Gianna Riccitelli

Default-mode network dysfunction and cognitive impairment in progressive MS

Objective: This study explores default-mode network (DMN) abnormalities in patients with secondary progressive (SP) and primary progressive (PP) multiple sclerosis (MS) and whether such abnormalities correlate with cognitive impairment and damage to selected white matter (WM) fiber bundles, quantified using diffusion tensor (DT) MRI tractography. Methods: Resting state (RS) functional MRI and DT MRI data were acquired from 33 patients with SPMS, 24 patients with PPMS, and 24 controls. Independent component analysis (ICA) was used to identify the DMN. SPM5 was used to assess within- and between-group activations. Results: Between-group differences in DMN activity were found in the left medial prefrontal cortex (mPFC), left precentral gyrus (PcG), and anterior cingulate cortex (ACC). Compared to controls, patients with SPMS had reduced activity in the mPFC (p = 0.01) and PcG (p = 0.02), while patients with PPMS had reduced activity in the PcG (p = 0.008) and the ACC (p = 0.002). Compared to patients with PPMS, patients with SPMS had increased ACC activity (p = 0.04). Reduction of RS activity in the ACC was more pronounced in cognitively impaired vs cognitively preserved patients with MS (p = 0.02). In patients with MS, DMN abnormalities correlated with the PASAT and word list test scores (r values ranging from 0.35 to 0.45) and DT MRI changes in the corpus callosum and the cingulum (r values ranging from 0.82 to 0.87). Conclusion: These results suggest that a dysfunction of the anterior components of the default-mode network may be among the factors responsible for the accumulation of cognitive deficits in patients with progressive multiple sclerosis.

Multiple Sclerosis: Effects of Cognitive Rehabilitation on Structural and Functional MR Imaging Measures—An Explorative Study

PURPOSE To evaluate brain changes after cognitive rehabilitation in patients with clinically stable relapsing-remitting (RR) multiple sclerosis (MS) by using neuropsychologic assessment and structural and functional magnetic resonance (MR) imaging techniques. MATERIALS AND METHODS The study was conducted with approval of the involved institutional review boards. Written informed consent was obtained from each participant. Twenty patients with RR MS and cognitive deficits at baseline were randomly assigned to undergo treatment (n = 10), which entailed computer-assisted cognitive rehabilitation of attention and information processing and executive functions, or to serve as a control subjects (n = 10) without cognitive rehabilitation. All patients underwent a standardized neuropsychologic assessment and MR imaging at baseline and after 12 weeks. Changes in gray matter (GM) volumes on three-dimensional T1-weighted images and changes in normal-appearing white matter (NAWM) architecture on diffusion-weighted images were assessed. Changes in functional activity at functional MR imaging during the Stroop task and at rest were also investigated by using linear models. RESULTS As compared with their performance at baseline, the patients in the treatment group improved at tests of attention and information processing and executive functions. Neither structural modifications to GM volume nor modifications to NAWM architecture were detected at follow-up in both groups. Functional MR imaging demonstrated modifications of the activity of the posterior cingulate cortex (PCC)/precuneus and dorsolateral prefrontal cortex (PFC) during the Stroop task, as well as modifications of the activity of the anterior cingulum, PCC and/or precuneus, left dorsolateral PFC, and right inferior parietal lobule at rest in the treatment group compared with the control group. In the treatment group, functional MR imaging changes were correlated with cognitive improvement (P < .0001 to .01). CONCLUSION Rehabilitation of attention and information processing and executive functions in RR MS may be effected through enhanced recruitment of brain networks subserving the trained functions.

