B cell depletion therapy does not resolve chronic active multiple sclerosis lesions.

BACKGROUND: Chronic active lesions (CAL) in multiple sclerosis (MS) have been observed even in patients taking high-efficacy disease-modifying therapy, including B-cell depletion. Given that CAL are a major determinant of clinical progression, including progression independent of relapse activity (PIRA), understanding the predicted activity and real-world effects of targeting specific lymphocyte populations is critical for designing next-generation treatments to mitigate chronic inflammation in MS. METHODS: We analyzed published lymphocyte single-cell transcriptomes from MS lesions and bioinformatically predicted the effects of depleting lymphocyte subpopulations (including CD20 B-cells) from CAL via gene-regulatory-network machine-learning analysis. Motivated by the results, we performed in vivo MRI assessment of PRL changes in 72 adults with MS, 46 treated with anti-CD20 antibodies and 26 untreated, over ∼2 years. FINDINGS: Although only 4.3% of lymphocytes in CAL were CD20 B-cells, their depletion is predicted to affect microglial genes involved in iron/heme metabolism, hypoxia, and antigen presentation. In vivo, tracking 202 PRL (150 treated) and 175 non-PRL (124 treated), none of the treated paramagnetic rims disappeared at follow-up, nor was there a treatment effect on PRL for lesion volume, magnetic susceptibility, or T1 time. PIRA occurred in 20% of treated patients, more frequently in those with ≥4 PRL (p = 0.027). INTERPRETATION: Despite predicted effects on microglia-mediated inflammatory networks in CAL and iron metabolism, anti-CD20 therapies do not fully resolve PRL after 2-year MRI follow up. Limited tissue turnover of B-cells, inefficient passage of anti-CD20 antibodies across the blood-brain-barrier, and a paucity of B-cells in CAL could explain our findings. FUNDING: Intramural Research Program of NINDS, NIH; NINDS grants R01NS082347 and R01NS082347; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Cariplo Foundation (grant #1677), FRRB Early Career Award (grant #1750327); Fund for Scientific Research (FNRS).

Effects of Ibudilast on Retinal Atrophy in Progressive Multiple Sclerosis Subtypes: Post Hoc Analyses of the SPRINT-MS Trial.

BACKGROUND AND OBJECTIVES: Ganglion cell + inner plexiform layer (GCIPL) thinning, measured by optical coherence tomography (OCT), reflects global neurodegeneration in multiple sclerosis (MS). Atrophy of the inner (INL) and outer nuclear layer (ONL) may also be prominent in progressive MS (PMS). The phase 2, SPRINT-MS trial found reduced brain atrophy with ibudilast therapy in PMS. In this post hoc analysis of the SPRINT-MS trial, we investigate (1) retinal atrophy (2) differences in response by subtype and (3) associations between OCT and MRI measures of neurodegeneration. METHODS: In the multicenter, double-blind SPRINT-MS trial, participants with secondary progressive MS (SPMS) or primary progressive MS (PPMS) were randomized to ibudilast or placebo. OCT and MRI data were collected every 24 weeks for 96 weeks. Extensive OCT quality control and algorithmic segmentation produced consistent results across Cirrus HD-OCT and Spectralis devices. Primary endpoints were GCIPL, INL, and ONL atrophy, assessed by linear mixed-effects regression. Secondary endpoints were associations of OCT measures, brain parenchymal fraction, and cortical thickness, assessed by partial Pearson correlations. RESULTS: One hundred thirty-four PPMS and 121 SPMS participants were included. GCIPL atrophy was 79% slower in the ibudilast (-0.07 ± 0.23 µm/y) vs placebo group (-0.32 ± 0.20 µm/y, p = 0.003). This effect predominated in the PPMS cohort (ibudilast: -0.08 ± 0.29 µm/y vs placebo: -0.60 ± 0.29 µm/y, a decrease of 87%, p < 0.001) and was not detected in the SPMS cohort (ibudilast: -0.21 ± 0.28 µm/y vs placebo: -0.14 ± 0.27 µm/y, p = 0.55). GCIPL, INL, and ONL atrophy rates correlated with whole brain atrophy rates across the cohort (r = 0.27, r = 0.26, and r = 0.20, respectively; p < 0.001). Power calculations from these data show future trials of similar size and design have ≥80% power to detect GCIPL atrophy effect sizes of approximately 40%. DISCUSSION: Ibudilast treatment decreased GCIPL atrophy in PMS, driven by the PPMS cohort, with no effect seen in SPMS. Modulated atrophy of retinal layers may be detectable in sample sizes smaller than the SPRINT-MS trial and correlate with whole brain atrophy in PMS, further highlighting their utility as outcomes in PMS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that ibudilast reduces composite ganglion cell + inner plexiform layer atrophy, without reduction of inner or outer nuclear layer atrophy, in patients with primary progressive MS but not those with secondary progressive MS.

