Evaluation of a connectivity-based imaging metric that reflects functional decline in Multiple Sclerosis

Cognitive impairment is a common symptom in individuals with Multiple Sclerosis (MS), but meaningful, reliable biomarkers relating to cognitive decline have been elusive, making evaluation of the impact of therapeutics on cognitive function difficult. Here, we combine pathway-based MRI measures of structural and functional connectivity to construct a metric of functional decline in MS. The Structural and Functional Connectivity Index (SFCI) is proposed as a simple, z-scored metric of structural and functional connectivity, where changes in the metric have a simple statistical interpretation and may be suitable for use in clinical trials. Using data collected at six time points from a 2-year longitudinal study of 20 participants with MS and 9 age- and sex-matched healthy controls, we probe two common symptomatic domains, motor and cognitive function, by measuring structural and functional connectivity in the transcallosal motor pathway and posterior cingulum bundle. The SFCI is significantly lower in participants with MS compared to controls (p = 0.009) and shows a significant decrease over time in MS (p = 0.012). The change in SFCI over two years performed favorably compared to measures of brain parenchymal fraction and lesion volume, relating to follow-up measures of processing speed (r = 0.60, p = 0.005), verbal fluency (r = 0.57, p = 0.009), and score on the Multiple Sclerosis Functional Composite (r = 0.67, p = 0.003). These initial results show that the SFCI is a suitable metric for longitudinal evaluation of functional decline in MS.

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Long-range connections are more severely damaged and relevant for cognition in multiple sclerosis

Brain ◽

10.1093/brain/awz355 ◽

2019 ◽

Vol 143 (1) ◽

pp. 150-160 ◽

Cited By ~ 6

Author(s):

Kim A Meijer ◽

Martijn D Steenwijk ◽

Linda Douw ◽

Menno M Schoonheim ◽

Jeroen J G Geurts

Keyword(s):

Multiple Sclerosis ◽

Functional Connectivity ◽

Fractional Anisotropy ◽

Long Range ◽

Short Range ◽

Brain Regions ◽

Healthy Controls ◽

Network Efficiency ◽

Structural Network ◽

The Impact

Abstract An efficient network such as the human brain features a combination of global integration of information, driven by long-range connections, and local processing involving short-range connections. Whether these connections are equally damaged in multiple sclerosis is unknown, as is their relevance for cognitive impairment and brain function. Therefore, we cross-sectionally investigated the association between damage to short- and long-range connections with structural network efficiency, the functional connectome and cognition. From the Amsterdam multiple sclerosis cohort, 133 patients (age = 54.2 ± 9.6) with long-standing multiple sclerosis and 48 healthy controls (age = 50.8 ± 7.0) with neuropsychological testing and MRI were included. Structural connectivity was estimated from diffusion tensor images using probabilistic tractography (MRtrix 3.0) between pairs of brain regions. Structural connections were divided into short- (length < quartile 1) and long-range (length > quartile 3) connections, based on the mean distribution of tract lengths in healthy controls. To determine the severity of damage within these connections, (i) fractional anisotropy as a measure for integrity; (ii) total number of fibres; and (iii) percentage of tract affected by lesions were computed for each connecting tract and averaged for short- and long-range connections separately. To investigate the impact of damage in these connections for structural network efficiency, global efficiency was computed. Additionally, resting-state functional connectivity was computed between each pair of brain regions, after artefact removal with FMRIB’s ICA-based X-noiseifier. The functional connectivity similarity index was computed by correlating individual functional connectivity matrices with an average healthy control connectivity matrix. Our results showed that the structural network had a reduced efficiency and integrity in multiple sclerosis relative to healthy controls (both P < 0.05). The long-range connections showed the largest reduction in fractional anisotropy (z = −1.03, P < 0.001) and total number of fibres (z = −0.44, P < 0.01), whereas in the short-range connections only fractional anisotropy was affected (z = −0.34, P = 0.03). Long-range connections also demonstrated a higher percentage of tract affected by lesions than short-range connections, independent of tract length (P < 0.001). Damage to long-range connections was more strongly related to structural network efficiency and cognition (fractional anisotropy: r = 0.329 and r = 0.447. number of fibres r = 0.321 and r = 0.278. and percentage of lesions: r = −0.219; r = −0.426, respectively) than damage to short-range connections. Only damage to long-distance connections correlated with a more abnormal functional network (fractional anisotropy: r = 0.226). Our findings indicate that long-range connections are more severely affected by multiple sclerosis-specific damage than short-range connections. Moreover compared to short-range connections, damage to long-range connections better explains network efficiency and cognition.

