Effect of augmenting cholinergic function on gait and balance.

BACKGROUND: Impaired mobility and falls are clinically important complications of Parkinson's disease (PD) and a major detractor from quality of life for which there are limited therapies. Pathological, neuroimaging and clinical evidence suggest that degeneration of cholinergic systems may contribute to impairments of balance and gait in PD. The proposed trial will examine the effects of augmentation of the cholinergic system on balance and gait. DESIGN: The study is a single-site, proof of concept, randomized, double-blind, cross-over trial in patients with PD. Each treatment period will be 6 weeks with a 6-week washout between treatments for a total of 18 weeks for each subject. Donepezil in 2.5 mg capsules or identical appearing placebo capsules will be increased from two per day (5 mg) to four capsules (10 mg) after 3 weeks, if tolerated. Subjects will have idiopathic Parkinson's disease, Hoehn and Yahr stages 2 to 4. We anticipate recruiting up to 100 subjects for screening to have 54 enrolled and 44 subjects complete both phases of treatment. Dropouts will be replaced. As this is a crossover trial, all subjects will be exposed to both donepezil and to placebo. The primary outcome measures will be the root mean square of the mediolateral sway when standing and the variability of the stride duration when walking for two minutes. Secondary outcomes will be the computerized Attention Network Test to examine three domains of attention and the Short-latency Afferent Inhibition (SAI), a physiological marker obtained with transcranial magnetic stimulation as a putative marker of cholinergic activity. DISCUSSION: The results of this study will be the most direct test of the hypothesized role of cholinergic neurotransmission in gait and balance. The study is exploratory because we do not know whether donepezil will affect gait, balance or attention, nor which measures of gait, balance or attention will be sensitive to drug manipulation. We hypothesize that change in cholinergic activity, as measured with SAI, will predict the relative effectiveness of donepezil on gait and balance. Our immediate goal is to determine the potential utility of cholinergic manipulation as a strategy for preventing or treating balance and gait dysfunction in PD. The findings of this trial are intended to lead to more sharply focused questions about the role of cholinergic neurotransmission in balance and gait and eventually to Phase II B trials to determine clinical utility of cholinergic manipulation to prevent falls and improve mobility. TRIAL REGISTRATION: This trial is registered at clinical trials.gov ( NCT02206620).

Dyskinesia and the antiparkinsonian response always temporally coincide: a retrospective study.

OBJECTIVE: To clinically characterize the temporal relationship between dyskinesia and the antiparkinsonian response when dyskinesia first emerges during long-term levodopa therapy and to determine if it is consistent with the hypothesized mechanism by which dyskinesia develops. METHODS: Dyskinesia and the antiparkinsonian response to levodopa during 2-hour levodopa infusions were monitored at intervals through the first 4 years of long-term levodopa therapy in 20 subjects with idiopathic Parkinson disease (PD) and previously untreated with levodopa. The onset and offset of the antiparkinsonian response and dyskinesia were compared when dyskinesia first appeared during the 4 years. The findings were compared to 20 subjects with PD on long-term levodopa with dyskinesia and motor fluctuations. RESULTS: The onset and offset of the antiparkinsonian response and dyskinesia generally coincided when dyskinesia first appeared during the 4 years and did not suggest any temporal dissociation of the 2 responses. Further, the latency to the onsets of dyskinesia and the antiparkinsonian response tended to shorten during long-term levodopa therapy, suggesting that both responses were sensitized by long-term levodopa. CONCLUSIONS: The similar onsets and offsets of the antiparkinsonian response and dyskinesia when dyskinesia first appears are not consistent with the postulated progressive decrease in threshold for dyskinesia during long-term levodopa therapy. Other mechanisms for the development of dyskinesia need to be considered.

Group B streptococcus induces trophoblast death.

Group B streptococcus (GBS) is one of the leading causes of neonatal infection; however the molecular mechanisms involved are not clearly known. Here we used high and low hemolytic GBS isolates and mutant GBS that lacks beta-hemolysin expression and showed that GBS infection or exposure to GBS hemolysin extract induces primary human trophoblast, placental fibroblast and JEG3 trophoblast cell line death, and that GBS-induced trophoblast death was beta-hemolysin dependent. The fibroblasts and trophoblasts provide an innate immune barrier between fetal and maternal circulation in the placenta. These data suggest that GBS may disrupt this barrier to invade fetal circulation.