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Advanced MRI techniques and cognitive impairment in multiple sclerosis

Advanced MRI techniques and cognitive impairment in multiple sclerosis
  • Neurology

Maria A. Rocca MD.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, and Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Cognitive impairment affects a large proportion of patients with multiple sclerosis (MS) involving significant levels of attention, information processing, executive functions, memory and visuo-spatial abilities.(1, 2) Cognitive dysfunction in MS patients impacts on a range of activities such as work, driving, social integration, and adherence to medication regimens. Improving knowledge of the pathophysiology of cognitive impairment in MS and of the mechanisms responsible for its evolution over time might contribute to development of better outcome measures and targets for innovative treatment strategies. With their ability to detect MS-related abnormalities, magnetic resonance imaging (MRI) techniques are a valuable tool to achieve these goals.

Focal lesions and cognitive impairment

Seminal studies of MS patients found only a modest association between T2-lesion burden of the whole brain or in specific sites of the cerebral white matter (WM) and neuropsychological test performance.(3)

The use of double inversion recovery (DIR) sequence has enabled detection of a portion of MS lesions located in the gray matter.(4)DIR imaging showed that cortical lesions (CLs) develop early in MS and increase in number and size with progression of the disease.(5) Using DIR, it was also found that CLs are very important in explaining both locomotor disability and cognitive impairment.(6) CLs are sparse in benign (B) forms of the disease(7) and in children with MS.(8)

Damage to the normal-appearing WM and GM and cognitive impairment

Abnormalities of the normal-appearing (NA) WM and GM injury are important in determining cognitive impairment in patients with MS, in addition to the role played by WM demyelinating lesions. The detection of NAWM abnormalities has been hitherto easier than that in GM through the use of quantitative MRI techniques such as magnetization transfer (MT) MRI, diffusion tensor (DT) MRI, and proton MR spectroscopy (1H-MRS).9 More recently, using high-field scanners, our ability to detect and quantify such abnormalities has improved further.

Changes in MT ratio (MTR), a measure based on the exchange of magnetization between free and bound protons and principally dependent on myelin content, have been found to correlate with overall cognitive performance better than lesion metrics or atrophy.(10) These correlations have been reported when whole brain MTR has been measured or when a region of interest based approach to sample NAWM has been used. More recently, reduction of cortical MTR(11) has also been found to correlate with measures of cognition in patients with benign MS (BMS). Using a voxel-based method, significant correlations were found between decrease of MTR value in specific cortical regions and PASAT performance in patients with primary progressive MS.(12) In addition, global MTR changes of the NAWM at illness onset predicted impairment in executive function in patients with RRMS when cognitively examined several years later.(13)

Diffusion weighted MRI abnormalities in NAWM have been found to predict speed of information deficits. DT MRI quantities from the NAWM and GM were similar between patients with BMS and cognitive impairment and those with SPMS.(14) Another DT MRI study(15) showed that corpus callosum (CC) damage, in terms of both focal lesions and diffuse injury, was more pronounced in BMS patients with cognitive impairment in comparison with those without. Using tract- based spatial statistics (TBSS), two recent studies(16, 17) have found correlations between impaired attention, working memory and speed of information processing and decreased FA in the CC and other tracts mainly connecting prefrontal cortical regions. Tract abnormalities overlapped only in part with lesion location highlighting the importance of lesion-independent NAWM abnormalities in cognition.

Decreases in N-acetyl-aspartate (NAA), a marker of neuronal and axonal viability, measured in frontal regions has been found to correlate with performance on tests of executive function,(18) while decreased NAA in the pontine locus coeruleus correlates with attentional measures.(19) It has also been recently reported that decreased NAA may be linked to carrier status for the HLA allele DRB1*1501 and this may, in turn, explain the greater illness severity and cognitive impairment in patients with this genotype.(20) Increases in myo-inositol (a glial and inflammatory marker) in the three years after a clinically isolated syndrome (CIS) has been found to predict poor executive function when patients were cognitively examined years later suggesting that early and widespread inflammatory damage to the NAWM may play an important role in cognition.(21)

