Faculty Bibliography

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: 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

Divergolide I (1) is a naphthoquinone ansamycin that exhibits broad antibacterial activity. Its tetracyclic ring system is believed to be biosynthetically assembled via ring contraction of a macrocyclic precursor (proto-divergolide) that is both a macrolactone and a macrolactam. We here report a convergent and enantioselective synthesis that delivers the target molecule in less than 20 linear steps. Our work establishes the absolute configuration of divergolide I, confirms its relative configuration, and demonstrates that the biomimetic cyclization of a proto-divergolide can be surprisingly selective.

A concise route to the azatricyclo[6.2.1.0^4,11]undecane core of (-)-dendrobine and (-)-mubironine C is described wherein an unstabilized azomethine ylide cycloaddition provides the complete carbon framework of the natural products. The cyclization precursor is made in short order from ( R)-carvone through an unconventional high-pressure Ireland-Claisen reaction. Attempts to install a final hydroxyl group through an intramolecular lactonization strategy and the observation of an unexpected and highly complex enal-ene product are also reported.

PURPOSE/OBJECTIVE:profiles in the longitudinal (z) direction and allow for next-nearest neighbor decoupling. METHODS:Two cylindrical 8-channel arrays having the same length and diameter, 1 of triangular coils and the other of rectangular coils, were constructed and compared in phantom imaging experiments using measures of excitation distribution for a variety of RF shim settings and geometry factor maps for different accelerations on different planes. RESULTS:Coupling between elements was -20 dB or better for all triangular coil pairs, but worse than -12 dB for several of the rectangular coil pairs. Both coils could produce adequate shims on a central transverse plane, but the same shim produced worse results off center for the triangular coil array than for the rectangular coil array. Compared to the rectangular coil array, the maximum geometry factor for the triangular coil array was reduced by a factor of 13.1 when using a 2-fold acceleration in the z-direction. CONCLUSION/CONCLUSIONS:profiles along the z-direction, although this also means that individual slices must be shimmed separately. This design is well suited for parallel transmit applications while also having high receive sensitivity.

An approach toward (-)-enterocin, an antibiotic isolated from Streptomyces hygroscopicus, is described. Its compact, heavily oxidized protoadamantane core represents a daunting challenge for an efficient synthesis. Convergent assembly of its 2-oxabicyclo[3.3.1]nonane core with a cuprate-mediated Barbier reaction is disclosed. Its functionalization to a suitable substrate for a biomimetic aldol to close the final ring of the natural product is evaluated.

Holographic speckle is a major impediment to computer-generated holographic (CGH) projections in applications ranging from display, optical tweezers, and machining to optogenetic neural control. We present an iterative phase retrieval algorithm that allows the projection of amplitude-controlled speckle-free one-dimensional patterns with a high degree of pattern uniformity. The algorithm, termed the weighted Gerchberg-Saxton with phase-control (GSW-PC), is shown to have the ability to simultaneously control both the phase and amplitude of projected patterns with high diffraction efficiencies. Furthermore, we show that the framework can address the challenge of projecting volumetric phase and amplitude-controlled patterns, by incorporating GSW-PC with the angular spectrum method. The algorithms' performance is numerically and experimentally tested, and further compared with conventional and modern CGH techniques.

Transcranial electric stimulation is a non-invasive tool that can influence brain activity; however, the parameters necessary to affect local circuits in vivo remain to be explored. Here, we report that in rodents and human cadaver brains, ~75% of scalp-applied currents are attenuated by soft tissue and skull. Using intracellular and extracellular recordings in rats, we find that at least 1 mV/mm voltage gradient is necessary to affect neuronal spiking and subthreshold currents. We designed an 'intersectional short pulse' stimulation method to inject sufficiently high current intensities into the brain, while keeping the charge density and sensation on the scalp surface relatively low. We verify the regional specificity of this novel method in rodents; in humans, we demonstrate how it affects the amplitude of simultaneously recorded EEG alpha waves. Our combined results establish that neuronal circuits are instantaneously affected by intensity currents that are higher than those used in conventional protocols.