Peak width of skeletonized mean diffusivity (PSMD) and cognitive functions in relapsing-remitting multiple sclerosis.

Peak width of skeletonized mean diffusivity (PSMD) is a new MRI marker, which has shown clinical relevance in some neurological conditions and, in preliminary data, in multiple sclerosis (MS). We aimed here to investigate, in a group of relapsing-remitting MS (RRMS) patients, the relationship between PSMD and cognitive performances, in comparison with other MRI measures. RRMS patients (n = 60) and normal controls (n = 15) underwent a 3 T MRI examination. MRI-based white matter (WM) lesion volume, microstructural integrity (assessed with Tract-Based Spatial Statistics of diffusion tensor imaging [DTI] images) and brain volumes (i.e., total brain, grey matter [GM] and WM) were computed. In addition, PSMD was calculated through "skeletonization" of WM tracts and diffusion histograms. Cognition was evaluated with Rao's Brief Repeatable Battery (BRB), which incorporated tests of verbal and visual memory, attention, concentration, information processing speed and verbal fluency. PSMD closely correlated with symbol digit modalities test (SDMT) (r = -0.70, p < 0.001) and, to a lesser extent, with verbal and visual memory tests. Multiple regression analysis showed that PSMD explained SDMT variance (R2 = 0.54, p < 0.001) more than other MRI measures. Results point out the relevance of microstructural damage, as assessed by PSMD, as a reliable marker of cognition in MS, especially in explaining dysfunction in information processing speed.

Subclinical motor impairment assessed with an engineered glove correlates with magnetic resonance imaging tissue damage in radiologically isolated syndrome.

BACKGROUND: An engineered glove measuring finger motor performance previously showed ability to discriminate early-stage multiple sclerosis (MS) patients from healthy controls (HCs). Radiologically isolated syndrome (RIS) classifies asymptomatic subjects with brain magnetic resonance imaging (MRI) abnormalities suggestive of multiple sclerosis. METHODS: Seventeen asymptomatic subjects with RIS and 17 HCs were assessed. They performed finger-to-thumb opposition sequences at their maximal velocity, metronome-paced bimanual movements and conventional and diffusion tensor MRI. RESULTS: Subjects with RIS showed lower (P = 0.005) maximal velocity and higher (P = 0.006) bimanual coordination impairment than HCs. In RIS, bimanual coordination correlated with T2-lesion volume, fractional anisotropy and radial diffusivity in the white matter. CONCLUSIONS: These findings point out the relevance of fine hand measures as a robust marker of subclinical disability.

Peak width of skeletonized mean diffusivity (PSMD) as marker of widespread white matter tissue damage in multiple sclerosis.

BACKGROUND: Peak width of skeletonized mean diffusivity (PSMD) is a novel and fully automated, MRI biomarker, which has shown clinical relevance in cerebral small vessel diseases (SVD). We aimed here to assess PSMD levels across the brain of patients with multiple sclerosis (MS), in comparison to normal controls (NC) and patients with CADASIL, a genetically defined form of severe SVD. METHODS: We assessed PSMD in relapsing-remitting (RR) MS patients (n = 47) in comparison to age-matched CADASIL patients (n = 25) and NC (n = 28). Diffusion Tensor Imaging data were acquired on 1.5T MR clinical scanner to automatically compute PSMD through "skeletonization" of WM tracts and diffusion histograms. RESULTS: RRMS had lower WM lesion volume (LV) than CADASIL (8.6 ±â€¯8.2 vs 24.4 ±â€¯17.4 cm3, p < 0.001). After correction for LV, PSMD values in MS were higher than in CADASIL patients (adjusted mean values: 4.5 vs 3.9 × 10-4 mm2/s, p = 0.03) and in both patient groups were higher than in NC (2.8 ±â€¯0.3 × 10-4 mm2/s, p < 0.001). PSMD values correlated with LV in both patient groups (r = 0.8, p < 0.001 in MS; r = 0.6, p = 0.002 in CADASIL). CONCLUSIONS: In both patient groups, PSMD was higher than in NC and closely correlated with LV, suggesting sensitivity in assessing brain tissue damage in these disorders. In MS patients, PSMD levels were higher than in CADASIL patients, despite the lower LV. This might be related to more severe normal-appearing WM abnormalities occurring in the MS brains. This novel, fully automated, MRI metric may represent a useful marker for a robust quantification of the diffuse WM tissue damage in MS.

