Received date: August 28, 2014; Accepted date: October 28, 2014; Published date: October 30, 2014
Citation: Nelson F, Poonawalla AH, Datta S, Banuelos RC, Rahbar MH, et al. (2014) Association of Multiple Sclerosis Related Cognitive Impairment with an MRI-Derived Composite Score. J Mult Scler 1:124. doi:10.4172/2376-0389.1000124
Copyright: ©2014 Nelson F et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Background: MRI-derived metrics such as atrophy, burden of disease (BOD), and cortical lesions (CL) have independently been reported to be associated with Multiple Sclerosis (MS) related cognitive impairment (CI). Composite scores combining some of these individual metrics have also been shown to improve correlations with MS-related physical disability; however the value of a composite score for MS-related CI has not yet been evaluated. In this study we assessed the relationship between CI and a quantitative composite score constructed from MRIderived metrics to include total white matter lesion volume, CL number, and normalized cerebrospinal fluid (nCSF), a measure of brain atrophy.
Methods: Thirty three (n=33) patients underwent neuropsychological testing and were classified into CI groups using a 4-point severity scale (0, 1, 2, 3) where zero indicates non-impaired, “1” represents borderline, “2” represents mild, and “3” represents moderate CI. Images obtained at 3T were segmented into tissue and lesion compartments from which BOD and nCSF were quantitatively measured. CL number was identified visually by consensus. BOD, nCSF, and CL number were then transformed to z-scores: zBOD, znCSF and zCL, and a composite score “Z3”was constructed from these measures. The associations between Z3 and CI and the individual transformed measures (z-scores) and CI were evaluated via ordinal logistic regression.
Results: Z3 was significantly associated with CI (OR=1.443, 95% Confidence Interval: 1.048-1.987, p=0.024) with a slightly larger OR than any individual measure. Of the individual measures, only BOD had a significant association with CI (OR=1.064, 95% Confidence Interval: 1.008-1.123, p=0.025). No significant association was found between atrophy or CL and CI.
Conclusion: The Z3 score is associated with increased CI severity. This association was mainly driven by BOD. Larger studies are needed to assess the potential advantage of a composite score over measures of white matter lesion burden alone.
MRI: Magnetic Resonance Imaging; MS: Multiple Sclerosis; CI: Cognitive Impairment; CL: Cortical Lesions; BOD: Burden of Disease; CNS: Central Nervous System; Gd: Gadolinium; nCSF: normalized CSF; EDSS: Expanded Disability Status Scale; NP: Neuropsychological; DIR: Double inversion recovery; PSIR: Phase sensitive inversion recovery; OR: Odds ratio
MRI is the most sensitive noninvasive imaging modality for visualization and characterization of MS lesions. There is a general enthusiasm for using MRI metrics as biomarkers in clinical trials and treatment evaluation [1,2]. However, MRI measures have not been accepted as biomarkers by regulatory authorities, in part due to the lack of understanding of their relationship with clinical outcomes . Currently there is no consensus on whether any single MRI derived measure (such as white matter lesion load, enhancing lesion volume, black hole volume or global/regional atrophy, to name a few) is sufficient to serve broadly as an imaging biomarker in MS .
Cognitive Impairment (CI) is an important cause of MS-related disability, contributing to the great interest of the MS community for better diagnostic and monitoring tools for CI. Individual MRI markers of tissue damage such as global atrophy and T2 lesion load have been shown to have significant correlations with CI [5-10]. Other MRIbased measures such as cortical, thalamic and callosal atrophy and their correlations with CI, have also been investigated in the literature, with varying results [11-15]. Other novel imaging techniques, such as double inversion recovery (DIR) which suppresses the white matter and the cerebrospinal fluid (CSF) signal providing a clear visualization of the cortical ribbon and phase sensitive inversion recovery (PSIR) which provides a sharp delineation between gray and white matter, have been applied to the study of CI. Recent studies on the application of these techniques report an increase in the detection sensitivity of cortical lesions (CL) and have established a role of CL in the pathophysiology of CI [16-20]. Despite irrefutable progress in this field, none of the aforementioned studies have provided enough evidence to definitively conclude that a single MRI measure can potentially be used as an MRI risk indicator of CI.