Trans-Synaptic Degeneration Following Acute Optic Neuritis in Multiple Sclerosis.

OBJECTIVE: To explore longitudinal changes in brain volumetric measures and retinal layer thicknesses following acute optic neuritis (AON) in people with multiple sclerosis (PwMS), to investigate the process of trans-synaptic degeneration, and determine its clinical relevance. METHODS: PwMS were recruited within 40 days of AON onset (n = 49), and underwent baseline retinal optical coherence tomography and brain magnetic resonance imaging followed by longitudinal tracking for up to 5 years. A comparator cohort of PwMS without a recent episode of AON were similarly tracked (n = 73). Mixed-effects linear regression models were used. RESULTS: Accelerated atrophy of the occipital gray matter (GM), calcarine GM, and thalamus was seen in the AON cohort, as compared with the non-AON cohort (-0.76% vs -0.22% per year [p = 0.01] for occipital GM, -1.83% vs -0.32% per year [p = 0.008] for calcarine GM, -1.17% vs -0.67% per year [p = 0.02] for thalamus), whereas rates of whole-brain, cortical GM, non-occipital cortical GM atrophy, and T2 lesion accumulation did not differ significantly between the cohorts. In the AON cohort, greater AON-induced reduction in ganglion cell+inner plexiform layer thickness over the first year was associated with faster rates of whole-brain (r = 0.32, p = 0.04), white matter (r = 0.32, p = 0.04), and thalamic (r = 0.36, p = 0.02) atrophy over the study period. Significant relationships were identified between faster atrophy of the subcortical GM and thalamus, with worse visual function outcomes after AON. INTERPRETATION: These results provide in-vivo evidence for anterograde trans-synaptic degeneration following AON in PwMS, and suggest that trans-synaptic degeneration may be related to clinically-relevant visual outcomes. ANN NEUROL 2023;93:76-87.

Effects of Myopia on Rates of Change in Optical Coherence Tomography Measured Retinal Layer Thicknesses in People with Multiple Sclerosis and Healthy Controls.

PURPOSE: To quantify the associations of myopia with longitudinal changes in retinal layer thicknesses in people with multiple sclerosis (PwMS) and healthy controls (HC). METHODS: A cohort of PwMS and HC with recorded refractive error (RE) prospectively scanned on Cirrus HD-OCT at the Johns Hopkins MS Center was assessed for inclusion. Exclusion criteria included OCT follow-up < 6 months, ocular comorbidities, incidental OCT pathologies, and inadequate scan quality. Eyes were classified as having high myopia (HM) (RE≤ -6 diopters), low myopia (LM) (RE> -6 and ≤ -3 diopters), or no myopia (NM) (RE> -3 and ≤ +2.75). Linear mixed-effects regression models were used in analyses. RESULTS: A total of 213 PwMS (eyes: 67 HM, 98 LM, 207 NM) and 80 HC (eyes: 26 HM, 37 LM, 93 NM) were included. Baseline average ganglion cell/inner plexiform (GCIPL) and peri-papillary retinal nerve fiber layer (pRNFL) thicknesses were lower in MS HM compared with MS NM (diff: -3.2 µm, 95% CI: -5.5 to -0.8, p = 0.008 and -5.3 µm, 95% CI: -9.0 to -1.7, p = 0.004, respectively), and similarly in HC HM, as compared with HC NM. Baseline superior, inferior, and nasal pRNFL thicknesses were lower in HM compared with NM, while temporal pRNFL thickness was higher, both in MS and HC (MS: 7.1 µm, 95% CI: 2.7-11.6, p = 0.002; HC: 4.7 µm, 95% CI: -0.3 to 9.7, p = 0.07). No longitudinal differences in rates of GCIPL change were noted between HM and LM vs. NM, either in MS or HC. CONCLUSION: Cross-sectional differences in average GCIPL and pRNFL thicknesses are commonly seen in people with HM as compared to reference normative values from people with NM and can lead to false attribution of pathology if RE is not taken into account. However, our study suggests that longitudinal changes in average GCIPL thickness in PwMS with myopia are similar in magnitude to PwMS with NM, and therefore are appropriate for monitoring disease-related pathology.

