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Safety and efficacy of ampreloxetine in symptomatic neurogenic orthostatic hypotension: a phase 2 trial

Kaufmann, Horacio; Vickery, Ross; Wang, Whedy; Kanodia, Jitendra; Shibao, Cyndya A; Norcliffe-Kaufmann, Lucy; Haumann, Brett; Biaggioni, Italo
PURPOSE/OBJECTIVE:In neurogenic orthostatic hypotension, blood pressure falls when upright owing to impaired release of norepinephrine, leading to dizziness. Ampreloxetine, a selective norepinephrine reuptake inhibitor, increases circulating norepinephrine levels. This study explored the safety of ampreloxetine and its effect on blood pressure and symptoms in patients with neurogenic orthostatic hypotension. METHODS:A multicenter ascending-dose trial (range 1-20 mg, Part A) was followed by a 1 day, double-blind, randomized, placebo-controlled study (median dose 15 mg, Part B). Eligible patients then enrolled in a 20-week, open-label, steady-state extension phase (median dose 10 mg, Part C) followed by a 4-week withdrawal. Assessments included the Orthostatic Hypotension Symptom Assessment Scale (item 1), supine/seated/standing blood pressure, and safety. RESULTS:Thirty-four patients (age 66 ± 8 years, 22 men) were enrolled. Part A: The proportion of participants with a positive response (i.e., increase from baseline in seated systolic blood pressure of ≥ 10 mmHg) was greater with the 5 and 10 mg ampreloxetine doses than with placebo or other active ampreloxetine doses. Part B: Seated blood pressure increased 15.7 mmHg 4 h after ampreloxetine and decreased 14.2 mmHg after placebo [least squares mean difference (95% CI) 29.9 mmHg (7.6-52.3); P = 0.0112]. Part C: Symptoms of dizziness/lightheadedness improved 3.1 ± 3.0 points from baseline and standing systolic blood pressure increased 11 ± 12 mmHg. After 4 weeks of withdrawal, symptoms returned to pretreatment levels. The effect of ampreloxetine on supine blood pressure was minimal throughout treatment duration. CONCLUSION/CONCLUSIONS:Ampreloxetine was well tolerated and improved orthostatic symptoms and seated/standing blood pressure with little change in supine blood pressure. TRIAL REGISTRATION/BACKGROUND:NCT02705755 (first posted March 10, 2016).
PMID: 34657222
ISSN: 1619-1560
CID: 5043052

Longitudinal changes in the macula and optic nerve in familial dysautonomia

Kfir, Jonathan; Wu, Mengfei; Liu, Mengling; Raju, Leela; Schuman, Joel S; Ishikawa, Hiroshi; Vanegas, Isabel M; Mendoza-Santiesteban, Carlos E; Palma, Jose-Alberto; Norcliffe-Kaufmann, Lucy; Morgenstein, Barr; Kaufmann, Horacio; Wollstein, Gadi
OBJECTIVE:Familial Dysautonomia (FD) disease, lacks a useful biomarker for clinical monitoring. In this longitudinal study we characterized the structural changes in the macula, peripapillary and the optic nerve head (ONH) regions in subjects with FD. METHODS:Data was consecutively collected from subjects attending the FD clinic between 2012 and 2019. All subjects were imaged with spectral-domain Optical Coherence Tomography (OCT). Global and sectoral measurements of mean retinal nerve fiber layer (RNFL) and macular ganglion cell and inner plexiform layer (GCIPL) thickness, and ONH parameters of rim area, average cup-to-disc (C:D) ratio, and cup volume were used for the analysis. The best fit models (linear, quadratic and broken stick linear model) were used to describe the longitudinal change in each of the parameters. RESULTS:91 subjects (149 eyes) with FD of ages 5-56 years were included in the analysis. The rate of change for average RNFL and average GCIPL thicknesses were significant before reaching a plateau at the age of 26.2 for RNFL and 24.8 for GCIPL (- 0.861 µm/year (95% CI - 1.026, - 0.693) and - 0.553 µm/year (95% CI - 0.645, - 0.461), respectively). Significant linear rate of progression was noted for all ONH parameters, except for a subset of subjects (24%), with no cupping that did not show progression in any of the ONH parameters. CONCLUSIONS:The rapidly declining RNFL and GCIPL can explain the progressive visual impairment previously reported in these subjects. Among all structural parameters, ONH parameters might be most suitable for longitudinal follow-up, in eyes with a measurable cup.
PMID: 33180192
ISSN: 1432-1459
CID: 4663032

