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February 07, 2012; 78 (6) Articles

Pattern of brain tissue loss associated with freezing of gait in Parkinson disease

V.S. Kostić, F. Agosta, M. Pievani, E. Stefanova, M. Ječmenica-Lukić, A. Scarale, V. Špica, M. Filippi
First published January 25, 2012, DOI: https://doi.org/10.1212/WNL.0b013e318245d23c
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Abstract

Objective: To investigate whether a specific pattern of gray matter (GM) tissue loss is associated with freezing of gait (FOG) in patients with Parkinson disease (PD).

Methods: Seventeen patients with PD with FOG (PD-FOG), 20 patients with PD with no FOG (PD-noFOG), and 34 healthy control subjects were recruited. PD-FOG and PD-noFOG patients were matched on an individual basis for age, disease duration, and Hoehn and Yahr stage. Patients were also administered a comprehensive neuropsychological battery focused on executive functions. The extent and distribution of GM atrophy were assessed using voxel-based morphometry.

Results: In patients with PD, the severity of FOG correlated with frontal executive deficits. Compared with healthy control subjects, PD-FOG patients showed a distributed pattern of GM atrophy including the dorsolateral prefrontal, medial, and lateral temporal, inferior parietal, and occipital cortices. PD-noFOG patients showed only small regions of GM atrophy in the bilateral frontal and temporal cortex. The left inferior frontal gyrus, left precentral gyrus, and left inferior parietal gyrus were more atrophic in PD-FOG patients relative to both healthy control subjects and PD-noFOG patients. In PD-FOG patients, the severity of FOG was associated with GM volumes of the frontal and parietal cortices bilaterally.

Conclusions: GM frontal and parietal atrophy occur in PD-FOG patients. FOG in PD seems to share with executive dysfunction and perception deficits a common pattern of structural damage to the frontal and parietal cortices.

GLOSSARY

ACE-R=
Addenbrooke's Cognitive Examination–Revised;
BG=
basal ganglia;
DARTEL=
diffeomorphic anatomic registration exponentiated lie algebra;
EXIT-25=
Executive Interview;
FAB=
Frontal Assessment Battery;
FGQ=
Freezing of Gait Questionnaire;
FOG=
freezing of gait;
FWE=
family-wise error;
GM=
gray matter;
HDRS=
Hamilton Depression Rating Scale;
HARS=
Hamilton Anxiety Rating Scale;
MLR=
mesencephalic locomotor region;
MMSE=
Mini-Mental State Examination;
MNI=
Montreal Neurological Institute;
PD=
Parkinson disease;
PD-FOG=
Parkinson disease with freezing of gait;
PD-noFOG=
Parkinson disease with no freezing of gait;
PPN=
pedunculopontine nucleus;
ROI=
region of interest;
TUG=
Timed Up & Go;
UPDRS III=
Unified Parkinson's Disease Rating Scale III;
VBM=
voxel-based morphometry;
WMH=
white matter hyperintensity.

Freezing of gait (FOG) is a unique and disturbing gait disorder usually observed in patients with Parkinson disease (PD), affecting approximately half of the patients in the advanced stages of the disease.1 FOG is defined as “an episodic inability (lasting seconds) to generate effective stepping in the absence of any known cause other than parkinsonism or high-level gait disorders.”1

FOG is considered a distinct clinical motor feature of PD, independent of bradykinesia and rigidity.1 The precise pathophysiology of FOG and the underlying neural network damage are unknown. A recent review of functional imaging studies of FOG in PD suggested that this phenomenon may be a consequence of the dysfunction of basal ganglia (BG)-thalamo-cortical circuitries, particularly those involving premotor and parietal areas.2 The relationship between regional brain volume loss and FOG in PD has not been fully investigated yet. To our knowledge, only one study investigated the regional brain atrophy in patients with PD with FOG (PD-FOG) and with no FOG (PD-noFOG).3 Although the whole brain analysis did not show any gray matter (GM) volume difference between the groups, when the focus was on the mesencephalic locomotor region (MLR) using a region of interest (ROI) approach, PD-FOG patients showed atrophy compared with PD-noFOG patients.3

Against this background, using voxel-based morphometry (VBM), we assessed whether a specific pattern of GM tissue loss is associated with FOG in patients with PD. MRI scans were obtained from PD-FOG and PD-noFOG patients, who were matched for age, disease duration, and disease stage, as well as from healthy control subjects.

METHODS

Subjects.

