Normative Data and Conversion Equation for Spectral-Domain Optical Coherence Tomography in an International Healthy Control Cohort.

BACKGROUND: Spectral-domain (SD-) optical coherence tomography (OCT) can reliably measure axonal (peripapillary retinal nerve fiber layer [pRNFL]) and neuronal (macular ganglion cell + inner plexiform layer [GCIPL]) thinning in the retina. Measurements from 2 commonly used SD-OCT devices are often pooled together in multiple sclerosis (MS) studies and clinical trials despite software and segmentation algorithm differences; however, individual pRNFL and GCIPL thickness measurements are not interchangeable between devices. In some circumstances, such as in the absence of a consistent OCT segmentation algorithm across platforms, a conversion equation to transform measurements between devices may be useful to facilitate pooling of data. The availability of normative data for SD-OCT measurements is limited by the lack of a large representative world-wide sample across various ages and ethnicities. Larger international studies that evaluate the effects of age, sex, and race/ethnicity on SD-OCT measurements in healthy control participants are needed to provide normative values that reflect these demographic subgroups to provide comparisons to MS retinal degeneration. METHODS: Participants were part of an 11-site collaboration within the International Multiple Sclerosis Visual System (IMSVISUAL) consortium. SD-OCT was performed by a trained technician for healthy control subjects using Spectralis or Cirrus SD-OCT devices. Peripapillary pRNFL and GCIPL thicknesses were measured on one or both devices. Automated segmentation protocols, in conjunction with manual inspection and correction of lines delineating retinal layers, were used. A conversion equation was developed using structural equation modeling, accounting for clustering, with healthy control data from one site where participants were scanned on both devices on the same day. Normative values were evaluated, with the entire cohort, for pRNFL and GCIPL thicknesses for each decade of age, by sex, and across racial groups using generalized estimating equation (GEE) models, accounting for clustering and adjusting for within-patient, intereye correlations. Change-point analyses were performed to determine at what age pRNFL and GCIPL thicknesses exhibit accelerated rates of decline. RESULTS: The healthy control cohort (n = 546) was 54% male and had a wide distribution of ages, ranging from 18 to 87 years, with a mean (SD) age of 39.3 (14.6) years. Based on 346 control participants at a single site, the conversion equation for pRNFL was Cirrus = -5.0 + (1.0 × Spectralis global value). Based on 228 controls, the equation for GCIPL was Cirrus = -4.5 + (0.9 × Spectralis global value). Standard error was 0.02 for both equations. After the age of 40 years, there was a decline of -2.4 µm per decade in pRNFL thickness ( P < 0.001, GEE models adjusting for sex, race, and country) and -1.4 µm per decade in GCIPL thickness ( P < 0.001). There was a small difference in pRNFL thickness based on sex, with female participants having slightly higher thickness (2.6 µm, P = 0.003). There was no association between GCIPL thickness and sex. Likewise, there was no association between race/ethnicity and pRNFL or GCIPL thicknesses. CONCLUSIONS: A conversion factor may be required when using data that are derived between different SD-OCT platforms in clinical trials and observational studies; this is particularly true for smaller cross-sectional studies or when a consistent segmentation algorithm is not available. The above conversion equations can be used when pooling data from Spectralis and Cirrus SD-OCT devices for pRNFL and GCIPL thicknesses. A faster decline in retinal thickness may occur after the age of 40 years, even in the absence of significant differences across racial groups.

Longitudinal Development of Peripapillary Hyper-Reflective Ovoid Masslike Structures Suggests a Novel Pathological Pathway in Multiple Sclerosis.

OBJECTIVE: Peripapillary hyper-reflective ovoid masslike structures (PHOMS) are a new spectral domain optical coherence tomography (OCT) finding. METHODS: This prospective, longitudinal study included patients (n = 212) with multiple sclerosis (MS; n = 418 eyes), 59 healthy controls (HCs; n = 117 eyes), and 267 non-MS disease controls (534 eyes). OCT and diffusion tensor imaging were used. RESULTS: There were no PHOMS in HC eyes (0/117, 0%). The prevalence of PHOMS was significantly higher in patients with MS (34/212, p = 0.001) and MS eyes (45/418, p = 0.0002) when compared to HCs (0/59, 0/117). The inter-rater agreement for PHOMS was 97.9% (kappa = 0.951). PHOMS were present in 16% of patients with relapsing-remitting, 16% of patients with progressive, and 12% of patients with secondary progressive disease course (2% of eyes). There was no relationship of PHOMS with age, disease duration, disease course, disability, or disease-modifying treatments. The fractional anisotropy of the optic radiations was lower in patients without PHOMS (0.814) when compared to patients with PHOMS (0.845, p = 0.03). The majority of PHOMS remained stable, but increase in size and de novo development of PHOMS were also observed. In non-MS disease controls, PHOMS were observed in intracranial hypertension (62%), optic disc drusen (47%), anomalous optic discs (44%), isolated optic neuritis (19%), and optic atrophy (12%). INTERPRETATION: These data suggest that PHOMS are a novel finding in MS pathology. Future research is needed to determine whether development of PHOMS in MS is due to intermittently raised intracranial pressure or an otherwise impaired "glymphatic" outflow from eye to brain. ANN NEUROL 2020;88:309-319.

A model for interrogating the clinico-radiological paradox in multiple sclerosis: Internuclear ophthalmoplegia.

BACKGROUND AND PURPOSE: The clinico-radiological paradox in multiple sclerosis (MS) is well recognized, relevant and yet poorly understood. The suitability of an in vivo model for the clinico-radiological paradox was tested, using internuclear ophthalmoplegia (INO) and the medial longitudinal fasciculus (MLF). METHODS: In this cross-sectional study lesions of the MLF were rated by an experienced MS neuroradiologist blinded to all other information. The presence of an INO was objectively determined by a validated infrared oculography protocol (DEMoNS). Clinical information, including the National Eye Institute Visual Function Questionnaire, was obtained. RESULTS: This study included 202 patients with MS. The clinico-radiological paradox occurred in 50 patients (25%). This consisted of 45 patients having an INO without an MLF lesion and five patients with an MLF lesion but without an INO. The visual function overall score was related to the presence of an INO (p = 0.016), but not to MLF lesions seen on magnetic resonance imaging (MRI) (p = 0.207). A consensus list of potential causes for the clinico-radiological paradox was compiled and the MRI images were deposited in a repository. CONCLUSION: This study provides an objective and quantitative model to investigate the clinico-radiological paradox. Our data suggest that pathology of the MLF is more frequently detected and more clinically relevant by infrared oculography than by MLF lesion rating on MRI.

Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters.

Optimal intereye difference thresholds by optical coherence tomography in multiple sclerosis: An international study.

OBJECTIVE: To determine the optimal thresholds for intereye differences in retinal nerve fiber and ganglion cell + inner plexiform layer thicknesses for identifying unilateral optic nerve lesions in multiple sclerosis. Current international diagnostic criteria for multiple sclerosis do not include the optic nerve as a lesion site despite frequent involvement. Optical coherence tomography detects retinal thinning associated with optic nerve lesions. METHODS: In this multicenter international study at 11 sites, optical coherence tomography was measured for patients and healthy controls as part of the International Multiple Sclerosis Visual System Consortium. High- and low-contrast acuity were also collected in a subset of participants. Presence of an optic nerve lesion for this study was defined as history of acute unilateral optic neuritis. RESULTS: Among patients (n = 1,530), receiver operating characteristic curve analysis demonstrated an optimal peripapillary retinal nerve fiber layer intereye difference threshold of 5µm and ganglion cell + inner plexiform layer threshold of 4µm for identifying unilateral optic neuritis (n = 477). Greater intereye differences in acuities were associated with greater intereye retinal layer thickness differences (p ≤ 0.001). INTERPRETATION: Intereye differences of 5µm for retinal nerve fiber layer and 4µm for macular ganglion cell + inner plexiform layer are robust thresholds for identifying unilateral optic nerve lesions. These thresholds may be useful in establishing the presence of asymptomatic and symptomatic optic nerve lesions in multiple sclerosis and could be useful in a new version of the diagnostic criteria. Our findings lend further validation for utilizing the visual system in a multiple sclerosis clinical trial setting. Ann Neurol 2019;85:618-629.

Infratentorial and spinal cord lesions: Cumulative predictors of long-term disability?