Since one of the major strengths of MRI is its multi-modal nature, a promising approach is to construct a CI biomarker from a combination of MRI-derived measures, each capturing a different aspect of the disease’s clinical course [21-25]. However, different MRI measures have different dimensions, such as lesion volume (measured in cc), tissue atrophy (measured as percent/ratio/fraction), or CL counts, reported numerically. In addition, the numerical values of each measure may differ widely, with tissue volumes several orders of magnitude larger than lesion volumes. These limitations may be overcome by using a z-score transformation where each measure is standardized creating a dimensionless measure. After the z-score transformation, different measures may simply be added together to form a composite measure, providing a more complete representation of the disease process than with any single MRI derived measure alone. The Z score assumes that the directions of the deviations are consistent in indicating a worse condition among all the measures in the composite score, and that the contributions of all z-scores are equally weighted.
MRI derived composite scores in MS
The use of composite scores has precedent in the MS literature. Quantitative measures derived from MRI such as the z-score have previously been investigated and correlated with measures of clinical disability like the Expanded Disability Status Scale (EDSS) . A composite measure of this type (Z4) was introduced in 2000 as part of the results of the North American Linomide Trial  and was shown to distinguish treatment groups at 3 months. The composite score Z4 included volume of Gd-enhancing tissue (reflecting active inflammation), total lesion volume (reflecting heterogeneous changes in tissue), T1 hypointense lesion volume (reflecting severe tissue alterations), and normalized cerebrospinal fluid (a measure of global atrophy). This composite score was described as follows: Z4=z (Gd lesions)+z(T1+T2 lesions)+z(T1 lesions)+z(nCSF). All of these metrics were measured as volume except for normalized cerebrospinal fluid (nCSF) which is measured as percent/ratio/fraction. Analysis showed that patients who worsened clinically also showed an increase in Z4, supporting the notion that a composite score of multiple MRI measures has clinical relevance . More recently, the same Z4 score was applied to cohorts from the TEriflunomide Multiple Sclerosis Oral trial (TEMSO), were teriflunomide doses of both 7 and 14 mg reduced the mean change from baseline in Z4 over time compared to placebo [28,29].
In the present work, to investigate the relationship of combined MRI-derived metrics with CI, we used a similar composite score the Z3 score which incorporates 1) the CL number, 2)T1+T2 lesion volume representing burden of disease (BOD), and 3) nCSF, representing global atrophy, all scores directionally compatible; larger being worse. We investigated the association between Z3 and CI severity using a 4-point impairment scale ranging from no impairment (normal) to moderate impairment, based on a complete battery of neuropsychological (NP) testing. We hypothesized that the Z3 score will be a better indicator of CI than any of the individual measures.
This was a single center, prospective study, approved by our institutional review board (HSC-MS-05-0333-Cortical lesion detection and correlation with cognitive impairment in multiple sclerosis). Volunteers included 39 MS patients enrolled in the study at The University of Texas Health Science Center at Houston; 6 subjects were excluded from the analysis due to inadequate image acquisition and one due to severe CI scores consistent with dementia and suggestive of a concomitant pathology. The analyzed cohort was comprised of 30 relapsing-remitting, 2 secondary-progressive, and 1 primaryprogressive MS patients with mean EDSS of 3.2 (range 1.0-6.0), who were drawn from an existing database of patients who were tested for evidence of CI within one year prior to the MRI scan. Each patient was evaluated by the same neuropsychologist (FP) who has extensive expertise in detection of MS related CI, the same neurocognitive battery was used in all subjects. Written informed consent was obtained from every participant prior to enrollment and subject eligibility was established based on NP test results as well as inclusion/ exclusion criteria as follows:
Inclusion criteria: 1) clinically definite MS by the McDonald criteria , 2) NP evaluation performed within one year from enrollment, 3) age 18 to 60 (to avoid confounding effects of age-related cognitive deficits), 4) EDSS score 6 or less, 5) brain MRI consistent with the clinical diagnosis of MS.
Exclusion criteria: 1) contraindications for MRI (pacemakers, metal implants, claustrophobia etc.), 2) history of clinical relapse or a high dose steroid treatment in the 3 months prior to the study, 3) history of drug or alcohol abuse, 4) acute or uncontrolled depression within 3 months from testing, and 5) history of treatment with immunosuppressive treatments.