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Review of Common Management Strategies for Fatigue in Multiple Sclerosis

International Journal of MS Care ◽

10.7224/1537-2073-1.2.23 ◽

1999 ◽

Vol 1 (2) ◽

pp. 23-31 ◽

Cited By ~ 4

Author(s):

A Chan

Keyword(s):

Multiple Sclerosis ◽

Management Strategies ◽

Active Role ◽

World Health ◽

Common Symptom ◽

Promotion Strategy ◽

Fatigue Management ◽

Health Organization ◽

The Individual ◽

The Impact

Abstract Fatigue is the most common symptom experienced by individuals with multiple sclerosis (MS), regardless of their disability level or the severity of the disease. The Fatigue Severity Scale and the Fatigue Impact Scale are standardized tools designed to measure the impact of fatigue on an individual's life. In addition to the use of medications, other fatigue management strategies include education, modification of activities and environment, compensation, and participation in physical exercises. Because the patient is required to take an active role in the implementation of these fatigue management strategies, his or her sense of control in disease management is enhanced, resulting in empowerment of the individual. According to the World Health Organization (WHO), empowerment is a health-promotion strategy for the individual and for populations. Therefore, having options and control in fatigue management is empowering and promotes health for individuals with MS.

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Diffusion tensor magnetic resonance imaging in very early onset pediatric multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458515596600 ◽

2015 ◽

Vol 22 (5) ◽

pp. 620-627 ◽

Cited By ~ 9

Author(s):

MA Rocca ◽

M Sonkin ◽

M Copetti ◽

E Pagani ◽

DL Arnold ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Multiple Sclerosis ◽

Magnetic Resonance ◽

Structural Integrity ◽

Linear Models ◽

Diffusion Tensor ◽

Mean Diffusivity ◽

Lesion Volume ◽

Resonance Imaging ◽

The Impact

Objectives: Active myelination during childhood may influence the impact of multiple sclerosis (MS) on brain structural integrity. We studied normal-appearing white matter (NAWM) in children with MS onset before age 12 years using diffusion tensor (DT) magnetic resonance imaging (MRI). Methods: DT MRI scans were obtained from 22 MS children with their first attack before age 12 years, and 31 healthy controls from two referral centers. Using probabilistic tractography, brain tissue integrity within interhemispheric, intrahemispheric, and projection tracts was compared between patients and site-matched controls. The impact of disease and age at MRI on tract NAWM fractional anisotropy (FA) and mean diffusivity (MD) values was evaluated using linear models. Results: Compared to controls, pediatric MS patients had reduced FA and increased MD of the bilateral superior longitudinal fasciculus and corpus callosum (CC), without center-by-group interaction. CC NAWM average FA was correlated with brain T2 lesion volume. In controls, the majority of the tracts analyzed showed a significant increase of FA and decrease of MD with age. Such a linear correlation was lost in patients. Conclusions: In very young pediatric MS patients, DT MRI abnormalities affect brain WM tracts differentially, and are only partially correlated with focal WM lesions. Impaired maturation of WM tracts with age may be an additional factor contributing to these findings.

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T1 cortical hypointensities and their association with cognitive disability in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458510377223 ◽

2010 ◽

Vol 16 (10) ◽

pp. 1203-1212 ◽

Cited By ~ 16

Author(s):

Francesca Bagnato ◽

Zeena Salman ◽

Robert Kane ◽

Sungyoung Auh ◽

Fredric K Cantor ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Impairment ◽

