Monica Falautano

Relation between MR abnormalities and patterns of cognitive impairment in multiple sclerosis

Objective This study correlated the extent of abnormalities detected by different magnetic resonance imaging (MRI) techniques [proton density (PD)-weighted, T1-weighted, and magnetization transfer imaging (MTI)] with the overall cognitive, frontal lobe, and memory impairments in patients with MS. Patients There were 30 clinically definite MS patients, with different disease courses. Exclusion criteria: psychoactivelsteroid treatments, mood disorders, acute relapse phase. Main Outcome Measures Neuropsychological test results. Total (TLL) and frontal (FLL) lesion loads assessed from PD-weighted, T1-weighted (22 patients), and MTI (22 patients) MRI scans. Average lesion MT ratios (MTR) and analysis of the MTR histograms from brain tissue axial slabs on MTI scans. Results Patients with frontal lobe deficits (n = 15) or memory impairment (n = 17) had a higher TLL on PD scans (p = 0.04 and p = 0.01, respectively). Patients with frontal lobe deficits had higher FLL on PD scans (p = 0.01) and TLL on MTI (p = 0.03) scans. No significant relationships between the extent of T1-weighted lesion loads and the presence of any neuropsychological impairment. Mean MTR of both MS lesions and whole brain tissue was lower in patients with frontal lobe impairment (p = 0.04). MRI lesion loads correlated significantly with some neuropsychological test scores. Conclusions Lesion loads on PD-weighted MRI and MTI-derived measures are associated with cognitive decline in MS patients. Overall macroscopic and microscopic brain damage is more important than the corresponding regional brain disease in determining deficits of selective cognitive domains.

Cognitive dysfunction in patients with mildly disabling relapsing–remitting multiple sclerosis: an exploratory study with diffusion tensor MR imaging

Previous studies assessing the magnetic resonance imaging (MRI) correlates of cognitive dysfunction in multiple sclerosis (MS) achieved conflicting results. Diffusion tensor (DT)-MRI provides metrics that are sensitive to the macro- and microscopic MS lesion load with increased specificity to the more destructive aspects of MS pathology than conventional imaging. We performed an exploratory study to assess the magnitude of the correlation between quantities derived from DT-MRI and measures of cognitive impairment in patients with relapsing-remitting (RR) MS.T2, T1, DT-MRI scans of the brain and an extensive battery of neuropsychological tests (exploring language, complex reasoning, attention and memory) were obtained from 34 RRMS patients. We measured T2 and T1 lesion volumes (LV) and brain volume. Average lesion mean diffusivity (D) and fractional anisotropy (FA) were calculated. D and FA histograms from the brain tissue (BT), the normal-appearing brain tissue (NABT), the normal-appearing white matter (NAWM) and the normal-appearing gray matter (NAGM) were also obtained. Nine patients (26.5%) were found to be cognitively impaired. Moderate correlations were found between symbol digit modalities test, verbal fluency test and 10/36 spatial recall test scores and T2 LV, T1 LV and average lesion, WBT, NABT, NAWM and NAGM values (r values ranging from -0.30 to -0.53). No correlations were found between any of the neuropsychological test scores and brain volume, average lesion FA and WBT FA.DT-MRI provides quantitative metrics that seem to reflect the severity of language, attention and memory deficits in patients with RRMS. This study also suggests that the extent and the intrinsic nature of the macroscopic lesions as well as the damage of the NAWM and NAGM all contribute to the neuropsychological deficits of RRMS patients.

