Abstract Background and aims Patient foramen ovale (PFO) is a stroke risk factor evaluated using transthoracic echocardiogram (TTE), transesophageal echocardiogram (TEE), transcranial Doppler ultrasound (TCD), and cardiac computed tomography (CCT). TCD is non-invasive, but its diagnostic performance relative to other modalities is unclear. We hypothesized that TCD has high sensitivity but low specificity for PFO detection. Methods We conducted an IRB-approved, single-center retrospective study of patients undergoing TCD for right-to-left shunt (RLS) detection between January 2024 and April 2025. Patients were identified from the Neurosonology Laboratory Quality Database. Records were reviewed for demographics, comorbidities, and TTE, TEE, and CCT findings. Sensitivity, specificity, and positive and negative predictive values were calculated for TCD, TTE, and CCT relative to TEE, the gold standard. The sensitivity and specificity of TCD versus TTE were compared using McNemar test. Results Ninety-two patients were included. Mean age was 52.66 ± 15.78 years, and 51% were female; qualifying events included ischemic stroke or transient ischemic attack. RLS was detected in 53 patients (57.6%) by TCD, 17 (30%) by TTE, 18 (28.5%) by TEE, and 3 (21%) by CCT. TCD demonstrated 94% sensitivity and 53% specificity, (PPV 66%, NPV 89%). TTE showed 50% sensitivity and 82% specificity (PPV: 75%, NPV 61%), while CCT showed 33% sensitivity and 100% specificity (PPV 100%, NPV 33.3%). TCD had significantly higher sensitivity than TTE for RLS detection (p=0.039) with a non-significant difference in specificity (p=0.062), using TEE as the reference. Conclusions TCD has high sensitivity for RLS detection in patients with ischemic stroke or transient ischemic attack. Conflict of interest Rachel Knopp: nothing to disclose; Kelly Flemming: nothing to disclose; Eugene Scharf: nothing to disclose; Zafer Keser: nothing to disclose; Jessica Prink: nothing to disclose; Shari Johnson: nothing to disclose; Guy Reeder: nothing to disclose; Robert Brown: nothing to disclose; William Harmsen: nothing to disclose; Muhib Khan: nothing to disclose Table 1 - belongs to Results

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) have known cardiovascular benefits. We aimed to assess the efficacy of GLP1-RA or SGLT2i initiation in reducing mortality or cardiovascular events in a community-based cohort of adults with ischemic stroke. Methods: Patients ≥18 years old admitted for acute ischemic stroke between Jan 2000 and June 2022 were identified using the Rochester Epidemiology Project. Subjects were considered exposed to SGLT-2i or GLP1-RA if they were treated with either medication after the index stroke and before the primary (all-cause mortality) or secondary outcomes (MI, recurrent ischemic stroke or composite). Kaplan-Meier curves and Cox models are shown in the Figures . Results: We included 7044 subjects, mean age 72±14 yr, 52% male, 94% white, over a median follow-up of 3 [1-7] years, 416 subjects (6%) had a second stroke, 426 (6%) had an incident MI and 3738 (53%) died. Those on SGLT2i/GLP1-RA had a decreased risk for mortality, incident MI, and composite in the univariate analysis. These associations remained significant after multivariable adjustment and were not affected by minimum time of exposure Figure 1&2 . SGLT2i/GLP1-RA use was associated with recurrent ischemic stroke in the multivariate analysis Figure 2C . All associations remained significant in most sub-analyses of individual medications except for the association between GLP1-RA and recurrent stroke Figure 3 Conclusions: SGLT2i or GLP-1 RA use was associated with decreased mortality and risk of myocardial infarction and recurrent stroke in patients with ischemic stroke.

Key interactive capabilities of NG-CHMs

Figure showing the NG-CHM Generator in the Galaxy bioinformatics platform.

Characterize the disease course, imaging/laboratory features and clinical outcomes of pathologically confirmed intravascular lymphoma with central nervous system (CNS) involvement.

