Faculty Bibliography

BACKGROUND:Multiple sclerosis (MS) patients with stable disease course might view continued treatment as unnecessary. However, guidelines regarding treatment discontinuation are currently lacking. OBJECTIVE:To assess the clinical course after treatment discontinuation in MS patients with long disease duration. METHODS:Patients who discontinued disease-modifying treatments (DMTs) and not resume treatment (n = 216) were extracted from New York State MS Consortium (NYSMSC) and followed across three time points (average 4.6 years). Stable course was defined as no change in Expanded Disability Status Scale (EDSS) scores (<1.0 increase if EDSS<6.0 or <0.5-point increase if EDSS≥6.0) from baseline (time 1) to DMT discontinuation (time 2). Both stable and worsening MS patients were later assessed again after the DMT discontinuation (time 3). Additional analyses were performed based on disease subtype, type of medication, age cut-off of 55 and EDSS of 6.0. RESULTS:From the cohort of 216 MS patients who discontinued DMT, 161 (72.5%) were classified as stable before DMT discontinuation. After DMT discontinuation, 53 previously stable MS patients (32.9%) experienced disability worsening/progression (DWP). 29.2 and 40% of previously stable RRMS and SPMS respectively had DWP after DMT discontinuation. Over two years after DMT discontinuation, the rate of DWP was similar between patients younger or older than 55 years (31.1% vs 25.9%, respectively). MS patients with EDSS≥6.0 had greater DWP when compared to less disabled patients while remaining on therapy as well as after discontinuation (40.7% vs 15.4%, p < 0.001 and 39.6% vs 15.2%, p < 0.001, respectively). CONCLUSION/CONCLUSIONS:MS patients with stable disease course experience DWP after treatment discontinuation, with no clear relation to age and disease subtype. Patients with EDSS≥6.0 are at higher risk for DWP.

Background There are multiple tools available to visualize the retinal and choroidal vasculature of the posterior globe. However, there are currently no reliable in vivo imaging techniques that can visualize the entire retrobulbar course of the retinal and ciliary vessels. Purpose To identify and characterize the central retinal artery (CRA) using cone-beam CT (CBCT) images obtained as part of diagnostic cerebral angiography. Materials and Methods In this retrospective study, patients with catheter DSA performed between October 2019 and October 2020 were included if CBCT angiography included the orbit in the field of view. The CBCT angiography data sets were postprocessed with a small field-of-view volume centered in the posterior globe to a maximum resolution of 0.2 mm. The following were evaluated: CRA origin, CRA course, CRA point of penetration into the optic nerve sheath, bifurcation of the CRA at the papilla, visualization of anatomic variants, and visualization of the central retinal vein. Descriptive statistical analysis was performed. Results Twenty-one patients with 24 visualized orbits were included in the analysis (mean age, 55 years ± 15; 14 women). Indications for angiography were as follows: diagnostic angiography (n = 8), aneurysm treatment (n = 6), or other (n = 7). The CRA was identified in all orbits; the origin, course, point of penetration of the CRA into the optic nerve sheath, and termination in the papilla were visualized in all orbits. The average length of the intraneural segment was 10.6 mm (range, 7-18 mm). The central retinal vein was identified in six of 24 orbits. Conclusion Cone-beam CT, performed during diagnostic angiography, consistently demonstrated the in vivo central retinal artery, demonstrating excellent potential for multiple diagnostic and therapeutic applications. © RSNA, 2021 Online supplemental material is available for this article.

BACKGROUND:There is growing recognition that wellness interventions should occur in context and acknowledge complex contributors to wellbeing, including individual needs, institutional and cultural barriers to wellbeing, as well as systems issues which propagate distress. The authors conducted a multiple-methods study exploring contributors to wellbeing for junior residents in diverse medical environments who participated in a brief resilience and stress-reduction curriculum, the Stress Management and Resiliency Training Program for Residents (SMART-R). METHODS:Using a waitlist-controlled design, the curriculum was implemented for post-graduate year (PGY)-1 or PGY-2 residents in seven residency programs across three sites. Every three months, residents completed surveys, including the Perceived Stress Scale-10, General Self-Efficacy Questionnaire, a mindfulness scale (CAMSR), and a depression screen (PHQ-2). Residents also answered free-text reflection questions about psychological wellbeing and health behaviors. RESULTS:The SMART-R intervention was not significantly associated with decreased perceived stress. Linear regression modeling showed that depression was positively correlated with reported stress levels, while male sex and self-efficacy were negatively correlated with stress. Qualitative analysis elucidated differences in these groups: Residents with lower self-efficacy, those with a positive depression screen, and/or female residents were more likely to describe experiencing lack of control over work. Residents with higher self-efficacy described more positive health behaviors. Residents with a positive depression screen were more self-critical, and more likely to describe negative personal life events. CONCLUSIONS:This curriculum did not significantly modify junior residents' stress. Certain subpopulations experienced greater stress than others (female residents, those with lower self-efficacy, and those with a positive depression screen). Qualitative findings from this study highlight universal stressful experiences early in residency, as well as important differences in experience of the learning environment among subgroups. Tailored wellness interventions that aim to support diverse resident sub-groups may be higher yield than a "one size fits all" approach. TRIAL REGISTRATION/BACKGROUND:NCT02621801 , Registration date: December 4, 2015 - Retrospectively registered.

