NODDI, diffusion tensor microstructural abnormalities and atrophy of brain white matter and gray matter contribute to cognitive impairment in multiple sclerosis.

BACKGROUND: Pathologically specific MRI measures may elucidate in-vivo the heterogeneous processes contributing to cognitive impairment in multiple sclerosis (MS). PURPOSE: Using diffusion tensor and neurite orientation dispersion and density imaging (NODDI), we explored the contribution of focal lesions and normal-appearing (NA) tissue microstructural abnormalities to cognitive impairment in MS. METHODS: One hundred and fifty-two MS patients underwent 3 T brain MRI and a neuropsychological evaluation. Forty-eight healthy controls (HC) were also scanned. Fractional anisotropy (FA), mean diffusivity (MD), intracellular volume fraction (ICV_f) and orientation dispersion index (ODI) were assessed in cortical and white matter (WM) lesions, thalamus, NA cortex and NAWM. Predictors of cognitive impairment were identified using random forest. RESULTS: Fifty-two MS patients were cognitively impaired. Compared to cognitively preserved, impaired MS patients had higher WM lesion volume (LV), lower normalized brain volume (NBV), cortical volume (NCV), thalamic volume (NTV), and WM volume (p ≤ 0.021). They also showed lower NAWM FA, higher NAWM, NA cortex and thalamic MD, lower NAWM ICV_f, lower WM lesion ODI, and higher NAWM ODI (false discovery rate-p ≤ 0.026). Cortical lesion number and microstructural abnormalities were not significantly different. The best MRI predictors of cognitive impairment (relative importance) (out-of-bag area under the curve = 0.727) were NAWM FA (100%), NTV (96.0%), NBV (84.7%), thalamic MD (43.4%), NCV (40.6%), NA cortex MD (26.0%), WM LV (23.2%) and WM lesion ODI (17.9%). CONCLUSIONS: Our multiparametric MRI study including NODDI measures suggested that neuro-axonal damage and loss of microarchitecture integrity in focal WM lesions, NAWM, and GM contribute to cognitive impairment in MS.

Current perspectives on the diagnosis and management of fatigue in multiple sclerosis.

INTRODUCTION: Fatigue is a common and debilitating symptom among multiple sclerosis (MS) patients with a prevalence up to 81% and with a considerable impact on quality of life. However, its subjective nature makes it difficult to define and quantify in clinical practice. Research aimed at a more precise definition and knowledge of this construct is thus continuously growing. AREAS COVERED: This review summarizes the most relevant updates available on PubMed up to 1 July 2022 regarding: the assessment methods that aim to measure the concept of fatigue (as opposed to fatigability), the possible treatment pathways currently available to clinicians, interconnection with the pathophysiological substrates and with the common comorbidities of MS, such as depression and mood disorders. EXPERT OPINION: The in-depth study of fatigue can help to better understand its actual impact on MS patients and can stimulate clinicians toward a more valid approach, through a targeted analysis of this symptom. Considering fatigue from a multidimensional perspective allows the use of patient-tailored methods for its identification and subsequent treatment by different professional figures. Better identification of methods and treatment pathways would reduce the extremely negative impact of fatigue on MS patients' quality of life.

Resting state effective connectivity abnormalities of the Papez circuit and cognitive performance in multiple sclerosis.

The Papez circuit is central to memory and emotional processes. However, little is known about its involvement in multiple sclerosis (MS). We aimed to investigate abnormalities of resting state (RS) effective connectivity (EC) between regions of the Papez circuit in MS and their relationship with cognitive performances. Sixty-two MS patients and 64 healthy controls (HC) underwent neuropsychological assessment, 3D T1-weighted, and RS functional MRI. RS EC analysis was performed using SPM12 and dynamic causal modeling. RS EC abnormalities were investigated using parametric empirical Bayes models and were correlated with cognitive scores. Compared to HC, MS patients showed (posterior probability > 0.95) higher EC between the right entorhinal cortex and right subiculum, and lower EC from the anterior cingulate cortex (ACC) to the posterior cingulate cortex (PCC), from left to right subiculum, from left anterior thalamus to ACC, and within ACC and PCC. Lower RS EC from the ACC to the PCC correlated with worse global cognitive scores (rho = 0.19; p = 0.03), worse visuospatial memory (rho = 0.19; p = 0.03) and worse semantic fluency (rho = 0.21; p = 0.02). Lower RS EC from the left to the right subiculum correlated with worse verbal memory (rho = 0.20; p = 0.02), lower RS EC within the ACC correlated with worse attention (rho = -0.19; p = 0.04) and more severe brain atrophy (rho = -0.26; p = 0.003). Higher EC from the right entorhinal cortex to right subiculum correlated with worse semantic fluency (rho = 0.21; p = 0.02). In conclusion, MS patients showed altered RS EC within the Papez circuit. Abnormal RS EC involving cingulate cortices and hippocampal formation contributed to explain cognitive deficits.

The role of cerebellar damage in explaining disability and cognition in multiple sclerosis phenotypes: a multiparametric MRI study.

