Axonal loss in multiple sclerosis lesions: Magnetic resonance imaging insights into substrates of disability

MS-MR Centre and Department of Radiology, Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands.
Annals of Neurology (Impact Factor: 9.98). 12/1999; 46(5):747-54. DOI: 10.1002/1531-8249(199911)46:53.3.CO;2-W
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Magnetic resonance imaging (MRI) monitoring of disease progression in multiple sclerosis is limited by the lack of correlation of abnormalities seen on T2-weighted imaging, and disability. We studied the histopathology of multiple sclerosis lesions, as depicted by MRI, in a large postmortem sample, focusing on axonal loss. Tissue samples from 17 patients were selected immediately postmortem for histopathological analysis on the basis of T2-weighted imaging, including normal appearing white matter and T1 hypointense lesions. In each region, we measured magnetization transfer ratios (MTR), T1 contrast ratio, myelin, and axonal density. T2 lesions (109 samples) were heterogeneous with regard to MRI appearance on T1 and MTR, whereas axonal density ranged from 0% (no residual axons) to 100% (normal axonal density). Of 64 T2 lesions, 17 were reactive (mild perivascular inflammation only), 21 active, 15 chronically active, and 11 chronically inactive. MTR and T1 contrast ratio correlated strongly with axonal density. Also in normal appearing white matter (24 samples), MTR correlated with axonal density. In conclusion, postmortem tissue sampling by using MRI revealed a range of pathology, illustrating the high sensitivity and low specificity of T2-weighted imaging. T1 hypointensity and MTR were strongly associated with axonal density, emphasizing their role in monitoring progression in multiple sclerosis.

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    • "To address this problem, we employed magnetization transfer imaging, which detects not only volumetric changes (as e.g. neuronal loss or tissue shrinkage) but also microstructural alterations dependent of tissue myelination, axonal density, or gliosis (Grossman et al., 1994; Hanyu et al., 2000; van Waesberghe et al., 1999; Wolff and Balaban, 1994). This analysis is therefore sensitive to lesions present at early stages of neurodegeneration , as it has previously been demonstrated for several other diseases (Eckert et al., 2004; Kiefer et al., 2009; Perez-Torres et al., 2014; Ridha "
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    ABSTRACT: Previous studies have shown that in amyotrophic lateral sclerosis (ALS) multiple motor and extra-motor regions display structural and functional alterations. However, their temporal dynamics during disease-progression are unknown. To address this question we employed a longitudinal design assessing motor- and novelty-related brain activity in two fMRI sessions separated by a 3-month interval. In each session, patients and controls executed a Go/NoGo-task, in which additional presentation of novel stimuli served to elicit hippocampal activity. We observed a decline in the patients’ movement-related activity during the 3-month interval. Importantly, in comparison to controls, the patients’ motor activations were higher during the initial measurement. Thus, the relative decrease seems to reflect a breakdown of compensatory mechanisms due to progressive neural loss within the motor-system. In contrast, the patients’ novelty-evoked hippocampal activity increased across 3 months, most likely reflecting the build-up of compensatory processes typically observed at the beginning of lesions. Consistent with a stage-dependent emergence of hippocampal and motor-system lesions, we observed a positive correlation between the ALSFRS-R or MRC-Megascores and the decline in motor activity, but a negative one with the hippocampal activation-increase. Finally, to determine whether the observed functional changes co-occur with structural alterations, we performed voxel-based volumetric analyses on magnetization transfer images in a separate patient cohort studied cross-sectionally at another scanning site. Therein, we observed a close overlap between the structural changes in this cohort, and the functional alterations in the other. Thus, our results provide important insights into the temporal dynamics of functional alterations during disease-progression, and provide support for an anatomical relationship between functional and structural cerebral changes in ALS.
