Using quantitative T2* 7-tesla (7T) MRI as a marker of demyelination and iron loss, we investigated, in patients with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple ...sclerosis (SPMS), spatial and tissue intrinsic characteristics of cortical lesion(s) (CL) types, and structural integrity of perilesional normal-appearing cortical gray matter (NACGM) as a function of distance from lesions.
Patients with MS (18 RRMS, 11 SPMS), showing at least 2 CL, underwent 7T T2* imaging to obtain (1) magnitude images for segmenting focal intracortical lesion(s) (ICL) and leukocortical lesion(s) (LCL), and (2) cortical T2* maps. Anatomical scans were collected at 3T for cortical surface reconstruction using FreeSurfer. Seventeen age-matched healthy participants served as controls.
ICL were predominantly located in sulci of frontal, parietal, and cingulate cortex; LCL distribution was more random. In MS, T2* was higher in both ICL and LCL, indicating myelin and iron loss, than in NACGM (p < 0.00003) irrespective of CL subtype and MS phenotype. T2* was increased in perilesional cortex, tapering away from CL toward NACGM, the wider changes being for LCL in SPMS. NACGM T2* was higher in SPMS relative to RRMS (p = 0.006) and healthy cortex (p = 0.02).
CL had the same degree of demyelination and iron loss regardless of lesion subtype and disease stage. Cortical damage expanded beyond visible CL, close to lesions in RRMS, and more diffusely in SPMS. Evaluation of NACGM integrity, beyond focal CL, could represent a surrogate marker of MS progression.
Background and purpose
To investigate the relationship between the functional connectivity (FC) of the sensorimotor and cognitive cerebellum and measures of structural damage in patients with ...multiple sclerosis (MS) and no physical disability.
Methods
We selected 144 relapsing–remitting MS patients with an Expanded Disability Status Scale score of ≤1.5 and 98 healthy controls from the Italian Neuroimaging Network Initiative database. From multimodal 3T magnetic resonance imaging (MRI), including functional MRI at rest, we calculated lesion load, cortical thickness, and white matter, cortical gray matter, and caudate, putamen, thalamic, and cerebellar volumes. Voxel‐wise FC of the sensorimotor and cognitive cerebellum was assessed with seed‐based analysis, and multiple regression analysis was used to evaluate the relationship between FC and structural damage.
Results
Whole brain, white matter, caudate, putamen, and thalamic volumes were reduced in patients compared to controls, whereas cortical gray matter was not significantly different in patients versus controls. Both the sensorimotor and cognitive cerebellum showed a widespread pattern of increased and decreased FC that were negatively associated with structural measures, indicating that the lower the FC, the greater the tissue loss. Lastly, among multiple structural measures, cortical gray matter and white matter volumes were the best predictors of cerebellar FC alterations.
Conclusions
Increased and decreased cerebellar FC with several brain areas coexist in MS patients with no disability. Our data suggest that white matter loss hampers FC, whereas, in the absence of atrophy, cortical volume represents the framework for FC to increase.
The cerebellum is one of the major sites affected by multiple sclerosis (MS) from early disease stages, and cognitive and sensorimotor cerebellar damage contributes to disability across MS phenotypes. This study evaluated functional connectivity (FC) in patients with MS and no disability. Mechanisms of both increased and decreased cerebellar FC coexist and were associated with volume loss, suggesting that cerebellar FC decrease is linked to white matter loss, whereas cerebellar FC may increase if gray matter is preserved. These alterations may underpin a preserved clinical status despite brain structural damage.
Patients with frontotemporal degeneration (FTD) often manifest parkinsonism, which likely results from cortical and subcortical degeneration of brain structures involved in motor control. We used a ...multimodal magnetic resonance imaging (MRI) approach to investigate possible structural and/or functional alterations in FTD patients with and without parkinsonism (Park+ and Park-).
Thirty FTD patients (12 Park+, 18 Park-) and 30 healthy controls were enrolled and underwent 3T MRI scanning. MRI analyses included: (1) surface-based morphometry; (2) basal ganglia and thalamic volumetry; (3) diffusion-based probabilistic tractography of fiber tracts connecting the supplementary motor area (SMA) and primary motor cortex (M1) to the putamen, globus pallidus, and thalamus; and (4) resting-state functional connectivity (RSFC) between the aforementioned regions.
Patients in Park+ and Park- groups showed comparable patterns of cortical thinning in frontotemporal regions and reduced thalamic volume with respect to controls. Only Park+ patients showed reduced putaminal volume and reduced fractional anisotropy of the fibers connecting the SMA to the globus pallidus, putamen, and thalamus, with respect to controls. Park+ patients also showed decreased RSFC between the SMA and putamen with respect to both Park- patients and controls.
The present findings support the hypothesis that FTD patients with parkinsonism are characterized by neurodegenerative processes in specific corticobasal ganglia-thalamocortical motor loops.
