Cognitive impairment is associated with subcortical magnetic resonance imaging grey matter T2 hypointensity in multiple sclerosis

Grey matter hypointensity on T2-weighted magnetic resonance imaging (MRI) scans, suggesting iron deposition, has been described in multiple sclerosis (MS) and is related to physical disability, disease course and brain atrophy. We tested the hypothesis that subcortical grey matter T2 hypointensity is related to cognitive impairment after adjusting for the effect of MRI lesion and atrophy measures. We studied 33 patients with MS and 14 healthy controls. Normalized T2 signal intensity in the caudate, putamen, globus pallidus and thalamus, total brain T1-hypointense lesion volume (T1LV), fluid-attenuated inversion-recovery-hyperintense lesion volume (FLLV) and brain parenchymal fraction (BPF) were obtained quantitatively. A neuropsychological composite score (NCS) encompassed new learning, attention, working memory, spatial processing and executive function. In each of the regions of interest, the normalized T2 intensity was lower in the MS versus control group (all P<0.001). Regression modelling tested the relative association between all MRI variables and NCS. Globus pallidus T2 hypointensity was the only variable selected in the final model (R2 = 0.301, P = 0.007). Pearson correlations between MRI and NCS were T1LV: r = -0.319; FLLV: r = -0.347; BPF: r = 0.374; T2 hypointensity of the caudate: r = 0.305; globus pallidus: r = 0.395; putamen: r = 0.321; and thalamus: r = 0.265. Basal ganglia T2 hypointensity and BPF demonstrated the strongest associations with cognitive impairment on individual cognitive subtests. Subcortical grey matter T2 hypointensity is related to cognitive impairment in MS, supporting the clinical relevance of T2 hypointensity as a biological marker of MS tissue damage. These data implicate a role for basal ganglia iron deposition in neuropsychological dysfunction.     

T1 hypointensity of the spinal cord in multiple sclerosis

It has recently been shown in multiple sclerosis (MS) that the volume of T1 hypointense lesions in the brain explains more of the variance in disability amongst patients than T2 lesion volume. T1 hypointense lesions may therefore represent areas of underlying pathology likely to be of functional significance, such as axonal loss. The spinal cord is a common area of involvement in MS and its dysfunction is likely to be responsible for much of the motor disability seen. Hence it serves as a useful model by which to examine the functional relevance of differing imaging sequences. We have therefore examined the relationship between T1 signal intensity in the spinal cord and disability in 60 patients with MS. We have also examined the relationship between T1 signal intensity and atrophy of the cord, as the latter is another potential marker of axonal loss. Sixty patients with MS underwent spinal cord imaging with a T1 weighted sequence to acquire axial sections of the cord at the C2 level. These sections were histogram matched to allow comparison of image intensity and a manual outlining technique was applied from which the mean cord intensity was calculated. Within the patient group there was a significant relationship between T1 signal intensity and disability as measured with the EDSS (r = −0.4, p < 0.005) and also between T1 signal intensity and atrophy (r = 0.36, p < 0.005). This study demonstrates that disability and atrophy are associated with a generalised reduction in cord signal on T1 weighted images. A lower T1 signal intensity in the spinal cord may be more pathologically specific than T2 hyperintensity and may represent underlying axonal loss, although gliosis and predominant white matter atrophy are alternative possibilities. Received: 7 April 2000, Received in revised form: 29 December 2000, Accepted: 10 January 2001     

Prediction of longitudinal brain atrophy in multiple sclerosis by gray matter magnetic resonance imaging T2 hypointensity