Clinical activity after fingolimod cessation: disease reactivation or rebound?

BACKGROUND AND PURPOSE: There is debate as to whether the apparent rebound after fingolimod discontinuation is related to the discontinuation itself or whether it is due to the natural course of highly active multiple sclerosis (MS). Our aim was to survey the prevalence of severe reactivation and rebound after discontinuation of fingolimod in a cohort of Italian patients with MS. METHODS: Patients with relapsing-remitting MS who were treated with fingolimod for at least 6 months and who stopped treatment for reasons that were unrelated to inefficacy were included in the analysis. RESULTS: A total of 100 patients who had discontinued fingolimod were included in the study. Fourteen patients (14%) had a relapse within 3 months after fingolimod discontinuation, and an additional 12 (12%) had a relapse within 6 months. According to this study's criteria, 10 patients (10%) had a severe reactivation. Amongst these patients, five (5%) had a reactivation that was considered to be a rebound. CONCLUSIONS: The present study showed that more than 26% of patients are at risk of having a relapse within 6 months after fingolimod discontinuation. Nevertheless, the risk of severe reactivations and rebound is lower than has been previously described.

Hippocampal and Deep Gray Matter Nuclei Atrophy Is Relevant for Explaining Cognitive Impairment in MS: A Multicenter Study.

BACKGROUND AND PURPOSE: The structural MR imaging correlates of cognitive impairment in multiple sclerosis are still debated. This study assessed lesional and atrophy measures of white matter and gray matter involvement in patients with MS acquired in 7 European sites to identify the MR imaging variables most closely associated with cognitive dysfunction. MATERIALS AND METHODS: Brain dual-echo, 3D T1-weighted, and double inversion recovery scans were acquired at 3T from 62 patients with relapsing-remitting MS and 65 controls. Patients with at least 2 neuropsychological tests with abnormal findings were considered cognitively impaired. Focal WM and cortical lesions were identified, and volumetric measures from WM, cortical GM, the hippocampus, and deep GM nuclei were obtained. Age- and site-adjusted models were used to compare lesion and volumetric MR imaging variables between patients with MS who were cognitively impaired and cognitively preserved. A multivariate analysis identified MR imaging variables associated with cognitive scores and disability. RESULTS: Twenty-three patients (38%) were cognitively impaired. Compared with those with who were cognitively preserved, patients with MS with cognitive impairment had higher T2 and T1 lesion volumes and a trend toward a higher number of cortical lesions. Significant brain, cortical GM, hippocampal, deep GM nuclei, and WM atrophy was found in patients with MS with cognitive impairment versus those who were cognitively preserved. Hippocampal and deep GM nuclei atrophy were the best predictors of cognitive impairment, while WM atrophy was the best predictor of disability. CONCLUSIONS: Hippocampal and deep GM nuclei atrophy are key factors associated with cognitive impairment in MS. These MR imaging measures could be applied in a multicenter context, with cognition as clinical outcome.

Regional cortical thinning in multiple sclerosis and its relation with cognitive impairment: A multicenter study.

OBJECTIVES: The objectives of this paper are to compare in a multicenter setting patterns of regional cortical thickness in patients with relapsing-remitting multiple sclerosis (RRMS) and cognitive impairment (CI) and those cognitively preserved (CP), and explore the relationship between cortical thinning and cognitive performance. METHODS: T1-weighted isotropic brain scans were collected at 3T from seven European centers in 60 RRMS patients and 65 healthy controls (HCs). Patients underwent clinical and neuropsychological examinations. Cortical thickness (CTh) measures were calculated using FreeSurfer (failing in four) and both lobar and vertex-based general linear model (GLM) analyses were compared between study groups. RESULTS: Twenty (36%) MS patients were classified as CI. Mean global CTh was smaller in RRMS patients compared to HCs (left 2.43 vs. 2.53 mm, right 2.44 vs. 2.54 mm, p < 0.001). Multivariate GLM regional analysis showed significantly more temporal thinning in CI compared to CP patients. Verbal memory scores correlated to regional cortical thinning in the insula whereas visual memory scores correlated to parietal thinning. CONCLUSIONS: This multicenter study showed mild global cortical thinning in RRMS. The extent of thinning is less pronounced than previously reported. Only subtle regional differences between CI and CP patients were observed, some of which related to specific cognitive domains.

