Association of Magnetic Resonance Imaging Markers of Cerebrovascular Disease Burden and Cognition
Background and Purpose—The present study sought to examine the association between the burden of cerebrovascular disease (CeVD) as assessed by multimodal magnetic resonance imaging and neurocognitive function.
Methods—Cognitively impaired patients and controls were tested on an extensive neuropsychological battery and underwent multimodal brain magnetic resonance imaging. CeVD markers determined from magnetic resonance imaging included the presence of multiple lacunes, multiple cerebral microbleeds, and moderate or severe white matter hyperintensities as markers for small-vessel disease and cortical stroke and intracranial stenosis as markers for large-vessel disease. A weighted CeVD burden score was constructed, and its association with global and domain-specific cognitive performance was investigated.
Results—A total of 305 cases and 94 controls were included in the analysis. A graded association of CeVD burden with neurocognitive function was found. Moreover, a clear threshold of CeVD burden was associated with severe impairment. White matter hyperintensities was associated with global neurocognitive deficits, whereas microbleeds were associated with domain-specific impairments.
Conclusions—The weighted CeVD burden score comprising markers of both small- and large-vessel diseases were associated with deficits in both global and domain-specific neurocognitive function. Additional studies are needed to validate the use of this CeVD burden score for the prediction of dementia.
Magnetic resonance imaging (MRI) markers of cerebrovascular disease (CeVD) include those for small-vessel disease (SVD) and large-vessel disease (LVD). CeVD is recognized as a major contributor to cognitive impairment and dementia, especially in Asian populations.1–3 Although a growing body of evidence suggests that MRI markers of CeVD can predict cognitive decline, previous studies investigating CeVD and neurocognitive function have mainly focused on either the association between (1) ischemic stroke and cognition or (2) SVD and cognition.4–6 However, the concept of total CeVD burden, encompassing both SVD and LVD, has not been extensively examined in relation to cognitive status. Huijts et al7 using an unweighted summation of SVD markers reported that the co-occurrence of lacunes, white matter hyperintensities (WMH), microbleeds, and enlarged perivascular spaces was inversely correlated with cognitive impairment. Staekenborg et al8 showed that mild cognitive impairment patients with coexisting severe WMH, more lacunes, and microbleeds at baseline had higher risk of converting to non-Alzheimer dementia at follow-up. Furthermore, vascular dementia (VaD) patients with co-occurring SVD and LVD showed significantly worse cognitive performance.9 These studies demonstrate that not all CeVD contributes equally to changes in cognition and the value of using a combined measure of CeVD burden to predict cognitive impairment. Moreover, a recent study using an unweighted SVD scale recommended that different cutoff points and weighting for MRI features should be investigated.10 Furthermore, it is important to consider whether each measure of CeVD, in any proposed scale, carries the same importance to patients11 and whether differential weighting of each MRI feature are needed to optimally predict outcomes of clinical importance, such as cognition. Therefore, we have explored whether a weighted assessment of total CeVD burden can improve understanding of the cognitive consequences of CeVD. Importantly, such a weighted total CeVD burden scale should be pragmatic and balance between practical use and the inherent complexity of disease, hence providing rapid and accurate quantification of global CeVD burden in both clinical practice and research settings.
We used a case–control design for the current study. Cases were recruited from 2 memory clinics in Singapore from August 2010 to June 2014.12 Cases were consecutive eligible patients with impairment in at least 1 cognitive domain on a locally validated standard neuropsychological battery (the Vascular Dementia Battery [VDB]).13 Domain impairment on the VDB was defined as ≥1.5 SD below education-adjusted norms. Controls with no cognitive impairment on the VDB were recruited from the community. Subjects were eligible if they were aged ≥50 years, had sufficient language skills for neuropsychological assessment, fulfilled diagnostic criteria specified below, and provided informed consent. Participants with a diagnosis of major psychiatric illness or substance abuse disorder, participants with cognitive impairment caused by history of traumatic brain injury, multiple sclerosis, tumor, epilepsy, systemic disease, and participants with significant visual and auditory abnormalities were excluded. Ethical approval was obtained from the National Healthcare Group Domain-Specific Review Board. Written informed consent was obtained in the preferred language of the participants, by bilingual study coordinators before recruitment into the study.
