Neurodegeneration involving putative respiratory neurons in Perry syndrome

Yoshio Tsuboi, Dennis W. Dickson, Kazuki Nabeshima, Ann M. Schmeichel, Zbigniew K. Wszolek, Tatsuo Yamada, Eduardo E. Benarroch

The objective of this study was to assess the potential involvement of ventral medullary neurons implicated in respiratory rhythmogenesis and chemosensitivity in a patient with Perry syndrome (autosomal dominant parkinsonism associated with depression, weight loss and central hypoventilation). Previous neuropathologic reports in Perry syndrome demonstrated neuronal loss in the substantia nigra with no or few Lewy bodies and no tau inclusions. Neurons in the pre-Bötzinger complex (preBötC) of the ventrolateral medulla, identified by their immunoreactivity for neurokinin-1 receptors (NK-1R), play an essential role in respiratory rhythmogenesis and serotonergic neurons in the medullary raphe in respiratory chemosensitivity, but their potential involvement in Perry syndrome has not yet been addressed. We conducted clinical and neuropathologic studies including immunohistochemistry examination in a new autopsied case clinically diagnosed as Perry syndrome. Our patient presented with parkinsonism at age 41. Subsequently, all cardinal features of Perry syndrome developed. He died of respiratory failure and sepsis at age 46. Hematoxylin-eosin staining revealed no significant pathology in the medulla. However, NK-1R, tyrosine hydroxylase (TH) and tryptophan hydroxylase (TrOH) immunoreactive neurons were significantly reduced in the ventrolateral medulla compared to controls. There was also loss of serotonergic neurons in the medullary raphe and ventral medullary surface. Severe neuronal loss in the substantia nigra, without alpha-synuclein or tau pathology but with loss of NK-1R and TH immunoreactive neurons in the ventrolateral medulla, and loss of serotonergic neurons in the medullary raphe and ventrolateral medulla may be a pathologic hallmark of Perry syndrome.