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Synucleinopathy diagnosis is “under the skin”: biopsy as the next generation tool for early detection

Synucleinopathies are neurodegenerative illnesses that cause phosphorylated alpha-synuclein protein (P-SYN) accumulation in the peripheral and central nervous systems. These illnesses share clinical characteristics, including progressive impairment and neurodegeneration. They include dementia with Lewy body (DLB), multiple system atrophy (MSA), Parkinson’s disease (PAD) and pure autonomic failure (PAF). Current pharmacology lacks disease-modifying medication for these illnesses, and many individuals diagnosed with synucleinopathies face diagnostic delays or misdiagnoses. There have been a number of studies published over the past 6-7 years that have identified skin biopsies as a potential effective source of material for detection of phosphorylated α-synuclein. With consistently high sensitivity (>80%) and specificity approaching 100%, the potential for skin biopsy as the clinical tool of choice for the diagnosis of synucleinopathies appeared to be high.

Publications have reported the use of both phosphorylated and non-phosphorylated α-synuclein as potentially relevant biomarkers. Non-phosphorylated α-synuclein is a ubiquitous protein and is noted in healthy subjects as well as disease states, but it does increase with disease progression. In contrast, phosphorylated α-synuclein has been shown to be 100% specific for disease compared with control subjects, but it may not correlate with disease severity. As a marker of disease, phosphorylated α-synuclein has been selected as the diagnostic tool of choice by most laboratories because of the very high specificity A reliable biomarker for identifying synucleinopathies, such as immunohistochemistry of cutaneous phosphorylated α-synuclein, is urgently needed. This test might be sensitive and specific. In a recent study published in JAMA, researchers evaluated the positivity rate of cutaneous deposition among individuals with these conditions.

Out of 428 patients (277 with synucleinopathy and 151 controls), 343 were included in the primary analysis [mean age, 70 years; 175 (51%) men]; 223 fulfilled the consensus criteria for synucleinopathy, and 120 met the criterion as controls following expert panel evaluation. Among those with synucleinopathy, 96 (28%) were diagnosed with Parkinson’s disease, 50 (15%) with Lewy body dementia, 55 (16%) with multiple system atrophy, and 22 (6.4%) with complete autonomic failure. The proportion of participants with P-SYN in their skin was 93% (n = 89) with Parkinson’s disease, 98% (n=54) with MSA, 96% (n=48) with Lewy body dementia, and 100% (n=22) with complete autonomic failure; four controls had cutaneous phosphorylated-SYN deposition. P-SYN detection in the subepidermal plexus varied, with MSA (49%, n=27) having a higher prevalence than Parkinson’s disease (3.1%, n=3), DLB (10%, n=5) or PAF (9.1%, n=2). The length-dependent small fiber neuropathy varies amongst synucleinopathy subtypes.

Neuropathy was most prevalent in DLB patients (78%, n=39), followed by those with Parkinson’s disease (63%, n = 60), PAF (46%, n=10), and MSA (22%, n=12). The overall P-SYN for all research participants corresponded with their exam results and surveys. P-SYN deposition by the study participants was associated with the period since MSA, PAF and PAD diagnosis. The findings demonstrated that cutaneous phospho-synuclein is present in >92% of participants, with skin biopsies, was tolerated well with minor side effects. However, there were 21% of misdiagnosed cases. Accurate diagnosis is critical for patient and family counseling, starting symptomatic treatment, and conducting clinical studies of possible disease-modifying medications. Neurology experts recommend skin biopsy as a novel method for movement problems. In addition, the findings might speed up medication development for synucleinopathies by enhancing patient homogeneity in clinical trials.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Gibbons CH et al. JAMA 2024 Mar 20:e240792.

Siepmann T et al. Eur J Neurol. 2023; 30(5):1281.

Gibbons CH et al. Biomark Med. 2022; 16(7):499.

Wang N et al. J Histochem Cytochem. 2020; 68(10):669.

Kim JY et al. J Clin Neurol. 2019; 15(2):135–142.

Donadio V et al. J Neurop Exp Neurol. 2018; 77(10):942.

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Dott. Gianfrancesco Cormaci
Dott. Gianfrancesco Cormaci
Laurea in Medicina e Chirurgia nel 1998, specialista in Biochimica Clinica dal 2002, ha conseguito dottorato in Neurobiologia nel 2006. Ex-ricercatore, ha trascorso 5 anni negli USA alle dipendenze dell' NIH/NIDA e poi della Johns Hopkins University. Guardia medica presso la casa di Cura Sant'Agata a Catania. In libera professione, si occupa di Medicina Preventiva personalizzata e intolleranze alimentari. Detentore di un brevetto per la fabbricazione di sfarinati gluten-free a partire da regolare farina di grano. Responsabile della sezione R&D della CoFood s.r.l. per la ricerca e sviluppo di nuovi prodotti alimentari, inclusi quelli a fini medici speciali.

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