Johns Hopkins University
Neurology and Neuroscience

Author Of 3 Presentations

Neuro-Ophthalmology Oral Presentation

PS15.04 - The presence of epiretinal membranes in multiple sclerosis may be associated with increased disability

Speakers
Presentation Number
PS15.04
Presentation Topic
Neuro-Ophthalmology
Lecture Time
13:27 - 13:39

Abstract

Background

Neuroglial cells are implicated in the pathobiology of Multiple sclerosis (MS). Müller glia, specialized radial glial cells of the retina responsible for helping maintain retinal neuronal integrity, are postulated to be activated in MS. Müller glia activation is also implicated in epiretinal membrane (ERM) formation, an aberrant healing response to retinal damage.

Objectives

To examine ERM prevalence in MS, and differences in expanded disability status scale (EDSS) and optical coherence tomography (OCT) measured retinal layer thicknesses, between MS patients with (ERM-MS) and without ERMs (non-ERM-MS).

Methods

In this cross-sectional study, 1463 MS patients (2926 eyes) underwent Cirrus spectral-domain OCT (with automated macular layer segmentation). All scans underwent qualitative and quantitative quality control (QC), and ERM presence was recorded. Excluding patients with optic neuritis history, ERM-MS (n=48) were matched 1:1 to non-ERM-MS based on age, body mass index (BMI) and sex. Fellow eye layer thicknesses of ERM-MS were compared to the average binocular layer thicknesses of non-ERM-MS patients, to investigate the possibility of a phenotype effect. Mixed effects linear regression models were used in analyses.

Results

ERM prevalence in this MS cohort was 4.9%. Post-matching mean age and BMI were respectively 60.7 years (SD 6.3) and 28.2 kg/m2 (SD 9.6) in ERM-MS, and 60.4 years (SD 5.7) and 27.5 kg/m2 (SD 8.9) in non-ERM-MS (p=0.7 for both). Both groups had 77.1% females. Median EDSS was 4 (IQR 2.5-6.5) in ERM-MS and 3 (IQR 1.5-6) in non-ERM-MS (difference: 1.1, CI: 0.2 – 1.9, p=0.021). Mean ganglion cell-inner plexiform layer (GCIPL) thickness was 67.1 um (SD 6.5) in ERM-MS and 70.2 um (SD 6.2) in non-ERM-MS (difference: -3.1, CI: -6.3 – -0.1, p=0.049). Moreover, mean retinal pigment epithelium (RPE) thickness was 31.6 um (SD 1.3) in ERM-MS and 32.4 um (SD 0.9) in non-ERM-MS (difference: -0.7 um, CI: -1.3 - -0.1, p=0.017).

Conclusions

Our findings suggest ERM-MS patients phenotypically have higher EDSS scores, and lower GCIPL and RPE thicknesses, as compared to non-ERM-MS patients. Blood-retinal barrier disruption due to retinal inflammation, among other reasons, may activate Müller glia in MS. This may help explain our finding that ERM presence in MS may be associated with disability. Moreover, RPE cells may be recruited in the ERM formation process, similarly explaining our finding of reduced RPE thickness among ERM-MS patients.

Collapse
Pathogenesis – Role of Glia Oral Presentation

YI01.04 - Generation of MHC class I and MHC class II reporter mice for investigation of antigen presentation by oligodendroglia

Speakers
Presentation Number
YI01.04
Presentation Topic
Pathogenesis – Role of Glia
Lecture Time
11:36 - 11:48

Abstract

Background

Emerging evidence from both human multiple sclerosis (MS) tissue and rodent experimental autoimmune encephalomyelitis (EAE) models has demonstrated that subsets of oligodendrocyte lineage cells are capable of expressing antigen presenting and processing molecules, including MHC class I and MHC class II molecules, in an inflammatory environment. Antigen presentation by inflammatory oligodendroglia (iOPCs/iOLs) to CD4 and CD8 T cells may result in cytotoxic death of oligodendroglia and perpetuation of the inflammatory response. However, the dynamics of MHC class I and MHC class II expression by oligodendrocyte lineage cells in an inflammatory environment are unknown.

Objectives

To better define these dynamic changes in phenotype, we developed two new mouse reporter lines by targeting Beta-2-microglobulin (B2m) and CD74 invariant chain (Ii) genes, which are upregulated by oligodendroglia in human MS and mouse EAE. Beta-2-microglobulin (B2m) is a component of both classical and non-classical MHC class I molecules and CD74 invariant chain (Ii) is involved in occupancy of the peptide binding groove of MHC class II molecules in the endoplasmic reticulum and formation of stable MHC class II-antigen complexes.

Methods

We generated reporter lines by Crispr/Cas9-mediated insertion of a P2A-TdTomato-WPRE-pA sequence, replacing the stop codon of B2m (for class I reporter) and CD74 (for class II reporter).

Results

Both B2m-TdT and CD74-TdT mice demonstrate robust reporter expression in cultured OPCs upon exposure to interferon gamma. In naïve CD74-TdT reporter mice, TdT reporter expression was not detected in the brain or spinal cord parenchyma, but strong expression was observed in peripheral immune cells in the meninges and choroid plexus. B2m-TdT reporter mice exhibited TdT reporter expression in microglia throughout the brain and spinal cord, and some expression in spinal cord white matter oligodendroglia near the meningeal surface. No TdT reporter expression was detected in brain oligodendroglia at baseline. Cortical stab injury in B2m-TdT reporter mice resulted in TdT reporter co-localization with Iba1+ microglia and Mac2+ macrophages within the lesion core and Olig2+CC1+ oligodendrocytes in the corpus callosum ipsilateral and contralateral to the stab injury.