Participant diagnoses were made at weekly consensus conference attended by neurologists, psychologists, and research personnel. All available clinical and investigational data were reviewed as a part of the diagnostic process.
Participants were categorized into the following 5 clinical diagnostic groups:
Nonvascular cognitive impairment–no dementia (CIND): with impairment of at least 1 cognitive domain on the VDB and functional independence hence not meeting Diagnostic and Statistical Manual-IV for dementia,14 and no documented history of stroke or transient ischemic attack.
Vascular CIND: in accordance with the CIND criteria, but with a documented history of stroke/transient ischemic attack.
Alzheimer dementia (AD): in accordance with National Institute of Neurological and Communicative Diseases and Stroke–Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria.15
VaD: in accordance with National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherché et l’Enseignement en Neurosciences (NINDS-AIREN) criteria.16
Controls had no objective cognitive impairment on the VDB.
MRI scans were performed on a 3T Siemens Magnetom Trio Tim scanner, using a 32-channel head coil. Several MRI brain sequences were performed to allow morphological and microstructure assessments, including T1-weighted magnetization prepared rapid gradient recalled echo, fluid attenuated inversion recovery, T2-weighted and susceptibility-weighted imaging.
MRI markers of CeVD were graded using the following criteria:
Cortical infarcts were defined as focal lesions involving cortical gray matter, signal following cerebrospinal fluid intensity, hyperintense rim on fluid attenuated inversion recovery images, and tissue loss of variable magnitude, with prominent adjacent sulci and ipsilateral ventricular enlargement.17
Intracranial stenosis was defined as narrowing exceeding 50% of the luminal diameter in any of the intracranial vessels assessed on 3-dimensional time of flight magnetic resonance angiography. The images were first visually assessed on the reconstruction images, and the final decision on stenosis (>50%) was made on the source images.18
Lacunes were defined as lesions, 3 to 15 mm in diameter, with low signal on T1-weighted image and fluid attenuated inversion recovery, a high signal on T2-weighted image, and a hyperintense rim with a center following cerebrospinal fluid intensity on fluid attenuated inversion recovery.12
WMH were graded using the Modified Fazekas scale.19
Microbleeds were defined on susceptibility-weighted imaging sequences using Brain Observer Micro Bleed Scale.20
Neuropsychological and Clinical Evaluation
The National Institute of Neurological Disorders and Stroke and Canadian Stroke Network vascular cognitive impairment battery was used21 as it is designed and validated for vascular cognitive impairment.22,23
In the present study, a modified National Institute of Neurological Disorders and Stroke and Canadian Stroke Network-Canadian Stroke Network protocol was administered by qualified psychologists to all participants. The protocol covers the following domains:
Working memory: digit span forward and backward.24
Language: 15-item modified Boston Naming Test.26
Visuomotor speed: Symbol Digit Modalities test.27
Visuospatial function: Rey Complex Figure Test28 Copy.
Recall and recognition: Rey Complex Figure Test immediate/delayed recall and recognition, Hopkins Verbal Learning Test29 immediate/delayed recall and recognition.
All individual test raw scores were transformed to standardized z scores using the mean and SD of the control group. The score for each domain was created by averaging the z scores of individual tests and standardized using the composite mean and SD of the control group. To obtain the global cognition domain z score for each patient, the domain z scores were averaged and standardized using the mean and SD of the control group.
Several cross-cultural adaptations were made: digit span tests were included as impairments of attention and working memory are present in vascular cognitive impairment.30 The Color Trail Test is a cultural analogue of the Trial Making Test included in the original National Institute of Neurological Disorders and Stroke and Canadian Stroke Network-Canadian Stroke Network protocol and has been validated in Asia.21 Participant’s depressive and neuropsychiatric symptoms were evaluated using the Geriatric Depression Scale31 and Neuropsychiatric Inventory.32
MRI markers of CeVD were transformed into binary variables and recorded as presence/absence of multiple lacunar infarcts, multiple microbleeds, cortical infarcts, intracranial stenosis, and moderate-to-severe severity of WMH on the Fazekas scale. CeVD burden scores were generated based on the strength of independent association between CeVD markers and global neurocognitive performance.