Predicting outcome in clinically isolated syndrome using machine learning.

We aim to determine if machine learning techniques, such as support vector machines (SVMs), can predict the occurrence of a second clinical attack, which leads to the diagnosis of clinically-definite Multiple Sclerosis (CDMS) in patients with a clinically isolated syndrome (CIS), on the basis of single patient's lesion features and clinical/demographic characteristics. Seventy-four patients at onset of CIS were scanned and clinically reviewed after one and three years. CDMS was used as the gold standard against which SVM classification accuracy was tested. Radiological features related to lesional characteristics on conventional MRI were defined a priori and used in combination with clinical/demographic features in an SVM. Forward recursive feature elimination with 100 bootstraps and a leave-one-out cross-validation was used to find the most predictive feature combinations. 30 % and 44 % of patients developed CDMS within one and three years, respectively. The SVMs correctly predicted the presence (or the absence) of CDMS in 71.4 % of patients (sensitivity/specificity: 77 %/66 %) at 1 year, and in 68 % (60 %/76 %) at 3 years on average over all bootstraps. Combinations of features consistently gave a higher accuracy in predicting outcome than any single feature. Machine-learning-based classifications can be used to provide an "individualised" prediction of conversion to MS from subjects' baseline scans and clinical characteristics, with potential to be incorporated into routine clinical practice.

Prevalence of patient-reported dysphagia in multiple sclerosis patients: an Italian multicenter study (using the DYMUS questionnaire).

OBJECTIVE: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) with a chronic course. Dysphagia represents one of the current challenges in clinical practice for the management of MS patients. Dysphagia starts to appear in mildly impaired MS subjects (EDSS 2-3) and becomes increasingly common in the most severely disabled subjects (EDSS 8-9). The aim of the present study was to evaluate the frequency and characteristics of patient-reported dysphagia in MS patients with a multicenter study using the recently developed DYMUS (DYsphagia in MUltiple Sclerosis) questionnaire. DESIGN: Data were collected in a multi-centre, cross-sectional study using a face-to-face structured questionnaire for clinical characteristics and the DYMUS questionnaire. RESULTS: 1875 patients were interviewed. The current study has shown a correlation between patient-reported dysphagia and EDSS and disease course but not with age, gender and disease duration. Questionnaires were divided into "patient-reported dysphagia-yes" (587, 31.3%) and "patient-reported dysphagia-no" (1288, 68.7%). Compared with the patient-reported dysphagia-no group, patients in patient-reported dysphagia-yes group had higher EDSS score (mean EDSS 4.6 vs. 2.8; p<0.001) and had a longer disease duration (mean duration 13 years vs. 11 years; p<0.001), while there was no significant difference in gender (32.7% vs. 30.5% male and 67.3% vs. 69.5% female) and in age composition (46.18 vs. 42.05). CONCLUSIONS: This study represents the largest, multi-centre sample of MS patients evaluated for patient-reported dysphagia utilizing an ad-hoc questionnaire for this condition.

Scoring treatment response in patients with relapsing multiple sclerosis.

BACKGROUND: We employed clinical and magnetic resonance imaging (MRI) measures in combination, to assess patient responses to interferon in multiple sclerosis. OBJECTIVE: To optimize and validate a scoring system able to discriminate responses to interferon treatment in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Our analysis included two large, independent datasets of RRMS patients who were treated with interferons that included 4-year follow-up data. The first dataset ("training set") comprised of 373 RRMS patients from a randomized clinical trial of subcutaneous interferon beta-1a. The second ("validation set") included an observational cohort of 222 RRMS patients treated with different interferons. The new scoring system, a modified version of that previously proposed by Rio et al., was first tested on the training set, then validated using the validation set. The association between disability progression and risk group, as defined by the score, was evaluated by Kaplan Meier survival curves and Cox regression, and quantified by hazard ratios (HRs). RESULTS: The score (0-3) was based on the number of new T2 lesions (>5) and clinical relapses (0,1 or 2) during the first year of therapy. The risk of disability progression increased with higher scores. In the validation set, patients with score of 0 showed a 3-year progression probability of 24%, while those with a score of 1 increased to 33% (HR = 1.56; p = 0.13), and those with score greater than or equal to 2 increased to 65% (HR = 4.60; p < 0.001). CONCLUSIONS: We report development of a simple, quantitative and complementary tool for predicting responses in interferon-treated patients that could help clinicians make treatment decisions.