Conclusions

Further investigation of MHC class I and MHC class II expression in oligodendroglia in the setting of inflammatory demyelinating models will help reveal the spatial and temporal dynamics of this phenotypic change in oligodendroglia.

Collapse
Neuromyelitis Optica and Anti-MOG Disease Oral Presentation

YI02.01 - Optic Neuritis-Independent Retinal Atrophy In Neuromyelitis Optica Spectrum Disorders

Speakers
Presentation Number
YI02.01
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease
Lecture Time
11:15 - 11:27

Abstract

Background

Prior studies have suggested that retinal neuro-axonal loss may occur in aquaporin-4 (AQP4)-IgG seropositive neuromyelitis optica spectrum disorder (NMOSD) in the absence of optic neuritis (ON), but data are conflicting.

Objectives

To examine whether patients with AQP4-IgG seropositive NMOSD exhibit progressive retinal neuro-axonal loss, independently of optic neuritis (ON) attacks.

Methods

In this single-center, longitudinal study, 32 AQP4-IgG+ NMOSD patients and 48 healthy controls (HC) were followed with serial spectral-domain optical coherence tomography (OCT). NMOSD patients with ON less than 6 months prior to baseline were excluded, while data from patients with ON during follow-up were censored at the last visit prior to ON. Rates of peri-papillary retinal nerve fiber layer (pRNFL) and macular ganglion cell+inner plexiform layer (GCIPL) thinning were compared between groups utilizing mixed-effects linear regression models adjusted for age, race and sex.

Results

Median follow-up duration was 4.3 years (IQR: 2.6 -7.5) for the NMOSD cohort and 4.0 years (IQR: 1.8 – 7.5) for the HC. We observed faster pRNFL (β=-0.25µm/year, 95%CI: -0.45 to -0.05, p=0.014) and GCIPL thinning (β=-0.09µm/year, 95%CI: -0.17 to 0, p=0.05) in NMOSD compared to HC eyes. This difference appeared to be driven by faster pRNFL and GCIPL thinning in NMOSD eyes without a history of ON compared to HC (GCIPL: β=-0.15µm/year, 95%CI: -0.25 to -0.05, p=0.005; pRNFL: β=-0.43µm/year, 95%CI: -0.67 to -0.19, p<0.001), while rates of pRNFL (β=-0.07µm/year , 95%CI: -0.31 to 0.16, p=0.53) and GCIPL (β=-0.01µm/year, 95%CI: -0.11 to 0.10, p=0.90) thinning did not differ between NMOSD-ON and HC eyes .

Furthermore, we explored the effects of non-ON relapses during follow-up on rates of pRNFL and GCIPL thinning. Ten patients had relapses during follow-up (9 transverse myelitis, 1 area postrema syndrome). Patients with relapses did not exhibit differences in rates of GCIPL (β=0.05µm/year, 95%CI:-0.10 to 0.20, p=0.51) or pRNFL thinning (pRNFL: β=0.08µm/year, 95%CI: -0.28 to 0.43, p=0.67), compared to those who were clinically stable.

Conclusions

In this longitudinal study, we observed progressive pRNFL and GCIPL atrophy in AQP4-IgG+ NMOSD eyes unaffected by ON. These results support that subclinical involvement of the anterior visual pathway may occur in AQP4-IgG+ NMOSD.

Collapse

Moderator Of 1 Session

Parallel Session Fri, Sep 11, 2020
Session Type
Parallel Session
Date
Fri, Sep 11, 2020
Time (ET)
10:15 - 11:45

Author Of 13 Presentations

Neuro-Ophthalmology Late Breaking Abstracts

LB1217 - Macular pigment concentration and distribution in multiple sclerosis (ID 2084)

Speakers
Presentation Number
LB1217
Presentation Topic
Neuro-Ophthalmology

Abstract

Background

Oxidative stress is implicated in inflammation and neurodegeneration in multiple sclerosis (MS). Similar to the brain, the retina is susceptible to reactive oxygen species (ROS). Macular pigment (MP), consisting primarily of the carotenoids lutein (L) and zeaxanthin (Z) blocks deleterious blue light, and provides anti-oxidant protection. To date, there has been a paucity of study of MP in MS.

Objectives

To examine MP concentration and distribution in MS eyes relative to healthy control (HC) eyes using macular pigment optical density (MPOD) imaging.

Methods

In this cross-sectional study, 27 MS patients (47 eyes) and 19 HCs (37 eyes) underwent MPOD imaging on a Spectralis (Heidelberg) device. MP absorbs blue light, but allows the free passage of green light. MPOD imaging involves the subtraction of blue from green wavelength auto-fluorescence macular scans, providing the optical density (OD) of MP. Radii of interest for MPOD were 0°, 0.23°, 0.51°, 0.98° and 1.99° degrees of eccentricity from the fovea, as well as peak, and half-peak MPOD locations. Study participants completed dietary L & Z screening questionnaires. Mixed effects linear regression models were used in analyses.