Dystonia is thought to be a network disorder due to abnormalities in the basal ganglia-thalamo-cortical circuit. We aimed to investigate the white matter (WM) microstructural damage of bundles ...connecting pre-defined subcortical and cortical regions in cervical dystonia (CD) and blepharospasm (BSP). Thirty-five patients (17 with CD and 18 with BSP) and 17 healthy subjects underwent MRI, including diffusion tensor imaging (DTI). Probabilistic tractography (BedpostX) was performed to reconstruct WM tracts connecting the globus pallidus, putamen and thalamus with the primary motor, primary sensory and supplementary motor cortices. WM tract integrity was evaluated by deriving their DTI metrics. Significant differences in mean, radial and axial diffusivity between CD and HS and between BSP and HS were found in the majority of the reconstructed WM tracts, while no differences were found between the two groups of patients. The observation of abnormalities in DTI metrics of specific WM tracts suggests a diffuse and extensive loss of WM integrity as a common feature of CD and BSP, aligning with the increasing evidence of microstructural damage of several brain regions belonging to specific circuits, such as the basal ganglia-thalamo-cortical circuit, which likely reflects a common pathophysiological mechanism of focal dystonia.
Abstract Aim To assess functional rearrangement following neurodegeneration in the thalamus and dentate nucleus in patients with progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). ...Methods We recruited 19 patients with PSP, 11 with CBS and 14 healthy subjects. All the subjects underwent resting-state (rs) fMRI using a 3T system. Whole brain functional connectivity of the thalamus and dentate nucleus were calculated by means of a seed-based approach with FEAT script in FSL toolbox. Thalamic volume was calculated by means of FIRST, and the dentate area by means of Jim software. Results Both thalamic volume and dentate area were significantly smaller in PSP and CBS patients than in healthy subjects. No significant difference emerged in thalamic volume between PSP and CBS patients, whereas dentate area was significantly smaller in PSP than in CBS. Thalamic functional connectivity was significantly reduced in both patient groups in various cortical, subcortical and cerebellar areas. By contrast, changes in dentate nucleus functional connectivity differed in PSP and CBS: it decreased in subcortical and prefrontal cortical areas in PSP, but increased asymmetrically in the frontal cortex in CBS. Conclusions Evaluating the dentate nucleus size and its functional connectivity may help to differentiate patients with PSP from those with CBS.
To investigate in vivo the spatial specificity of the interdependence between intracortical and white matter (WM) pathologic changes as function of cortical depth and distance from the cortex in ...multiple sclerosis (MS), and their independent contribution to physical and cognitive disability.
This study was institutional review board-approved and participants gave written informed consent. In 34 MS patients and 17 age-matched control participants, 7-T quantitative T2* maps, 3-T T1-weighted anatomic images for cortical surface reconstruction, and 3-T diffusion tensor images (DTI) were obtained. Cortical quantitative T2* maps were sampled at 25%, 50%, 75% depth from pial surface. Tracts of interest were reconstructed by using probabilistic tractography. The relationship between DTI metrics voxelwise of the tracts and cortical integrity in the projection cortex was tested by using multilinear regression models.
In MS, DTI abnormal findings along tracts correlated with quantitative T2* changes (suggestive of iron and myelin loss) at each depth of the cortical projection area (P < .01, corrected). This association, however, was not spatially specific because abnormal findings in WM tracts also related to cortical pathologic changes outside of the projection cortex of the tract (P < .001). Expanded Disability Status Scale pyramidal score was predicted by axial diffusivity along the corticospinal tract (β = 4.6 × 10(3); P < .001), Symbol Digit Modalities Test score by radial diffusivity along the cingulum (β = -4.3 × 10(4); P < .01), and T2* in the cingulum cortical projection at 25% depth (β = -1.7; P < .05).
Intracortical and WM injury are concomitant pathologic processes in MS, which are not uniquely distributed according to a tract-cortex-specific pattern; their association may reflect a common stage-dependent mechanism.
Objective
In multiple sclerosis (MS), using simultaneous magnetic resonance–positron emission tomography (MR‐PET) imaging with 11C‐PBR28, we quantified expression of the 18kDa translocator protein ...(TSPO), a marker of activated microglia/macrophages, in cortex, cortical lesions, deep gray matter (GM), white matter (WM) lesions, and normal‐appearing WM (NAWM) to investigate the in vivo pathological and clinical relevance of neuroinflammation.
Methods
Fifteen secondary‐progressive MS (SPMS) patients, 12 relapsing–remitting MS (RRMS) patients, and 14 matched healthy controls underwent 11C‐PBR28 MR‐PET. MS subjects underwent 7T
T2*‐weighted imaging for cortical lesion segmentation, and neurological and cognitive evaluation. 11C‐PBR28 binding was measured using normalized 60‐ to 90‐minute standardized uptake values and volume of distribution ratios.