White Matter ◽

Statistical Significance ◽

Verbal Learning ◽

Lesion Volume ◽

Cognitive Disability ◽

3.0 Tesla ◽

Multiple Sclerosis Patients ◽

The Impact

Background: Neocortical lesions (NLs) largely contribute to the pathology of multiple sclerosis (MS), although their relevance in patients’ disability remains unknown. Objective: To assess the incidence of T1 hypointense NLs by 3.0-Tesla magnetic resonance imaging (MRI) in patients with MS and examine neocortical lesion association with cognitive impairment. Methods: In this case-control study, 21 MS patients and 21 age-, sex- and years of education-matched healthy volunteers underwent: (i) a neuropsychological examination rating cognitive impairment (Minimal Assessment of Cognitive Function in MS); (ii) a 3.0-Tesla MRI inclusive of an isotropic 1.0 mm3 three-dimensional inversion prepared spoiled gradient-recalled-echo (3D-IRSPGR) image and T1- and T2-weighted images. Hypointensities on 3D-IRSPGR lying in the cortex, either entirely or partially were counted and association between NLs and cognitive impairment investigated. Results: A total of 95 NLs were observed in 14 (66.7%) patients. NL+ patients performed poorer (p = 0.020) than NLpatients only on the delayed recall component of the California Verbal Learning Test. This difference lost statistical significance when a correction for white matter lesion volume was employed. Conclusions: Although T 1 hypointense NLs may be present in a relatively high proportion of multiple sclerosis patients, the impact that they have in cognitive impairment is not independent from white matter disease.

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Has your patient's multiple sclerosis lesion burden or brain atrophy actually changed?

Multiple Sclerosis Journal ◽

10.1191/1352458504ms1061oa ◽

2004 ◽

Vol 10 (4) ◽

pp. 402-406 ◽

Cited By ~ 16

Author(s):

Xingchang Wei ◽

Charles RG Guttmann ◽

Simon K Warfield ◽

Michael Eliasziw ◽

J Ross Mitchell

Keyword(s):

Multiple Sclerosis ◽

Measurement Error ◽

Brain Tissue ◽

Brain Atrophy ◽

Multiple Sclerosis Lesion ◽

Lesion Volume ◽

Measurement Variability ◽

Brain Parenchymal Fraction ◽

Significant Change ◽

Brain Parenchymal

Changes in mean magnetic resonance imaging (MRI)-derived measurements between patient groups are often used to determine outcomes in therapeutic trials and other longitudinal studies of multiple sclerosis (MS). However, in day-to-day clinical practice the changes withinindividual patients may also be of interest. In this paper, we estimated the measurement error of an automated brain tissue quantification algorithm and determined the thresholds for statistically significant change of MRI-derived T2 lesion volume and brain atrophy in individual patients. Twenty patients with MS were scanned twice within 30 min. Brain tissue volumes were measured using the computer algorithm. Brain atrophy was estimated by calculation of brain parenchymal fraction. The threshold of change between repeated scans that represented statistically significant change beyond measurement error with 95% certainty was 0.65 mL for T2 lesion burden and 0.0056 for brain parenchymal fraction. Changes in lesion burden and brain atrophy below these thresholds can be safely (with 95% certainty) explained by measurement variability alone. These values provide clinical neurologists with a useful reference to interpret MRI-derived measures in individual patients.

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The relationship between cognitive function and high-resolution diffusion tensor MRI of the cingulum bundle in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458515576983 ◽

2015 ◽

Vol 21 (14) ◽

pp. 1794-1801 ◽

Cited By ~ 25

Author(s):

Katherine A Koenig ◽

Ken E. Sakaie ◽

Mark J Lowe ◽

Jian Lin ◽

Lael Stone ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Function ◽

Episodic Memory ◽

Diffusion Tensor ◽

Posterior Cingulate Cortex ◽

Cognitive Testing ◽

Information Processing Speed ◽

Cingulum Bundle ◽

Relationship Of ◽

The Relationship

Background: Imaging can provide noninvasive neural markers of disease progression in multiple sclerosis (MS) that are related to behavioral and cognitive symptoms. Past work suggests that diffusion tensor imaging (DTI) provides a measure of white matter pathology, including demyelination and axonal counts. Objectives: In the current study, the authors investigate the relationship of DTI measures in the cingulum bundle to common deficits in MS, including episodic memory, working memory, and information processing speed. Methods: Fifty-seven patients with MS and 17 age- and education-matched controls underwent high-spatial resolution diffusion scans and cognitive testing. Probabilistic tracking was used to generate tracks from the posterior cingulate cortex to the entorhinal cortex. Results: Radial and axial diffusivity values were significantly different between patients and controls ( p < 0.031), and in patients bilateral diffusion measures were significantly related to measures of episodic memory and speed of processing ( p < 0.033). Conclusions: The tractography-based measures of posterior cingulum integrity reported here support further development of DTI as a viable measure of axonal integrity and cognitive function in patients with MS.