Results

Mean MPOD at 0° was 0.52 density units (d.u.) (SD 0.14) in MS and 0.63 d.u. (SD 0.18) in HC eyes (difference: -0.10 d.u., CI: -0.18 - -0.01, p=0.027). The median MPOD peak location eccentricity was 0.08° (IQR: 0 - 0.12) in MS and 0.04° (IQR: 0 - 0.08) in HC eyes (difference: 0.10°, CI: 0.01 - 0.20, p=0.031). Mean MPOD at the peak location was -0.09 d.u. lower in MS eyes relative to HC eyes (CI: -0.18 - -0.01, p=0.04). In addition, the half-peak MPOD location, similar to the MPOD peak location, was situated further from the fovea in MS eyes relative to HC eyes (difference: 0.28°, CI: 0.10 - 0.47, p=0.002). Analyses adjusted for age, body mass index, sex, and L & Z dietary scores, showed similar differences for MPOD at 0° eccentricity, and at the peak MPOD location, between MS and HC eyes.

Conclusions

Our findings suggest MP concentrations are reduced in MS eyes, with peak and half-peak MPOD locations shifted further from the fovea than in HC eyes. Increases in ROS consuming antioxidant MPs, and/or dysfunction in proteins transferring carotenoids to the fovea, among other reasons, may help explain reductions in MPOD in MS eyes. Our preliminary finding warrant further study, in larger, prospective MS cohorts, including determination of their clinical relevance.

Collapse
Biomarkers and Bioinformatics Poster Presentation

P0036 - Cerebral hypometabolism is a marker of disease severity in multiple sclerosis: a non-invasive imaging study using T2-Relaxation-Under-Spin-Tagging MRI (ID 1856)

Speakers
Presentation Number
P0036
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Metabolic dysfunction at a cellular level is a crucial element of progressive neuronal dysfunction, and ultimately neurodegeneration in multiple sclerosis (MS). Changes in retinal superficial vascular plexus (SVP) density, which is known to be reduced in MS, may in part reflect metabolic demand in the neuronal layers of the retina, and could accordingly provide insight regarding concurrent metabolic alterations in the brain.

Objectives

To compare cerebral metabolism in people with MS (PwMS) to healthy controls (HCs) using T2-Relaxation-Under-Spin-Tagging (TRUST) and phase-contrast (PC) MRI, and assess whether cerebral hypometabolism is related to reduced SVP density measured using optical coherence tomography angiography (OCTA).

Methods

In this cross-sectional study, PwMS and HC underwent TRUST and PC MRI to derive the oxygen extraction fraction (OEF; a measure of the efficiency of cerebral tissue in extracting oxygen from circulating blood) and cerebral metabolic rate of oxygen consumption (CMRO2; a volume-adjusted measure of cerebral tissue metabolism). A subset of PwMS underwent OCTA, with quantification of retinal SVP density using a deep neural network based-algorithm. Statistical analyses were adjusted for age and intra-subject inter-eye correlations, where relevant.

Results

We included 49 PwMS and 80 HCs. Overall, OEF was lower, and CMRO2 trended towards being lower, in PwMS as compared to HCs (OEF: 35.9% [SD 5.1] vs. 40.9%, [SD 5.1], p=0.04; CMRO2: 156.3 umol/mL/min [SD 23.9] vs. 158.7 umol/mL/min [SD 19.9], p=0.08). Lower CMRO2 was associated with longer MS disease duration (p=0.02), higher expanded disability status scale score (p=0.01) and lower subcortical gray matter volume fraction (p=0.04). Additionally, lower CMRO2 was associated with higher age in PwMS (p=0.02), but not in HCs (p=0.19), in whom effective neurovascular coupling is expected to maintain a fairly constant rate with aging. Lower OEF correlated with lower retinal SVP density in PwMS (r=0.32, p=0.02).

Conclusions

Cerebral hypometabolism is evident in PwMS compared to HCs, and is associated with longer disease duration and greater disability. Furthermore, alterations in cerebral metabolism are mirrored by alterations in retinal SVP density, supporting the utility of these non-invasive imaging techniques to measure inter-linked pathobiological processes. The ability to detect metabolic dysfunction in-vivo in PwMS may help facilitate the identification of new therapeutic targets and outcome measures for clinical trials.

Collapse
Biomarkers and Bioinformatics Poster Presentation

P0057 - Decline in serum neurofilament is associated with decreased clinical and radiological disease activity over two years of dimethyl fumarate treatment (ID 1294)

Speakers
Presentation Number
P0057
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Dimethyl fumarate (DMF) treatment is associated with a decrease in serum neurofilament light chain (sNfL) in patients with relapsing-remitting multiple sclerosis (RRMS). sNfL is an exploratory biomarker of MS disease activity. Additional data describing the association between sNfL and disease activity are needed to further investigate this biomarker as a potential predictor of treatment response, which could enable a more holistic disease monitoring approach to treatment.

Objectives

To describe variation in sNfL levels with respect to clinical and radiological disease activity in DMF-treated patients.

Methods

DMF-treated patients with RRMS and complete 2Y follow-up data were analyzed. Serum samples were collected, and routine clinical and radiological assessments were conducted at baseline (BL) and at regular intervals. sNfL concentrations were measured by Single Molecule Array (SiMoA). Normative sNfL data from a cohort of 135 healthy adult controls (age range 21-82 years) were used as a comparator. Age-normative sNfL cutoffs were defined based on the 95th percentile of sNfL levels.