BACKGROUND: Cerebellar involvement is not comprehensively studied from an MRI point of view in multiple sclerosis (MS). We aimed to quantify cerebellar damage and identify predictors of physical disability and cognitive dysfunction in MS patients, and to characterize patients with cerebellar disability. METHODS: In this prospective study, 164 (89 relapsing-remitting and 75 progressive) MS patients and 53 healthy controls were enrolled. Subjects underwent 3T MRI with sequences for assessing lesions and atrophy in cerebellum, supratentorial brain, brainstem and cervical cord. Cerebellar peduncle diffusion-tensor metrics were also derived. Random forest models identified MRI predictors of Expanded Disability Status Scale (EDSS) score and cognition z-score. Hierarchical clustering was applied on MRI metrics in patients with cerebellar disability. RESULTS: In MS patients, predictors of higher EDSS score (out-of-bag-R2 = 0.83) were: lower cord grey matter (GM) and global areas, brain volume, GM volume (GMV), cortical GMV, cerebellum lobules I-IV and vermis GMV; and higher cord GM and brainstem lesion volume (LV). Predictors of lower cognition z-score (out-of-bag-R2 = 0.25) were: higher supratentorial and superior cerebellar peduncle LV; and lower brain, thalamus and basal ganglia volumes, GMV, cerebellum lobule VIIIb and Crus II GMV. In patients with cerebellar disability, we found three clusters with homogenous MRI metrics: patients with high brain lesion volumes (including cerebellar peduncles), those with marked cerebellum GM atrophy and patients with severe cord damage. CONCLUSIONS: Damage to cerebellum GM and connecting structures has a relevant role in explaining cognitive dysfunction and physical disability in MS. Data-driven MRI clustering might improve our knowledge of MRI-clinical correlations.

Divergent time-varying connectivity of thalamic sub-regions characterizes clinical phenotypes and cognitive status in multiple sclerosis.

We aimed to investigate abnormal time-varying functional connectivity (FC) for thalamic sub-regions in multiple sclerosis (MS) and their clinical, cognitive and MRI correlates. Eighty-nine MS patients (49 relapsing-remitting [RR] MS; 40 progressive [P] MS) and 53 matched healthy controls underwent neurological, neuropsychological and resting state fMRI assessment. Time-varying connectivity (TVC) was quantified using sliding-window seed-voxel correlation analysis. Standard deviation of FC across windows was taken as measure of TVC, while mean connectivity across windows expressed static FC. MS patients showed reduced TVC vs controls between most of thalamic sub-regions and fronto-temporo-occipital regions. At the same time, they showed increased static FC between all thalamic sub-regions and structurally connected cortico-subcortical regions. TVC reduction was mainly driven by RRMS; while PMS exhibited a variable pattern of TVC abnormalities, characterized by reduced TVC between frontal/motor thalamic seeds and default-mode network areas and increased TVC vs controls/RRMS between posterior thalamic sub-regions and occipito-temporo-insular cortices, associated with severity of clinical disability. Compared with controls, both cognitively preserved and impaired patients showed reduced TVC between anterior thalamic sub-regions and frontal cortex. Cognitively impaired patients also showed increased TVC of the right postcentral thalamic sub-region with the cingulate cortex and postcentral gyrus vs both controls and cognitively preserved patients. Divergent patterns of TVC thalamic abnormalities were found between RRMS and PMS patients. TVC reduction in RRMS may represent the attempt of thalamic network to keep with stable connections. Conversely, increased TVC of posterior thalamic sub-regions characterized PMS and cognitively impaired MS, possibly reflecting maladaptive mechanisms.

Functional and structural MRI correlates of executive functions in multiple sclerosis.

BACKGROUND: Executive dysfunctions, including difficulties in attention, working memory, planning, and inhibition affect 15%-28% of multiple sclerosis (MS) patients. OBJECTIVES: To investigate structural and functional magnetic resonance imaging (MRI) abnormalities underlying executive function (EF) in MS patients. METHODS: A total 116 MS patients and 65 controls underwent resting-state (RS) and diffusion-weighted sequences and neuropsychological examination, including Wisconsin Card Sorting Test (WCST) to test EF. Brain RS cognitive networks and fractional anisotropy (FA) from a priori selected white matter tracts were derived. Associations of WCST scores with RS functional connectivity (FC) and FA abnormalities were investigated. RESULTS: In MS patients, predictors of working memory/updating were: lower corpus callosum (CC) FA, lower left working-memory network (WMN), right WMN RS FC for worse performance; lower executive control network (ECN), higher default-mode network (DMN), and salience network (SN) RS FC for better performance (R2 = 0.35). Predictors of attention were lower CC genu FA, lower left WMN, and DMN RS FC for worse performance; higher left WMN and ECN RS FC for better performance (R2 = 0.24). Predictors of worse shifting/inhibition were lower CC genu and superior cerebellar peduncle (SCP) FA, lower left WMN RS FC for worse performance; and higher ECN RS FC for better performance (R2 = 0.24). CONCLUSIONS: CC and SCP microstructural damage and RS FC abnormalities in cognitive networks underlie EF frailty in MS.

