Skin Biopsy May Help to Distinguish Multiple System Atrophy–Parkinsonism from Parkinson's Disease With Orthostatic Hypotension

Donadio, Vincenzo; Incensi, Alex; Rizzo, Giovanni; Micco, Rosa De; Tessitore, Alessandro; Devigili, Grazia; Sorbo, Francesca Del; Bonvegna, Salvatore; Infante, Rossella; Magnani, Martina; Zenesini, Corrado; Vignatelli, Luca; Cilia, Roberto; Eleopra, Roberto; Tedeschi, Gioacchino; Liguori, Rocco

doi:10.1002/mds.28126

Cited by 57 publications

(60 citation statements)

References 44 publications

(134 reference statements)

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“…The deposition morphology characteristics was identical to that of p-syn in the substantia nigra by autopsy ( 5 , 6 ). P-syn was found in synucleinopathies, such as PD, Lewy bodies (DLB), and multiple system atrophy (MSA), but not in normal controls and taupathies ( 7 – 12 ). These evidences indicated cutaneous p-syn could be a reliable peripheral biomarker for PD diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Optimization of the Detection Method for Phosphorylated α-Synuclein in Parkinson Disease by Skin Biopsy

et al. 2020

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Background: Recent studies have found deposition of phosphorylated α-synuclein (p-syn) in Parkinson disease (PD) patients' skin, indicating p-syn may be a potential biomarker of PD. However, the sensitivity of the p-syn detection varied largely from 5. 3 to 100%, this influenced the clinical use of this detection method to some extent. Objective: This study aimed to optimize the skin biopsy method for detecting p-syn deposition in patients with PD. Methods: Ninety PD patients and 30 healthy controls underwent skin biopsies at 2–3 of the following sites: the distal leg, thigh, cervical region, or forearm. Skin biopsy samples were cut to 50- and 15-μm thickness sections. Deposition of p-syn were detected by using double immunofluorescence labeling of protein gene production 9.5 (PGP9.5) /p-syn. Statistical data analysis was performed using SPSS 25.0 software. Results: Deposition of p-syn were found in 75/90 PD patients but not in healthy controls ( p < 0.001). The positive deposition rate of p-syn in the single cervical site was significantly higher than that in the distal leg, thigh, and forearm site. Two samples from the cervical region had a higher p-syn positive rate compared to single cervical site (90.5 vs. 66.7%, p = 0.037). There was no significant difference between the p-syn positive rate of samples from the distal leg/cervical sites and 2 samples from cervical region (80 vs. 90.5%, p = 0.261). Next, the p-syn positive deposition rate of 2-biopsy samples including distal leg/cervical sites and double samples in the cervical site were comparable to the 3-biopsy samples. The 50-μm section had a significantly higher p-syn positive rate than the 15-μm section ( p = 0.049). Conclusions: Two biopsy sites (cervical/distal leg) or 2 samples from the cervical site were considered to be priority biopsy sites for detecting p-syn in PD patients. Thick sections may provide a higher p-syn positive rate than thin sections for skin biopsies. These findings provide an optimized p-syn detection method, indicate the valuable pathology biomarker of PD and will promote the clinical use of skin biopsy in the future.

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Section: Introductionmentioning

confidence: 99%

Optimization of the Detection Method for Phosphorylated α-Synuclein in Parkinson Disease by Skin Biopsy

et al. 2020

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“…The distribution pattern of p‐syn in PD in concern with biopsy sites had been published with controversy in recent years, indicating the heterozygous factors may influence the deposition. To our knowledge, two patterns had been reported, one was proximal‐distal gradient which was the main pattern reported by two groups, 9,10,26‐29 the other was homogenous pattern reported by Doppler in 2018 and another group in Switzerland 30,31 . Although a more distal distribution tendency was found in Doppler’s article, no significant difference was found between the distal and proximal sites (12/25 vs. 8/25).…”

Section: Discussionmentioning

confidence: 81%

“…PD patients with orthostatic hypotension (PD + OH) and without OH (PD‐OH) demonstrated both the above two distribution patterns recently, 28 suggesting sources of PD patients in concern with clinical profiles such as autonomic symptoms may also influence the p‐syn distribution pattern. The phenomenon was further supported by Donadio’s article in 2020, where all PD + OH patients displayed p‐syn deposits without a proximal–distal gradient 29 . Although the Doppler’s group and the Switzerland group reported a homogeneous p‐syn pattern, 30,31 none of the autonomic function especially OH was not clarified in the two articles.…”