Results

Forty-one patients with 2Y follow-up data were included. Mean (SD) age and disease duration were 37.5 (10.1) and 6.0 (6.5) years, respectively, with mean (SD) time on DMF treatment 43.8 (9.15) months. Twenty-nine (70.7%) patients were treated with a previous MS therapy. Nineteen (46.3%) and 22 (53.7%) patients were below and above age-normative sNfL level at BL, respectively. Over 2Y, mean (95% CI) sNfL level decreased from 8.5 (7.1, 10.2) to 3.4 (2.0, 4.0) pg/ml, representing a 36.6% annual decrease, and 60% decrease over 2Y. Patients experienced a 71.1% (95% CI: 38.8%, 86.3%) reduction in ARR from 1Y prior to BL (0.463, 95% CI [0.279, 0.724]) to 2Y (0.134 [0.067, 0.24]), and 75.6% (59.4%, 87.1%) patients were free of new T2 lesions at 2Y. sNfL was below age-normative level in 53.7% (37.6%, 69%) of patients at BL vs 97.6% (85.6%, 99.9%) at 2Y. Patients with sNfL below age-normative level at BL generally remained below this threshold. At 2Y, patients both above and below age-normative sNfL level at BL experienced low cumulative ARR (95% CI) of 0.132 (0.043, 0.307) and 0.136 (0.05, 0.297), respectively, representing reductions of 75% and 66.7%.

Conclusions

DMF-treated patients reached NfL levels approaching that of healthy controls over 2Y with a reduction in disease activity, regardless of sNfL level at BL in this real-world setting. These data support a correlation between reductions in sNfL levels and decreased disease activity over 2Y of treatment, and potential of sNfL as a biomarker of treatment response that could be assessed during treatment in addition to standard of care monitoring.

Supported by: Biogen.

Collapse
Biomarkers and Bioinformatics Poster Presentation

P0083 - Gadolinium improves detection of central vein lesions in MS using 3T FLAIR*. (ID 1404)

Abstract

Background

The central vein sign (CVS) is a proposed MRI diagnostic biomarker for multiple sclerosis (MS). Use of gadolinium (Gd) in the CVS literature has been inconsistent, and it is unknown whether Gd improves detection of CVS when using FLAIR*.

Objectives

To determine if, and to what extent, gadolinium injection improves detection of CVS lesions when using FLAIR* imaging.

Methods

A cross-sectional multicenter study recruited adults clinically and/or radiologically suspected of having MS. High-isotropic-resolution, T2*-weighted segmented echo-planar imaging (T2*-EPI) was acquired pre- and post-injection of Gd-based contrast agent at 3T; pre-Gd 3D FLAIR images were also acquired. T2*-EPI and FLAIR images were processed on the QMENTA platform to generate FLAIR* images. FLAIR* pre-Gd and post-Gd scans from this substudy of 30 patients at 5 sites were analyzed. FLAIR images were used to create T2 lesion masks. Subsequently, FLAIR* images were evaluated in a random order. Lesions were categorized as CVS+, CVS-, or excluded based on the North American Imaging in MS (NAIMS) Criteria by two trained raters blinded to clinical data and Gd use. The proportion of CVS+ lesions was calculated for each scan, and differences in CVS detection based on Gd use were assessed by a Wilcoxon rank-sum test. Diagnostic performance was compared against McDonald 2017 Criteria.

Results

The mean participant age was 45 years (SD: 12); 23 (77%) were women. 14 (47%) met McDonald 2017 Criteria for MS, while 16 (53%) did not (“non-MS”). A total of 487 CVS+ lesions and 976 CVS- lesions were evaluated. The percentage of CVS+ lesions post-Gd in the MS group (median 67% [IQR 30%]) was higher than pre-Gd (41% [47%], p<0.001). There was no apparent difference in percentage of CVS+ lesion in the non-MS group (post-Gd: 10% [23%]; pre-Gd: 5% [29%]; p=0.1). In the MS group, 12/14 (86%) had ≥40% CVS+ lesions on post-Gd imaging, whereas only 8/14 (57%) exceeded that threshold on pre-Gd imaging. When evaluating CVS performance using the 40% CVS+ threshold, the sensitivity and specificity of the CVS post-Gd for MS were 86% and 81%, respectively, compared to 54% and 86% pre-Gd.

Conclusions

The detection of the CVS using FLAIR* at 3T is improved when Gd is used. Based on these results, a multicenter prospective CVS diagnostic study, sponsored by NINDS and NAIMS, will use Gd in the study protocol. Future clinical use of the CVS should balance the increased costs and potential risks of Gd use with the risks of misdiagnosis due to missing CVS on non-contrast imaging.

Collapse
Biomarkers and Bioinformatics Poster Presentation

P0103 - Liothyronine treatment of MS patients alters proteins in CSF related to angiogenesis and immune function (ID 438)

Speakers
Presentation Number
P0103
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Thyroid hormones have effects on a variety of glial and immune cell populations that appear to be involved in the pathogenesis of multiple sclerosis (MS). Since tri-iodothyronine (T3) is believed to mediate the most important thyroid hormone actions, liothyronine (synthetic T3) may have the potential to induce reparative mechanisms and limit neurodegeneration in MS.

Objectives

To utilize proteomics to assess the effect of liothyronine treatment on the cerebrospinal fluid (CSF) proteome in MS.

