Acta Neuropathol (2007) 113:75–80 DOI 10.1007/s00401-006-0150-0 123 ORIGINAL PAPER Involvement of hypocretin neurons in multiple system atrophy Eduardo E. Benarroch · Ann M. Schmeichel · Paola Sandroni · Phillip A. Low · Joseph E. Parisi Received: 14 August 2006 / Revised: 8 September 2006 / Accepted: 13 September 2006 / Published online: 7 November 2006  Springer-Verlag 2006 Abstract Hypocretin/Orexin (Hcrt/Orx) neurons of the posterolateral hypothalamus have been implicated in control of sleep and autonomic function. Sleep dis- orders and autonomic failure are important manifesta- tions of multiple system atrophy (MSA). We sought to determine whether Hcrt/Orx neurons were involved in this disorder. Hypothalamus was obtained from seven subjects with neuropathologically conWrmed MSA, and seven age-matched controls. 50 m sections obtained throughout the posterior hypothalamus were immunostained for Hcrt-1 and -synuclein. In MSA, there was a marked reduction of the total numbers of Hcrt/Orx neurons compared to controls (1,009 § 190 cells in MSA vs. 3,206 § 185 in controls, P < 0.0001). There were abundant glial cytoplasmic inclusions in the area of distribution of Hcrt/Orx neurons in MSA. This is the Wrst demonstration of loss of Hcrt/Orx neu- rons in MSA, which is consistent with a system degen- eration of neurons involved in homeostatic function, including sleep and autonomic regulation, in this disorder. Keywords Hypothalamus · Glial cytoplasmic inclusions · -Synuclein · Sleep Introduction Neurons of the posterior lateral hypothalamus synthe- sizing hypocretin (Hcrt) [also called orexin (Orx)] send extensive projections to the hypothalamus, brain stem, and spinal cord, among other regions. Depletion of Hcrt/Orx neurons occurs in narcolepsy [2, 5, 24], indi- cating the important role of these neurons in the regu- lation phase switch between wakefulness and sleep [6, 23]. However, these neurons also have extensive pro- jections to brain stem and spinal autonomic nuclei con- trolling blood pressure, gastrointestinal function, and thermoregulation [4, 14, 22]. At these levels, Hcrt/Orx activates sympathetic and parasympathetic outXows [14, 22]. Multiple system atrophy (MSA) is a condition char- acterized by severe autonomic failure, associated with Parkinsonism, cerebellar ataxia, or both [11, 27], whereas autonomic failure is a cardinal feature of MSA, excessive daytime sleepiness, and other sleep disorders are also common [1, 10, 26]. For example, irresistible onset of sleep during acute levodopa chal- lenge has been reported in MSA [12]. Given the role of Hcrt/Orx neurons in both sleep and autonomic control, involvement of these cells could contribute both to sleep disturbances and autonomic manifestations of MSA. Normal Hcrt/Orx levels in cerebrospinal Xuid (CSF) have been reported in dementia with Lewy bodies associated with excessive daytime sleepiness [3, 12, 18]. To our knowledge, involvement of the Hcrt/Orx sys- tem in MSA has not been systematically studied. In this study, we sought to determine whether there is involve- ment of Hcrt/Orx neurons in MSA and determine whether there is accumulation of glial cytoplasmic E. E. Benarroch (&) · A. M. Schmeichel · P. Sandroni · P. A. Low · J. E. Parisi Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA e-mail: benarroch.eduardo@mayo.edu J. E. Parisi Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA