Faculty Bibliography

Huntington disease, a neurodegenerative disease characterized by progressive motor, behavioral, and cognitive decline, is caused by a CAG trinucleotide repeat expansion in the huntingtin gene on chromosome 4. Current treatments target symptom management because there are no disease-modifying therapies at this time. Investigation of RNA-based and DNA-based treatment strategies are emerging and hold promise of possible future disease-modifying therapy.

Children with cleft and craniofacial conditions commonly present with concurrent airway anomalies, which often manifest as sleep disordered breathing. Craniofacial surgeons and members of the multidisciplinary team involved in the care of these patients should appreciate and understand the scope of airway pathology as well as the proper means of airway assessment. This review article details the prevalence and assessment of sleep disordered breathing in patients with craniofacial anomalies, with emphasis on indications, limitations, and interpretation of polysomnography.

Background and aims: Dementia is considered a nonsupportive diagnostic feature for multiple system atrophy (MSA). Nevertheless, post-mortem verified dementia with Lewy bodies and Parkinson's disease masquerade as MSA. Cognitive impairment (CI), especially executive dysfunction, may occur in MSA patients. It is, however, unclear whether CI manifests in early disease stages.
Objective(s): To compare the prevalence of CI in MSA versus other Lewy Body disorders (LBD), including dementia with Lewy bodies and Parkinson's disease, in early (<3 years from symptom onset) versus more advanced disease stages (>=3 years from symptom onset).
Method(s): A total of 364 patients (LBD: n=83; MSA: n=281) of the natural history study of synucleinopathies register have been analysed. Consensus diagnostic criteria for dementia with Lewy bodies, Parkinson's disease and MSA were applied. To assess CI, the Montreal Cognitive Assessment (MoCA) has been used.
Result(s): In early disease stages, median MoCA scores did not differ significantly between MSA and LBD. In advanced disease stages, MSA patients had a significantly higher median MoCA score compared to LBD patients (27 versus 25, p=0.006). Comparison of the median MoCA Scores of LBD versus MSA patients at early and advanced disease stages
Conclusion(s): In patients with longer disease duration severity of CI helps to differentiate LBD from MSA

OBJECTIVE:To outline strategies for the treatment of migraine which do not require in-person visits to clinic or the emergency department, and to describe ways that health insurance companies can remove barriers to quality care for migraine. BACKGROUND:COVID-19 is a global pandemic causing widespread infections and death. To control the spread of infection we are called to observe "social distancing" and we have been asked to postpone any procedures which are not essential. Since procedural therapies are a mainstay of headache care, the inability to do procedures could negatively affect our patients with migraine. In this manuscript we review alternative therapies, with particular attention to those which may be contra-indicated in the setting of COVID-19 infection. DESIGN/RESULTS/UNASSIGNED:The manuscript reviews the use of telemedicine visits and acute, bridge, and preventive therapies for migraine. We focus on evidence-based treatment where possible, but also describe "real world" strategies which may be tried. In each section we call out areas where changes to rules from commercial health insurance companies would facilitate better migraine care. CONCLUSIONS:Our common goal as health care providers is to maximize the health and safety of our patients. Successful management of migraine with avoidance of in-person clinic and emergency department visits further benefits the current urgent societal goal of maintaining social distance to contain the COVID-19 pandemic.

BACKGROUND:Optical coherence tomography (OCT) studies have demonstrated differences between people with schizophrenia and controls. Many questions remain including the agreement between scanners. The current study seeks to determine inter-device agreement of OCT data in schizophrenia compared to controls and to explore the relations between OCT and visual function measures. METHODS:Participants in this pilot study were 12 individuals with schizophrenia spectrum disorders and 12 age- and sex-matched controls. Spectralis and Cirrus OCT machines were used to obtain retinal nerve fiber layer (RNFL) thickness and macular volume. Cirrus was used to obtain ganglion cell layer + inner plexiform layer (GCL + IPL) thickness. Visual function was assessed with low-contrast visual acuity and the King-Devick test of rapid number naming. RESULTS:There was excellent relative agreement in OCT measurements between the two machines, but poor absolute agreement, for both patients and controls. On both machines, people with schizophrenia showed decreased macular volume but no difference in RNFL thickness compared to controls. No between-group difference in GCL + IPL thickness was found on Cirrus. Controls showed significant associations between King-Devick performance and RNFL thickness and macular volume, and between low-contrast visual acuity and GCL + IPL thickness. Patients did not show significant associations between OCT measurements and visual function. CONCLUSIONS:Good relative agreement suggests that the offset between machines remains constant and should not affect comparisons between groups. Decreased macular volume in individuals with schizophrenia on both machines supports findings of prior studies and provides further evidence that similar results may be found irrespective of OCT device.

