Validation of the Montreal Cognitive Assessment Versus Mini-Mental State Examination Against Hypertension and Hypertensive Arteriopathy After Transient Ischemic Attack or Minor Stroke
Background and Purpose—Lack of reduced cognitive impairment with blood pressure (BP) lowering in trials may reflect use of the Mini-Mental State Examination (MMSE), which is insensitive to mild cognitive impairment after cerebrovascular events compared with the Montreal Cognitive Assessment. We determined relationships between impairment on MMSE versus Montreal Cognitive Assessment (MoCA) with the major physiological determinant of vascular cognitive impairment: hypertension and hypertensive arteriopathy.
Methods—Cognitive impairment in consecutive patients 6 months after transient ischemic attack or minor stroke was defined as significant, mild, or none (MMSE<23, 23–26, ≥27; MoCA<20, 20–24, ≥25) and related to 20 premorbid systolic BP readings, home BP measurement (3 measurements, 3×daily for 1 month), and hypertensive arteriopathy (creatinine, stroke versus transient ischemic attack, leukoaraiosis) by ordinal regression.
Results—Of 463 patients, 45% versus 28% had at least mild cognitive impairment on the MoCA versus MMSE (P<0.001). Hypertensive arteriopathy was more strongly associated with cognitive impairment on the MoCA than MMSE (creatinine: odds ratio=3.99; 95% confidence interval, 2.06–7.73 versus 2.16, 1.08–4.33; event: 1.53, 1.06–2.19 versus 1.23, 0.81–1.85; leukoaraiosis: 2.09, 1.42–3.06 versus 1.34, 0.87–2.07). Premorbid and home BP measurement systolic BP were more strongly associated with impairment on vascular subdomains of the MoCA than MMSE (odds ratio/10 mm Hg: visuospatial 1.29 versus 1.05; attention 1.18 versus 1.07; language 1.22 versus 0.91; naming 1.07 versus 0.86).
Conclusions—The stronger relationship between impairment on the MoCA with hypertensive arteriopathy, independent of age, indicates a greater sensitivity for vascular-origin cognitive impairment. Use of MoCA should improve sensitivity for cognitive impairment and treatment effects in future studies.
Vascular cognitive impairment may result from chronic subcortical arteriopathy1 or acute cerebrovascular events, especially on the background of reduced cerebrovascular reserve.2 Hypertension is the strongest risk factor for both acute cerebrovascular events3 and subcortical arteriopathy4 and is strongly associated with cognitive impairment.5 However, randomized controlled trials of antihypertensive medications6,7 have not demonstrated consistent delays in cognitive decline, despite reductions in blood pressure (BP). One explanation is that most studies used the Mini-Mental State Examination (MMSE) to screen for cognitive decline, which is optimized for detecting Alzheimer-type cognitive impairment with early language and memory dysfunction but not for early visuospatial and executive dysfunction seen in vascular-type impairment.
Recent studies after transient ischemic attack (TIA) or minor stroke reported higher rates of cognitive impairment on the Montreal Cognitive Assessment (MoCA) versus MMSE,8,9 due partly to the visuospatial/executive components of the MoCA and the greater sensitivity to single-domain cognitive impairment.10–12 However, these studies compared the short tests with a more detailed cognitive battery, and it remains uncertain whether the MoCA is a better marker than the MMSE of underlying cerebrovascular damage or if it will better predict progression to dementia. It is possible that the MoCA is simply a harder test and is not specific for clinically relevant vascular cognitive impairment.
If the additional cognitive impairment identified by the MoCA is related to vascular disease, then cognitive impairment on the MoCA, particularly in visuoexecutive and attentional domains, should be more strongly associated with hypertension and hypertensive arteriopathy than on the MMSE, identifying a population at increased risk of future cognitive decline.10 In a population-based study of TIA and nondisabling stroke, we, therefore, compared the association between cognitive impairment on the MoCA and the MMSE with premorbid or current hypertension and hypertensive arteriopathy.
Consecutive patients were recruited between April 2008 and January 2012 from the Oxford Vascular Study (OXVASC) TIA and minor stroke clinic, usually within 24 hours of referral.13 The OXVASC population consists of ≈92 000 individuals registered with 100 primary care physicians in Oxfordshire, United Kingdom. Patients with possible TIA or minor stroke are referred by the OXVASC general practitioners or Emergency Department staff to the OXVASC study clinic. All consenting patients with probable TIA or minor stroke are reviewed by a stroke physician including a standardized medical history and examination, ECG, and routine blood tests, with face-to-face follow-up at 1, 3, 6, 12, and 60 months. Patients undergo a stroke protocol MRI brain and contrast-enhanced magnetic resonance angiography of the extracranial brain-supplying arteries unless contraindicated, with the remaining patients having a computed tomography-brain and either a carotid Doppler ultrasound or computed tomography angiogram. Most patients also undergo transcranial Doppler ultrasound, echocardiography and 5 days of ambulatory cardiac monitoring.