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The link between resting-state functional connectivity and cognition in MS patients

Multiple Sclerosis Journal ◽

10.1177/1352458513495584 ◽

2013 ◽

Vol 20 (3) ◽

pp. 338-348 ◽

Cited By ~ 42

Author(s):

Álvaro J Cruz-Gómez ◽

Noelia Ventura-Campos ◽

Antonio Belenguer ◽

Cesar Ávila ◽

Cristina Forn

Keyword(s):

Functional Connectivity ◽

Resting State ◽

Cognitive Status ◽

Control Group ◽

Cognitively Impaired ◽

Lesion Volume ◽

Resting State Functional Connectivity ◽

Frontoparietal Network ◽

Brain Parenchymal Fraction ◽

Brain Parenchymal

Objective: The objective of this paper is to explore differences in resting-state functional connectivity between cognitively impaired and preserved multiple sclerosis (MS) patients. Methods: Sixty MS patients and 18 controls were assessed with the Brief Repeatable Battery of Neuropsychological Tests (BRB-N). A global Z score of the BRB-N was obtained and allowed us to classify MS patients as cognitively impaired and cognitively preserved ( n = 30 per group). Functional connectivity was assessed by independent component analysis of resting-state networks (RSNs) related to cognition: the default mode network, left and right frontoparietal and salience network. Between-group differences were evaluated and a regression analysis was performed to describe relationships among cognitive status, functional connectivity and radiological variables. Results: Compared to cognitively preserved patients and healthy controls, cognitively impaired patients showed a lesser degree of functional connectivity in all RSNs explored. Cognitively preserved patients presented less connectivity than the control group in the left frontoparietal network. Global Z scores were positively and negatively correlated with brain parenchymal fraction and lesion volume, respectively. Conclusion: Decreased cognitive performance is accompanied by reduced resting state functional connectivity and directly related to brain damage. These results support the use of connectivity as a powerful tool to monitor and predict cognitive impairment in MS patients.

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Brain atrophy in relapsing multiple sclerosis: relationship to relapses, EDSS, and treatment with interferon β-1a

Multiple Sclerosis Journal ◽

10.1177/135245850000600601 ◽

2000 ◽

Vol 6 (6) ◽

pp. 365-372 ◽

Cited By ~ 73

Author(s):

Richard A Rudick ◽

Elizabeth Fisher ◽

Jar-Chi Lee ◽

Jeffrey T Duda ◽

Jack Simon

Keyword(s):

Multiple Sclerosis ◽

Clinical Trial ◽

Brain Atrophy ◽

Surrogate Marker ◽

Phase Iii ◽

Therapeutic Effects ◽

Lesion Volume ◽

Interferon Β ◽

Brain Parenchymal ◽

The Brain

Brain atrophy is a relevant surrogate marker of the disease process in multiple sclerosis (MS) because it represents the net effect of various pathological processes leading to brain tissue loss. There are various approaches to quantifying central nervous system atrophy in MS. We have focused on a normalized measure of whole brain atrophy, the brain parenchymal fraction (BPF). BPF is defined as the brain parenchymal volume, divided by the volume within the surface of the brain. We applied this method to an MRI data set generated during a phase III clinical trial of interferon β-1a (AVONEX). The purpose of the current study is to further explore clinical and MRI correlates of the BPF, particularly as they relate to relapse rate and Kurtzke's Expanded Disability Status Score (EDSS); and to further explore the therapeutic effects observed in interferon β-1a recipients. Of all demographic and disease measures in the clinical trial data base, T2 lesion volume most closely correlated with BPF in cross sectional studies, and was the baseline factor most closely correlated with progressive brain atrophy in the subsequent 2 years. We also observed that change in T2 lesion volume was the disease measure most closely correlated with change in BPF during 2 years of observation. Of interest, relapse number and EDSS change during 2 years were only weakly correlated with BPF change during the same period. Disability progression, defined as sustained worsening of at least 1.0 EDSS points from baseline, persisting at least 6 months, was associated with significantly greater brain atrophy progression. We observed a therapeutic effect of interferon β-1a in the second year of the clinical trial, and this beneficial effect was not accounted for by change in gadolinium enhanced lesion volume, or by corticosteroid medication within 40 days of the final MRI scan. The BPF is an informative surrogate marker for destructive pathological processes in relaping MS patients, and is useful in demonstrating treatment effects in controlled clinical trials. The significance of progressive brain atrophy during relapsing MS will be assessed by measuring clinical and MRI changes in prospective follow up studies.

