Stefan D. Roosendaal

Regional DTI differences in multiple sclerosis patients

Diffusion tensor imaging (DTI) measures have shown to be sensitive to white matter (WM) damage in multiple sclerosis (MS), not only inside focal lesions but also in user-defined regions in the so-called normal-appearing white matter (NAWM). New analysis techniques for DTI measures are now available that allow for hypothesis-free localization of damage. We performed DTI measurements of 30 MS patients selected for low focal lesion loads, and of 31 age-matched healthy controls and analyzed these using tract-based spatial statistics (TBSS). Patients were found to have a lower fractional anisotropy (FA) compared to controls in a number of brain regions, including the fornices, the left corona radiata, the inferior longitudinal fasciculus in both hemispheres, both optic radiations, and parts of the corpus callosum. In the regions of reduced FA, an increase in radial diffusivity and a less pronounced increase of axial diffusivity were found. Neurocognitive assessment showed that patients had normal visuospatial memory performance, just-normal attention, and impaired processing speed; the latter was associated with abnormal FA in the corpus callosum, an area which was relatively devoid of lesions visible on proton density-weighted images in our patients. TBSS can be useful in future studies with other MS patient samples to provide an unbiased localization of damage and generate location-specific hypotheses.

Extensive Hippocampal Demyelination in Multiple Sclerosis

Abstract Memory impairment is especially prominent within the spectrum of cognitive deficits in multiple sclerosis (MS), and a crucial role for hippocampal pathology may therefore be expected in this disease. This study is the first to systematically assess hippocampal demyelination in MS. Hippocampal tissue samples of 19 chronic MS cases and 7 controls with non-neurologic disease were stained immunohistochemically for myelin proteolipid protein. Subsequently, number, location, and size of demyelinated lesions were assessed. Furthermore, the specimens were stained for HLA-DR to investigate microglia/macrophage activity. An unexpectedly high number of lesions (n = 37) was found in 15 of the 19 MS cases. Mixed intrahippocampal-perihippocampal lesions, which were more often found in cases with cognitive decline, were large and did not respect anatomical borders. Moderate microglial activation was frequently observed at the edges of these mixed lesions. Isolated intrahippocampal lesions were also frequently found. These were smaller than the mixed lesions and had a specific anatomical predilection: the cornu ammonis 2 subregion and the hilus of the dentate gyrus were consistently spared. Microglial activation was rare in isolated intrahippocampal lesions. Our results indicate that hippocampal demyelination is frequent and extensive in MS and that anatomical localization, size, and inflammatory activity vary for different lesion types.

Grey matter volume in a large cohort of MS patients: relation to MRI parameters and disability

Background: Although grey matter damage in multiple sclerosis is currently recognized, determinants of grey matter volume and its relationship with disability are not yet clear. Objectives: The objectives of the study were to measure grey and white matter volumes across different disease phenotypes; identify MRI parameters associated with grey matter volume; and study grey and white matter volume as explanatory variables for clinical impairment. Methods: This is a cross-sectional study in which MRI data of 95 clinically isolated syndrome, 657 relapsing–remitting, 125 secondary-progressive and 50 primary-progressive multiple sclerosis patients from three centres were acquired. Grey and white matter volumes were determined, together with T2 and T1 lesion volumes. Physical disability was assessed with the Expanded Disability Status Scale, cognitive impairment with the Paced Auditory Serial Addition Task. Data were analysed using multiple regression. Results: Grey matter volume was lower in relapsing–remitting patients (mean [SD]: 0.80 [0.05] L) than in clinically isolated syndrome patients (0.82 [0.05] L), and even greater relative atrophy was found in secondary-progressive patients (0.77 [0.05] L). In contrast, white matter volume in secondary-progressive patients was comparable to that in relapsing–remitting patients. Grey matter volume was the strongest independent predictor of physical disability and cognitive impairment, and was associated with both T2 and T1 lesion volume. Conclusions: Our findings show that grey matter volume is lower in secondary-progressive than in relapsing–remitting disease. Grey matter volume explained physical and cognitive impairment better than white matter volume, and is itself associated with T2 and T1 lesion volume.

