Try a new search

Format these results:

Searched for:

person:norcll01

in-biosketch:yes

Total Results:

169


Fear conditioning as a pathogenic mechanism in the postural tachycardia syndrome

Norcliffe-Kaufmann, Lucy; Palma, Jose Alberto; Martinez, Jose; Camargo, Celeste; Kaufmann, Horacio
Despite its increasing recognition and extensive research, there is no unifying hypothesis on the pathophysiology of the postural tachycardia syndrome. In this cross-sectional study, we examined the role of fear conditioning and its association with tachycardia and cerebral hypoperfusion upon standing in 28 patients with postural tachycardia syndrome (31 ± 12 years old, 25 women) and 21 matched controls. We found that patients had higher somatic vigilance (p = 0.0167) and more anxiety (p < 0.0001). They also had a more pronounced anticipatory tachycardia right before assuming the upright position in a tilt-table test (p = 0.015), a physiologic indicator of fear conditioning to orthostasis. While standing, patients had faster heart rate (p < 0.001), higher plasma catecholamine levels (p = 0.020), lower end-tidal CO2 (p = 0.005), and reduced middle cerebral artery blood flow velocity (p = 0.002). Multi-linear logistic regression modeling showed that both epinephrine secretion and excessive somatic vigilance predicted the magnitude of the tachycardia and the hyperventilation. These findings suggest that the postural tachycardia syndrome is a functional psychogenic disorder in which standing may acquire a frightful quality, so that even when experienced alone, it elicits a fearful conditioned response. Heightened somatic anxiety is associated with and may predispose to a fear-conditioned hyperadrenergic state when standing. Our results have therapeutic implications.
PMID: 35802513
ISSN: 1460-2156
CID: 5280662

Reply: Is postural tachycardia syndrome a psychogenic disorder?; Notes on establishing fear conditioning as causal in the postural orthostatic tachycardia syndrome; Patients with POTS fear that data on abnormal haemodynamic physiology have been ignored; and 'Psychogenic' POTS: the NYU team misinterprets association as causation

Norcliffe-Kaufmann, Lucy; Palma, Jose Alberto; Kaufmann, Horacio
PMID: 36151960
ISSN: 1460-2156
CID: 5335842

Patient-Reported Symptoms in the Global Multiple System Atrophy Registry

Palma, Jose-Alberto; Krismer, Florian; Meissner, Wassilios G; Kuijpers, Mechteld; Millar-Vernetti, Patricio; Perez, Miguel A; Fanciulli, Alessandra; Norcliffe-Kaufmann, Lucy; Bower, Pam; Wenning, Gregor K; Kaufmann, Horacio
Background/UNASSIGNED:The Global Multiple System Atrophy Registry (GLOMSAR) was established in 2013. It is an online patient-reported contact registry open and free that relies on self-reported diagnosis by the patient or caregiver. Objectives/UNASSIGNED:To report the demographics of patients enrolled in GLOMSAR and the results of an ancillary online symptom questionnaire. Methods/UNASSIGNED:Patients enrolled in GLOMSAR were invited to complete a custom-designed online questionnaire about disease onset and symptom prevalence. Results/UNASSIGNED:At the time of writing, there were 1083 participants in GLOMSAR, of which 33% (365) completed the questionnaire. The onset and frequency of most symptoms was similar to those reported in the literature in physician-reported studies. Some were understudied or not typically associated with multiple system atrophy (MSA), including reduced female sexual sensation (55%), forgetfulness (60%), pseudobulbar affect (37%), olfactory changes (36%), and visual hallucinations (21%). Conclusions/UNASSIGNED:Patient-reported studies and ancillary online questionnaires are valid, underused research tools useful to advance our knowledge on understudied MSA features and highlight the patients' voice.
PMCID:9547130
PMID: 36247899
ISSN: 2330-1619
CID: 5360142

Stress and the baroreflex

Norcliffe-Kaufmann, Lucy
The stress response to emotions elicits the release of glucocorticoids from the adrenal cortex, epinephrine from the adrenal medulla, and norepinephrine from the sympathetic nerves. The baroreflex adapts to buffer these responses to ensure that perfusion to the organs meets the demands while maintaining blood pressure within a within a narrow range. While stressor-evoked autonomic cardiovascular responses may be adaptive for the short-term, the recurrent exaggerated cardiovascular stress reactions can be maladaptive in the long-term. Prolonged stress or loss of the baroreflex's buffering capacity can predispose episodes of heightened sympathetic activity during stress leading to hypertension, tachycardia, and ventricular wall motion abnormalities. This review discusses 1) how the baroreflex responds to acute and chronic stressors, 2) how lesions in the neuronal pathways of the baroreflex alter the ability to respond or counteract the stress response, and 3) the techniques to assess baroreflex sensitivity and stress responses. Evidence suggests that loss of baroreflex sensitivity may predispose heightened autonomic responses to stress and at least in part explain the association between stress, mortality and cardiovascular diseases.
PMID: 35086020
ISSN: 1872-7484
CID: 5137072

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 (ClinicalTrials.gov: 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.
PMCID:7868077
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.
PMCID:8054964
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.
PMCID:7946812
PMID: 33589841
ISSN: 1546-1718
CID: 4808032