Mesaros et al.
Neuropsychological evaluation. The Rao's Brief Repeatable Battery (RBRB)e1 consists of five tests: a) Selective Reminding test (SRT) (including Immediate Recall: Long-Term Storage [SRT-L] and Consistent Long-Term Retrieval [SRT-C]; and Delayed Recall [SRT-D]) for verbal learning/memory and delayed recall assessment; b) The 10/36 Spatial Recall Test (SPART) for visuospatial memory, which included the immediate recall (SPART-T) and delayed recall (SPART-D) assessment; c) Symbol Digit Modalities Test (SDMT), which examines visual processing speed and sustained attention; d) Paced Auditory Serial Addition Test (3” version) (PASAT 3), which measures sustained and divided attention, working memory and information processing speed; and e) the World List Generation (WLG) for verbal fluency on semantic stimulus testing. We used Serbian translations of the neuropsychological tests included in the BRBN. The BRBN tests were translated and culturally adapted into Serbian by two neurologists (JD, SM) and two professional English-Serbian translators with experience in healthcare terminology. A standard back-translation methodology for the production of the Serbian version was used.
The CII was obtained by a grading systeme2 applied to each patient score in every cognitive test, dependent on the number of SDs below the mean normative value.e3 For each test, a score of 0 was assigned if a patient scored at or above the control mean. A score of 1 was assigned if a patient scored below the control mean but within 1 SD of that mean. A score of 2 was assigned if the patient achieved a score ≥1 SD below the control mean. All scores, calculated depending on patient’s performance at the different neuropsychological tests, were summed up. In this way, the CII, a global measure of cognitive dysfunction for each patient, was obtained.
MRI acquisition. Using a 1.5 Tesla system (Avanto, Siemens, Erlangen, Germany) the following images of the brain were acquired from all subjects: a) axial dual-echo (DE) turbo spin echo (TSE) (repetition time [TR]=2650 ms, echo time [TE]=28-113 ms, echo train length [ETL]=5, number of slices=50, slice thickness=2.5 mm with no gap, matrix size=512x512, field of view [FOV]=250x250 mm2), b) axial pulsed-gradient spin-echo (PGSE) echo-planar (TR=6400 ms, TE=93 ms, number of slices=40, slice thickness=2.5 mm with no gap, matrix size=128x128, FOV=240x240 mm2), with diffusion-encoding gradients applied in 12 non collinear directions (b factor=1000sec/mm2, number of averages=8), and c) sagittal three-dimensional (3D) T1-weighted magnetization prepared rapid acquisition gradient echo (MP-RAGE) (TR=2000 ms, TE=3.93 ms, inversion time [TI]=1100 ms, number of slices=208, slice thickness=0.9 mm, matrix size=256x224, FOV=236x270 mm2). All scans were positioned following published guidelines.e4
MRI post-processing. T2 lesion load (LL) was measured using a local thresholding segmentation technique (Jim 5, Xinapse Systems Ltd., Northants, UK). On the MP-RAGE scans, normalized brain volume (NBV), GM volume (GMV), and WM volume (WMV) were measured using the cross-sectional version of the Structural Imaging Evaluation of Normalized Atrophy (SIENAx) software.e5
DT images were first corrected for distortion induced by eddy currents, then the DT was estimated by linear regression, and mean diffusivity (MD) and fractional anisotropy (FA) maps derived.e6 MD histograms of the NAWM and GM and FA histograms of the NAWM were produced as described elsewhere.e7 For each histogram, the average MD and FA were calculated.
An FA atlas was created based on data from 24 healthy subjects (15 women and 9 men, mean age=31.8 years, range=21-40), with no previous history of neurological dysfunction (reference group).e8 Then, using DT MRI tractography, probability maps of WM tracts serving different cognitive functions, including the CC, IFOF, UF, cingulum, arcuate fasciculus, inferior longitudinal fasciculus, SCP, and MCP were produced. The sTCP and OR were also studied as “control” WM tracts, since they are thought not to be involved directly in cognition. The sTCP included somatosensory fibers from the internal caspule to the postcentral gyrus.e9
The trajectories of the different tracts were obtained by placing regions-of-interest (ROIs) believed to contain sections of the desired WM tracts on both FA and colour coded maps of the principal diffusion direction, as described elsewhere.e8, e10 Although the fornix has a role in cognitive performance,e11 it was excluded from the analysis due to its small size and the fact that diffusivity parameters for the fornix may be altered by partial volume effects from the surrounding cerebrospinal fluid.