Structural and functional MRI correlates of Stroop control in benign MS

The objective of this study was to assess the functional and structural substrates of cognitive network changes in patients with benign multiple sclerosis (BMS), using an analysis of effective connectivity and MR tractography. Using a 3‐Tesla scanner, we acquired dual‐echo, diffusion tensor (DT) and functional MRI during the performance of the Stroop task from 15 BMS patients and 19 healthy controls. DT MRI tractography was used to calculate DT derived metrics from several white matter (WM) fiber bundles, thought to be involved in cognitive performance. DT MRI metrics from WM fiber bundles not directly related with cognitive performance were also derived. Effective connectivity analysis was performed using statistical parametric mapping. MS patients had significantly abnormal DT MRI metrics in all the structures analyzed. Compared with controls, MS patients had more significant activations of several areas of the cognitive network involved in Stroop performance, bilaterally. Compared with controls, BMS patients also had increased connectivity strengths between several cortical areas of the sensorimotor network and the right (R) inferior frontal gyrus and the R cerebellum, as well as decreased connectivity strengths with the anterior cingulate cortex. Coefficients of altered connectivity were moderately correlated with structural MRI metrics of tissue damage within intra‐ and inter‐hemispheric cognitive‐related WM fiber bundles, while no correlations were found with the remaining fiber bundles studied, suggesting that functional cortical changes in patients with BMS might represent an adaptive response driven by damage of specific WM structures. Hum Brain Mapp, 2009.

Brain reserve and cognitive reserve in multiple sclerosis: What you’ve got and how you use it

Objective: We first tested the brain reserve (BR) hypothesis in multiple sclerosis (MS) by examining whether larger maximal lifetime brain volume (MLBV; determined by genetics) protects against disease-related cognitive impairment, and then investigated whether cognitive reserve (CR) gained through life experience (intellectually enriching leisure activities) protects against cognitive decline independently of MLBV (BR). Methods: Sixty-two patients with MS (41 relapsing-remitting MS, 21 secondary progressive MS) received MRIs to estimate BR (MLBV, estimated with intracranial volume [ICV]) and disease burden (T2 lesion load; atrophy of gray matter, white matter, thalamus, and hippocampus). Early-life cognitive leisure was measured as a source of CR. We assessed cognitive status with tasks of cognitive efficiency and memory. Hierarchical regressions were used to investigate whether higher BR (ICV) protects against cognitive impairment, and whether higher CR (leisure) independently protects against cognitive impairment over and above BR. Results: Cognitive status was positively associated with ICV (R2 = 0.066, p = 0.017). An ICV × disease burden interaction (R2 = 0.050, p = 0.030) revealed that larger ICV attenuated the impact of disease burden on cognition. Controlling for BR, higher education (R2 = 0.047, p = 0.030) and leisure (R2 = 0.090, p = 0.001) predicted better cognition. A leisure × disease burden interaction (R2 = 0.037, p = 0.030) showed that leisure independently attenuated the impact of disease burden on cognition. Follow-up analyses revealed that BR protected against cognitive inefficiency, not memory deficits, whereas CR was more protective against memory deficits than cognitive inefficiency. Conclusion: We provide evidence of BR in MS, and show that CR independently protects against disease-related cognitive decline over and above BR. Lifestyle choices protect against cognitive impairment independently of genetic factors outside of ones control.

Gray matter damage predicts the accumulation of disability 13 years later in MS

Objectives: To assess the value of conventional and magnetization transfer (MT) MRI measures of white matter (WM) and gray matter (GM) damage, and their 12-month change, in predicting long-term disability and cognitive impairment in multiple sclerosis (MS). Methods: Conventional and MT MRI brain scans were obtained at baseline and at 12 months in 73 patients, who were followed prospectively with clinical visits and rating of the Expanded Disability Status Scale score and the MS severity score (MSSS) for a median period of 13.3 years. At 13-year follow-up, a neuropsychological assessment was also performed when possible. T2-hyperintense and T1-hypointense lesion volumes, GM fraction (GMF), WM fraction, thalamic fraction, average lesion MT ratio (MTR), average GM MTR, average normal-appearing WM MTR, and thalamic MTR were measured. Random forest and multivariable analyses were performed to identify the predictors of neurologic deterioration and cognitive impairment at 13 years. Results: At 13-year follow-up, 66% of patients showed significant worsening of disability and 37% had worsened cognitively. The multivariable model, in which Expanded Disability Status Scale deterioration at final follow-up was the dependent variable, identified baseline GMF (odds ratio [OR] = 0.79, p = 0.01) as the only predictor of worsening of disability (C-index = 0.69). Baseline disease duration (OR = 1.50, p = 0.08) and average GM MTR (OR = 0.87, p = 0.03) were independent variables associated with cognitive deterioration (C-index = 0.97). Baseline MSSS (β = 0.50, p < 0.0001) and baseline GMF (β = −0.32, p = 0.0005) predicted MSSS at follow-up (r2 = 0.45). Conclusions: GM damage is one of the key factors associated with long-term accumulation of disability and cognitive impairment in MS.