Cognitive and psychosocial features of childhood and juvenile MS

Objective: To assess the impact of multiple sclerosis (MS) on cognitive and psychosocial functioning in childhood and juvenile cases. Methods: We used an extensive neuropsychological battery assessing IQ, memory, attention/concentration, executive functions, and language. Fatigue and depression were also measured. An interview on school and daily living activities was obtained from the parents. Performance of cases was compared with that of demographically matched healthy controls. Results: Sixty-three patients and 57 healthy controls were assessed. Five patients (8%) exhibited a particularly low IQ (<70). Criteria for cognitive impairment (failure on at least three tests) were fulfilled in 19 patients (31%), whereas 32 patients (53%) failed at least two tests. Beyond deficits in memory, complex attention, and executive functions, the profile of deficits was characterized by involvement of linguistic abilities. In the regression analysis, the only significant predictor of cognitive impairment was an IQ score lower than 90 (odds ratio [OR] 18.2, 95% CI 4.6–71.7, p < 0.001). Considering the IQ score as a dependent variable, the only significant predictor was represented by younger age at onset (OR 0.7, 95% CI 0.5–0.9, p = 0.009). Depressive symptoms were reported by 6% of the cases, and fatigue was reported by 73% of the cases. MS negatively affected school and everyday activities in 56% of the subjects. Conclusions: In childhood and juvenile cases, multiple sclerosis (MS) is associated with cognitive impairment and low IQ scores, the latter related to younger age at onset. These aspects are of critical importance in helping children and adolescents with MS to manage their difficulties and psychosocial challenges.

The contribution of voxel-based morphometry in staging patients with mild cognitive impairment

Objective: To assess whether different patterns of regional gray matter loss in patients with mild cognitive impairment (MCI) are associated with different risks of conversion to Alzheimer disease (AD), using MRI and voxel-based morphometry (VBM). Methods: The authors recruited 22 patients with MCI, 22 patients with probable AD, and 20 healthy subjects (HS). T1 volumes from each subject were postprocessed according to an optimized VBM protocol. All patients were clinically followed up (mean [SD] time = 28.7 [5.7] months), and patients with MCI were reclassified into two groups (converters and nonconverters to AD). Results: When comparing patients with AD to HS, widespread areas of reduced gray matter density were found predominantly in temporal, frontal, and parietal lobes and in the insula. Comparing MCI converters and nonconverters with HS, the converters showed more widespread areas of reduced gray matter density than nonconverters, with a pattern of abnormalities similar to that seen in patients with AD. Conversely, when comparing the same groups with patients with AD, MCI nonconverters showed a pattern of gray matter density similar to that of HS. Areas of decreased gray matter density were also found in MCI converters compared with nonconverters. Conclusions: Different patterns of gray matter density distribution in patients with mild cognitive impairment may be associated to different rates of conversion to Alzheimer disease.

Cognitive and psychosocial features in childhood and juvenile MS Two-year follow-up

Objective: To assess the evolution of cognitive and psychosocial functioning in a cohort of childhood and juvenile multiple sclerosis (MS) cases after a mean period of 2 years had elapsed since baseline evaluation. Methods: In this cohort study, we used the same extensive neuropsychological battery with alternative versions of the tests assessing memory, attention/concentration, executive functions, and language. Fatigue and depression were also measured. An interview on school and daily living activities was obtained from the parents. The cognitive performance of the patients was compared with that of demographically matched healthy controls (HC). Results: Fifty-six patients and 50 HC were assessed. At follow-up, criteria for cognitive impairment (failure on at least 3 tests) were fulfilled in 39 patients (70%) and 75% of the cases were classified as having a deteriorating cognitive performance. Changes were prominent in tests of verbal memory, complex attention, verbal fluency, and receptive language. In the regression analysis, the only significant predictor of cognitive deterioration was older age of the subject (odds ratio 1.9, 95% confidence interval 1.2–2.9, p = 0.003). Psychiatric disorders, most frequently depression, were diagnosed in 12 patients (30.5%). Fatigue was reported by 21% of the patients. MS negatively affected school and everyday activities in 30% to 40% of the subjects. Conclusions: Our findings confirm the importance of systematic assessment of cognitive and psychosocial issues in children and teens with MS. The progressive nature of the cognitive difficulties emphasizes the need for developing effective treatment strategies.