Once eligibility was established by the neuropsychologist, recruitment was done via a telephone call or an invitation letter. Eligible patients were referred for one imaging session and patient eligibility was confirmed prior to enrollment. All personnel except for the neuropsychologist were blinded to the subjects’ cognitive status and the neuropsychologist was blinded to the MRI findings. Each patient enrolled attended a 2 hour session that included: 1) collection of demographics and disease history, 2) neurologicalexam/EDSS score assessment, and 3) MRI of the brain without gadolinium.
A comprehensive battery of standardized NP tests that evaluated a broad range of cognitive domains was administered by a board certified neuropsychologist with extensive expertise in MS-related CI. A complete list of tests grouped by cognitive function is summarized in Table 1.
|Memory||Wechsler Memory Scale-R (WMS-R)
Auditory-verbal learning test
|Ability and achievement||Wechsler Adult Intelligence Scale â€“III (WAIS-III)|
|Verbal functions and language skills||Aphasia screening test
Drawings on command
Controlled oral word association (COWA)
|Motor function||Sensory-Perceptual examination
Finger tapping test (FTT)
Grooved Pegboard test (GPT)
Hand dynamometer or gripped
|Attention concentration and tracking
|Paced Auditory Serial Addition Test (PASAT)
Trial Making Test
|Executive function||Wisconsin Card Sorting Test (WCST)|
|Personal adjustment and
Personality Inventory-2 (MMPI)
Table 1: Neuropsychological testing.
All MRI scans were performed on a Philips 3T Intera scanner with a Quasar Plus gradient system (maximum gradient amplitude 80 mT/m, slew rate 200 T/m/s) and a six channel SENSE-compatible head coil. Following the three-plane pilot scan for locating the brain region of interest, the axial DIR and PSIR images were acquired with 0.94 mm x 0.94 mm in-plane resolution (256x256 matrix and 24 cm square FOV) and 44 contiguous slices of 3.0 mm thickness. SENSE encoding was employed along the A/P direction for DIR and PSIR with a SENSE factor (R) of 2.0. Scan times were 7.5 minutes for DIR and 4.2 minutes for PSIR. Axial dual-spin fast-echo and FLAIR images were also acquired with identical image geometry as PSIR and DIR. 3D fast field echo images of 1mm section thickness were also obtained for estimation of brain atrophy and for spatial normalization of images. T1-weighted images with no gadolinium contrast were used to identify and quantify T1-hypointense lesions. The entire MRI protocol was completed in less than one hour.
The clinical interpretation of the NP test results for each individual patient was based on an integrated approach which takes into account standard test scores consistent with brain dysfunction, test score patterns, and the qualitative aspects of the examination. Based on an extensive assessment of executive and memory functions, CI was defined as patterns of impairment in two or more tests in comparison with established normative data. Individual test results were classified as non-impaired if the standard score did not deviate from the normative data. Borderline impairment was classified as below 1 standard deviation (SD) from the normative data. Mild impairment was classified as 1.5 SD below the normative data. Moderate impairment was classified as 2 SD below the mean. The specific classification of each patient was made by a board-certified neuropsychologist with extensive experience in the evaluation of cognitive functions in patients with MS. Since CI in MS is generally not homogeneous and there is great variability from patient to patient, the neuropsychologist used his clinical judgment in classifying each patient following the criteria established. Individual results were classified on a 4-point scale (0, 1, 2, 3) where zero indicates nonimpaired (normal), “1” represents borderline, “2” represents mild, and “3” represents moderate CI.
Each patient underwent an MRI of the brain according to a protocol that included standard T1 and T2 weighted scans and two optimized sequences for detection of CL; DIR, and PSIR, for acquisition parameters please see Table 2.
|Sequence||Â Â Â Â Plane||TR msec||TE msec||TI msec||Image matrix||FOV mm||Slice mm||SENSE|
Table 2: Image acquisition parameters for MRI pulse sequences in the MS imaging protocol.
