Cognitive impairment and memory disorders in relapsing–remitting multiple sclerosis: the role of white matter, gray matter and hippocampus (original) (raw)
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American Journal of Neuroradiology, 2016
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. ABBREVIATIONS: CI ϭ cognitively impaired; CL ϭ cortical lesion; CP ϭ cognitively preserved; DIR ϭ double inversion recovery; EDSS ϭ Expanded Disability Status Scale; HC ϭ healthy controls; LV ϭ lesion volumes; WCST ϭ Wisconsin Card Sorting Test C ognitive impairment is a frequent finding in patients with multiple sclerosis, with 40%-70% of patients showing cognitive deficits. 1 The most affected domains are attention, information-processing speed, executive functions, and memory and visuospatial abilities. 1 Given its dramatic effect on the activities of patients' daily lives, there is a critical need to define the pathophysiologic mechanisms of cognitive impairment in MS, to develop markers for its monitoring, and to identify valid therapeutic strategies. Many studies tried to characterize the structural MR imaging correlates of cognitive impairment in patients with MS. T2 and T1 lesion volumes were found to be generally higher in patients with
Cognitive impairment may result in significant disability in patients with Multiple Sclerosis (MS). Previous Magnetic Resonance Imaging (MRI) studies on cognition in MS were mainly based on measures of gross brain involvement. This study, using voxel-based morphometry (VBM), aims to investigate associations between the regional distribution of grey matter (GM) damage and cognitive performance in patients with MS. Eighteen MS patients underwent an extensive neuropsychological battery and MRI, including T2-weighted scans and T1-weighted volumes. A group of 18 healthy individuals were also investigated by MRI and served as controls for the VBM. A cross-sectional analysis was first performed, to assess the pattern of regional GM atrophy in MS patients. Then, the impact of regional GM damage on patients' neuropsychological performance was investigated by multiple regression analyses in the patient group. Correlations between global indexes of brain damage and neuropsychological measures were also assessed for comparison with previous literature. The comparison between MS patients and healthy controls revealed a widespread pattern of regional GM atrophy. Consistent with previous studies, associations were found between neuropsychological scores, and global brain atrophy and T2-lesion volumes. Critically, significant associations were found between scores on the Symbol Digit Modalities test and Long Delay Cued Recall on the California Verbal Learning Test, and regional GM volumes in well localized areas of the prefrontal, parietal, temporal, and insular cortex. This study confirms that global assessments of brain damage correlate with measures of cognitive impairment in MS. Interestingly, VBM contributes to clarify those brain regions that more likely determine the cognitive deficits observed in patients. These findings clarify the pathophysiology of cognitive impairment in MS, and propose measures which could be considered for longitudinal monitoring of patients.
Human Brain Mapping, 2011
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 32:1535-1543,
2021
Cognitive impairment (CI) is frequently present in multiple sclerosis patients. Despite ongoing research, the neurological substrates have not been fully elucidated. In this study we investigated the contribution of gray and white matter in the CI observed in mildly disabled relapsing-remitting multiple sclerosis (RRMS) patients. For that purpose, 30 patients with RRMS (median EDSS = 2), and 30 age- and sex-matched healthy controls were studied. CI was assessed using the symbol digit modalities test (SDMT) and the memory alteration test. Brain magnetic resonance imaging, diffusion tensor imaging (DTI), voxel-based morphometry (VBM), brain segmentation, thalamic vertex analysis, and connectivity-based thalamic parcellation analyses were performed. RRMS patients scored significantly lower in both cognitive tests. In the patient group, significant atrophy in the thalami was observed. Multiple regression analyses revealed associations between SDMT scores and GM volume in both hemisphere...
PLOS ONE, 2015
New treatment options may make "no evidence of disease activity" (NEDA: no relapses or disability progression and no new/enlarging MRI lesions, as opposed to "evidence of disease activity" (EDA) with at least one of the former), an achievable goal in relapsing-remitting multiple sclerosis (RRMS). The objective of the present study was to determine whether early RRMS patients with EDA at one-year follow-up had different disability, cognition, treatment and gray matter (GM) atrophy rates from NEDA patients and healthy controls (HC). RRMS patients (mean age 34 years, mean disease duration 2.2 years) were examined at baseline and one-year follow-up with neurological (n = 72), neuropsychological (n = 56) and structural MRI (n = 57) examinations. Matched HC (n = 61) were retested after three years. EDA was found in 46% of RRMS patients at follow-up. EDA patients used more first line and less second line disease modifying treatment than NEDA (p = 0.004). While the patients groups had similar disability levels at baseline, they differed in disability at followup (p = 0.010); EDA patients progressed (EDSS: 1.8-2.2, p = 0.010), while NEDA patients improved (EDSS: 2.0-1.7, p<0.001). Cognitive function was stable in both patient groups. Subcortical GM atrophy rates were higher in EDA patients than HC (p<0.001). These results support the relevance of NEDA as outcome in RRMS and indicate that pathological neurodegeneration in RRMS mainly occur in patients with evidence of disease activity. ambitious goal of multiple sclerosis (MS) therapy. The rationale for this concept is that MS treatment should aim for no signs of disease activity; neither new relapses, disability progression nor new/enlarging white matter (WM) lesions.
