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Journal of the Neurological S

Editorial

bImportance samplingQ: A strategy to overcome

the clinical/MRI paradox in MS?

The pathology of multiple sclerosis (MS) is character-

ized by the formation of macroscopic, discrete foci of

tissue damage in the central nervous system. These lesions

are readily seen on T2-weighted MRI scans, thus making

conventional MRI an extremely sensitive tool to diagnose

MS and to monitor its evolution [1]. Nevertheless, a

discrepancy exists between the clinical and the neuro-

imaging aspects of MS, indicating that MRI-visible

damage is not sufficient to explain the entire spectrum of

the clinical manifestations of the disease. The possible

explanations for this bclinical/MRI paradoxQ include, on

the one hand, the well known limitations of conventional

MRI, i.e., its inability to quantify and characterize MS-

related damage occurring within and outside T2-visible

lesions [2], and, on the other, the low reliability of the

expanded disability status scale (EDSS) scale [3], which,

however, still represents the most frequently used tool to

quantify the severity of neurological impairment and

disability in MS patients. Thus, it sounds conceivable that

the best strategy to overcome this paradox would consist

of increasing the specificity of both MRI-derived and

clinical measures.

Diffusion MRI has the potential to overcome the

aforementioned limitations of conventional imaging, by

providing in vivo quantitative information about the

structural characteristics of biological tissues. Measures

of diffusion well reflect the structural properties of brain

white and gray matter, as well as their changes due to

pathological features [4]. Since the free motion of water

is restricted by layers of the myelin sheath and a higher

diffusivity is generally measured along axonal fibers than

perpendicular to them, MS-related demyelination and

axonal loss may lead to increased water diffusivity and

reduced anisotropy. Several pieces of evidence suggest

that diffusion MRI is sensitive to MS damage and able to

detect its evolution over relatively short periods of time,

leading to improved correlations with clinical findings

[5]. Recently, several methods have been developed to

investigate the anatomical connections between different

0022-510X/$ - see front matter D 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.jns.2005.06.002

brain regions which are based on the directional

information provided by the proton self-diffusion mea-

sured with diffusion tensor (DT) MRI [6–8]. Diffusion-

based tractography may further increase the specificity of

DT MRI findings by correlating measures of anisotropy

along the tractography-derived white matter tracts with

clinical disability. Wilson et al. [8] investigated patients

with relapsing–remitting (RR) MS using DT MRI and a

tractography algorithm, which mapped the pyramidal

tracts by following a trajectory based upon the principal

diffusion direction in each adjacent voxel. Results showed

that the relative anisotropy and a novel measure, which

was derived from the compounded relative anisotropy

along tractography-derived pyramidal tracts, were lower

in patients and correlated with the EDSS and the

pyramidal functional system scores. Likewise, in another

preliminary study Tench et al. [7] automatically identified

voxels from the same tract based on the similarity of

trajectory path shapes. Specifically, the corpus callosum

and pyramidal tracts were mapped by this method and

the average diffusion coefficient (ADC) was measured.

The ADC was significantly higher in patients than in

controls, and higher in the corpus callosum than in the

pyramidal tracts for both groups. In a more recent study

using an ad hoc postprocessing technique for DT fiber

tracking of the pyramidal tracts in patients at the earliest

clinical stage of MS, a regional increase of average

diffusivity was correlated with the presence of motor

impairment [9].

Against this background, the results of the study by

Lin et al. [10] support the notion that, thanks to the

application of DT tractography, the strategy of

bimportance samplingQ in MS enables us to quantify in

vivo the severity of pathological features related to

specific clinical impairment. In patients with RRMS,

Lin et al. [10] mapped the pyramidal tracts and the

corpus callosum using DT tractography and correlated the

ADC values, as well as the MRI-visible lesion burden, in

these regions with clinical measures thought to specifi-

ciences 237 (2005) 1–3

Editorial2

cally reflect their functioning. These measures were the

patients’ scores of pyramidal functional system (FSS) and

paced auditory serial addition test (PASAT), the latter

being an index of short-term memory and sustained

attention. Correlation analysis showed that ADC of the

pyramidal tracts explained about 25% of the pyramidal

FSS variance, while ADC of the corpus callosum

explained more than 33% of the PASAT score variance.

Interestingly, neither the overall brain nor the pyramidal

tract/corpus callosum T2 lesion loads showed any

correlation with the patients’ clinical status, albeit being

related with ADC values in these two regions. This

confirms that the pathological features occurring outside

conventional MRI-visible abnormalities in MS have an

impact, which is far from being negligible, on the accrual

of neurological disability. However, when interpreting the

results of DT tractography studies, caution has to be

exercised because all methods are limited by the spatial

resolution of DT images. Crossing and looping fibers

within single voxels cannot be resolved easily, and

erroneous connections can be traced. Even if this is

likely to be less than an issue for the pathways studied

by Lin et al. [10], only the development of more

sophisticated and complex techniques for diffusivity

measurement, as well as the increase of DT MRI

resolution, will most probably improve tractography

results in brain regions where there are crossing,

branching or bkissingQ fibers.

Can we say that bimportance samplingQ is the best

strategy to overcome the clinical/MRI paradox of MS?

The results of several recent studies, which were

conducted with a variety of quantitative MR-based

techniques, seem to indicate that the assessment of gray

matter damage, rather than that of the overall brain

disease burden, can provide us with meaningful correlates

of MS patients’ motor and cognitive impairment, as well

as with paraclinical predictors of short-term disease

evolution [11–13]. The quantitative MR-based assessment

of spinal cord damage, which, as expected, has yielded

stronger correlations between neuroimaging aspects and

locomotor impairment in the more disabling forms of

MS, can also be considered an bimportance samplingQstrategy [14,15]. In contrast with this, however, other

methods, such as the histogram analysis of magnetization

transfer or DT MRI, may lack spatial resolution, but

provide us with a more comprehensive assessment of the

actual, bglobalQ damage in a bdiffuseQ disease like MS in

[1]. The latter strategy has, indeed, shown its potential as

a tool to monitor and predict the clinical evolution of MS

[16]. Finally, the presence of cortical reorganization

following MS injury, whose adaptive role in limiting

the clinical deficits has been highlighted by functional

MRI studies [17], also explains why bimportance

samplingQ may not suffice to monitor the progression of

the disease. As a consequence, the complexity of MS

would most probably deserve a multiparametric MRI

approach rather than a generic one based on a single

neuroimaging technique [18]. In this context, the study of

Lin et al. [10] confirms the importance of looking for

more specific and selective clinical and MRI measures of

impairment, which, however, should be viewed as a

component of a more sophisticated approach to the

disease work-up rather than represent a stand-alone

strategy.

References

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[2] Miller DH, Thompson AJ, Filippi M. Magnetic resonance studies of

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[3] Goodkin DE, Cookfair D, Wende K, Bourdette D, Pullicino P,

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Editorial 3

[15] Valsasina P, Rocca MA, Agosta F, Benedetti B, Horsfield MA, Gallo

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Marco Rovaris

Massimo FilippiTNeuroimaging Research Unit,

Department of Neurology,

Scientific Institute and University Ospedale H San Raffaele,

via Olgettina 60-20132 Milan, Italy

Tel./fax: +39 2 26433054.

E-mail address: filippi.massimo@hsr.it.

TCorresponding author.

8 June 2005