Faculty Bibliography

Synucleinopathies, including Parkinson's disease (PD), Dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are all characterized by aggregation and deposition of alpha-synuclein in the brain. Developing reliable bio-markers that can distinguish among the synucleinopathies is an urgent public health need. Multiple observations suggest that misfolding and self-association of alpha-synuclein into oligo-mers and aggregates cause neural dysfunction and neurode-generation in these diseases. Nonetheless, diagnosis of synucleinopathies is challenging due to overlapping symptoms among the synucleinopathies themselves and with other atypical parkinsonian syndromes. Exosomes are nano-sized vesicles shed by 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 isolated from patient blood could serve as a biomarker for synu-cleinopathoies. Major objectives of this study were: 1) To determine if measuring alpha-synuclein in serum exosomes from neurons and oligodendrocytes can distinguish between healthy controls and patients with PD or MSA, 2) To test whether analyzing alpha-synuclein in neuronal and oligodendrog-lial exosomes can distinguish between PD and MSA. Neuro-nal and oligodendroglial exosomes were isolated from serum of 50 controls, 50 patients with PD, and 30 patients with MSA. alpha-Synuclein concentration was measured using electro-chemiluminescence ELISA. Significantly higher concentrations of alpha-synuclein were found in both neuronal and oligodendroglial exosomes from patients than in controls. alpha-Synuclein in oligodendroglial exosomes distinguished patients with MSA from healthy controls with 100.0% sensi-tivity 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 90.0% sensitivity and 90.0% specificity. In conclusion, alpha-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 blood test

Patients with hereditary sensory and autonomic neuropathy type III(HSAN III) exhibit marked gait disturbances. The cause of the gaitataxia is not known, but we recently showed that functional musclespindle afferents in the leg, recorded via intraneural microelectrodesinserted into the peroneal nerve, are absent in HSAN III, althoughlarge-diameter cutaneous afferents are intact. Moreover, there is atight correlation between loss of proprioceptive acuity at the knee andthe severity of gait impairment. Here we tested the hypothesis thatmanual motor performance is also compromised in HSAN III,attributed to the predicted absence of muscle spindles in the intrinsicmuscles of the hand. Manual performance in the Purdue pegboardtask was assessed in 12 individuals with HSAN III and 12 age-matched healthy controls. The mean (+/- SD) pegboard score (number ofpins inserted in 30 s) was 8.1 +/- 1.9 and 8.6 +/- 1.8 for the left andright hand respectively, significantly lower than the scores for thecontrols (14.3 +/- 2.9 and 15.5 +/- 2.0; P <0.0001). In five patients weinserted a tungsten microelectrode into the ulnar nerve at the wrist.No spontaneous or stretch-evoked muscle afferent activity could beidentified in any of the 11 fascicles supplying intrinsic muscles of thehand, whereas rich tactile afferent activity could be recorded from 4cutaneous fascicles. We conclude that functional muscle spindles areabsent in the hand, and likely absent in the long finger flexors andextensors, and that this largely accounts for the poor manual motorperformance in HSAN III

Introduction: Deep brain stimulation (

Objective: To assess the diagnostic yield of early-onset autonomicfailure in distinguishing the parkinsonian variant of multiple systematrophy from Parkinson's disease.
Method(s): Three-hundred and three patients with an MRI-supporteddiagnosis of multiple system atrophy-Parkinsonian (n = 71) orParkinson's disease (n = 232)-were retrospectively studied.According to their disease stage and duration at the time of cardiovascular autonomic function testing, patients were divided into earlydisease (Hoehn and Yahr stage\3 AND/OR disease duration\2 years) or advanced disease (Hoehn and Yahr stage C 3AND disease duration C 2 years) and features predictive of multiplesystem atrophy at last-available visit were investigated. A diagnosticprobability score was generated based on the discriminant variables inthe early disease group.
Result(s): In patients at early disease, the presence of orthostatichypotension (OR 6.50, 1.6-26.7 95% CI, p = 0.009), urinary disturbances (OR 22.1, 3.7-150.9 95% CI, p = 0.002) and posturalinstability (OR 27.9, 2.9-269.4 95% CI, p = 0.004) predicted multiplesystem atrophy at last-available visit. By assigning 1 point per abovementioned clinical feature, a cumulative probability score C 2 (scorerange 0-3) showed a 74.1% sensitivity and 90.1% specificity for afinal diagnosis of multiple system atrophy-Parkinsonian. Atadvanced disease, the presence of urinary disturbances (OR 3.0,1.0-8.7 95% CI, p = 0.05), but not of orthostatic hypotension, wasdistinctive of multiple system atrophy.
Interpretation(s): Autonomic failure featured both in Parkinson's disease and multiple system atrophy, but its early developmentanticipated a diagnosis of multiple system atrophy at follow-up.Parkinsonian patients presenting with 2 or more clinical features outof urinary disturbances, orthostatic hypotension or postural instabilitywithin the first 2 years of disease, have a high probability of sufferingfrom the parkinsonian variant of multiple system atrophy