    Clinical neuroimaging 07/2014; 5. DOI:10.1016/j.nicl.2014.07.007 · 2.53 Impact Factor
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    • "“Black holes” are nonenhancing hypointense lesions on T1-weighted imaging that are correlated with areas of focal chronic axonal damage and loss on histopathology [40]. Therefore, the evolution of active lesions into T1-hypointense lesions represents irreversible tissue damage, and their accumulation is associated with disability accrual (rs = 0.46) [41–43]. In a recent multivariable analysis, worsening of EDSS score over 10 years in 58 patients with RRMS was associated with a combination of baseline T1-hypointense lesion count and increasing T1 lesion volume (r = 0.61, P < 0.001) [44]. "
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    ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease that manifests as acute relapses and progressive disability. As a primary endpoint for clinical trials in MS, disability is difficult to both characterize and measure. Furthermore, the recovery from relapses and the rate of disability vary considerably among patients. Given these challenges, investigators have developed and studied the performance of various outcome measures and surrogate endpoints in MS clinical trials. This review defines the outcome measures and surrogate endpoints used to date in MS clinical trials and presents challenges in the design of both adult and pediatric trials.
    05/2014; 2014:262350. DOI:10.1155/2014/262350
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    • "WM fiber pathways form the brain communication network; thus, the physical condition of a given pathway can determine the efficiency of signal transmissions between brain regions and might thereby influence behaviors relying on that pathway (Fields, 2008; Johansen-Berg, 2010; Johansen-Berg et al., 2010; Scholz et al., 2009). In this framework, the increasing sensorimotor impairment observed in PwMS over the disease course could be mainly due to the progression of WM damage, that is present in these patients since the early stages (Evangelou et al., 2000; Ferguson et al., 1997; Ge et al., 2005; van Waesberghe et al., 1999). In particular, reductions in the microstructural integrity of the corpus callosum (CC) have been shown to be associated with decreased sensorimotor performance, impairment in visuomotor learning and deficit in bimanual coordination (Bonzano et al., 2008, 2011a,b; Larson et al., 2002; Pelletier et al., 1992). "
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    ABSTRACT: Upper limb impairments can occur in patients with multiple sclerosis, affecting daily living activities; however there is at present no definite agreement on the best rehabilitation treatment strategy to pursue. Moreover, motor training has been shown to induce changes in white matter architecture in healthy subjects. This study aimed at evaluating the motor behavioral and white matter microstructural changes following a 2-month upper limb motor rehabilitation treatment based on task-oriented exercises in patients with multiple sclerosis. Thirty patients (18 females and 12 males; age=43.3±8.7years) in a stable phase of the disease presenting with mild or moderate upper limb sensorimotor deficits were randomized into two groups of 15 patients each. Both groups underwent twenty 1-hour treatment sessions, three times a week. The "treatment group" received an active motor rehabilitation treatment, based on voluntary exercises including task-oriented exercises, whilst the "control group" underwent passive mobilization of the shoulder, elbow, wrist and fingers. Before and after the rehabilitation protocols, motor performance was evaluated in all patients with standard tests. Additionally, finger motor performance accuracy was assessed by an engineered glove. In the same sessions, every patient underwent diffusion tensor imaging to obtain parametric maps of fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. The mean value of each parameter was separately calculated within regions of interest including the fiber bundles connecting brain areas involved in voluntary movement control: the corpus callosum, the corticospinal tracts and the superior longitudinal fasciculi. The two rehabilitation protocols induced similar effects on unimanual motor performance, but the bimanual coordination task revealed that the residual coordination abilities were maintained in the treated patients whilst they significantly worsened in the control group (p=0.002). Further, in the treatment group white matter integrity in the corpus callosum and corticospinal tracts was preserved whilst a microstructural integrity worsening was found in the control group (fractional anisotropy of the corpus callosum and corticospinal tracts: p=0.033 and p=0.022; radial diffusivity of the corpus callosum and corticospinal tracts: p=0.004 and p=0.008). Conversely, a significant increase of radial diffusivity was observed in the superior longitudinal fasciculi in both groups (p=0.02), indicating a lack of treatment effects on this structure, showing damage progression likely due to a demyelination process. All these findings indicate the importance of administering, when possible, a rehabilitation treatment consisting of voluntary movements. We also demonstrated that the beneficial effects of a rehabilitation treatment are task-dependent and selective in their target; this becomes crucial towards the implementation of tailored rehabilitative approaches.
    NeuroImage 12/2013; 90. DOI:10.1016/j.neuroimage.2013.12.025 · 6.36 Impact Factor
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