Cortical reorganization

Using functional magnetic resonance imaging (fMRI), modifications of brain activation have been demonstrated consistently in all MS phenotypes, with different experimental paradigms. fMRI abnormalities in MS patients occur relatively early in the disease, even in patients with CIS and pediatric MS,(22) and tend to vary over the course of the disease, not only after an acute relapse, but also in clinically stable patients.(23)

The correlations found between functional and structural MRI abnormalities in MS patients have suggested that increased recruitment of “critical” cortical networks may help to limit the functional impact of MS-related damage. However, increased cortical recruitment cannot continue indefinitely and a lack or exhaustion of the “classical” adaptive mechanisms has been suggested as a possible factor responsible for an unfavorable clinical evolution (as it is the case of patients with the progressive forms of the disease),(24) accelerated cognitive decline(25, 26) and development of specific disease-related symptoms, such as fatigue.(27) More recently, the analysis of brain function at rest has shown a reduced activity of the anterior regions of the default-mode network in patients with progressive MS, which correlates with cognitive impairment.(28)


The application of conventional and quantitative MRI techniques has contributed to improve the understanding of the mechanisms responsible for the development of cognitive deficits in patients with MS. Available data suggest that focal WM lesions do play a role, but the overall effect of T2-visible lesions on MS related cognitive impairment is limited. The location of lesions in critical brain areas appears to be important and, in this context, the improved capability to detect cortical lesions is likely to provide additional pieces of information central to this issue. Irreversible tissue loss, measured in terms of global and regional atrophy, is robustly associated with cognitive deficits. The impact of WM damage on cognition may be mediated by a disruption of crucial tracts or interference with specific functional nodes. In addition to all these aspects, other components of MS pathology, such as diffuse damage to the NAWM and GM and the strength of functional connections between distant functional areas are likely to play a role in determining patients’ cognitive profile. Indeed, the application of fMRI demonstrated different patterns of cortical activations according to the disease phenotype, which are likely to have an adaptive role, at least in some stages of the disease.



[1]  Amato MP, Zipoli V, Portaccio E. Multiple sclerosis-related cognitive changes: a review of cross-sectional and longitudinal studies. J Neurol Sci 2006;245:41-46.

[2]  Chiaravalloti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurol 2008;7:1139-1151.

[3]  Rovaris M, Comi G, Filippi M. MRI markers of destructive pathology in multiple sclerosis-related cognitive dysfunction. J Neurol Sci 2006;245:111-116.

[4]  Geurts JJ, Bo L, Pouwels PJ, Castelijns JA, Polman CH, Barkhof F. Cortical lesions in multiple sclerosis: combined postmortem MR imaging and histopathology. AJNR Am J Neuroradiol 2005;26:572-577.

[5]  Calabrese M, Rocca M, Atzori M, et al. A three-year MRI study of cortical lesions in relapse-onset multiple sclerosis. Ann Neurol 2010;67:376-383.

[6]  Calabrese M, Agosta F, Rinaldi F, et al. Cortical lesions and atrophy associated with cognitive impairment in relapsing-remitting multiple sclerosis. Arch Neurol 2009;66:1144-1150.

[7]  Calabrese M, Filippi M, Rovaris M, et al. Evidence for relative cortical sparing in benign multiple sclerosis: a longitudinal magnetic resonance imaging study. Mult Scler 2009;15:36-41.

[8]  Absinta M, Rocca MA, Moiola L, et al. Cortical lesions in children with multiple sclerosis. Neurology 2011;76:910-913.

[9]  Bakshi R, Thompson AJ, Rocca MA, et al. MRI in multiple sclerosis: current status and future prospects. Lancet Neurol 2008;7:615-625.

[10]  Filippi M, Tortorella C, Rovaris M, et al. Changes in the normal appearing brain tissue and cognitive impairment in multiple sclerosis. J Neurol Neurosurg Psychiatry 2000;68:157-161.

[11]  Amato MP, Portaccio E, Stromillo ML, et al. Cognitive assessment and quantitative magnetic resonance metrics can help to identify benign multiple sclerosis. Neurology 2008;71:632-638.

[12]  Khaleeli Z, Cercignani M, Audoin B, Ciccarelli O, Miller DH, Thompson AJ. Localized grey matter damage in early primary progressive multiple sclerosis contributes to disability. Neuroimage 2007;37:253-261.

[13]  Summers M, Fisniku L, Anderson V, Miller D, Cipolotti L, Ron M. Cognitive impairment in relapsing-remitting multiple sclerosis can be predicted by imaging performed several years earlier. Mult Scler 2008;14:197-204.

[14]  Rovaris M, Riccitelli G, Judica E, et al. Cognitive impairment and structural brain damage in benign multiple sclerosis. Neurology 2008;71:1521-1526.

[15]  Mesaros S, Rocca MA, Riccitelli G, et al. Corpus callosum damage and cognitive dysfunction in benign MS. Hum Brain Mapp 2009;30:2656-2666.

[16]  Roosendaal SD, Geurts JJ, Vrenken H, et al. Regional DTI differences in multiple sclerosis patients. Neuroimage 2009;44:1397-1403.

[17]  Dineen RA, Vilisaar J, Hlinka J, et al. Disconnection as a mechanism for cognitive dysfunction in multiple sclerosis. Brain 2009;132:239-249.

[18]  Staffen W, Zauner H, Mair A, et al. Magnetic resonance spectroscopy of memory and frontal brain region in early multiple sclerosis. J Neuropsychiatry Clin Neurosci 2005;17:357-363.

[19]  Gadea M, Martinez-Bisbal MC, Marti-Bonmati L, et al. Spectroscopic axonal damage of the right locus coeruleus relates to selective attention impairment in early stage relapsing-remitting multiple sclerosis. Brain 2004;127:89-98.

[20]  Okuda DT, Srinivasan R, Oksenberg JR, et al. Genotype-Phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures. Brain 2009;132:250-259.

[21]  Summers M, Swanton J, Fernando K, et al. Cognitive impairment in multiple sclerosis can be predicted by imaging early in the disease. J Neurol Neurosurg Psychiatry 2008;79:955-958.

[22]  Rocca MA, Absinta M, Moiola L, et al. Functional and structural connectivity of the motor network in pediatric and adult-onset relapsing-remitting multiple sclerosis. Radiology 2010;254:541-550.

[23]  Filippi M, Rocca MA. Functional MR imaging in multiple sclerosis. Neuroimaging Clin N Am 2009;19:59-70.

[24]  Filippi M, Rocca MA, Falini A, et al. Correlations between structural CNS damage and functional MRI changes in primary progressive MS. Neuroimage 2002;15:537-546.

[25]  Penner IK, Rausch M, Kappos L, Opwis K, Radu EW. Analysis of impairment related functional architecture in MS patients during performance of different attention tasks. J Neurol 2003;250:461-472.

[26]  Rocca MA, Riccitelli G, Rodegher M, et al. Functional MR Imaging Correlates of Neuropsychological Impairment in Primary-Progressive Multiple Sclerosis. AJNR Am J Neuroradiol 2010;31:1240-1246.

[27]  Rocca MA, Agosta F, Colombo B, et al. fMRI changes in relapsing-remitting multiple sclerosis patients complaining of fatigue after IFNbeta-1a injection. Hum Brain Mapp 2007;28:373-382.

[28]  Rocca MA, Valsasina P, Absinta M, et al. Default-mode network dysfunction and cognitive impairment in progressive MS. Neurology 2010;74:1252-1259.

Terms of use

This is a copyrighted resource for the sole purpose of education. Resource may be used for classroom training only and must remain as is, including the branding and EXCEMED logo. It is backed by a publishing license, signed by the author.

Milan, Italy
Oct 30 - 31, 2014
Target audience
Clinicians and scientists currently involved in MS and/or NMO management., Radiologists
by Excemed

MS Alumni

The MS Alumni programme is an educational initiative of EXCEMED that is intended to provide ongoing support for young physicians and specialists in neurology.