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: 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

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

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

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:Blunted tachycardia during hypotension is a characteristic feature of patients with autonomic failure, but the range has not been defined. This study reports the range of orthostatic heart rate (HR) changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. METHODS:Patients evaluated at sites of the U.S. Autonomic Consortium (NCT01799915) underwent standardized autonomic function tests and full neurological evaluation. RESULTS:We identified 402 patients with orthostatic hypotension (OH) who had normal sinus rhythm. Of these, 378 had impaired sympathetic activation, i.e., neurogenic OH, and based on their neurological examination were diagnosed with Parkinson disease, dementia with Lewy bodies, pure autonomic failure or multiple system atrophy. The remaining 24 patients had preserved sympathetic activation and their OH was classified as non-neurogenic, due to volume depletion, anemia or polypharmacy. Patients with neurogenic OH had twice the fall in systolic blood pressure (SBP) [-44±25 vs. -21±14 mmHg (mean±SD), p<0.0001] but only one third of the increase in HR than those with non-neurogenic OH (8±8 vs. 25±11 bpm, p<0.0001). A ΔHR/ΔSBP ratio of 0.492 bpm/mmHg had excellent sensitivity (91.3%) and specificity (88.4%) to distinguish between patients with neurogenic vs. non-neurogenic OH (AUC=0.96, p<0.0001). Within patients with neurogenic OH, HR increased more in those with multiple system atrophy (p=0.0003), but there was considerable overlap with patients with Lewy body disorders. INTERPRETATION/CONCLUSIONS:A blunted HR increase during hypotension suggests a neurogenic cause. A ΔHR/ΔSBP ratio lower than 0.5 bpm/mmHg is diagnostic of neurogenic OH.