Methods

We utilized CSF collected from 18 patients with MS enrolled in a single center trial of oral liothyronine for 24 weeks. Participants received liothyronine according to a standardized dose-titration schedule. Participants continued their maintenance MS immune therapies during the study. Eligibility criteria included euthyroid patients, 18-58 years old, 2010 McDonald MS and Expanded Disability Status Scale (EDSS) score 3.0-7.5. Main exclusion was known thyroid dysfunction. The primary outcome was safety and tolerability of liothyronine. CSF was collected at baseline and end of study (24 weeks) as an exploratory outcome for treatment response. SOMAscan platform (DNA aptamer based detection of proteins) was used to detect and quantify a panel of 1314 proteins in the CSF.

Results

Study participants had a mean age of 45.9 ± 8.8 years, F:M ratio of 7:9, relapsing disease (11/16), mean disease duration of 9 years and median EDSS of 3.5. Of the measured proteins, 46 changed (19 increased and 27 decreased) over the course of the study (p<0.05). These included proteins related to immune function such as TACI, NKp46, IgA and IgD and angiogenesis such as Cadherin-5, sTIE-1 and ANGPT2. Enrichment analyses using PANTHER and STRING databases noted that the biological processes that were over-represented included – angiogenesis and innate and adaptive immune function. Angiogenesis related proteins predominantly demonstrated an increase with liothyronine treatment while the majority of immune related proteins decreased with treatment.

Conclusions

Changes in CSF proteins involved in central nervous system immune cell function and promotion of angiogenesis were seen with a short course of liothyronine treatment in people with MS. A larger clinical trial would help determine whether these observed changes have a biological effect that is clinically meaningful.

Collapse
Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0261 - Paramagnetic rim lesions are specific to multiple sclerosis: an international multicenter 3T MRI study (ID 1025)

Abstract

Background

In multiple sclerosis (MS), a subset of chronic active white matter lesions are identifiable on MRI by their paramagnetic rims, and increasing evidence supports their association with clinical disease severity.

Objectives

To assess the prevalence and MS-specificity of paramagnetic rim lesions (PRL) on 3-tesla susceptibility-based MR brain images in MS vs non-MS cases in a multicenter sample drawn from 5 academic research hospitals at sites in Europe (Brussels, Lausanne, Milan) and the United States (NIH and JHU).

Methods

On submillimetric 3D T2*-segmented EPI brain MRI, the presence of PRL and central vein sign (CVS) were evaluated in the supratentorial brain of adults with MS (n=329) and non-MS neurological conditions (n=83). Non-MS cases were grouped as follows: (1) other-inflammatory neurological diseases (n=41); (2) HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP; n=10); (3) HIV-infected (n=10); (4) non-inflammatory neurological diseases (n=22).

ROC curve analysis, with diagnosis as dependent variable (MS vs non-MS), was applied to examine the diagnostic accuracy for each biomarker (PRL and CVS). Youden’s index method was used to obtain the optimal cutoff value for each biomarker.

Results

PRL were detected in 172/329 (52%) of MS cases vs. 6/83 non-MS cases (7%).

In MS, 58% of progressive cases had at least one PRL, compared to 50% of relapsing cases. MS cases with more than 4 PRL were more likely to have higher disability scores (EDSS, MSSS and ARMSS), but not significantly longer disease duration or older age.

In non-MS cases, PRL were seen exclusively in only a few inflammatory/infectious neurological conditions, including Susac syndrome (3 cases), neuromyelitis optica spectrum disorder (1 case), Sjögren disease (1 case) and HAM/TSP (1 case). Unlike in MS, PRL in non-MS cases were not associated with a high frequency of CVS+ lesions.

The identification of at least one PRL (optimal cutoff) was associated with high diagnostic specificity (93%), but relatively low sensitivity (52%) and accuracy (area under ROC curve=0.77), whereas CVS detection alone (optimal cutoff 35.5-38%) could better discriminate MS from non-MS cases with high specificity (96%), sensitivity (99%), and accuracy (area under ROC curve=0.99). The combination of the two biomarkers further improved the specificity (99%), but sensitivity remained low (59%).

Conclusions

PRL yielded high specificity for MS lesions. Future prospective multicenter studies should further validate its role as a diagnostic biomarker.

Collapse
Epidemiology Poster Presentation

P0444 - Characterization of US-based Hispanic Americans with multiple sclerosis (ID 1185)

Abstract

Background

Background: Multiple sclerosis (MS) incidence in Hispanic Americans (HA) is increasing, highlighting the need to understand disease features and clinical course trends among this subpopulation.

Objectives

Objective: To compare demographic features and clinical characteristics of a large population of HA and non-Hispanic Caucasian Americans (NHCA) with MS.

Methods

Methods: MS PATHS is a network of MS Centers in the United States (n=7) and Europe (n=3) contributing standardized data acquired during routine care. US-based MS PATHS participants who self-reported as HA (irrespective of race) or as NHCA, and compared the groups according to demographic (sex, years of education, smoking status, BMI, employment, and insurance status), MS clinical (self-reported disability via Patient Determined Disease Steps [PDDS]), and neuro-performance (via the MS Performance Test (MSPT): walking, manual dexterity, and processing speed) features. Odds ratios and mean differences for PDDS and neuro-performance outcomes were adjusted for age, sex, disease duration and subtype, smoking status, BMI, insurance status, employment status, and years of education. Z-score is compared to a representative healthy population.

