Hypothalamic α-synuclein and its relation to autonomic symptoms and neuroendocrine abnormalities in Parkinson disease

Parkinson's disease (PD) is a complex neurodegenerative disorder presenting with defining motor features and a variable combination of nonmotor symptoms. There is growing evidence suggesting that hypothalamic involvement in PD may contribute to the pathogenesis of nonmotor symptoms. Initial neuropathologic studies demonstrated histologic involvement of hypothalamic nuclei by Lewy pathology, i.e., neuronal aggregates including Lewy bodies (round eosinophilic inclusions with a halo found in the neuronal perikarya) and other inclusions in neuronal processes such as Lewy neurites. Recent studies using more sensitive immunohistochemistry have shown that synuclein deposition is common in all hypothalamic nuclei and can happen at preclinical stages of the disease. Several neuropathologic changes, including synuclein deposition, neuronal loss, and adaptative morphologic changes, have been described in neurochemically defined specific hypothalamic cell populations with a potential role in the pathogenesis of nonmotor symptoms such as autonomic dysfunction, blood pressure control, circadian rhythms, sleep, and body weight regulation. The clinical implications of these hypothalamic neuropathologic changes are not fully understood and a direct clinical correlation may be challenging due to the multifactorial pathogenesis of the symptomatology and the additional involvement of other peripheral regulatory mechanisms. Future neuropathologic research using histological and functional assessments should establish the potential role of hypothalamic dysfunction on clinical burden, symptomatic therapies, and disease biomarkers in PD.