Skin alpha-synuclein deposit patterns: A predictor of Parkinson's disease subtypes

Han, Yihang; Wu, Di; Wang, Yanjuan; Xie, Jian; Zhang, Zhijun

doi:10.1016/j.ebiom.2022.104076

Cited by 15 publications

(5 citation statements)

References 58 publications

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“…Using a ring drill extractor (USHIO, Tokyo, Japan), we conducted a three-millimeter punch biopsy taken from a proximal location (C7 paravertebral: 5 cm from the midline). Multiple studies have reported a significant proximal-distal gradient of pathological αSyn in patients with PD, demonstrating a spine gradient with the cervical site expressing the highest positivity 62 , 63 .…”

Section: Methodsmentioning

confidence: 99%

A skin-specific α-Synuclein seeding amplification assay for diagnosing Parkinson’s disease

Kuang,

Mao,

Gan

et al. 2024

npj Parkinsons Dis.

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The seeding amplification assay (SAA) has recently emerged as a valuable tool for detecting α-synuclein (αSyn) aggregates in various clinically accessible biospecimens. Despite its efficiency and specificity, optimal tissue-specific conditions for distinguishing Parkinson’s disease (PD) from non-PD outside the brain remain underexplored. This study systematically evaluated 150 reaction conditions to identify the one with the highest discriminatory potential between PD and non-synucleinopathy controls using skin samples, resulting in a modified SAA. The streamlined SAA achieved an overall sensitivity of 92.46% and specificity of 93.33% on biopsy skin samples from 332 PD patients and 285 controls within 24 h. Inter-laboratory reproducibility demonstrated a Cohen’s kappa value of 0.87 (95% CI 0.69–1.00), indicating nearly perfect agreement. Additionally, αSyn seeds in the skin were stable at −80 °C but were vulnerable to short-term exposure to non-ultra-low temperatures and grinding. This study thoroughly investigated procedures for sample preprocessing, seed amplification, and storage, introducing a well-structured experimental framework for PD diagnosis using skin samples.

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Section: Methodsmentioning

confidence: 99%

A skin-specific α-Synuclein seeding amplification assay for diagnosing Parkinson’s disease

Kuang,

Mao,

Gan

et al. 2024

npj Parkinsons Dis.

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“…While clinical findings of PD and DLB are prominently associated with aberrant α-synuclein deposits in the central nervous system, pathologic α-synuclein can also be found in the peripheral nervous system. In fact, diagnosis of these disorders can be strongly supported by the identification of phosphosynuclein in dermal cutaneous nerve fibers present in skin punch biopsies ( 3 ). Also, single photon emission computed tomography (SPECT) scanning after intravenous injection of the sympathomimetic amine 123 I- meta -iodobenzylguanidine ( 123 I-MIBG) has demonstrated reduction in peripheral noradrenergic innervation of the heart in patients with PD ( 4 ).…”

Section: Early Nonmotor Symptoms In Lewy Body Diseasementioning

confidence: 99%

Getting to the heart of Lewy body disease

Goodheart,

Blackstone

2024

Journal of Clinical Investigation

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Early identification of neurodegenerative diseases before extensive neuronal loss or disabling symptoms have occurred is imperative for effective use of disease-modifying therapies. Emerging data indicate that central Lewy body diseases — Parkinson disease and dementia with Lewy bodies — can begin in the peripheral nervous system, opening up a therapeutic window before central involvement. In this issue of the JCI , Goldstein et al. report that cardiac 18 F-dopamine positron emission tomography reveals lower activity selectively in individuals with several self-reported Parkinson disease risk factors who later develop Parkinson disease or dementia with Lewy bodies. Accurately identifying which at-risk individuals will develop central Lewy body disease will optimize early patient selection for disease-modifying therapies.

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“…Furthermore, in PD, in cardiac sympathetic nerves, unmyelinated axons account for the overwhelming majority (98.2%) of axons with α-synuclein aggregates, and they are lost at a higher frequency [77,78]. In the skin of PD patients, α-synuclein deposits were found in unmyelinated nerve fibers of the autonomic nervous system in association with length-dependent nerve fiber loss [79]. Braak and colleagues [19,20] postulated that poor axonal myelination is a cause of stress because it is associated with a higher requirement of energy for the transmission of impulses [80].…”

Section: Shared Features Among Neurons Susceptible To Pdmentioning

confidence: 99%

Parkinson’s Disease: Cells Succumbing to Lifelong Dopamine-Related Oxidative Stress and Other Bioenergetic Challenges

Watanabe,

Dijkstra,

Nagatsu

2024

IJMS

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The core pathological event in Parkinson’s disease (PD) is the specific dying of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). The reasons why SNc DA neurons are especially vulnerable and why idiopathic PD has only been found in humans are still puzzling. The two main underlying factors of SNc DA neuron vulnerability appear related to high DA production, namely (i) the toxic effects of cytoplasmic DA metabolism and (ii) continuous cytosolic Ca2+ oscillations in the absence of the Ca2+-buffer protein calbindin. Both factors cause oxidative stress by producing highly reactive quinones and increasing intra-mitochondrial Ca2+ concentrations, respectively. High DA expression in human SNc DA neuron cell bodies is suggested by the abundant presence of the DA-derived pigment neuromelanin, which is not found in such abundance in other species and has been associated with toxicity at higher levels. The oxidative stress created by their DA production system, despite the fact that the SN does not use unusually high amounts of energy, explains why SNc DA neurons are sensitive to various genetic and environmental factors that create mitochondrial damage and thereby promote PD. Aging increases multiple risk factors for PD, and, to a large extent, PD is accelerated aging. To prevent PD neurodegeneration, possible approaches that are discussed here are (1) reducing cytoplasmic DA accumulation, (2) blocking cytoplasmic Ca2+ oscillations, and (3) providing bioenergetic support.

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Skin alpha-synuclein deposit patterns: A predictor of Parkinson's disease subtypes

Cited by 15 publications

References 58 publications

A skin-specific α-Synuclein seeding amplification assay for diagnosing Parkinson’s disease

A skin-specific α-Synuclein seeding amplification assay for diagnosing Parkinson’s disease

Getting to the heart of Lewy body disease

Parkinson’s Disease: Cells Succumbing to Lifelong Dopamine-Related Oxidative Stress and Other Bioenergetic Challenges

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