Background: The presence of subclinical optic nerve (ON) injury in youth living with pediatric-onset MS has not been fully elucidated. Magnetization transfer saturation (MTsat) is an advanced magnetic resonance imaging (MRI) parameter sensitive to myelin density and microstructural integrity, which can be applied to the study of the ON. Objective: The objective of this study was to investigate the presence of subclinical ON abnormalities in pediatric-onset MS by means of magnetization transfer saturation and evaluate their association with other structural and functional parameters of visual pathway integrity. Methods: Eleven youth living with pediatric-onset MS (ylPOMS) and no previous history of optic neuritis and 18 controls underwent standardized brain MRI, optical coherence tomography (OCT), Magnetoencephalography (MEG)-Visual Evoked Potentials (VEPs), and visual battery. Data were analyzed with mixed effect models. Results: While ON volume, OCT parameters, occipital MEG-VEPs outcomes, and visual function did not differ significantly between ylPOMS and controls, ylPOMS had lower MTsat in the supratentorial normal appearing white matter (−0.26 nU, p = 0.0023), and in both in the ON (−0.62 nU, p < 0.001) and in the normal appearing white matter of the optic radiation (−0.56 nU, p = 0.00071), with these being positively correlated (+0.57 nU, p = 0.00037). Conclusions: Subclinical microstructural injury affects the ON of ylPOMS. This may appear as MTsat changes before being detectable by other currently available testing.

Objectives To determine to what extent acute demyelinating episodes versus chronic degenerative phenomena drive retinal neuroaxonal damage in pediatric acquired demyelinating syndromes (ADS). Methods We acquired optical coherence tomography (OCT) data (follow-up range: 2 weeks - 5 years, at variable intervals from presentation) in pediatric participants who had multiple sclerosis (MS), monophasic ADS, or were healthy. Multivariable mixed effects models were used to assess the association of the number of demyelinating episodes (either optic neuritis [ON], or non-ON relapses) with changes in retinal nerve fiber layer (RNFL) or ganglion cell layer-inner plexiform layer (GCIPL) thickness. Results 64 OCT sans from 23 MS, and 33 scans from 12 monophasic ADS participants were compared with 68 scans from 62 healthy participants. The first ON episode had the biggest impact on RNFL or GCIPL thickness in monophasic ADS (RNFL:-7.9 mu m, CI=5.5, p = 0.0056; GCIPL:-8.4 mu m, CI=4.4, p = 0.0002) and MS (RNFL:-16 mu m, CI = 3.7, p < 10(-6); GCIPL:-15 mu m, CI = 2.6, p < 10(-6)). Non-ON relapses were also associated with small but significant retinal thickness reductions in MS (RNFL:-2.6 mu m/relapse, CI = 1.4, p = 0.0003; GCIPL:-2.8 mu m/ relapse, CI = 0.89, p < 10(-6)). MS participants showed progressive GCIPL thinning independent of acute demyelinating episodes (-2.7 mu m/year, CI = 1.9, p = 0.0058). Conclusions We showed a prominent impact of early ON episodes on OCT measures of neuroaxonal structure in patients with ADS. We also demonstrated negative effects of non-ON relapses, and the presence of chronic retinal neurodegenerative changes, in youth with MS.

