Alpha-synuclein aggregates in epicardial fat tissue in living subjects without parkinsonism

Navarro‐Otano, Judith; Gelpí, Ellen; Mestres, Carlos A.; Quintana, Eduard; Rauek, Sebastian; Ribalta, Teresa; Santiago, Verónica; Tolosa, Eduardo

doi:10.1016/j.parkreldis.2012.07.005

Cited by 42 publications

(36 citation statements)

References 30 publications

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“…The observed distribution of AS pathology in our subjects and in previous studies, suggests that the sympathetic cardiac and stellate/paravertebral ganglia would be informative targets for identifying AS aggregates in living subjects, and we have recently studied epicardial fat autonomic tissue obtained during surgery and observed AS/pAS in 8% of subjects without parkinsonism . The obvious difficulties and risks involved in the access of such tissues through biopsy makes them unfeasible for diagnostic purposes.…”

Section: Discussionsupporting

confidence: 69%

Multiple organ involvement by alpha‐synuclein pathology in Lewy body disorders

et al. 2014

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Lewy body (LB) diseases are characterized by alpha-synuclein (AS) aggregates in the central nervous system (CNS). Involvement of the peripheral autonomic nervous system (pANS) is increasingly recognized, although less studied. The aim of this study was to systematically analyze the distribution and severity of AS pathology in the CNS and pANS. Detailed postmortem histopathological study of brain and peripheral tissues from 28 brain bank donors (10 with Parkinson's disease [PD], 5 with dementia with LB [DLB], and 13 with non-LB diseases including atypical parkinsonism and non-LB dementia). AS aggregates were found in the pANS of all 15 LB disease cases (PD, DLB) in stellate and sympathetic ganglia (100%), vagus nerve (86.7%), gastrointestinal tract (86.7%), adrenal gland and/or surrounding fat (53.3%), heart (100%), and genitourinary tract (13.3%), as well as in 1 case of incidental Lewy body disease (iLBD). A craniocaudal gradient of AS burden in sympathetic chain and gastrointestinal tract was observed. DLB cases showed higher amounts of CNS AS aggregates than PD cases, but this was not the case in the pANS. No pANS AS aggregates were detected in Alzheimer's disease (AD) cases with or without CNS AS aggregates. All pathologically confirmed LB disease cases including 1 case of iLBD had AS aggregates in the pANS with a craniocaudal gradient of pathology burden in sympathetic chain and gastrointestinal tract. AS was not detected in the pANS of any AD case. These findings may help in the search of peripheral AS aggregates in vivo for the early diagnosis of PD.

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Section: Discussionsupporting

confidence: 69%

Multiple organ involvement by alpha‐synuclein pathology in Lewy body disorders

et al. 2014

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“…ILBD is associated with neuronal loss in the SN and decreased striatal TH immunoreactivity . The concept of ILBD has been expanded to living individuals without parkinsonism in whom α‐synuclein aggregates are detected in peripheral autonomic nervous tissues . Evaluations of postmortem ILBD cases have identified isolated RBD, olfactory dysfunction, infrequent bowel movements, and subtle cognitive deficits during life.…”

Section: Discussionmentioning

confidence: 99%

Neuropathology of prodromal Lewy body disease

et al. 2014

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“…Many of the subjects exhibited prodromal PD symptoms such as acting dreams and constipation, but no patient was diagnosed with PD at the time of the study. The authors suggest that follow-up studies of these patients are crucial to determine if patients will later be diagnosed with PD and to implicate the early detection of phosphorylated α-synuclein-ir in cardiac nerve bundles as a biomarker for PD [69].…”

Section: Discussionmentioning

confidence: 99%

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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Alpha-synuclein aggregates in epicardial fat tissue in living subjects without parkinsonism

Cited by 42 publications

References 30 publications

Multiple organ involvement by alpha‐synuclein pathology in Lewy body disorders

Multiple organ involvement by alpha‐synuclein pathology in Lewy body disorders

Neuropathology of prodromal Lewy body disease

Cardiac Sympathetic Denervation in 6-OHDA-Treated Nonhuman Primates

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