Alice Favaretto

Cortical lesions and atrophy associated with cognitive impairment in relapsing-remitting multiple sclerosis.

BACKGROUND Neuropsychological deficits in patients with multiple sclerosis (MS) have been shown to be associated with the major pathological substrates of the disease, ie, inflammatory demyelination and neurodegeneration. Double inversion recovery sequences allow cortical lesions (CLs) to be detected in the brain of patients with MS. Modern postprocessing techniques allow cortical atrophy to be assessed reliably. OBJECTIVE To investigate the contribution of cortical gray matter lesions and tissue loss to cognitive impairment in patients with relapsing-remitting MS. DESIGN Cross-sectional survey. SETTING Referral, hospital-based MS clinic. Patients Seventy patients with relapsing-remitting MS. MAIN OUTCOME MEASURES Neuropsychological performance was tested using the Rao Brief Repeatable Battery of Neuropsychological Tests, version A. Patients who scored 2 SDs below the mean normative values on at least 1 test of the Rao Brief Repeatable Battery of Neuropsychological Tests, version A, were considered to be cognitively impaired. A composite cognitive score (the cognitive impairment index) was computed. T2 hyperintense white matter lesion volume, contrast-enhancing lesion number, CL number and volume, normalized brain volume, and normalized neocortical gray matter volume were also assessed. RESULTS Twenty-four patients with relapsing-remitting MS (34.3%) were classified as cognitively impaired. T2 hyperintense white matter lesion volume and contrast-enhancing lesion number were not different between cognitively impaired and cognitively unimpaired patients. Cognitively impaired patients had a higher CL number (P = .01) and volume (P < .001) and decreased normalized brain volume (P = .02) and normalized neocortical gray matter volume (P = .002) when compared with cognitively unimpaired patients. Multivariate analysis revealed that age (beta = 0.228; P = .02), CL volume (beta = 0.452; P < .001), and normalized neocortical gray matter volume (beta = 0.349; P < .001) were independent predictors of the cognitive impairment index (r(2) = 0.55; F = 23.903; P < .001). CONCLUSION The burden of CLs and tissue loss are among the major structural changes associated with cognitive impairment in relapsing-remitting MS.

A 3-year magnetic resonance imaging study of cortical lesions in relapse-onset multiple sclerosis.

We assessed the occurrence, extent, and frequency of formation of cortical lesions (CLs) in patients with relapsing‐remitting (RR) and secondary progressive (SP) multiple sclerosis (MS), and their relationship with cortical atrophy and disability progression.

The predictive value of gray matter atrophy in clinically isolated syndromes

Background: Although gray matter (GM) atrophy is recognized as a common feature of multiple sclerosis (MS), conflicting results have been obtained in patients with clinically isolated syndromes (CIS). Methodologic and clinical constraints may take account for literature discrepancies. Methods: A total of 105 patients presenting with CIS and 42 normal controls (NC) were studied. At baseline, 65/105 patients with CIS met the criterion of dissemination in space of lesions (DIS+). All patients were clinically assessed by means of the Expanded Disability Status Scale every 6 months and underwent MRI evaluation at study entry and then annually for 4 years. Global and regional cortical thickness and deep GM atrophy were assessed using Freesurfer. Results: No significant reduction in GM atrophy was observed between the entire CIS group and the NC, excepting for the cerebellum cortical volume. When the 59 patients with CIS (46 DIS+, 13 DIS−) who converted to MS during the follow-up were compared to the NC, a significant atrophy in the precentral gyrus, superior frontal gyrus, thalamus, and putamen was observed (p ranging from 0.05 to 0.001). The multivariate analysis identified the atrophy of superior frontal gyrus, thalamus, and cerebellum as independent predictors of conversion to MS. CIS with atrophy of such areas had a double risk of conversion compared to DIS+ (odds ratio 9.6 vs 5.0). Conclusion: Selective GM atrophy is relevant in patients with CIS who convert early to MS. The inclusion of GM analysis in the MS diagnostic workup is worthy of further investigation.

