Brain Advance Access originally published online on April 30, 2007
Brain 2007 130(6):1577-1585; doi:10.1093/brain/awm090
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Hypocretin (orexin) loss in Parkinson's disease
1Department of Neurology, Leiden University Medical Center, Leiden, 2Netherlands Institute for Neurosciences, Amsterdam ZO, 3Department of Neurology, Radboud University Nijmegen Medical Center, Nijmegen, 4Department of clinical Chemistry and 5Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
Corresponding to: Prof. Dick Swaab, MD, Netherlands Institute for Neuroscience, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands E-mail: d.f.swaab{at}nin.knaw.nl
The hypothalamic hypocretin (orexin) system plays a central role in the regulation of various functions, including sleep/wake regulation and metabolism. There is a growing interest in hypocretin function in Parkinson's disease (PD), given the high prevalence of non-motor symptoms such as sleep disturbances in this disorder. However, studies measuring CSF hypocretin levels have yielded contradictory results. In PD patients and matched controls, we (i) estimated the number of hypocretin neurons in post-mortem hypothalami using immunocytochemistry and an image analysis system (ii) quantified hypocretin levels in post-mortem ventricular CSF and (iii) prefrontal cortex using a radioimmunoassay. Furthermore, presence of Lewy bodies was verified in the hypothalamic hypocretin cell area. Data are presented as median (25th–75th percentile). We showed a significant decrease between PD patients and controls in (i) the number of hypocretin neurons (PD: 20 276 (13 821–31 229); controls: 36 842 (32 546–50 938); P = 0.016); (ii) the hypocretin-1 concentration in post-mortem ventricular CSF (PD: 365.5 pg/ml (328.0–448.3); controls: 483.5 (433.5–512.3); P = 0.012) and (iii) the hypocretin-1 concentrations in prefrontal cortex (PD: 389.6 pg/g (249.2–652.2); controls: 676.6 (467.5–883.9); P = 0.043). Hypocretin neurotransmission is affected in PD. The hypocretin-1 concentration in the prefrontal cortex was almost 40% lower in PD patients, while ventricular CSF levels were almost 25% reduced. The total number of hypocretin neurons was almost half compared to controls.
Key Words: narcolepsy; hypocretin; orexin; sleep; Parkinson's disease; hypothalamus
Abbreviations: CSF, Cerebrospinal fluid; EDS, Excessive Daytime Sleepiness; IR, Immunoreactive; NBB, Netherlands Brain Bank; PD, Parkinson's disease; PMD, Post-mortem delay; REM-sleep, Rapid eye movement sleep; RIA, Radioimmunoassay
Received October 23, 2006. Revised February 28, 2007. Accepted March 22, 2007.
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