Microstructural White Matter Alterations in Cognitively Impaired Patients at Early Stages of Multiple Sclerosis

Abstract Purpose As conventional quantitative magnetic resonance imaging (MRI) parameters are weakly associated with cognitive impairment (CI) in early multiple sclerosis (MS), we explored microstructural white matter alterations in early MS or clinically isolated syndrome (CIS) comparing patients with or without CI. Methods Based on a preceding tract-based spatial statistics analysis (3 Tesla MRI) which contrasted 106 patients with early MS or CIS and 49 healthy controls, diffusion metrics (fractional anisotropy, FA, mean diffusivity, MD) were extracted from significant clusters using an atlas-based approach. The FA and MD were compared between patients with (Ci_P n = 14) and without (Cp_P n = 81) cognitive impairment in a subset of patients who underwent CI screening. Results The FA was reduced in Ci_P compared to Cp_P in the splenium of corpus callosum (p = 0.001), right parahippocampal cingulum (p = 0.002) and fornix cres./stria terminalis (0.042), left posterior corona radiata (p = 0.012), bilateral cerebral peduncles, medial lemniscus and in cerebellar tracts. Increased MD was detected in the splenium of corpus callosum (p = 0.01). The CI-related localizations overlapped only partially with MS lesions. Conclusion Microstructural white matter alterations at disease onset were detectable in Ci_P compared to Cp_P in known cognitively relevant fiber tracts, indicating the relevance of early treatment initiation in MS and CIS.

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White matter abnormalities in the corpus callosum with cognitive impairment in Parkinson disease

Neurology ◽

10.1212/wnl.0000000000006646 ◽

2018 ◽

Vol 91 (24) ◽

pp. e2244-e2255 ◽

Cited By ~ 16

Author(s):

Ian O. Bledsoe ◽

Glenn T. Stebbins ◽

Doug Merkitch ◽

Jennifer G. Goldman

Keyword(s):

Cognitive Impairment ◽

White Matter ◽

Corpus Callosum ◽

Parkinson Disease ◽

Information Transfer ◽

Diffusion Tensor ◽

Anterior Segment ◽

Mean Diffusivity ◽

Cognitive Domain ◽

White Matter Abnormalities

ObjectiveTo evaluate microstructural characteristics of the corpus callosum using diffusion tensor imaging (DTI) and their relationships to cognitive impairment in Parkinson disease (PD).MethodsSeventy-five participants with PD and 24 healthy control (HC) participants underwent structural MRI brain scans including DTI sequences and clinical and neuropsychological evaluations. Using Movement Disorder Society criteria, PD participants were classified as having normal cognition (PD-NC, n = 23), mild cognitive impairment (PD-MCI, n = 35), or dementia (PDD, n = 17). Cognitive domain (attention/working memory, executive function, language, memory, visuospatial function) z scores were calculated. DTI scalar values, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), were established for 5 callosal segments on a midsagittal plane, single slice using a topographically derived parcellation method. Scalar values were compared among participant groups. Regression analyses were performed on cognitive domain z scores and DTI metrics.ResultsParticipants with PD showed increased AD values in the anterior 3 callosal segments compared to healthy controls. Participants with PDD had significantly increased AD, MD, and RD in the anterior 2 segments compared to participants with PD-NC and most anterior segment compared to participants with PD-MCI. FA values did not differ significantly between participants with PD and participants with HC or among PD cognitive groups. The strongest associations for the DTI metrics and cognitive performance occurred in the most anterior and most posterior callosal segments, and also reflected fronto-striatal and posterior cortical type cognitive deficits, respectively.ConclusionsMicrostructural white matter abnormalities of the corpus callosum, as measured by DTI, may contribute to PD cognitive impairment by disrupting information transfer across interhemispheric and callosal–cortical projections.

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White matter abnormalities across different epilepsy syndromes in adults: an ENIGMA Epilepsy study

10.1101/2019.12.19.883405 ◽

2019 ◽

Author(s):

Sean N Hatton ◽

Khoa H Huynh ◽

Leonardo Bonilha ◽

Eugenio Abela ◽

Saud Alhusaini ◽

...

