Faculty Bibliography

Objective: A 12-week randomized, placebo-controlled, multicenter study assessed the safety, changes in glia marker translocator protein (TSPO, PET examinations), and efficacy of two doses of AZD3241 and placebo in patients with Multiple System Atrophy (MSA). Background: AZD3241 is a potent, selective, brain-permeable myeloperoxidase (MPO) inhibitor being investigated for potential utility in modifying the course of multiple system atrophy. Design/Methods: Patients with MSA and mixed/high affinity binding to TSPO were randomized in a 1:1:1 ratio (placebo, 300 and 600 mg BID). The primary endpoint was safety and tolerability during the trial. The primary imaging endpoint was within-group change in the total distribution volume (VT) of the radioligand [11C]PBR28 binding to TSPO in the striatum. The effect of AZD3241 on symptoms was examined using the Unified Multiple System Atrophy Rating Scale (UMSARS). Results: 59 MSA patients were randomized at 17 sites and received study treatment (20 placebo, 19 300 mg BID AZD3241, 20 600 mg BID AZD3241). AZD3241 was safe and well tolerated. AZD3241 treatment with either dose regimen had no statistically significant effect on VT at 12 weeks compared to baseline. Placebo-treated patients had a numerically larger increase in the UMSARS from baseline to week 12 compared to either treatment group; betweengroup differences, though small, were consistent and dose-related. Conclusion: Overall, the study PET results do not support the hypothesis that inhibition of myeloperoxidase by AZD3241 in MSA patients has an effect on glia function in the brain, but further studies should explore the potential clinical efficacy of this compound

Objective: To evaluate the efficacy of droxidopa on symptoms of neurogenic orthostatic hypotension (nOH) and activities of daily living using the Orthostatic Hypotension Questionnaire (OHQ) in patients with multiple system atrophy (MSA). Background: Droxidopa is an oral prodrug of norepinephrine with demonstrated efficacy in patients with primary autonomic failure (pure autonomic failure, MSA, and Parkinson disease) who have nOH. Design/Methods: We conducted a subset analysis of data from three droxidopa (Studies NOH301, NOH302, NOH303) clinical trials which enrolled over 400 patients with primary autonomic failure, including 95 patients with MSA, 56 of which were randomized into double-blind treatment periods of the studies. Changes in symptoms of nOH and in symptom impact on activities of daily living were measured via the OHQ. Safety was measured via the incidence and severity of adverse events. Results: There were statistically significant (P<=0.05) improvements in OHQ composite score after droxidopa treatment versus placebo in the combined analysis of Studies NOH301 and NOH302, although the total number of MSA patients was relatively small. Patients treated with droxidopa demonstrated numerically greater improvements than placebo-treated patients in nine of ten OHQ items. Standing systolic blood pressure improved with droxidopa treatment. Data suggests that 4-6 weeks of treatment may be required to reach full symptomatic benefit with the drug. Importantly, despite the progressive nature of MSA, the symptomatic and blood pressure benefits were maintained through 3 months of open label extension treatment. Droxidopa was well tolerated and safe in MSA patients and the overall population. Conclusions: Droxidopa was shown in this post hoc, subset analysis to be a useful therapy for the treatment and management of nOH in MSA patients, providing symptomatic relief associated with improvement in standing blood pressure and an excellent safety profile

Objective: We investigated whether activation of afferent and central baroreceptor pathways could differentiate between Lewy body disorders and MSA. Background: Clinical distinction between multiple system atrophy (MSA) and Lewy body disorders with motor involvement (Parkinson disease [PD] and dementia with Lewy bodies [DLB]) is sometimes challenging. Methods: Cross-sectional study including 35 patients with probable or possible MSA and 24 patients with Lewy body disorders (20 with PD and 4 with DLB). All subjects had neurogenic orthostatic hypotension. Subjects underwent complete autonomic testing with measurement of plasma levels of catecholamines and vasopressin after 10-min in the resting supine position and after 10-min of passive head-up tilt. Results: Thirty-five patients with probable MSA (22 MSA-C, 13 MSA-P) and 24 patients with Lewy body disorders (20 with PD, 4 with DLB) were included. All patients had documented neurogenic orthostatic hypotension. In patients with PD and DLB upright tilt induced marked hypotension and a significant increase in plasma vasopressin (from 0.82 +/- 0.77 to 4.85 +/- 13.9 pmol/l in PD (p = 0.0027); from 1.18 +/- 0.81 to 5.1 +/- 3.76 pmol/l in DLB (p = 0.11). In patients with MSA, upright tilt also elicited profound hypotension but circulating levels of vasopressin did not increase significantly (from 0.51 +/- 0.08 to 0.70 +/- 0.71 pmol/l, p = 0.092). Plasma norepinephrine did not increase significantly on head-up tilt in any of the subjects. A plasma vasopressin concentration during upright tilt of<=0.8 pmol/l in a patient with neurogenic orthostatic hypotension had a sensitivity of 91%, a specificity of 64%, and a negative predictive value of 83.3% for a diagnosis of MSA. Conclusions: Our results indicate that afferent and central baroreceptor pathways involved in vasopressin release are preserved in Lewy body disorders but impaired in MSA. Thus a patient with a vasopressin when standing of[0.8 pg/ml makes a diagnosis of MSA unlikely

