Gray matter trophism, cognitive impairment, and depression in patients with multiple sclerosis

Background: Cognitive impairment and depression frequently affects patients with multiple sclerosis (MS). However, the relationship between the occurrence of depression and cognitive impairment and the development of cortical atrophy has not been fully elucidated yet. Objectives: To investigate the association of cortical and deep gray matter (GM) volume with depression and cognitive impairment in MS. Methods: Three-dimensional (3D) T1-weighted scans were obtained from 126 MS patients and 59 matched healthy controls. Cognitive impairment was assessed using the Brief Repeatable Battery of Neuropsychological Tests and depression with the Montgomery-Asberg Depression Rating Scale (MADRS). Using FreeSurfer and FIRST software, we assessed cortical thickness (CTh) and deep GM volumetry. Magnetic resonance imaging (MRI) variables explaining depression and cognitive impairment were investigated using factorial and classification analysis. Multivariate regression models correlated GM abnormalities with symptoms severity. Results: Compared with controls, MS patients exhibited widespread bilateral cortical thinning involving all brain lobes. Depressed MS showed selective CTh decrease in fronto-temporal regions, whereas cognitive impairment MS exhibited widespread fronto-parietal cortical and subcortical GM atrophy. Frontal cortical thinning was the best predictor of depression ( C-statistic = 0.7), whereas thinning of the right precuneus and high T2 lesion volume best predicted cognitive impairment ( C-statistic = 0.8). MADRS severity correlated with right entorhinal cortex thinning, whereas cognitive impairment severity correlated with left entorhinal and thalamus atrophy. Conclusion: MS-related depression is linked to circumscribed CTh changes in areas deputed to emotional behavior, whereas cognitive impairment is correlated with cortical and subcortical GM atrophy of circuits involved in cognition.

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Cortical atrophy accelerates as cognitive decline worsens in multiple sclerosis

Neurology ◽

10.1212/wnl.0000000000008198 ◽

2019 ◽

Vol 93 (14) ◽

pp. e1348-e1359 ◽

Cited By ~ 10

Author(s):

Anand J.C. Eijlers ◽

Iris Dekker ◽

Martijn D. Steenwijk ◽

Kim A. Meijer ◽

Hanneke E. Hulst ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Decline ◽

Gray Matter ◽

Structural Mri ◽

Cortical Atrophy ◽

Lesion Volume ◽

Volume Increase ◽

Atrophy Rate ◽

Gray Matter Atrophy ◽

Deep Gray Matter

ObjectiveTo determine which pathologic process could be responsible for the acceleration of cognitive decline during the course of multiple sclerosis (MS), using longitudinal structural MRI, which was related to cognitive decline in relapsing-remitting MS (RRMS) and progressive MS (PMS).MethodsA prospective cohort of 230 patients with MS (179 RRMS and 51 PMS) and 59 healthy controls was evaluated twice with 5-year (mean 4.9, SD 0.94) interval during which 22 patients with RRMS converted to PMS. Annual rates of cortical and deep gray matter atrophy as well as lesion volume increase were computed on longitudinal (3T) MRI data and correlated to the annual rate of cognitive decline as measured using an extensive cognitive evaluation at both time points.ResultsThe deep gray matter atrophy rate did not differ between PMS and RRMS (−0.82%/year vs −0.71%/year, p = 0.11), while faster cortical atrophy was observed in PMS (−0.87%/year vs −0.48%/year, p < 0.01). Similarly, faster cognitive decline was observed in PMS compared to RRMS (p < 0.01). Annual cognitive decline was related to the rate of annual lesion volume increase in stable RRMS (r = −0.17, p = 0.03) to the rate of annual deep gray matter atrophy in converting RRMS (r = 0.50, p = 0.02) and annual cortical atrophy in PMS (r = 0.35, p = 0.01).ConclusionsThese results indicate that cortical atrophy and cognitive decline accelerate together during the course of MS. Substrates of cognitive decline shifted from worsening lesional pathology in stable RRMS to deep gray matter atrophy in converting RRMS and to accelerated cortical atrophy in PMS only.

