Faculty Bibliography

Multiple system atrophy (MSA) is a neurodegenerative disease with two motor phenotypes: parkinsonian (MSA-P) and cerebellar (MSA-C). To elucidate whether in addition to the motor abnormalities there are other significant differences between these phenotypes, we performed a retrospective review of 100 patients (61 males, 39 females) with a diagnosis of possible (12 %), or probable (88 %) MSA. Four patients eventually had post-mortem confirmation (i.e., definite MSA). Sixty percent were classified as having MSA-P and 40 % as MSA-C. MSA-C and MSA-P patients had similar male prevalence (60 %), age of onset (56 +/- 9 years), and frequency of OH (69 %). Brain MRI abnormalities were more frequent in MSA-C patients (p < 0.001). Mean survival was 8 +/- 3 years for MSA-C and 9 +/- 4 years for MSA-P patients (p = 0.22). Disease onset before 55 years predicted longer survival in both phenotypes. Initial autonomic involvement did not influence survival. We conclude that patients with both motor phenotypes have mostly similar survivals and demographic distributions. The differences here identified could help counseling of patients with MSA.

To define the retinal phenotype of subjects with familial dysautonomia (FD). A cross-sectional study was carried out in 90 subjects divided in three groups of 30 each (FD subjects, asymptomatic carriers and controls). The study was developed at the Dysautonomia Center, New York University Medical Center. All subjects underwent spectral domain optical coherence tomography (OCT) and full neuro-ophthalmic examinations. In a subset of affected subjects, visual evoked potentials and microperimetry were also obtained. We compared the retinal nerve fiber layer (RNFL) thickness from OCT between the three groups. OCT showed loss of the RNFL in all FD subjects predominantly in the maculopapillary region (63 % temporally, p < 0.0001; and 21 % nasally, p < 0.005). RNFL loss was greatest in older FD subjects and was associated with decreased visual acuity and color vision, central visual field defects, temporal optic nerve pallor, and delayed visual evoked potentials. Asymptomatic carriers of the FD gene mutation all had thinner RNFL (12 % globally, p < 0.005). OCT and clinical neuro-ophthalmological findings suggest that maculopapillary ganglion cells are primarily affected in FD subjects, leading to a specific optic nerve damage that closely resembles mitochondrial optic neuropathies. This raises the possibility that reduced IKAP levels may affect mitochondrial proteins and their function in the nervous system, particularly in the retina.

BACKGROUND: No available treatments slow or halt progression of multiple system atrophy, which is a rare, progressive, fatal neurological disorder. In a mouse model of multiple system atrophy, rifampicin inhibited formation of alpha-synuclein fibrils, the neuropathological hallmark of the disease. We aimed to assess the safety and efficacy of rifampicin in patients with multiple system atrophy. METHODS: In this randomised, double-blind, placebo-controlled trial we recruited participants aged 30-80 years with possible or probable multiple system atrophy from ten US medical centres. Eligible participants were randomly assigned (1:1) via computer-generated permuted block randomisation to rifampicin 300 mg twice daily or matching placebo (50 mg riboflavin capsules), stratified by subtype (parkinsonian vs cerebellar), with a block size of four. The primary outcome was rate of change (slope analysis) from baseline to 12 months in Unified Multiple System Atrophy Rating Scale (UMSARS) I score, analysed in all participants with at least one post-baseline measurement. This study is registered with ClinicalTrials.gov, number NCT01287221. FINDINGS: Between April 22, 2011, and April 19, 2012, we randomly assigned 100 participants (50 to rifampicin and 50 to placebo). Four participants in the rifampicin group and five in the placebo group withdrew from study prematurely. Results of the preplanned interim analysis (n=15 in each group) of the primary endpoint showed that futility criteria had been met, and the trial was stopped (the mean rate of change [slope analysis] of UMSARS I score was 0.62 points [SD 0.85] per month in the rifampicin group vs 0.47 points [0.48] per month in the placebo group; futility p=0.032; efficacy p=0.76). At the time of study termination, 49 participants in the rifampicin group and 50 in the placebo group had follow-up data and were included in the final analysis. The primary endpoint was 0.5 points (SD 0.7) per month for rifampicin and 0.5 points (0.5) per month for placebo (difference 0.0, 95% CI -0.24 to 0.24; p=0.82). Three (6%) of 50 participants in the rifampicin group and 12 (24%) of 50 in the placebo group had one or more serious adverse events; none was thought to be related to treatment. INTERPRETATION: Our results show that rifampicin does not slow or halt progression of multiple system atrophy. Despite the negative result, the trial does provide information that could be useful in the design of future studies assessing potential disease modifying therapies in patients with multiple system atrophy. FUNDING: National Institutes of Health, Mayo Clinic Center for Translational Science Activities, and Mayo Funds.