Leptomeningeal and perivenular infiltrates are important contributors to cortical grey matter damage and disease progression in multiple sclerosis (MS). Whereas perivenular inflammation induces vasculocentric lesions, leptomeningeal involvement follows a subpial “surface‐in” gradient. To determine whether similar gradient of damage occurs in deep grey matter nuclei, we examined the dorsomedial thalamic nuclei and cerebrospinal fluid (CSF) samples from 41 postmortem secondary progressive MS cases compared with 5 non‐neurological controls and 12 controls with other neurological diseases. CSF/ependyma‐oriented gradient of reduction in NeuN+ neuron density was present in MS thalamic lesions compared to controls, greatest (26%) in subventricular locations at the ependyma/CSF boundary and least with increasing distance (12% at 10 mm). Concomitant graded reduction in SMI31+ axon density was observed, greatest (38%) at 2 mm from the ependyma/CSF boundary and least at 10 mm (13%). Conversely, gradient of major histocompatibility complex (MHC)‐II+ microglia density increased by over 50% at 2 mm at the ependyma/CSF boundary and only by 15% at 10 mm and this gradient inversely correlated with the neuronal (R = −0.91, p < 0.0001) and axonal (R = −0.79, p < 0.0001) thalamic changes. Observed gradients were also detected in normal‐appearing thalamus and were associated with rapid/severe disease progression; presence of leptomeningeal tertiary lymphoid‐like structures; large subependymal infiltrates, enriched in CD20+ B cells and occasionally containing CXCL13+ CD35+ follicular dendritic cells; and high CSF protein expression of a complex pattern of soluble inflammatory/neurodegeneration factors, including chitinase‐3‐like‐1, TNFR1, parvalbumin, neurofilament‐light‐chains and TNF. Substantial “ependymal‐in” gradient of pathological cell alterations, accompanied by presence of intrathecal inflammation, compartmentalized either in subependymal lymphoid perivascular infiltrates or in CSF, may play a key role in MS progression.Summary for Social MediaImaging and neuropathological evidences demonstrated the unique feature of “surface‐in” gradient of damage in multiple sclerosis (MS) since early pediatric stages, often associated with more severe brain atrophy and disease progression. In particular, increased inflammation in the cerebral meninges has been shown to be strictly associated with an MS‐specific gradient of neuronal, astrocyte, and oligodendrocyte loss accompanied by microglial activation in subpial cortical layers, which is not directly related to demyelination.To determine whether a similar gradient of damage occurs in deep grey matter nuclei, we examined the potential neuronal and microglia alterations in the dorsomedial thalamic nuclei from postmortem secondary progressive MS cases in combination with detailed neuropathological characterization of the inflammatory features and protein profiling of paired CSF samples.We observed a substantial “subependymal‐in” gradient of neuro‐axonal loss and microglia activation in active thalamic lesions of progressive MS cases, in particular in the presence of increased leptomeningeal and cerebrospinal fluid (CSF) inflammation. This altered graded pathology was found associated with more severe and rapid progressive MS and increased inflammatory degree either in large perivascular subependymal infiltrates, enriched in B cells, or within the paired CSF, in particular with elevated levels of a complex pattern of soluble inflammatory and neurodegeneration factors, including chitinase 3‐like‐1, TNFR1, parvalbumin, neurofilament light‐chains and TNF.These data support a key role for chronic, intrathecally compartmentalized inflammation in specific disease endophenotypes. CSF biomarkers, together with advance imaging tools, may therefore help to improve not only the disease diagnosis but also the early identification of specific MS subgroups that would benefit of more personalized treatments. ANN NEUROL 2022;92:670–685

Long-term cognitive deficits have been observed in some children who experience an acquired demyelinating syndrome (ADS). We examined changes in cognitive functioning over the first two years following incident ADS andtested whether normalized brain and thalamic volume accounted for decline over time. Twenty-five youth (mean age 12.8 years) with ADS, 9 of whom were diagnosed with multiple sclerosis (MS) and 16 of whom experienced monophasic ADS (monoADS), underwent two neuropsychological evaluationsand MRI scans at approximately6- and 24-months post ADS-onset. We examined changes in cognitive outcomes over time and between patient groups. Generalized linear mixed-effect regression models were used to examine the association of normalized brain and thalamic volumesbetween the two timepointswith cognitive z-scores. Cognitive performance was within the age-expected range for both groups and remained stable over time on 15 measures. In the combined sample of monoADS and MS patients, declines (p < .05) were noted on the Symbol Digit Modalities Test (SDMT), the Auditory Working Memory (AWM), and the WJ-III Visual Matching (VisMat)tests, but did not survive FDR correction. Clinically significant declines, as measured by the Reliable Change Index, were observed on the SDMT,AWM, and VisMattests by 19, 42, and 32%, respectively. Lower normalized brain volume at 6-months predicted a negative change in SDMT (B = 0.45, 95%CI: 0.07,0.83) and AWM (B = 0.30, 95%CI: 0.13, 0.47). Chronicity of demyelination is not required for cognitive decline nor for reduced brain volume, suggesting that even a single demyelinating event may negatively impact cognitive potential in children.

Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is now recognized as distinct from multiple sclerosis (MS). Objective: To evaluate the importance of considering myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin-G (IgG) serology when applying MS diagnostic criteria in children. Methods: Within a prospective cohort of children meeting MS criteria (median follow-up = 6 years, interquartile range (IQR) = 4–9), we measured MOG-IgG in serial archived serum obtained from presentation, and compared imaging and clinical features between seropositive and seronegative participants. Results: Of 65 children meeting MS criteria (median age = 14.0 years, IQR = 10.9–15.1), 12 (18%) had MOG-IgG at disease onset. Seropositive participants were younger, had brain magnetic resonance imaging (MRI) features atypical for MS, rarely had cerebrospinal fluid (CSF) oligoclonal bands (2/8, 25%), and accumulated fewer T2 lesions over time. On serial samples, 5/12 (42%) were persistently seropositive, 5/12 (42%) became seronegative, and 2/12 (17%) had fluctuating results. All 12 children experienced a disease course different from typical MS. Conclusion: While children with MOG-IgG can have clinical, CSF, and MRI features conforming to MS criteria, the presence of MOG-IgG is associated with atypical features and predicts a non-MS disease course. Given MOG-IgG seropositivity can wane over time, testing at first attack is of considerable importance for the diagnosis of MOGAD.

Background: The use of advanced magnetic resonance imaging (MRI) techniques in MS research has led to new insights in lesion evolution and disease outcomes. It has not yet been determined if, or how, pre-lesional abnormalities in normal-appearing white matter (NAWM) relate to the long-term evolution of new lesions. Objective: To investigate the relationship between abnormalities in MRI measures of axonal and myelin volume fractions (AVF and MVF) in NAWM preceding development of black-hole (BH) and non-BH lesions in people with MS. Methods: We obtained magnetization transfer and diffusion MRI at 6-month intervals in patients with MS to estimate MVF and AVF during lesion evolution. Lesions were classified as either BH or non-BH on the final imaging visit using T1 maps. Results: Longitudinal data from 97 new T2 lesions from 9 participants were analyzed; 25 lesions in 8 participants were classified as BH 6–12 months after initial appearance. Pre-lesion MVF, AVF, and MVF/AVF were significantly lower, and T1 was significantly higher, in the lesions that later became BHs ( p < 0.001) compared to those that did not. No significant pre-lesion abnormalities were found in non-BH lesions ( p > 0.05). Conclusion: The present work demonstrated that pre-lesion abnormalities are associated with worse long-term lesion-level outcome.

Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with complex human traits, but only a fraction of variants identified in discovery studies achieve significance in replication studies. Replication in genome-wide association studies has been well-studied in the context of Winner's Curse, which is the inflation of effect size estimates for significant variants due to statistical chance. However, Winner's Curse is often not sufficient to explain lack of replication. Another reason why studies fail to replicate is that there are fundamental differences between the discovery and replication studies. A confounding factor can create the appearance of a significant finding while actually being an artifact that will not replicate in future studies. We propose a statistical framework that utilizes genome-wide association studies and replication studies to jointly model Winner's Curse and study-specific heterogeneity due to confounding factors. We apply this framework to 100 genome-wide association studies from the Human Genome-Wide Association Studies Catalog and observe that there is a large range in the level of estimated confounding. We demonstrate how this framework can be used to distinguish when studies fail to replicate due to statistical noise and when they fail due to confounding.