Faculty Bibliography

Sialidosis type 1 is a rare lysosomal storage disorder caused by mutations of the neuraminidase gene. Specific features suggesting this condition include myoclonus, ataxia and macular cherry-red spots. However, phenotypic variability exists. Here, we present detailed clinical and video description of three patients with this rare condition. We also provide an in-depth characterization of eye movement abnormalities, as an additional tool to investigate pathophysiological mechanisms and to facilitate diagnosis. In our patients, despite phenotypic differences, eye movement deficits largely localized to the cerebellum.

BACKGROUND:It is estimated that up to 40% of Alzheimer's Disease and Related Dementias cases can be prevented or delayed by addressing modifiable factors including those that influence vascular risk (hypertension, obesity, smoking, physical activity, diabetes). Prevention may be particularly important in the vascular dementia subtypes. Despite the supporting evidence, the rates of medical therapy to reduce vascular risk are not well described. METHOD/METHODS:We assessed the utilization of statins, aspirin, and blood pressure (BP) medications in adults age ≥65 years cared for at NYU Langone Health, as recorded in the electronic health record. We included two cohorts: cohort 1 included patients who were diagnosed with vascular dementia (VaD) at NYU Langone Barlow Center for Memory Evaluation between January 1, 2015 and June 24, 2019. Cohort 2 extended the inclusion to seniors with VD diagnosis by any NYU Langone physician. Definitions for vascular dementia, the covariates assessed, and medications that we included in each category are shown in Tables 1-3. RESULT/RESULTS:We included 419 and 3745 patients in cohort 1 and cohort 2, respectively. Table 4 shows the characteristics and medication adherence in cohorts 1 and 2. In cohort 1, the prescription rates for statins, aspirin, and BP medications were 66%, 66%, 70%. In cohort 2, the rates for statin, aspirin, and BP medications were 56%, 46%, and 65%, respectively. The differences between prescription rates in cohort 1 and 2 for the three medication groups were statistically significant (p<0.05). CONCLUSION/CONCLUSIONS:Our analysis of the utilization of cardiovascular medications among patients with vascular dementia illuminates potential gaps both among patients who receive care at specialty clinics, as well as the overall population with vascular dementia. The rates of medication utilization are higher for patients under the care of cognitive neurologists. Electronic health records can help identify large cohorts of patients who may benefit from improved access to preventative measures including cardiovascular medications.

Background and Purpose:Antiplatelet therapy is key for preventing thrombotic events after transient ischemic attack or ischemic stroke. Although the role of aspirin is well established, there is emerging evidence for the role of short-term dual antiplatelet therapy (DAPT) in preventing recurrent stroke. Methods:We conducted a systematic review and study-level meta-analyses of randomized controlled trials comparing outcomes of early initiation of short-term DAPT (aspirin+P2Y12 inhibitor for up to 3 months) versus aspirin alone in patients with acute stroke or transient ischemic attack. Primary efficacy outcome was risk of recurrent stroke and primary safety outcome was incidence of major bleeding. Secondary outcomes studied were risk of any ischemic stroke, hemorrhagic stroke, major adverse cardiovascular events, and all-cause death. Pooled risk ratios (RRs) and CIs were calculated using a random-effects model. Results:Four trials with a total of 21 459 patients were included. As compared to aspirin alone, DAPT had a lower risk of recurrent stroke (RR, 0.76 [95% CI, 0.68–0.83]; P<0.001; I2=0%) but a higher risk of major bleeding events (RR, 2.22 [95% CI, 1.14–4.34], P=0.02, I2=46.5%). Patients receiving DAPT had a lower risk of major adverse cardiovascular events (RR, 0.76 [95% CI, 0.69–0.84], P<0.001, I2=0%) and recurrent ischemic events (RR, 0.74 [95% CI, 0.67–0.82], P<0.001, I2=0%). Conclusions:As compared to aspirin alone, short-term DAPT within 24 hours of high-risk transient ischemic attack or mild-moderate ischemic stroke reduces the risk of recurrent stroke at the expense of higher risk of major bleeding.

Recently, Vesuna et al. proposed a novel circuit mechanism underlying dissociative states using optogenetics and pharmacology in mice in combination with intracranial recordings and electrical stimulation in an epilepsy patient. Specifically, the authors identified a posteromedial cortical delta-rhythm that underlies states of dissociation. In the following, we would like to critically review these findings in the context of the human literature on dissociation as well as highlight the challenges in translational neuroscience to link complex behavioral phenotypes in psychiatric syndromes to circumscribed circuit mechanisms.

