Faculty Bibliography

Introduction: Autonomic dysfunction in Parkinson's disease (PD) is common and a major determinant of poor outcomes. The primary aim of this study was to examine the relationship of longitudinal changes in autonomic symptom burden and longitudinal changes in activity of daily living (ADL) function.
Method(s): Data from the Parkinson's Progression Markers Initiative (PPMI), a natural history database of patients with newly diagnosed (within 2 years) PD, were used for this analysis. Datapoints from visit 6 (24 months after enrollment), and visit 12 (60 months after enrollment) were investigated, along with baseline data. We examined the impact of longitudinal changes in the Scales for Outcomes in Parkinson's disease-Autonomic (SCOPA-AUT) on longitudinal changes in the Schwab and England ADL function scale. As a secondary analysis, we performed a mediation analysis to investigate whether longitudinal changes in symptoms of depression, as measured with the Geriatric Depression Scale (GDS), mediate the relationship between longitudinal changes in autonomic symptom burden and ADL function.
Result(s): Though changes in autonomic symptom burden, cognitive function, depression, and motor function all correlated with ADL function, only changes in ADL function and depression were associated with changes in autonomic symptom burden. We found that longitudinal change in autonomic symptoms was a significant predictor of change in ADL function at 24 months and 60 months, with the cardiovascular subscore proving to be a major driver of this association. Mediation analysis revealed that the association between autonomic symptoms and ADL function is partially mediated by depression severity.
Conclusion(s): Longitudinal changes in autonomic symptoms appear to impact ADL function in early PD, both directly and indirectly through their impact on depressive symptoms. Future investigation is warranted into the impact of treatment of autonomic symptoms and depressive symptoms on outcomes of ADL function and quality of life measures in PD

Background: Multiple system atrophy (MSA) is a fatal and poorly understood rare neurodegenerative disorder. Here we describe the baseline characteristics of patients with MSA enrolled in a prospective multicenter and multinational NIH-sponsored Natural History Study of the Synucleinopathies.
Method(s): Patients with a clinical diagnosis of probable or possible MSA were prospectively enrolled at 11 participating centers. Demographic data, clinical variables, and autonomic testing results were included.
Result(s): 293 patients with MSA (125 women) have been enrolled. MSA-C was predominant (154 patients, 52.6%). Mean age at symptom onset was 57.6+/-8.4 (mean+/-SD) and at enrollment was 62.0+/-7.8 years old. UMSARS-1 was 21.1+/-7.6 and UMSARS-2 was 21.2+/-9.1. MoCA score was 26.3+/-4.4 indicating normal cognition. In the supine position, blood pressure (systolic BP/diastolic BP) was 143.0+/-25.2/84.0+/-14.5 mmHg, and heart rate was 75.0+/-11.5 bpm. After 3-min head-up tilt, BP fell to 113.1+/-25.5/69.6+/-15.9 mmHg and HR increased to 82.9+/-12.7 bpm. Supine plasma norepinephrine levels were 365.4+/-408.5 pg/ml and increased only to 449.8+/-277.2 pg/ml upon head-up tilt indicating impaired baroreflex-mediated sympathetic activation. The University of Pennsylvania Smell Identification Test (UPSIT) score was 28.5+/-8.1 indicating preserved olfaction. Probable rapid eye movement (REM) sleep behavior disorder was reported by 85%.
Conclusion(s): This is the largest cross-sectional sample of patients with MSA recruited consecutively reported so far. Our results confirm that: i) symptom onset in MSA is remarkable consistent at 57 years; ii) overt cognitive impairment is not a typical feature; iii) sympathetic and cardiovagal deficits are present; iv) olfaction is preserved, and; v) probable REM behavior disorder is very frequent. The prospective follow-up of these patients will provide additional information on the natural history of the disease

Background: Disease progression of multiple system atrophy (MSA) as measured by the Unified Multiple System Atrophy Rating Scale (UMSARS) varied significantly in natural history studies. Reported 1-year UMSARS-1 and UMSARS-2 progression rates ranged from 3.9 to 6.5 and 3.5 to 8.2, respectively. We hypothesize that this variability is due, at least in part, to differences in severity at enrollment and a potential ceiling effect in the scale, so that patients in more advanced stages may appear to worsen less, which would have important implications for clinical trial design.
Method(s): We analyzed the rate of change in the UMSARS in a large international cohort of well-characterized patients with a clinical diagnosis of possible or probable MSA enrolled in the Natural History Study of Synucleinopathies. Annualized progression rates were obtained using 2-year follow-up data.
Result(s): 293 patients (62.0+/-7.8 years old) with MSA were enrolled. Disease duration was 4.5+/-3.6 years. 98 patients completed 1-year evaluations and 48 completed the 2-year evaluation. The 12-month progression rates were 5.5+/-5.3 for the UMSARS-I, 6.6+/-5.2 for the UMSARS-II, and 11.9+/-9.8 for the total score. The 24-month progression rates were 10.8+/-7.1 for the UMSARS-I, 12.5+/-7.9 for the UMSARS-II, and 22.6+/-13.7 for the total score. Annualized progression rates were divided according to their baseline UMSARS-I and UMSARS II. There was a significant (p=0.0461) inverse relationship between rate of progression and UMSARS-I at baseline. A similar, but not significant trend was observed with UMSARS-II at baseline.
Conclusion(s): The rate of progression as measured by UMSARS is influenced by the baseline disease severity. A ceiling effect should be considered when planning enrollment, power calculations, and outcome measures in clinical trials

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.