Analysis of the Adrenal Gland Is Useful for Evaluating Pathology of the Peripheral Autonomic Nervous System in Lewy Body Disease

Fumimura, Yuichi; Ikemura, Masako; Saito, Yuko; Sengoku, Renpei; Kanemaru, Kazutomi; Sawabe, Motoji; Arai, Tomio; Ito, Genta; Iwatsubo, Takeshi; Fukayama, Masashi; Mizusawa, Hidehiro; Murayama, Shigeo

doi:10.1097/nen.0b013e3180517454

Cited by 114 publications

(103 citation statements)

References 36 publications

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“…Neuropathological studies have confirmed cardiac nerve loss showing reduced tyrosine hydroxylase (TH) and neurofilament immunostaining in epicardial nerve bundles [14], [15], [16]. In addition, Lewy bodies (intracytoplasmic inclusions composed mainly of aggregated α-synuclein), which are a classical pathological feature of PD, have been described in cardiac nerve structures including cardiac plexus [17], cardiac ganglia within the interatrial groove, epicardial bundles and nerves that innervate the myocardium, as well as in the adrenal medulla [18], [19].…”

Section: Introductionmentioning

confidence: 76%

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Cardiac Sympathetic Denervation in 6-OHDA-Treated Nonhuman Primates

et al. 2014

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Cardiac sympathetic neurodegeneration and dysautonomia affect patients with sporadic and familial Parkinson's disease (PD) and are currently proposed as prodromal signs of PD. We have recently developed a nonhuman primate model of cardiac dysautonomia by iv 6-hydroxydopamine (6-OHDA). Our in vivo findings included decreased cardiac uptake of a sympathetic radioligand and circulating catecholamines; here we report the postmortem characterization of the model. Ten adult rhesus monkeys (5–17 yrs old) were used in this study. Five animals received 6-OHDA (50 mg/kg iv) and five were age-matched controls. Three months post-neurotoxin the animals were euthanized; hearts and adrenal glands were processed for immunohistochemistry. Quantification of immunoreactivity (ir) of stainings was performed by an investigator blind to the treatment group using NIH ImageJ software (for cardiac bundles and adrenals, area above threshold and optical density) and MBF StereoInvestigator (for cardiac fibers, area fraction fractionator probe). Sympathetic cardiac nerve bundle analysis and fiber area density showed a significant reduction in global cardiac tyrosine hydroxylase-ir (TH; catecholaminergic marker) in 6-OHDA animals compared to controls. Quantification of protein gene protein 9.5 (pan-neuronal marker) positive cardiac fibers showed a significant deficit in 6-OHDA monkeys compared to controls and correlated with TH-ir fiber area. Semi-quantitative evaluation of human leukocyte antigen-ir (inflammatory marker) and nitrotyrosine-ir (oxidative stress marker) did not show significant changes 3 months post-neurotoxin. Cardiac nerve bundle α-synuclein-ir (presynaptic protein) was reduced (trend) in 6-OHDA treated monkeys; insoluble proteinase-K resistant α-synuclein (typical of PD pathology) was not observed. In the adrenal medulla, 6-OHDA monkeys had significantly reduced TH-ir and aminoacid decarboxylase-ir. Our results confirm that systemic 6-OHDA dosing to nonhuman primates induces cardiac sympathetic neurodegeneration and loss of catecholaminergic enzymes in the adrenal medulla, and suggests that this model can be used as a platform to evaluate disease-modifying strategies aiming to induce peripheral neuroprotection.

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Section: Introductionmentioning

confidence: 76%

“…In PD, Lewy bodies have been observed in ganglia within the adrenal medulla and periadrenal fatty tissue [18], [19], [82]. Phosphorylated α-synuclein-ir fibers have been observed as punctate or diffuse staining in the adrenal medulla of PD patients [68].…”

Section: Discussionmentioning

confidence: 99%

Cardiac Sympathetic Denervation in 6-OHDA-Treated Nonhuman Primates

et al. 2014

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“…In addition, one prospective longitudinal study has examined surgically resected tissue samples and then followed the patients for PD symptom development [19]. It remains to be seen whether the sympathetic or parasympathetic branch becomes involved first or whether the pathological process commences in both branches simultaneously [23,[34][35][36]. The ultimate goal of such autopsy-based Fig.…”

Section: Discussionmentioning

confidence: 98%

Peripheral Lewy body pathology in Parkinson's disease and incidental Lewy body disease: Four cases

Tredici

Duda

2011

Journal of the Neurological Sciences

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“…However, findings in the adrenal bodies, the classic inclusion site of the adrenal gland, were negative. 93 Of the 18 patients in this sample with PD, all had Lewy bodies in the adrenal gland. The adrenal pathology did not correspond to any symptomatology of adrenal insufficiency, except orthostatic hypotension, which may also be due to sympathetic lesions elsewhere.…”

Section: Adrenal Glandmentioning

confidence: 98%

Lesions outside the CNS in Parkinson's disease

2009

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Parkinson's disease (PD) is not a simple movement disorder induced just by loss of dopaminergic neurons in the substantia nigra pars compacta. Apparently, the substantia nigra is not the only or the first brain region damaged in PD. Moreover, older and recent studies have shown that the degenerative process in PD is much more extensive and affects not only the central nervous system (CNS) but also the peripheral autonomic nervous system and the organs outside the brain that the latter innervates. These include mainly the gastrointestinal tract, the heart, kidneys, urogenital system, and skin. Additional extra-CNS organs that are involved in PD include the eye and the adrenal gland. This article reviews the anatomical, physiological, and clinical features of extracerebral manifestations of PD, and describes their relevance to the etiology and pathogenesis of the disease. It establishes this illness as a systemic CNS and peripheral disorder that warrants new hypotheses regarding its causation and progression.

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Analysis of the Adrenal Gland Is Useful for Evaluating Pathology of the Peripheral Autonomic Nervous System in Lewy Body Disease

Cited by 114 publications

References 36 publications

Cardiac Sympathetic Denervation in 6-OHDA-Treated Nonhuman Primates

Cardiac Sympathetic Denervation in 6-OHDA-Treated Nonhuman Primates

Peripheral Lewy body pathology in Parkinson's disease and incidental Lewy body disease: Four cases

Lesions outside the CNS in Parkinson's disease

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