Cortical lesion load associates with progression of disability in multiple sclerosis

Cortical inflammatory lesions have been correlated with disability and cortical atrophy in multiple sclerosis. The extent to which cortical lesion load is associated with longer-term physical and cognitive disability in different multiple sclerosis phenotypes has not yet been investigated. Thus, a 5-year prospective longitudinal study was carried on in a large group of patients with multiple sclerosis. Three hundred and twelve consecutive patients suffering from multiple sclerosis (157 relapsing remitting, 35 paediatric, 45 benign, 44 primary progressive and 31 secondary progressive) were enrolled in a 5-year prospective clinical and neuroimaging study. Several magnetic resonance parameters (including cortical lesion number and volume, contrast-enhancing cortical lesions and grey matter atrophy) were analysed to find associations with clinical and cognitive outcomes. Patients with high cortical lesion load had higher Expanded Disability Status Scale increase (median = 1.5; range = 0-3) during the study than both patients with low cortical lesion load (median = 1.0; range = 1-3, P < 0.001) and without cortical lesions (median = 0.5; range = -1 to 2, P < 0.001). Compared with clinically stable patients, 101 (32.4%) patients showing clinical progression at 5 years had the highest rate of cortical lesion accumulation (P < 0.001). Stepwise regression analysis revealed significant and independent contributions from age (β = 0.55), cortical lesion volume (β = 0.58), T(2) white matter lesion volume (β = 0.34) and grey matter fraction (β = 0.42) as predictors (final model with r(2 )= 0.657, P < 0.001) of Expanded Disability Status Scale change. Disease duration (β = 0.52, P < 0.001), cortical lesion volume (β = 0.67, P < 0.001), grey matter fraction (β = 0.56, P < 0.001) and T(2) white matter lesion volume (β = 0.31, P = 0.040) at baseline were found to be independent predictors of cognitive status at the end of the study. While confirming the relevance of cortical pathology in all multiple sclerosis phenotypes, but benign, our study suggests that grey matter and white matter changes in multiple sclerosis occur, at least, partly independently, and that grey matter, more than white matter, damage is associated with physical and cognitive disability progression. Thus, the combination of grey and white matter parameters gives a more comprehensive view of multiple sclerosis pathology and allows a better understanding of the progressive phase of the disease, which, however, seems more related to cortical damage than to subcortical white matter changes.

Basal ganglia and frontal/parietal cortical atrophy is associated with fatigue in relapsing—remitting multiple sclerosis

Background: Fatigue is one of the most frequent symptoms suffered by patients affected by multiple sclerosis. The patho-physiological basis of multiple sclerosis-related fatigue remains to be elucidated. Objective: Our aim was to investigate whether a particular pattern of deep and/or cortical grey matter atrophy is associated with fatigue in patients with multiple sclerosis. Methods: A total of 152 patients with relapsing—remitting multiple sclerosis were evaluated with the Expanded Disability Status Scale, the Fatigue Severity Status Scale (FSS), the Modified Fatigue Impact Scale and the Beck Depression Inventory. The thalamic and basal ganglia volume and the regional cortical thickness were analysed by means of FreeSurfer. Results: Based on Fatigue Severity Status Scale score, patients were divided into fatigued (FSS ≥ 4, 71 patients, 46.6%) and non-fatigued (FSS < 4, 81 patients, 53.4%). A significant atrophy of striatum, thalamus, superior frontal gyrus and inferior parietal gyrus was observed in fatigued patients compared with non-fatigued patients. The cognitive domain of Modified Fatigue Impact Scale significantly correlated with the volume of the striatum and with the cortical thickness of the posterior parietal cortex and middle frontal gyrus (R = 0.51—0.61), while the physical domain of Modified Fatigue Impact Scale significantly correlated with striatum volume and superior frontal gyrus cortical thickness (R = 0.50—0.54). Conclusions: The regional analysis of deep and cortical grey matter atrophy suggests an association between the neurodegenerative process taking place in the striatum—thalamus—frontal cortex pathway and the development of fatigue in relapsing—remitting multiple sclerosis. The inclusion of the posterior parietal cortex as one of the best predictors of the Modified Fatigue Impact Scale cognitive domain suggests the major role of the posterior attentional system in determining cognitive fatigue in relapsing—remitting multiple sclerosis.