Visual Pathway Involvement in NMDA Receptor Encephalitis: A Clinical, Optical Coherence Tomography, and 18-Fluorodeoxyglucose PET/CT Approach.

BACKGROUND: Anti-NMDA receptor (NMDAR) encephalitis patients have been reported to exhibit visual dysfunction without retinal thinning. The objective of our study was to examine the involvement of the visual pathway structure and function in anti-NMDAR encephalitis by assessing postrecovery visual function and retinal structure, and acute-phase occipital cortex function. METHODS: In this cross-sectional study, patients diagnosed with anti-NMDAR encephalitis per consensus criteria underwent postrecovery visual acuity (VA) testing and optical coherence tomography (OCT) with automated retinal layer segmentation. Clinical data and acute-phase brain 18F-fluorodeoxyglucose (FDG) PET/CT (performed within 90 days of symptom onset, assessed qualitatively and semi-quantitatively) were retrospectively analyzed. VA and OCT measures were compared between anti-NMDAR and age, sex, and race-matched healthy controls (HC). When available, FDG-PET/CT metabolism patterns were analyzed for correlations with VA, and OCT measures. RESULTS: A total of 16 anti-NMDAR (32 eyes) and 32 HC (64 eyes) were included in the study. Anti-NMDAR exhibited lower low-contrast VA (2.5% contrast: -4.4 letters [95% CI; -8.5 to -0.3]; P = 0.04, 1.25% contrast: -6.8 letters [95%CI; -12 to -1.7]; P = 0.01) compared with HC, but no differences were found on OCT-derived retinal layer thicknesses. Acute-phase FDG-PET/CT medial occipital cortex metabolism did not correlate with follow-up low-contrast VA or ganglion cell/inner plexiform layer thickness (GCIPL) (n = 7, 2.5% contrast: r = -0.31; P = 0.50, 1.25% contrast: r = -0.34; P = 0.45, GCIPL: r = -0.04; P = 0.94). CONCLUSIONS: Although the visual system seems to be involved in anti-NMDAR encephalitis, no retinal structural or occipital cortex functional abnormalities seem to be responsible for the visual dysfunction. When detected acutely, occipital lobe hypometabolism in anti-NMDAR encephalitis does not seem to associate with subsequent retrograde trans-synaptic degenerative phenomena, potentially reflecting reversible neuronal/synaptic dysfunction in the acute phase of the illness rather than neuronal degeneration.

Mitochondrial measures in neuronally enriched extracellular vesicles predict brain and retinal atrophy in multiple sclerosis.

BACKGROUND: Mitochondrial dysfunction plays an important role in multiple sclerosis (MS) disease progression. Plasma extracellular vesicles are a potential source of novel biomarkers in MS, and some of these are derived from mitochondria and contain functional mitochondrial components. OBJECTIVE: To evaluate the relationship between levels of mitochondrial complex IV and V activity in neuronally enriched extracellular vesicles (NEVs) and brain and retinal atrophy as assessed using serial magnetic resonance imaging (MRI) and optical coherence tomography (OCT). METHODS: Our cohort consisted of 48 people with MS. NEVs were immunocaptured from plasma and mitochondrial complex IV and V activity levels were measured. Subjects underwent OCT every 6 months and brain MRI annually. The associations between baseline mitochondrial complex IV and V activities and brain substructure and retinal thickness changes were estimated utilizing linear mixed-effects models. RESULTS: We found that higher mitochondrial complex IV activity and lower mitochondrial complex V activity levels were significantly associated with faster whole-brain volume atrophy. Similar results were found with other brain substructures and retinal layer atrophy. CONCLUSION: Our results suggest that mitochondrial measures in circulating NEVs could serve as potential biomarkers of disease progression and provide the rationale for larger follow-up longitudinal studies.

