Faculty Bibliography

BACKGROUND:SMPD1 (acid-sphingomyelinase) variants have been associated with Parkinson's disease in recent studies. The objective of this study was to further investigate the role of SMPD1 mutations in PD. METHODS:SMPD1 was sequenced in 3 cohorts (Israel Ashkenazi Jewish cohort, Montreal/Montpellier, and New York), including 1592 PD patients and 975 controls. Additional data were available for 10,709 Ashkenazi Jewish controls. Acid-sphingomyelinase activity was measured by a mass spectrometry-based assay in the New York cohort. α-Synuclein levels were measured in vitro following CRISPR/Cas9-mediated knockout and siRNA knockdown of SMPD1 in HeLa and BE(2)-M17 cells. Lysosomal localization of acid-sphingomyelinase with different mutations was studied, and in silico analysis of their effect on acid-sphingomyelinase structure was performed. RESULTS:SMPD1 mutations were associated with PD in the Ashkenazi Jewish cohort, as 1.4% of PD patients carried the p.L302P or p.fsP330 mutation, compared with 0.37% in 10,709 Ashkenazi Jewish controls (OR, 3.7; 95%CI, 1.6-8.2; P = 0.0025). In the Montreal/Montpellier cohort, the p.A487V variant was nominally associated with PD (1.5% versus 0.14%; P = 0.0065, not significant after correction for multiple comparisons). Among PD patients, reduced acid-sphingomyelinase activity was associated with a 3.5- to 5.8-year earlier onset of PD in the lowest quartile versus the highest quartile of acid-sphingomyelinase activity (P = 0.01-0.001). We further demonstrated that SMPD1 knockout and knockdown resulted in increased α-synuclein levels in HeLa and BE(2)-M17 dopaminergic cells and that the p.L302P and p.fsP330 mutations impair the traffic of acid-sphingomyelinase to the lysosome. CONCLUSIONS:Our results support an association between SMPD1 variants, acid-sphingomyelinase activity, and PD. Furthermore, they suggest that reduced acid-sphingomyelinase activity may lead to α-synuclein accumulation. © 2019 International Parkinson and Movement Disorder Society.

Background: Adult MS research has identified an increased prevalence of various autoimmune conditions among family members of diagnosed patients. There has not been comparable studies of pediatric MS populations, while this cohort may represent a unique population from a risk factors perspective.
Objective(s): This study was undertaken to quantify the incidence of autoimmune conditions among first and second degree relatives of pediatric MS patients as compared to controls. The study sought to quantify both the rate, type and patterns of diagnoses seen throughout family members of pediatric MS patients.
Method(s): A multi center case-control study of risk factors for pediatric MS has been ongoing for since 2011. Pediatric patients with a diagnosis of MS and pediatric controls were recruited to provide data and biologic specimens for a number of research projects. Included in this effort was the acquisition of family history questionnaires. The medical data from these questionnaires were analyzed for the presence of certain medical diagnoses among first and second degree relatives. Logistic regression models were used to test for differences between cases and controls in reporting a family history of autoimmune diseases, when adjusting for sex, race, age, ethnicity, and mother's education level. Odds ratios and 95% confidence intervals were calculated based on the logistic regression models.
Result(s): Several conditions were found to have statistically significant differences in prevalence among first and second degree family members of MS patients as compared to controls. Diabetes, thyroid disorders and rheumatoid arthritis has the most notable differences between patients and controls while eczema and psoriasis were not different. The odds ratio of any family history of autoimmune disease was 2.27 among cases compared to controls. The odds ratio of an autoimmune disease among family members was significantly higher among paternal relatives as compared to maternal relatives (eg OR of 6.37 compared to 2.64).
Conclusion(s): This study has identified an increased prevalence of certain autoimmune disorders among first and second degree family members of pediatric MS patients. This aligns with prior findings among adult populations that found higher rates of autoimmune disorders among family members of adult onset MS patients. Novel to this study was the difference in relative risk of autoimmune conditions occurring in paternal versus maternal family members

