Cognitive Dysfunction in MS: Bridging the Gap Between Neurocognitive Deficits, Neuropsychological Batteries and MRI

Erica Grazioli; Ann E Yeh; Ralph HB Benedict; Joy Parrish; Bianca Weinstock-Guttman


Future Neurology. 2008;3(1):49-59. 

In This Article

Neuroimaging & Cognitive Corrolates

Conventional and nonconventional MRI measures are correlated with NP impairment in MS, including whole-brain atrophy,[44,45] third ventricle size,[46] cortical volume,[47] lesion volume[48] and diffusion entropy.[49] Rao examined three MRI variables in MS patients, including total lesion area, ventricular-brain ratio and size of the corpus callosum. Regression analyses found total lesion area to predict dysfunction in memory, abstract/conceptual reasoning, language and visuospatial problem solving.[48] Another study by Nocentini correlated lesion burden in frontal and non-frontal regions with attention, memory, planning, problem solving and conceptual reasoning.[50] T1 lesion volume (r = 0.32) was weakly associated with PASAT performance in a study by Ciccarelli.[51] Whole-brain white matter volume is also correlated with overall cognitive functioning.[52] Locatelli and colleagues found regional brain parenchymal volume of the frontal lobes was more strongly correlated with performance on the PASAT (r = 0.77), Stroop Test (r = 0.56) and the standard raven progressive matrices (r = 0.33) than measures of whole-brain atrophy.[53] The extent of focal lesions in the frontal lobes has also been shown to be associated with cognitive functioning, particularly the executive functions as measured by the Wisconsin card sorting test.[54]

In studies by Benedict et al., third ventricle width accounted for more variance in cognitive function in MS than the lesion volume measures.[55,56] When third ventricle width was excluded from statistical analysis, brain volume measured as brain parenchymal fraction accounted for most of the variance, suggesting that atrophy measures are more strongly correlated with cognitive impairment than lesion measures, although correlations with lesion measures are also significant.[55,56] It was speculated that the robust relationship with atrophy may have been due to thalamic atrophy, as the thalamic hemispheres border the third ventricle. This hypothesis was recently proven to be accurate. Houthchens et al. found lower thalamic volumes in MS patients than in controls and correlated normalized thalamic volume in MS to cognitive performance using the COWAT, JLO, CVLT, BVMT, PASAT and SDMT (r = 0.506-0.724).[57]

Subcortical deep gray matter nuclei T2 hypointensities were also shown to correlate with measures of cognitive function in MS. Caudate hypointensity correlates with the CVLT-II delayed recall and the BVMT-R delayed recall. T2-hypointensity of the globus pallidus correlates with the COWAT and JLO. Hypointensity on T2-weighted images of both the caudate and globus pallidus is associated with impairment on the SDMT. Gray matter hypointensity on T2 MRI imaging is thought to reflect iron deposition, possibly suggesting a pathological role for iron deposition in the development of cognitive dysfunction in MS.[58]

Significant correlations have also been found between specific grey matter volumes involving the cerebral cortex and cognitive test results, as shown in Table 2 . Left frontal lobe atrophy is associated with impaired auditory/verbal memory on the CVLT-II and impairment on the PASAT, and right frontal lobe atrophy is associated with impaired visual memory on the BVMT-R. SDMT scores were correlated with a number of gray matter regions but most strongly with right superior frontal lobe atrophy. These associations held when accounting for third ventricle width.[59] A recent 2.5-year duration, longitudinal study by Amato et al. found that neocortical volume loss was significantly associated with worsening performance over time on the Rao BRBNT in MS. No correlation was demonstrated with total brain or T2 lesion volumes.[60]

Nonconventional MRI measures, such as magnetization transfer ratio (MTR) and diffusion imaging, may have the potential for higher pathologic specificity. Low MTRs indicate a reduced ability for the molecules of the brain to exchange energy with water molecules. Decreased MTR is found not only in the areas identified as abnormal in the conventional MRI, but also in the so-called normal appearing white matter in MS patients, possibly reflecting microscopic damage to myelin and/or axons.[61] Scores on the PASAT, Stroop test and verbal fluency test have been correlated with MTR.[62]

DWI measures the mobility of water in tissues, thereby providing information about the orientation and geometry. The diffusion of water is typically reduced in organized tissues such as the brain's white and gray matter. Diffusivity in these tissues is affected by the pathological processes of demyelination and neurodegeneration in MS. Entropy is a diffusion calculation that can be thought of as a measure of disorganization of tissue. Entropy values are lower in normal controls than in all subtypes of MS patients.[63] Significant correlations exist between diffusion weighted imaging and entropy in MS patients and cognitive impairment in the domains of memory, learning, attention and executive function as assessed by the CVLT-II TL, CVLT-II DR, BVMT-R, PASAT, SDMT, D-KEFS sorting and D-KEFS description. The strongest associations between entropy and performance are on the SDMT, which measures processing speed and working memory.[49]

MRI spectroscopy is a nonconventional MRI technique that noninvasively creates a metabolic map of the brain. A number of studies have demonstrated a reduction in the N-acteyl aspartate/creatine (NAA/Cr) ratio in MS lesions[64,65,66,67] and normal appearing white matter of MS patients.[68] A relationship exists between NAA and cognitive function in MS. MS patients with the lowest frontal lobe NAA/Cr ratios performed significantly worse on the spatial working memory test, suggesting that subtle frontal lobe pathology may contribute to executive function deficits.[69] Left periventricular NAA levels correlate with performance on the verbal selective reminding test and right periventricular NAA levels correlate with the Tower of Hanoi performance, a measure of executive function.[70]

Functional MRI (fMRI) is also beginning to be explored in MS. The cortical activation patterns of MS patients undergoing the paced visual serial addition test (PVSAT), a visual analogue to the PASAT, were recorded during fMRI. In MS patients, the right frontal cortex (Brodmann areas 6, 8 and 9) was activated more than in controls. In addition, the left hemispheric Brodmann area 39 was activated. No differences were seen between MS patients and controls on the MS functional composite (MSFC) or PASAT.[71] An additional study found more activity in the left medial prefrontal region in MS patients than controls, with both groups demonstrating comparable performance on the Stroop test.[72] The different patterns of activation in MS patients with intact performance on cognitive testing compared with controls may be interpreted as an expression of neural plasticity in MS. However, in a study in which MS patients scored significantly worse on cognitive tests than controls, no significant differences in fMRI areas of activation were observed. This may suggest that adaptive mechanisms may be exhausted in later disease ( Table 3 lists imaging studies and their cognitive correlates).[73]


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