OBJECTIVE: The objective of the study was to determine whether early infratentorial and/or spinal cord lesions are long-term cumulative predictors of disability progression in multiple sclerosis (MS). METHODS: We selected 153 MS patients from the longitudinal Amsterdam MS cohort. Lesion analysis was performed at baseline and year 2. Disability progression after 6 and 11 years was measured using the Expanded Disability Status Scale (EDSS) and EDSS-plus (including 25-foot walk and 9-hole peg test). Patients with spinal cord or infratentorial lesions were compared for the risk of 6- and 11-year disability progression to patients without spinal cord or infratentorial lesions, respectively. Subsequently, patients with lesions on both locations were compared to patients with only spinal cord or only infratentorial lesions. RESULTS: Baseline spinal cord lesions show a higher risk of 6-year EDSS progression (odds ratio (OR): 3.6, p = 0.007) and EDSS-plus progression (OR: 2.5, p = 0.028) and 11-year EDSS progression (OR: 2.8, p = 0.047). Patients with both infratentorial and spinal cord lesions did not have a higher risk of 6-year disability progression than patients with only infratentorial or only spinal cord lesions. CONCLUSION: The presence of early spinal cord lesions seems to be a dominant risk factor of disability progression. Simultaneous presence of early infratentorial and spinal cord lesions did not undisputedly predict disability progression.

Monitoring retinal changes with optical coherence tomography predicts neuronal loss in experimental autoimmune encephalomyelitis.

BACKGROUND: Retinal optical coherence tomography (OCT) is a clinical and research tool in multiple sclerosis, where it has shown significant retinal nerve fiber (RNFL) and ganglion cell (RGC) layer thinning, while postmortem studies have reported RGC loss. Although retinal pathology in experimental autoimmune encephalomyelitis (EAE) has been described, comparative OCT studies among EAE models are scarce. Furthermore, the best practices for the implementation of OCT in the EAE lab, especially with afoveate animals like rodents, remain undefined. We aimed to describe the dynamics of retinal injury in different mouse EAE models and outline the optimal experimental conditions, scan protocols, and analysis methods, comparing these to histology to confirm the pathological underpinnings. METHODS: Using spectral-domain OCT, we analyzed the test-retest and the inter-rater reliability of volume, peripapillary, and combined horizontal and vertical line scans. We then monitored the thickness of the retinal layers in different EAE models: in wild-type (WT) C57Bl/6J mice immunized with myelin oligodendrocyte glycoprotein peptide (MOG35-55) or with bovine myelin basic protein (MBP), in TCR2D2 mice immunized with MOG35-55, and in SJL/J mice immunized with myelin proteolipid lipoprotein (PLP139-151). Strain-matched control mice were sham-immunized. RGC density was counted on retinal flatmounts at the end of each experiment. RESULTS: Volume scans centered on the optic disc showed the best reliability. Retinal changes during EAE were localized in the inner retinal layers (IRLs, the combination of the RNFL and the ganglion cell plus the inner plexiform layers). In WT, MOG35-55 EAE, progressive thinning of IRL started rapidly after EAE onset, with 1/3 of total loss occurring during the initial 2 months. IRL thinning was associated with the degree of RGC loss and the severity of EAE. Sham-immunized SJL/J mice showed progressive IRL atrophy, which was accentuated in PLP-immunized mice. MOG35-55-immunized TCR2D2 mice showed severe EAE and retinal thinning. MBP immunization led to very mild disease without significant retinopathy. CONCLUSIONS: Retinal neuroaxonal damage develops quickly during EAE. Changes in retinal thickness mirror neuronal loss and clinical severity. Monitoring of the IRL thickness after immunization against MOG35-55 in C57Bl/6J mice seems the most convenient model to study retinal neurodegeneration in EAE.

The clinical value of the patient-reported multiple sclerosis neuropsychological screening questionnaire.

BACKGROUND: Cognitive problems are difficult to identify in patients with multiple sclerosis (MS). OBJECTIVE: To investigate the clinical applicability of the patient-reported MS Neuropsychological Screening Questionnaire (MSNQ-P). METHODS: Cut-off scores were determined to differentiate between cognitively impaired (n = 90), mildly cognitively impaired (n = 115), and cognitively preserved (n = 147) MS patients using receiver operating characteristic analyses. RESULTS: We could not define specific and sensitive cut-off scores. Higher scores (≥27) did indicate cognitive impairment. Among patients with a higher education, lower scores (<12) indicated intact cognition. CONCLUSION: Certain scores can indicate intact or impaired cognitive function. Still, MSNQ-P scores should be interpreted with caution.

