Faculty Bibliography

We previously reported a pathogenic de novo p.R342W mutation in the transcriptional corepressor CTBP1 in four independent patients with neurodevelopmental disabilities [1]. Here, we report the clinical phenotypes of seven additional individuals with the same recurrent de novo CTBP1 mutation. Within this cohort, we identified consistent CtBP1-related phenotypes of intellectual disability, ataxia, hypotonia, and tooth enamel defects present in most patients. The R342W mutation in CtBP1 is located within a region implicated in a high affinity-binding cleft for CtBP-interacting proteins. Unbiased proteomic analysis demonstrated reduced interaction of several chromatin-modifying factors with the CtBP1 W342 mutant. Genome-wide transcriptome analysis in human glioblastoma cell lines expressing -CtBP1 R342 (wt) or W342 mutation revealed changes in the expression profiles of genes controlling multiple cellular processes. Patient-derived dermal fibroblasts were found to be more sensitive to apoptosis during acute glucose deprivation compared to controls. Glucose deprivation strongly activated the BH3-only pro-apoptotic gene NOXA, suggesting a link between enhanced cell death and NOXA expression in patient fibroblasts. Our results suggest that context-dependent relief of transcriptional repression of the CtBP1 mutant W342 allele may contribute to deregulation of apoptosis in target tissues of patients leading to neurodevelopmental phenotypes.

INTRODUCTION/BACKGROUND:C-PBR28. METHODS:for both tracers. RESULTS:C-PBR28 for high-affinity binders, and more than 9 times larger for mixed-affinity binders. CONCLUSION/CONCLUSIONS:C-ER176 are expected to have higher statistical power and thus require fewer subjects.

PURPOSE/OBJECTIVE:Familial dysautonomia (FD) is a rare autosomal recessive disease that affects the development of sensory and autonomic neurons, including those in the cranial nerves. We aimed to determine whether conventional brain magnetic resonance imaging (MRI) could detect morphologic changes in the trigeminal nerves of these patients. METHODS:Cross-sectional analysis of brain MRI of patients with genetically confirmed FD and age- and sex-matched controls. High-resolution 3D gradient-echo T1-weighted sequences were used to obtain measurements of the cisternal segment of the trigeminal nerves. Measurements were obtained using a two-reader consensus. RESULTS:in controls (P < 0.001). No association between trigeminal nerve area and age was found in patients or controls. CONCLUSIONS:Using conventional MRI, the caliber of the trigeminal nerves was significantly reduced bilaterally in patients with FD compared to controls, a finding that appears to be highly characteristic of this disorder. The lack of correlation between age and trigeminal nerve size supports arrested neuronal development rather than progressive atrophy.

The precise modulation of regional cerebral blood flow during neural activation is important for matching local energetic demand and supply and clearing brain metabolites. Here we discuss advances facilitated by high-resolution optical in vivo imaging techniques that for the first time have provided direct visualization of capillary blood flow and its modulation by neural activity. We focus primarily on studies of microvascular flow, mural cell control of vessel diameter, and oxygen level-dependent changes in red blood cell deformability. We also suggest methodological standards for best practices when studying microvascular perfusion, partly motivated by recent controversies about the precise location within the microvascular tree where neurovascular coupling is initiated, and the role of mural cells in the control of vasomotility.

The claustrum is a thin grey matter structure which is involved in a wide brain network. Previous studies suggested a link between claustrum and Parkinson's Disease (PD), showing how α-synuclein pathology may affect claustral neurons as well as how α-synuclein immunoreactivity may correlate with the onset of cognitive dysfunctions. Our aim is to investigate, via diffusion MRI, claustral structural network changes in drug naïve PD patients, with the goal to understand whether such changes may contribute to cognitive decline in PD. 15 drug naïve PD patients and 15 age-matched controls were enrolled; MR protocol was performed on a 3T scanner. Whole brain probabilistic tractography was obtained using Constrained Spherical Deconvolution (CSD) diffusion model. Connectivity matrices were estimated based on a robust anatomical parcellation of structural T1w images. In PD group, impaired subnetworks were correlated with psychological examinations. We found decreased claustral connectivity in PD patients compared to controls, especially with areas mainly involved in visuomotor and attentional systems. Moreover, we found a positive correlation between MoCA and density of pathways connecting ipsilaterally claustrum to left (r = 0.578, p = 0.021) and right (r = 0.640, p = 0.020) Pars Orbitalis. Our results support the hypothesis of claustral involvement in cognitive decline in drug naïve PD patients.

