{"doi":"10.1002/mds.30272","title":"Reply to: “Refutation of the <scp>αSyn</scp> ‐ <scp>SAA</scp> ‐Based Staging for Parkinson's Progression (Neuronal α‐Synuclein Disease‐Integrated Staging System <scp>[NSD</scp> ‐ <scp>ISS]</scp> )”","abstract":"We appreciate Espay et al.'s letter1 written in response to our recently published article.2 Interestingly, we found these comments not a “refutation” of the Neuronal α-Synuclein Disease-Integrated Staging System (NSD-ISS) research framework, but largely an endorsement of this approach, highlighting a need for additional research to study and refine it, with which we agree. We fully agree that the field currently lacks quantitative fluid and imaging biomarkers to define progression through all disease stages; we and others are focused on developing quantitative alpha-synuclein (α-syn) and other key markers of neurodegeneration. Despite this limitation, we demonstrated that NSD-ISS provides a valuable research framework to guide future disease-targeting clinical trials. The focus of our article was on participants diagnosed clinically with “typical” early Parkinson's disease (PD), and we showed that overall they progress, as expected, through pivotal early NSD stages (ie, Stages 2–4) over a 5-year period. This confirmation of progression through the staging system will inform clinical trials. We also agree that the NSD-ISS staging system will likely identify large numbers of Stage 1 individuals who may not become symptomatic during life, or only after many years, similar to what has been reported for Alzheimer's disease. This likelihood is supported by emerging data that 6–8% of otherwise healthy individuals above the age of 60 years have evidence of α-syn pathology,3 but the prevalence of clinical PD in this age group is only 1%. Detecting additional biomarkers that determine which Stage 1 NSD-ISS individuals are likely to progress is a current research focus, to enable recruitment for clinical trials, to prevent disease progression, and, ultimately, population screening. For now, the Parkinson's Progression Markers Initiative (PPMI) is prioritizing recruitment of individuals in NSD Stage 2A as the next step in assessing early NSD and its progression. Development of an α-syn blood biomarker or a synuclein positron emission spectrometry (PET) tracer would allow PPMI to assess Stage 1 as well. Our current article focusing on 5-year progression through and from Stages 2–4 shows that initiation of symptomatic motor therapy resulted in some stage reversion from Stages 3 (8%) and 4 (41%). We highlighted that this is an expected effect of anchoring Stages 3–6 to functional impairment rather than quantitative biomarkers, as the former can be affected by effective treatments. Ultimately, assessment of functional impairment in conjunction with impact on biology will be the essential drivers for documenting therapeutic efficacy that is most meaningful for patients and provides support for regulatory approval, and will distinguish symptomatic therapies from disease-targeted therapies.4 The NSD-ISS was put forward as an initial research framework with a goal for evolution, with clear anticipation that this will happen as the field develops and validates new biomarkers and functional measures. The NSD-ISS research framework informs the progression of disease in the key “early PD” population and will evolve to inform progression of all stages of NSD as biomarker research evolves. The world of neurodegenerative diseases (eg, Alzheimer's disease, Huntington's disease, multiple sclerosis) has moved into the era of biological definitions, in combination with clinical measures anchored to degree of functional impairment, to enable development of disease-targeted therapies that millions of individuals suffering from these devastating diseases impatiently await. We have eagerly embraced this new era while humbly recognizing that our framework is just the first step in an ongoing, rapidly evolving process that will require a concerted effort from all of us in the global research community. (1) Manuscript Preparation: A. Writing of the First Draft, B. Editing and Final Approval.T.S.: 1A. T.S., L.M.C., K.L.P., C.M.K., D.W., B.D., K.M.: 1B. Data sharin","journal":"Movement Disorders","year":2025,"id":558352,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9525,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":246440,"name":"Lana M. Chahine","orcid":"0000-0003-2521-7196","position":1,"is_corresponding":false},{"id":279151,"name":"Kathleen L. Poston","orcid":"0000-0003-3424-7143","position":2,"is_corresponding":false},{"id":482494,"name":"Catherine Kopil","orcid":"0000-0001-8678-7550","position":3,"is_corresponding":false},{"id":80309,"name":"Daniel Weintraub","orcid":"0000-0003-0633-7168","position":4,"is_corresponding":false},{"id":1198608,"name":"Billy Dunn","orcid":"0000-0002-4314-5993","position":5,"is_corresponding":false},{"id":80317,"name":"Kenneth Marek","orcid":"0000-0002-4197-5627","position":6,"is_corresponding":false},{"id":246441,"name":"Tanya Simuni","orcid":"0000-0002-2347-1644","position":0,"is_corresponding":true}],"reference_count":4,"raw_metadata":null,"created_at":"2026-07-19T02:55:25.969263Z","pmid":"40579845","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}