Seventeen PD-FOG and 20 PD-noFOG right-handed patients4 were recruited from the Outpatient Clinics, Department of Neurology, University of Belgrade, Serbia. All patients except one were taking levodopa (in combination with a dopamine receptor agonist in 27 patients). All these patients experienced levodopa-related motor fluctuations, and 35 had mild to moderate levodopa-induced dyskinesia. Patients were examined in the morning during the off period, i.e., approximately 12 hours after the intake of the last dose of dopaminergic medication. Disease stage was scored using the Hoehn and Yahr stage score,5 disease severity using the Unified Parkinson's Disease Rating Scale III (UPDRS III),6 and global cognitive function using the Mini-Mental State Examination (MMSE).7 Inclusion criteria were the following: age ≥45 years, Hoehn and Yahr stage score <4 (off), stable and optimized antiparkinsonian treatment during the 4 weeks before study entry, and MMSE score ≥25. Patients were excluded if they had significant comorbidities limiting gait, such as cardiovascular or cerebrovascular disorders including strokes, history of traumatic brain injury, hydrocephalus, or intracranial mass, rheumatic or orthopedic disease, visual disturbances impairing walking abilities, or musculoskeletal disorders; major depression8; anticholinergic treatment; and other causes of focal or diffuse brain damage, including lacunae and extensive cerebrovascular disorders on routine MRI. Thirty-four healthy individuals (mainly partners or accompanying persons) served as control subjects.

Patients were classified as PD-FOG if the following conditions were satisfied: a) score >1 on the Freezing of Gait Questionnaire (FGQ) item 39 and at least 2 of the following: b) observation of FOG by 2 experienced neurologists (including the Timed Up & Go [TUG] test with obstacles10); c) the participant's verbal account of whether he or she had experienced FOG; and d) the recognition in the patient's experience of typical FOG when this was identified and described to him or her by a physician. Fourteen PD-FOG and no PD-noFOG patients experienced FOG during the TUG test. None of the patients with a FGQ item 3 score ≤1 showed abnormalities for criteria b, c, and d. PD-FOG and PD-noFOG patients were matched on an individual basis for age, disease duration, and off Hoehn and Yahr stage. Seven patients from the PD-noFOG group had a relatively high total FGQ score (from 6 to 10). In these patients, the major (or exclusive) contribution to the score came from the gait items 1 and 2 (maximum 8 points) and to a lesser degree from a low score on freezing item 3 and 6 (maximum 1 point). However, none of them had a score >1 on FGQ item 3 or fulfilled other criteria suggestive of FOG.

Within 48 hours from MRI, an experienced neuropsychologist, who was unaware of the clinical and MRI data, administered a neuropsychological and behavioral evaluation, including the Addenbrooke's Cognitive Examination–Revised (ACE-R),11 Frontal Assessment Battery (FAB),12 Executive Interview (EXIT-25),13 and Hamilton Depression Rating Scale (HDRS)14 and Hamilton Anxiety Rating Scale (HARS).15

Standard protocol approvals and patient consents.

Approval was received from the local ethics standards committee on human experimentation, and written informed consent was obtained from all subjects participating in the study.

MRI acquisition and analysis.

MRI scans were acquired using a 1.5-T system (Avanto; Siemens, Erlangen, Germany). Dual-echo turbo spin-echo and T1-weighted magnetization–prepared rapid acquisition gradient echo sequences were acquired as described previously.16 MRI analysis was performed by an experienced observer, blinded to clinical findings. White matter hyperintensities (WMHs), if any, were identified on dual-echo scans. WMH load was measured using Jim 4.0 (http://www.xinapse.com/Manual/index.html).

VBM was performed using SPM8 and the diffeomorphic anatomic registration exponentiated lie algebra (DARTEL) registration method.17 1) T1-weighted images were segmented using the standard unified segmentation model in SPM8 to produce gray matter (GM), white matter, and CSF probability maps in the Montreal Neurological Institute (MNI) space; 2) original T1-weighted images were imported into DARTEL, 3) rigidly aligned, 4) segmented a second time (using the segmentation parameters from steps 1 and 5) resampled to 1.5-mm isotropic voxels; 6) GM segments were coregistered; and 7) the flow fields were applied to the rigidly aligned segments to warp them to the common DARTEL space and modulated using the Jacobian determinants. Because DARTEL warps to a common space that is smaller than MNI space, the modulated images from DARTEL were normalized to the MNI template using an affine transformation estimated from the DARTEL GM template and the a priori GM probability map. Images were smoothed with an 8-mm full-width at half-maximum Gaussian kernel.