Natalizumab may reduce cognitive changes and brain atrophy rate in relapsing-remitting multiple sclerosis--a prospective, non-randomized pilot study.

BACKGROUND AND PURPOSE: The development of treatment strategies for cognitive impairment in multiple sclerosis (MS) is still in its infancy. The objective of this prospective, non-randomized, pilot study was to assess the possible efficacy of treatment with natalizumab in comparison with interferon beta (IFNB) in a group of relapsing-remitting patients with MS. METHODS: We included 12 patients treated with natalizumab and 14 with IFNB. At baseline and at follow-up, cognitive functioning was assessed through Rao's Brief Repeatable Battery. All the patients underwent brain MR study with the assessment of T2 lesion volumes, neocortical volume, normalized brain volume and percentage brain volume change (PBVC). Evolution of cognitive performance was assessed using available normative data for the Italian population. Treatment comparisons were assessed through the Mann-Whitney U-test, anova for repeated measures and linear multivariate regression analyses. RESULTS: After a mean follow-up of 1.5 years, the mean number of neuropsychological tests with a deteriorating performance was significantly lower in patients treated with natalizumab (0.7 ± 0.7 vs. 1.7 ± 1.4; P = 0.031). Likewise, PBVC was significantly lower in natalizumab-treated subjects than that observed in patients treated with IFNB (-0.51% ± 0.47% vs. -1.18% ± 0.98%; P = 0.050). CONCLUSION: Our results suggest a potential beneficial effect of natalizumab therapy on cognitive functioning in MS, possibly mediated by a reduction of brain atrophy.

Association of MRI metrics and cognitive impairment in radiologically isolated syndromes.

OBJECTIVE: To evaluate cognitive changes in a cohort of radiologically isolated syndromes (RIS) suggestive of multiple sclerosis (MS) and to assess their relationship with quantitative magnetic resonance (MR) measures such as white matter (WM), lesion loads, and cerebral atrophy. METHODS: We assessed the cognitive performance in a group of 29 subjects with RIS recruited from 5 Italian MS centers and in a group of 26 patients with relapsing-remitting MS (RRMS). A subgroup of 19 subjects with RIS, 26 patients with RRMS, and 21 healthy control (HC) subjects also underwent quantitative MR assessments, which included WM T1 and T2 lesion volumes and global and cortical brain volumes. RESULTS: Cognitive impairment of the same profile as that of RRMS was found in 27.6% of our subjects with RIS. On MR scans, we found comparable levels of lesion loads and brain atrophy in subjects with RIS and well-established RRMS. In subjects with RIS, high T1 lesion volume (ρ = 0.526, p = 0.025) and low cortical volume (ρ = -0.481, p = 0.043) were associated with worse cognitive performance. CONCLUSIONS: These findings emphasize the importance of including accurate neuropsychological testing and quantitative MR metrics in subjects with RIS suggestive of MS. They can provide a better characterization of these asymptomatic subjects, potentially useful for diagnostic and therapeutic decisions.

Cortical lesions in radiologically isolated syndrome.

OBJECTIVE: To assess the presence of cortical lesions (CLs) as detected by MRI in subjects with radiologically isolated syndrome (RIS). METHODS: Fifteen subjects with RIS underwent an MRI examination, including a double inversion recovery sequence for CL assessment. T2-hyperintense white matter (WM) lesion volume (LV) and normalized volumes of brain and cortex were also obtained. RESULTS: Thirty-four CLs were identified in 6 of 15 (40%) subjects with RIS and predominantly distributed in frontotemporal lobes. CLs were frequent in subjects with RIS with immunoglobulin G oligoclonal bands on CSF, cervical cord lesions, and dissemination in time on brain MRI. WM LV was higher in subjects with CLs than in those without CLs (11.5 ± 10.1 vs 3.9 ± 2.8 cm(3), p = 0.04). Indeed, CL number and volume correlated with WM LV (r = 0.57, p = 0.03 and r = 0.61, p = 0.01). All subjects with CLs were classified in a previous study as having a very high probability of having relapsing-remitting multiple sclerosis (MS) on a logistic regression analysis of quantitative MRI indices. CONCLUSIONS: We found CLs in subjects with RIS, a condition characterized by the unanticipated MRI finding of WM lesions highly suggestive of MS in the absence of a clinical scenario. CLs were mainly localized to the frontotemporal lobes and were associated with important markers of evolution to MS.