Association of Serum Neurofilament Light Chain With Inner Retinal Layer Thinning in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Serum neurofilament light chain (sNfL) and optical coherence tomography (OCT)-derived retinal measures (including peripapillary retinal nerve fiber layer [pRNFL] and macular ganglion cell layer/inner plexiform layer [GCIPL] thickness) have been proposed as biomarkers of neurodegeneration in multiple sclerosis (MS). However, studies evaluating the associations between sNfL and OCT-derived retinal measures in MS are limited. METHODS: In this retrospective analysis of a longitudinal, observational, single-center cohort study, sNfL levels were measured in people with MS and healthy controls (HCs) using single molecule array. Participants with MS were followed with serial OCT for a median follow-up of 4.5 years. Eyes with optic neuritis (ON) within 6 months of baseline OCT or ON during follow-up were excluded. Age-normative cutoffs of sNfL were derived using the HC data, and MS participants with sNfL greater than the 97.5th percentile for age were classified as having elevated sNfL (sNfL-E). Analyses were performed with mixed-effects linear regression models and adjusted for age, sex, race, and history of ON. RESULTS: A total of 130 HCs (age: 42.4 ± 14.2 years; 62% female) and 403 people with MS (age: 43.1 ± 12.0 years; 78% female) were included. Elevated sNfL levels were present at baseline in 80 participants with MS (19.9%). At baseline, sNfL-E participants had modestly lower pRNFL (-3.03 ± 1.50 µm; p = 0.044) and GCIPL thickness (-2.74 ± 1.02 µm; p = 0.007). As compared with those with sNfL within the reference range, eyes from NfL-E participants exhibited faster longitudinal thinning of the pRNFL (45% faster; -0.74 vs -0.51 µm/y; p = 0.015) and GCIPL (25% faster; -0.35 vs -0.28 µm/y; p = 0.021). Significant differences in rates of pRNFL and GCIPL thinning between sNfL groups were found only in those with relapsing-remitting MS but not progressive MS. DISCUSSION: Elevated baseline sNfL is associated with accelerated rates of retinal neuroaxonal loss in relapsing-remitting MS, independent of overt ON, but may be less reflective of retinal neurodegeneration in progressive MS.

Optic Neuritis-Independent Retinal Atrophy in Neuromyelitis Optica Spectrum Disorder.

BACKGROUND: A limited number of studies have investigated the presence of ongoing disease activity independent of clinical relapses in neuromyelitis optica spectrum disorder (NMOSD), and data are conflicting. The objective of our study was to examine whether patients with aquaporin-4 (AQP4)-IgG seropositive NMOSD exhibit progressive retinal neuroaxonal 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 and visual acuity (VA) assessments. NMOSD patients with ON less than 6 months before baseline were excluded, whereas data from patients with ON during follow-up were censored at the last visit before ON. VA worsening was defined as a decrease in monocular letter acuity ≥5 letters for high-contrast VA and ≥7 letters for low-contrast VA. Analyses were performed with mixed-effects linear regression models adjusted for age, sex, and race. RESULTS: The median follow-up duration was 4.2 years (interquartile range: 1.8-7.5). Relative to HC, NMOSD eyes had faster peripapillary retinal nerve fiber layer (pRNFL) (ß = -0.25 µm/year faster, 95% confidence interval [CI]: -0.45 to -0.05, P = 0.014) and GCIPL thinning (ß = -0.09 µm/year faster, 95% CI: -0.17 to 0, P = 0.05). This difference seemed to be driven by faster pRNFL and GCIPL thinning in NMOSD eyes without a history of ON compared with HC (GCIPL: ß = -0.15 µm/year faster; P = 0.005; pRNFL: ß = -0.43 µm/year faster, P < 0.001), whereas rates of pRNFL (ß: -0.07 µm/year, P = 0.53) and GCIPL (ß = -0.01 µm/year, P = 0.90) thinning did not differ between NMOSD-ON and HC eyes. Nine NMOSD eyes had VA worsening during follow-up. 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.

Socioeconomic disparity is associated with faster retinal neurodegeneration in multiple sclerosis.