Widespread cortical thinning characterizes patients with MS with mild cognitive impairment

Background: Although cognitive dysfunction affects a relevant portion of patients with multiple sclerosis (MS), its pathologic substrate has not been clarified and it does not seem entirely explained by white matter changes. Methods: A total of 100 consecutive patients with relapsing remitting MS (RRMS) and 42 normal controls (NC) were enrolled in the study. Cognitive performance was assessed by Raos Brief Repeatable Battery of Neuropsychological Tests (BRB). Regional cortical thickness (CTh) was evaluated by Freesurfer. Results: Thirty-one patients with RRMS failed 1 or 2 tests of BRB and were considered to have a mild cognitive impairment (mCI-RRMS), while 8 patients failed at least 3 tests and were classified as markedly impaired (sCI-RRMS). The mean CTh of mCI-RRMS and sCI-RRMS group was significantly lower than in NC (p < 0.001) and cognitively normal patients with RRMS (CN-RRMS) (p < 0.001). The regional analysis revealed significant cortical thinning in frontal and temporal regions (frontotemporal thinning) of CN-RRMS compared to NC, while a widespread pattern of cortical thinning was observed in mCI-RRMS and in sCI-RRMS compared to both CN-RRMS and NC. A correlation was observed between cognitive score (CS) and the mean CTh (r = −0.69, p < 0.001) and between CS and CTh of almost all the cortical areas analyzed (r value between −0.20 and −0.65, p < 0.01). A correlation was found between T2-WM-LV and mean CTh (r = −0.31, p = 0.004) or CS (r = 0.21, p = 0.031). The multivariate analysis confirmed a widespread cortical thinning as the best predictor of cognitive impairment. Conclusions: A widespread pattern of cortical thinning characterizes patients with cognitive dysfunction, suggesting such dysfunction as expression of a more aggressive and widespread cortical pathology.

Cortical lesions in primary progressive multiple sclerosis A 2-year longitudinal MR study

Background: In primary progressive multiple sclerosis (PPMS), a discrepancy exists between the modest brain white matter (WM) lesion burden and the severity of neurologic disability. Double-inversion recovery (DIR) sequences have improved MRI sensitivity in the detection of cortical lesions (CLs) in patients with relapsing-onset MS. Objective: This 2-year longitudinal study was designed to assess the frequency, extent, and rate of formation of CLs in PPMS and their relationship with T2 lesion volume (LV), gray matter (GM) atrophy, and disability. Methods: Forty-eight patients with PPMS underwent clinical and magnetic resonance examinations at baseline and after 2 years. The number and volume of CLs, WM T2 LV, and GM fraction (GMf) were assessed at baseline and at follow-up. Results: At baseline, CLs were detected in 81.2% of patients with PPMS. At least one new CL was found in 28 patients during the follow-up. In patients with PPMS, CL and T2 WM LVs increased over the follow-up. At baseline, CL number and volumes were significantly correlated with T2 WM LV, GMf, disease duration, and Expanded Disability Status Scale score, as well as with increasing GM atrophy and disability during the follow-up. A multivariate analysis showed that CL volume at baseline was an independent predictor of percentage GM volume change and disability accumulation during the subsequent 2-year period. Conclusions: Cortical lesions are a frequent finding in primary progressive multiple sclerosis. The extent of such abnormalities is associated with the extent of cortical atrophy and clinical disability, and is able to predict their changes over a medium time period.

Evidence for relative cortical sparing in benign multiple sclerosis: a longitudinal magnetic resonance imaging study