Background: Alzheimer's disease (AD) is the most common form of dementia affecting 5.7 million individuals in the U.S. alone. While treatment approaches have predominantly focused on the reduc-tion of amyloid beta plaques, there has been a concerted shift to also target tau pathology, another major pathological marker of AD. There is no current treatment for AD, however profound efforts have been made in developing an immunotherapy approach. We have focused on activating Toll-like receptor 9 (TLR9), a stimulatory receptor of the innate immune system, in attempts to ameliorate the immune system's dysfunctional clearance. Our earlier studies revealed that stimulation of the innate immunity via TLR9 agonist, CpG ODN, in 3xTg-AD mice can alleviate all pathological hallmarks of AD (Ab, tau, CAA) and improve behavioral deficits without toxicity. Given the importance of tau related pathology, we designed an experiment to more directly determine the effect of CpG-ODN on tau pathology. This was done through rTg4510 mice, a tauopathy mouse model which develops robust forebrain tangle pathology without concurrent amyloid pathology.
Method(s): The rTg4510 mice were injected with either the TLR9 agonist Class B CpG-ODN or saline at monthly intervals (3 to 11 months of age). After the treatment period, immunohistochemistry and biochemical analyses (western blot) were performed. Peripheral immune response analyses (Th1/Th2 Luminex technology) are underway.
Result(s): Histological evaluation of CpG-ODN effect on hippo-campal and cortical brain regions revealed region specific reductions in PHF1 and MC1 immunoreactivity in CpG-ODN treated animals. Preliminary western blot analyses showed a significant reduction in total PHF1 phospho-tau levels (low-speed supernatant fraction) in the CpG-ODN-treated group in comparison to the saline-treated animals. Additionally, CpG-ODN treatment was not associated with increased insoluble tau pathology in sarcosyl fractions. Unlike previous attempts to simulate innate immunity, our method of immunomodulation demonstrated a modest, yet beneficial, effect on tau related pathology.
Conclusion(s): Overall, the present findings, together with our earlier research, demonstrate promising preclinical evidence for the potential use of TLR9 ligand CpG ODN as a disease modifying drug for Alzheimer's disease and other tau related dementias

BACKGROUND:In children with spastic cerebral palsy (CP), the treatment of equinus foot with Achilles tendon lengthening (ATL) surgery is associated with high incidence of overcorrection, which may result in crouch gait. AIM/OBJECTIVE:We aimed to assess if gait pattern in preoperative time could be a predictor of the surgery outcome. DESIGN/METHODS:Cross-sectional retrospective study. SETTING/METHODS:Movement Analysis Lab of IRCCS San Raffaele Pisana Hospital in Rome (Italy). POPULATION/METHODS:Eighteen children (mean age 9.6±4.7 years) with spastic diplegia CP who underwent bilateral ATL surgery to correct equinus foot were involved. METHODS:Participants underwent 3D gait analysis before and approximately 12 months after surgery. Primary measures were spatiotemporal, kinematic (summarized by Gait Variable Scores, GVSs) and kinetic parameters. The gait patterns for each leg was defined from kinematic data, using a quantitative classification: plantar flexor knee extension (PFKE) index. The CP group was split into true equinus and jump gait. RESULTS:The equinus foot was successfully corrected as demonstrated by the improvement of GVS ankle dorsi-plantarflexion. However, there was a high rate of overcorrection in the true equinus, characterized by increases in knee flexion-extension GVS (8.7° pre vs. 16.7° post P<0.05) and knee flexion angle at initial contact (5.2° vs. 20.6° P<0.05) and by a decrease in the maximum ankle power generated at push-off (1.49 vs. 0.83 W/kg P<0.05). CONCLUSIONS:Assessment of motor phenotype in preoperative time are good predictors of the results of ATL surgery. In children with true equinus gait, the increase of knee flexion subsequent to ATL is an early indicator that this technique will lead to crouch gait. These results show the influence of true equinus and jump gait patterns on the outcomes of the ATL. CLINICAL REHABILITATION IMPACT/CONCLUSIONS:Therefore, we propose that this approach could have clinical value to evaluate and prescribe rehabilitation in children with CP disease, proposing different solutions depending on motor phenotype.

BACKGROUND:Fatigue is one of the most commonly experienced symptoms in multiple sclerosis (MS). The neural correlates of fatigue in MS, in general and specifically in early onset, remain poorly understood. This study employed resting-state fMRI (rsfMRI) to investigate the functional connectivity of fatigue in MS patients with early age onset. METHODS:Twenty-seven relapsing-remitting MS patients (20 ± 7yo at the age of diagnosis and 26.0 ± 5.5yo at the time of study) were recruited and 22 patients were studied. Structural and rsfMRI sequences were performed on a 3-Tesla Seimens MRI scanner. Seed-based analysis was performed using CONN Functional Connectivity Toolbox for Statistic Parametric Mapping. The Fatigue Severity Scale (FSS) and the Modified Fatigue Impact scale (MFIS) as well as EDSS, Beck Depression Inventory, and symptomatology were measured. Non-fatigued (N = 12) and fatigued patients (N = 10) were separated based on FSS scores, with a score of 5 or greater being classified as fatigued. Group differences in rsfMRI between non-fatigued and fatigued patients were analyzed. Correlations between these functional connectivity differences and behavioral fatigue scores were also analyzed. RESULTS: = 0.402, p = 0.006). Correlations remained significant after accounting for depression scores. CONCLUSIONS:rsfMRI identified Alterations in two distinct connections (the connectivity between insula and posterior cingulate gyrus and between the right thalamus and right precentral gyrus) that differed between fatigued and non-fatigued patients, as well as correlated with cognitive fatigue severity. These findings suggest that disruption of sensorimotor, high-order motor, and non-motor executive function likely contributes to the neural mechanism of fatigue in MS. Knowledge of the neural mechanisms of underlying MS fatigue could inform more effective treatment strategies.