Pronounced focal and diffuse brain damage predicts short-term disease evolution in patients with clinically isolated syndrome suggestive of multiple sclerosis.

BACKGROUND: In clinically isolated syndrome (CIS), the role of quantitative magnetic resonance imaging (MRI) in detecting prognostic markers is still debated. OBJECTIVE: To evaluate measures of diffuse brain damage (such as brain atrophy and the ratio of N-acetylaspartate to creatine (NAA/Cr)) in patients with CIS, in addition to focal lesions, as predictors of 1-year disease evolution. METHODS: 49 patients with CIS underwent MRI scans to quantify T2-lesions (T2-L) and gadolinium-enhanced lesion (GEL) number at baseline and after 1 year. Along with 25 healthy volunteers, they also underwent combined MRI/magnetic resonance spectroscopy examination to measure normalized brain volumes (NBVs) and NAA/Cr. Occurrence of relapses and new T2-L was recorded over 1 year to assess disease evolution. RESULTS: Occurrence of relapses and/or new T2-L over 1 year divided patients with CIS into 'active' and 'stable' groups. Active patients had lower baseline NAA/Cr and NBV. Baseline T2-L number, GEL, NAA/Cr and NBV predicted subsequent disease activity. Multivariable logistic regression models showed that both 'focal damage' (based on T2-L number and GEL) and 'diffuse damage' (based on NBV and NAA/Cr) models predicted disease activity at 1 year with great sensitivity, specificity and accuracy. This was best when the four MRI measures were combined (80% sensitivity, 89% specificity, 83% accuracy). CONCLUSIONS: Quantitative MRI measures of diffuse tissue damage such as brain atrophy and NAA/Cr, in addition to measures of focal demyelinating lesions, may predict short-term disease evolution in patients with CIS, particularly when used in combination. If confirmed in larger studies, these findings may have important clinical and therapeutic implications.

Clinical relevance of brain volume changes in patients with cerebrotendinous xanthomatosis.

OBJECTIVE: To quantify total and regional brain damage in subjects with cerebrotendinous xanthomatosis (CTX) using MR based quantitative measures. BACKGROUND: CTX is a rare inherited disorder characterised by progressive neurological impairment. Appropriate therapy can slow disease progression. Measures of brain volume changes have been used in several neurological disorders due to their value in assessing disease outcome and monitoring patients' evolution. METHODS: 24 CTX patients underwent conventional MRI to measure total and regional brain volumes. In five CTX patients who started therapy at baseline, clinical and MRI examinations were repeated after 2 years. Clinical disability, overall cognitive performance and cerebellar function were evaluated using the modified Rankin Scale (RS), Mini Mental Status Examination (MMSE) and cerebellar functional system score (CB-FSS). RESULTS: Measures of normalised brain, cortical and cerebellar volumes were lower in CTX patients than in healthy controls (p<0.01). Instead, there were no differences in normalised white matter volumes between the two groups (p=0.1). At regional analysis, a significant volume decrease was found in each cortical region (p<0.01 for all regions). Normalised cortical volumes correlated closely with age (r=-0.9, p<0.0001), RS (r=-0.65, p<0.001) and MMSE (r=-0.60, p<0.01). Normalised cerebellar volumes correlated closely with CB-FSS scores (r=-0.58, p<0.01). In the five CTX patients followed over time, the annual brain volume decrease was -1.1 ± 0.2%. CONCLUSIONS: Cortical volume, rather than white matter volume, is diffusely decreased in CTX patients and correlates closely with the patient's clinical status. These data provide evidence for the presence of clinically relevant neuronal-axonal damage in the brains of CTX patients.

Validation of the DYMUS questionnaire for the assessment of dysphagia in multiple sclerosis.