Results

Results: Compared to NHCA (n=9003), HA (n=609) had earlier MS symptom onset (mean 28.6y [SD:10.7y] vs 33.6y [11.3y]; p<0.001) and younger age at diagnosis (31.6y [10.9y] vs 36.6y [10.9y]; p<0.001). HA were more likely to have mild disability by the PDDS, compared to NHCA (OR 0.62, 95% CI [-0.89, -0.06], p=0.02). However, HA had worse performance on both manual dexterity times (z score: 0.31 [0.14, 0.47], p<0.001), and cognitive processing speed score (# correct: 0.37 [0.27-0.47], p<0.0001). 25-foot walking speed was not different between the groups (z score:0.09 [-0.23,0.41], p=0.56).

Conclusions

Conclusion: Using standardized data collection in this large MS sample, HA compared to NHCA patients were found to have younger age of onset and diagnosis and higher levels of cognitive and manual dexterity slowing. However, HA were less likely to rate themselves with severe disability on the PDDS. As the groups did not differ in walking speed, this may reflect the scale relatively weighting ambulation over other functions or other language/cultural differences.

Collapse
Imaging Poster Presentation

P0542 - Assessment of central vein sign conspicuity in multicenter 3T FLAIR* imaging (ID 985)

Abstract

Background

The central vein sign (CVS) is a proposed diagnostic biomarker for MS that can be identified using FLAIR*. The robustness of 3T FLAIR*, with and without the injection of gadolinium contrast agent (Gd), for imaging the CVS in a multicenter setting has not yet been demonstrated.

Objectives

To assess the conspicuity of the CVS on 3T FLAIR* imaging acquired across different sites with and without the injection of Gd.

Methods

A cross-sectional multicenter study recruited adults with a clinical and/or radiological suspicion of having MS from 10 sites within the North American Imaging in MS (NAIMS) Cooperative. High-isotropic-resolution T2*-weighted segmented echo-planar imaging (T2*-EPI) was acquired at 3T, pre- and post-injection of Gd, along with 3D FLAIR on different scanner brands and models. T2*-EPI and FLAIR images were processed on an online imaging platform (QMENTA) to generate FLAIR* images. To objectively assess the conspicuity of the CVS inside MS lesions, lesions and veins were segmented automatically and used to compute lesion-to-vein contrast-to-noise ratio (CNR) measures. ANOVA was used to compare CNR values across sites with post-hoc Tukey Honest Significant Difference testing. Multiple testing between sites was considered by controlling the false discovery rate. One-sided paired t-testing was used to compare the overall lesion-to-vein CNR values between pre- and post-Gd FLAIR*.

Results

Seventy-eight patients from nine sites were included in the analysis; one site was excluded due to low enrollment. The overall mean(coefficient of variation, CV) lesion-to-vein CNR values across the nine sites were 0.35(14%) and 0.37(12%) for pre- and post-Gd FLAIR*, respectively. Excluding an additional site that used an unharmonized FLAIR acquisition, the resulting mean(CV) CNR values were 0.36(12%) for pre-Gd and 0.37(11%) for post-Gd FLAIR*. Across most sites, there was a significant improvement in lesion-to-vein CNR measures for post-Gd compared to pre-Gd FLAIR* [mean difference = 0.011, p < 0.001, 95% CI: (0.008,0.015)].

Conclusions

Lesion-to-vein CNR measures across sites are in line with values first published for 3T FLAIR* and demonstrate the robustness of 3T FLAIR* for imaging the CVS in a multicenter setting. Moreover, there was an increase in vein conspicuity with improvement in CNR on post-Gd FLAIR*. Based on these results, a prospective multicenter NAIMS CVS diagnostic study, sponsored by NINDS, will use 3T FLAIR* imaging with Gd in the study protocol.

Collapse
Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0685 - AQP4-IgG and MOG-IgG related optic neuritis – prevalence, optical coherence tomography findings, visual outcomes: systematic review and meta-analysis (ID 860)

Speakers
Presentation Number
P0685
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Optic neuritis (ON) is a cardinal manifestation of multiple sclerosis (MS), aquaporin-4 (AQP4)-IgG, and myelin oligodendrocyte glycoprotein (MOG)-IgG associated disease. However, the prevalence of AQP4-IgG seropositivity and MOG-IgG seropositivity in isolated ON is unclear, and studies comparing visual outcomes and optical coherence tomography (OCT)-derived structural retinal measures between MS-ON, AQP4-ON, and MOG-ON eyes are limited by small sample sizes.

Objectives

1) To assess the prevalence of AQP4-IgG and MOG-IgG seropositivity among patients presenting with isolated ON; 2) To compare visual outcomes and OCT measures between AQP4-ON, MOG-ON, and MS-ON eyes.

Methods

In this systematic review and meta-analysis, a total of 65 eligible studies were identified by Pubmed search. Statistical analyses were performed with random-effects models.