Corpus callosum damage and cognitive dysfunction in benign MS

Corpus callosum (CC), the largest compact white matter fiber bundle of the human brain involved in interhemispheric transfer, is frequently damaged in the course of multiple sclerosis (MS). Cognitive impairment is one of the factors affecting quality of life of patients with benign MS (BMS). The aim of this study was to investigate the relationship between the cognitive profile of BMS patients and the extent of tissue damage in the CC. Brain conventional and DT MRI scans were acquired from 54 BMS patients and 21 healthy controls. Neuropsychological tests (NPT) exploring memory, attention, and frontal lobe cognitive domains were administered to the patients. DT tractography was used to calculate the mean diffusivity (MD) and fractional anisotropy (FA) of the CC normal appearing white matter (NAWM). An index of CC atrophy was also estimated. Nine (17%) BMS patients fulfilled criteria for cognitive impairment. Compared with controls, BMS had significantly different CC diffusivity and volumetry (P < 0.001). Compared with cognitively preserved patients, those with CI had significantly higher CC lesion volume (LV) (P = 0.02) and NAWM MD (P = 0.02). The scores obtained at PASAT were significantly correlated with CC T2 LV, and NAWM FA and MD (r values ranging from −0.31 to 0.66, P values ranging from 0.04 to <0.001). Cognitive impairment in BMS is associated with the extent of CC damage in terms of both focal lesions and diffuse fiber bundle injury. MRI assessment of topographical distribution of tissue damage may represent a rewarding strategy for understanding the subtle clinical deficits of patients with BMS. Hum Brian Mapp 2009.

Cognitive impairment in multiple sclerosis is associated to different patterns of gray matter atrophy according to clinical phenotype.

Objective: To investigate whether cognitive impairment in multiple sclerosis (MS) patients is associated to different patterns of gray matter (GM) atrophy and T2‐visible lesion distribution according to the clinical phenotype. Experimental Design: Twenty‐two relapsing remitting (RR), 29 secondary progressive (SP), and 22 primary progressive (PP) MS patients, and 39 healthy controls underwent high‐field structural magnetic resonance imaging and an extensive neuropsychological battery. Voxel‐wise distribution of GM damage and T2‐lesions was compared between cognitively impaired (CI) and cognitively preserved (CP) patients according to their clinical phenotype. Principal Observations: Thirty‐nine MS patients were CI. In all MS groups, regional GM loss was correlated with cognitive impairment. Different patterns of regional distribution of GM atrophy and T2‐visible lesions were found between CI vs. CP MS patients, according to their clinical phenotype. No areas were significantly more atrophied in CI SPMS vs. CI RRMS patients. Conversely, compared with CI PPMS, CI SPMS patients had a significant GM loss in several regions of the fronto‐temporal lobes, the left hypothalamus and thalami. While in RRMS and SPMS patients there was a correspondence between presence of T2 visible lesions and GM atrophy in several areas, this was not the case in PPMS patients. Conclusion: Distinct patterns of regional distribution of GM damage and T2‐visible lesions are associated with cognitive impairment in MS patients with different clinical phenotypes. The correspondence between lesion formation and GM atrophy distribution varies in the different forms of MS. Hum Brain Mapp, 2010.