Plasma phosphorylated-tau181 (p-tau181) showed the potential for Alzheimer's diagnosis and prognosis, but its role in detecting cerebral pathologies is unclear. We aimed to evaluate whether it could serve as a marker for Alzheimer's pathology in the brain. A total of 1189 participants with plasma p-tau181 and PET data of amyloid, tau or FDG PET were included from ADNI. Cross-sectional relationships of plasma p-tau181 with PET biomarkers were tested. Longitudinally, we further investigated whether different p-tau181 levels at baseline predicted different progression of Alzheimer's pathological changes in the brain. We found plasma p-tau181 significantly correlated with brain amyloid (Spearman ρ = 0.45, P < 0.0001), tau (0.25, P = 0.0003), and FDG PET uptakes (-0.37, P < 0.0001), and increased along the Alzheimer's continuum. Individually, plasma p-tau181 could detect abnormal amyloid, tau pathologies and hypometabolism in the brain, similar with or even better than clinical indicators. The diagnostic accuracy of plasma p-tau181 elevated significantly when combined with clinical information (AUC = 0.814 for amyloid PET, 0.773 for tau PET, and 0.708 for FDG PET). Relationships of plasma p-tau181 with brain pathologies were partly or entirely mediated by the corresponding CSF biomarkers. Besides, individuals with abnormal plasma p-tau181 level (>18.85 pg/ml) at baseline had a higher risk of pathological progression in brain amyloid (HR: 2.32, 95%CI 1.32-4.08) and FDG PET (3.21, 95%CI 2.06-5.01) status. Plasma p-tau181 may be a sensitive screening test for detecting brain pathologies, and serve as a predictive biomarker for Alzheimer's pathophysiology.

Alpha-synuclein seed amplification assays (αSyn-SAAs) are promising diagnostic tools for Parkinson's disease (PD) and related synucleinopathies. They enable detection of seeding-competent alpha-synuclein aggregates in living patients and have shown high diagnostic accuracy in several PD and other synucleinopathy patient cohorts. However, there has been confusion about αSyn-SAAs for their methodology, nomenclature, and relative accuracies when performed by various laboratories. We compared αSyn-SAA results obtained from three independent laboratories to evaluate reproducibility across methodological variations. We utilized the Parkinson's Progression Markers Initiative (PPMI) cohort, with DATSCAN data available for comparison, since clinical diagnosis of early de novo PD is critical for neuroprotective trials, which often use dopamine transporter imaging to enrich their cohorts. Blinded cerebrospinal fluid (CSF) samples for a randomly selected subset of PPMI subjects (30 PD, 30 HC, and 20 SWEDD), from both baseline and year 3 collections for the PD and HC groups (140 total CSF samples) were analyzed in parallel by each lab according to their own established and optimized αSyn-SAA protocols. The αSyn-SAA results were remarkably similar across laboratories, displaying high diagnostic performance (sensitivity ranging from 86 to 96% and specificity from 93 to 100%). The assays were also concordant for samples with results that differed from clinical diagnosis, including 2 PD patients determined to be clinically inconsistent with PD at later time points. All three assays also detected 2 SWEDD subjects as αSyn-SAA positive who later developed PD with abnormal DAT-SPECT. These multi-laboratory results confirm the reproducibility and value of αSyn-SAA as diagnostic tools, illustrate reproducibility of the assay in expert hands, and suggest that αSyn-SAA has potential to provide earlier diagnosis with comparable or superior accuracy to existing methods.

BACKGROUND AND OBJECTIVES/OBJECTIVE:To explore efficacy/safety of natalizumab, a humanized monoclonal anti-α4-integrin antibody, as adjunctive therapy in adults with drug-resistant focal epilepsy. METHODS:Participants with ≥6 seizures during the 6-week baseline period were randomized 1:1 to receive natalizumab 300 mg IV or placebo every 4 weeks for 24 weeks. Primary efficacy outcome was change from baseline in log-transformed seizure frequency, with a predefined threshold for therapeutic success of 31% relative reduction in seizure frequency over the placebo group. Countable seizure types were focal aware with motor signs, focal impaired awareness, and focal to bilateral tonic-clonic. Secondary efficacy endpoints/safety were also assessed. RESULTS:= 0.22). Adverse events were reported in 24 (75%) and 22 (65%) participants receiving natalizumab vs placebo. DISCUSSION/CONCLUSIONS:Although the threshold to demonstrate efficacy was not met, there were no unexpected safety findings and further exploration of possible anti-inflammatory therapies for drug-resistant epilepsy is warranted. TRIAL REGISTRATION INFORMATION/UNASSIGNED:The ClinicalTrials.gov registration number is NCT03283371. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class I evidence that IV natalizumab every 4 weeks, compared to placebo, did not significantly change seizure frequency in adults with drug-resistant epilepsy. The study lacked the precision to exclude an important effect of natalizumab.