Abstract
Cerebral amyloid angiopathy (CAA) is a contributor to cognitive impairment in the elderly. We hypothesized that the posterior cortical predilection of CAA would cause visual-processing impairment. We systematically evaluated visuospatial abilities in 22 non-demented CAA patients. Neurocognitive evaluation demonstrated visuoperceptual impairment (23% on Benton Facial Recognition Test [BFRT] and 13.6% on Benton Judgment of Line Orientation Test [BJLO]). BFRT was inversely correlated with white matter hyperintensities volume and BJLO with parietal cerebral microbleeds. This pilot study highlights the presence of visual-processing deficits in CAA. The impairment could be related to global disease severity in addition to local brain injury.
Keywords
INTRODUCTION
Cerebral amyloid angiopathy (CAA) is an important contributor to cognitive impairment in the elderly [1, 2] and is characteristically associated with a high prevalence of characteristic markers of small vessel disease, including white matter hyperintensities (WMH) and strictly lobar cerebral microbleeds (CMBs) [3]. Individuals with moderate-to-severe CAA pathology have lower performance in specific cognitive domains, most notably executive dysfunction processing speed and memory [2, 4]. MRI studies have demonstrated an occipital predilection of neuroimaging markers of CAA [5], in line with the distribution of CAA pathology [6]. Posterior lesions can be associated with lower performance on tasks assessing visuospatial abilities [7], but the specific effects of CAA on visuospatial function has not been explored.
A variety of tests designed to probe the visuospatial functioning has been developed for neuropsychological assessment. The Benton Facial Recognition Test (BFRT) [7, 8] and the Benton Judgment of Line Orientation Test (BJLO) [7, 9] are two well validated and widely used tests with available normative data that respectively probe visuoperceptual discrimination of unfamiliar faces and judgment of spatial relationships. The posterior regions predominantly serving these functions include the parietal, parietal-occipital and occipito-temporal regions, especially in the right hemisphere [7].
In the current study, we sought to systematically evaluate visuospatial abilities in CAA patients, given the known posterior predilection of CAA neuroimaging markers. In particular, we aimed to: (a) investigate the frequency of visual processing deficits in this patient population and explore if visual processing is more affected than other cognitive skills; and (b) investigate if visual processing deficits are related to local brain injury or global disease severity based on neuroimaging markers.
MATERIALS AND METHODS
Patients
This study is a cross-sectional analysis of data from an ongoing longitudinal cohort study of CAA at Massachusetts General Hospital recruited from an outpatient stroke clinic setting. Twenty-two non-demented patients fulfilling the Boston criteria [10] for probable or definite CAA who underwent research MRI (July 2014 – July 2015) were eligible for the current study. Eleven patients (50%) were also included in a previous study [2]. Blind persons (n = 1) and patients with a Mini-Mental State Examination (MMSE)≤24 (n = 1) were excluded. The Institutional Review Board approved the study and informed consent was obtained from all participants.
Clinical and neuropsychological evaluation
Demographic information, vascular risk factors, and history of intracerebral hemorrhage (ICH) were recorded. Patients systematically underwent standardized neuropsychological assessment as previously described [11] including assessment of functions including verbal memory, processing speed, attention and executive functioning. Available published normative data were used for comparison and corrected score or Z-scores (with percentiles) for each cognitive test were calculated. The neuropsychological evaluation also included apathy/depression self-report scales, a brief vision screening interview, the BFRT (short form) [8] and the BJLO [9] and MMSE pentagon drawings.
MRI protocol
Study participants underwent detailed structural 1.5 T (n = 13) or 3 T (n = 9) (on the basis of time of enrollment) MRI scans (Siemens Healthcare,Germany) according to study protocol [11]. There were no differences between 1.5T and 3T subjects, particularly in visual discrimination impairment. Imaging for all patients included T1-weighted, FLAIR, both T2*-gradient echo (GRE) and susceptibility-weighted imaging (SWI) as previously defined [11]. MRI were reviewed blinded to all clinical and neuropsychological data by trained observers, according to STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) [12]. MRI scanning were conducted in the same day as neuropsychological tests (n = 18), while 4 patients underwent tests less than 2 months after MRI.
The details of neuropsychological protocol and neuroimaging evaluation are presented in the Supplementary Material.
Statistical analysis
Discrete variables are presented as count (%) and continuous variables as mean (SD) or median (25%, 75% quartiles) as appropriate. A correlation analysis between neuropsychological tests and neuroimaging variables was performed using non-parametric correlation tests (Spearman’s rho).
For comparisons on demographic characteristics, neuropsychological features, and neuroimaging markers between the group of patients with and without BFRT impairment, the independent samples Mann-Whitney U test and Pearson Chi-square test were applied to non-normally distributed continuous variables and to categorical variables, respectively. In this comparison analysis, we applied Bonferroni’s correction for multiple comparisons, resetting the critical level of significance according to the number of variables considered (p < 0.0003 for cognitive functions and p < 0.0005 for neuroimaging features).
Other statistical significance level was set at 0.05.
The SPSS 21 statistical package was used for statistical analysis (IBM Corp., Armonk, NY).