Keyword(s):

White Matter ◽

Corpus Callosum ◽

Temporal Lobe Epilepsy ◽

Fractional Anisotropy ◽

Temporal Lobe ◽

Hippocampal Sclerosis ◽

Mean Diffusivity ◽

White Matter Abnormalities ◽

Fiber Tracts ◽

External Capsule

AbstractThe epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analyzed from 1,069 non-epileptic controls and 1,249 patients: temporal lobe epilepsy with hippocampal sclerosis (N=599), temporal lobe epilepsy with normal MRI (N=275), genetic generalized epilepsy (N=182) and nonlesional extratemporal epilepsy (N=193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fiber tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at p<0.001). Across “all epilepsies” lower fractional anisotropy was observed in most fiber tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. Less robust effects were seen with mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Those with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced differences in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and in mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of microstructural abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibers in a large multicentre study of epilepsy. Overall, epilepsy patients showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding new insights into pathological substrates that may be used to guide future therapeutic and genetic studies.

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Corpus Callosum and Cingulum Tractography in Parkinson's Disease

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100010751 ◽

2010 ◽

Vol 37 (5) ◽

pp. 595-600 ◽

Cited By ~ 28

Author(s):

Katie Wiltshire ◽

Luis Concha ◽

Myrlene Gee ◽

Thomas Bouchard ◽

Christian Beaulieu ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Impairment ◽

White Matter ◽

Corpus Callosum ◽

Diffusion Tensor ◽

Mean Diffusivity ◽

Imaging Method ◽

Motor Symptoms ◽

Mri Scans

Background:In Parkinson's disease (PD) cell loss in the substantia nigra is known to result in motor symptoms; however widespread pathological changes occur and may be associated with non-motor symptoms such as cognitive impairment. Diffusion tensor imaging is a quantitative imaging method sensitive to the micro-structure of white matter tracts.Objective:To measure fractional anisotropy (FA) and mean diffusivity (MD) values in the corpus callosum and cingulum pathways, defined by diffusion tensor tractography, in patients with PD, PD with dementia (PDD) and controls and to determine if these measures correlate with Mini-Mental Status Examination (MMSE) scores in parkinsonian patients.Methods:Patients with PD (17 Males [M], 12 Females [F]), mild PDD (5 M, 1F) and controls (8 M, 7F) underwent cognitive testing and MRI scans. The corpus callosum was divided into four regions and the cingulum into two regions bilaterally to define tracts using the program DTIstudio (Johns Hopkins University) using the fiber assignment by continuous tracking algorithm. Volumetric MRI scans were used to measure white and gray matter volumes.Results:Groups did not differ in age or education. There were no overall FA or MD differences between groups in either the corpus callosum or cingulum pathways. In PD subjects the MMSE score correlated with MD within the corpus callosum. These findings were independent of age, sex and total white matter volume.Conclusions:The data suggest that the corpus callosum or its cortical connections are associated with cognitive impairment in PD patients.

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Cognitive impairment and the regional distribution of cerebellar lesions in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458517730132 ◽

2017 ◽

Vol 24 (13) ◽

pp. 1687-1695 ◽

Cited By ~ 5

Author(s):

Sean M Tobyne ◽

Wilson B Ochoa ◽

J Daniel Bireley ◽

Victoria MJ Smith ◽

Jeroen JG Geurts ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Impairment ◽