RATIONALE/BACKGROUND:Posttraumatic epilepsy (PTE) is a common cause of morbidity in children after a traumatic brain injury (TBI), occurring in 10-20% of children following severe TBI. PTE is diagnosed after two or more unprovoked seizures occurring 1-week post TBI. More often, studies have focused on children with epilepsy due to severe TBI. We aim to understand the utility of head computed tomography (HCT), EEG, and the risk of developing drug-resistant epilepsy in children after mild TBI. METHOD/METHODS:We retrospectively studied 321 children with TBI at a tertiary pediatric referral center during a 10-year period. Mild TBI was defined as loss of consciousness (LOC) or amnesia < 30 min, moderate TBI as LOC or amnesia between 30 min and 1 day, and severe TBI as LOC or amnesia > 1 day, subdural hemorrhage, or contusion. Multiple clinical variables were reviewed, including past and present antiepileptic drug(s), seizure control, and mode of injury. First and subsequent post-TBI EEGs/prolonged video-EEGs were obtained acutely, subacutely, and/or chronically (range, day 1-3 years, median 1 month). Descriptive analyses were conducted using medians and ranges for continuous data. Categorical data were reported using frequencies and percentages, while comparisons between groups were made using Fisher's exact test for small sample sizes. RESULTS:< 0.005. Six patients (75%) had MRIs, of which five (63%) were normal. Two patients (#1, 7) did not have MRIs, while one patient's (#4) MRI was unavailable. Five patients (63%) had a seizure <24 h post TBI, while the rest had seizures after the first week of injury. CONCLUSION/CONCLUSIONS:Children with epilepsy due to mild TBI, loss of consciousness, or amnesia < 30 min are more likely to have normal HCT and EEG and to be on 0-1 AED. Limitations of our study include the small sample size and retrospective design. The current findings add to the paucity of data in children who suffer from epilepsy due to mild TBI.

BACKGROUND AND PURPOSE:Dual antiplatelet therapy has been shown to reduce the risk of recurrent stroke in patients with minor stroke or transient ischemic attack. However, whether the effect of dual antiplatelet therapy is modified by pretreatment antiplatelet status is unclear. METHODS:This is a post hoc analysis of the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke). Patients were divided into 2 groups based on pretreatment antiplatelet use. The primary outcome was ischemic stroke within 90 days of randomization. RESULTS:for interaction = 0.685. CONCLUSIONS:In patients with minor stroke and high-risk transient ischemic attack, dual antiplatelet therapy reduces the risk of ischemic stroke regardless of premorbid antiplatelet use.

Sudden unexplained death in childhood (SUDC) is an understudied problem. Whole-exome sequence data from 124 "trios" (decedent child, living parents) was used to test for excessive de novo mutations (DNMs) in genes involved in cardiac arrhythmias, epilepsy, and other disorders. Among decedents, nonsynonymous DNMs were enriched in genes associated with cardiac and seizure disorders relative to controls (odds ratio = 9.76, P = 2.15 × 10^-4). We also found evidence for overtransmission of loss-of-function (LoF) or previously reported pathogenic variants in these same genes from heterozygous carrier parents (11 of 14 transmitted, P = 0.03). We identified a total of 11 SUDC proband genotypes (7 de novo, 1 transmitted parental mosaic, 2 transmitted parental heterozygous, and 1 compound heterozygous) as pathogenic and likely contributory to death, a genetic finding in 8.9% of our cohort. Two genes had recurrent missense DNMs, RYR2 and CACNA1C Both RYR2 mutations are pathogenic (P = 1.7 × 10^-7) and were previously studied in mouse models. Both CACNA1C mutations lie within a 104-nt exon (P = 1.0 × 10^-7) and result in slowed L-type calcium channel inactivation and lower current density. In total, six pathogenic DNMs can alter calcium-related regulation of cardiomyocyte and neuronal excitability at a submembrane junction, suggesting a pathway conferring susceptibility to sudden death. There was a trend for excess LoF mutations in LoF intolerant genes, where ≥1 nonhealthy sample in denovo-db has a similar variant (odds ratio = 6.73, P = 0.02); additional uncharacterized genetic causes of sudden death in children might be discovered with larger cohorts.

Task-specific focal dystonia is characterized by muscle contraction(s) during a specific task, resulting in abnormal postures or movements. Specifically, writer's cramp involves the upper extremity during the act of writing. Musician's dystonia has a highly variable presentation, and thus makes therapeutic options more limited. Treatments include oral pharmacologic agents, neuromodulation, surgery and, most often, botulinum toxin (BoNT) injection. Selection of target muscles for toxin injection continues to be an area of active research for these task-specific movements. We present a review of the literature selected from a predefined search of the MEDLINE and ClinicalTrials.gov databases. We include six controlled studies of botulinum toxin for the management of writer's cramp and focal task-specific dystonia (FTSD), including musician's dystonia. Overall, 139 patients were included across all studies, with 99 individuals injected for writer's cramp and the remaining 40 individuals with FTSD. The age range of all patients was 18-80 years old. We included studies that utilized only the BoNT-A serotype. These studies utilized various severity scales to quantify response to toxin injection, with ratings of instrument or pen control included as subjective ratings. Of the included 139 patients in this review, pooled data for toxin response show that 73% of patients who received the drug demonstrated improvement. Specific techniques for muscle localization and targeting were difficult to study as variable methods were employed. This remains an area of ongoing exploration.