BACKGROUND: Gray matter magnetic resonance imaging T2 hypointensity, a marker of iron deposition, is associated with clinical impairment and brain atrophy in cross-sectional studies of multiple sclerosis. Treatment with intramuscular interferon beta-1a limits brain atrophy in the second year of treatment. OBJECTIVE: To test whether T2 hypointensity predicts brain atrophy and whether interferon affects this relationship. DESIGN: Post hoc analysis. SETTING: A multicenter treatment trial conducted at tertiary care comprehensive multiple sclerosis centers.Patients Patients with multiple sclerosis who took part in a 2-year clinical trial in which they received intramuscular interferon beta-1a (30 mug/wk) or placebo. MAIN OUTCOME MEASURES: Deep gray matter T2 hypointensity, brain parenchymal fraction (BPF), and total T2, gadolinium-enhancing, and T1 lesion volumes. RESULTS: T2 hypointensity in various gray matter areas correlated with baseline BPF (r = 0.19-0.39; P = .001-.03). In placebo-treated patients (n = 68), baseline T2 hypointensity predicted the change in BPF in the first year and throughout 2 years (r = 0.26-0.42; P<.001-.03). T2 hypointensity was chosen in regression modeling as the best predictor of BPF change at the 1-year (R(2) = 0.23; P = .002) and 2-year (R(2) = 0.33; P<.001) time points after accounting for all magnetic resonance imaging variables. In the interferon group (n = 65), no relationship existed between baseline T2 hypointensity and BPF change. CONCLUSIONS: Gray matter T2 hypointensity predicts the progression of brain atrophy in placebo- but not interferon beta-1a-treated patients. This predictive effect is seen as early as the first year. We hypothesize that interferon beta may exert its effect on brain atrophy in part by reducing a cascade of events that involve iron deposition as a mediator of neurotoxicity or as a disease epiphenomenon.     

Transcranial brain sonography findings related to neuropsychological impairment in multiple sclerosis

Cognitive dysfunction, fatigue and mood disorder contribute to the neuropsychological impairment that is common in multiple sclerosis (MS). The present paper reviews application of transcranial brain sonography (TCS) in MS patients and TCS findings related to neuropsychological dysfunction. TCS is a new neuroimaging method displaying tissue echogenicity of the brain through the intact skull. Whereas the cortex can not be discriminated from the subcortical white matter with TCS, subcortical brain structures such as ventricles and basal ganglia can be adequately displayed. Even though TCS proved sensitive and reliable in measuring widths of third and lateral ventricles in a number of neurodegenerative diseases, relatively few TCS studies on MS patients have been reported. Data of these studies suggest a good correlation of cognitive dysfunction and width of third ventricle which can be measured reliably with TCS. Moreover, abnormal TCS findings of basal ganglia were associated with cognitive impairment. However, TCS findings of midbrain structures, basal ganglia and ventricles did not correlate with fatigue or depression in MS patients. TCS has the advantages of low costs, short investigation times and unlimited repeatability. The use of third-ventricle and basalganglia TCS for predicting and monitoring neuropsychological impairment in MS patients, however, needs to be elucidated in further studies.     

Transcranial brain sonography findings related to neuropsychological impairment in multiple sclerosis

Journal of Neurology - Cognitive dysfunction, fatigue and mood disorder contribute to the neuropsychological impairment that is common in multiple sclerosis (MS). The present paper reviews...     

多发性硬化伴认知功能障碍磁共振成像研究进展

多发性硬化是临床常见的中枢神经系统脱髓鞘疾病,可伴发认知功能障碍,其发生机制迄今尚未阐明。越来越多MRI新技术的广泛应用,为从神经影像学角度阐述多发性硬化伴认知功能障碍的发生机制提供重要依据。本文对近年关于多发性硬化伴认知功能障碍的MRI研究进展进行概述。     

Increased level of cerebrospinal fluid β2–microglobulin is related to neurologic impairment in multiple sclerosis

beta 2-microglobulin was measured in the CSF of 33 MS patients (age range 26-66 years) and compared with the 95% confidence interval determined in an age-matched reference group of 32 patients without neurologic disease. Six MS (18%) had moderately increased concentrations and this subgroup was characterized by severe neurologic impairment according to Kurtzke's expanded disability scale. Increased CSF beta 2-microglobulin concentration in MS may reflect lesion formation.     