The MMSE was administered at the beginning and the MoCA at the end of a 45-minute appointment at 6-month follow-up. Subjects who were unable to complete cognitive testing owing to dysphasia, inability to use the dominant arm, illness, or poor English were excluded as described previously.9,10 A score of ≥27 on the MMSE14 and ≥25 on the MoCA15 indicated normal cognitive function, with scores of <23 on the MMSE and <20 on the MoCA indicating significant cognitive impairment likely to impair function, according to recommendations from previous TIA and stroke cohorts.8,9,16
Clinic BP was measured twice at ascertainment and the 1-month follow-up visit in the nondominant arm, by trained personnel, in the sitting position after 5 minutes of rest. The lifetime medical record held by the primary care physician was manually reviewed, and all recorded premorbid BPs ascertained. Up to 20 readings were used for determination of premorbid BP, with sensitivity analyses using readings during the last 5 years or from 5 to 10 years before the event.
From the day of recruitment to ≥1 month, patients performed sets of 3 home BP measurements (HBPM), 3× daily (on waking, midmorning, and before sleep) with a Bluetooth-enabled, regularly calibrated, telemetric IEM Stabil-o-Graph or A&D UA-767BT BP monitor. Patients were instructed to perform readings in the nondominant arm or the arm with the higher reading if the mean systolic BP (SBP) differed by >20 mm Hg between arms, after 5 minutes of sitting. At the 1-month follow-up, 24-hour ambulatory BP monitoring (ABPM) measurements were performed with an A&D TM-2430 monitor in the nondominant arm, fitted by a trained study nurse, at 30 minutes intervals during the day and 60 minute intervals at night. During readings, patients were asked to avoid excessive activity, to sit down, and to keep a diary of the day.
Patients continued HBPM after 1 month, if required, until adequate BP control was achieved. Mean BP was treated to a target of <130/80 on HBPM or ABPM, except in the presence of haemodynamically significant stenosis (bilateral carotid stenosis >70% or end-artery stenosis >70%) when targets were determined individually. Antihypertensive treatment was tailored to the individual patient but most commonly was a combination of perindopril arginine 5 mg and indapamide 1.25 mg, followed by amlodipine 5 to 10 mg with subsequent choices at the physician’s discretion.
Leukoaraiosis was assessed on axial T2 scans according to the Fazekas scale17 and on both MRI and computed tomography on a simple 4 point scale: none, mild, moderate, or severe by experienced observers (M.S./L.L.) blinded to clinical and physiological data.18 Creatinine was measured at ascertainment. Finally, the nature and severity of the initial event was categorized as stroke or TIA, as a marker of degree of end-organ injury associated with a history of hypertension.
Mean and maximum SBP and diastolic BP on HBPM were derived from the last 2 readings at each time point, including readings from 7 days after the initial assessment. Mean and maximum SBP and diastolic BP on awake 24-hour ABPM were derived after automated and manual exclusion of artefactual measurements according to predefined criteria.19 Mean premorbid SBP and diastolic BP were derived from the past 20 years recorded in the primary care record, from readings in the 5 years before the notification event, and from readings 5 to 10 years before this event.
MoCA and MMSE scores were categorized as none, mild, or significant cognitive impairment as defined above. Relationships with discrete variables were determined by χ2 tests while relationships with continuous measures were determined by ANOVA, with post hoc comparisons of significant versus none (Tukey). Association of level of cognitive impairment with hypertensive arteriopathy, leukoaraiosis, and demographic characteristics was determined by ordinal regression. All analyses were performed before and after adjustment for age and sex.
Of 492 patients with cognitive assessments (95% of all patients), 463 (94%) had both an MMSE and a MoCA performed, of whom 452 (98%) performed HBPM, 427 (92%) had ≥3 premorbid BPs recorded, and 422 (91%) had a 24-hour ABPM at 1 month. There were a median of 31 (22–71) days of HBPM (mean 8.7 readings per day) and 15 (6–31) premorbid BP readings on separate occasions per patient. The mean age was 69.2 (SD, 12.9) years, 53% were men, 55% hypertensive, 15% diabetic, 40% had known dyslipidaemia, and 14% were current smokers.
