Paola Grossi

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.

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.

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.

Clinical and diagnostic aspects of multiple sclerosis and acute monophasic encephalomyelitis in pediatric patients: a single centre prospective study.

Objective The purpose of the study was to compare and contrast the initial presenting demographic, clinical, neuroimaging, and laboratory features in a cohort of children affected from multiple sclerosis (MS) or acute disseminated encephalomyelitis (ADEM). Methods A 12-year prospective study was conducted in 68 pediatric patients (age ≤ 17 years) who presented with a first episode of central nervous system inflammation suggestive of a demyelinating multifocal pathology. All patients had undergone magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) examination. The mean follow-up period, as at ending on December 31, 2007, was 6.8 ± 2.7 years (range 3.2–12.6 years). Results At clinical onset, children who developed MS during the follow-up (48 patients; 34 females, 14 males; mean age at onset: 14.4 ± 2.5) significantly differed from children affected by ADEM (20 patients; 8 females, 12 males; mean age at onset: 8.1 ± 3.8 ) for the following parameters: prevalence of females affected (female/male ratio: 2.8 versus 0.6, P = 0.03); mean age at onset (P < 0.001); monosymptomatic onset (73% vs 30%, P = 0.002); encephalopathy-like onset (0% vs 50%, P < 0.001); presence of oligoclonal IgG bands (IgGOB) in CSF (83% vs 10%, P < 0.001); and periventricular (79% vs 20%, P < 0.001), brain stem (12.5% vs 60%, P = 0.000), and basal ganglia (10% vs 50%, P < 0.001) lesions at MRI. Conclusions Our findings depict a pattern of demographic, clinical, neuroimaging, and laboratory findings that can help to distinguish, at clinical onset, children suffering from ADEM from those who will develop MS. Childhood-onset MS seems not to differ from adult-onset MS from both clinical and paraclinical features.

Cortical pathology and cognitive impairment in multiple sclerosis

Cognitive impairment constitutes a relevant clinical aspect of multiple sclerosis (MS). Depending on the disease phase and type, 40–65% of MS patients develop various degrees of cognitive dysfunction. Pathological and MRI studies have failed to demonstrate the existence of a strict relationship between cognitive impairment and subcortical white matter pathology. The correlation is also poor when MRI metrics of whole brain (white plus gray matter) atrophy are considered. Over the last decade, increasing observations have provided evidence of a primary role of cortical pathology – that is, inflammatory focal lesions (cortical lesions) and atrophy (cortical thickness) – in determining global and/or selective cognitive disability in MS. By applying a new semi-automated software (Freesurfer) to analyze the global and regional cortical thickness and the double inversion recovery sequence to identify cortical lesions, it has been observed that specific cognitive deficits, such as memory impairment, attention deficits and reduced mental processing speed, could be better explained by cortical structural abnormalities rather than subcortical white matter lesions. Therefore, MRI evaluation of cortical pathology should be included in the routine examination of MS patients, especially those with initial signs/symptoms of cognitive dysfunctions.

Cortical pathology in multiple sclerosis patients with epilepsy: a 3 year longitudinal study

Introduction The cause of epilepsy in multiple sclerosis (MS) has not yet been elucidated. The relevance of cortical pathology (cortical lesions and thickness) in MS patients with and without epilepsy was evaluated in a longitudinal study. Methods 32 relapsing–remitting MS patients with epilepsy (RRMS/E) and 60 matched RRMS patients without epilepsy were included in a 3 year longitudinal study. The following clinical and MR parameters were analysed: Expanded Disability Status Scale (EDSS), cognitive score (CS), cortical lesion (CL) number and volume, grey matter fraction (GMf), global cortical thickness (CTh), T2 white matter lesion volume (T2WMLV), new CLs and new WM lesions. Results At baseline (T0), CLs were observed in 27/32 (84.4%) RRMS/E and in 26/60 (43.3%) RRMS (p<0.001) patients, and the RRMS/E group had a higher number (10.2±8.9 vs 4.5±2.4; p<0.001) and total volume (2.0±1.3 vs 0.7±0.8 cm3; p<0.001) of CLs compared with the RRMS group. No significant difference in T2WMLV was observed. Global CTh was lower in RRMS/E (2.12±0.19 vs 2.35±0.14 mm; p<0.001), and this group also showed a decline in cognition (CS 10.9±6.3 vs 6.2±3.5; p<0.001). After 3 years (T1), the RRMS/E group had a higher accumulation of new CLs (3.4±3.2 vs 1.2±1.1; p<0.001) and faster reduction of GMf (p=0.022) while the two groups did not differ in the number of new WM and new Gad+ lesions. Discussion RRMS/E had a more severe and rapidly evolving cortical pathology (CLs and atrophy) compared with RRMS without epilepsy. The RRMS/E group was also characterised by more pronounced cognitive decline, higher EDSS and higher prevalence of men.