Correction to: Longitudinal changes in the macula and optic nerve in familial dysautonomia

Kfir, Jonathan; Wu, Mengfei; Liu, Mengling; Raju, Leela; Schuman, Joel S; Ishikawa, Hiroshi; Vanegas, M Isabel; Mendoza-Santiesteban, Carlos E; Palma, Jose-Alberto; Norcliffe-Kaufmann, Lucy; Morgenstein, Barr; Kaufmann, Horacio; Wollstein, Gadi
PMID: 33388930
ISSN: 1432-1459
CID: 4738402

Limitations of the Unified Multiple System Atrophy Rating Scale as outcome measure for clinical trials and a roadmap for improvement

Palma, Jose-Alberto; Vernetti, Patricio Millar; Perez, Miguel A; Krismer, Florian; Seppi, Klaus; Fanciulli, Alessandra; Singer, Wolfgang; Low, Phillip; Biaggioni, Italo; Norcliffe-Kaufmann, Lucy; Pellecchia, Maria Teresa; Martí, Maria José; Kim, Han-Joon; Merello, Marcelo; Stankovic, Iva; Poewe, Werner; Betensky, Rebecca; Wenning, Gregor; Kaufmann, Horacio
PURPOSE/OBJECTIVE:The unified multiple system atrophy (MSA) rating scale (UMSARS) was developed almost 20 years ago as a clinical rating scale to capture multiple aspects of the disease. With its widespread use, the shortcomings of the UMSARS as a clinical outcome assessment (COA) have become increasingly apparent. We here summarize the shortcomings of the scale, confirm some of its limitations with data from the Natural History Study of the Synucleinopathies (NHSS), and suggest a framework to develop and validate an improved COA to be used in future clinical trials of disease-modifying drugs in patients with MSA. METHODS:Expert consensus assessment of the limitations of the UMSARS and recommendations for the development and validation of a novel COA for MSA. We used UMSARS data from the ongoing NHSS ( NCT01799915) to showcase some of these limitations. RESULTS:The UMSARS in general, and specific items in particular, have limitations to detect change resulting in a ceiling effect. Some items have specific limitations including unclear anchoring descriptions, lack of correlation with disease severity, susceptibility to improve with symptomatic therapies (e.g., orthostatic hypotension, constipation, and bladder dysfunction), and redundancy, among others. CONCLUSIONS:Because of the limitations of the UMSARS, developing and validating an improved COA is a priority. The time is right for academic MSA clinicians together with industry, professional societies, and patient advocacy groups to develop and validate a new COA.
PMID: 33554315
ISSN: 1619-1560
CID: 4780452

Expanding the Genotypic Spectrum of Congenital Sensory and Autonomic Neuropathies Using Whole-Exome Sequencing

Palma, Jose-Alberto; Yadav, Rachita; Gao, Dadi; Norcliffe-Kaufmann, Lucy; Slaugenhaupt, Susan; Kaufmann, Horacio
Objective/UNASSIGNED:To test the hypothesis that many patients presenting with congenital insensitivity to pain have lesser known or unidentified mutations not captured by conventional genetic panels, we performed whole-exome sequencing in a cohort of well-characterized patients with a clinical diagnosis of congenital hereditary sensory and autonomic neuropathy with unrevealing conventional genetic testing. Methods/UNASSIGNED:We performed whole-exome sequencing (WES) in 13 patients with congenital impaired or absent sensation to pain and temperature with no identified molecular diagnosis from a conventional genetic panel. Patients underwent a comprehensive phenotypic assessment including autonomic function testing, and neurologic and ophthalmologic examinations. Results/UNASSIGNED:). Conclusions/UNASSIGNED:Our results expand the genetic landscape of congenital sensory and autonomic neuropathies. Further validation of some identified variants should confirm their pathogenicity. WES should be clinically considered to expedite diagnosis, reduce laboratory investigations, and guide enrollment in future gene therapy trials.
PMID: 33884296
ISSN: 2376-7839
CID: 4847922