Cognitive impairment in patients with multiple sclerosis is associated with atrophy of the inner retinal layers.

BACKGROUND: Inner retinal layer (IRL) atrophy is a potential biomarker for neurodegeneration in multiple sclerosis (MS). OBJECTIVE: To investigate the relationship between cognitive impairment and IRL atrophy in MS. METHODS: Cross-sectional study design, including 217 patients and 59 healthy controls. Subjects were investigated clinically, underwent retinal optical coherence tomography (OCT) and comprehensive cognitive assessments. The association between these modalities was evaluated by regression analyses. RESULTS: Of the patients, 44.2% were cognitively impaired. In the absence of multiple sclerosis-associated optic neuritis (MSON), cognitively impaired patients had a significantly lower mean peripapillary retinal nerve fiber layer (pRNFL, Δ: 8.13 µm, p < 0.001) and mean macular ganglion cell-inner plexiform layer (mGCIPL, Δ: 11.50 µm, p < 0.001) thickness compared to cognitively preserved patients. There was a significant association between the presence of cognitive impairment and pRNFL (odds ratio (OR): 1.11, 95% confidence interval (CI): 1.04-1.18, p = 0.001) and mGCIPL (OR = 1.11, 95% CI = 1.05-1.18, p < 0.001) atrophy. This association was masked by the severe IRL atrophy seen following MSON. CONCLUSION: The strong relationship between cognitive impairment across multiple cognitive domains and atrophy of the pRNFL and mGCIPL in patients who never suffered from MSON suggests that OCT is useful in assessing central nervous system neurodegeneration in MS.

Retinal atrophy in relation to visual functioning and vision-related quality of life in patients with multiple sclerosis.

BACKGROUND: Inner retinal layer atrophy in patients with multiple sclerosis (MS) has been validated as a structural imaging biomarker for neurodegeneration. OBJECTIVE: To determine how retinal layer thickness relates to high-contrast visual acuity (HCVA), low-contrast visual acuity (LCVA) and vision-related quality of life (QoL) and to investigate the effect of previous episodes on MS-associated optic neuritis (MSON). METHODS: Spectral-domain optical coherence tomography (SD-OCT) was performed in 267 patients with MS. Images were segmented for the peripapillary retinal nerve fiber layer (pRNFL) and the macular ganglion cell inner plexiform layer (GCIPL). Ophthalmological evaluations included history of MSON, HCVA, LCVA, and vision-related QoL. RESULTS: Independent of MSON, HCVA and LCVA were significantly associated with pRNFL and GCIPL thicknesses. Vision-related QoL was positively associated with pRNFL (ß = 0.92, p = 0.06) and GCIPL (ß = 0.93, p = 0.02) thicknesses. These associations were independent of MSON. Not only binocular but also monocular atrophy of the inner retinal layers was associated with lower vision-related QoL. CONCLUSION: This study showed that retinal atrophy has a significant impact on visual functioning in patients with MS. OCT may therefore provide useful insight to patients with visual dysfunction, and our findings support including OCT and vision-related QoL measures into optic neuritis treatment trials.

Cerebrospinal fluid mtDNA concentration is elevated in multiple sclerosis disease and responds to treatment.

BACKGROUND: Mitochondrial dysfunction is increasingly recognized as an important feature of multiple sclerosis (MS) pathology and may be relevant for clinical disease progression. However, it is unknown whether mitochondrial DNA (mtDNA) levels in the cerebrospinal fluid (CSF) associate with disease progression and therapeutic response. OBJECTIVES: To evaluate whether CSF concentrations of mtDNA in MS patients can serve as a marker of ongoing neuropathology and may be helpful to differentiate between MS disease subtypes. To explore the effect of disease-modifying therapies on mtDNA levels in the CSF. METHODS: CSF mtDNA was measured using a digital polymerase chain reaction (PCR) CSF mtDNA in two independent MS cohorts. The cohorts included 92 relapsing-remitting multiple sclerosis (RRMS) patients, 40 progressive multiple sclerosis (PMS) patients (27 secondary progressive and 13 primary progressive), 50 various neurologic disease controls, and 5 healthy controls. RESULTS: Patients with PMS showed a significant increase in CSF mtDNA compared to non-inflammatory neurologic disease controls. Patients with higher T2 lesion volumes and lower normalized brain volumes showed increased concentration of mtDNA. Patients treated with fingolimod had significantly lower mtDNA copy levels at follow-up compared to baseline. CONCLUSION: Our results showed a non-specific elevation of concentration of mtDNA in PMS patients. mtDNA concentrations respond to fingolimod and may be used to monitor biological effect of this treatment.