Swallowing problems can complicate the course of multiple sclerosis (MS). However, no validated questionnaire for the assessment of dysphagia in MS is currently available. We previously developed a 10-item DYsphagia in Multiple Sclerosis questionnaire (DYMUS). In the present study, this questionnaire was submitted to a validation process. Thirteen Italian MS centres took part in this research in which DYMUS was administered to 1734 consecutive MS patients during routine checkups outside relapse. The questionnaire showed very good internal consistency (Cronbach's alpha = 0.914). It was then subdivided into two subscales, both of which also showed very good internal consistency: Cronbach's alpha was 0.885 for the 'dysphagia for solids' subscale and 0.864 for the 'dysphagia for liquids' subscale. The DYMUS questionnaire was found to be an easy and reliable tool for detecting dysphagia and also for the preliminary selection of patients requiring more specific instrumental analyses, and those suitable for aspiration prevention programmes.

Neuropsychological and MRI measures predict short-term evolution in benign multiple sclerosis.

OBJECTIVE: To assess whether neuropsychological tests and MRI measures could be used as predictors of short-term disease evolution in a population of patients with benign multiple sclerosis (B-MS). BACKGROUND: The definition of B-MS is controversial. Recent data suggest that neuropsychological tests and MRI measures can provide valuable information for a more correct definition and interpretation of B-MS. METHODS: Sixty-three patients with B-MS (Expanded Disability Status Scale [EDSS] < or =3.0 and disease duration > or =15 years) underwent neuropsychological assessment using the Rao's Brief Repeatable Neuropsychological Battery and the Stroop Test. At that time, conventional brain MRI and magnetization transfer (MT) imaging was performed. White matter lesion load, global and regional brain volumes, and MT ratio in lesions and normal-appearing brain were measured. After a mean follow-up of 5 years, patients still having an EDSS score < or =3.5 were classified as still benign, whereas patients who had developed a secondary progressive course or who had an EDSS score > or =4.0 were defined as no longer benign (NLB). RESULTS: At end of follow-up, 29% of patients were classified as NLB. Male gender (hazard ratio [HR] = 2.9; 95% confidence interval [CI] 1.2-7.5; p = 0.02), number of neuropsychological tests failed (HR = 1.4; 95% CI 1.1-1.7; p = 0.003), and T1-weighted lesions (HR = 1.3; 95% CI 1.1-1.5; p = 0.002) were related to NLB status. In a model including these 3 variables, the NLB status was predicted with an accuracy of 82%. CONCLUSIONS: Cognitive assessment and MRI metrics can predict short-term disease evolution in benign multiple sclerosis (B-MS). This information can be useful to correctly identify patients with B-MS.

Structural and metabolic brain abnormalities in preclinical cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy.

OBJECTIVE: To assess, by using quantitative MRI metrics, structural and metabolic brain abnormalities in subjects with preclinical cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). BACKGROUND: Brain MRI abnormalities have been occasionally reported in preclinical CADASIL subjects. However, very little is known as to when the brain tissue damage starts to accumulate, what brain regions are primarily involved and whether the brain damage is significant in subjects who have no overt clinical manifestations of the disease. METHODS: Twelve subjects (mean age 40 years; range 26-55 years; males/females 6/6) with genetically proven CADASIL and no clinical signs of the disease underwent conventional MRI and proton MR spectroscopic imaging ((1)H-MRSI) to measure white matter (WM) lesion volume (LV), global and regional cerebral volumes, and WM levels of N-acetylaspartate (NAA) normalised to creatine (Cr). MR values were compared with those of 13 age- and sex-matched healthy controls. RESULTS: All preclinical CADASIL showed WM lesions (range 0.2 to 26 cm(3)). They were mostly distributed in the frontal and parietal regions, with the highest probability in the corona radiata. On (1)H-MRSI examination, NAA/Cr values were lower in preclinical CADASIL than in HC, particularly in the corona radiata (p<0.01). Normalised brain and cortical volumes were also lower in preclinical CADASIL than in HC (p<0.01), particularly in the frontal cortex. CONCLUSIONS: The pathological process occurring in CADASIL leads to damage of WM and neocortex much before the evidence of clinical symptoms. At this preclinical stage, this seems to take place prevalently in the frontal brain region.