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Cognitive functions in multiple sclerosis: impact of gray matter integrity

Multiple Sclerosis Journal ◽

10.1177/1352458513503722 ◽

2013 ◽

Vol 20 (4) ◽

pp. 424-432 ◽

Cited By ~ 28

Author(s):

Sara Llufriu ◽

Eloy Martinez-Heras ◽

Juan Fortea ◽

Yolanda Blanco ◽

Joan Berenguer ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Performance ◽

Gray Matter ◽

Cognitive Functions ◽

Diffusion Tensor ◽

Lesion Volume ◽

Memory And Attention ◽

Diffusion Tensor Images ◽

Explained Variance ◽

The Impact

Objectives: Our aim was to investigate the impact of gray matter (GM) integrity on cognitive performance in multiple sclerosis (MS), and its relationship with white matter (WM) integrity and presence of lesions. Methods: Sixty-seven patients with MS and 26 healthy controls underwent voxel-based analysis of diffusion tensor images (DTI) in GM and tract-based spatial statistics (TBSS) from WM to identify the regional correlations between cognitive functions and integrity. Lesion probability mapping (LPM) was generated for correlation analysis with cognition. Multiple linear regression analyses were used to identify the imaging measures associated with cognitive scores. Results: Compared with controls, patients showed abnormal DTI indices in several GM regions and in most WM tracts. Impairment in DTI indices in specific GM regions was associated with worse performance of distinct cognitive functions. Those regions showed anatomical correspondence with cognitively relevant tracts in TBSS and LPM. The combination of regional GM and WM DTI and lesion volume accounted for 36–51% of the variance of memory and attention scores. Regional GM DTI explained less than 5% of that variance. Conclusion: GM and WM integrity of specific networks influences cognitive performance in MS. However, GM damage assessed by DTI only adds a small increment to the explained variance by WM in predicting cognitive functioning.

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The Effect of Body Mass Index on Brain Volume and Cognitive Function in Relapsing–Remitting Multiple sclerosis: A CombiRx Secondary Analysis

Journal of Central Nervous System Disease ◽

10.1177/11795735211042173 ◽

2021 ◽

Vol 13 ◽

pp. 117957352110421

Author(s):

Aliza Bitton Ben-Zacharia ◽

Malvin N. Janal ◽

Abraham A. Brody ◽

Jerry Wolinsky ◽

Fred Lublin ◽

...

Keyword(s):

Multiple Sclerosis ◽

Body Mass Index ◽

Cognitive Function ◽

Body Mass ◽

Multivariate Regression ◽

Mixed Model ◽

Brain Volume ◽

Relapsing Remitting ◽

The Mean ◽

The Impact

Background Multiple sclerosis (MS) is an autoimmune disease leading to physical, emotional and cognitive disability. High body mass index (BMI) may impact cognitive function and brain volume in MS. Yet, there is paucity of evidence addressing the impact of BMI on cognitive function and brain volume in MS. Objectives The purpose of this study was to examine the effects of BMI on normal appearing brain volume and cognitive function in patients with relapsing–remitting MS. Methods A secondary data analysis of the NIH CombiRx study was conducted. Multivariate regression and mixed model analyses were executed to analyze the effect of BMI on brain volume and cognitive function. Results The mean baseline age of the 768 participants was 38.2(SD = 9.4) years. 73% were female and 88.8% were Caucasian. The mean BMI was 28.8 kg/m2(SD = 6.7). The multivariate regression and mixed model analyses failed to show a clinical effect of BMI on brain volume and cognitive function. Conclusion BMI did not show an effect on cognitive function and brain volume among MS patients. Although there is increased interest in the effects of modifiable factors on the course of MS, the effects of BMI on brain volume and cognitive function are debatable and warrant further research. ClinicalTrials.gov NCT00211887

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