Spearman correlation coefficients between clinical variables and sleep variables.

*<p>Significant after FDR correction; BMI  =  Body Mass Index; UPDRS  =  Unified Parkinson.</p><p>Disease Rating Scale; RDI  =  Respiratory Disturbance Index; RERA  =  Respiratory Effort Related Arousal.</p

Participant Characteristics.

<p>SD  =  Standard Deviation; M  =  Male; F  =  Female; UPDRS  =  Unified.</p><p>Parkinson Disease Rating Scale; LED  =  Levodopa Equivalent Dose;</p><p>MMSE  =  Mini Mental State Examination; BMI  =  Body Mass Index;</p><p>PDSS  =  Parkinson’s Disease Sleepiness Scale; ESS  =  Epworth.</p><p>Sleepiness Scale, BQ  =  Berlin Questionnaire.</p

Mean (SD) of sleep parameters and the number of events on the Respiratory Disturbance Index.

<p>SD  =  Standard Deviation; RDI  =  Respiratory Disturbance Index; RERA  =  Respiratory Effort Related Arousal; Stage N1–N3 =  non-REM stage 1–3; Stage R  =  REM stage; Min O<b>₂</b>  =  Minimal oxygen saturation; Arousals/hr  =  Arousals per hour of sleep.</p

Spearman correlation coefficients between sleep variables from polysomnography and subjective sleep measures.

<p>None significant after multiple comparisons correction.</p><p>Epworth  =  Epworth sleepiness scale; PDSS  =  Parkinson’s Disease Sleep Scale;</p><p>REM  =  Rapid Eye Movement sleep; Min O₂  =  Minimum Oxygen Saturation;</p><p>MSLT  =  Multiple Sleep Latency Tests; RDI  =  Respiratory Disturbance Index.</p

Correlations between participant RDIs and A) [¹¹C]DASB caudal brainstem BPs; B) [¹¹C]DTBZ striatal BPs.

<p>Correlations between participant RDIs and A) [¹¹C]DASB caudal brainstem BPs; B) [¹¹C]DTBZ striatal BPs.</p

Investigation of Proposed Activity of Clarithromycin at GABA_A Receptors Using [¹¹C]Flumazenil PET

Clarithromycin is a potential treatment for hypersomnia acting through proposed negative allosteric modulation of GABA_A receptors. We were interested whether this therapeutic benefit might extend to Parkinson’s disease (PD) patients because GABAergic neurotransmission is implicated in postural control. Prior to initiating clinical studies in PD patients, we wished to better understand clarithromycin’s mechanism of action. In this work we investigated whether the proposed activity of clarithromycin at the GABA_A receptor is associated with the benzodiazepine binding site using <i>in vivo</i> [¹¹C]­flumazenil positron emission tomography (PET) in primates and <i>ex vivo</i> [³H]­flumazenil autoradiography in rat brain. While the studies demonstrate that clarithromycin does not change the <i>K</i>_d of FMZ, nor does it competitively displace FMZ, there is preliminary evidence from the primate PET imaging studies that clarithromycin delays dissociation and washout of flumazenil from the primate brain in a dose-dependent fashion. These findings would be consistent with the proposed GABA_A allosteric modulator function of clarithromycin. While the results are only preliminary, further investigation of the interaction of clarithromycin with GABA receptors and/or GABAergic medications is warranted, and therapeutic applications of clarithromycin alone or in combination with flumazenil, to treat hyper-GABAergic status in PD at minimally effective doses, should also be pursued