Faculty Bibliography

PURPOSE/OBJECTIVE:Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy (HSAN-3) that is clinically characterized by impaired pain and temperature perception and abnormal autonomic function. Patients with FD have gastrointestinal dysmotility and report a range of gastrointestinal symptoms that have yet to be systematically evaluated. The aim of this study was to establish the frequency and severity of gastrointestinal symptoms in patients with FD. METHODS:The validated National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) survey questionnaire, together with additional FD-specific questions, were distributed to 202 living patients with genetically confirmed FD who had been identified from the New York University FD Patient Registry or, when relevant, to their respective caretaker. As a comparison group, we used a general US adult population for whom PROMIS scores were available (N = 71,812). RESULTS:Of the 202 questionnaires distributed, 77 (38%) were returned, of which 53% were completed by the patient. Median age of the respondents was 25 years, and 44% were male. Gastrostomy tube was the sole nutrition route for 25% of the patients, while 53% were reliant on the gastrostomy tube only for liquid intake. The prevalence of gastrointestinal symptoms was significantly higher in each of the eight domains of PROMIS in patients with FD than in the controls. Gastrointestinal symptoms as measured by raw scores on the PROMIS scale were significantly less severe in the FD patient group than in the control population in all domains with the exception of the abdominal pain domain. The surveys completed by caregivers reported the same burden of symptoms as those completed only by patients. CONCLUSION/CONCLUSIONS:Gastrointestinal symptoms affect nearly all patients with FD. Gastrointestinal symptoms are more prevalent in adult patients with FD than in the average US adult population but are less severe in the former.