Cognitive Functions and White Matter Tract Damage in Amyotrophic Lateral Sclerosis: A Diffusion Tensor Tractography Study

BACKGROUND AND PURPOSE: ALS is predominantly a disease of the motor system, but cognitive and behavioral symptoms also are observed. DT MR imaging is sensitive to microstructural changes occurring in WM tracts of patients with ALS. In this study, we investigated the association between cognitive functions and extramotor WM tract abnormalities in ALS patients. MATERIALS AND METHODS: DT MR imaging was obtained from 16 nondemented patients with ALS and 15 healthy controls. Patients with ALS underwent a neuropsychologic and behavioral evaluation. DT tractography was used to asses the integrity of the CST, corpus callosum, and the major long-range association tracts. The relationship between DT MR imaging metrics and cognitive functions was tested by using linear model analyses, adjusting for age and clinical disability. RESULTS: Eleven patients (69%) scored below the fifth percentile in at least 1 cognitive test, and 2 of them had a mild executive impairment. Performances at tests assessing attention and executive functions correlated with DT MR imaging metrics of the corpus callosum, CST, and long association WM tracts bilaterally, including the cingulum, inferior longitudinal, inferior fronto-occipital, and uncinate fasciculi. Verbal learning and memory test scores were associated with fornix DT MR imaging values, whereas visual-spatial abilities correlated with left uncinate fractional anisotropy. CONCLUSIONS: WM tract degeneration is associated with neuropsychologic deficits in patients with ALS. DT tractography holds promise to gain insight into the role of the brain WM network abnormalities in the development of cognitive impairment in patients with ALS.

Influence of the topography of brain damage on depression and fatigue in patients with multiple sclerosis

Objectives: Involvement of selected central nervous system (CNS) regions has been associated with depression and fatigue in MS. We assessed whether specific regional patterns of lesion distribution and atrophy of the gray (GM) and white matter (WM) are associated with these symptoms in MS. Methods: Brain dual-echo and 3D T1-weighted images were acquired from 123 MS patients (69 depressed (D), 54 non-depressed (nD), 64 fatigued, 59 non-fatigued) and 90 controls. Lesion distribution, GM and WM atrophy were estimated using VBM and SPM8. Results: Gender, age, disease duration and conventional MRI characteristics did not differ between D-MS and nD-MS patients. Fatigued patients experienced higher EDSS and depression than non-fatigued ones. Lesion distribution and WM atrophy were not related to depression and fatigue. Atrophy of regions in the frontal, parietal and occipital lobes had a combined effect on depression and fatigue. Atrophy of the left middle frontal gyrus and right inferior frontal gyrus were selectively related to depression. No specific pattern of GM atrophy was found to be related to fatigue. Conclusions: Depression in MS is linked to atrophy of cortical regions located in the bilateral frontal lobes. A distributed pattern of GM atrophy contributes to the concomitant presence of depression and fatigue in these patients.

Voxelwise assessment of the regional distribution of damage in the brains of patients with multiple sclerosis and fatigue.

BACKGROUND AND PURPOSE: Fatigue affects up to 90% of patients with MS. We assessed the regional distribution of lesions and atrophy of the normal-appearing WM and GM in patients with RRMS with fatigue compared with HC and patients with similar characteristics, but without fatigue. MATERIALS AND METHODS: From 14 patients with RRMS without fatigue, 10 with RRMS with fatigue, and 14 HC, we acquired brain dual-echo and high-resolution T1-weighted scans. Voxel-wise distributions of GM, WM damage, and T2 lesions were compared between patients with fatigued and nonfatigued MS by using SPM5 software. We report results at P < .05, FWE corrected. RESULTS: T2 lesion distribution and regional WM atrophy did not differ between patients with fatigued and nonfatigued MS. Compared with HC, patients with MS had significant WM atrophy in the posterior part of the corpus callosum and significant GM atrophy of the left superior frontal sulcus, left precentral gyrus, posterior cingulate cortex, right thalamus, and left middle frontal gyrus. No additional areas of atrophy were found in patients with nonfatigued MS compared with HC, whereas patients with fatigued MS also had atrophy of the left central sulcus. Atrophy in the left central sulcus and the precentral gyrus was more severe in patients with fatigued versus nonfatigued MS. In patients with MS, significant correlations were found between fatigue severity and GM atrophy in the left precentral gyrus (r = −0.73, P < .0001 uncorrected). CONCLUSIONS: Atrophy of the primary sensorimotor area is likely to contribute to MS-related fatigue.