More patients had at least mild cognitive impairment (45% versus 28%; P<0.001) and more had significant cognitive impairment (14.3% versus 6.7%; P<0.001) on the MoCA versus the MMSE, despite similar demographic characteristics (Table I in the online-only Data Supplement). There was no significant difference in number of BPs performed by patients with significant cognitive impairment compared with noncognitively impaired patients (mean home BPs: significantly impaired versus not: MoCA 102 versus 119, P=0.12; MMSE 92 versus 119, P=0.08).
Mean and maximum home SBP were higher in patients with significant cognitive impairment when defined by the MoCA than the MMSE compared with patients with mild or no cognitive impairment, with a significant trend across the 3 groups (Table 1). There were no consistent differences for mean or maximum diastolic BP when patients were classified according to either test. Awake mean and maximum SBP on ABPM at 1 month after ascertainment were also higher in patients with significant cognitive impairment, but only when defined according to the MoCA (Table 1), while premorbid mean and maximum SBP increased systematically across all levels of cognitive impairment on the MoCA. In contrast, on the MMSE patients with mild cognitive impairment had the highest premorbid mean SBP, with no significant difference between significantly cognitively impaired patients and nonimpaired patients (Table 1). Markers of hypertensive arteriopathy were more strongly associated with cognitive impairment on the MoCA than the MMSE (Table 2) with a stronger relationship for patients with stroke versus TIA, a higher creatinine, and more frequent and more severe leukoaraiosis, at least before adjustment.
All cognitive subdomains were more strongly associated with mean SBP on the MoCA than on the MMSE, except for orientation. However, the visuospatial/executive subdomain of the MoCA was most strongly associated with mean SBP before and after adjustment for age and sex (Table II in the online-only Data Supplement), with a 29% greater chance of a lower score per 10 mm Hg increase in SBP. Drawing interlocking pentagons, the only visuospatial/executive test on the MMSE, was also strongly associated with mean SBP on HBPM (Table 3), but the only other domains associated with mean BP were weak univariate associations with recall and orientation. This partly reflected a ceiling effect with the MMSE, with more patients achieving full marks in most domains: visuospatial (MMSE 84% versus MoCA 37.6%, P<0.001); language (91.4% versus 37.1%, P<0.001); naming (98.5% versus 82.3%, P<0.001); recall (52.9% versus 13%, P<0.001); orientation (74.7% versus 79.7%, P<0.001). However, the visuospatial domain determined a greater proportion of the interindividual variance in total score with the MoCA compared with the MMSE (15.6% versus 8.1% of total variance uniquely explained by subdomains).
Cognitive impairment detected by the MoCA after TIA or nondisabling stroke was strongly associated with hypertensive arteriopathy and an elevated mean and maximum SBP on postevent HBPM, on 24-hour ABPM, and on premorbid BP readings. The MoCA test was significantly more sensitive than the MMSE at screening for hypertension-associated cognitive impairment because of stronger associations within all cognitive subdomains and a greater contribution of visuospatial/executive tests to the total MoCA score.
Dementia affects 5% to 7% of people ≥60 years old worldwide, costing European Union-15 countries ≈$189 billion per year, increasing to ≈115 million people by 2050.20 However, there is currently no effective treatment for the prevention of either the onset or progression of cognitive impairment. Hypertension5 and cerebrovascular disease2 are particularly strongly associated with dementia and are the most modifiable risk factors for the prevention of cognitive decline. Unfortunately, although randomization to a nitrendipine-based regimen in the Syst-Eur trial21 reduced the future risk of cognitive decline, this has not been consistently replicated in secondary prevention studies6,7 and not confirmed by meta-analyses.22 However, trials have predominantly used the MMSE for cognitive screening, although it is insensitive to milder impairment and to visuospatial/executive dysfunction, which are preferentially affected in vascular cognitive impairment6 and result in significant functional impairment and death.23
In previous studies, the MoCA defined more patients as being cognitively impaired than the MMSE in populations with cerebrovascular disease,10–12 had a greater sensitivity for cognitive impairment defined by a gold standard neuropsychological battery,9,11 and showed greater differences in cognitive profile between TIA and patients with stroke, memory research subjects,23 and patients with coronary disease.24 Unfortunately, these studies, including those from our group, have not compared tests with physiological measures that are independent of cognitive assessment and could simply indicate that the MoCA is a harder test. Our study demonstrated a strong physiological association between the additional cognitive impairment identified by the MoCA test and both premorbid hypertension and hypertensive arteriopathy, including powerful markers of systemic small-vessel arteriopathy that occurs both as a result and cause of hypertension, such as creatinine25 and leukoaraiosis,4 suggesting a physiological basis for the additional sensitivity of the MoCA.