It is now well recognized that there is a premotor phase of Parkinson's disease (PD) with hyposmia and REM sleep behavior disorder caused by degeneration of specific CNS neurons. Most patients with PD describe autonomic symptoms at the time of diagnosis suggesting that these features may have potential sensitivity as clinical biomarkers of the premotor phase. The recognition that damage to peripheral autonomic neurons is present in the early stages of PD has led to a search for specific abnormalities in autonomic function that could serve as predictive biomarkers. There is evidence that constipation, urinary and sexual dysfunction and more recently decreased cardiac chronotropic response during exercise, are part of the premotor parkinsonian phenotype. The sensitivity and specificity of these features has yet to be accurately assessed. We briefly review the evidence for autonomic dysfunction as biomarker of premotor PD.

Objective: To determine the prevalence and impact of depression in patients with multiple system atrophy (MSA). Methods: 31 patients with a diagnosis of probable MSA (age 61 +/- 8.8 years, mean +/- SD), 15 (5 men, 10 women) with predominant cerebellar ataxia (MSA-C) and 16 (9 men and 7 women) with predominant parkinsonism (MSA-P) were enrolled in the study. All assessments were performed at baseline and repeated after 6-12 months. After complete neurological examination and autonomic testing, patients completed the Zung Depression scale, Spielberg's state-trait anxiety scales, Body Vigilance Scale, Scale for Outcomes in Parkinson disease-autonomic (SCOPA-AUT), the Composite Autonomic Symptom Score (COMPASS) and Short Form Quality of Life (SF36) scale. A trained investigator administered the Unified Multiple System Atrophy Scale (UMSARS-I and UMSARSII) and the Orthostatic Hypotension Questionnaire (OHQ). Results: Twenty patients (65 %) scored as having depressive symptoms (10 mild, 8 moderate and 2 severe). Depressed patients had significantly higher scores of trait-anxiety (p<0.02) and body vigilance (p<0.04), higher UMSARS-I scores at follow-up (p<0.02) with faster progression of symptoms from baseline to follow-up visit, and more pronounced symptoms of orthostatic hypotension (p< 0.003). Depression scores correlated with lower physical (p<0.02) and social functioning (p<0.001) on the SF36-quality-of-life questionnaire, with the gastrointestinal dysfunction domain (p<0.005) of the SCOPA questionnaire, with the COMPASS score (p<0.01) and with higher UMSARS-I (p<0.02) and UMSARS-II (p<0.01) scores at follow-up. For each unit increase in the depression scale the UMSARS-I increased by 0.214 points (p<0.056) and UMSARS-II increased by 0.035 points per month (p<0.046). Conclusion: Depression affects more than half of MSA patients. It impacts the perceived progression and severity of motor and autonomic symptoms and is associated with decreased physical and social functioning. Appropriate psychologic!

Spinal pseudomeningoceles are extramural cerebrospinal fluid (CSF) collections that communicate with the CSF space around the spinal cord. We describe an 81-year-old man who presented with recurrent episodes of brief loss of consciousness (LOC) and collapse following an L3-4 discectomy complicated by the development of a spinal pseudomeningocele containing approximately 200 cc of CSF (as determined by MRI). LOC occurred both when standing and when the pseudomeningocele in his back was compressed when laying down. Transcranial Doppler (TCD) of his right middle cerebral artery (MCA) during manual compression of the pseudomeningocele (in the sitting position) showed maintained systolic but absent diastolic blood flow while systemic blood pressure was unchanged. When standing, TCD of the MCA showed similar findings and a small fall in systemic blood pressure. The absence of blood pressure changes and the observed TCD pattern in the MCA, which is consistent with collapse of the artery during diastole, suggest that the episodes of loss of consciousness were due to increased intracranial pressure (ICP). Increased ICP is easily explained as a result of displacement of CSF from the pseudomenigocele towards the cranium. Standing, however, should cause a reduction in ICP as CSF could travel down towards the lumbar pseudomeningocele. Possible explanations of increased ICP while standing include involuntary Valsalva-like maneuver similar to "cough syncope," mechanical obstruction preventing CSF outflow, or external compression of the pseudomeningocele by extensor back muscles. In patients with syncopal episodes following discectomies the possibility of a pseudomeningocele should be considered