Results
Relative to controls, MS subjects exhibited abnormally high 11C‐PBR28 binding across the brain, the greatest increases being in cortex and cortical lesions, thalamus, hippocampus, and NAWM. MS WM lesions showed relatively modest TSPO increases. With the exception of cortical lesions, where TSPO expression was similar, 11C‐PBR28 uptake across the brain was greater in SPMS than in RRMS. In MS, increased 11C‐PBR28 binding in cortex, deep GM, and NAWM correlated with neurological disability and impaired cognitive performance; cortical thinning correlated with increased thalamic TSPO levels.
Interpretation
In MS, neuroinflammation is present in the cortex, cortical lesions, deep GM, and NAWM, is closely linked to poor clinical outcome, and is at least partly linked to neurodegeneration. Distinct inflammatory‐mediated factors may underlie accumulation of cortical and WM lesions. Quantification of TSPO levels in MS could prove to be a sensitive tool for evaluating in vivo the inflammatory component of GM pathology, particularly in cortical lesions. Ann Neurol 2016;80:776–790
Using quantitative T
* at 7 Tesla (T) magnetic resonance imaging, we investigated whether impairment in selective cognitive functions in multiple sclerosis (MS) can be explained by pathology in ...specific areas and/or layers of the cortex. Thirty-one MS patients underwent neuropsychological evaluation, acquisition of 7 T multi-echo T
* gradient-echo sequences, and 3 T anatomical images for cortical surfaces reconstruction. Seventeen age-matched healthy subjects served as controls. Cortical T
* maps were sampled at various depths throughout the cortex and juxtacortex. Relation between T
*, neuropsychological scores and a cognitive index (CI), calculated from a principal component analysis on the whole battery, was tested by a general linear model. Cognitive impairment correlated with T
* increase, independently from white matter lesions and cortical thickness, in cortical areas highly relevant for cognition belonging to the default-mode network (p < 0.05 corrected). Dysfunction in different cognitive functions correlated with longer T
* in selective cortical regions, most of which showed longer T
* relative to controls. For most tests, this association was strongest in deeper cortical layers. Executive dysfunction, however, was mainly related with pathology in juxtameningeal cortex. T
* explained up to 20% of the variance of the CI, independently of conventional imaging metrics (adjusted-R
: 52-67%, p < 5.10
). Location of pathology across the cortical width and mantle showed selective correlation with impairment in differing cognitive domains. These findings may guide studies at lower field strength designed to develop surrogate markers of cognitive impairment in MS.
Interferon beta is a well established disease-modifying agent used for relapsing-remitting multiple sclerosis. Despite treatment, a relevant proportion of patients continue to experience clinical ...(ie, relapses, worsening of disability) and magnetic resonance imaging (MRI) activity. Early identification of responders and nonresponders to interferon beta is strongly recommended to select patients who need a prompt switch to another disease-modifying agent and to ultimately avoid accumulation of fixed disability over time. Detecting responders and nonresponders to interferon beta can be challenging, mainly because of the lack of a clear and shared clinical definition of response to treatment. Clinical features at the start of treatment should be considered as prognostic factors, but MRI parameters assessed during treatment, such as contrast-enhancing lesions or new T2-hyperintense lesions, may be sensitive markers of response to interferon beta. Quantitative scoring systems derived from a combination of relapses and MRI activity have recently been proposed as practical tools for use in the everyday clinical setting. Blood biomarkers, such as neutralizing antibodies to interferon beta and Myxovirus resistance protein A, provide further useful information for detecting responders and nonresponders to interferon beta. However, since the presence of neutralizing antibodies can only partially explain the nonresponse to interferon beta, biomarkers of interferon beta activity possibly related to the pathogenesis of the disease could represent a future step toward a tailored, long-lasting effective treatment against multiple sclerosis. Keywords: interferon beta, responders, nonresponders, multiple sclerosis
Using quantitative T2* at 7 Tesla (T) magnetic resonance imaging, we investigated whether impairment in selective cognitive functions in multiple sclerosis (MS) can be explained by pathology in ...specific areas and/or layers of the cortex. Thirty-one MS patients underwent neuropsychological evaluation, acquisition of 7 T multi-echo T2* gradient-echo sequences, and 3 T anatomical images for cortical surfaces reconstruction. Seventeen age-matched healthy subjects served as controls. Cortical T2* maps were sampled at various depths throughout the cortex and juxtacortex. Relation between T2*, neuropsychological scores and a cognitive index (CI), calculated from a principal component analysis on the whole battery, was tested by a general linear model. Cognitive impairment correlated with T2* increase, independently from white matter lesions and cortical thickness, in cortical areas highly relevant for cognition belonging to the default-mode network (p < 0.05 corrected). Dysfunction in different cognitive functions correlated with longer T2* in selective cortical regions, most of which showed longer T2* relative to controls. For most tests, this association was strongest in deeper cortical layers. Executive dysfunction, however, was mainly related with pathology in juxtameningeal cortex. T2* explained up to 20% of the variance of the CI, independently of conventional imaging metrics (adjusted-R2: 52-67%, p < 5.10- 4). Location of pathology across the cortical width and mantle showed selective correlation with impairment in differing cognitive domains. These findings may guide studies at lower field strength designed to develop surrogate markers of cognitive impairment in MS.
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