The contribution of MRI in assessing cognitive impairment in multiple sclerosis

Cognitive impairment affects a large proportion of patients with multiple sclerosis (MS) and has a profound impact on their daily-life activities. Improving the knowledge of the pathophysiology of cognitive impairment in MS and of the mechanisms responsible for its evolution over time might contribute to development of better outcome measures and targets for innovative treatment strategies. Due to their ability to detect MS-related abnormalities, MRI techniques are a valuable tool to achieve these goals. Following an updated overview of the assessment methods and profile of cognitive impairment in patients with MS, this review provides a state-of-the-art summary of the main results obtained from the application of conventional and modern magnetic resonance- based techniques to quantify MS-related damage, in terms of macroscopic lesions, as well as involvement of the normal-appearing white matter and gray matter and their association with cognitive impairment. The possible role of brain cortical reorganization in limiting the clinical consequences of disease-related damage is also discussed. Finally, the utility of the previous techniques to monitor the progression of cognitive deficits over time and the efficacy of possible therapeutic strategies is considered.     

Chemokine receptor expression on T cells is related to new lesion development in multiple sclerosis

The expression of chemokine receptors CCR5 and CXCR3 on CD4 and CD8 positive T cells in blood, measured by flow cytometry, was studied in 124 patients with different clinical subtypes of multiple sclerosis (MS) and 22 healthy controls. In a subgroup of patients (n=69) from whom MRI was available, chemokine receptor expression was correlated to the annualised changes in T1 and T2 lesion load.It was found that CCR5 and CXCR3 on both cell types might have impact on annualised increase in T2 lesion load, but not on T1 lesion load. Our results suggest that chemokines may play a more important role in the development of new lesions in MS than in the long-term outcome of those lesions.     

Structural MRI correlates of cognitive impairment in patients with multiple sclerosis

In a multicenter setting, we applied voxel‐based methods to different structural MR imaging modalities to define the relative contributions of focal lesions, normal‐appearing white matter (NAWM), and gray matter (GM) damage and their regional distribution to cognitive deficits as well as impairment of specific cognitive domains in multiple sclerosis (MS) patients. Approval of the institutional review boards was obtained, together with written informed consent from all participants. Standardized neuropsychological assessment and conventional, diffusion tensor and volumetric brain MRI sequences were collected from 61 relapsing‐remitting MS patients and 61 healthy controls (HC) from seven centers. Patients with ≥2 abnormal tests were considered cognitively impaired (CI). The distribution of focal lesions, GM and WM atrophy, and microstructural WM damage were assessed using voxel‐wise approaches. A random forest analysis identified the best imaging predictors of global cognitive impairment and deficits of specific cognitive domains. Twenty‐three (38%) MS patients were CI. Compared with cognitively preserved (CP), CI MS patients had GM atrophy of the left thalamus, right hippocampus and parietal regions. They also showed atrophy of several WM tracts, mainly located in posterior brain regions and widespread WM diffusivity abnormalities. WM diffusivity abnormalities in cognitive‐relevant WM tracts followed by atrophy of cognitive‐relevant GM regions explained global cognitive impairment. Variable patterns of NAWM and GM damage were associated with deficits in selected cognitive domains. Structural, multiparametric, voxel‐wise MRI approaches are feasible in a multicenter setting. The combination of different imaging modalities is needed to assess and monitor cognitive impairment in MS. Hum Brain Mapp 37:1627‐1644, 2016. © 2016 Wiley Periodicals, Inc.     

T2 hypointensity in the deep gray matter of patients with multiple sclerosis: a quantitative magnetic resonance imaging study.

