{"doi":"10.1002/mds.30028","title":"Biomarker‐Based Approach to α‐Synucleinopathies: Lessons from Neuropathology","abstract":"Recently, proposals have attempted to reclassify Lewy body diseases in vivo by merging the long-established clinicopathological entities of Parkinson's disease (PD), Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB), and some also to include rapid eye movement (REM)-sleep behavior disorder (RBD). A position paper1 and a personal view paper2 proposed biomarker-based staging and classification of these conditions. As both papers emphasize,1, 2 clinical diagnosis has challenges and limitations including early diagnosis that reflects the pathogenesis and clinical staging hindered by disease heterogeneity even within the same proteinopathy types. The suggested staging system is founded on the idea that diagnoses should rely on biomarkers, independent of the clinical syndrome, and the term neuronal α-synuclein disease (NSD) is proposed to redefine these conditions.1 Together with the paper on biological classification2 it was proposed that the detection of α-synuclein in cerebrospinal fluid (CSF) or skin and dopaminergic dysfunction assessed via positron emission tomography (PET) or single photon emission computed tomography (SPECT) possess the necessary sensitivity and specificity to identify the gold standard neuropathological alterations associated with Lewy body diseases.1, 2 We welcome these initial attempts to redefine these diseases incorporating biological constructs, particularly for the early and in vivo diagnosis of these disorders. Imaging and biofluid biomarkers for neurodegeneration have potential advantages in assessing disease presence and progression during life and have made major contributions in the research setting, most notably in enriching clinical trials for Alzheimer's disease (AD). Biology-based disease definition and classification has always been a central focus of neuropathology. As noted in the original publications,1, 2 this initial research framework will require much work to fill gaps in technology and knowledge, validate, and improve as we attempt transition from research biomarkers to disease surrogates. For example, currently α-synuclein seeding amplification assays (SAA) lack sensitivity and specificity for brain region and cell type, features known from neuropathology to be critically important to clinical outcomes. Our goal is to share the collective experience of our international group of neuropathology experts by suggesting future research priorities to further improve the proposed research frameworks. The first description of Lewy bodies detectable on hematoxylin and eosin staining3 and glial cytoplasmic inclusions in multiple system atrophy (MSA), observed first using Gallyas silver staining4 was followed by the discovery of the central role of α-synuclein, which linked these diseases together as α-synucleinopathies.5 Application of various anti-α-synuclein antibodies used in immunohistochemistry6-8 revealed a wide range of cytopathologies beyond the classical Lewy bodies, diffusely distributed in neuronal processes and the perikarya, and beyond that, in astrocytes9-12 and oligodendroglia.11, 13 In MSA, the pathognomonic glial cytoplasmic inclusions (“Papp-Lantos bodies”)4 are accompanied by neuronal cytoplasmic and nuclear inclusions.14 New subtypes of MSA, where neuronal α-synuclein pathology in the limbic system is a predominant feature, have also been recognized.15, 16 Several genes associated with the clinical features of PD are unaccompanied by Lewy bodies on neuropathological examination. Other, not PD-related mutations and genetic conditions, including those in PRNP (ie, genetic prion disease),17 APP,18 PSEN 1, PSEN 2,19 and trisomy 2120 (ie, AD-related neuropathology), infantile neurodegenerative disorders,21 or neurodegeneration with brain iron accumulation,22 can also show Lewy body or other types of α-synuclein pathology. From a neuropathological viewpoint, two major categories of conditions with α-synuclein pathology can be distinguished: those where α-sy","journal":"Movement Disorders","year":2024,"id":431253,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.959,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":109118,"name":"Lea T. Grinberg","orcid":"0000-0002-6809-0618","position":1,"is_corresponding":false},{"id":291678,"name":"Glenda M. 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