White Matter ◽

Regional Distribution ◽

Disease Onset ◽

Cognitive Status ◽

Cerebellar Lesion ◽

Lesion Load ◽

Cerebellar White Matter ◽

Cerebellar Lesions

Background: Cerebellar lesions are often reported in relapsing-remitting multiple sclerosis (RRMS) and have been associated with impaired motor function and cognitive status. However, prior research has primarily focused on summary measures of cerebellar involvement (e.g. total lesion load, gray/white matter volume) and not on the effect of lesion load within specific regions of cerebellar white matter. Objective: Spatially map the probability of cerebellar white matter lesion (CWML) occurrence in RRMS and explore the relationship between cognitive impairment and lesion (CWML) location within the cerebellum. Methods: High-resolution structural magnetic resonance imaging (MRI) was acquired on 16 cognitively impaired (CI) and 15 cognitively preserved (CP) RRMS subjects at 3T and used for lesion identification and voxel-based lesion-symptom mapping (VLSM). Results: CI RRMS demonstrated a predilection for the middle cerebellar peduncle (MCP). VLSM results indicate that lesions of the MCP are significantly associated with CI in RRMS. Measures of cerebellar lesion load were correlated with age at disease onset but not disease duration. Conclusion: A specific pattern of cerebellar lesions involving the MCP, rather than the total CWML load, contributes to cognitive dysfunction in RRMS. Cerebellar lesion profiles may provide a biomarker of current or evolving risk for cognitive status change in RRMS.

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Clinical significance of atrophy and white matter mean diffusivity within the thalamus of multiple sclerosis patients

Multiple Sclerosis Journal ◽

10.1177/1352458513478675 ◽

2013 ◽

Vol 19 (11) ◽

pp. 1478-1484 ◽

Cited By ~ 64

Author(s):

Ralph HB Benedict ◽

Hanneke E Hulst ◽

Niels Bergsland ◽

Menno M Schoonheim ◽

Michael G Dwyer ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Impairment ◽

White Matter ◽

Cognitive Processing ◽

Diffusion Tensor ◽

Mean Diffusivity ◽

Brain Magnetic Resonance Imaging ◽

Cognitive Tests ◽

Explained Variance ◽

Multiple Sclerosis Patients

Background: Gray-matter (GM) atrophy is strongly predictive of cognitive impairment in multiple sclerosis (MS) patients. The thalamus is the region where the atrophy/cognition correlation is most robust. However, few studies have assessed diffusion tensor imaging (DTI) metrics within the thalamus. Objective: This study was designed to determine if thalamus white matter DTI predicts cognitive impairment after accounting for the effects of volume loss. Methods: We enrolled 75 MS patients and 18 healthy controls undergoing 3T brain magnetic resonance imaging (MRI). Thalamus volumes were calculated on 3D T1 images. Voxelwise analyses of DTI metrics were performed within the thalamic white matter tracts. Neuropsychological (NP) testing, acquired using consensus standard methods, contributed measures of memory, cognitive processing speed and executive function. Results: All cognitive tests were significantly predicted ( R2 =0.31, p<0.001) by thalamus volume after accounting for influence of demographics. Mean diffusivity was retained in regression models predicting all cognitive tests, adding from 7–13% of additional explained variance ( p<0.02) after accounting for thalamus volume. Conclusions: We confirm the significant role of thalamus atrophy in MS-associated cognitive disorder, and further report that subtle thalamus pathology as detected by DTI adds incremental explained variance in predicting cognitive impairment.

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Disconnection as a mechanism for social cognition impairment in multiple sclerosis

Neurology ◽

10.1212/wnl.0000000000004060 ◽

2017 ◽

Vol 89 (1) ◽

pp. 38-45 ◽

Cited By ~ 23

Author(s):

Sonia Batista ◽

Carolina Alves ◽

Otília C. d’Almeida ◽

Ana Afonso ◽

Ricardo Félix-Morais ◽

...