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

Chia, Ruth; Sabir, Marya S; Bandres-Ciga, Sara; Saez-Atienzar, Sara; Reynolds, Regina H; Gustavsson, Emil; Walton, Ronald L; Ahmed, Sarah; Viollet, Coralie; Ding, Jinhui; Makarious, Mary B; Diez-Fairen, Monica; Portley, Makayla K; Shah, Zalak; Abramzon, Yevgeniya; Hernandez, Dena G; Blauwendraat, Cornelis; Stone, David J; Eicher, John; Parkkinen, Laura; Ansorge, Olaf; Clark, Lorraine; Honig, Lawrence S; Marder, Karen; Lemstra, Afina; St George-Hyslop, Peter; Londos, Elisabet; Morgan, Kevin; Lashley, Tammaryn; Warner, Thomas T; Jaunmuktane, Zane; Galasko, Douglas; Santana, Isabel; Tienari, Pentti J; Myllykangas, Liisa; Oinas, Minna; Cairns, Nigel J; Morris, John C; Halliday, Glenda M; Van Deerlin, Vivianna M; Trojanowski, John Q; Grassano, Maurizio; Calvo, Andrea; Mora, Gabriele; Canosa, Antonio; Floris, Gianluca; Bohannan, Ryan C; Brett, Francesca; Gan-Or, Ziv; Geiger, Joshua T; Moore, Anni; May, Patrick; Krüger, Rejko; Goldstein, David S; Lopez, Grisel; Tayebi, Nahid; Sidransky, Ellen; Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto; Kaufmann, Horacio; Shakkottai, Vikram G; Perkins, Matthew; Newell, Kathy L; Gasser, Thomas; Schulte, Claudia; Landi, Francesco; Salvi, Erika; Cusi, Daniele; Masliah, Eliezer; Kim, Ronald C; Caraway, Chad A; Monuki, Edwin S; Brunetti, Maura; Dawson, Ted M; Rosenthal, Liana S; Albert, Marilyn S; Pletnikova, Olga; Troncoso, Juan C; Flanagan, Margaret E; Mao, Qinwen; Bigio, Eileen H; Rodríguez-Rodríguez, Eloy; Infante, Jon; Lage, Carmen; González-Aramburu, Isabel; Sanchez-Juan, Pascual; Ghetti, Bernardino; Keith, Julia; Black, Sandra E; Masellis, Mario; Rogaeva, Ekaterina; Duyckaerts, Charles; Brice, Alexis; Lesage, Suzanne; Xiromerisiou, Georgia; Barrett, Matthew J; Tilley, Bension S; Gentleman, Steve; Logroscino, Giancarlo; Serrano, Geidy E; Beach, Thomas G; McKeith, Ian G; Thomas, Alan J; Attems, Johannes; Morris, Christopher M; Palmer, Laura; Love, Seth; Troakes, Claire; Al-Sarraj, Safa; Hodges, Angela K; Aarsland, Dag; Klein, Gregory; Kaiser, Scott M; Woltjer, Randy; Pastor, Pau; Bekris, Lynn M; Leverenz, James B; Besser, Lilah M; Kuzma, Amanda; Renton, Alan E; Goate, Alison; Bennett, David A; Scherzer, Clemens R; Morris, Huw R; Ferrari, Raffaele; Albani, Diego; Pickering-Brown, Stuart; Faber, Kelley; Kukull, Walter A; Morenas-Rodriguez, Estrella; Lleó, Alberto; Fortea, Juan; Alcolea, Daniel; Clarimon, Jordi; Nalls, Mike A; Ferrucci, Luigi; Resnick, Susan M; Tanaka, Toshiko; Foroud, Tatiana M; Graff-Radford, Neill R; Wszolek, Zbigniew K; Ferman, Tanis; Boeve, Bradley F; Hardy, John A; Topol, Eric J; Torkamani, Ali; Singleton, Andrew B; Ryten, Mina; Dickson, Dennis W; Chiò, Adriano; Ross, Owen A; Gibbs, J Raphael; Dalgard, Clifton L; Traynor, Bryan J; Scholz, Sonja W
The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
PMID: 33589841
ISSN: 1546-1718
CID: 4808032