Background Using double inversion recovery (DIR) MRI, cortical lesions can be seen in the brain of patients with multiple sclerosis (MS). The burden of such lesions seems to be well correlated with the severity of MS-related disability. Objective To investigate whether the extent of cortical damage in patients with benign MS (BMS) might contribute to explain their favorable clinical status. Methods Forty-eight patients with BMS (Expanded Disability Status Scale [EDSS] score ≤3.0 and disease duration ≥15 years) and 96 patients with non-disabling, early relapsing–remitting (RR) MS (EDSS score ≤3.0 and disease duration ≤5 years) were studied. Brain MRI, including a DIR and a fluid-attenuated inversion recovery (FLAIR) sequence, was acquired at baseline and after 12 months. On DIR images, intracortical (ICL) and cortical-subcortical lesions (CSL) were identified and their number and volume calculated. Total white matter (WM) lesion volume was quantified on FLAIR images. Results Compared with early RRMS, patients with BMS had lower number of ICL at both study time points (P ≤ 0.001 for both comparisons). At one-year follow-up, a significant increase of ICL and CSL number and total volume was observed only in early patients with RRMS. The number and volume of cortical lesions was not correlated with WM lesion volume. Total ICL number at baseline, total cortical lesion volume at baseline, and total cortical lesion volume change were independent predictors of MS phenotype. Conclusion In patients with BMS, the selective sparing of the cortex from disease-related focal pathology might be one of the factors associated to their favorable clinical status, independently of the (possible) accrual of WM lesions.

No MRI evidence of cortical lesions in neuromyelitis optica

Background: Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease of the CNS in which a pathogenic role of anti-aquaporin-4 (AQP4) antibodies has been suggested. Although AQP4 is expressed in human cortex, recent histologic studies have failed to find any evidence of cortical demyelination in NMO. Objective: To evaluate, in vivo, the occurrence of focal and diffuse cortical pathology in NMO. Methods: We studied 30 patients with NMO, 30 patients with relapsing-remitting multiple sclerosis (RRMS), and 30 normal controls (NC). RRMS and NC were age- and gender-matched to NMO. The presence of cortical lesions (CLs) was evaluated on double inversion recovery sequence and cortical thickness (CTh) by the application of Freesurfer on 3 volumetric fast field echo T1-weighted images. Results: No CL was observed in NC or in NMO, while 83 CLs were identified in 20/30 (66.7%) patients with RRMS. Although NMO did not differ from NC in the global CTh, a mild thinning was observed in some cortical areas (postcentral [p = 0.018], precentral [p = 0.009], and calcarine [p = 0.015] gyri) and in the thalamus (p = 0.036). Global and regional cortical thickness was significantly decreased in RRMS compared to both NMO and NC. Discussion: Our in vivo data further suggest that the immune-mediated pathologic process occurring in NMO spares most of the cortex. NMO differs from multiple sclerosis, where CLs and atrophy are frequently found, even in early disease phases. Thus, MRI analysis of the cortex may be a potential diagnostic tool, especially in ambiguous cases.

Effect of disease-modifying drugs on cortical lesions and atrophy in relapsing–remitting multiple sclerosis

Objective: To measure the effects of disease-modifying drugs (DMDs) on the development of cortical lesions (CL) and cortical atrophy in patients with relapsing–remitting multiple sclerosis (RRMS). Methods: RRMS patients (n = 165) were randomized to subcutaneous (sc) interferon (IFN) beta-1a (44 mcg three times weekly), intramuscular (im) IFN beta-1a (30 mcg weekly) or glatiramer acetate (GA; 20 mg daily). The reference population comprised 50 untreated patients. Clinical and MRI examinations were performed at baseline, 12 months and 24 months. Results: One hundred and forty-one treated patients completed the study. After 12 months, 37/50 (74%) of untreated patients developed ≥1 new CL (mean 1.6), compared with 30/47 (64%) of im IFN beta-1a-treated patients (mean 1.2, p = 0.021), 24/48 (50%) of GA-treated patients (mean 0.8, p = 0.001) and 12/46 (26%) of sc IFN beta-1a-treated patients (mean 0.4, p < 0.001). After 24 months, ≥1 new CL was observed in 41/50 (82%) of untreated (mean 3.0), 34/47 (72%) of im IFN beta-1a-treated (mean 1.6, p < 0.001), 30/48 (62%) of GA-treated (mean 1.3, p < 0.001) and 24/46 (52%) of sc IFN beta-1a-treated patients (mean 0.8, p < 0.001). Mean grey matter fraction decrease in DMD-treated patients at 24 months ranged from 0.7 to 0.8 versus 1.0 in untreated patients (p = 0.023). Conclusions: Disease-modifying drugs significantly decreased new CL development and cortical atrophy progression compared with untreated patients, with faster and more pronounced effects seen with sc IFN beta-1a than with im IFN beta-1a or GA.