Faculty Bibliography

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: 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: The Multiple System Atrophy (MSA) Criteria Revision Steering Group identified the weaknesses of current set of diagnostic criteria for MSA and discussed a need for its revision. Background: Typically MSA is diagnosed half way through its clinical disease course. However, early diagnosis is critical if any diseasemodifying treatment is to be applied. Methods: The Steering Group includes investigators experienced in Parkinsonian, cerebellar, autonomic, neuroimaging, sleep, genetic and postmortem aspects of MSA. Shortcomings of the current diagnostic criteria for MSA were addressed through the personal communication. Results: The first criteria for MSA diagnosis were published in 1989, the first Consensus Criteria in 1998, and the second Consensus Criteria in 2008. A study of "red flags" was also published in 2008 but the results not incorporated into the criteria. In a recent large autopsy study by Koga et al., 2015 38% of cases diagnosed in life with MSA did not have it, the largest misdiagnosed group having dementia with Lewy bodies. In a study examining validity of Consensus Criteria (Osaki et al., 2009), sensitivity for MSA diagnosis was 41% for possible and 18% for probable at first visit, whereas at last visit these figures were 92 and 63% respectively. There is clearly a need for improved sensitivity and specificity of diagnosis of MSA, especially at its earliest stages. Conclusions: It is time in 2018 to revisit and revise the Consensus Criteria for the diagnosis of MSA

Objectives: (1) To determine if measuring alpha-synuclein in exosomes from neurons and oligodendrocytes can distinguish between healthy controls and patients with Parkinson disease (PD) or multiple system atrophy (MSA). (2) To test whether analyzing alpha-synuclein in neuronal and oligodendroglial exosomes can distinguish between PD and MSA. Background: Developing reliable biomarkers that can distinguish among synucleinopathies is an urgent public health need. In particular PD and atypical Parkinsonian disorders are often misdiagnosed at early stages. Exosomes are nano-sized vesicles shed by most cells, which carry biomolecules of the parent cell and provide a rich source of biomarkers. Recently, alpha-synuclein was shown to transfer via exosomes suggesting that measuring alpha-synuclein in brain-derived exosomes could serve as a biomarker for synucleinopathies. Methods: Neuronal and oligodendroglial exosomes were isolated from serum of 50 healthy individuals, 50 patients with PD, and 24 patients with MSA. a-Synuclein concentration was measured using electrochemiluminescence ELISA. Results: Significantly higher concentrations of alpha-synuclein were found in both neuronal and oligodendroglial exosomes from patients than in controls. a-Synuclein in oligodendroglial exosomes distinguished patients with MSA from healthy controls with 100.0% sensitivity and 96% specificity. The absolute values of alpha-synuclein in neuronal and oligodendroglial exosomes provided moderate separation between the PD and MSA groups, yet the individual ratio between the two cell types allowed separating the two disease groups with 91.7% sensitivity and 86.0% specificity. Conclusion: a-Synuclein in brain-derived blood exosomes provides a sensitive biomarker for distinguishing patients with MSA from healthy controls and from patients with PD using a simple blood test

Background: Depressive symptoms are common in patients with multiple system atrophy (MSA). We aimed to determine the prevalence of depression in MSA and its impact on quality of life and disease progression. Methods: MSA patients enrolled in a natural history study to determine the natural progression of disease. Patients completed psychiatric (Zung Depression scale, Spielberg's anxiety scale and Body vigilance scale) and autonomic (OHQ, COMPASS, UMSARS-I and II, SCOPA-Autonomic and SF36 Quality of life scale) rating scales, and underwent autonomic and cardiovascular assessments at baseline, and then followed at regular intervals for repeat assessments. Results: Forty-five MSA patients (mean age 61.8 years, 4.3 years disease duration) were included. Thirty patients (67%) scored as having depression on the Zung depression scale (15 mild, 13 moderate, and 2 severe). Seventy-three percent had orthostatic hypotension (OH). Depressed patients had higher trait/state anxiety and body vigilance scores than non-depressed patients. Depressed patients had significantly higher OHQ scores on each of the 6 OHSA items and each of the OHDAS items (OH interference with activities of standing and walking). Trait-anxiety and depression correlated with OHSA and OHDAS items. Depressed patients reported greater OHQ scores for the same amount of blood pressure change than nondepressed. Linear regression showed significant effect of depression on progression of UMSARS-II scores. Depression correlated with orthostatic and urinary function symptoms on the COMPASS scale. Conclusion: Depression is common in MSA and is associated with faster disease progression and higher burden of autonomic symptoms. Recognizing and treating depression may improve quality of life and ameliorate symptoms

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.

Background: Allgrove syndrome (triple A syndrome) is a rare autosomal recessive disorder first described by endocrinologist Jeremy Allgrove in 1978 in two siblings with adrenal insufficiency, achalasia, and alacrima. Onset is usually within the first decade of life. Other features include adrenocorticotropic hormone (ACTH) unresponsiveness, and varying degrees of neurologic dysfunction. In 2002, mutations in the AAAS gene located on chromosome 12q13, which encodes for the nuclear pore protein ALADIN, were reported as the cause of the disease. The autonomic features of the disorder remain poorly understood with only ~ 100 cases in the literature, most of which were described before the availability of genetic testing. Methods: Case series of 2 patients with genetically confirmed Allgrove syndrome. Results: Case # 1: 9-year-old girl of East Indian descent presented with alacrima since birth. At age 6, she developed adrenal insufficiency manifesting as hyperpigmentation and fatigue. Genetic testing confirmed she was homozygous for the pathogenic variant c.1432C>T p.Arg478Ter. The patient had no achalasia and neurological exam was normal. Cardiovascular autonomic testing was normal. Case # 2: 39-year-old Hispanic woman presented with alacrima, achalasia, ACTH resistance, and sensorimotor polyneuropathy at the age of 13 years. Autonomic testing revealed adrenergic impairment with orthostatic hypotension together with cholinergic dysfunction and decreased heart rate variability. Genetic testing confirmed two heterozygous mutations: 1) Heterozygous Exon 6, R155P, base 464 CGT to CCT; 2) Heterozygous IVSC14 + 1G to A. Mutation 1 had not been previously reported. Conclusions: Allgrove syndrome is a rare pediatric-onset disorder with variable presentation. Neurological signs (autonomic dysfunction, hyperreflexia, dysarthria, ataxia, sensory impairment, weakness, cognitive deficits) and ACTH resistance may only manifest after many years or decades. As the number of genetically confirmed cases grows, there is a need to understand the autonomic phenotype, which should perhaps be considered the 4th A