Neuropsychological impairment in multiple sclerosis patients: the role of (juxta)cortical lesion on FLAIR:

In this study we evaluated the correlation between neuropsychological impairment (measured with the Brief Repeatable Battery Neuropsychological Tests) and (juxta)cortical lesions detected with FLAIR and the relative sensitivity of the FLAIR sequence compared to spin-echo MRI sequences in detecting (juxta)cortical MS lesions. A total of 39 patients with definite MS were evaluated by MRI with a conventional and fast spin echo sequence and fast FLAIR sequence, and neuropsychological tests of the Brief Repeatable Battery Neuropsychological tests were performed. The Z-score of all subtests were used to calculate a Cognitive Impairment Index. The results show that a high number of (juxta)cortical lesions is detected with thin slice FLAIR (30% of all lesions seen). This percentage was not superior to spin-echo, reflecting the thin slice thickness (3 mm) we used. The lesions detected with FLAIR were to a certain degree different ones than the lesions detected with the other techniques. While the number of non-cortical lesions correlated with the expanded disability status scale (r=0.32, P=0.045), the number of (juxta)cortical lesions detected with the FLAIR showed a correlation (r=0.34, P=0.035) with the Cognitive Impairment Index. Our study underlines the high number of (juxta)cortical lesions in MS and the value of thin slice FLAIR sequence to detect such lesions with MRI. It also stresses the importance of (juxta)cortical lesions on determining neuropsychological impairment.

Electroencephalographic coherence analysis in multiple sclerosis: correlation with clinical, neuropsychological, and MRI findings

OBJECTIVE To explore functional corticocortical connections in multiple sclerosis by means of coherence of the EEG, and to evaluate their correlations with the degree of cognitive impairment and with brain lesion load assessed by MRI. METHODS EEG coherence was studied from 28 patients with clinically definite multiple sclerosis. Ten minutes of resting EEG were recorded with 20 scalp electrodes, with binaural reference. FFT power and coherence were calculated in artifact free epochs of 1 second and compared with values from 22 control subjects of comparable age and sex distribution. Patients also underwent MRI (n=27) and neuropsychological examination (n=21). RESULTS Compared with controls, patients with multiple sclerosis showed increased θ power in the frontotemporal-central regions (p<0.005). θ Band coherence was decreased between homologous areas (p<0.02). α Band coherence was decreased both in the local and long distance connections (p<0.0005). These findings were most striking both in patients with high MRI subcortical lesion load and in patients with cognitive involvement. A significant correlation was found between interhemispheric θ (p=0.02) and α (p=0.017) and anteroposterior α (p=0.013) coherence and subcortical MRI lesion load, but not with exclusively periventricular lesion load. CONCLUSIONS These findings support the hypothesis that cognitive impairment in multiple sclerosis is mostly dependent on involvement of corticocortical connections related to demyelination and/or axonal loss within the white matter immediately underlying the cortex.

A diffusion tensor MRI study of patients with MCI and AD with a 2-year clinical follow-up

Objective The authors assessed whether brain changes detected by diffusion tensor (DT) MRI can improve the understanding of structural damage in Alzheimers disease (AD) and are associated with different risks of conversion to AD in amnestic mild cognitive impairment (aMCI). Methods Twenty-one aMCI patients, 21 AD patients and 20 healthy subjects underwent conventional and DT MRI at baseline. All subjects were clinically followed up over 2 years; at the end of follow-up, aMCI were grouped into converters to AD (aMCI-C) and non-converters (aMCI-NC). The mean diffusivity (MD) and fractional anisotropy (FA) were obtained from total grey matter (GM) and white matter (WM), and from several GM and WM regions of interest (ROIs). On T1-weighted images, normalised volumes of the whole brain (NBV), GM (NGMV) and WM were measured. Results A significant ‘trend’ of worsening with a trajectory ‘normal/aMCI/AD’ was found for NBV and NGMV, total GM and WM MD, total WM FA, as well as for diffusivity abnormalities in several GM and WM ROIs, mainly located in posterior brain regions. aMCI-C had GM and WM changes similar to those seen in AD, whereas aMCI-NC showed a DT MRI pattern similar to that of healthy subjects. DT MRI metrics that better distinguished aMCI-C from aMCI-NC were MD of total GM and WM, hippocampi, anterior insulae, frontal and parietal WM, occipital GM and WM, and FA of temporal WM. Volumetric variables were not able to distinguish the two aMCI subgroups (aMCI-C and aMCI-NC). Conclusions Subtle brain diffusivity changes occur from the prodromal stages of AD, mainly in posterior brain regions, and spread over the course of the disease to involve the frontal lobe. In aMCI, the severity of microstructural damage within and beyond the medial temporal lobe is associated with an increased short-term risk to develop AD.