BACKGROUND:Familial dysautonomia (Riley-Day syndrome, hereditary sensory autonomic neuropathy type-III) is a rare genetic disease caused by impaired development of sensory and afferent autonomic nerves. As a consequence, patients develop neurogenic dysphagia with frequent aspiration, chronic lung disease, and chemoreflex failure leading to severe sleep disordered breathing. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of respiratory disorders in familial dysautonomia. METHODS:We performed a systematic review to summarize the evidence related to our questions. When evidence was not sufficient, we used data from the New York University Familial Dysautonomia Patient Registry, a database containing ongoing prospective comprehensive clinical data from 670 cases. The evidence was summarized and discussed by a multidisciplinary panel of experts. Evidence-based and expert recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. RESULTS:Recommendations were formulated for or against specific diagnostic tests and clinical interventions. Diagnostic tests reviewed included radiological evaluation, dysphagia evaluation, gastroesophageal evaluation, bronchoscopy and bronchoalveolar lavage, pulmonary function tests, laryngoscopy and polysomnography. Clinical interventions and therapies reviewed included prevention and management of aspiration, airway mucus clearance and chest physical therapy, viral respiratory infections, precautions during high altitude or air-flight travel, non-invasive ventilation during sleep, antibiotic therapy, steroid therapy, oxygen therapy, gastrostomy tube placement, Nissen fundoplication surgery, scoliosis surgery, tracheostomy and lung lobectomy. CONCLUSIONS:Expert recommendations for the diagnosis and management of respiratory disease in patients with familial dysautonomia are provided. Frequent reassessment and updating will be needed.

PURPOSE/OBJECTIVE:Patients suffering from cardiovascular autonomic failure often develop neurogenic supine hypertension (nSH), i.e., high blood pressure (BP) in the supine position, which falls in the upright position owing to impaired autonomic regulation. A committee was formed to reach consensus among experts on the definition and diagnosis of nSH in the context of cardiovascular autonomic failure. METHODS:As a first and preparatory step, a systematic search of PubMed-indexed literature on nSH up to January 2017 was performed. Available evidence derived from this search was discussed in a consensus expert round table meeting in Innsbruck on February 16, 2017. Statements originating from this meeting were further discussed by representatives of the American Autonomic Society and the European Federation of Autonomic Societies and are summarized in the document presented here. The final version received the endorsement of the European Academy of Neurology and the European Society of Hypertension. RESULTS:In patients with neurogenic orthostatic hypotension, nSH is defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, measured after at least 5 min of rest in the supine position. Three severity degrees are recommended: mild, moderate and severe. nSH may also be present during nocturnal sleep, with reduced-dipping, non-dipping or rising nocturnal BP profiles with respect to mean daytime BP values. Home BP monitoring and 24-h-ambulatory BP monitoring provide relevant information for a customized clinical management. CONCLUSIONS:The establishment of expert-based criteria to define nSH should standardize diagnosis and allow a better understanding of its epidemiology, prognosis and, ultimately, treatment.

OBJECTIVE:Familial dysautonomia (FD) is an autosomal recessive disorder characterized by impaired development of sensory and afferent autonomic nerves. Untreated sleep-disordered breathing (SDB) has been reported to increase the risk of sudden unexpected death in FD. We aimed to describe the prevalence and characteristics of SDB in FD. PATIENTS/METHODS/METHODS:measurements during different sleep stages. RESULTS:Overall, 85% of adults and 91% of pediatric patients had some degree of SDB. Obstructive sleep apneas were more severe in adults (8.5 events/h in adults vs. 3.5 events/h in children, p = 0.04), whereas central apneas were more severe (10.8 vs. 2.8 events/h, p = 0.04) and frequent (61.8% vs. 45%, p = 0.017) in children. Overall, a higher apnea-hypopnea index was associated with increased severity of hypoxia and hypoventilation, although in a significant fraction of patients (67% and 46%), hypoxemia and hypoventilation occurred independent of apneas. CONCLUSION/CONCLUSIONS:monitoring during polysomnography in all patients with FD to detect SDB.