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NODDI microstructural abnormalities in normal-appearing gray matter and white matter contribute to cognitive impairment in multiple sclerosis

Journal of the Neurological Sciences ◽

10.1016/j.jns.2021.118088 ◽

2021 ◽

Vol 429 ◽

pp. 118088

Author(s):

Paolo Preziosa ◽

Lorenzo Conti ◽

Elisabetta Pagani ◽

Olga Marchesi ◽

Maria Rocca ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Impairment ◽

White Matter ◽

Gray Matter

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7T quantitative magnetization transfer (qMT) of cortical gray matter in multiple sclerosis correlates with cognitive impairment

NeuroImage ◽

10.1016/j.neuroimage.2019.116190 ◽

2019 ◽

Vol 203 ◽

pp. 116190 ◽

Cited By ~ 3

Author(s):

Lydia J. McKeithan ◽

Bailey D. Lyttle ◽

Bailey A. Box ◽

Kristin P. O’Grady ◽

Richard D. Dortch ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Impairment ◽

Gray Matter ◽

Magnetization Transfer ◽

Cortical Gray Matter

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Word-finding difficulty is a prevalent disease-related deficit in early multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458519881760 ◽

2019 ◽

Vol 26 (13) ◽

pp. 1752-1764 ◽

Cited By ~ 3

Author(s):

Rachel Brandstadter ◽

Michelle Fabian ◽

Victoria M Leavitt ◽

Stephen Krieger ◽

Anusha Yeshokumar ◽

...

Keyword(s):

Multiple Sclerosis ◽

Gray Matter ◽

Objective Assessment ◽

Lesion Volume ◽

Healthy Controls ◽

Patient Report ◽

Word Finding ◽

Cognitive Complaint ◽

Two Samples ◽

Patient Reported

Background: Persons with multiple sclerosis (MS) commonly report word-finding difficulty clinically, yet this language deficit remains underexplored. Objective: To investigate the prevalence and nature of word-finding difficulty in persons with early MS on three levels: patient report, cognitive substrates, and neuroimaging. Methods: Two samples of early MS patients ( n = 185 and n = 55; ⩽5 years diagnosed) and healthy controls ( n = 50) reported frequency/severity of cognitive deficits and underwent objective assessment with tasks of rapid automatized naming (RAN), measuring lexical access speed, memory, word generation, and cognitive efficiency. High-resolution brain magnetic resonance imaging (MRI) derived measurements of regional cortical thickness, global and deep gray matter volume, and T2 lesion volume. Relationships among patient-reported word-finding difficulty, cognitive performance, and neural correlates were examined. Results: Word-finding difficulty was the most common cognitive complaint of MS patients and the only complaint reported more by patients than healthy controls. Only RAN performance discriminated MS patients with subjective word-finding deficits from those without subjective complaints and from healthy controls. Thinner left parietal cortical gray matter independently predicted impaired RAN performance, driven primarily by the left precuneus. Conclusion: Three levels of evidence (patient-report, objective behavior, regional gray matter) support word-finding difficulty as a prevalent, measurable, disease-related deficit in early MS linked to left parietal cortical thinning.

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Deep learning segmentation of gadolinium-enhancing lesions in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458520921364 ◽

2020 ◽

pp. 135245852092136 ◽

Cited By ~ 1

Author(s):

Ivan Coronado ◽

Refaat E Gabr ◽

Ponnada A Narayana

Keyword(s):