Statistical analysis.

SPSS (version 16.0; SPSS Inc., Chicago, IL) was used to compare demographic and clinical variables between groups using analysis of variance or a χ2 test. The correlations between neuropsychological findings and FGQ scores were tested using Pearson correlation coefficient. p < 0.05 was considered as significant.

Using SPM8, between-group GM differences were tested using analyses of covariance adjusted for age, total intracranial volume and MMSE, HDRS, and HARS scores. The following comparisons were performed: all PD vs controls, PD-FOG vs controls, and PD noFOG vs controls. A conjunction analysis was performed to identify GM regions specifically atrophied in PD-FOG patients compared with those in both control subjects and PD-noFOG patients.18 In PD-FOG patients, the correlation between GM atrophy and total FGQ score was assessed using a multiple regression model, adjusted for age, total intracranial volume, and UPDRS III and FAB scores. The level of significance was set at p < 0.05, family-wise error (FWE)–corrected, and at a more liberal threshold of p < 0.001, uncorrected for multiple comparisons within 10 contiguous voxels.

RESULTS

Demographic, clinical, and cognitive findings.

Subject groups were similar in terms of age, gender, and years of education (table 1). One or more WMHs were found in 30 control subjects, 13 PD-FOG patients, and 15 PD-noFOG patients. The characteristics of WMHs were always nonspecific, and the mean WMH lesion load was similarly low in all groups. PD-FOG patients had higher UPDRS III and FGQ scores than PD-noFOG patients.

View this table:
Table 1

Sociodemographic, clinical, cognitive features, and conventional MRI of the study groupsa

PD-FOG patients had a lower MMSE score (p = 0.004 vs control subjects; p = 0.04 vs PD-noFOG patients) and higher HDRS (p = 0.01 vs control subjects; p = 0.04 vs PD-noFOG patients), and HARS (p = 0.002 vs control subjects; p = 0.02 vs PD-noFOG patients) scores compared with control subjects and PD-noFOG patients. PD-FOG patients showed lower ACE-R (p = 0.004) and FAB (p < 0.001) total scores than control subjects and a higher EXIT-25 score than control subjects (p < 0.001) and PD-noFOG patients (p = 0.04). A trend toward lower ACE-R (p = 0.07) and FAB (p = 0.06) total scores was found in PD-FOG vs PD-noFOG patients. In patients with PD, the FGQ total score correlated with 2 ACE-R subtest scores, i.e., verbal fluency (r = −0.33; p = 0.05) and visuospatial skills (r = −0.39; p = 0.02) and with the FAB total (r = −0.37; p = 0.03) and EXIT-25 (r = 0.44; p = 0.01) scores.

GM atrophy in patients with PD.

In all patients with PD vs control subjects, atrophied GM regions included the right caudate nucleus, left inferior frontal gyrus, and right hippocampus/amygdala (p < 0.05, FWE) (figure 1A, table e-1 on the Neurology® Web site at www.neurology.org). Additional regions of atrophy (p < 0.001, uncorrected) were found in the left caudate nucleus, bilateral middle and right superior frontal gyri, left midcingulate cortex, bilateral inferior and middle temporal gyri, right superior temporal gyrus, bilateral inferior and superior parietal gyri, right precuneus, right postcentral gyrus, left middle and right superior occipital gyri, and left cuneus.

Figure 1
Figure 1 Gray matter (GM) atrophy: Patients with Parkinson disease (PD) vs healthy control subjects

Areas of GM tissue loss in all patients with PD (A), patients with PD with freezing of gait (B), and patients with PD with no freezing of gait (C) compared with healthy control subjects are shown. Results are superimposed on representative axial slices of the Montreal Neurological Institute template, at a threshold of p < 0.001, uncorrected.

