Free water elimination (FWE) in brain diffusion MRI has been shown to improve tissue specificity in human white matter characterization both in health and in disease. Relative to the classical diffusion tensor imaging (DTI) model, FWE is also expected to increase sensitivity to microstructural changes in longitudinal studies. However, it is not clear if these two models differ in their test-retest reproducibility. This study compares a bi-tensor model for FWE with DTI by extending a previous longitudinal-reproducibility 3T multisite study (10 sites, 7 different scanner models) of 50 healthy elderly participants (55–80 years old) scanned in two sessions at least one week apart. We computed the reproducibility of commonly used DTI metrics (FA: fractional anisotropy, MD: mean diffusivity, RD: radial diffusivity and AXD: axial diffusivity), derived either using a DTI model or a FWE model. The DTI metrics were evaluated over 48 white matter regions of the JHU-ICBM-DTI-81 white-matter labels atlas, and reproducibility errors were assessed. We found that relative to the DTI model, FWE significantly reduced reproducibility errors in most areas tested. In particular, for the FA and MD metrics there was an average reduction of approximately 1% in the reproducibility error. The reproducibility scores did not significantly differ across sites. This study shows that FWE improves sensitivity and is thus promising for clinical applications, with the potential to identify more subtle changes. The increased reproducibility allows for smaller sample size or shorter trials in studies evaluating biomarkers of disease progression or treatment effects.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Dopamine agonists used in Parkinson's disease patients are associated with excessive daytime sleepiness and sleep attacks occurring without prior warning. • Parkinson's disease accounts in itself for a variety of sleep disorders. It is therefore important to study the drug-induced sleepiness in healthy volunteers.• In healthy subjects, pramipexole has proved to decrease alertness and ropinirole to reduce sleep latency.
WHAT THIS STUDY ADDS• Results from our study show that pramipexole reduces the mean sleep latency as measured by the Multiple Sleep Latency Test in healthy volunteers, hence providing an objective measure of increased sleepiness.• Furthermore, the reduction in sleep latency was not associated with a subjective impression of increased sleepiness.• Such dissociation may underlie the occurrence of sleep attacks without prior warning.
AIMSTo assess the sleepiness induced by pramipexole, a D2/D3-dopamine receptor agonist commonly used in Parkinson's disease and restless legs syndrome, without the problem of the confounding factors related to the disease.
METHODSPlacebo, bromocriptine (2.5 mg), L-dopa (100 mg) and pramipexole (0.5 mg) were administered in a single oral dose on four separate days, with at least a 2-week wash-out period in a randomized cross-over design. Induced somnolence was assessed using Multiple Sleep Latency Test (MSLT) and subjective scaling of vigilance. Twelve male subjects (26.3 Ϯ 5.5 years old) without anxiety, mood, sleep or sedation disorders were enrolled.
RESULTSPramipexole significantly reduced mean sleep latency compared with placebo 3 h 30 min [-6.1 min (-9.8, -2.4), P = 0.002] and 5 h 30 min [-5.6 min (-7.7, -3.5), P = 0.003] after administration. In addition, the total duration of sleep during the tests was higher with pramipexole than with placebo [+6.0 min (2.3, 9.7), P < 0.001]. These differences were not observed with L-dopa and bromocriptine in comparison with placebo. The induced sleepiness was not associated with an increase in subjective somnolence scaling, indicating that this adverse event may occur without prior warning.
CONCLUSIONSThese results show that a single oral dose of pramipexole induces sleepiness as assessed by MSLT in healthy young subjects, independent of disease-related sleep dysfunction.
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