The correlation between individual CeVD markers was examined and reported as φ coefficient values. Independent associations between presence of individual CeVD markers (determinants) with global and domain-specific cognitive performance (per SD increase, outcome variables) were assessed using the general linear model, controlling for age, sex, education, ethnicity, other vascular risk factors such as hypertension, hyperlipidemia, diabetes mellitus, ischemic heart disease, smoking history, and other MRI markers.
Subsequently, ANOVAs were used to relate different CeVD burden scores with global and domain-based cognitive performance in 2 steps: step 1, controlling for age, sex, education, ethnicity, hypertension, and diabetes mellitus; step 2, also controlled for other vascular risk factors such as hyperlipidemia, ischemic heart disease, and smoking history. In addition, as multiple testing was performed for domain-specific z scores, the Bonferroni correction was used to obtain an adjusted significance level for each domain-specific test: ≈0.05/6=0.008. All analyses were performed using standard statistical software (Statistical Package for Social Science [SPSS] version 21; SPSS Inc).
A total of 143 cases with dementia (116 AD and 27 VaD), 162 CIND (62 vascular CIND and 100 nonvascular CIND) and 94 controls were recruited. Seven patients without available MRI scans were excluded from the analysis (4 patients with AD, 2 patients with CIND, and 1 patient with VaD). Table 1 shows the characteristics of study participants.
The presence of WMH was significantly correlated with multiple lacunes (φ=0.28; P<0.001) and multiple microbleeds (φ=0.27; P<0.001). In addition, multiple lacunes were associated with multiple microbleeds (φ=0.27; P<0.001) and cortical infarcts (φ=0.28; P<0.001). Intracranial stenosis was associated solely with cortical infarcts (φ=0.30; P<0.001).
Moderate-to-severe WMH was independently associated with lower global cognition (β [SE]=−0.21 [0.16]; P<0.001), as well as performance on all individual cognitive domains. For individual cognitive domains, multiple microbleeds was associated with poor performance on visuomotor speed (β [SE]=−0.12 [0.04]; P<0.008), visuoconstruction (β [SE]=−0.12 [0.08]; P<0.008), executive function (β [SE]=−0.10 [0.09]; P<0.008), and language (β [SE]=−0.10 [0.08]; P<0.008; Table 2). Although no other CeVD indicator showed an independent association with global cognition, the presence of any ≥2 CeVD indicators was found to be significantly associated with worse global cognitive performance (β [SE]=−0.09 [0.18]; P<0.01), independent of WMH.
On the basis of linear regression coefficient established between CeVD indicators and cognitive performance as above, we devised a weighted CeVD burden score with 2 points awarded when moderate or severe WMH was present and one point awarded when at least 2 CeVD markers were present.
Hence, a 4-category CeVD burden score was generated:
None/very mild CeVD burden score 0: none/mild WMH and <2 other CeVD indicators.
Mild CeVD burden score 1: none/mild WMH and ≥2 other CeVD indicators.
Moderate CeVD burden score 2: moderate/severe WMH and <2 other CeVD indicators.
Severe CeVD burden score 3: moderate/severe WMH and ≥2 other CeVD indicators.
Overall, 116 participants scored 0, 45 scored 1, 118 scored 2, and 120 scored 3 on the CeVD burden index. Global and domain-based cognitive performance on each CeVD burden severity level is demonstrated in the Figure. Frequencies of the individual CeVD markers and total CeVD burden index scores in the 4 clinical diagnostic groups (nonvascular CIND and, vascular CIND, AD, and VaD) are presented in Table 3.
Using ANOVA, subjects with CeVD burden index score 2 to 3 showed significantly worse global and domain-specific neurocognitive performance than those with CeVD burden index score 0 to 1. In addition, subjects with severe CeVD showed a greater effect on cognitive performance, especially in visuoconstruction domain (Table 4). Interaction between diagnostic groups and CeVD burden index was also examined and was not significant (F(9,939)=0.46; P=0.90). This indicates that the CeVD index scale can be applied regardless of subject’s diagnosis.