Frequency and burden of gastrointestinal symptoms in familial dysautonomia

Ramprasad, Chethan; Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto; Levy, Joseph; Zhang, Yian; Spalink, Christy L; Khan, Abraham; Smukalla, Scott; Kaufmann, Horacio; Chen, Lea Ann
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.
PMID: 33025279
ISSN: 1619-1560
CID: 4631552

Autoantibodies blocking M3 muscarinic receptors cause postganglionic cholinergic dysautonomia

Palma, Jose-Alberto; Gupta, Achla; Sierra, Salvador; Gomes, Ivone; Balgobin, Bhumika; Norcliffe-Kaufmann, Lucy; Devi, Lakshmi A; Kaufmann, Horacio
A 10-year-old girl presented with ileus, urinary retention, dry mouth, lack of tears, fixed dilated pupils, and diffuse anhidrosis 7-days after a febrile illness. We hypothesized that her syndrome was due to autoimmunity against muscarinic acetylcholine receptors, blocking their activation. Using an indirect enzyme-linked immunosorbent assay for all five muscarinic receptors (M1 -M5 ) we identified in the patient's serum antibodies that selectively bound to M3 receptors. In-vitro functional studies confirmed that these autoantibodies selectively blocked M3 receptor activation. Thus, autoantibodies against M3 acetylcholine receptors can cause acute postganglionic cholinergic dysautonomia. This article is protected by copyright. All rights reserved.
PMID: 32833276
ISSN: 1531-8249
CID: 4583782


Mai, Xingchen; Reyentovich, Alex; Norcliffe-Kaufmann, Lucy; Moazami, Nader; Frontera, Jennifer A
BACKGROUND:Despite innovations in left ventricular assist devices (LVAD) technology, stroke remains a leading cause of morbidity and mortality in this population. Major clinical trials of LVAD have used various definitions and approaches to measuring stroke outcomes which may limit comparison of stroke risk between different devices. METHODS:Data from the five major LVAD randomized, controlled, trials was abstracted to compare definitions of stroke (composite, ischemic, hemorrhagic and disabling) and stroke event rates across trials. Methodological limitations and suggestions to improve research and clinical practices for stroke and LVAD were identified. RESULTS:Comparison of stroke events across LVAD clinical trials is confounded by methodological variability including heterogeneity in stroke definitions, non-standardized evaluation of stroke etiology, oversimplification of stroke severity classification, and inconsistent event rate reporting due to data censoring at the time of death or transplant. Variability in the study of stroke in LVAD patients limits the ability to compare devices and design prevention strategies to mitigate stroke risk. CONCLUSIONS:Based on this review, we propose that future clinical trials: 1) utilize standardized stroke definitions and define stroke subtypes, 2) ensure that neurologists are integrated in study design and event adjudication, 3) include more thorough evaluations of stroke etiology using multimodality techniques, and 4) adopt the National Institutes of Health Stroke Scale to define stroke severity.
PMID: 32289297
ISSN: 1552-6259
CID: 4383402

Von Economo Neuron Pathology in Familial Dysautonomia: Quantitative Assessment and Possible Implications

Jacot-Descombes, Sarah; Keshav, Neha; Brosch, Carla Micaela Santos; Wicinski, Bridget; Warda, Tahia; Norcliffe-Kaufmann, Lucy; Kaufmann, Horacio; Varghese, Merina; Hof, Patrick R
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.
PMID: 32954436
ISSN: 1554-6578
CID: 4614852