Objective: The Movement Disorder Society (MDS)-endorsed MSA study group (MODIMSA) identified a need to develop a systematic review on diagnostic tests in patients with multiple system atrophy (MSA). Background: The diagnosis of MSA is a primarily clinical exercise, despite development of numerous ancillary tests that differ in their diagnostic performance, availability and costs. Design/methods: We systematically reviewed original reports published before December 2016 with at least 10 MSA subjects per study defined by post-mortem verification, clinically probable, or clinically probable plus possible MSA according to consensus criteria and at least one reference group of diseased subjects. Results: A total of 363 relevant citations on diagnostic tests in MSA were critically analyzed. Cardiovascular autonomic tests and bladder ultrasonography contribute to the diagnosis of autonomic failure. None of the fluid biomarkers is sufficiently robust for the diagnosis of MSA, since most of the assays are not standardized and commercially available for wider testing. CoQ2 mutation testing is recommended in familial Japanese MSA-cerebellar cases. Screening for MSA mimic genes should be considered to refine clinical diagnosis. Visual interpretation of conventional MRI by experts, quantitative assessment of regional cerebral atrophy, diffusion imaging, iron sensitive sequences and automated techniques for quantitative MRI analysis are useful, but diagnostic accuracy of different MRI abnormalities across the studies is highly variable. [18F]FDG-PET, [123I]IBZM-SPECT, cardiac [123I]MIBG-SPECT and certain neuropsychological tests may also aid, but are not sufficient for the diagnosis of MSA. Reported data regarding neuroendocrine tests, external sphincter electromyography, transcranial parenchymal sonography, video polysomnography, levodopa challenge test, olfactory testing and skin and enteric biopsy are inconsistent. Conclusion: Based on this comprehensive literature review, several investigative measures may assist in the diagnostic work-up of patients with suspected MSA. The best current guidelines for MSA diagnosis are still clinical phenotype and inexorable progression

Objective: To define which factors predict the pressor response to droxidopa in patients with neurogenic orthostatic hypotension (nOH). Background: Droxidopa, a synthetic norepinephrine precursor, was recently approved to treat symptomatic nOH. The pressor response is variable with some patients responding to doses of 100 mg while others requiring up to 600 mg three times/day. It is not known which factors predict the magnitude of the pressor response to droxidopa. Methods: We prospectively evaluated the BP response to increasing doses of droxidopa in patients with nOH in an outpatient setting. BP supine and after 3-min standing was measured before and 1-h after oral administration of 100 mg of droxidopa. Droxidopa was progressively increased until (1) complete relief of symptoms, (2) supine systolic BP[180 mmHg, (3) occurrence of side effects, or (4) the maximum dose of 600 mg was reached. Results: Sixteen subjects with nOH (6 with Parkinson disease, 5 with pure autonomic failure-PAF-, 3 with autoimmune autonomic ganglionopathy-AAG-, and 2 with multiple system atrophy) were evaluated. Mean BP was 126 +/- 28/72 +/- 11 mmHg supine, and 89 +/- 19/53 +/- 15 mmHg after 3-min standing (fall of 37/18 mmHg). Mean plasma norepinephrine while supine was 192 +/- 216 pg/ml. Maximum droxidopa dose during the titration was 212 +/- 102 mg (range 100-400 mg). Droxidopa increased BP to an average of 148 +/- 53/90 +/- 13 mmHg supine and 135 +/- 38/66 +/- 16 mmHg after 3-min standing (p<=0.001). Plasma norepinephrine levels were inversely correlated with higher systolic BP after-3 min standing following droxidopa treatment (R2 = 0.42; p = 0.023). Four patients (3 with AAG and 1 with PAF) with very low plasma norepinephrine levels (<=90 pg/ml) experienced transient nausea, vomiting, and abdominal pain during titration with dosages of 200 mg. In these patients, treatment with 100 mg/day was effective and well tolerated. Diagnostic categories did not predict response to droxidopa. Conclusions: In patients with nOH, lower plasma norepinephrine levels are associated with a greater pressor response to droxidopa. This response is probably related to the degree of denervation supersensitivity. Supine norepinephrine levels may be useful to predict appropriate dosing of droxidopa in the clinical setting

