Faculty Bibliography

Introduction: Deep brain stimulation (

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 & Autonomic Neuropathy type III exhibit marked ataxia, including gait disturbances. We recently showed that functional muscle spindle afferents in the leg, recorded via intraneural microelectrodes inserted into the peroneal nerve, are absent in HSAN III, although large-diameter cutaneous afferents are intact. Moreover, there is a tight correlation between loss of proprioceptive acuity at the knee and the severity of gait impairment. We tested the hypothesis that manual motor performance is also compromised in HSAN III, attributed to the predicted absence of muscle spindles in the intrinsic muscles of the hand. Manual performance in the Purdue pegboard task was assessed in 12 individuals with HSAN III and 11 age-matched healthy controls. The mean (SD) pegboard score (number of pins inserted in 30 s) was 8.11.9 and 8.61.8 for the left and right hand respectively, significantly lower than the scores for the controls (15.01.3 and 16.01.1; p<0.0001). Performance was not improved after applying kinesiology tape over the joints of the hand. In five patients we inserted a tungsten microelectrode into the ulnar nerve at the wrist. No spontaneous or stretch-evoked muscle afferent activity could be identified in any of the 11 fascicles supplying intrinsic muscles of the hand, whereas rich tactile afferent activity could be recorded from four cutaneous fascicles. We conclude that functional muscle spindles are absent in the hand, and most likely absent in the long finger flexors and extensors, and that this largely accounts for the poor manual motor performance in HSAN III.

OBJECTIVE:To test whether the plasma levels of norepinephrine (NE) in patients with neurogenic orthostatic hypotension (nOH) predict their pressor response to droxidopa. METHODS:This was an observational study, which included patients with nOH. All patients had standardized autonomic function testing including determination of venous plasma catecholamine levels drawn through an indwelling catheter while resting supine. This was followed by a droxidopa titration with 100 mg increments in successive days until relief of symptoms, side effects, or the maximum dose of 600 mg was reached. No response was defined as an increase of <10 mm Hg in systolic blood pressure (BP) after 3-minute standing 1 hour after droxidopa administration. Nonlinear regression models were used to determine the relationship between BP response and plasma NE levels. RESULTS:= 0.0023). CONCLUSIONS:In patients with nOH, lower supine resting plasma NE levels are associated with a greater pressor effect of droxidopa treatment. This finding should help identify patients with nOH most likely to respond to standard doses of droxidopa. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class I evidence that lower supine plasma NE levels accurately identify patients with nOH more likely to have a greater pressor effect from droxidopa.