Background and aims: Inadequate norepinephrine (NE) release in neurogenic orthostatic hypotension (nOH) causes fall in standing blood pressure. Ampreloxetine, a novel, long-acting NE reuptake inhibitor may improve symptoms of nOH. The objective of this study was to explore durability of effect and safety of once-daily oral ampreloxetine for symptomatic treatment of nOH.
Method(s): In an open-label, phase 2, exploratory study, subjects received ampreloxetine (3-20mg) once-daily for up to 20 weeks, with 4-week follow-up after ampreloxetine withdrawal and restarting alternative pressor agents. Assessments included Orthostatic Hypotension Symptom Assessment Item 1 (OHSA#1; dizziness, lightheadedness, feeling faint), OHSA/Orthostatic Hypotension Daily Activities Scale (OHDAS) composite scores, and change in Patient Global Impression of Severity (PGI-S).
Result(s): Seventeen symptomatic subjects (baseline OHSA#1 score >4) were enrolled (mean age, 65 years). At Weeks 4 and 20, mean (SD) improvement on OHSA#1 was -3.8 (3.1) and -3.1 (3.0) point, and ~77% and ~86% of subjects reported >=1-point improvement, respectively. Improvement, seen as early as Week 1, was sustained throughout the study. Deterioration to baseline severity was observed after ampreloxetine withdrawal. Similar trends were seen in OHSA/OHDAS composite scores, and change in PGI-S. Most common adverse events (AEs) were urinary tract infection (24%), hypertension (19%) and headache (14%), with no study-drug-related serious AEs. Ampreloxetine showed durable symptom improvement over 20 weeks, with return to baseline severity after ampreloxetine withdrawal. Ampreloxetine was well tolerated.
Conclusion(s): These encouraging findings of durable symptom improvement with open-label ampreloxetine treatment are being evaluated in ongoing Phase 3, doubleblind, confirmatory studies in subjects with nOH

Blindness and vision impairment are unpredictable complications of tuberculous meningitis (TBM) that are often unrecognized in the acute stages of illness due to inability to assess vision in patients with depressed levels of consciousness or confusion. We present a patient with definite TBM confirmed by positive Xpert MTB/RIF assay of cerebrospinal fluid (CSF) who developed binocular blindness two weeks after diagnosis and initiation of standard anti-tuberculosis treatment (ATT). Ophthalmological exam demonstrated complete bilateral abducens nerve palsies, impaired pupillary responses to light, normal optic discs, and visual acuity of hand motion only in each eye. Brain CT showed progressive enlargement of the third and lateral ventricles. We managed the patient medically with dexamethasone, acetazolamide, and substitution of moxifloxacin for ethambutol. Serial brain CTs confirmed gradual resolution of hydrocephalus. The patient had complete neurological recovery at six months except for residual blindness in the right eye. Visual acuity in the left eye recovered to normal (20/20). The assessment and management of vision impairment in TBM is discussed.

OBJECTIVE:To establish cytometry profiles associated with disease stages and immunotherapy in MS. METHODS:Demographic/clinical data and peripheral blood samples were collected from 227 patients with MS and 82 sex- and age-matched healthy controls (HCs) enrolled in a cross-sectional study at 4 European MS centers (Spain, Italy, Germany, and Norway). Flow cytometry of isolated peripheral blood mononuclear cells was performed in each center using specifically prepared antibody-cocktail Lyotubes; data analysis was centralized at the Genoa center. Differences in immune cell subsets were assessed between groups of untreated patients with relapsing-remitting or progressive MS (RRMS or PMS) and HCs and between groups of patients with RRMS taking 6 commonly used disease-modifying drugs. RESULTS:T-regulatory and B-regulatory cells. CONCLUSIONS:Our highly standardized, multisite cytomics data provide further understanding of treatment impact on MS immunophenotype and could pave the way toward monitoring immune cells to help clinical management of MS individuals.