Disease course in multiple sclerosis is notably heterogeneous, and few prognostic indicators have been consistently associated with multiple sclerosis severity. In the general population, socioeconomic disparity is associated with multimorbidity and may contribute to worse disease outcomes in multiple sclerosis. Herein, we assessed whether indicators of socioeconomic status are associated with disease progression in patients with multiple sclerosis using highly sensitive imaging tools such as optical coherence tomography, and determined whether differential multiple sclerosis management or comorbidity mediate any observed socioeconomic status-associated effects. We included 789 participants with longitudinal optical coherence tomography and low contrast letter acuity (at 1.25 and 2.5%) in whom neighbourhood- (derived via nine-digit postal codes) and participant-level socioeconomic status indicators were available ≤10 years of multiple sclerosis symptom onset. Sensitivity analyses included participants with socioeconomic status indicators available ≤3years of symptom onset (n = 552). Neighbourhood-level indicators included state and national area deprivation indices, median household income and the Agency for Healthcare Research and Quality (AHRQ) Socioeconomic Status Index. Participant-level indicators included education level. Biannual optical coherence tomography scans were segmented to quantify thickness of the composite macular ganglion cell+inner plexiform (GCIPL) layer. We assessed the association between socioeconomic status indicators and GCIPL atrophy or low contrast letter acuity loss using mixed models adjusting for demographic (including race and ethnicity) and disease-related characteristics. We also assessed socioeconomic status indicators in relation to multiple sclerosis therapy changes and comorbidity risk using survival analysis. More disadvantaged neighbourhood-level and patient-level socioeconomic status indicators were associated with faster retinal atrophy. Differences in rate of GCIPL atrophy for individuals in the top quartile (most disadvantaged) relative to the bottom quartile (least) for state area deprivation indices were -0.12 µm/year faster [95% confidence interval (CI): -0.19, -0.04; P = 0.003], for national area deprivation indices were -0.08 µm/year faster (95% CI: -0.15, -0.005; P = 0.02), for household income were -0.11 µm/year faster (95% CI: -0.19, -0.03; P = 0.008), for AHRQ Socioeconomic Status Index were -0.12 µm/year faster (95% CI: -0.19, -0.04) and for education level were -0.17 µm/year faster (95% CI: -0.26, -0.08; P = 0.0002). Similar associations were observed for socioeconomic status indicators and low contrast letter acuity loss. Lower socioeconomic status was associated with higher risk of incident comorbidity during follow-up. Low socioeconomic status individuals had faster rates of therapy escalation, suggesting the association between socioeconomic status and GCIPL atrophy may not be explained by differential contemporaneous multiple sclerosis therapy management. In conclusion, socioeconomic disparity is associated with faster retinal neurodegeneration in multiple sclerosis. As low socioeconomic status was associated with a higher risk of incident comorbidities that may adversely affect multiple sclerosis outcomes, comorbidity prevention may mitigate some of the unfavourable socioeconomic status-associated consequences.

Association of Spectral-Domain OCT With Long-term Disability Worsening in Multiple Sclerosis.

OBJECTIVE: To evaluate whether a retinal spectral-domain optical coherence tomography (SD-OCT) assessment at baseline is associated with long-term disability worsening in people with multiple sclerosis (PwMS), we performed SD-OCT and Expanded Disability Status Scale (EDSS) assessments among 132 PwMS at baseline and at a median of 10 years later. METHODS: In this prospective, longitudinal study, participants underwent SD-OCT, EDSS, and visual acuity (VA) assessments at baseline and at follow-up. Statistical analyses were performed using generalized linear regression models, adjusted for age, sex, race, multiple sclerosis (MS) subtype, and baseline disability. We defined clinically meaningful EDSS worsening as an increase of ≥2.0 if baseline EDSS score was <6.0 or an increase of ≥1.0 if baseline EDSS score was ≥6.0. RESULTS: A total of 132 PwMS (mean age 43 years; 106 patients with relapsing-remitting MS) were included in analyses. Median duration of follow-up was 10.4 years. In multivariable models excluding eyes with prior optic neuritis, relative to patients with an average baseline ganglion cell + inner plexiform layer (GCIPL) thickness ≥70 µm (the mean GCIPL thickness of all eyes at baseline), an average baseline GCIPL thickness <70 µm was associated with a 4-fold increased odds of meaningful EDSS worsening (adjusted odds ratio [OR] 3.97, 95% confidence interval [CI] 1.24-12.70; p = 0.02) and an almost 3-fold increased odds of low-contrast VA worsening (adjusted OR 2.93, 95% CI 1.40-6.13; p = 0.04). CONCLUSIONS: Lower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS. Accordingly, SD-OCT at a single time point may help guide therapeutic decision-making among individual PwMS. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that lower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS.

