Involvement of hypocretin neurons in multiple system atrophy

Hypocretin/Orexin (Hcrt/Orx) neurons of the posterolateral hypothalamus have been implicated in control of sleep and autonomic function. Sleep disorders and autonomic failure are important manifestations 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 confirmed MSA, and seven age-matched controls. 50 μm sections obtained throughout the posterior hypothalamus were immunostained for Hcrt-1 and α-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 first demonstration of loss of Hcrt/Orx neurons in MSA, which is consistent with a system degeneration of neurons involved in homeostatic function, including sleep and autonomic regulation, in this disorder.