Switching natalizumab to fingolimod within 6 weeks reduces recurrence of disease activity in MS patients.

BACKGROUND: Natalizumab is an effective treatment in relapsing-remitting multiple sclerosis (MS). Mainly because of the risk of progressive multifocal leukoencephalopathy (PML), a substantial proportion of John Cunningham (JC) virus-positive patients switch to fingolimod. Previous reports show a clear benefit when the duration of a washout (WO) period of natalizumab is 0-3 months in comparison to longer WO periods. However, there is no consensus regarding the optimal duration of a WO period under 3 months. OBJECTIVE: We compared MS disease activity after different WO periods. In addition, we investigated several factors that possibly influence recurrence of disease activity, including serum natalizumab concentration and lymphocyte counts. METHODS: From a prospective observational cohort study of natalizumab-treated patients, we selected 52 patients who switched to fingolimod. We divided the patients in three groups (<6 weeks, 6-8 weeks, >8 weeks WO). Serum natalizumab concentration and lymphocyte count were assessed during and after natalizumab treatment. RESULTS: Patients with a WO period of >8 weeks had a significant higher recurrence of disease activity (odds ratio, 6.8; 95% confidence interval, 1.4-32.8) compared to patients with a WO period of <6 weeks. Serum natalizumab concentration and lymphocyte count did not predict recurrence of disease activity. INTERPRETATION: A short WO period decreases the risk of recurrence of disease activity. The possible impact of a short WO period on the risk of carry-over PML in JC virus-positive patients remains uncertain.

The International Multiple Sclerosis Visual System Consortium: Advancing Visual System Research in Multiple Sclerosis.

BACKGROUND: The International Multiple Sclerosis Visual System Consortium (IMSVISUAL) was formed in November 2014 with the primary goal of improving research, care, and education regarding the role of the visual system in multiple sclerosis (MS) and related disorders. METHODS: In this review, we describe the formation, goals, activities, and structure of IMSVISUAL, as well as the relationship of IMSVISUAL with the Americas Committee for Treatment and Research in MS (ACTRIMS). Finally, we provide an overview of the work IMSVISUAL has completed to date, as well as an outline of research projects ongoing under the auspices of IMSVISUAL. RESULTS: IMSVISUAL has 140 members worldwide and continues to grow. Through IMSVISUAL-related research, optical coherence tomography (OCT)-derived peripapillary retinal nerve fiber layer (pRNFL) thinning has been established as a predictor of future disability in MS. IMSVISUAL has also developed guidelines for reporting OCT studies in MS. Moreover, a systematic review performed by IMSVISUAL found that not only are pRNFL and ganglion cell + inner plexiform layer (GCIPL) thicknesses reduced in patients with MS (particularly in eyes with prior optic neuritis [ON]), but that inner nuclear layer measures may be higher among MS ON eyes, relative to healthy control eyes. Currently, there are several ongoing IMSVISUAL projects that will establish a role for visual outcomes in diagnosing MS and quantifying the effects of emerging therapies in clinical trials. CONCLUSIONS: The development of IMSVISUAL represents a major collaborative commitment to defining the role of visual outcomes in high-quality, large-scale studies that generate definitive and instructive findings in the field of MS. As a consortium, IMSVISUAL has completed several international collaborative projects, is actively engaged in numerous ongoing research studies, and is committed to expanding the role of vision research in MS and related disorders.

Cortical atrophy patterns in multiple sclerosis are non-random and clinically relevant.

