Risa Isonaka1, Patti Sullivan1, Yunden Jinsmaa1, Abraham Corrales1, David S Goldstein2. 1. Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive MSC-1620, Building 10 Room 8N260, Bethesda, MD, 20892-1620, USA. 2. Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive MSC-1620, Building 10 Room 8N260, Bethesda, MD, 20892-1620, USA. goldsteind@ninds.nih.gov.
Abstract
OBJECTIVE: Lewy body forms of primary chronic autonomic failure (CAF) such as incidental Lewy body disease (ILBD), Parkinson's disease (PD), and pure autonomic failure evolving into dementia with Lewy bodies (PAF+DLB) feature cardiac sympathetic denervation, whereas multiple system atrophy (MSA) in most cases does not. What links Lewy bodies with cardiac sympathetic denervation in CAF? In familial PD, abnormalities of the alpha-synuclein (AS) gene cause CAF and cardiac sympathetic denervation; and in sporadic PD, brainstem Lewy bodies contain AS co-localized with tyrosine hydroxylase (TH), a marker of catecholaminergic neurons. Cytotoxicity from AS deposition within sympathetic neurons might explain noradrenergic denervation in Lewy body forms of CAF. We used immunofluorescence microscopy (IM) to explore this possibility in sympathetic ganglia obtained at autopsy from CAF patients. METHODS: Immunoreactive AS and TH were imaged in sympathetic ganglion tissue from 6 control subjects (2 with ILBD), 5 PD patients (1 with concurrent PSP), and 3 patients with CAF (2 PAF + DLB, 1 MSA). RESULTS: MSA involved normal ganglionic TH and no AS deposition. In ILBD TH was variably decreased, and TH and AS were co-localized in Lewy bodies. In PD TH was substantially decreased, and TH and AS were co-localized in Lewy bodies. In PAF + DLB TH was virtually absent, but AS was present in Lewy bodies. The PD + PSP patient had AS co-localized with tau but not TH. CONCLUSIONS: Sympathetic denervation and intraneuronal AS deposition are correlated across CAF syndromes, consistent with a pathogenic contribution of synucleinopathy to cardiac noradrenergic deficiency in Lewy body diseases.
OBJECTIVE: Lewy body forms of primary chronic autonomic failure (CAF) such as incidental Lewy body disease (ILBD), Parkinson's disease (PD), and pure autonomic failure evolving into dementia with Lewy bodies (PAF+DLB) feature cardiac sympathetic denervation, whereas multiple system atrophy (MSA) in most cases does not. What links Lewy bodies with cardiac sympathetic denervation in CAF? In familial PD, abnormalities of the alpha-synuclein (AS) gene cause CAF and cardiac sympathetic denervation; and in sporadic PD, brainstem Lewy bodies contain AS co-localized with tyrosine hydroxylase (TH), a marker of catecholaminergic neurons. Cytotoxicity from AS deposition within sympathetic neurons might explain noradrenergic denervation in Lewy body forms of CAF. We used immunofluorescence microscopy (IM) to explore this possibility in sympathetic ganglia obtained at autopsy from CAFpatients. METHODS: Immunoreactive AS and TH were imaged in sympathetic ganglion tissue from 6 control subjects (2 with ILBD), 5 PDpatients (1 with concurrent PSP), and 3 patients with CAF (2 PAF + DLB, 1 MSA). RESULTS: MSA involved normal ganglionic TH and no AS deposition. In ILBD TH was variably decreased, and TH and AS were co-localized in Lewy bodies. In PDTH was substantially decreased, and TH and AS were co-localized in Lewy bodies. In PAF + DLB TH was virtually absent, but AS was present in Lewy bodies. The PD + PSPpatient had AS co-localized with tau but not TH. CONCLUSIONS: Sympathetic denervation and intraneuronal AS deposition are correlated across CAF syndromes, consistent with a pathogenic contribution of synucleinopathy to cardiac noradrenergic deficiency in Lewy body diseases.
Authors: Lucy Norcliffe-Kaufmann; Horacio Kaufmann; Jose-Alberto Palma; Cyndya A Shibao; Italo Biaggioni; Amanda C Peltier; Wolfgang Singer; Phillip A Low; David S Goldstein; Christopher H Gibbons; Roy Freeman; David Robertson Journal: Ann Neurol Date: 2018-03-10 Impact factor: 10.422
Authors: Risa Isonaka; Avi Z Rosenberg; Patti Sullivan; Abraham Corrales; Courtney Holmes; Yehonatan Sharabi; David S Goldstein Journal: Hypertension Date: 2019-04 Impact factor: 10.190
Authors: Risa Isonaka; Christopher H Gibbons; Ningshan Wang; Roy Freeman; David S Goldstein Journal: Clin Auton Res Date: 2019-10-31 Impact factor: 4.435
Authors: Risa Isonaka; David S Goldstein; William Zhu; Esther Yoon; Debra Ehrlich; Alice B Schindler; Angela D Kokkinis; Marya S Sabir; Sonja W Scholz; Sara Bandres-Ciga; Cornelis Blauwendraat; Pedro Gonzalez-Alegre; Grisel Lopez; Ellen Sidransky; Derek P Narendra Journal: Mov Disord Date: 2021-06-02 Impact factor: 9.698