Background: Stroke code activations are a valuable tool in providing prompt care to stroke patients who may be eligible for treatments such as tPA and endovascular interventions. However, stroke codes involve the immediate attention of many members of the healthcare team and significant hospital resources. The National Institutes of Health Stroke Scale (NIHSS) is commonly used to evaluate stroke severity; however, even patients with an NIHSS score of zero can have ongoing neurologic symptoms and disability. Confusion over the goals of stroke codes and the appropriate situations for their use may contribute to unnecessary activations.
Objective(s): The purpose of this analysis was to evaluate the frequency of stroke code activations in situations where activating a stroke code provides little potential benefit in terms of therapeutic options over a non-emergent neurology consult.
Method(s): We reviewed the records for all emergency department (ED) stroke code activations over the first five months of 2018, looking specifically at cases with an NIHSS score of zero. Within this pool, we identified cases where the patient was documented as being asymptomatic during initial ED evaluation as their symptoms had resolved (transient ischemic attack), as well as those who had been symptomatic for over 24 hours and were outside the therapeutic window. These patients were not eligible for emergent therapeutic intervention. Thus, these were cases in which a stroke code activation was avoidable.
Result(s): Of the 120 stroke codes with an NIHSS of zero, 39 (32.5%) involved patients whose symptoms had completely resolved prior to arrival. Another three cases involved patients who had been symptomatic for over 24 hours and were outside the therapeutic window. Thus, of the stroke code activations with an NIHSS of zero in this time period, 42 (35%) were avoidable as these patients would not have been considered candidates for emergent treatment.
Conclusion(s): Clarification and reinforcement of appropriate criteria for stroke code activation have the potential to reduce overutilization of resources in situations unlikely to affect acute therapeutic management. Addressing this would allow for a reduction in the burden on healthcare professionals and ED resources

BACKGROUND:Pathological and genetic evidence implicates toxic effects of aggregated α-synuclein in the pathophysiology of neuronal dysfunction and degeneration in Parkinson's disease. Immunotherapy targeting aggregated α-synuclein is a promising strategy for delaying disease progression. OBJECTIVE:This study (NCT02459886) evaluated the safety, tolerability, and pharmacokinetics of BIIB054, a human-derived monoclonal antibody that preferentially binds to aggregated α-synuclein, in healthy volunteers and participants with Parkinson's disease. METHODS:A total of 48 healthy volunteers (age 40-65, 19 women) and 18 Parkinson's disease participants (age 47-75, 5 women, Hoehn and Yahr stage ≤2.5) were in the study. Volunteers were enrolled into 6 single-dose cohorts of BIIB054 (range 1-135 mg/kg) or placebo, administered intravenously; Parkinson's disease participants received a single dose of BIIB054 (15 or 45 mg/kg) or placebo. All participants were evaluated for 16 weeks with clinical, neuroimaging, electrocardiogram, and laboratory assessments. Serum and cerebrospinal fluid BIIB054 concentrations were measured. BIIB054/α-synuclein complexes were measured in plasma. RESULTS:Most adverse events were mild and assessed by investigators as unrelated to the study drug. Pharmacokinetic parameters for volunteers and the Parkinson's disease participants were similar. BIIB054 serum exposure and maximum concentrations were dose proportional during the dose range studied. In volunteers and the Parkinson's disease participants, the serum half-life of BIIB054 was 28 to 35 days; the cerebrospinal fluid-to-serum ratio ranged from 0.13% to 0.56%. The presence of BIIB054/α-synuclein complexes in plasma was confirmed; all Parkinson's disease participants showed almost complete saturation of the BIIB054/α-synuclein complex formation. CONCLUSIONS:BIIB054 has favorable safety, tolerability, and pharmacokinetic profiles in volunteers and Parkinson's disease participants, supporting further clinical development. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Tick-borne infections-including tick-borne encephalitis viruses, represented in the United States by rare infections with Powassan and deer tick viruses, and more often Lyme disease-are of increasing importance to neurologists. Lyme neuroborreliosis (LNB) causes all or part of a triad including meningitis, radiculoneuritis, and cranial neuritis. Rarely, parenchymal brain and spinal cord involvement occur, with focal findings on examination and magnetic resonance imaging (MRI). LNB diagnosis requires plausible exposure, objective evidence of nervous system involvement, and, generally, positive two-tier serology. Central nervous system (CNS) LNB is almost always accompanied by abnormal cerebrospinal fluid (CSF) (cells, protein), often with intrathecal antibody production, which is determined by concentration-adjusted comparison of serum and CSF antibody. Measuring CSF antibody in isolation and nucleic acid-based testing of CSF are not useful in LNB and should be avoided. LNB treatment is highly effective with a 2- to 3-week course of antibiotics. Increasing evidence suggests that LNB not involving the CNS parenchyma can be treated successfully with oral doxycycline.

: Supine hypertension commonly occurs in patients with neurogenic orthostatic hypotension due to autonomic failure. Supine hypertension promotes nocturnal sodium excretion and orthostatic hypotension, thus, interfering with quality of life. Perusal of the literature on essential hypertension and smaller scale investigations in autonomic failure patients also suggest that supine hypertension may predispose to cardiovascular and renal disease. These reasons provide a rationale for treating supine hypertension. Yet, treatment of supine hypertension, be it through nonpharmacological or pharmacological approaches, may exacerbate orthostatic hypotension when patients get up during the night. Fall-related complications may occur. More research is needed to define the magnitude of the deleterious effects of supine hypertension on cardiovascular, cerebrovascular, and renal morbidity and mortality. Integration of more precise cardiovascular risk assessment, efficacy, and safety data, and the prognosis of the underlying condition causing autonomic failure is required for individualized management recommendations.