroke and the contribution of previously reported candidate gene and genome-wide associations. Stroke 2012;43:3161-3167. 20. Traylor M, Farrall M, Holliday EG, et al. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. Lancet Neurol 2012;11:951-962.