Quantitative MRI Analysis
Image analysis, including segmentation for tissue quantization was performed using integrated operator assisted automated image analysis (MRI-AP)  and database management (CTS) software packages developed at our institution. In brief, all images acquired in different series (FLAIR, dual echo, T1-images etc.) were retrospectively aligned. Images were stripped of the extra-meningeal tissues, filtered using the anisotropic diffusion filter, corrected for the bias field, and intensity normalized . Segmentation of GM, WM, and T2-hyperintense lesion volume were based on the dual echo and FLAIR, images using the hidden Markov random field expectationmaximization (HMRF-EM) algorithm and Parzen window classification .
The measure of whole brain atrophy used was nCSF . T1- hypointense lesions were automatically identified and quantified using the procedure described by Datta et al., 2006 . BOD was calculated as the sum of T2-hyperintense and T1-hypointense component lesion volumes, obtained from tissue segmentation (Figure 1).
CL were identified on DIR and validated on PSIR as previously detailed . Lesions were classified using DIR/PSIR as (a) purely intracortical (IC, total confinement within the cortical ribbon) and (b) mixed (MX, originating in the cortex but with at least 25% subcortical extension); for the purpose of this analysis both types (IC and MX) were considered cortical. Lesion identification and classification was done by 2 experienced raters (FN and AP) by consensus and without knowledge of the NP test results.
Statistical analysis/Composite Z-score calculation
Individual Z-scores for each of the measures CL, BOD (T2+T1), and nCSF were computed by subtracting the sample mean of the measure from the original score and dividing it by its sample standard deviation. The composite z-score Z3 was then calculated as the sum of the three individual scores: Z3=zBOD+znCSF+zCL.
Factor analysis of the three Z-scores was performed to justify equal weights used in the composite score. The factor loadings from factor analysis were 0.66, 0.63, and 0.50 for the standardized variables zCL, znCSF, and zBOD, respectively. The similarity in size of the factor loadings indicates that equal weighs are reasonable for these three variables in the Z3 composite score. Based on our factor analysis, the composite score accounts for about 91% of the variation in these variables. The outcome variable CI is a measure of the severity or degree of disease and consists of the categories non-impaired, borderline, mild, and moderate as described earlier. In our analyses we treated CI as an ordinal variable by using ordinal logistic regression. Initially, univariable ordinal logistic regression was carried out to determine which variables were associated with CI. Specifically, the demographic variables gender and age, the MRI-based metrics CL, nCSF, and BOD, and the composite score Z3, were individually included in the logistic models as the independent variable. Multivariable ordinal logistic regression models were also fit to control for potential confounding due to demographic variables age and gender. For both univariable and multivariable ordinal logistic regression models, proportional odds were assumed. Statistical analysis was performed using the SAS 9.3 statistical software (SAS Inc., Cary, NC).
Of the 33 patients, 24.2 % (n=8) were found to be non-impaired (normal), 24.2% (n=8) were found to be borderline, and 51.5 % were found to be in the mild (n=10) and moderate (n=7) range of impairment (30.3% and 21.2%, respectively). Univariable ordinal logistic regression models showed that the individual variables associated with CI were age (p=0.030), BOD (p=0.037) and the composite score Z3 (p=0.052) the latter marginally significant . For the association between the composite score Z3 and CI, a unit increase in Z3 translates to an odds increase of 1.352 of having greater CI. The associations of CI to gender, CL, and nCSF were not significant (all p>0.100). Details regarding measures of associations are summarized in Table 3.
The validity of the proportional odds assumption was tested and confirmed for all univariable and multivariable models at 5% level of significance.
|Independent Variable||Â ORa||95% Confidence Interval||P-value|
|Gender (Male as reference)||0.944||(0.250, 3.573)||0.933|
|aUnadjusted Odds Ratio (OR) *Significant at 5% level|
Table 3: Factors associated with the Outcome Variable CI based on
Univariable Ordinal Logistic Regression Models.
After adjusting for age, the composite score Z3 was significantly associated with CI (OR=1.443, 95% Confidence Interval: 1.048-1.987, p=0.024). This association was slightly stronger than that of any of the individual measures, of which only BOD was significant (OR=1.064, 95% Confidence Interval: 1.008-1.123, p=0.025), additional details are provided in Table 4.
|Outcome Variable||Independent Variable (Z-score)||Â ORa||95% Confidence Interval||Â P-value|
|aAge-adjusted OR *Significant at 5% level|
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