Association of Age at Onset With Gray Matter Volume and White Matter Microstructural Abnormalities in People With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: To investigate whether age at onset influences brain gray matter volume (GMV) and white matter (WM) microstructural abnormalities in adult patients with multiple sclerosis (MS), given its influence on clinical phenotype and disease course. METHODS: In this hypothesis-driven cross-sectional study, we enrolled 67 patients with pediatric-onset MS (POMS) and 143 sex- and disease duration (DD)-matched randomly selected patients with adult-onset MS (AOMS), together with 208 healthy controls. All participants underwent neurologic evaluation and 3T MRI acquisition. MRI variables were standardized based on healthy controls, to remove effects of age and sex. Associations with DD in patients with POMS and patients with AOMS were studied with linear models. Time to reach clinical and MRI milestones was assessed with product-limit approach. RESULTS: At DD 1 year, GMV and WM fractional anisotropy (FA) were abnormal in AOMS but not in POMS. Significant interaction of age at onset (POMS vs AOMS) into the association with DD was found for GMV and WM FA. The crossing point of regression lines in POMS and AOMS was at 20 years of DD for GMV and 14 for WM FA. For POMS and AOMS, median DD was 29 and 19 years to reach Expanded Disability Status Scale score 3 (p < 0.001), 31 and 26 years to reach abnormal Paced Auditory Serial Addition Task, 3-second version (p = 0.01), 24 and 18 years to reach abnormal GMV (p = 0.04), and 19 and 17 years to reach abnormal WM FA (p = 0.36). DISCUSSION: Younger patients are initially resilient to MS-related damage. Then, compensatory mechanisms start failing with loss of WM integrity, followed by GM atrophy and finally disability.

Unraveling the substrates of cognitive impairment in multiple sclerosis: A multiparametric structural and functional magnetic resonance imaging study.

BACKGROUND: Cognitive impairment frequently affects multiple sclerosis (MS) patients. However, its neuroanatomical correlates still need to be fully explored. We investigated the contribution of structural and functional magnetic resonance imaging (MRI) abnormalities in explaining cognitive impairment in MS. METHODS: Brain dual-echo, diffusion tensor, 3D T1-weighted and resting-state (RS) MRI sequences were acquired from 276 MS patients and 102 healthy controls. Using random forest analysis, the contribution of regional white matter (WM) lesions, WM fractional anisotropy (FA) abnormalities, gray matter (GM) atrophy and RS functional connectivity (FC) alterations to cognitive impairment in MS patients was investigated. RESULTS: Eighty-four MS patients (30.4%) were cognitively impaired. The best MRI predictors of cognitive impairment (relative importance [%]) (out-of-bag area under the curve [AUC] = 0.795) were (a) WM lesions in the right superior longitudinal fasciculus (100%), left anterior thalamic radiation (93.4%), left posterior corona radiata (78.5%), left medial lemniscus (74.2%), left inferior longitudinal fasciculus (70.4%), left optic radiation (68.7%), right middle cerebellar peduncle (60.6%) and right optic radiation (53.5%); (b) decreased FA in the splenium of the corpus callosum (64.3%), left optic radiation (61.0%), body of the corpus callosum (51.9%) and fornix (50.9%); and (c) atrophy of the left precuneus (91.4%), right cerebellum crus I (84.4%), right caudate nucleus (78.6%), left thalamus (76.2%) and left supplementary motor area (59.8%). The relevance of these MRI measures in explaining cognitive impairment was confirmed in a cross-validation analysis (AUC =0.765). CONCLUSION: Structural damage in strategic WM and GM regions explains cognitive impairment in MS patients more than RS FC abnormalities.

Effect of cognitive reserve on structural and functional MRI measures in healthy subjects: a multiparametric assessment.

BACKGROUND: Cognitive reserve (CR) contributes to inter-individual variability of cognitive performance and to preserve cognitive functioning facing aging and brain damage. However, brain anatomical and functional substrates of CR still need to be fully explored in young healthy subjects (HS). By evaluating a relatively large cohort of young HS, we investigated the associations between CR and structural and functional magnetic resonance imaging (MRI) measures in early adulthood. METHODS: A global Cognitive Reserve Index (CRI), combining intelligence quotient, leisure activities and education, was measured from 77 HS and its brain anatomical and functional substrates were evaluated through a multiparametric MRI approach. Substrates of the three subdomains (cognitive/social/physical) of leisure activities were also explored. RESULTS: Higher global and subdomain CRIs were associated with higher gray matter volume of brain regions involved in motor and cognitive functions, such as the right (R) supplementary motor area, left (L) middle frontal gyrus and L cerebellum. No correlation with measures of white matter (WM) integrity was found. Higher global and subdomains CRIs were associated with lower resting-state functional connectivity (RS FC) of L postcentral gyrus and R insula in sensorimotor network, L postcentral gyrus in salience network and R cerebellum in the executive-control network. Moreover, several CRIs were also associated with higher RS FC of R cuneus in default-mode network. CONCLUSIONS: CR modulates structure and function of several brain motor and cognitive networks responsible for complex cognitive functioning already in young HS. CR could promote optimization of the recruitment of brain networks.