Section: Discussionmentioning

confidence: 86%

“…The phenomenon was further supported by Donadio's article in 2020, where all PD + OH patients displayed psyn deposits without a proximal-distal gradient. 29 Although the Doppler's group and the Switzerland group reported a homogeneous p-syn pattern, 30,31 none of the autonomic function especially OH was not clarified in the two articles. In this manuscript, we demonstrated a homogeneous distribution pattern of p-syn in the G2385R carrier group, the percent of patients with complaint of orthostatic intolerance was higher (3/12) than that (6/47) in noncarrier PD patients.…”

Section: Discussionmentioning

confidence: 93%

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Peripheral synucleinopathy in Parkinson disease with LRRK2 G2385R variants

Yang

Wang

Yuan³

et al. 2021

Ann Clin Transl Neurol

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Objective Recent studies demonstrated cutaneous phosphorylated α synuclein (p‐syn) deposition in idiopathic and some monogenetic Parkinson disease (PD) patients, suggesting synucleinopathy identical to that in the brain. Although the LRRK2 Gly2385Arg (G2385R) variant is a common PD risk factor in the Chinese population, the pathogenesis of PD with G2385R variant has not been reported. We investigated whether synucleinopathy and small fiber neuropathy (SFN) are associated with the G2385R variant. Methods We performed genotyping in 59 PD patients and 30 healthy controls from the skin biopsy database. The scale of SFN was assessed, as well as bright‐field immunohistochemistry against antiprotein gene product 9.5 (PGP9.5) and double‐labeling immunofluorescence with anti‐PGP9.5 and anti‐p‐syn. Results (1) p‐syn deposited in the skin nerve fibers of G2385R carrier PD patients, which was a different pattern from noncarriers, without no difference observed between proximal and distal regions; (2) decreased distal intraepidermal nerve fiber density was found in both the G2385R carrier and the noncarrier PD group, and was negatively correlated with composite autonomic symptom score‐31 item (COMPASS‐31) scores; (3) PD patients with the G2385R variant showed a more peculiar clinical profile than noncarriers with a higher nonmotor symptoms scale, COMPASS‐31 score, and levodopa equivalent dose, in addition to an increased prevalence of certain autonomic symptoms or rapid eye movement sleep behavior disorders. Interpretation Synucleinopathy is related to the LRRK2 G2385R genotype and implies a different pathogenesis in G2385R variant carriers and noncarriers. This study also extended the clinical profiles of PD patients with the G2385R variant.

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“…In addition to early diagnosis of PD, abnormally aggregated α-Syn in skin nerve fibers might also be used for differential diagnosis with other diseases. Donadio et al (2020) recently reported that the distribution difference of p-α-Syn in cutaneous nerves might help to distinguish MSA Parkinsonism type from PD with orthostatic hypotension. Wang et al also used RT-QuIC/PMCA and found that skin α-Syn had aggregation seeding activity that was significantly higher in individuals with PD and other synucleinopathies, compared with those with tauopathies and non-neurodegenerative controls (Wang Z. et al, 2020).…”

Section: The α-Syn Species In Rbcsmentioning

confidence: 99%

Biomarkers and the Role of α-Synuclein in Parkinson’s Disease

Wang

Liu

et al. 2021

Front. Aging Neurosci.

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Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the presence of α-synuclein (α-Syn)-rich Lewy bodies (LBs) and the preferential loss of dopaminergic (DA) neurons in the substantia nigra (SN) pars compacta (SNpc). However, the widespread involvement of other central nervous systems (CNS) structures and peripheral tissues is now widely documented. The onset of the molecular and cellular neuropathology of PD likely occurs decades before the onset of the motor symptoms characteristic of PD, so early diagnosis of PD and adequate tracking of disease progression could significantly improve outcomes for patients. Because the clinical diagnosis of PD is challenging, misdiagnosis is common, which highlights the need for disease-specific and early-stage biomarkers. This review article aims to summarize useful biomarkers for the diagnosis of PD, as well as the biomarkers used to monitor disease progression. This review article describes the role of α-Syn in PD and how it could potentially be used as a biomarker for PD. Also, preclinical and clinical investigations encompassing genetics, immunology, fluid and tissue, imaging, as well as neurophysiology biomarkers are discussed. Knowledge of the novel biomarkers for preclinical detection and clinical evaluation will contribute to a deeper understanding of the disease mechanism, which should more effectively guide clinical applications.

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Skin Biopsy May Help to Distinguish Multiple System Atrophy–Parkinsonism from Parkinson's Disease With Orthostatic Hypotension

Cited by 57 publications

References 44 publications

Optimization of the Detection Method for Phosphorylated α-Synuclein in Parkinson Disease by Skin Biopsy

Optimization of the Detection Method for Phosphorylated α-Synuclein in Parkinson Disease by Skin Biopsy

Peripheral synucleinopathy in Parkinson disease with LRRK2 G2385R variants

Biomarkers and the Role of α-Synuclein in Parkinson’s Disease

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