Introduction: Inappropriate activation of Wnt/beta-catenin signaling plays a role in some cancers. beta-catenin (beta-cat) levels in the cell can be regulated by a cadherin-mediated sequestration into membrane-bound and free cytosolic pools, with the later translocating to the nucleus and driving TCF-mediated transcriptional activity following Wnt signal transduction. While sequencing has shown that MM lacks the mutations that typically lead to constitutive beta-cat activation seen in other cancers, we and others have demonstrated that Wnt/beta-catenin signaling is nonetheless activated in MM and can regulate MM growth. The mechanism driving beta-cat stabilization and activation in MM is unclear. E- and N-cadherin (N-cad) expression is elevated in MM compared to plasma cells from healthy donors. We hypothesized that that cadherins can regulate Wnt/beta-catenin signaling in MM.
Material(s) and Method(s): We detected different forms of beta-cat expression in a panel of human MM cell lines (HMCLs) and CD138 PC from MM patients by several approaches. Cadherin gain- or loss-of-function MM models were produced by expressing wild-type N-cad in MMS1 and ARP1 (lack endogenous N-cadherin expression) using a lentiviral system to create stable cell lines (N-Cad/MMS1 and N-cad/ARP1) and empty vector control (EV/MMS1, and EV-ARP1). We knocked down N-cadherin in the JJN3 cell line expressing high level of endogenous N-cadherin using shRNA specific for N-cad (shNcad/JJN3) or scrambled control shRNA (shCont/JJN3) by lentiviral-mediated transfection. We used a TCF reporter system to evaluate beta-cat transcriptional activity as previously described.
Result(s): We surveyed 25 HMCLs and CD138-selected plasma cells from 72 newly diagnosed MM for active beta-cat with an antibody that specifically recognizes the unphosphorylated active form of beta-cat. Higher levels of cytosolic and/or nuclear beta-cat protein were seen in 13 of 25 (52%) HMCLs and 36 of 72 (50%) primary MM PC. Correlation of beta-cat protein levels with global mRNA expression levels in primary PC revealed significant correlation with only one gene, CDH2 (N-cad). Remarkably, those primary MM with high beta-cat levels but low CDH2 levels expressed high levels of E-cadherin/CHD1 mRNA. This posed the question of whether CDH2 is a direct target of TCF/beta-cat transcriptional activity or whether high levels of CDH2 lead to increased levels of beta-cat protein via sequestration. Both CDH2 mRNA and protein were correlated with beta-cat protein but not beta-cat mRNA in 23/25 HMCLs. Co-immunoprecipitation revealed that N-cad and beta-cat complexes could be identified in HMCLs and primary MM. Consistent with N-cad-mediated stabilization of beta-cat both total and unphosphorylated beta-cat levels and TCF activity were significantly elevated in N-cad/MMS1 and N-Cad/ARP1 cells relative to controls. In contrast, shRNA mediated knockdown of N-cad led to a loss of both N-cad and beta-cat protein levels and TCF-dependent transcription activity relative to controls. These findings provide evidence that beta-cat/TCF signaling can be regulated by N-cad in MM. CDH2 mRNA is significantly elevated in the MS and HY subgroups of MM. To search for a potential mechanism of CDH2 transcriptional regulation in MS MM, we compared TCF activity and beta-cat protein levels in MS versus non-MS HMCLs. TCF activity and active beta-cat were elevated in MS versus non-MS forms of MM and B-cell lymphoma lacking N-cadherin. To determine if MMSET is required to up-regulate N-cad expression, we depleted the full-length MMSET protein in KMS11 cells. The results revealed a dramatic loss of total and unphosphorylated beta-cat protein, but not mRNA, and loss of both CDH2 mRNA and protein relative to controls. These data suggest that MMSET can regulate the transcription of the CDH2 gene. MMS1 and ARP1 cells stably expressing N-cad exhibited enhanced adhesion to bone marrow stromal cells and decreased sensitivity to bortezomib (Bzb). In contrast, blocking N-cadherin-mediated adhesion by CDH2 shRNA increased sensitivity to Bzb. These results suggests that N-cad/beta-cat complexes can contribute to adhesion-mediated drug resistance in MM.
Conclusion(s): Taken together, these findings establish that beta-cat is stabilized by N-cadherin-, and likely E-cadherin-, adhesins junction formation in MM. This in turn leads to an increased pool of beta-cat that can drive TCF transcriptional activation as well participate in cadherin-mediated cell adhesion and drug resistance. Disclosures: Davies: Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Walker: Bristol Myers Squibb: Research Funding; Sanofi: Speakers Bureau.
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