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Gray matter relaxation rates show different correlation patterns for cognitive impairment and physical disability in Multiple Sclerosis.1Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy, 2Department of Neurosciences, Reproductive Science and Odontostomatology, University "Federico II", Naples, Italy, 3Biostructure and Bioimaging Institute, National Research Council, Naples, Italy
Synopsis
To assess voxelwise in gray matter the correlation between relaxation rates and both physical and cognitive impairment in MS, R1 and R2 relaxation rate maps from 241 Relapsing-Remitting MS patients were assessed voxelwise for correlation with EDSS and the percentage of impaired cognitive test.
Inverse correlation between EDSS and R2 were detected throughout the brain, while inverse correlations with R1 were mostly limited to perirolandic and supramarginal cortices.
Cognitive impairment correlated negatively with R1, and to a lesser extent with R2, in the limbic system and dorsolateral prefrontal cortices.
Background
Regional gray matter (GM) atrophy1–10 and microstructural alterations (assessed using DTI11, MTR12,13, and R2*14–16), have shown preferential correlations with cognitive scores in specific cortical regions, relevant to the tested cognitive domains, although the independence of these patterns is unknown.On the other hand, physical disability scores correlate with MTR parameters17–24, GM relaxation rates25,26, and DTI-derived measures, when averaged over the whole GM, while previous voxel-based analyses, limited to R2*14 and diffusivity27 measures, failed in localizing these correlations in the cortex.
Aim of this retrospective study was to assess the role of regional microstructural GM changes, as measured by a voxel-based analysis of R1 and R2 relaxation rate maps, in determining physical disability and cognitive impairment in relapsing-remitting multiple sclerosis (RR‑MS), taking also into account the effect of atrophy by covarying at voxel level for the GM concentration.
Methods
MRI studies from 241 patients with clinically definite RR‑MS (141 females; mean age 34.6±7.9 y; disease duration 4,9±5.4 y; EDSS 2.4±0.9, range 1-5), collected as part of patient participation in clinical trials, observational studies or clinical practice, were retrospectively selected based on the availability of an MRI study suitable for multiparametric relaxometric segmentation, along with an EDSS collected within 1 month from the MRI.In 186 patients, the results of a the Rao’s Brief Repeatable Battery (BRB)28 and the Stroop test29, also acquired within one month from the MRI scan, were used to calculate a Cognitive Index (CI, the percentage of impaired tests)26.
MRI studies had been acquired at 1.5T using four different acquisition protocols (Figure 1) each including a single-echo T1-weighted and a double-echo PD/T2-weighted sequence, with equal echo time for T1 and PD volumes, as required by the relaxation rate calculation procedure.
For each study, pre-processing steps included the following:
- Automated rigid body
co-registration30 of the T1w and PD/T2w volumes;
- Calculation of the R1, R2 and
PD maps according to the general formula of the signal intensity in the
transverse steady state31–34;
- Multiparametric segmentation
of the relaxation rate maps into GM, normal and abnormal WM, and CSF, using a
fully automated relaxometric method35,36, which has shown an excellent correlation with the manual
definition of the MS lesions35 and does not need lesion masking or filling37;
- Normalization38 of the GM maps to the MNI space using the SPM GM
template;
- Application of the resulting
normalization matrix to the R1 and R2 maps;
- Smoothing (8mm FWHM) of the
normalized GM, R1 and R2 maps.
Correlations of R1 and R2 with EDSS and CI were then separately assessed voxelwise using the “Biological Parameter Mapping” software package39, including as nuisance covariates MRI protocol, age, sex, disease duration, T2-lesion volume, EDSS (only for correlations with CI), and the GM maps (to remove the effects of the local degree of GM atrophy).
Results
Clusters of significant correlation with EDSS and CI are shown in Figure 2 for R1 and in Figure 3 for R2, superimposed on the average of the normalized GM maps of the 241 patients.When testing correlations between CI and GM relaxation rates, limited clusters of significant inverse correlation with R2 were found bilaterally in the left middle frontal and precentral gyri, and in the parahippocampal GM on the right.
Larger clusters of inverse correlation of CI with R1 were found bilaterally in the middle frontal gyri and mesial temporal GM, as well as in the left midcingulate and in the right medial parieto-occipital cortices.
When EDSS was included in the model, no cluster of correlation between CI and R2 remained significant, while significant clusters of inverse correlation could still be demonstrated for R1 in the precuneus, in dorso-lateral prefrontal regions, and in the midcingulate cortex.
When testing correlations between EDSS and GM relaxation rates, extensive clusters of inverse correlation with R2 values were present bilaterally throughout the brain, the most significant being in the right pre- and post-central gyri.
For R1, clusters of inverse correlation with EDSS were less diffuse, restricted to bilateral perirolandic and supramarginal cortices, with additional clusters in the Cruz I of the right cerebellar hemisphere, and in the posterior part of the left middle temporal gyrus.
Discussion and conclusion
Current results, given the differential effect of pathological changes on R2 (mainly influenced by demyelination, edema and inflammatory lesions presence) and R1 (mainly influenced by neuronal loss)41,42, suggest an extensive correlation in the cortex between microstructural changes and physical disability, with a preferential role of the sensorimotor cortices, where neuronal loss may play a specific role, while neuronal loss in the limbic system and dorsolateral prefrontal cortices appear more strictly related to the cognitive symptoms.Further studies are needed, possibly coupling other measures of microstructural integrity (e.g. MTR and DTI-derived) to relaxation rates, to confirm these findings and to clarify the pathophysiological meaning of these correlations.
Acknowledgements
Funding by the CNR Strategic Project “The Aging: Technological and Molecular Innovations Aiming to Improve the Health of Older Citizens” (http://www.progettoinvecchiamento.it) and by the Italian Ministry for Education, University and Research (Project MOLIM ONCOBRAIN LAB) is gratefully acknowledged.References
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Figures
Figure 1 - MRI Protocols
Conventional Spin-Echo sequences used for MRI relaxometric brain tissue segmentation. WFS: Water-fat shift
Figure 2
Clusters of significant inverse correlation of R1 with EDSS and CI, superimposed on the average of the normalized GM maps of the 241 patients. Z coordinates are in mm in the MNI space.
Figure 3
Clusters of significant inverse correlation of R2 with EDSS and CI, superimposed on the average of the normalized GM maps of the 241 patients. Z coordinates are in mm in the MNI space.