Increased QT variability in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

BACKGROUND AND PURPOSE: Although sudden death (SD) accounts for numerous cases of premature mortality in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the risk factors responsible for this dramatic event remain unclear. We sought possible differences in the QT variability index (QTVI) -- a well-known index of temporal dispersion in myocardial repolarization strongly associated with the risk of SD -- between a group of patients with CADASIL and healthy controls. METHODS: A total of 13 patients with CADASIL and 13 healthy volunteers underwent a 5-min electrocardiogram recording to calculate the QTVI. All the patients also underwent a clinical assessment, including functional status by Rankin score, and a magnetic resonance imaging (MRI) brain scan for quantitative analysis of T2-weighted (T2-W) and T1-weighted (T1-W) lesion volume (LV). RESULTS: Short-term QT-interval analysis showed significantly higher QTVI (P = 0.029) in patients than in controls. In patients, notwithstanding the limitations of the small sample size, QTVI also well correlated with T1-W LV (r = 0.747, P = 0.003) and T2-W LV (r = 0.731, P = 0.005). CONCLUSION: Because patients with CADASIL have increased temporal cardiac repolarization variability as assessed by QTVI, this mechanism could underlie these patients' risk of SD. Whether this easily assessed, non-invasive marker could be used to stratify the risk of malignant ventricular arrhythmias in patients with CADASIL and, possibly, to guide their therapeutic management warrants confirmation from larger prospective studies.

Cognitive assessment and quantitative magnetic resonance metrics can help to identify benign multiple sclerosis.

BACKGROUND: The definition of benign multiple sclerosis (B-MS) is still controversial. This mainly takes into account the subject's motor ability, with little or no relevance to other important features such as cognition. Moreover, no paraclinical markers are currently available to reliably identify patients who will remain benign in the long term. OBJECTIVES: To assess, by using quantitative magnetic resonance (MR) metrics, differences in tissue damage between B-MS patients after dividing them into two groups on the basis of their cognitive performance. METHODS: Forty-seven B-MS patients (Expanded Disability Status Scale score /=15 years) underwent neuropsychological assessment through the Rao Brief Repeatable Battery and the Stroop Test. At that time, B-MS patients underwent conventional brain MR and magnetization transfer (MT) imaging. White matter lesion load, global and regional brain volumes, and MT ratio (MTr) in lesions and normal-appearing brain were measured. Quantitative MR measures were compared in cognitively impaired (CI-MS) and cognitively preserved (CP-MS) patients and in 24 demographically matched healthy controls. Test performance was correlated with MR changes in specific cortical regions. RESULTS: Eleven patients were classified as CI-MS, and 36 were classified as CP-MS. Both T2-weighted and T1-weighted lesion loads were higher (p = 0.05 and 0.001) in CI-MS than in CP-MS patients. Furthermore, CI-MS patients were characterized by more pronounced decrease in neocortical volume (p = 0.005) and cortical MTr (p = 0.02) values than CP-MS patients. Finally, test performance correlated significantly with MR changes in relevant cortical regions. CONCLUSIONS: Cognitive assessment and quantitative magnetic resonance can help to reliably identify benign multiple sclerosis patients.

Prominent brain axonal damage and functional reorganization in "pure" adrenomyeloneuropathy.

BACKGROUND: Cerebral involvement is usually absent in pure adrenomyeloneuropathy (AMN). Recently, nonconventional MR studies have reported brain abnormalities in patients with pure AMN, providing evidence that occult cerebral involvement may occur in this disease. It remains unclear, however, whether these brain abnormalities reflect centripetal extension of spinal cord long-tract axonopathy or can be the expression of a pathologic process largely involving the brain. METHODS: Conventional MRI and proton MR spectroscopic imaging (1H-MRSI) data of four patients with pure AMN were compared to those of four men with spinal cord injury (SCI) and 10 age-matched healthy men (HM). Resonance intensity areas of N-acetylaspartate (NAA) and choline were calculated as ratios to creatine (Cr) in voxels located in white matter (WM) regions. Functional MRI (fMRI) data during simple motor task were obtained in a separate session in three patients with AMN and three age-matched HM. RESULTS: Conventional MRI examinations were normal in all patients. On 1H-MRSI, NAA/Cr values were lower in all WM regions of patients with AMN than in those of patients with SCI (p < 0.05) and HM (p < 0.01). In contrast, patients with SCI showed NAA/Cr values lower than HM only in the periventricular WM (p = 0.04). At fMRI, patients with AMN showed a more pronounced activation than HM in all movement-associated cortical regions contralateral to the hand moved and an exclusive voxel activation of the primary motor, somatosensory, and posterior parietal cortices ipsilateral to the hand moved. CONCLUSIONS: CNS damage in pure adrenomyeloneuropathy is not confined exclusively to spinal cord and seems to primarily involve the brain.