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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

Different phenoconversion pathways in pure autonomic failure with versus without Lewy bodies

Goldstein, David S; Isonaka, Risa; Lamotte, Guillaume; Kaufmann, Horacio
Pure autonomic failure (PAF) is a rare disease in which chronic neurogenic orthostatic hypotension (nOH) dominates the clinical picture. Longitudinal studies have reported that PAF can phenoconvert to a central synucleinopathy with motor or cognitive involvement-i.e., to Parkinson disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA). These studies have classified patients clinically as having PAF based on nOH without an identified secondary cause or clinical evidence of motor or cognitive impairment due to central neurodegeneration. This approach lumps together two nOH syndromes that are pathologically and neurochemically distinct. One is characterized by intraneuronal cytoplasmic alpha-synuclein aggregates (i.e., Lewy bodies) and degeneration of postganglionic sympathetic neurons, as in PD and DLB; the other is not, as in MSA. Clinical and postmortem data show that the form of PAF that involves sympathetic intraneuronal synucleinopathy and noradrenergic deficiency can phenoconvert to PD or DLB-but not to MSA. Conversely, PAF without these features leaves open the possibility of premotor MSA.
PMID: 34669076
ISSN: 1619-1560
CID: 5043312

α-Synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes Parkinson's disease from multiple system atrophy

Dutta, Suman; Hornung, Simon; Kruayatidee, Adira; Maina, Katherine N; Del Rosario, Irish; Paul, Kimberly C; Wong, Darice Y; Duarte Folle, Aline; Markovic, Daniela; Palma, Jose-Alberto; Serrano, Geidy E; Adler, Charles H; Perlman, Susan L; Poon, Wayne W; Kang, Un Jung; Alcalay, Roy N; Sklerov, Miriam; Gylys, Karen H; Kaufmann, Horacio; Fogel, Brent L; Bronstein, Jeff M; Ritz, Beate; Bitan, Gal
The diagnosis of Parkinson's disease (PD) and atypical parkinsonian syndromes is difficult due to the lack of reliable, easily accessible biomarkers. Multiple system atrophy (MSA) is a synucleinopathy whose symptoms often overlap with PD. Exosomes isolated from blood by immunoprecipitation using CNS markers provide a window into the brain's biochemistry and may assist in distinguishing between PD and MSA. Thus, we asked whether α-synuclein (α-syn) in such exosomes could distinguish among healthy individuals, patients with PD, and patients with MSA. We isolated exosomes from the serum or plasma of these three groups by immunoprecipitation using neuronal and oligodendroglial markers in two independent cohorts and measured α-syn in these exosomes using an electrochemiluminescence ELISA. In both cohorts, α-syn concentrations were significantly lower in the control group and significantly higher in the MSA group compared to the PD group. The ratio between α-syn concentrations in putative oligodendroglial exosomes compared to putative neuronal exosomes was a particularly sensitive biomarker for distinguishing between PD and MSA. Combining this ratio with the α-syn concentration itself and the total exosome concentration, a multinomial logistic model trained on the discovery cohort separated PD from MSA with an AUC = 0.902, corresponding to 89.8% sensitivity and 86.0% specificity when applied to the independent validation cohort. The data demonstrate that a minimally invasive blood test measuring α-syn in blood exosomes immunoprecipitated using CNS markers can distinguish between patients with PD and patients with MSA with high sensitivity and specificity. Future optimization and validation of the data by other groups would allow this strategy to become a viable diagnostic test for synucleinopathies.
PMID: 33991233
ISSN: 1432-0533
CID: 4889422

Correction to: α-Synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes Parkinson's disease from multiple system atrophy

Dutta, Suman; Hornung, Simon; Kruayatidee, Adira; Maina, Katherine N; Del Rosario, Irish; Paul, Kimberly C; Wong, Darice Y; Duarte Folle, Aline; Markovic, Daniela; Palma, Jose-Alberto; Serrano, Geidy E; Adler, Charles H; Perlman, Susan L; Poon, Wayne W; Kang, Un Jung; Alcalay, Roy N; Sklerov, Miriam; Gylys, Karen H; Kaufmann, Horacio; Fogel, Brent L; Bronstein, Jeff M; Ritz, Beate; Bitan, Gal
PMID: 34028589
ISSN: 1432-0533
CID: 4908432

Predictors of the Pressor Response to the Norepinephrine Transporter Inhibitor, Atomoxetine, in Neurogenic Orthostatic Hypotension

Shibao, Cyndya A; Palma, Jose-Alberto; Celedonio, Jorge E; Martinez, Jose; Kaufmann, Horacio; Biaggioni, Italo
[Figure: see text].
PMID: 34176285
ISSN: 1524-4563
CID: 4964952

What is the best method to diagnose a vasovagal syncope? [Editorial]

Wieling, Wouter; Kaufmann, Horacio
PMID: 33961160
ISSN: 1619-1560
CID: 4874132

Dysphagia in multiple system atrophy consensus statement on diagnosis, prognosis and treatment