Evidence of subclinical quantitative retinal layer abnormalities in AQP4-IgG seropositive NMOSD.

BACKGROUND: Prior studies have suggested that subclinical retinal abnormalities may be present in aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive neuromyelitis optica spectrum disorder (NMOSD), in the absence of a clinical history of optic neuritis (ON). OBJECTIVE: Our aim was 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 154 HC eyes were studied with spectral-domain optical coherence tomography (OCT). RESULTS: Total foveal thickness did not differ between AQP4-nonON and HC eyes. AQP4-nonON eyes exhibited lower outer nuclear layer (ONL) and inner photoreceptor segment (IS) thickness at the fovea (ONL: -4.01 ± 2.03 µm, p = 0.049; IS: -0.32 ± 0.14 µm, p = 0.029) and surrounding macula (ONL: -1.98 ± 0.95 µm, p = 0.037; IS: -0.16 ± 0.07 µm, p = 0.023), compared to HC. Macular retinal nerve fiber layer (RNFL: -1.34 ± 0.51 µm, p = 0.009) and ganglion cell + inner plexiform layer (GCIPL: -2.44 ± 0.93 µm, p = 0.009) thicknesses were also lower in AQP4-nonON compared to HC eyes. Results were similar in sensitivity analyses restricted to AQP4-IgG+ patients who had never experienced ON in either eye. CONCLUSIONS: AQP4-nonON eyes exhibit evidence of subclinical retinal ganglion cell neuronal and axonal loss, as well as structural evidence of photoreceptor layer involvement. These findings support that subclinical anterior visual pathway involvement may occur in AQP4-IgG+ NMOSD.

Serum ceramide levels are altered in multiple sclerosis.

BACKGROUND: Sphingolipids are myelin components and inflammatory signaling intermediates. Sphingolipid metabolism may be altered in people with multiple sclerosis (PwMS), but existing studies are limited by small sample sizes. OBJECTIVES: To compare the levels of serum ceramides between PwMS and healthy controls (HCs) and to determine whether ceramide levels correlate with disability status, as well as optical coherence tomography (OCT)-derived rates of retinal layer atrophy. METHODS: We performed targeted lipidomics analyses for 45 ceramides in PwMS (n = 251) and HCs (n = 68). For a subset of PwMS, baseline and 5-year Expanded Disability Status Scale (EDSS) assessments (n = 185), or baseline and serial spectral-domain OCT (n = 180) were assessed. RESULTS: Several ceramides, including hexosylceramides, lactosylceramides, and dihydroceramides, were altered in PwMS compared with HCs. Higher levels of Cer16:0 were associated with higher odds of EDSS worsening at 5 years in univariable (odds ratio (OR) = 3.84, 95% confidence interval (CI) = 1.41-10.43) and multivariable analyses accounting for age, sex, and race (OR = 2.97, 95% CI = 1.03-8.59). Each 1 ng/mL higher concentration of Hex-Cer22:0 and DH-HexCer22:0 was associated with accelerated rates (µm/year) of ganglion cell + inner plexiform layer (-0.138 ± 0.053, p = 0.01; -0.158 ± 0.053, p = 0.003, respectively) and peripapillary retinal nerve fiber layer thinning (-0.305 ± 0.107, p = 0.004; -0.358 ± 0.106, p = 0.001, respectively). CONCLUSION: Ceramide levels are altered in PwMS and may be associated with retinal neurodegeneration and physical disability.

Optical Coherence Tomography and Optical Coherence Tomography Angiography Findings After Optic Neuritis in Multiple Sclerosis.

