Disturbances in melatonin secretion and circadian sleep-wake regulation in Parkinson disease.

OBJECTIVE: Using salivary dim light melatonin onset (DLMO) and actigraphy, our study sought to determine if Parkinson disease (PD) patients demonstrate circadian disturbance compared to healthy controls. Additionally, our study investigated if circadian disturbances represent a disease-related process or may be attributed to dopaminergic therapy. METHODS: Twenty-nine patients with PD were divided into unmedicated and medicated groups and were compared to 27 healthy controls. All participants underwent neurologic assessment and 14 days of actigraphy to establish habitual sleep-onset time (HSO). DLMO time and area under the melatonin curve (AUC) were calculated from salivary melatonin sampling. The phase angle of entrainment was calculated by subtracting DLMO from HSO. Overnight polysomnography (PSG) was performed to determine sleep architecture. RESULTS: DLMO and HSO were not different across the groups. However, the phase angle of entrainment was more than twice as long in the medicated PD group compared to the unmedicated PD group (U = 35.5; P = .002) and was more than 50% longer than controls (U = 130.0; P = .021). The medicated PD group showed more than double the melatonin AUC compared to the unmedicated group (U = 31; P = 0.001) and controls (U = 87; P = .001). There was no difference in these measures comparing unmedicated PD and controls. CONCLUSIONS: In PD dopaminergic treatment profoundly increases the secretion of melatonin. Our study reported no difference in circadian phase and HSO between groups. However, PD patients treated with dopaminergic therapy unexpectedly showed a delayed sleep onset relative to DLMO, suggesting dopaminergic therapy in PD results in an uncoupling of circadian and sleep regulation.

Modeling freezing of gait in Parkinson's disease with a virtual reality paradigm.

Freezing of gait is a paroxysmal and disabling symptom that commonly affects patients in the latter stages of Parkinson's disease, however the intermittent nature of this symptom makes it difficult to study in the clinical setting. Our research group has previously reported a correlation between self-reported freezing of gait symptoms and performance on a seated virtual reality gait task. In this study, we sought to determine whether behavioral measures recorded on this task were correlated with actual clinical measures of freezing of gait recorded in a cohort of 38 Parkinson's disease patients whilst in their clinically defined 'off' state. Firstly, patients with freezing of gait had a significantly larger frequency of spontaneous motor arrests recorded on the virtual reality gait task than 'non-freezers'. In addition, in those 24 patients with clinically proven freezing of gait, the number and percentage of time spent with freezing on the virtual reality task were both moderately correlated with the duration of freezing of gait recorded on the timed up-and-go tasks. These findings suggest that the freezing behavior observed during a virtual reality gait task may share similar neural substrates to freezing of gait. Such a relationship could offer a potential avenue for modeling the phenomenon of freezing of gait in Parkinson's disease, allowing for the exploration of the neural correlates of freezing.

Circadian profiles in young people during the early stages of affective disorder.

Although disturbances of the circadian system are strongly linked to affective disorders, no known studies have examined melatonin profiles in young people in early stages of illness. In this study, 44 patients with an affective disorder underwent clinical and neuropsychological assessments. They were then rated by a psychiatrist according to a clinical staging model and were categorized as having an 'attenuated syndrome' or an 'established disorder'. During the evening, salivary melatonin was sampled under dim light conditions over an 8-h interval and for each patient, the time of melatonin onset, total area under the curve and phase angle (difference between time of melatonin onset and time of habitual sleep onset) were computed. Results showed that there was no difference in the timing of melatonin onset across illness stages. However, area under the curve analyses showed that those patients with 'established disorders' had markedly reduced levels of melatonin secretion, and shorter phase angles, relative to those with 'attenuated syndromes'. These lower levels, in turn, were related to lower subjective sleepiness, and poorer performance on neuropsychological tests of verbal memory. Overall, these results suggest that for patients with established illness, dysfunction of the circadian system relates clearly to functional features and markers of underlying neurobiological change. Although the interpretation of these results would be greatly enhanced by control data, this work has important implications for the early delivery of chronobiological interventions in young people with affective disorders.

Assessing the utility of Freezing of Gait Questionnaires in Parkinson's Disease.

There are currently two validated questionnaires, the Freezing of Gait Questionnaire and the New Freezing of Gait Questionnaire, that are intended to assess the degree of freezing of gait in patients with Parkinson's disease. However, to date no study has attempted to determine whether ratings on these questionnaires accurately reflect the severity (frequency and duration) of actual freezing episodes experienced by patients. We studied twenty-four patients with Parkinson's disease who self-reported significant freezing while in their practically-defined 'off' state. Prior to clinical assessment they completed both freezing of gait questionnaires before being video-recorded while performing a series of timed up-and-go tasks, which incorporated turning, rotating and passing through narrow gaps. The rating of video recordings by two independent observers identified a total of 530 freezing events. The frequency and duration of freezing episodes for each patient were calculated and correlated with questionnaire ratings. Scores on either questionnaire did not correlate with either the frequency or duration of freezing episodes experienced by patients during objective assessment. These results suggest the need to re-evaluate the utility of questionnaires in the assessment of freezing of gait. Furthermore, these results highlight the need for accurate objective methods of identifying freezing events when assessing future clinical interventions aimed at reducing this potentially disabling symptom of Parkinson's disease.

Mutagenesis of Streptococcus equi and Streptococcus suis by transposon Tn917.

Genetic tools for studying streptococci are much less sophisticated than those that are available for many other bacterial genera. In this paper, we describe the development of a transposon mutagenesis system that we have used to mutate two important veterinary streptococci, Streptococcus equi and Streptococcus suis. The system uses a temperature-sensitive suicide vector to deliver Tn917 via electroporation, transposing Tn917 into the chromosomal DNA of the two streptococci. The transposon insertions can be rescued from the streptococcal chromosomes by plasmid rescue and selection in E. coli, with subsequent insertion site analysis by DNA sequencing. Transposition appeared to have occurred in an essentially random fashion when chromosomal DNA of S. suis and S. equi mutants was analysed by Southern blotting. However, when analysis of 60 S. equi mutants was carried out using the S. equi genome sequence database, 60% of transposon insertions had occurred within a 15 kb region of the genome whereas the other insertions appeared to have occurred essentially randomly. This finding suggests that Southern blot analysis for assessing the randomness of transposon libraries may need to be interpreted with caution. However, this observation notwithstanding, the Tn917 based system described in this paper will facilitate the study of S. suis and S. equi.

Generation and characterization of a defined mutant of Streptococcus suis lacking suilysin.

A defined allelic-replacement mutant of the sly gene, encoding a thiol-activated cytolysin, from a European isolate of Streptococcus suis serotype 2 was generated and characterized. Unlike the parental strain, it is nonhemolytic, noncytotoxic for cultured macrophage-like cells, avirulent in a mouse infection model, yet only slightly attenuated in a porcine model of systemic infection.