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Abstract

Parkinson disease (PD) is the second most common neurodegenerative disease, and the most common synucleinopathy, as alpha-synuclein (α-syn), a prion-like protein, plays an important pathophysiologic role in its onset and progression. Although neuropathologic changes begin many years before the onset of motor manifestations, diagnosis still relies on the identification of the motor symptoms, which hinders to formulate an early diagnosis. Because α-syn misfolding and aggregation precede clinical manifestations, the possibility to identify these phenomena in patients with PD would allow us to recognize the disease at the earliest, premotor phases, as a consequence of the transition from a clinical to a molecular diagnosis. Seed amplification assays (SAAs) are a group of techniques that currently support the diagnosis of prion subacute encephalopathies, namely Creutzfeldt-Jakob disease. These techniques enable the detection of minimal amounts of prions in CSF and other matrices of affected patients. Recently, SAAs have been successfully applied to detect misfolded alpha-synuclein (α-syn) in CSF, olfactory mucosa, submandibular gland biopsies, skin, and saliva of patients with Parkinson disease (PD) and other synucleinopathies. In these categories, they can differentiate PD and dementia with Lewy bodies (DLBs) from control subjects, even in the prodromal stages of the disease. In differential diagnosis, SAAs satisfactorily differentiated PD, DLB, and multiple system atrophy (MSA) from nonsynucleinopathy parkinsonisms. The kinetic analysis of the SAA fluorescence profiles allowed the identification of synucleinopathy-dependent α-syn fibrils conformations, commonly referred to as strains, which have demonstrated diagnostic potential in differentiating among synucleinopathies, especially between Lewy body diseases (LBDs) (PD and DLB) and MSA. In front of these highly promising data, which make the α-syn seeding activity detected by SAAs as the most promising diagnostic biomarker for synucleinopathies, there are still preanalytical and analytical issues, mostly related to the assay standardization, which need to be solved. In this review, we discuss the key findings supporting the clinical application of α-syn SAAs to identify PD and other synucleinopathies, the unmet needs, and future perspectives.

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Published In

Neurology®
Volume 99Number 5August 2, 2022
Pages: 195-205
PubMed: 35914941

Publication History

Received: January 13, 2022
Accepted: May 10, 2022
Published online: June 3, 2022
Published in issue: August 2, 2022

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From the Section of Neurology, Lab of Clinical Neurochemistry, Department of Medicine and Surgery, University of Perugia, Italy (G.B., F.P.P., L.G., L.P.); and Unit of Neurology 5 and Neuropathology (C.M.G.D.L., F.M.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
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Chiara Maria Giulia De Luca, MSc https://orcid.org/0000-0002-6233-8272
From the Section of Neurology, Lab of Clinical Neurochemistry, Department of Medicine and Surgery, University of Perugia, Italy (G.B., F.P.P., L.G., L.P.); and Unit of Neurology 5 and Neuropathology (C.M.G.D.L., F.M.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
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Federico Paolini Paoletti, MD, PhD https://orcid.org/0000-0001-9623-1900
From the Section of Neurology, Lab of Clinical Neurochemistry, Department of Medicine and Surgery, University of Perugia, Italy (G.B., F.P.P., L.G., L.P.); and Unit of Neurology 5 and Neuropathology (C.M.G.D.L., F.M.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
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Lorenzo Gaetani, MD, PhD https://orcid.org/0000-0003-3967-8954
From the Section of Neurology, Lab of Clinical Neurochemistry, Department of Medicine and Surgery, University of Perugia, Italy (G.B., F.P.P., L.G., L.P.); and Unit of Neurology 5 and Neuropathology (C.M.G.D.L., F.M.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
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From the Section of Neurology, Lab of Clinical Neurochemistry, Department of Medicine and Surgery, University of Perugia, Italy (G.B., F.P.P., L.G., L.P.); and Unit of Neurology 5 and Neuropathology (C.M.G.D.L., F.M.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Disclosure
Scientific Advisory Boards:
1.
None
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
None
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
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1.
NONE
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1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
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1.
NONE
Research Support, Government Entities:
1.
NONE
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1.
NONE
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1.
None
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Lucilla Parnetti, MD, PhD https://orcid.org/0000-0001-5722-3967
From the Section of Neurology, Lab of Clinical Neurochemistry, Department of Medicine and Surgery, University of Perugia, Italy (G.B., F.P.P., L.G., L.P.); and Unit of Neurology 5 and Neuropathology (C.M.G.D.L., F.M.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Disclosure
Scientific Advisory Boards:
1.
None
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
None
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1.
NONE
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1.
NONE
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1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
None
Stock/stock Options/board of Directors Compensation:
1.
NONE
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1.
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Notes

Correspondence Dr. Parnetti [email protected]
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Submitted and externally peer reviewed. The handling editor was Peter Hedera, MD, PhD.

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