Keyword(s):

Multiple Sclerosis ◽

Social Cognition ◽

White Matter ◽

Corpus Callosum ◽

Diffusion Tensor ◽

Brain Mri ◽

Mean Diffusivity ◽

Uncinate Fasciculus ◽

Neural Basis ◽

Cognition Impairment

Objective:To assess the contribution of microstructural normal-appearing white matter (NAWM) damage to social cognition impairment, specifically in the theory of mind (ToM), in multiple sclerosis (MS).Methods:We enrolled consecutively 60 patients with MS and 60 healthy controls (HC) matched on age, sex, and education level. All participants underwent ToM testing (Eyes Test, Videos Test) and 3T brain MRI including conventional and diffusion tensor imaging sequences. Tract-based spatial statistics (TBSS) were applied for whole-brain voxel-wise analysis of fractional anisotropy (FA) and mean diffusivity (MD) on NAWM.Results:Patients with MS performed worse on both tasks of ToM compared to HC (Eyes Test 58.7 ± 13.8 vs 81.9 ± 10.4, p < 0.001, Hedges g −1.886; Videos Test 75.3 ± 9.3 vs 88.1 ± 7.1, p < 0.001, Hedges g −1.537). Performance on ToM tests was correlated with higher values of FA and lower values of MD across widespread white matter tracts. The largest effects (≥90% of voxels with statistical significance) for the Eyes Test were body and genu of corpus callosum, fornix, tapetum, uncinate fasciculus, and left inferior cerebellar peduncle, and for the Videos Test genu and splenium of corpus callosum, fornix, uncinate fasciculus, left tapetum, and right superior fronto-occipital fasciculus.Conclusions:These results indicate that a diffuse pattern of NAWM damage in MS contributes to social cognition impairment in the ToM domain, probably due to a mechanism of disconnection within the social brain network. Gray matter pathology is also expected to have an important role; thus further research is required to clarify the neural basis of social cognition impairment in MS.

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Assessment of White Matter Lesions in Parkinson's Disease: Voxel-based Analysis and Tract-based Spatial Statistics Analysis of Parkinson's Disease with Mild Cognitive Impairment

Current Neurovascular Research ◽

10.2174/1567202617666200901181842 ◽

2020 ◽

Vol 17 (4) ◽

pp. 480-486

Author(s):

Wei Pu ◽

Xudong Shen ◽

Mingming Huang ◽

Zhiqian Li ◽

Xianchun Zeng ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

White Matter ◽

Corpus Callosum ◽

Fractional Anisotropy ◽

Spatial Statistics ◽

Diffusion Tensor ◽

Tract Based Spatial Statistics

Objective: Application of diffusion tensor imaging (DTI) to explore the changes of FA value in patients with Parkinson's disease (PD) with mild cognitive impairment. Methods: 27 patients with PD were divided into PD with mild cognitive impairment (PD-MCI) group (n = 7) and PD group (n = 20). The original images were processed using voxel-based analysis (VBA) and tract-based spatial statistics (TBSS). Results: The average age of pd-mci group was longer than that of PD group, and the course of disease was longer than that of PD group. Compared with PD group, the voxel based analysis-fractional anisotropy (VBA-FA) values of PD-MCI group decreased in the following areas: bilateral frontal lobe, bilateral temporal lobe, bilateral parietal lobe, bilateral subthalamic nucleus, corpus callosum, and gyrus cingula. Tract-based spatial statistics-fractional anisotropy (TBSS-FA) values in PD-MCI group decreased in bilateral corticospinal tract, anterior cingulum, posterior cingulum, fornix tract, bilateral superior thalamic radiation, corpus callosum(genu, body and splenium), bilateral uncinate fasciculus, bilateral inferior longitudinal fasciculus, bilateral superior longitudinal fasciculus, bilateral superior fronto-occipital fasciculus, bilateral inferior fronto-occipital fasciculus, and bilateral parietal-occipital tracts. The mean age of onset in the PD-MCI group was greater than that in the PD group, and the disease course was longer than that in the PD group. Conclusion: DTI-based VBA and TBSS post-processing methods can detect abnormalities in multiple brain areas and white matter fiber tracts in PD-MCI patients. Impairment of multiple cerebral cortex and white matter fiber pathways may be an important causes of cognitive dysfunction in PD-MCI.