CONTEXT: While gray matter T2 hypointensity in multiple sclerosis (MS) has been associated with physical disability and clinical course, previous studies have relied on visual magnetic resonance imaging (MRI) assessments. OBJECTIVE: To quantitatively determine if T2 hypointensity is associated with conventional MRI and clinical findings in MS. DESIGN: Case-control study. SETTING: University-affiliated community-based hospital. SUBJECTS: Sixty patients with MS and 50 controls. MAIN OUTCOME MEASURES: T2 intensities of the substantia nigra, red nucleus, thalamus, putamen, globus pallidus, and caudate; third ventricular width; total brain T1 (hypointense) and T2 (hyperintense) lesion volumes; Expanded Disability Status Scale (physical disability) score; and disease course. RESULTS: Deep gray matter T2 hypointensity was present in patients with MS in all structures (P<.005) except for the substantia nigra. T2 hypointensity was associated with third ventricle enlargement and higher T2 but not T1 plaque load. The regression model predicting third ventricle width included caudate T2 hypointensity (P =.006). The model predicting T2 lesion load included globus pallidus T2 hypointensity (P =.001). Caudate T2 hypointensity was the only variable associated with disability score in regression modeling (P =.03). All T2 hypointensities differentiated the secondary progressive from the relapsing-remitting clinical courses. The final model (P<.001) predicting clinical course retained T2 hypointensity of the thalamus, caudate, and putamen but not MRI plaques or atrophy. CONCLUSIONS: Gray matter T2 hypointensity in MS is associated with brain atrophy and is a stronger predictor of disability and clinical course than are conventional MRI findings. While longitudinal studies are warranted, these results suggest that pathologic iron deposition is a surrogate marker of the destructive disease process.     

Brain MRI lesions and atrophy are related to depression in multiple sclerosis

It is unclear whether brain MRI lesions are associated with depression in multiple sclerosis (MS). Neurological dysfunction in depressed (n= 19) and non-depressed (n = 29) MS patients was rated by expanded disability status scale (EDSS). EDSS was weakly predictive of the presence of (p = 0.03) and severity of (p = 0.01) depression. After correcting for EDSS, the presence of depression was predicted by superior frontal and superior parietal hypointense TI lesions (p<0.01); the severity of depression was predicted by superior frontal, superior parietal and temporal TI lesions, lateral and third ventricular enlargement, and frontal atrophy (p<0.01). Depression was not related to bright T2 lesions or enhancement. We conclude that atrophy and cortical-subcortical disconnection due to frontal and parietal white matter destructive lesions may contribute to depression in MS.     

Hyperhomocysteinemia is associated with cognitive impairment in multiple sclerosis

Hyperhomocysteinemia (HHcy) has been associated with cognitive impairment in various neurological diseases. Cognitive impairment occurs early in multiple sclerosis (MS). Conflicting data have been reported regarding plasma total homocysteine (tHcy) levels in MS patients, and the impact of HHcy on cognitive impairment in MS is not known. This study investigated whether plasma total homocysteine levels are increased in MS and if HHcy is associated with cognitive impairment in MS. We compared tHcy levels in 94 patients with MS and 53 healthy age-matched controls. We used a neuropsychological test battery that included the Raven's Coloured Progressive Matrices, the Visual Search Test, the Trail Making Test A and B, the Immediate and Delayed Recall of a Short Story, the 30 Paired Word Associates, the Rey-Osterrieth Complex Figure Test, and the Semantic and Verbal Fluency Tests. Clinical (sex, age, type of MS, relapse, disease duration, coexisting disease, smoking habit, and physical disability) and laboratory variables (HHcy, low serum levels of folate and vit.B12, MTHFR genotype) were evaluated for their ability to predict cognitive impairment. The mean tHcy was higher in patients (13.19 micromol/L, SD5.58) than in controls (9.81 micromol/L, SD2.53; p < 0.001). Univariate analysis determined the following factors to be associated with cognitive impairment: higher age at observation, chronic progressive course of disease, longer disease duration,moderate or severe physical disability, and frequency of HHcy. With multivariate regression analysis, there remained a significant association only between frequency of HHcy and cognitive impairment (beta 0.262, p = 0.01). We conclude that tHcy levels are increased in MS and that HHcy is associated with cognitive impairment in this disease.