Neurogenic orthostatic hypotension (nOH) is one of the most debilitating nonmotor symptoms in patients with Parkinson disease and other synucleinopathies. Patients with Parkinson disease and nOH suffer from more hospitalizations, emergency room visits, more telephone calls and e-mails to providers, and have a significantly shorter survival compared to patients with Parkinson disease and no nOH. Overall, health-related costs in patients with Parkinson disease and OH are 2.5-fold higher compared to patients with Parkinson disease without OH. Therefore, the development of effective therapies for patients with Parkinson disease and nOH should be a research priority. In recent years, better understanding of the pathophysiology of nOH has resulted in the identification of novel therapeutic targets and the development and approval of effective drug therapies, such as midodrine and droxidopa. We here review the design and endpoint selection for clinical trials of nOH in patients with Parkinson disease and other synucleinopathies, recapitulate the results of completed and ongoing clinical trials for nOH, and discuss common challenges and their potential remedies.
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Background: Inadequate norepinephrine (NE) release in neurogenic orthostatic hypotension (nOH) causes blood pressure to fall on standing and debilitating symptoms of cerebral hypoperfusion. Ampreloxetine, a novel, long-acting NE reuptake inhibitor, potentiates the effects of endogenous NE, and may improve symptoms of nOH. The objective of the study was to explore the durability of effect and safety of once-daily oral ampreloxetine for the symptomatic treatment of nOH in subjects with synucleinopathies.
Method(s): In an open-label, phase 2, exploratory, multicenter study, subjects received open-label ampreloxetine (3-20 mg) 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 and Orthostatic Hypotension Daily Activities Scale (OHDAS) composite scores, and Patient Global Impression of Severity (PGI-S).
Result(s): Seventeen symptomatic subjects (baseline OHSA#1 score >4) were enrolled (mean age, 65 years). At Week 4, mean (SD) improvement on OHSA#1 was -3.8 (3.1) points; approximately 77% of subjects reported >=1-point improvement (minimal clinically important difference). At Week 20, mean improvement was -3.1 (3.0) points; approximately 86% reported >=1-point improvement. Symptom improvement was observed as early as Week 1 and was sustained throughout the study. Deterioration to baseline symptom severity was after ampreloxetine withdrawal. Similar trends were seen in OHSA and OHDAS composite scores, and PGI-S. Most common adverse events were urinary tract infection (24%), hypertension (19%), and headache (14%), with no study-drug related serious adverse events.
Conclusion(s): Ampreloxetine showed durable symptom improvement in symptomatic subjects with nOH over 20 weeks, with return to baseline symptom severity after ampreloxetine withdrawal. Ampreloxetine was well tolerated with a favorable safety profile. These encouraging open-label findings are being evaluated further in ongoing Phase 3, double-blind, confirmatory studies in subjects with nOH and synucleinopathies.
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Background: To assess acute clinical effects and safety of single-dose oral ampreloxetine, a novel, long-acting, selective norepinephrine reuptake inhibitor in subjects with neurogenic orthostatic hypotension (nOH).
Method(s): In a 5-day dosing study, subjects received placebo on Day 1, followed by ascending doses of ampreloxetine (range:1-20 mg). A subset of subjects were randomized to placebo or ampreloxetine in a 1-day double-blind study. Assessments included change in seated and standing systolic blood pressure (SBP), and Orthostatic Hypotension Symptom Assessment-Item 1 (OHSA#1; dizziness, lightheadedness, feeling faint).
Result(s): Of 34 subjects (mean age, 66 years), 15 and 13 subjects received ampreloxetine 10 and 20 mg, respectively, as maximum tolerated dose. Ampreloxetine 10 mg showed the most consistent response for increase in seated SBP relative to placebo (mean [SD] change in seated SBP 4.9 [20.1] mmHg more than placebo 4 hours post-dose). In the double-blind study (ampreloxetine, n=5 [median dose, 10 mg]; placebo, n=5), relative to placebo, for the ampreloxetine treatment group, increase in seated (mean difference from placebo, 29.9 mmHg at 4 hours post-dose; p < 0.05) and 3-minute standing SBP (mean difference, 35.0 mmHg at 4 hours post-dose) was more pronounced for the ampreloxetine treatment group to 9 hours and 10 hours post-dose, respectively, and 3-minute standing SBP was more pronounced for subjects randomized to ampreloxetine up to 10 hours post-dose. Twice as many subjects in the ampreloxetine treatment arm reported symptom improvement on OHSA#1. Most common adverse events were headache and urinary tract infection, with no serious events.
Conclusion(s): In subjects with nOH, 10 mg ampreloxetine produced a consistent increase in seated SBP relative to placebo. Compared to placebo, ampreloxetine showed greater increase in seated and standing SBP up to 10 hours post-dose, and greater symptom improvement. Ampreloxetine was well tolerated. These results support assessment of longer-term effects of ampreloxetine in nOH.
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Background: In neurogenic orthostatic hypotension (nOH), blood pressure (BP) falls due to inadequate norepinephrine (NE) release when upright. Ampreloxetine, a novel, long-acting NE reuptake inhibitor, potentiates effects of endogenous NE and has shown durable symptom improvement in subjects with nOH associated with synucleinopathies. The objective of this study was to evaluate measures of BP regulation in subjects with symptomatic nOH treated with open-label ampreloxetine.
Method(s): In a phase 2, multicenter, exploratory study, subjects received ampreloxetine once-daily (3-20 mg) for up to 20 weeks, with 4-week follow-up after ampreloxetine withdrawal and restarting other pressor agents. Assessments included Orthostatic Hypotension Symptom Assessment Item 1 score (OHSA#1; dizziness, lightheadedness, feeling faint); standing, sitting, and supine systolic BP (SBP); standing duration; and plasma NE.
Result(s): Seventeen symptomatic subjects (baseline OHSA#1 score >4) were enrolled (mean age, 65 years). Standing and sitting SBP, standing duration, plasma NE, and symptoms improved from Weeks 1 to 20. Mean increase in 3-minute standing SBP from baseline was 9.0 mmHg at Week 4 and 10.8 mmHg at Week 20; >50% of subjects maintained SBP >80 mmHg. Sitting SBP changes were less, with little change in supine SBP. At Week 4, 67% of subjects could stand for >5 mins, 31% improvement from baseline. NE plasma levels rose from pre-dose to Week 4 (1664.93-2231.67 pmol/l). After ampreloxetine withdrawal and restarting other pressor agents, standing SBP remained increased; however, nOH symptoms deteriorated to baseline. Ampreloxetine was well tolerated.
Conclusion(s): Ampreloxetine has previously demonstrated durable symptom improvement in nOH. Symptom improvement was accompanied by increase in standing and sitting SBP, standing duration, and NE plasma levels, with little effect on supine SBP. These encouraging findings are being evaluated further in ongoing Phase 3, double-blind, confirmatory studies in subjects with nOH and synucleinopathies.
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Objective: To confirm: 1) clinical efficacy and safety of once-daily oral ampreloxetine in a 4-week double-blind (

