Faculty Bibliography

Dysfunction of the autonomic nervous system afflicts most patients with Parkinson disease and other synucleinopathies such as dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure, reducing quality of life and increasing mortality. For example, gastrointestinal dysfunction can lead to impaired drug pharmacodynamics causing a worsening in motor symptoms, and neurogenic orthostatic hypotension can cause syncope, falls, and fractures. When recognized, autonomic problems can be treated, sometimes successfully. Discontinuation of potentially causative/aggravating drugs, patient education, and nonpharmacological approaches are useful and should be tried first. Pathophysiology-based pharmacological treatments that have shown efficacy in controlled trials of patients with synucleinopathies have been approved in many countries and are key to an effective management. Here, we review the treatment of autonomic dysfunction in patients with Parkinson disease and other synucleinopathies, summarize the nonpharmacological and current pharmacological therapeutic strategies including recently approved drugs, and provide practical advice and management algorithms for clinicians, with focus on neurogenic orthostatic hypotension, supine hypertension, dysphagia, sialorrhea, gastroparesis, constipation, neurogenic overactive bladder, underactive bladder, and sexual dysfunction. © 2018 International Parkinson and Movement Disorder Society.

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

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.

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

Objectives: To report the preliminary results of the GLOMSAR survey for MSA. Background: Multiple system atrophy (MSA) is a rare fatal synucleinopathy characterized by Parkinsonian, pyramidal, cerebellar, and autonomic features in any combination. The GLObal MSA Registry (GLOMSAR) was established as an online contact registry for patients with MSA. Methods: Members of the Autonomic Disorders Consortium developed a web-based questionnaire comprising of 40-item with yes/no questions to evaluate the chronology and full spectrum of symptoms of MSA. GLOMSAR registrants were contacted by email on April 26 2017 and the survey was administered by the NIH's Rare Diseases Clinical Research Network (RDCRN). Results: Within 7 days, 155 registrants with MSA completed all 40 questions. Mean age was 62 years (range 30-92) and 58% were male. Frequent presenting symptoms were difficultly moving (28%), trouble with blood pressure or urination (23%), REM sleep behavior disorder (i.e., dream reenactment 23%) and falls (14%). Sixty-eight percent had been treated with levodopa and 30% experienced some benefit from it. Fifty-five percent reported using a wheelchair. Urinary incontinence was present in 65 and 30% required intermittent or indwelling urinary catheterization. Constipation occurred in 78%. Visual problems were reported in 65%. Of men, 91% reported erectile dysfunction; of women, 65% reported decreased genital sensation. Other findings included a high prevalence of depression (59%), hallucinations (21%) and a history of head trauma/concussion (22%). Conclusion: The GLOMSAR contact registry and web-based MSA survey are feasible ways to reach patients with MSA. This may be useful to support clinical research in this rare disease

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

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

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 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