Contrasting either PD-FOG or PD-noFOG patients with control subjects yielded the following results (table e-1). PD-FOG patients showed a pattern of GM atrophy relative to control subjects resembling that obtained in the whole patient sample (figure 1B). Namely, PD-FOG patients had GM atrophy in the left inferior and right middle frontal cortices (p < 0.05, FWE). With use of a more liberal statistical threshold (p < 0.001, uncorrected), regions of GM atrophy in PD-FOG patients included the bilateral dorsal frontal cortex, caudate nuclei, left midcingulate cortex, right hippocampus/amygdala, bilateral middle temporal gyrus, left inferior and right superior temporal gyri, bilateral inferior and superior parietal cortex, right precuneus, bilateral postcentral gyrus, left middle occipital cortex and cuneus, and right superior occipital gyrus. Compared with control subjects, the PD-noFOG patients showed a less severe pattern of GM atrophy (figure 1C), including the caudate nuclei, left inferior frontal gyrus, bilateral middle and superior frontal gyri, right hippocampus/amygdala, left middle and right superior temporal gyri, bilateral inferior temporal gyrus, left superior parietal gyrus, and right postcentral gyrus (p < 0.001, uncorrected).

When GM atrophy was assessed in PD-FOG patients vs both control subjects and PD-noFOG patients using a conjunction analysis (p < 0.001, uncorrected) (figure 2), atrophy of the left inferior frontal gyrus ([−50, 27, 30], z = 3.78), left precentral gyrus ([−42, 9, 34], z = 3.34), and left inferior parietal gyrus ([−50, −37, 39], z = 3.35) was detected. No areas of GM atrophy were found in PD-noFOG patients relative to both healthy control subjects and PD-FOG patients.

Figure 2
Figure 2 Gray matter (GM) atrophy: Patients with Parkinson disease with freezing of gait (PD-FOG) vs patients with Parkinson disease with no freezing of gait (PD-noFOG)

Regions of GM atrophy in PD-FOG patients relative to both healthy control subjects and PD-noFOG patients, as assessed using the conjunction analysis, are shown. Results are superimposed on representative axial slices of the Montreal Neurological Institute template, at a threshold of p < 0.001, uncorrected.

Correlation analysis.

In PD-FOG patients, the FGQ total score was associated with GM volumes of the left superior, middle, and inferior frontal gyri and right superior frontal, middle cingulate, and posterior cingulate gyri (p < 0.001, uncorrected) (table 2, figure 3). Such relationships were independent of UPDRS III and FAB scores. No GM volumes were associated with ACE-R, FAB, and EXIT-25 scores.

View this table:
Table 2

Regions of gray matter atrophy associated with total score on the Freezing of Gait Questionnaire in patients with Parkinson disease with freezing of gaita

Figure 3
Figure 3 Correlation analysis

(A) Regions of gray matter (GM) atrophy associated with the total score on the Freezing of Gait Questionnaire (FGQ) in patients with Parkinson disease with freezing of gait (PD-FOG) (results are superimposed on representative axial slices of the Montreal Neurological Institute template, at a threshold of p < 0.001, uncorrected). (B) Scatterplots of the correlation between the FGQ total score and the left middle (r = −0.56, z = 4.14), and inferior frontal (r = −0.47, z = 3.87) gyri. (C) SPM8 design matrix of the multiple regression model used to test the correlations, showing the metric of interest (freezing; blue square) and the covariates (total intracranial volume, age, Frontal Assessment Battery [FAB] total score, and Unified Parkinson's Disease Rating Scale III [UPDRS III] score). TIV = total intracranial volume.

DISCUSSION

The findings of this study agree with the hypothesis that a specific pattern of brain network damage, in particular that involving frontal and parietal cortices, contributes to the presence of FOG in PD. Our results will be discussed in the context of 2 possible scenarios, which suggest the role of frontal executive dysfunctions and an altered perceptual judgment in determining FOG in patients with PD.

In keeping with previous studies,19,20 PD-FOG patients demonstrated a global cognitive dysfunction and frontal executive deficits compared with PD-noFOG patients. We also found correlations between the FOG severity in patients with PD and frontal executive dysfunction. Although the relationship between cognitive function and FOG is complex, a decreased ability to focus attention to a motor program and to continue such a program when other stimuli need to be integrated can be associated with an increased incidence of FOG in PD. Even in young healthy subjects, gait is not completely automatic, but requires a certain amount of attention.21 In PD, gait becomes increasingly attention-demanding and worsens when patients perform additional tasks (i.e., dual or multiple).22 In general, dual-tasking relies on executive functions and the ability to divide attention. When multiple functional domains (i.e., motor, cognitive, and limbic) are activated in patients with PD, paroxysmal episodes of executive activation of the output nuclei of the BG and inhibition of thalamus and brainstem nuclei (i.e., pedunculopontine nucleus [PPN]) may occur, which in turn may trigger FOG.23