RESULTS
Our cohort consisted of 22 non-demented patients with probable CAA. Mean age was 69.9±6.0 years and 18 (81.8%) patients were males. Table 1 provides details on the clinical symptoms of the CAA patients.
The mean number of CMBs was 123.45±175.50 (ranging 0–715). Based on neuropsychological evaluation, the patients exhibited a cognitive profile in the normal range in all domains, except in one executive function test (Trails B z-score = –3.1±4.9, < 1st percentile) and in visuospatial function as measured by the BFRT and BJLO (Table 2). The mean BFRT score was 44.64±6.26 (52th, 33rd–59th percentile) and mean BJLO score 25.8±6.3 (<60th percentile). Five (22.7%) patients showed impairment on the BFRT test (≤11th percentile) and 3 (13.6%) showed impairment on the BJLO test (≤9th percentile). Of these, there were 2 patients (without significant eye problems) who were impaired on both tests. Figure 1 is an illustrative example of CMB distribution in one patient with severely impaired performance on the BFRT (BFRT<1st percentile).
In correlation analysis between visuospatial function and neuroimaging markers, the BFRT score showed an inverse moderate correlation with WMH volume (Spearman’s rho = –0.513, p = 0.0015). No correlation with focal ICH lesions (presence, number, and location), total CMBs counts and cortical superficial siderosis, age, and visual processing tests was found. The BJLO score was associated with lower total lobar parietal CMBs counts (Spearman’s rho = –0.513, p = 0.0015). There is a trend (but not statically significant) for correlation between BJLO score and total brain volume (TBV) (rho = 0.417, p = 0.0054).
Comparing patients with and without visuoperceptual discrimination impairment, there were no statistically significant differences, particularly regarding ICH and other main neuroimaging characteristics and other cognitive tests (including pentagon drawings) and behavior/mood factors (Supplementary Table 1).
DISCUSSION
We evaluated visuospatial abilities in non-demented patients with CAA, a clinical feature not commonly investigated in patients with the disease, systematically applying two tests specifically designed to probe the visuospatial functioning. Visuoperceptual impairment was present in 23% of patients, without other significant cognitive deficits. This is slightly higher than previously reported in neurological patients with focal brain damage in right, left or both hemispheres [13]. Although our neuropsychological tests are not directly comparable because different normative data used, the visual processing impairment appears more affected than other relatively spared cognitive skills, because tests evaluating verbal memory, processing speed, and attention resulted in the normal range.
We found that the lower performance on a visual discrimination test correlated with the burden and topographic distribution of select neuroimaging markers of CAA and not with focal occipital intracerebral hemorrhage. Specifically, WMH volume and CMBs in parietal were inversely correlated with BFRT and BJLO scores, respectively. We can speculate that the visual processing impairment is due to global disease severity (e.g., measurable by total neuroimaging lesion burden or WMH volume), in addition to local brain injury in structures important for processing visual information (e.g., parietal areas). Low visuospatial discrimination test performances were also slightly related with TBV (in line with previous literature suggesting atrophic brain changes may contribute to worse visual discrimination in normal adults [14] and Alzheimer’s disease patients [15]).
Interestingly, because the group with visual discrimination impairment was comparable in terms of cognitive profile with the group without visual discrimination impairment, these findings suggest that visual discrimination deficits may develop in a subgroup of patients with CAA.
Visuospatial abilities have been previously investigated, as part of a wider cognitive evaluation, in older community-dwelling persons with and without dementia in the Religious Orders Study [4]. This study does not show a relationship between CAA pathological severity and visuospatial function [4]. The fact our pilot study used neuroimaging biomarkers instead of pathology to assess CAA severity and our limited sample size may account for this disparity. However, our study did show a relationship between WMH volume and BFRT, also a relationship between CMBs in the parietal lobe and BJLO score, which were not explicitly addressed in the previous study.
Our study has several limitations. The main one is the small sample size, because it is a specific and exploratory study. This precludes us from performing multivariate analyses that could demonstrate an independent association between CAA neuroimaging markers and visuospatial deficits. Secondly, because we lack a control group, it is uncertain whether these visual discrimination deficits are present at the same rate in non-CAA populations. However, comparison with age-adjusted normative scores would suggest that patients with CAA have increased impairment in visual discrimination abilities compared to healthy individuals [7, 13]. Thirdly, it is possible that differing MRI field strengths used in a subgroup of patients could lead to bias in our results. However, comparison of patients undergoing 3T versus 1.5T scan did not show differences in visual discrimination impairment between groups.
This pilot study suggests that visuospatial deficits in patients with CAA are both present and measureable. Visuospatial deficits may have clinical importance in identifying cognitively normal CAA patients with increased CAA-related small vessel disease burden.
ACKNOWLEDGMENTS
This work was supported by the NIH (grants R01AG047975, R01AG026484, P50AG005134, K23AG02872605).
G. Boulouis was supported by a J. William Fulbright Research Scholarschip and a Monahan Foundation Biomedical Research Grant.
Authors’ disclosures available online (http://j-alz.com/manuscript-disclosures/16-0927r2).