Neurofunctional Modulation of Brain Regions by the Observation of Pointing and Grasping Actions

Previous neuroimaging research on healthy humans has provided evidence for a neural system underlying the observation of another persons hand actions. However, whether the neural processes involved in this capacity are activated by the observation of other transitive hand actions such as pointing remains unknown. Therefore, using functional magnetic resonance imaging we investigated the neural mechanisms underlying the observation of static images representing the hand of a human model pointing to an object (pointing condition), grasping an object (grasping condition), or resting in proximity of an object (control condition). The results indicated that activity within portions of the lateral occipitotemporal and the somatosensory cortices modulates according to the type of observed transitive actions. Specifically, these regions were more activated for the grasping than for the pointing condition. In contrast, the premotor cortex, a neural marker of action observation, did not show any differential activity when contrasting the considered experimental conditions. Our findings may provide novel insights regarding a possible role of extrastriate and somatosensory brain areas for the perception of distinct types of human hand-object interactions.

No evidence of JC virus reactivation in natalizumab treated multiple sclerosis patients: an 18 month follow-up study.

Background and aim Natalizumab, used as therapy for multiple sclerosis (MS), has been associated with progressive multifocal leucoencephalopathy (PML), a potentially fatal disease caused by JC virus (JCV), which is not predictable by specific markers. This study evaluated whether JCV reactivation occurred in the urine and/or plasma in 42 MS patients treated with natalizumab over 18 months, and followed by a thorough monitoring programme. Methods 42 patients (F/M: 24/18, mean age 34.4±8.9 years) were followed-up by: urine and plasma JCV-DNA PCR assay, immune cell subsets analysis, clinical and MRI evaluation, quality of life, fatigue and mood assessment. Results JCV data. At baseline, 11/42 (26%) patients had JCV viruria, persistent at serial controls. One patient acquired viruria at month 1 and one patient at month 12. No patient had JCV viraemia at baseline; three patients acquired viraemic (one at month 6, one at month 13 (both transiently) and one at month 12 (persistently viraemic)). The prevalence of JCV in both urine and plasma did not change significantly from baseline to months 12 and 18. No patient had clinical or MRI evidence of PML. Immunological data. Circulating B cells showed greater expansion (300% increase in absolute number) since the first infusion. NK cell count doubled with no change in percentage while T cell count increased with a reduced percentage, reflecting a clear redistribution in the lymphocyte compartment. CD4+ and CD8+ T cells increased proportionally, with no change in their percentage. Clinical data. 27 patients (64%) were disease free after 1 year. A marked improvement in quality of life was reported by 72% of patients. Conclusions No evidence of subclinical JCV reactivation was found in our natalizumab treated MS patients up to 18 months of therapy, notwithstanding the marked increase in circulating B cells observed. Moreover, the efficacy of natalizumab, its tolerability and the positive impact on quality of life were confirmed in this study.

Cortical lesions and cognitive impairment in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system. In the last decade, pathological and magnetic resonance imaging (MRI) studies have shown that a significant portion of inflammatory lesions are located in the grey matter, especially in the cerebral cortex, of MS patients. Cortical inflammatory lesions (CL) can be demonstrated in vivo in MS patients by double inversion recovery (DIR) MRI sequence. Neuropsychological deficits constitute a major clinical aspect of MS, being demonstrated in a percentage ranging from 40 to 65% of patients, and have been shown to be associated with cortical demyelination and atrophy. Recent DIR studies in MS patients having different clinical forms of the disease have disclosed that CL burden not only correlates with the severity of physical disability, but is also one of the major structural changes associated with disease-related cognitive impairment.