Grey matter atrophy is common in multiple sclerosis. However, in contrast with other neurodegenerative diseases, it is unclear whether grey matter atrophy in multiple sclerosis is a diffuse 'global' process or develops, instead, according to distinct anatomical patterns. Using source-based morphometry we searched for anatomical patterns of co-varying cortical thickness and assessed their relationships with white matter pathology, physical disability and cognitive functioning. Magnetic resonance imaging was performed at 3 T in 208 patients with long-standing multiple sclerosis (141 females; age = 53.7 ± 9.6 years; disease duration = 20.2 ± 7.1 years) and 60 age- and sex-matched healthy controls. Spatial independent component analysis was performed on cortical thickness maps derived from 3D T1-weighted images across all subjects to identify co-varying patterns. The loadings, which reflect the presence of each cortical thickness pattern in a subject, were compared between patients with multiple sclerosis and healthy controls with generalized linear models. Stepwise linear regression analyses were used to assess whether white matter pathology was associated with these loadings and to identify the cortical thickness patterns that predict measures of physical and cognitive dysfunction. Ten cortical thickness patterns were identified, of which six had significantly lower loadings in patients with multiple sclerosis than in controls: the largest loading differences corresponded to the pattern predominantly involving the bilateral temporal pole and entorhinal cortex, and the pattern involving the bilateral posterior cingulate cortex. In patients with multiple sclerosis, overall white matter lesion load was negatively associated with the loadings of these two patterns. The final model for physical dysfunction as measured with Expanded Disability Status Scale score (adjusted R(2) = 0.297; P < 0.001) included the predictors age, overall white matter lesion load, the loadings of two cortical thickness patterns (bilateral sensorimotor cortex and bilateral insula), and global cortical thickness. The final model predicting average cognition (adjusted R(2) = 0.469; P < 0.001) consisted of age, the loadings of two cortical thickness patterns (bilateral posterior cingulate cortex and bilateral temporal pole), overall white matter lesion load and normal-appearing white matter integrity. Although white matter pathology measures were part of the final clinical regression models, they explained limited incremental variance (to a maximum of 4%). Several cortical atrophy patterns relevant for multiple sclerosis were found. This suggests that cortical atrophy in multiple sclerosis occurs largely in a non-random manner and develops (at least partly) according to distinct anatomical patterns. In addition, these cortical atrophy patterns showed stronger associations with clinical (especially cognitive) dysfunction than global cortical atrophy.

Multi-parametric structural magnetic resonance imaging in relation to cognitive dysfunction in long-standing multiple sclerosis.

BACKGROUND: Cognitive deficits are common in multiple sclerosis. Most previous studies investigating the imaging substrate of cognitive deficits in multiple sclerosis included patients with relatively short disease durations and were limited to one modality/brain region. OBJECTIVE: To identify the strongest neuroimaging predictors for cognitive dysfunction in a large cohort of patients with long-standing multiple sclerosis. METHODS: Extensive neuropsychological testing and multimodal 3.0T MRI was performed in 202 patients with multiple sclerosis and 52 controls. Cognitive scores were compared between groups using Z-scores. Whole-brain, white matter, grey matter, deep grey matter and lesion volumes; cortical thickness, (juxta)cortical and cerebellar lesions; and extent and severity of diffuse white matter damage were measured. Stepwise linear regression was used to identify the strongest predictors for cognitive dysfunction. RESULTS: All cognitive domains were affected in patients. Patients showed extensive atrophy, focal pathology and damage in up to 75% of the investigated white matter. Associations between imaging markers and average cognition were two times stronger in cognitively impaired patients than in cognitively preserved patients. The final model for average cognition consisted of deep grey matter DGMV volume and fractional anisotropy severity (adjusted R²=0.490; p<0.001). CONCLUSION: From all imaging markers, deep grey matter atrophy and diffuse white matter damage emerged as the strongest predictors for cognitive dysfunction in long-standing multiple sclerosis.

Unraveling the relationship between regional gray matter atrophy and pathology in connected white matter tracts in long-standing multiple sclerosis.

INTRODUCTION: Gray matter (GM) atrophy is common in multiple sclerosis (MS), but the relationship with white matter (WM) pathology is largely unknown. Some studies found a co-occurrence in specific systems, but a regional analysis across the brain in different clinical phenotypes is necessary to further understand the disease mechanism underlying GM atrophy in MS. Therefore, we investigated the association between regional GM atrophy and pathology in anatomically connected WM tracts. METHODS: Conventional and diffusion tensor imaging was performed at 3T in 208 patients with long-standing MS and 60 healthy controls. Deep and cortical GM regions were segmented and quantified, and both lesion volumes and average normal appearing WM fractional anisotropy of their associated tracts were derived using an atlas obtained by probabilistic tractography in the controls. Linear regression was then performed to quantify the amount of regional GM atrophy that can be explained by WM pathology in the connected tract. RESULTS: MS patients showed extensive deep and cortical GM atrophy. Cortical atrophy was particularly present in frontal and temporal regions. Pathology in connected WM tracts statistically explained both regional deep and cortical GM atrophy in relapsing-remitting (RR) patients, but only deep GM atrophy in secondary-progressive (SP) patients. CONCLUSION: In RRMS patients, both deep and cortical GM atrophy were associated with pathology in connected WM tracts. In SPMS patients, only regional deep GM atrophy could be explained by pathology in connected WM tracts. This suggests that in SPMS patients cortical GM atrophy and WM damage are (at least partly) independent disease processes.