European Journal of Neurology, 2008
Background and purpose: We have studied the relationship between neuropsychological impairment and magnetic resonance imaging (MRI) measures in mildly disabling relapsing-remitting multiple sclerosis (RRMS). Methods: We compared measures of lesion burden and atrophy in 52 patients with Expanded Disability Status Scale £ 3.0. Neuropsychological testing explored various cognitive domains: attention and processing speed (APS), verbal and visual memory (VerbM; VisM), visual/constructional processes (VC), executive functions and motor programming/coordination. Specific and global index scores were derived to classify patients as deteriorated or not deteriorated by comparing their performance with 51 matched normal control subjects. Brain MRI analysis included proton density (PD)-lesion volume and T1-hypointensity volume, measures of central atrophy, including the third ventricle width, and corpus callosum (CC). Results: Patients with either APS, MCP or Verbal Learning impairments had a higher ventricular atrophy than unimpaired. The atrophy of the CC was only associated to VisM dysfunction. Patients with VisM deficits had higher lesion load on PD images. After controlling for age and education a higher third ventricle width was the best predictor for global and specific cognitive impairment. Conclusion: Our results suggest that cognitive impairment in RR patients with mild disease is better explained by atrophic changes than by total lesion load.
Multiple Sclerosis Journal, 2020
Background: When persons with multiple sclerosis (MS) report memory decline but objective memory performance is normal, there is a bias toward believing objective test results.Objective: Investigate whether subjective memory decline or objective memory performance is more related to hippocampal and hippocampal subfield volumes in early MS.Methods: Persons with early MS (n = 185; ⩽5.0 years diagnosed) completed a subjective memory ques-tionnaire; an objective memory composite was derived from four memory tests. Total hippocampal and subfield volumes were derived from high-resolution 3.0 T magnetic resonance images (MRIs). Partial correlations assessed links between hippocampal volumes and both subjective and objective memory, controlling for age, sex, mood, and pre-morbid intelligence quotient (IQ).Results: Lower total hippocampal and CA1 volumes were related to worse subjective memory but not objective memory (controlling for multiple comparisons). Correlations between subjective memory and both CA1 and subiculum were significantly stronger than were correlations between objective memory and these subfields. Patients in the worst tertile of subjective memory complaints (but not objective memory) had lower hippocampal volumes than 35 demographically similar healthy controls.Conclusion: Patient-report is inherently a longitudinal assessment of within-person memory change in everyday life, which may be more sensitive to subtle disease-related changes than cross-sectional objective tests. Findings align with the aging literature.
Clinical and imaging assessment of cognitive dysfunction in multiple sclerosis
The Lancet Neurology, 2015
In patients with multiple sclerosis (MS), grey matter damage is widespread and might underlie many of the clinical symptoms, especially cognitive impairment. This relation between grey matter damage and cognitive impairment has been lent support by fi ndings from clinical and MRI studies. However, many aspects of cognitive impairment in patients with MS still need to be characterised. Standardised neuropsychological tests that are easy to administer and sensitive to disease-related abnormalities are needed to gain a better understanding of the factors aff ecting cognitive performance in patients with MS than exists at present. Imaging measures of the grey matter are necessary, but not suffi cient to fully characterise cognitive decline in MS. Imaging measures of both lesioned and normal-appearing white matter lend support to the hypothesis of the existence of an underlying disconnection syndrome that causes clinical symptoms to trigger. Findings on cortical reorganisation support the contribution of brain plasticity and cognitive reserve in limiting cognitive defi cits. The development of clinical and imaging biomarkers that can monitor disease development and treatment response is crucial to allow early identifi cation of patients with MS who are at risk of cognitive impairment.
Relation between MR abnormalities and patterns of cognitive impairment in multiple sclerosis
Neurology, 1998
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.
Multiple sclerosis (Houndmills, Basingstoke, England), 2016
We investigated whether diffusion tensor imaging (DTI) could reveal early hippocampal damage and clinically relevant correlates of memory impairment in persons with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS). A total of 37 persons with CIS, 32 with MS and 36 controls prospectively included from 2011 to 2014 were tested for cognitive performances and scanned with 3T-magnetic resonance imaging (MRI) to assess volumetric and DTI changes within the hippocampus, whole brain volume and T2-lesion load. While there was no hippocampal atrophy in the CIS group, hippocampal fractional anisotropy (FA) was significantly decreased compared to controls. Decrease in hippocampal FA together with increased mean diffusivity (MD) was even more prominent in MS patients. In CIS, hippocampal MD was correlated with episodic verbal memory performance (r = -0.57, p = 0.0002 and odds ratio (OR) = 0.058, 95% confidence interval (CI) = 0.0057-0.59, p = 0.016 adjusted for age, gende...