Compared with PD-noFOG patients, PD-FOG patients demonstrated a more severe frontal and parietal GM atrophy. To date, only one previous study used VBM to investigate anatomic differences between PD-FOG and PD-noFOG patients.3 Although the whole brain analysis did not show GM differences between patients, the ROI analysis demonstrated that PD-FOG patients experienced atrophy of the MLR compared with PD-noFOG patients.3 These authors also investigated motor imagery of walking using fMRI and found a reduced recruitment of the mesial frontal and posterior parietal regions and an overrecruitment of the MLR in PD-FOG.3 They suggest that FOG emerged when an altered cortical gait control was combined with limited ability of the MLR to react to it, particularly during challenging events. Deep brain stimulation of the PPN, a major component of the MLR, was shown to improve gait in PD-FOG patients, albeit with variable benefits.24 The contribution of PPN alterations to the development of FOG in PD has also been suggested by a recent diffusion tensor MRI study showing an abnormal PPN structural connectivity in 2 PD-FOG patients.25 The discrepancy between our and previous VBM findings3 is likely to be a reflection of the different statistical approaches used, because we tested whole brain results using a different (more liberal) statistical threshold and did not perform an ROI analysis. As a consequence, we cannot exclude involvement of the MLR in our PD-FOG patients.

The frontal-parietal network has a role in executive functions. The prefrontal cortex, which was atrophied in PD-FOG patients, is central in performance monitoring and is involved in the allocation and coordination of attentional resources.26 fMRI studies of PD suggested that increased activation of the ventrolateral prefrontal cortices is the neural correlate of attentional control.27 In particular, the left inferior frontal gyrus may be responsible for the interference resolution during dual tasking28 and the successful implementation of response inhibition.29 The possible significance of frontal regions in determining FOG in PD is supported further by our finding that the FGQ score is associated with frontal GM volumes. The performance of various executive tasks in healthy humans is also associated with the functional recruitment of parietal areas. The left inferior parietal gyrus is involved in the attentional shifting necessary to maintain simultaneously activated auditory and visual information.30 Lesions or virtual lesions, induced by transcranial magnetic stimulation of the left inferior parietal cortex, induce deficits in motor attention tasks.31 In keeping with the hypothesis that a frontoparietal network sustains executive functioning, a PET study showed that left-sided foci of activity in the middle frontal gyrus, inferior parietal gyrus, and cerebellum are involved in dual-task performance.30 Taken together, these findings suggest that executive dysfunctions, dual-task interference, and FOG may share underlying structural damage to the frontal and parietal cortices in patients with PD. Clearly, the results reported do not exclude the possibility that these changes are coincidental to other unobserved pathologies that are more directly causal to FOG.

Perceptual judgment deficits have been described in PD32 and were found to be more severe in PD-FOG patients.33 Some of the indicators of FOG (such as a shortened step length, increased gait variability, and increased base of support) develop well before the arrival to a narrow passage, thus suggesting that online perceptual processes interrupt the initial motor plan to pass through a doorway.33 All these disturbances become more pronounced as the passage is narrowed, indicating that PD is associated with exaggerated responses to action-relevant visual information.34 PD can also be associated with “compression” of perceptual space, i.e., doorways may be perceived to be narrower than they actually are, thus inducing walking problems.35 The most likely candidates for involvement in such a visuomotor control system is a nondopaminergic network, which mediates visual inputs to gait, involving the prefrontal and parietal cortices. The left posterior dorsolateral prefrontal cortex, with a possible contribution from the left inferior parietal lobule, probably performs a comparison of signals from sensory processing areas during perceptual decision making. The lateral premotor cortex is highly recruited when patients with PD control their actions using external rather than internal cues and during locomotor affordance processing.36 The inferior parietal lobule is activated during vestibular stimulation and also responds to several other stimuli (somatosensory, visual, and optokinetic) and reacts to both visuomotor and visuo-proprioceptive incongruence during action execution.37 In addition, regions of the inferior parietal cortex are involved in the integration of perceptual spatiotemporal information.38 Our data suggest that frontal and parietal atrophy may predispose patients with PD to an altered visuomotor control of gait and contribute to the development of FOG.