Functional brain networks: linking thalamic atrophy to clinical disability in multiple sclerosis, a multimodal fMRI and MEG study.

Thalamic atrophy is known to be one of the most important predictors for clinical dysfunction in multiple sclerosis (MS). As the thalamus is highly connected to many cortical areas, this suggests that thalamic atrophy is associated with disruption of cortical functional networks. We investigated this thalamo-cortical system to explain the presence of physical and cognitive problems in MS. Functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) were performed in 86 MS patients and 21 healthy subjects. We computed cortical functional networks for fMRI and MEG by respectively the Pearson's correlation coefficient and the phase lag index using the same automated anatomical labeling atlas for both modalities. Thalamo-cortical functional connectivity was only estimated using fMRI. We computed conventional network metrics such as clustering coefficient and path length and analyzed the minimum spanning tree (MST), a subnetwork and backbone of the original network. MS patients showed reduced thalamic volumes and increased thalamo-cortical connectivity. MEG cortical functional networks showed a lower level of integration in MS in terms of the MST, whereas fMRI cortical networks did not differ between groups. Lower integration of MEG cortical functional networks was both related to thalamic atrophy as well as to increased thalamo-cortical functional connectivity in fMRI and to worse cognitive and clinical status. This study demonstrated for the first time that thalamic atrophy is associated with global disruption of cortical functional networks in MS and this global disruption of network activity was related to worse cognitive and clinical function in MS. Hum Brain Mapp 36:603-618, 2015. © 2014 Wiley Periodicals, Inc.

Toward the use of proxy reports for estimating long-term patient-reported outcomes in multiple sclerosis.

BACKGROUND: Assessment of disease impact in multiple sclerosis (MS) is usually driven by information obtained directly from patients using patient-reported outcomes. However, when patients' response in longitudinal studies is less reliable or missing, proxy respondents may be used. OBJECTIVE: The objective of this paper is to evaluate whether long-term patient scores can be reliably estimated using scores obtained from proxies. METHODS: Baseline, six-month and two-year data were collected from 155 patients and proxies on the physical scale of the Multiple Sclerosis Impact Scale (MSIS-29). Linear regression analyses were performed with the patient two-year scores as outcome, proxy two-year scores as predictor and other variables that could contribute to a better prediction of the patient follow-up score. RESULTS: The patient follow-up score could be predicted rather accurately (R(2) = 0.74) using the patient baseline score and the proxy follow-up score. The correlation between observed and predicted scores was 0.86. The model performed well in different follow-up durations and even better in an external cohort. CONCLUSION: A simple model of a constant value (intercept), the patient baseline score and the proxy follow-up score can predict patients' follow-up score on the physical impact of MS.

Disruption of structural and functional networks in long-standing multiple sclerosis.

Both gray matter atrophy and disruption of functional networks are important predictors for physical disability and cognitive impairment in multiple sclerosis (MS), yet their relationship is poorly understood. Graph theory provides a modality invariant framework to analyze patterns of gray matter morphology and functional coactivation. We investigated, how gray matter and functional networks were affected within the same MS sample and examined their interrelationship. Magnetic resonance imaging and magnetoencephalography (MEG) were performed in 102 MS patients and 42 healthy controls. Gray matter networks were computed at the group-level based on cortical thickness correlations between 78 regions across subjects. MEG functional networks were computed at the subject level based on the phase-lag index between time-series of regions in source-space. In MS patients, we found a more regular network organization for structural covariance networks and for functional networks in the theta band, whereas we found a more random network organization for functional networks in the alpha2 band. Correlation analysis revealed a positive association between covariation in thickness and functional connectivity in especially the theta band in MS patients, and these results could not be explained by simple regional gray matter thickness measurements. This study is a first multimodal graph analysis in a sample of MS patients, and our results suggest that a disruption of gray matter network topology is important to understand alterations in functional connectivity in MS as regional gray matter fails to take into account the inherent connectivity structure of the brain.