Results

In adults with isolated ON, AQP4-IgG seroprevalence was 4% in non-Asian and 27% in Asian populations, whereas MOG-IgG seroprevalence was 8% and 20% respectively. In children, AQP4-IgG seroprevalence was 0.4% in non-Asian and 15% in Asian populations, whereas MOG-IgG seroprevalence was 47% and 31% respectively. AQP4-ON eyes had lower peri-papillary retinal nerve fiber layer (pRNFL; -11.7μm, 95% CI: -15.2 to -8.3μm) and macular ganglion cell + inner plexiform layer (GCIPL; -9.0μm, 95% CI -12.5 to -5.4μm) thicknesses compared with MS-ON eyes, but these measures did not differ between AQP4-ON and MOG-ON eyes (pRNFL: -1.9μm, 95% CI: -9.1 to 5.4μm; GCIPL: -2.6μm, 95% CI: -8.9 to 3.8μm). Similar to AQP4-ON, pRNFL (-11.2μm, 95% CI -21.5 to -0.9μm) and GCIPL (-6.1μm, 95% CI -10.8 to -1.3μm thicknesses were lower in MOG-ON compared to MS-ON eyes. Visual outcomes were worse in AQP4-ON compared to both MOG-ON (mean logMAR difference: 0.60, 95% CI 0.39 to 0.81) and MS-ON eyes (mean logMAR difference: 0.68, 95% CI 0.40 to 0.96), but were similar in MOG-ON and MS-ON eyes (mean logMAR difference: 0.04, 95% CI: -0.05 to 0.14).

Conclusions

AQP4-IgG and MOG-IgG associated disease are important diagnostic considerations in adults presenting with isolated ON, especially in Asian populations. Furthermore, MOG-IgG seroprevalence is especially high in pediatric isolated ON, in both non-Asian and Asian populations. Despite a similar severity of GCIPL and pRNFL thinning in AQP4-ON and MOG-ON, AQP4-ON is associated with markedly worse visual outcomes.

Collapse
Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0713 - Evidence of subclinical quantitative retinal layer abnormalities in aquaporin-4-IgG seropositive NMOSD (ID 862)

Speakers
Presentation Number
P0713
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Aquaporin-4-IgG (AQP4-IgG) seropositive Neuromyelitis Optica Spectrum Disorder (NMOSD) typically presents with discrete attacks of optic neuritis (ON) and transverse myelitis, and insidious subclinical disease activity is considered a rare occurrence. Prior optical coherence tomography (OCT) studies have suggested that subclinical retinal abnormalities, including lower foveal thickness and altered foveal morphology, may be present in AQP4-IgG+ NMOSD in the absence of a clinical history of ON; however, existing studies were relatively small.

Objectives

To compare retinal layer thicknesses at the fovea and surrounding macula between AQP4-IgG+ NMOSD eyes without a history of ON (AQP4-nonON) and healthy controls (HC).

Methods

In this single-center cross-sectional study, 83 AQP4-nonON and 153 HC eyes were studied with spectral-domain OCT. Statistical analyses were performed with generalized estimating equations (GEE) and were adjusted for age, sex and race.

Results

Total foveal thickness did not differ between AQP4-nonON and HC eyes (-3.55±3.79μm, p=0.35). AQP4-nonON eyes exhibited lower outer nuclear layer (ONL) and inner photoreceptor segment (IS) thickness at the fovea (ONL: -4.01±2.03μm, p=0.049; IS: -0.32±0.14μm, p=0.029) and surrounding macula (ONL: -1.98±0.95μm, p=0.037; IS: -0.16±0.07μm, p=0.023), compared to HC. Macular retinal nerve fiber layer (mRNFL: -1.34±0.51μm, p=0.009) and ganglion cell + inner plexiform layer (GCIPL: -2.44±0.93μm, p=0.009) thicknesses were also lower in AQP4-nonON compared to HC eyes. The magnitude of the estimated differences was similar in sensitivity analyses restricted to AQP4-IgG+ patients who had never experienced ON in either eye (n=33 patients; mRNFL: -1.33±0.60μm, p=0.026; GCIPL: -2.59±1.12μm, p=0.021; macular ONL: -2.01±1.04μm, p=0.052; macular IS: -0.16±0.08μm, p=0.031; foveal ONL: -3.78±2.28μm, p=0.10; foveal IS: -0.28±0.19μm, p=0.14).

Conclusions

AQP4-nonON eyes exhibited evidence of subclinical retinal ganglion cell neuronal and axonal loss, as well as structural evidence of photoreceptor layer involvement. These results remained largely unaltered in analyses limited to patients who had never experienced ON, suggesting that they are likely related to processes that are independent of clinically overt ON attacks. These findings support that subclinical anterior visual pathway involvement may occur in AQP4-IgG+ NMOSD, and may relate to a primary retinal process or subclinical optic neuropathy.

Collapse
Neuroprotection, Regeneration and/or Remyelination Poster Presentation

P0774 - Bryostatin-1 modulates CNS innate immunity and augments remyelination (ID 1755)

Speakers
Presentation Number
P0774
Presentation Topic
Neuroprotection, Regeneration and/or Remyelination

Abstract

Background

Chronic, compartmentalized activation of central nervous system (CNS) innate immune cells drives progression and prevents remyelination in multiple sclerosis (MS), yet therapies targeting this aspect of inflammation do not exist. Bryostatin-1 (bryo-1) is a clinically safe, brain-penetrant macrocyclic lactone we previously found to have anti-inflammatory effects on peripheral myeloid cells, promoting a shift to tolerogenic/regulatory phenotypes and thereby attenuating rodent experimental autoimmune encephalomyelitis (EAE). The therapeutic target mediating this effect remains uncertain, and it is not known whether bryo-1 directly impacts CNS-resident (rather than peripheral) innate myeloid cells with downstream effects on myelin repair.