Some limitations of our study should be mentioned. First, this is a cross-sectional study; thus, it remains unresolved whether the changes we found represent the state or trait characteristics of our patient cohort. Second, FOG is very difficult to draw out in laboratory settings, and, therefore, we cannot exclude the possibility that those patients categorized as PD-noFOG may experience FOG in their home settings. However, they were categorized as PD-noFOG based on the FGQ, clinical examination including the TUG test, self-report, and denial of recognition in their experience of the typical FOG phenotype when this was demonstrated to them, making it unlikely that they would be experiencing any sort of FOG at the time of the present study. Third, the significance threshold for group comparisons and conjunction analysis was set at p < 0.001, uncorrected, and it might have led to false-positive results. However, in previous VBM studies of patients with PD, the results rarely survived correction for multiple comparisons. In addition, the conjunction analysis is the most statistically robust procedure to look for commonalities and differences between groups, and it is also very conservative.18 Finally, results were not adjusted for the UPDRS III scores, which are not applicable to control subjects, and, therefore, we cannot exclude the possibility that GM atrophy in PD-FOG patients is, at least partially, related to a greater disease severity. However, when the correlation between GM atrophy and FOG severity was tested in PD-FOG patients and the UPDRS III was entered in the analysis as a covariate, we found that FOG was associated with frontal and parietal atrophy, suggesting a contribution of such a network to the development of FOG.

In line with the hypothesis that patients with PD who develop FOG may have a “distinct neuropathological profile that enhances freezing outbursts,”39 our results suggest that a greater involvement of the frontal and parietal networks associated with abnormalities of cognitive and attentional activities as well as the sensorimotor control of gait may be a contributing factor to the development of FOG in patients with PD.

AUTHOR CONTRIBUTIONS

Dr. Kostić: study concept or design, drafting/revising the manuscript for content, analysis or interpretation of data, study supervision or coordination, obtaining funding. Dr. Agosta: study concept or design, acquisition of data, statistical analysis, drafting/revising the manuscript for content, analysis or interpretation of data. Dr. Pievani: acquisition of data, statistical analysis. Dr. Stefanova: acquisition of data, statistical analysis. Dr. Ječmenica-Lukić: acquisition of data. Dr. Scarale: acquisition of data. Dr. Špica: acquisition of data. Dr. Filippi: study concept or design, drafting/revising the manuscript for content, analysis or interpretation of data, study supervision or coordination.

DISCLOSURE

Dr. Kostić has served on a scientific advisory board for Boehringer Ingelheim; has received speaker honoraria from Novartis, Boehringer Ingelheim, Libra (Merck Serono), Lundbeck, Inc., and GlaxoSmithKline; and receives research support from the Ministry of Science and Technology of the Republic of Serbia. Dr. Agosta has received funding for travel from Teva Pharmaceutical Industries Ltd. and has received speaker honoraria from Bayer Schering Pharma, sanofi-aventis, and Serono Symposia International Foundation. Dr. Pievani reports no disclosures. Dr. Stefanova has received funding for travel and speaker honoraria from Lundbeck, Inc., Novartis, GlaxoSmithKline, Pfizer Inc, and Boehringer Ingelheim. Dr. Ječmenica-Lukić has received funding for travel from Boehringer Ingelheim. Dr. Scarale reports no disclosures. Dr. Špica has received funding for travel from Boehringer Ingelheim and GlaxoSmithKline. Dr. Filippi serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd. and Genmab A/S; has received funding for travel from Bayer Schering Pharma, Biogen-Dompè, Genmab A/S, Merck Serono, and Teva Pharmaceutical Industries Ltd.; serves as a consultant to Bayer Schering Pharma, Biogen-Dompè, Genmab A/S, Merck Serono, Pepgen Corporation, and Teva Pharmaceutical Industries Ltd.; serves on speakers' bureaus for Bayer Schering Pharma, Biogen-Dompè, Genmab A/S, Merck Serono, and Teva Pharmaceutical Industries Ltd.; receives research support from Bayer Schering Pharma, Biogen-Dompè, Genmab A/S, Merck Serono, Teva Pharmaceutical Industries Ltd., Fondazione Italiana Sclerosi Multipla, and Fondazione Mariani; and serves on editorial boards of the American Journal of Neuroradiology, BMC Musculoskeletal Disorders, Clinical Neurology and Neurosurgery, Erciyes Medical Journal, Journal of Neuroimaging, Journal of Neurovirology, Magnetic Resonance Imaging, Multiple Sclerosis, Neurological Sciences, and Lancet Neurology.

Footnotes

  • Study funding: Supported in part by a grant from the Ministry of Science and Technology of the Republic of Serbia (grant 175090).

  • Supplemental data at www.neurology.org

  • Received April 13, 2011.
  • Accepted August 3, 2011.

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