Faculty Bibliography

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

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

Hereditary sensory and autonomic neuropathy type III (HSAN III)features a marked ataxic gait that progressively worsens over time.We recently assessed whether proprioceptive disturbances can explainthe ataxia. Proprioception at the knee joint was assessed using passivejoint angle matching in 18 patients and 14 age-matched controls; fivepatients with cerebellar ataxia were also studied. Ataxia was quantified using the Brief Ataxia Rating Score, which ranged from 7 to26/30. Patients with HSAN III performed poorly in judging jointposition at the knee: mean (+/- SE) absolute error was 8.7 +/- 1.0 andthe range was very wide (2.8-18.1); conversely, absolute error wasonly 2.7 +/- 0.3 (1.6-5.5) in the controls and 3.0 +/- 0.2 (2.1-3.4) in the cerebellar patients. This error was positively correlated tothe degree of ataxia in patients with HSAN III but not in patients withcerebellar ataxia. However, using the same approach at the elbowrevealed no significant differences in mean error in 12 patients withHSAN III (4.8 +/- 1.2; 3.0-7.2) and 12 age-matched controls(4.1 +/- 1.1; 2.1-5.5). Interestingly, microelectrode recordingsfrom the peroneal nerve showed a complete absence of spontaneousor stretch-evoked muscle afferent activity, confirmed in the ulnarnerve. Clearly, the lack of muscle spindles compromised proprioception at the knee but not at the elbow, and we suggest that patientswith HSAN III have learned to rely more on proprioceptive signalsfrom the skin around the elbow. Indeed, applying longitudinal stripsof elastic tape around the joint to increase tensile strain in the skinimproved proprioception at the knee but not the elbow

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.