The improved sensitivity of the MoCA for hypertension-associated cognitive impairment was found across multiple cognitive domains because of ceiling effects with the MMSE, but the strongest association was for visuospatial/executive dysfunction. This contributed more to variation in the overall MoCA score than in the MMSE score, resulting in greater overall sensitivity for vascular-type cognitive impairment associated with hypertension10 and cerebrovascular disease.1 Previous studies have not validated the subdomains of the MoCA, despite these domains being built into its design. Therefore, our study also provides the first objective validation of these subdomains for vascular-type cognitive impairment. Furthermore, our study suggests that the failure of randomized controlled trials to demonstrate improvements in cognitive dysfunction with BP reduction may partly result from the low sensitivity of the MMSE for screening for hypertension-associated, vascular cognitive impairment. Use of the MoCA should be more effective at detecting clinically important reductions in cognitive decline after BP treatment.
After a stroke, cognitive dysfunction can result from the effects of the cerebrovascular event itself,8 from associated small vessel disease,10 from recurrent events,8 or from a combination of these and coexisting neurodegenerative disease.8,26 Therefore, cognitive impairment on the MoCA may identify patients at a particularly increased risk of future cognitive decline because of both chronic cerebrovascular disease and recurrent cerebrovascular events, who may particularly benefit from BP reduction. Trials using the MoCA in this population may be more sensitive to benefits of BP-lowering treatment, which has previously been difficult to demonstrate in primary prevention populations.
Our study has limitations. First, although our sample was population based, it included relatively healthy patients with cerebrovascular disease able to perform HBPM and excluded patients with severe dementia or major stroke. This limits generalizing the results to patients with major stroke but reduces the probability of selection bias favoring patients with right hemisphere strokes. However, this is the ideal population where strategies to prevent cognitive decline may bring the greatest benefits. Second, there is currently insufficient follow-up to determine whether the MoCA was sensitive or specific for the progression of hypertension-associated cognitive impairment or the development of dementia. The alternative approach of validating the MoCA and MMSE against more detailed neuropsychological testing also suggested that the MoCA had greater diagnostic accuracy for mild cognitive impairment.9 However, simply because one cognitive test is better correlated with another does not necessarily mean that it is the best. Our new observations that the MoCA is more strongly associated with physiological measures provides additional evidence of utility that avoids the shortcomings of using other cognitive tests as the gold standard. Third, there was no formal assessment of depression which could have an effect on the cognitive scores. Fourth, the MMSE was routinely performed at the start and the MoCA at the end of each follow-up appointment, and therefore, there is a theoretical risk of some systematic difference in performance. However, this would not be expected to bias the associations with independent physiological measures or selectively affect the association with more specific vascular cognitive subdomains. Fifth, there were nonsignificantly fewer BPs recorded by patients with greater cognitive impairment. However, less accurate recordings in more cognitively impaired patients would be expected to increase the variance in readings in this group and reduce any association with hypertension. Finally, premorbid BP readings were not available in some patients, but these were largely young patients without any cognitive impairment.
The MoCA identified more hypertension-associated cognitive impairment than the MMSE, implying a pathophysiologically relevant basis for differences between scores. This results from a greater sensitivity to hypertension-associated cognitive impairment in multiple subdomains but particularly due visuospatial/executive dysfunction. The poor sensitivity of the MMSE to hypertension-associated cognitive impairment may explain the lack of efficacy of antihypertensive medications in randomized controlled trials. Future studies should determine whether the MoCA may identify a cohort of patients at a particularly increased risk of future cognitive decline in whom targeted BP-lowering treatment may be of benefit.
We acknowledge the use and facilities of the Acute Vascular Imaging Centre, Oxford.
Sources of Funding
Oxford Vascular Study is funded by the Wellcome Trust, UK Medical Research Council, Dunhill Medical Trust, Stroke Association, National Institute for Health Research (NIHR), Thames Valley Primary Care Research Partnership, and the NIHR Biomedical Research Centre, Oxford. P.M. Rothwell is in receipt of a NIHR and Wellcome Trust Senior Investigator Awards.
Guest Editor for this article was Costantino Iadecola, MD.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.114.006309/-/DC1.
- Received May 30, 2014.
- Revision received August 30, 2014.
- Accepted September 4, 2014.
- © 2014 American Heart Association, Inc.
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