OBJECTIVE:/UNASSIGNED:Despite the potential benefits of mobile mental health apps, real-world results indicate engagement issues because of low uptake and sustained use. This review examined how studies have measured and reported on user engagement indicators (UEIs) for mental health apps. METHODS:/UNASSIGNED:A systematic review of multiple databases was performed in July 2018 for studies of mental health apps for depression, bipolar disorder, schizophrenia, and anxiety that reported on UEIs, namely usability, user satisfaction, acceptability, and feasibility. The subjective and objective criteria used to assess UEIs, among other data, were extracted from each study. RESULTS:/UNASSIGNED:Of 925 results, 40 studies were eligible. Every study reported positive results for the usability, satisfaction, acceptability, or feasibility of the app. Of the 40 studies, 36 (90%) employed 371 indistinct subjective criteria that were assessed with surveys, interviews, or both, and 23 studies used custom subjective scales, rather than preexisting standardized assessment tools. A total of 25 studies (63%) used objective criteria-with 71 indistinct measures. No two studies used the same combination of subjective or objective criteria to assess UEIs of the app. CONCLUSIONS:/UNASSIGNED:The high heterogeneity and use of custom criteria to assess mental health apps in terms of usability, user satisfaction, acceptability, or feasibility present a challenge for understanding real-world low uptake of these apps. Every study reviewed claimed that UEIs for the app were rated highly, which suggests a need for the field to focus on engagement by creating reporting standards and more carefully considering claims.

OBJECTIVE:/UNASSIGNED:To explore cognitive strategies clinicians apply while performing a medication reconciliation task, handling incomplete and conflicting information. BACKGROUND:/UNASSIGNED:Medication reconciliation is a method clinicians apply to find and resolve inconsistencies in patients' medications and medical conditions lists. The cognitive strategies clinicians use during reconciliation are unclear. Controlled lab experiments can explore how clinicians make sense of uncertain, missing, or conflicting information and therefore support the development of a human performance model. We hypothesize that clinicians apply varied cognitive strategies to handle this task and that profession and experience affect these strategies. METHOD:/UNASSIGNED:130 clinicians participated in a tablet-based experiment conducted in a large American teaching hospital. They were asked to simulate medication reconciliation using a card sorting task (CaST) to organize medication and medical condition lists of a specific clinical case. Later on, they were presented with new information and were asked to add it to their arrangements. We quantitatively and qualitatively analyzed the ways clinicians arranged patient information. RESULTS:/UNASSIGNED:Four distinct cognitive strategies were identified ("Conditions first": n = 76 clinicians, "Medications first": n = 7, "Crossover": n = 17, and "Alternating": n = 10). The strategy clinicians applied was affected by their experience ( p = .02) but not by their profession. At the appearance of new information, clinicians moved medication cards more frequently (75.2 movements vs. 49.6 movements, p < .001), suggesting that they match medications to medical conditions. CONCLUSION:/UNASSIGNED:Clinicians apply various cognitive strategies while reconciling medications and medical conditions. APPLICATION:/UNASSIGNED:Clinical information systems should support multiple cognitive strategies, allowing flexibility in organizing information.

Electrophysiological activity measured at the scalp surface using electroencephalography or magnetoencephalography (EEG or MEG) contains prominent ongoing rhythmic activity across a mixture of different frequency bands. This rhythmic oscillatory activity is present during both rest and task performance. The most visible rhythm in the adult human brain is in the band between approximately 8-12 Hz, and is referred to as alpha activity. While sometimes dismissed by neurophysiologists as a nuisance biological artefact, since it often interferes with the recording of event-related potentials (ERPs), there has been an explosion of research linking it to specific functional roles in cognition and behavior over the past two decades. Here, we review some of the research into the functional significance of alpha oscillations with respect to attention and expectation. We focus our discussion on how the amplitude and phase of alpha activity might be involved in the prioritization of relevant sensory input. In addition to summarizing the literature, we also endeavor to provide a critical appraisal as well as highlight limitations and conceptual gaps in the field.

PRIMARY OBJECTIVE/OBJECTIVE:To examine the efficacy of heart rate variability biofeedback (HRV-BF) to treat emotional dysregulation in persons with acquired brain injury. DESIGN/METHODS:A secondary analysis of a quasi-experimental study which enrolled 13 individuals with severe chronic acquired brain injury participating in a community-based programme. Response-to-treatment was measured with two HRV resonance indices (low frequency activity [LF] and low frequency/high frequency ratio [LF/HF]). MAIN OUTCOME/RESULTS:Behavior Rating Inventory of Executive Function-informant report (emotional control subscale [EC]). RESULTS:Results show significant correlation between LF and EC with higher LF activity associated with greater emotional control; the association between LF/HF pre-post-change score and EC is not statistically significant. A moderation model, however, demonstrates a significant influence of attention on the relation between LF/HF change and EC when attention level is high, with an increase in LF/HF activity associated with greater emotional control. CONCLUSIONS:HRV-BF is associated with large increases in HRV, and it appears to be useful for the treatment of emotional dysregulation in individuals with severe acquired brain injury. Attention training may enhance an individual's emotional control.