A Magnetic Resonance Imaging Voxel-Based Morphometry Study of Regional Gray Matter Atrophy in Patients With Benign Multiple Sclerosis

BACKGROUND Evidence is accumulating that indicates that a selected assessment of gray matter (GM) damage is able to provide strong paraclinical correlates of multiple sclerosis (MS) severity. OBJECTIVE To investigate the pattern of regional GM atrophy in patients with benign MS (BMS) vs those with secondary progressive MS (SPMS) to better elucidate the factors associated with a favorable status in patients with MS. DESIGN Cross-sectional survey from January 2006 to August 2007. SETTING Referral, hospital-based MS clinics. Patients Sixty patients with BMS, 35 patients with SPMS, and 21 healthy volunteers. MAIN OUTCOME MEASURES Neuropsychological tests exploring memory, attention, and frontal lobe cognitive domains were administered to BMS patients. A voxel-based morphometry analysis of GM concentration was performed using statistical parametric mapping and a threshold of 0.05, corrected for multiple comparisons. RESULTS Twelve BMS patients (20%) had an abnormal performance on 3 or more neuropsychological tests. Compared with healthy individuals, BMS patients had a reduced GM volume in the subcortical and frontoparietal regions. Compared with BMS patients, those with SPMS had a significant GM loss in the cerebellum. No differences between BMS and SPMS patients were found when only BMS patients with cognitive impairment or those with shorter disease duration (15-19 years) and higher Expanded Disability Status Scale scores (>2.0) were considered. CONCLUSIONS Cerebellar GM atrophy seems to be a major determinant of irreversible locomotor disability in MS. The absence of cognitive impairment and a longer disease duration or lower Expanded Disability Status Scale score may identify those BMS patients with the potential for a favorable disease evolution.

Fatigue and its relationships with cognitive functioning and depression in paediatric multiple sclerosis

Background: There is limited information on fatigue and its clinical and psychosocial correlates in children and adolescents with multiple sclerosis (MS). Objective: To assess the relationships between fatigue, cognitive functioning and depression in paediatric MS. Methods: The study cohort consisted of patients with MS recruited for an Italian collaborative study on cognitive and psychosocial functioning in paediatric MS. The present assessment included evaluation of fatigue on the Pediatric Quality of Life Inventory-Multidimensional Fatigue Scale, cognitive functioning on an extensive neuropsychological battery and depression on the Children’s Depression Inventory (CDI). A psychiatric interview through the Kiddie-SADS-Present and Lifetime Version was also administered. Results: In total, 57 patients with relapsing–remitting MS were compared with 70 healthy controls. Percentages of fatigued patients ranged from 9% to 14% according to self-reports, and from 23% to 39% according to parent reports. Fatigue was significantly related with higher scores on the CDI (p < 0.03). Higher levels of self-reported cognitive fatigue were associated with impaired performance on a problem-solving test, whereas higher levels of parent-reported cognitive fatigue were associated with impairment on tests of verbal learning, processing speed, complex attention and verbal comprehension. Conclusions: Our data show that fatigue can affect a sizeable proportion of paediatric MS patients, and confirm the association between fatigue and depressive symptoms in MS. They also highlight the difficulties of fatigue assessment in the paediatric population and provide a few clues to further research in the field.