Calandra-Buonaura, Giovanna; Alfonsi, Enrico; Vignatelli, Luca; Benarroch, Eduardo E; Giannini, Giulia; Iranzo, Alex; Low, Phillip A; Martinelli, Paolo; Provini, Federica; Quinn, Niall; Tolosa, Eduardo; Wenning, Gregor K; Abbruzzese, Giovanni; Bower, Pamela; Antonini, Angelo; Bhatia, Kailash P; Bonavita, Jacopo; Pellecchia, Maria Teresa; Pizzorni, Nicole; Tison, François; Ghorayeb, Imad; Meissner, Wassilios G; Ozawa, Tetsutaro; Pacchetti, Claudio; Pozzi, Nicolò Gabriele; Vicini, Claudio; Schindler, Antonio; Cortelli, Pietro; Kaufmann, Horacio
Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a combination of autonomic failure plus cerebellar syndrome and/or parkinsonism. Dysphagia is a frequent and disabling symptom in MSA and its occurrence within 5 years of motor onset is an additional diagnostic feature. Dysphagia can lead to aspiration pneumonia, a recognized cause of death in MSA. Guidelines for diagnosis and management of dysphagia in MSA are lacking. An International Consensus Conference among experts with methodological support was convened in Bologna to reach consensus statements for the diagnosis, prognosis, and treatment of dysphagia in MSA. Abnormalities of the oral and pharyngeal phases of swallowing, esophageal dysfunction and aspiration occur in MSA and worsen as the disease progresses. According to the consensus, dysphagia should be investigated through available screening questionnaires and clinical and instrumental assessment (videofluoroscopic study or fiberoptic endoscopic evaluation of swallowing and manometry) at the time of MSA diagnosis and periodically thereafter. There is evidence that dysphagia is associated with poor survival in MSA, however effective treatments for dysphagia are lacking. Compensatory strategies like diet modification, swallowing maneuvers and head postures should be applied and botulinum toxin injection may be effective in specific conditions. Percutaneous endoscopic gastrostomy may be performed when there is a severe risk of malnutrition and pulmonary complications, but its impact on survival is undetermined. Several research gaps and unmet needs for research involving diagnosis, prognosis, and treatment were identified.
PMID: 33839029
ISSN: 1873-5126
CID: 4845492

Correction to: A-synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes parkinson's disease from multiple system atrophy

Dutta, Suman; Hornung, Simon; Kruayatidee, Adira; Maina, Katherine N; del Rosario, Irish; Paul, Kimberly C; Wong, Darice Y; Duarte Folle, Aline; Markovic, Daniela; Palma, Jose-Alberto; Serrano, Geidy E; Adler, Charles H; Perlman, Susan L; Poon, Wayne W; Kang, Un Jung; Alcalay, Roy N; Sklerov, Miriam; Gylys, Karen H; Kaufmann, Horacio; Fogel, Brent L; Bronstein, Jeff M; Ritz, Beate; Bitan, Gal
A correction to this paper has been published: https:
PSYCH:2021-49944-001
ISSN: 1432-0533
CID: 4900962

A-synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes parkinson's disease from multiple system atrophy

Dutta, Suman; Hornung, Simon; Kruayatidee, Adira; Maina, Katherine N; del Rosario, Irish; Paul, Kimberly C; Wong, Darice Y; Duarte Folle, Aline; Markovic, Daniela; Palma, Jose-Alberto; Serrano, Geidy E; Adler, Charles H; Perlman, Susan L; Poon, Wayne W; Kang, Un Jung; Alcalay, Roy N; Sklerov, Miriam; Gylys, Karen H; Kaufmann, Horacio; Fogel, Brent L; Bronstein, Jeff M; Ritz, Beate; Bitan, Gal
The diagnosis of Parkinson's disease (PD) and atypical parkinsonian syndromes is difficult due to the lack of reliable, easily accessible biomarkers. Multiple system atrophy (MSA) is a synucleinopathy whose symptoms often overlap with PD. Exosomes isolated from blood by immunoprecipitation using CNS markers provide a window into the brain's biochemistry and may assist in distinguishing between PD and MSA. Thus, we asked whether alpha-synuclein (alpha-syn) in such exosomes could distinguish among healthy individuals, patients with PD, and patients with MSA. We isolated exosomes from the serum or plasma of these three groups by immunoprecipitation using neuronal and oligodendroglial markers in two independent cohorts and measured alpha-syn in these exosomes using an electrochemiluminescence ELISA. In both cohorts, alpha-syn concentrations were significantly lower in the control group and significantly higher in the MSA group compared to the PD group. The ratio between alpha-syn concentrations in putative oligodendroglial exosomes compared to putative neuronal exosomes was a particularly sensitive biomarker for distinguishing between PD and MSA. Combining this ratio with the alpha-syn concentration itself and the total exosome concentration, a multinomial logistic model trained on the discovery cohort separated PD from MSA with an AUC = 0.902, corresponding to 89.8% sensitivity and 86.0% specificity when applied to the independent validation cohort. The data demonstrate that a minimally invasive blood test measuring alpha-syn in blood exosomes immunoprecipitated using CNS markers can distinguish between patients with PD and patients with MSA with high sensitivity and specificity. Future optimization and validation of the data by other groups would allow this strategy to become a viable diagnostic test for synucleinopathies. (PsycInfo Database Record (c) 2021 APA, all rights reserved)
PSYCH:2021-47020-001
ISSN: 1432-0533
CID: 4883332

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