BACKGROUND:Chronic lung disease is a leading cause of premature death in patients with familial dysautonomia (FD). A significant number of patients have obstructive airway disease, yet it is not known whether this is pharmacologically reversible. METHODS:We conducted a double-blind, placebo-controlled, randomized clinical trial comparing the beta 2 agonist albuterol with the muscarinic blocker ipratropium bromide in patients homozygous for the IKBKAP founder mutation. Albuterol, ipratropium bromide, and placebo were administered on 3 separate days via nebulizer in the seated position. Airway responsiveness was evaluated using spirometry and impulse oscillometry 30 min post dose. Cardiovascular effects were evaluated by continuous monitoring of blood pressure, RR intervals, cardiac output, and systemic vascular resistance. RESULTS:A total of 14 patients completed the trial. Neither active agent had significant detrimental effects on heart rate or rhythm or blood pressure. Albuterol and ipratropium were similar in their bronchodilator effectiveness causing significant improvement in forced expiratory volume in 1-s (FEV1, p = 0.002 and p = 0.030). Impulse oscillometry measures were consistent with a reduction in total airway resistance post nebulization (resistance at 5 Hz p < 0.006). CONCLUSION/CONCLUSIONS:Airway obstruction is pharmacologically reversible in a number of patients with FD. In the short term, both albuterol and ipratropium were well tolerated and not associated with major cardiovascular adverse events.

Multiple system atrophy (MSA) is a rare neurodegenerative disorder with substantial knowledge gaps despite recent gains in basic and clinical research. In order to make further advances, concerted international collaboration is vital. In 2014, an international meeting involving leaders in the field and MSA advocacy groups was convened in Las Vegas, Nevada, to identify critical research areas where consensus and progress was needed to improve understanding, diagnosis, and treatment of the disease. Eight topic areas were defined: pathogenesis, preclinical modeling, target identification, endophenotyping, clinical measures, imaging biomarkers, nonimaging biomarkers, treatments/trial designs, and patient advocacy. For each topic area, an expert served as a working group chair and each working group developed priority-ranked research recommendations with associated timelines and pathways to reach the intended goals. In this report, each groups' recommendations are provided.

OBJECTIVE:To assess vestibular function in patients with familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy - caused by a mutation in the IKBKAP gene (c.2204 + 6 T>C) - and characterized by marked gait ataxia. METHODS:Cervical and vestibular evoked myogenic potentials (cVEMPs and oVEMPs) were recorded from the sternocleidomastoid (SCM) and extraocular muscles in 14 homozygous patients, 2 heterozygous patients, and 15 healthy controls during percussion of the forehead. RESULTS:cVEMP and oVEMP amplitudes were significantly lower, and peak latencies significantly delayed, in the FD patients. There were no differences in overall EMG during attempted maximal voluntary contractions of the SCM muscle, suggesting intact efferent function. The two heterozygotes with a minor haplotype missense (R696P) mutation in exon 19 of the IKBKAP gene had cVEMP responses less affected than the homozygous. CONCLUSIONS:The founder mutation in the IKBKAP gene affects the development of vestibular afferent pathways, leading to attenuated cVEMPs. SIGNIFICANCE/CONCLUSIONS:Vestibular abnormalities may contribute to the gait ataxia in FD.

Cardiovascular autonomic dysfunctions, including neurogenic orthostatic hypotension, supine hypertension and post-prandial hypotension, are relatively common in patients with Parkinson disease. Recent evidence suggests that early autonomic impairment such as cardiac autonomic denervation and even neurogenic orthostatic hypotension occur prior to the appearance of the typical motor deficits associated with the disease. When neurogenic orthostatic hypotension develops, patients with Parkinson disease have an increased risk of mortality, falls, and trauma-related to falls. Neurogenic orthostatic hypotension reduces quality of life and contributes to cognitive decline and physical deconditioning. The co-existence of supine hypertension complicates the treatment of neurogenic orthostatic hypotension because it involves the use of drugs with opposing effects. Furthermore, treatment of neurogenic orthostatic hypotension is challenging because of few therapeutic options; in the past 20 years, the US Food and Drug Administration approved only two drugs for the treatment of this condition. Small, open-label or randomized studies using acute doses of different pharmacologic probes suggest benefit of other drugs as well, which could be used in individual patients under close monitoring. This review describes the pathophysiology of neurogenic orthostatic hypotension and supine hypertension in Parkinson disease. We discuss the mode of action and therapeutic efficacy of different pharmacologic agents used in the treatment of patients with cardiovascular autonomic failure.