Resting-state networks in awake five- to eight-year old children

During the first 6–7 years of life children undergo a period of major neurocognitive development. Higher‐order cognitive functions such as executive control of attention, encoding and retrieving of stored information and goal‐directed behavior are present but less developed compared to older individuals. There is only very limited information from functional magnetic resonance imaging (fMRI) studies about the level of organization of functional networks in children in the early school period. In this study we perform continuous resting‐state functional connectivity MRI in 5‐ to 8‐year‐old children in an awake state to identify and characterize resting‐state networks (RSNs). Temporal concatenation independent component analysis (ICA) approach was applied to analyze the data. We identified 14 components consisting of regions known to be involved in visual and auditory processing, motor function, attention control, memory, and the default mode network (DMN). Most networks, in particular those supporting basic motor function and sensory related processing, had a robust functional organization similar to mature adult patterns. In contrast, the DMN and other RSNs involved in higher‐order cognitive functions had immature characteristics, revealing incomplete and fragmented patterns indicating less developed functional connectivity. We therefore conclude that the DMN and other RSNs involved in higher order cognitive functioning are detectable, yet in an immature state, at an age when these cognitive abilities are mastered. Hum Brain Mapp, 2011.

Structural and Functional Hippocampal Changes in Multiple Sclerosis Patients with Intact Memory Function

PURPOSE To investigate changes in hippocampal functional connectivity and structural measures of hippocampal damage in multiple sclerosis (MS) patients with intact spatial memory, a cognitive domain frequently affected in progressive MS. MATERIALS AND METHODS The study protocol was approved by the institutional ethics review board; all subjects gave written informed consent prior to participation. Twenty-five MS patients with intact spatial memory function were compared with 30 age- and sex-matched controls. Hippocampal volume differences, based on manually drawn masks, were evaluated by using the Student t test. Additionally, focal hippocampal lesions and mean diffusivity were obtained as descriptive measures of structural hippocampal damage. Multiple regression analyses of the resting-state functional magnetic resonance (MR) imaging data were performed for each subject by using hippocampal time series. Between-group analyses were conducted with a mixed-effects model, corrected for multiple comparisons by a cluster defining threshold level of z = 2 and a corrected cluster size significance level of P < .05. RESULTS Right hippocampal volume was significantly lower in MS patients as compared with controls (P < .01). Left hippocampal volume was also lower in MS patients compared with controls, but not significantly so (P = .09). Resting-state functional connectivity between the hippocampus and its anatomic input or target areas, including the anterior cingulate gyrus, thalamus, and prefrontal cortex, were significantly decreased in MS patients. Decreased hippocampal functional connectivity was more pronounced in a subgroup of MS patients with hippocampal atrophy, although subtle decreases of functional connectivity were also found in patients with normal hippocampal volume. CONCLUSION In MS patients, substantial abnormalities of hippocampal functional connectivity are already present before spatial memory function is impaired, especially in those patients with more pronounced hippocampal atrophy. Longitudinal studies should now assess whether these functional connectivity and structural changes may precede memory impairment in MS.

In vivo MR imaging of hippocampal lesions in multiple sclerosis.

To investigate whether a recently improved version of the three‐dimensional double inversion‐recovery (3D‐DIR) technique enables the in vivo detection of hippocampal lesions in multiple sclerosis (MS).

Gender-related differences in functional connectivity in multiple sclerosis

Background: Gender effects are strong in multiple sclerosis (MS), with male patients showing a worse clinical outcome than female patients. Functional reorganization of neural activity may contribute to limit disability, and possible gender differences in this process may have important clinical implications. Objectives: The aim of this study was to explore gender-related changes in functional connectivity and network efficiency in MS patients. Additionally, we explored the association of functional changes with cognitive function. Methods: Sixty subjects were included in the study, matched for age, education level and intelligence quotient (IQ). Male and female patients were matched for disability, disease duration and white matter lesion load. Two cognitive domains often impaired in MS, i.e. visuospatial memory and information processing speed, were evaluated in all subjects. Functional connectivity between brain regions and network efficiency was explored using resting-state functional magnetic resonance imaging and graph analysis. Differences in cognitive and functional characteristics between groups, and correlations with cognitive performance, were examined. Results: Male patients showed worse performance on cognitive tests than female and male controls, while female patients were cognitively normal. Decreases in functional connectivity and network efficiency, observed in male patients, correlated with reduced visuospatial memory (r = −0.6 and r = −0.5, respectively). In the control group, no cognitive differences were found between genders, despite differences in functional connectivity between healthy men and women. Conclusions: Functional connectivity differences were found in male patients only and were related to impaired visuospatial memory. These results underline the importance of gender in MS and require further investigation in larger and longitudinal studies.