Multiple Sclerosis ◽

Deep Learning ◽

Network Performance ◽

Three Dimensional ◽

Proton Density ◽

Dice Similarity Coefficient ◽

Lesion Volume ◽

Imaging Data ◽

Post Contrast ◽

Fluid Attenuated Inversion Recovery

Objective: The aim of this study is to assess the performance of deep learning convolutional neural networks (CNNs) in segmenting gadolinium-enhancing lesions using a large cohort of multiple sclerosis (MS) patients. Methods: A three-dimensional (3D) CNN model was trained for segmentation of gadolinium-enhancing lesions using multispectral magnetic resonance imaging data (MRI) from 1006 relapsing–remitting MS patients. The network performance was evaluated for three combinations of multispectral MRI used as input: (U5) fluid-attenuated inversion recovery (FLAIR), T2-weighted, proton density-weighted, and pre- and post-contrast T1-weighted images; (U2) pre- and post-contrast T1-weighted images; and (U1) only post-contrast T1-weighted images. Segmentation performance was evaluated using the Dice similarity coefficient (DSC) and lesion-wise true-positive (TPR) and false-positive (FPR) rates. Performance was also evaluated as a function of enhancing lesion volume. Results: The DSC/TPR/FPR values averaged over all the enhancing lesion sizes were 0.77/0.90/0.23 using the U5 model. These values for the largest enhancement volumes (>500 mm3) were 0.81/0.97/0.04. For U2, the average DSC/TPR/FPR values were 0.72/0.86/0.31. Comparable performance was observed with U1. For all types of input, the network performance degraded with decreased enhancement size. Conclusion: Excellent segmentation of enhancing lesions was observed for enhancement volume ⩾70 mm3. The best performance was achieved when the input included all five multispectral image sets.

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Cortical Microstructural Alterations in Mild Cognitive Impairment and Alzheimer’s Disease Dementia

Cerebral Cortex ◽

10.1093/cercor/bhz286 ◽

2020 ◽

Vol 30 (5) ◽

pp. 2948-2960 ◽

Cited By ~ 6

Author(s):

Nicholas M Vogt ◽

Jack F Hunt ◽

Nagesh Adluru ◽

Douglas C Dean ◽

Sterling C Johnson ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cortical Thickness ◽

Gray Matter ◽

Brain Regions ◽

Cortical Atrophy ◽

Microstructural Alterations ◽

Additional Information

Abstract In Alzheimer’s disease (AD), neurodegenerative processes are ongoing for years prior to the time that cortical atrophy can be reliably detected using conventional neuroimaging techniques. Recent advances in diffusion-weighted imaging have provided new techniques to study neural microstructure, which may provide additional information regarding neurodegeneration. In this study, we used neurite orientation dispersion and density imaging (NODDI), a multi-compartment diffusion model, in order to investigate cortical microstructure along the clinical continuum of mild cognitive impairment (MCI) and AD dementia. Using gray matter-based spatial statistics (GBSS), we demonstrated that neurite density index (NDI) was significantly lower throughout temporal and parietal cortical regions in MCI, while both NDI and orientation dispersion index (ODI) were lower throughout parietal, temporal, and frontal regions in AD dementia. In follow-up ROI analyses comparing microstructure and cortical thickness (derived from T1-weighted MRI) within the same brain regions, differences in NODDI metrics remained, even after controlling for cortical thickness. Moreover, for participants with MCI, gray matter NDI—but not cortical thickness—was lower in temporal, parietal, and posterior cingulate regions. Taken together, our results highlight the utility of NODDI metrics in detecting cortical microstructural degeneration that occurs prior to measurable macrostructural changes and overt clinical dementia.

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Quality of life, depression and fatigue in mildly disabled patients with relapsing–remitting multiple sclerosis receiving subcutaneous interferon beta-1a: 3-year results from the COGIMUS (COGnitive Impairment in MUltiple Sclerosis) study

Multiple Sclerosis Journal ◽

10.1177/1352458511401943 ◽

2011 ◽

Vol 17 (8) ◽

pp. 991-1001 ◽

Cited By ~ 34

Author(s):

F Patti ◽

MP Amato ◽

M Trojano ◽

S Bastianello ◽

MR Tola ◽

...