DT-MRI derived maps of NAWM and T2-visible lesions were non-linearly transformede12 to the reference FA atlas, using the FA maps to calculate the transformations. These transformations were also applied to the masks of each tract from the reference group to obtain, after averaging, probability maps of the tracts. Tract probability maps were masked with the skeletonized FA atlas (using FSL software) to limit the analysis to their core and minimize partial volume effects. The resulting maps of the tracts were applied to the non-linearly transformed patients’ maps to calculate average MD and FA of NAWM. T2 LV and lesion diffusivity measures inside each tract were also calculated using non-skeletonized maps.e8 For WM tracts with a bilateral location in the brain, the average of the MD and FA values measured in the right and left hemisphere entered the analysis.
e1. Rao SMtCFSGotNMSS, ed. A manual for the Brief Repeatable Battery of Neuropsychological Tests in multiple sclerosis. Milwaukee, WI: Medical Collage of Wisconsin, 1990.
e2. Camp SJ, Stevenson VL, Thompson AJ, et al. Cognitive function in primary progressive and transitional progressive multiple sclerosis: a controlled study with MRI correlates. Brain 1999;122 ( Pt 7):1341-1348.
e3. Boringa JB, Lazeron RH, Reuling IE, et al. The brief repeatable battery of neuropsychological tests: normative values allow application in multiple sclerosis clinical practice. Mult Scler 2001;7:263-267.
e4. Miller DH, Barkhof F, Berry I, Kappos L, Scotti G, Thompson AJ. Magnetic resonance imaging in monitoring the treatment of multiple sclerosis: concerted action guidelines. J Neurol Neurosurg Psychiatry 1991;54:683-688.
e5. Smith SM, De Stefano N, Jenkinson M, Matthews PM. Normalized accurate measurement of longitudinal brain change. J Comput Assist Tomogr 2001;25:466-475.
e6. Basser PJ, Pierpaoli C. Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. J Magn Reson B 1996;111:209-219.
e7. Ceccarelli A, Rocca MA, Falini A, et al. Normal-appearing white and grey matter damage in MS. A volumetric and diffusion tensor MRI study at 3.0 Tesla. J Neurol 2007;254:513-518.
e8. Pagani E, Filippi M, Rocca MA, Horsfield MA. A method for obtaining tract-specific diffusion tensor MRI measurements in the presence of disease: application to patients with clinically isolated syndromes suggestive of multiple sclerosis. Neuroimage 2005;26:258-265.
e9. Yamada K, Nagakane Y, Yoshikawa K, et al. Somatotopic organization of thalamocortical projection fibers as assessed with MR tractography. Radiology 2007;242:840-845.
e10. Rocca MA, Pagani E, Absinta M, et al. Altered functional and structural connectivities in patients with MS: a 3-T study. Neurology 2007;69:2136-2145.
e11. Copenhaver BR, Rabin LA, Saykin AJ, et al. The fornix and mammillary bodies in older adults with Alzheimer's disease, mild cognitive impairment, and cognitive complaints: a volumetric MRI study. Psychiatry Res 2006;147:93-103.
e12. Rohde GK, Aldroubi A, Dawant BM. The adaptive bases algorithm for intensity-based nonrigid image registration. IEEE Trans Med Imaging 2003;22:1470-1479.
List of abbreviations:
AL: average lesion, B: benign, C-index: classification index, CC: corpus callosum, CII: cognitive impairment index, CP: cognitively preserved, DE: dual echo, DT: diffusion tensor, EDSS: expanded disability status scale, ETL: echo train length, FA: fractional anisotropy, FOV: field of view, GM: gray matter, GMV: gray matter volume, LL: lesion load, MCP: middle cerebellar peduncle, MD: mean diffusivity, MDS: multi-dimensional scaling, MP-RAGE: magnetization prepared rapid acquisition gradient echo, MS: multiple sclerosis, NAWM: normal-appearing white matter, NBV: normalized brain volume, OR: optic radiation, PASAT: paced auditory serial addition test, PGSE: pulsed-gradient spin-echo echo-planar, PP: primary progressive, RBRB: Rao's brief repeatable battery, RF:random forest, ROIs: regions-of-interest, RR: relapsing remitting, SCP: superior cerebellar peduncle, SD: standard deviation, SDMT: symbol digit modalities test, SPART: 10/36 spatial recall test, SPART-D: 10/36 spatial recall test-delayed recall, SPART-T: 10/36 spatial recall test- immediate recall, SRCC: Spearman rank correlation coefficient, SRT: selective reminding test, SRT-C: selective reminding test-consistent long-term retrieval, SRT-D: selective reminding test-delayed recall, SRT-L: selective reminding test-long-term storage, sTCP: sensory thalamocortical projections, SIENAx: structural image evaluation of normalized atrophy, IFOF: inferior fronto-occipital fasciculus, SP: secondary progressive, TBSS: tract-based spatial statistics, TE: echo time, TI: inversion time, TR: repetition time, TSE: turbo spin echo, UF: uncinate fasciculus, WLG: world list generation, WM: white matter, WMV: white matter volume.