Objective: To develop a clinical score to distinguish between the parkinsonian variant of multiple system atrophy (MSA-P) and Parkinson's disease (PD).
Background(s): The differential diagnosis between MSA-P and PD is often difficult, particularly early in the disease course.
Method(s): We compared patients with probable MSA-P and with PD with a disease duration of <3 years, selected from those who were enrolled in the Natural History Study of the Synucleinopathies, an international prospective observational study. Detailed clinical neurological, and autonomic parameters were assessed at enrollment using UMSARS part I, II and IV; Schrag quality of life (QoL) scale; burden of autonomic dysfunction by COMPASS-31 scale; smell function using the UPSIT; cardiovascular autonomic function using heart rate variability during deep-breathing, analysis of the Valsalva maneuver, orthostatic stress test, plasma catecholamine levels during supine rest and after head-up tilt; and cognitive evaluation using MoCA. Positive and negative likelihood ratios (LR) were obtained for each variable assessed. Multiple iterations of a composite score based on sequential addition of variables with the highest diagnostic accuracy were created by multiplying each variable's LR and applying a logarithmic function.
Result(s): Fifty-eight MSA-P and 53 PD patients had a disease duration of less than 3 years. The vast majority of patients had been diagnosed within the last 12 months (81% MSA-P and 66% PD patients). MSA-P patients were more frequently female (53% vs. 30% p<0.05) and younger at diagnosis (63+/-8 years vs. 71+/-8 years, p<0.001). A 7-item score comprising the bladder weighted subscore of the COMPASS-31, UMSARS's part 1, UPSIT, hyperreflexia, the motor subscore of Schrag's MSA quality of life scale, falls within 3 years of diagnosis, and new or increased snoring resulted in a ROC curve AUC of 0.983, with excellent 93% sensitivity and 98% specificity to distinguish early MSA-P from PD.
Conclusion(s): We propose a scale of 7 clinical items to distinguish early stage MSA-P from PD. It considers urinary function, olfactory function, corticospinal signs, performance of activities of daily living, motor symptoms burden on quality of life, frequent early falls and sleep disordered breathing. We are now prospectively validating the scale to determine its predictive value in our prodromal cohort. (Figure Presented)

Objective: To study the rate of progression of multiple system atrophy (MSA) and assess for a potential ceiling effect of the Unified Multiple System Atrophy Rating Scale (UMSARS).
Background(s): Disease progression of MSA as measured by UMSARS varied significantly in natural history studies. Reported 1-year UMSARS-1 and UMSARS-2 progression rates ranged from 3.9 to 6.5 and 3.5 to 8.2 respectively. We hypothesize that this variability is due, at least in part, to differences in severity at enrollment and a potential ceiling effect in the scale, so that patients in more advanced stages may appear to worsen less, which would have important implications for clinical trial design.
Method(s): We analyzed the rate of change in the UMSARS in a large international cohort of well-characterized patients with a clinical diagnosis of possible or probable MSA enrolled in the Natural History Study of Synucleinopathies. Annualized progression rates were obtained using 2-year follow-up data.
Result(s): Three hundred and forty nine patients (61.4+/-7.9 years old) with MSA were enrolled. Disease duration was 4.5+/-5.1 years. 143 patients completed 1-year evaluations and 61 completed the 2-year evaluation. The 12-month progression rates were 5.4+/-5.1 for the UMSARS-I, 5.9+/-5.3 for the UMSARS-II, and 11.8+/-9.6 for the total score. The 24-month progression rates were 10.8+/-7.3 for the UMSARS-I, 12.2+/-7.9 for the UMSARSII, and 22.6+/-13.7 for the total score. Annualized progression rates were divided according to their baseline UMSARS-I and UMSARS II. There was a significant (p = 0.0153) inverse relationship between rate of progression and UMSARS-I at baseline. A similar, but not significant trend was observed with UMSARS-II at baseline.
Conclusion(s): The rate of progression as measured by UMSARS is influenced by the baseline disease severity. A possible ceiling effect should be considered when planning enrollment, power calculations, and outcome measures in clinical trials

Von Economo neurons (VENs) and fork cells are principally located in the anterior cingulate cortex (ACC) and the frontoinsular cortex (FI). Both of these regions integrate inputs from the autonomic nervous system (ANS) and are involved in decision-making and perception of the emotional states of self and others. Familial dysautonomia (FD) is an orphan disorder characterized by autonomic dysfunction and behavioral abnormalities including repetitive behavior and emotional rigidity, which are also seen in autism spectrum disorder. To understand a possible link between the ANS and the cortical regions implicated in emotion regulation we studied VENs and fork cells in an autonomic disorder. We determined the densities of VENs, fork cells, and pyramidal neurons and the ratio of VENs and fork cells to pyramidal neurons in ACC and FI in 4 FD patient and 6 matched control brains using a stereologic approach. We identified alterations in densities of VENs and pyramidal neurons and their distributions in the ACC and FI in FD brains. These data suggest that alterations in migration and numbers of VENs may be involved in FD pathophysiology thereby supporting the notion of a functional link between VENs, the ANS and the peripheral nervous system in general.