Keyword(s):

Quality Of Life ◽

Multiple Sclerosis ◽

Cognitive Impairment ◽

Interferon Beta ◽

Rating Scale ◽

Cognitive Status ◽

Treatment Dose ◽

Relapsing Remitting ◽

Composite Scores

Background: The precise relationships among quality of life, depression, fatigue and cognitive impairment in multiple sclerosis (MS) are complex and poorly understood. Objective: To assess the effects of subcutaneous interferon beta-1a on quality of life, depression and fatigue over 3 years in the COGIMUS study, and to examine the relationship between these outcomes and baseline cognitive status. Methods: COGIMUS was an observational 3-year trial assessing cognitive function in 459 patients with relapsing–remitting MS treated with subcutaneous interferon beta-1a. Results: In total, 331 patients completed the study (168 received interferon beta-1a, 44 µg subcutaneously three times weekly, and 163 received interferon beta-1a, 22 µg subcutaneously three times weekly). Mean MS Quality of Life-54 (MSQoL-54) composite scores did not change over time. There were no significant differences between groups in MSQoL-54 composite scores when patients were grouped by treatment dose and baseline cognitive status. Mean (standard deviation) Hamilton Depression Rating Scale score decreased from 6.8 (4.9) at baseline to 5.8 (5.9) at year 3. Mean total Fatigue Impact Scale scores were low (<30) at all time points. Conclusion: Quality of life, depression and fatigue remained largely stable over 3 years; no effects of treatment dose or baseline cognitive status were found.

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Gray Matter Damage Predicts the Accumulation of Disability and Cognitive Impairment 13 Years Later in Patients with Multiple Sclerosis (S51.005)

Neurology ◽

10.1212/wnl.78.1_meetingabstracts.s51.005 ◽

2012 ◽

Vol 78 (Meeting Abstracts 1) ◽

pp. S51.005-S51.005 ◽

Cited By ~ 1

Author(s):

M. Rocca ◽

P. Preziosa ◽

M. Copetti ◽

G. C. Riccitelli ◽

R. Messina ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Impairment ◽

Gray Matter

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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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The relationship between white matter fiber damage and gray matter perfusion in large-scale functionally defined networks in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458517691149 ◽

2017 ◽

Vol 23 (14) ◽

pp. 1884-1892 ◽

Cited By ~ 4

Author(s):

Ashley Y Ma ◽

Rita C Vitorino ◽

Seyed-Parsa Hojjat ◽

Alannah D Mulholland ◽

Liying Zhang ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Gray Matter ◽

Large Scale ◽

Progressive Multiple Sclerosis ◽

Functional Networks ◽

Lesion Volume ◽

Fiber Damage ◽

Damage Extent ◽

The Relationship

Background: Recent studies utilizing perfusion as a surrogate of cortical integrity show promise for overall cognition, but the association between white matter (WM) damage and gray matter (GM) integrity in specific functional networks is not previously studied. Objective: To investigate the relationship between WM fiber integrity and GM node perfusion within six functional networks of relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS) patients. Methods: Magnetic resonance imaging (MRI) and neurocognitive testing were performed on 19 healthy controls (HC), 39 RRMS, and 45 SPMS patients. WM damage extent and severity were quantified with T2-hyper/T1-hypointense (T2h/T1h) lesion volume and degree of perfusion reduction in lesional and normal-appearing white matter (NAWM), respectively. A two-step linear regression corrected for confounders was employed. Results: Cognitive impairment was present in 20/39 (51%) RRMS and 25/45 (53%) SPMS patients. GM node perfusion was associated with WM fiber damage severity (WM hypoperfusion) within each network—including both NAWM ( R2 = 0.67–0.89, p < 0.0001) and T2h ( R2 = 0.39–0.62, p < 0.0001) WM regions—but was not significantly associated ( p > 0.01) with WM fiber damage extent (i.e. T2h/T1h lesion volumes). Conclusion: Overall, GM node perfusion was associated with severity rather than extent of WM network damage, supporting a primary etiology of GM hypoperfusion.

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