Objectives: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder that is characterized by selective degeneration of both upper and lower motor neurons, resulting in paralysis of skeletal muscle and respiratory failure, with death occurring within 2-5 years of diagnosis. 90% of cases are sporadic, and of the 10% that are familial more than 20 genes (>150 mutations) have been found to be associated with ALS, most notably copper/zinc superoxide dismutase (SOD1). SOD1 mutant proteins are believed to cause toxicities in degenerating neurons. Studies suggest that the neuronal and non-neuronal cell contributions to the onset and progression of ALS are complex. It was proposed that there are two phases of neuroinflammation in the spinal cord - the first being an early neuroprotective phase followed by a second late neurotoxic phase. One of the challenges in the study of neuroinflammation is that it is difficult to serially track the disease process, as there are no bona fide biomarkers for onset and progression in ALS. For this reason, we use PET with [¹¹C]PBR28 to track microglial neuroinflammation in the brain and spinal cord. We and others have shown that the receptor for advanced glycation end products (RAGE) is highly expressed in human ALS spinal cord, particularly in microglia, and to an increased degree compared to that of age-matched control subjects. Our previous studies with myeloid/microglia deletion of Ager and treatment with sRAGE (soluble RAGE) suggested that RAGE impairs survival and motor function in Sod1G93Amice. The ultimate goal is to test the hypothesis that RAGE inhibition in either initiation or progression phases of the ALS will prolong survival and maintain motor function in adult Sod1G93Amice.
Method(s): MicroPET/CT (Inveon, Siemens) with [¹¹C]PBR28 was used to track and compare microglial neuroinflammation in the brain and spinal cord of WT vs. ALS mice (110-120 day old), also after treatment with RAGE inhibitors (subject identity was blind to study investigator and data analyst). Using IRW (Inveon Research Workplace, Siemens), several ROIs in the thoracic and lumbar spinal cord (T13, L1, L2, L3) were drawn on the fused PET/CT images to obtain the regional SUVs. An automated atlasbased methodology using Firevoxel (https://urldefense.proofpoint.com/v2/url?u=https-3A__wp.nyu.edu_Firevoxel&d=DwIBAg&c=j5oPpO0eBH1iio48DtsedeElZfc04rx3ExJHeIIZuCs&r=CY_mkeBghQnUPnp2mckgsNSbUXISJaiBQUhM-Uz9W58&m=_uGsTvUTTD_GxqvwK245ZUiiSbzVraIboytFijFDOwU&s=RlC-AQtmqr84rzBwvDmgK_FCVdvbCfsFvuN-dVODTpM&e= ) that we previously developed was used for brain mapping and segmentation to derive regional timeactivity curves (TAC) and SUVs for 20 brain regions.
Result(s): Dynamic regional SUV [¹¹C]PBR28 binding data were obtained and averaged SUVs derived from the last 5 frames (with steady and less variable intensity levels) were compared. Results derived from both spinal cord and brain regions displayed a similar trend with two obvious clusters. Reduced binding was observed for ALS group as compared to WT. RAGE inhibitor-treated ALS mi ce showed increased binding (brain SUV avg. 0.402+/-0.0382 over 20 ROIs) as compared to vehicle-treated (0.157+/-0.0339), suggesting that RAGE inhibition may contribute to the restoration of homeostasis in ALS animals (i.e., their bindings after treatment were closer to those in WT (0.485+/-0.171)). Notably, hypothalamus, brain stem, and olfactory bulb consistently exhibited higher binding, suggesting their role in this regulation.
Conclusion(s): Inconsistent outcomes have been reported in the literature when comparing TSPO ligand binding for imaging neuroinflammation. Our data are consistent with findings from several recent studies; i.e., reduced PBR28 binding was associated with disease state (e.g., in patients with PTSD or alcoholism). A notion that the reduced binding might reflect competition from endogenous TSPO ligands such as cholesterol can't be excluded. The strategies described here will test the hypothesis that pharmacological antagonism of RAGE signal transduction in either initiation or progression phases of the ALS will prolong survival and maintain motor function in adult Sod1G93Amice