Functional adaptive changes within the hippocampal memory system of patients with multiple sclerosis

Memory deficits are highly prevalent in multiple sclerosis (MS). As the hippocampus is crucial to memory processing, a functional magnetic resonance imaging (fMRI) task was used to investigate changes in hippocampal function in MS patients with and without cognitive decline. Fifty patients with MS, (34 cognitively preserved (CP) and 16 cognitively impaired (CI)) and 30 healthy controls completed an episodic memory fMRI task (encoding and retrieval) that was used to specifically activate the hippocampus. During encoding of correctly remembered items, increased brain activation was seen in the parahippocampal areas bilaterally and in the left anterior cingulate gyrus in the CP patients compared to the controls (unclustered, Z ≥ 3.1, P ≤ 0.001). No brain areas showed less activation. In CI patients the right (para)hippocampal areas and the prefrontal cortex showed less brain activation compared to controls (cluster‐corrected, P < 0.05). The posterior cingulate gyrus and the left precuneus showed increased activation in CI patients when compared to controls (unclustered Z ≥ 3.1, P ≤ 0.001). No significant differences were found on structural MRI measures between the CP and CI patients. These results suggest the presence of functional adaptation in the memory network before cognitive decline becomes evident in MS, as displayed by the increased brain activation in the hippocampal‐cingulate memory system in CP patients. Interestingly, CI patients showed less activation in the hippocampal network during correct encoding. These findings are important for future cognitive therapeutic studies, since cognitive intervention might be most effective before cognitive impairment is present and when adaptive changes of the brain are most prominent. Hum Brain Mapp 33:2268–2280, 2012.

Longitudinal gray matter changes in multiple sclerosis—Differential scanner and overall disease-related effects

Voxel‐based morphometry (VBM) has been used repeatedly in single‐center studies to investigate regional gray matter (GM) atrophy in multiple sclerosis (MS). In multi‐center trials, across‐scanner variations might interfere with the detection of disease‐specific structural abnormalities, thereby potentially limiting the use of VBM. Here we evaluated longitudinally inter‐site differences and inter‐site comparability of regional GM in MS using VBM. Baseline and follow up 3D T1‐weighted magnetic resonance imaging (MRI) data of 248 relapsing‐remitting (RR) MS patients, recruited in two clinical centers, (center1/2: n = 129/119; mean age 42.6 ± 10.7/43.3 ± 9.3; male:female 33:96/44:75; median disease duration 150 [72–222]/116 [60–156]) were acquired on two different 1.5T MR scanners. GM volume changes between baseline and year 2 while controlling for age, gender, disease duration, and global GM volume were analyzed. The main effect of time on regional GM volume was larger in data of center two as compared to center one in most of the brain regions. Differential effects of GM volume reductions occured in a number of GM regions of both hemispheres, in particular in the fronto‐temporal and limbic cortex (cluster P corrected <0.05). Overall disease‐related effects were found bilaterally in the cerebellum, uncus, inferior orbital gyrus, paracentral lobule, precuneus, inferior parietal lobule, and medial frontal gyrus (cluster P corrected <0.05). The differential effects were smaller as compared to the overall effects in these regions. These results suggest that the effects of different scanners on longitudinal GM volume differences were rather small and thus allow pooling of MR data and subsequent combined image analysis. Hum Brain Mapp, 2011.

MRI criteria differentiating asymptomatic PML from new MS lesions during natalizumab pharmacovigilance

Objective Differentiation between progressive multifocal leukoencephalopathy (PML) and new multiple sclerosis (MS) lesions on brain MRI during natalizumab pharmacovigilance in the absence of clinical signs and symptoms is challenging but is of substantial clinical relevance. We aim to define MRI characteristics that can aid in this differentiation. Methods Reference and follow-up brain MRIs of natalizumab-treated patients with MS with asymptomatic PML (n=21), or asymptomatic new MS lesions (n=20) were evaluated with respect to characteristics of newly detected lesions by four blinded raters. We tested the association with PML for each characteristic and constructed a multivariable prediction model which we analysed using a receiver operating characteristic (ROC) curve. Results Presence of punctate T2 lesions, cortical grey matter involvement, juxtacortical white matter involvement, ill-defined and mixed lesion borders towards both grey and white matter, lesion size of >3 cm, and contrast enhancement were all associated with PML. Focal lesion appearance and periventricular localisation were associated with new MS lesions. In the multivariable model, punctate T2 lesions and cortical grey matter involvement predict for PML, while focal lesion appearance and periventricular localisation predict for new MS lesions (area under the curve: 0.988, 95% CI 0.977 to 1.0, sensitivity: 100%, specificity: 80.6%). Interpretation The MRI characteristics of asymptomatic natalizumab-associated PML lesions proved to differ from new MS lesions. This led to a prediction model with a high discriminating power. Careful assessment of the presence of punctate T2 lesions, cortical grey matter involvement, focal lesion appearance and periventricular localisation allows for an early diagnosis of PML.