The main finding of the current study is that increasing CeVD burden, defined by a combination of WMH and other SVD/LVD markers of CeVD, is inversely related to global cognitive status and predominantly associated with disturbances of executive function, language, and visuoconstruction.
In line with previous studies showing an association of multiple CeVD events on cognition,7–9 we found that the presence of any ≥2 CeVD markers was significantly associated with worse global cognitive performance. In addition, we found a threshold effect of CeVD indicating that a moderate level of burden was associated with greater impairment in both global and domain-based neurocognitive function. These effects not only underline the cumulative nature of CeVD burden but also suggest that SVD and LVD markers can be used to indicate when a critical level of CeVD burden is reached.
Global and domain-based neurocognitive scores were disproportionately influenced by the severity of WMH. Previous studies have shown the association of WMH with impairments in domain5,6,33 and general cognition.34 Although WMH and lacunes often occur together, the independent effect of WMH on cognition has frequently been reported in cross-sectional studies,35 including the cognitively normal elderly,36 and are more prominent and consistent than the effect of lacunes.6 In longitudinal studies, change in WMH was found to predict decline in global function, independent of age and other risk factors associated with disability. Moreover, this effect was also independent of baseline atrophy and infarcts.37 Furthermore, a combined measure of baseline atrophy and WMH was associated with rapid cognitive decline.38 Putatively, this association between WMH and cognition is because of a disruption in cortical–subcortical connectivity leading to reduced information processing speed and impaired executive function, which form a large part of general cognitive.35,36,39 In the present study, mild CeVD, consisting of little or no WMH and the presence of other CeVD markers, was associated with domain-based impairments, whereas moderate-to-severe CeVD, with moderate WMH and less emphasis on other markers, is more likely to be associated with global cognition impairment. Hence, the relative influences of CeVD markers need to be considered.
Notably, the independent effect of microbleeds with impairment on visuoconstruction, executive function, visuomotor speed, and language domains is in line with several population-based studies34,40,41 and suggests that microbleeds also exacerbate the progression of certain cognitive deficits. Both microbleeds and WMH are linked to cerebral amyloid angiopathy42,43 and the deposition of β-amyloid in cerebral vessel walls.41 Significantly, of the 120 patients with severe CeVD, >80% presented with both lesions; therefore, it is conceivable that the association of severe CeVD with domain deficits could be because of the co-occurrence of WMH and microbleeds. In view of the importance of cerebral amyloid angiopathy in AD, the independent and combined effects of these aspects of CeVD should be considered in future longitudinal studies.
The present study has strengths and weaknesses. Among the strengths, the combination of weighted indices of both SVD and LVD into a single burden score provided a quantitative means of examining the effect of CeVD on cognition and may prove to be useful clinically. A further strength was the use of a comprehensive neuropsychological battery that, unlike previous studies, was able to generate both domain and global cognitive indexes. The main limitation of the study is that the CeVD total burden scale was built and tested from the same data set. Hence, further validation with separate data sets is recommended. Another limitation is that only 27 patients with VaD were included in the analyses. Therefore, no analysis of the applicability of the CeVD burden score in a VaD population was performed. Furthermore, this study had a relatively small sample size (n=94) of controls not matched with cases in age and education. This limits the accuracy of z score calculation because these variables differ across CeVD severity groups (Table I in the online-only Data Supplement), which are not fully controlled for by the use of age and education as covariates. Finally, because only patients with AD/VaD were recruited into the present study, the results cannot be generalized to other forms of dementia.
We found that the weighted CeVD scale is useful in elucidating the burden of CeVD on neurocognitive function. Our findings suggest that there is a threshold of CeVD burden at which cognitive abilities are severely compromised, but further studies are required to establish the predictive value of this scale in both advanced CeVD and dementia.
Sources of Funding
This study was supported by the Singapore National Medical Research Council centre grants NMRC/NUHCS/2010 and NMRC/NUHS/2010 (project no. R-184-006-184-511).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.115.010700/-/DC1.
- Received July 8, 2015.
- Revision received July 23, 2015.
- Accepted July 27, 2015.
- © 2015 American Heart Association, Inc.
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