Objective: To determine the efficacy of rifampicin in multiple system atrophy (MSA). Background: MSA is a rapidly progressive disorder characterized by autonomic failure with parkinsonism and/or cerebellar ataxia. Its hallmark is glial cytoplasmic inclusions consisting of aggregated a-synuclein. In a transgenic mouse model of MSA, rifampicin inhibits formation and disaggregates a-synuclein fibrils and improves both behavioral and neuropathological changes. Methods: We undertook a randomized, double-blind, placebo-controlled 12-month clinical safety/efficacy study of 100 subjects with possible or probable MSA, 50 % randomized to active drug (rifampicin 300 mg BID), 50 % to placebo (riboflavin capsules BID). Subjects were recruited from 10 US sites. Inclusion criteria: men and women ages 30-80 years;<4 years from diagnosis; expected survival C3 years; MMSE >24. The primary outcome measure was rate of change from baseline to 12 months in total UMSARS I score (minus Q11). A planned interim analysis was conducted after 30 subjects had completed 12 months. Results: 100 subjects were randomized: 43 % women and 57 % men, mean age 61.1 +/- 9.2 (mean +/- SD, age range 41.7-79.9 years, 48 % possible MSA, 52 % probable MSA. There were 18 serious adverse events, none considered likely due to treatment. 9 subjects withdrew from study. The DSMB recommended the study stop as futility criteria were met. In final analysis on 100 subjects, the primary endpoint for placebo was 0.5 +/- 0.5, rifampicin 0.5 +/- 0.7, p = 0.82. Conclusions: No beneficial effects were observed of rifampicin in slowing or halting the progression of MSA. The ARDC consortium has established an infrastructure to carry out studies in MSA and has demonstrated the feasibility of conducting clinical trials

Afferent baroreflex failure occurs in the genetic disorder familial dysautonomia (FD) and in patients with acquired lesions of the afferent baroreflex pathways. Afferent baroreflex failure is characterized by extremely labile blood pressure, with paroxysmal hypertension due to unrestrained norepinephrine release, which may result in targetorgan damage. These hypertensive episodes are traditionally managed with the alpha-2-receptor agonist clonidine, but this produces profound hypotension, fatigue and rebound hypertension. Carbidopa is a competitive reversible inhibitor of the enzyme dopa-decarboxylase that does not cross the blood brain barrier. Here we examined the effect of carbidopa on norepinephrine production and blood pressure variability in 12 patients with FD and 3 with acquired afferent baroreflex failure. Patients underwent a 24-h urine collection and simultaneous ambulatory blood pressure monitoring at baseline (pretreatment) and while taking carbidopa. Catecholamine excretion was measured using high performance liquid chromatography (HPLC). Blood pressure variability was calculated from the standard deviation of blood pressure values captured at 20-min intervals during waking hours. Mean dose of carbidopa was 500 mg per day. Compared to baseline, carbidopa significantly reduced norepinephrine excretion (32 +/- 9 vs. 12 +/- 1 lg/gCr, p<0.001) and blood pressure variability (25 +/- 3 vs. 19 +/- 3 mmHg, p<0.03). Carbidopa reduced the highest blood pressure value captured on ambulatory monitoring from 175 +/- 6 to 155 +/- 9 mmHg (p<0.03), while the lowest captured blood pressure values were similar pre and post-treatment. Carbidopa inhibits the downstream production of norepinephrine and is a novel approach to treating paroxysmal hypertension in patients with genetic or acquired afferent baroreflex failure

Familial dysautonomia (FD) is caused by a splicing error in the IKBKAP gene that encodes human Elongator protein-1 (ELP-1). In these patients, exon 20 is frequently skipped duringmRNA splicing, but cells retain the ability to produce a lowlevel of normal (wild-type) IKBKAPmRNAand normal protein. Phosphatidylserine (PS, Sharp-thought), an acidic phospholipid, has been shown to raise elongator protein-1 levels by increasing IKBKAPtranscription in fibroblast cell-lines derived fromFD patients and, more recently, in a mouse model of FD. Given that PS is available over the counter, weconducted a study to determinewhether PS raises IKBKAP gene expression in patients with FD. We enrolled 7 patients with FD, 16-23 years old, in an open-label titration protocol. Patients were examined at baseline (visit 1), after 2 months of taking 300 mg/day (visit 2) and again after 2 months of taking 600 mg/day of PS(visit 3).Bloodwas taken at each visit. Sampleswere de-identified and investigators blinded to the sample identity. Blood was treated with Tri- Reagent, and RNA extracted according to manufacturers specifications. Quantitative polymerase chain reaction (qPCR) was performed to measure the level of normal IKBKAPmRNA. PSwas well tolerated and there were no adverse events or unexpected laboratory abnormalities. After 2 months of taking 300 mg of PS per day, there was a trend for IKBKAP mRNA levels to increase. After 2 months of 600 mg of PS per day, IKBKAPmRNAexpression increased between 2 and 8 fold in all but one patient (p<0.01). Our results indicate that PS safely raises wild-type IKBKAP mRNA levels in blood from patients with FD, opening an exciting potential therapeutic path for treatment. Clinical trials to determine whether restoring Elongator protein 1 levels impacts the phenotype are underway