Objectives

1) To identify the mechanistic target of bryo-1 in innate myeloid cells; 2) To determine whether bryo-1 alters the phenotype of CNS-resident innate immune cells; 3) To evaluate the impact of immune modulation with bryo-1 on remyelination in lysolecithin-induced demyelination.

Methods

A combination of pharmacologic and genetic tools were used to determine the mechanistic target of bryo-1 mediating its effects in cultured macrophages and EAE. To determine whether bryo-1 acts directly on CNS-resident innate immune cells, we examined the effects of bryo-1 on microglia and astrocyte phenotype both in vitro and in two in vivo models – lysolecithin-induced demyelination and late-stage C57BL/6J EAE. Finally, we examined the effect of systemic treatment with bryo-1 on myelin repair following lysolecithin-induced demyelination.

Results

We found that the immunologic effects of bryo-1 are mediated by protein kinase C (PKC), both in vitro and in vivo. In cultured microglia and in vivo models, bryo-1 prevents pro-inflammatory activation and promotes homeostatic/regenerative phenotypic markers. Preliminary studies have shown that systemic treatment with bryo-1 augments re-population of oligodendrocyte-lineage cells and remyelination within demyelinated lesions.

Conclusions

PKC mediates the effects of bryo-1 on innate immune phenotype and represents a therapeutic target for future studies. Bryo-1 promotes a regenerative phenotype within CNS-resident microglia, both in vitro and in vivo, with preliminary data suggesting a potential downstream impact on myelin repair. Given its established safety profile in humans in trials of cancer and Alzheimer’s disease, bryo-1 holds promise as a modulator of compartmentalized inflammation in progressive MS.

Collapse
Neuroprotection, Regeneration and/or Remyelination Poster Presentation

P0775 - Development of a screening platform that uses genome engineered hPSC-Derived OPCs for the discovery of remyelination promoting compounds (ID 1677)

Speakers
Presentation Number
P0775
Presentation Topic
Neuroprotection, Regeneration and/or Remyelination

Abstract

Background

Promoting remyelination of neurons in the central nervous system (CNS) is a promising approach for treatment of multiple sclerosis (MS) and other demyelinating neurodegenerations. Currently, the systems being used to screen for such remyelinating drugs predominantly use rodent cells. Given the important differences in mouse and human oligodendrocyte (OL) development and gene expression, validating and expanding the mouse studies in a human system is important. In addition, drug discovery performed with human cells has a better probability to identify leads that will translate into effective treatments.

Objectives

The goal of this project was to develop a human stem cell-derived oligodendrocyte precursor cell (OPC)-based platform for high-throughput as well as high-content screening (HTS and HTC) of potential myelination promoting compounds.

Methods

We used CRISPR/Cas9-based genome editing to modify three OPC and OL specific genes in a hESC line (WA09). First, an identification and purification (IAP) tag was knocked-in just prior to the translational stop site of the endogenous PDGFRα, a marker gene for OPCs. The IAP tag consists of tdTomato and a unique mouse cell-surface protein, Thy1.2, separated by a 2A peptide. In this IAP system, upon PDGFRα expression, tdTomato localizes to the cytoplasm whereas Thy1.2 localizes to the cell surface, allowing the PDGFRα expressing OPCs to be immunopurified via Thy1.2 microbeads. We also knocked-in GFP and secreted Nano luciferase (secNluc) reporter proteins such that they are driven by the OL maturation and myelination markers PLP1 and MBP respectively. Since the secNanoLuc is separated from the MBP gene product by a 2A sequence, NanoLuc is secreted into the culture media when MBP is expressed. This allows the NanoLuc activity, which represents the MBP expression, to be quantitated using a small aliquot of the cell culture media. In addition, since the GFP expression is representative of PLP1 expression, image-based high-content screening (HCS) can also be performed with these cells.

Results

We have screened several libraries of bioactive molecules, and identified a number of compounds that promote maturation of human OLs. As a validation of our assay system, several of the compounds we identified, including muscarinic receptor antagonists, Cytochrome P450 inhibitors, SERMs and ROCK inhibitors were recently reported as myelination promoting compounds in a rodent OPC in vitro model system. Additionally, several molecules and potential targets that have not been previously implicated in OL differentiation and function were also identified.

Conclusions

We developed a human OPC-based drug screening platform for the discovery of remyelinating compounds. HTS performed using this platform identified a number of lead molecules that promote OL maturation, and could enhance myelination.

Collapse
Invited Presentations Invited Abstracts

TC21.01 - Presentation 01 (ID 650)

Speakers
Authors
Presentation Number
TC21.01
Presentation Topic
Invited Presentations

Presenter Of 1 Presentation

Invited Presentations Invited Abstracts

TC21.01 - Presentation 01 (ID 650)

Speakers
Authors
Presentation Number
TC21.01
Presentation Topic
Invited Presentations

Moderator Of 1 Session

Teaching Course Fri, Sep 11, 2020
Session Type
Teaching Course
Date
Fri, Sep 11, 2020

Invited Speaker Of 1 Presentation

Invited Presentations Invited Abstracts

TC21.01 - Presentation 01 (ID 650)

Speakers
Authors
Presentation Number
TC21.01
Presentation Topic
Invited Presentations