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Cognitive Issues in Pediatric Multiple Sclerosis

Brain Sciences ◽

10.3390/brainsci11040442 ◽

2021 ◽

Vol 11 (4) ◽

pp. 442

Author(s):

Emilio Portaccio ◽

Ermelinda De Meo ◽

Angelo Bellinvia ◽

Maria Pia Amato

Keyword(s):

Multiple Sclerosis ◽

Cognitive Impairment ◽

Cognitive Decline ◽

Pediatric Patients ◽

Leisure Activities ◽

Disease Onset ◽

Cognitive Profiles ◽

Brain Growth ◽

Network Activation ◽

Definition Of

Multiple sclerosis (MS) is one of the leading causes of disability in young adults. The onset of MS during developmental age makes pediatric patients particularly susceptible to cognitive impairment, resulting from both disease-related damage and failure of age-expected brain growth. Despite different test batteries and definitions, cognitive impairment has been consistently reported in approximately one-third of pediatric patients with MS. However, the lack of a uniform definition of cognitive impairment and the adoption of different test batteries have led to divergent results in terms of cognitive domains more frequently affected across the cohorts explored. This heterogeneity has hampered large international collaborative studies. Moreover, research aimed at the identification of risk factors (e.g., demographic, clinical, and radiological features) or protective factors (e.g., cognitive reserve, leisure activities) for cognitive decline is still scanty. Mood disorders, such as depression and anxiety, can be detected in these patients alongside cognitive decline or in isolation, and can negatively affect quality of life scores as well as academic performances. By using MRI, cognitive impairment was attributed to damage to specific brain compartments as well as to abnormal network activation patterns. However, multimodal MRI studies are still needed in order to assess the contribution of each MRI metric to cognitive impairment. Importantly, longitudinal studies have recently demonstrated failure of age-expected brain growth and of white matter (WM) and gray matter (GM) maturation plays a relevant role in determining cognitive dysfunction, in addition to MS-related direct damage. Whether these growth retardations might result in specific cognitive profiles according to the age at disease onset has not been studied, yet. A better characterization of cognitive profiles in pediatric MS patients, as well as the definition of neuroanatomical substrates of cognitive impairment and their longitudinal evolution are needed to develop efficient therapeutic strategies against cognitive impairment in this patient population.

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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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Associations of cigarette smoking with gray and white matter in the UK Biobank

10.31234/osf.io/wyvnm ◽

2019 ◽

Author(s):

Joshua Gray ◽

Matthew Thompson ◽

Chelsie Benca-Bachman ◽

Max Michael Owens ◽

Mikela Murphy ◽

...

Keyword(s):

White Matter ◽

Cigarette Smoking ◽

Gray Matter ◽

Brain Structure ◽

Mean Diffusivity ◽

Medial Lemniscus ◽

Uk Biobank ◽

Matter Volume ◽

Increased Risk ◽

The Uk

Chronic cigarette smoking is associated with increased risk for myriad health consequences including cognitive decline and dementia, but research on the link between smoking and brain structure is nascent. We assessed the relationship of cigarette smoking (ever smoked, cigarettes per day, and duration) with gray and white matter using the UK Biobank cohort (gray matter N = 19,615; white matter N = 17,760), adjusting for numerous demographic and health confounders. Ever smoked and duration were associated with smaller total gray matter volume. Ever smoked was associated with reduced volume of the right VIIIa cerebellum, as well as elevated white matter hyperintensity volumes. Smoking duration was associated with reduced total white matter volume. With regard to specific tracts, ever smoked was associated with reduced fractional anisotropy in the left cingulate gyrus part of the cingulum, left posterior thalamic radiation, and bilateral superior thalamic radiation and increased mean diffusivity in the middle cerebellar peduncle, right medial lemniscus, bilateral posterior thalamic radiation, and bilateral superior thalamic radiation. Overall, we found significant associations of cigarette exposure with global measures of gray and white matter. Furthermore, we found select associations of ever smoked, but not cigarettes per day or duration, with specific gray and white matter regions. These findings inform our understanding of the connections between smoking and variation in brain structure and clarify potential mechanisms of risk for common neurological sequelae.

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