Background: In people with multiple sclerosis (MS), optic neuritis (ON) results in inner retinal layer thinning, and reduced density of the retinal microvasculature. Objective: To compare inter-eye differences (IEDs) in macular optical coherence tomography (OCT) and OCT angiography (OCTA) measures in MS patients with a history of unilateral ON (MS ON) vs. MS patients with no history of ON (MS non-ON), and to assess how these measures correlate with visual function outcomes after ON. Methods: In this cross-sectional study, people with MS underwent OCT and OCTA. Superficial vascular plexus (SVP) density of each eye was quantified using a deep neural network. IEDs were calculated with respect to the ON eye in MS ON patients, and with respect to the right eye in MS non-ON patients. Statistical analyses used mixed-effect regression models accounting for intra-subject correlations. Results: We included 43 MS ON patients (with 92 discrete OCT/OCTA visits) and 14 MS non-ON patients (with 24 OCT/OCTA visits). Across the cohorts, mean IED in SVP density was -2.69% (SD 3.23) in MS ON patients, as compared to 0.17% (SD 2.39) in MS non-ON patients (p = 0.002). When the MS ON patients were further stratified according to time from ON and compared to MS non-ON patients with multiple cross-sectional analyses, we identified that IED in SVP density was significantly increased in MS ON patients at 1-3 years (p = < 0.001) and >3 years post-ON (p < 0.001), but not at <3 months (p = 0.21) or 3-12 months post-ON (p = 0.07), while IED in ganglion cell + inner plexiform layer (GCIPL) thickness was significantly increased in MS ON patients at all time points post-ON (p ≦ 0.01 for all). IED in SVP density and IED in GCIPL thickness demonstrated significant relationships with IEDs in 100% contrast, 2.5% contrast, and 1.25% contrast letter acuity in MS ON patients (p < 0.001 for all). Conclusions: Our findings suggest that increased IED in SVP density can be detected after ON in MS using OCTA, and detectable changes in SVP density after ON may occur after changes in GCIPL thickness. IED in SVP density and IED in GCIPL thickness correlate well with visual function outcomes in MS ON patients.

Intranasal insulin in Alzheimer's dementia or mild cognitive impairment: a systematic review.

BACKGROUND AND AIMS: Due to common pathophysiological findings of Alzheimer's disease (AD) with diabetes mellitus (DM), insulin has been suggested as a possible treatment of AD or mild cognitive impairment (MCI). A safe alternative of IV insulin is intranasal (IN) insulin. The aim of this systematic review is to investigate the effects of IN insulin on cognitive function of patients with either AD or MCI. METHODS: A literature search of the electronic databases Medline, Scopus and CENTRAL was performed to identify RCTs investigating the effect of IN insulin administration on cognitive tasks, in patients with AD or MCI. RESULTS: Seven studies (293 patients) met our inclusion criteria. Most studies showed that verbal memory and especially story recall was improved after IN insulin administration. Sometimes the effect was restricted for apoe4 (-) patients. Intranasal insulin did not affect other cognitive functions. However, there were some positive results in functional status and daily activity. Data suggested that different insulin types and doses may have different effects on different apoe4 groups. In addition, the effects of treatment on Αß levels differed from study to study. Finally, IN insulin resulted in minor adverse effects. CONCLUSIONS: Intranasal insulin improved story recall performance of apoe4 (-) patients with AD or MCI. Other cognitive functions were not affected, but there were some positive results in functional status and daily activity. Since IN insulin is a safe intervention, future studies should be conducted with larger doses and after proper selection of patients and insulin types.

Atrial fibrillation and cognitive function in patients with heart failure: a systematic review and meta-analysis.

Cognitive impairment and dementia are established complications of heart failure (HF) in adult patients and impair medication adherence and self-care. Atrial fibrillation (AF) is suggested to play an independent role in the cognitive decline in patients with HF. The objective of this systematic review was to assess the effect of AF on cognitive function in these patients. Medline (PubMed), Scopus, and the CENTRAL databases were queried from their inception up to April 30, 2016. The search included primary research articles evaluating the effect of AF on cognition in HF patients. There were five eligible studies, including a total of 1670 patients with HF; of these, 449 (26.9%) had AF. Different AF types were studied, including persistent, paroxysmal, or permanent. Four cognitive tests were used to assess cognitive function (Mini-Mental State Examination, Short Portable Mental Status Questionnaire, Modified Mini-Mental Examination, and Montreal cognitive assessment tool). Using the inverse variance method and a random effects model, we observed that presence of AF was significantly associated with increased risk of cognitive impairment in HF patients (odds ratio [OR], 1.94; 95% confidence interval [CI], 1.30-2.87), although with significant heterogeneity (I 2  = 39%). This heterogeneity can be attributed to the different populations and types of AF studied as well as to varying cognitive assessment methods. Concomitant AF may exacerbate cognitive dysfunction in HF patients. However, data are sparse and heterogeneous. Well-designed, prospective studies are needed to (a) establish a causative link and (b) identify the underlying mechanism in order to design appropriate interventions to attenuate risk of cognitive impairment in patients with HF.