Faculty Bibliography

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).

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.

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.

[Figure: see text].

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.

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.

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.