Neuronal alpha-Synuclein Disease Integrated Staging System performance in PPMI, PASADENA, and SPARK baseline cohorts
ABSTRACT The Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with underlying Lewy body pathology, including Parkinson’s disease (PD), Parkinson’s disease dementia, and dementia with Lewy bodies (DLB), and stage them based on underlying biology and increasing degree of functional impairment. The objectives of this paper were to 1) develop both biologic and clinical data-informed definitions for the NSD-ISS; 2) apply these definitions across the disease continuum; and 3) evaluate time to onset of key clinical outcomes based on baseline NSD stage.Methods We utilized data from the PPMI, an observational study and PASADENA and SPARK, two independent interventional studies. Individuals currently defined by clinical features as PD, Prodromal, or Healthy Controls were classified based on biological, clinical, and functional anchors and assigned to one of seven NSD-ISS stages at baseline. Biomarker anchors included synuclein (S) assessed by cerebrospinal fluid (CSF) alpha-synuclein seed amplification assay (n-asyn SAA), dopamine (D) assessed by dopamine transporter imaging (DaTscan), and genetic status (G). Clinical and functional anchors were derived from MDS-UPDRS Parts I-III and the Montreal Cognitive Assessment. The onset of key clinical outcomes for each stage was assessed over 12 years of follow-up.Results Across the three studies 1,741 participants had SAA data and of these 1,030 (59%) were S+ consistent with NSD. Among sporadic PD, 683/736 (93%) were NSD and the distribution for Stages 2B, 3, and 4 was 25%, 63%, and 9%, respectively. Among these individuals, median (95% CI) time to developing a clinical outcome was 8.3 (6.2, 10.1), 5.9 (4.1, 6.0), and 2.4 (1.0, 4.0) years for those staged at baseline as 2B, 3, and 4, respectively.Conclusion We propose data driven biologic and clinical anchors for NSD-ISS. Our data highlight baseline heterogeneity of the individuals currently defined as early PD that impacts progression to clinically meaningful milestones. Validation of the anchors in longitudinal cohorts is necessary..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 17. Feb. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Dam, Tien [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2024.02.14.24302818 |
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| PPN (Katalog-ID): |
XBI042526167 |
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| 520 | |a ABSTRACT The Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with underlying Lewy body pathology, including Parkinson’s disease (PD), Parkinson’s disease dementia, and dementia with Lewy bodies (DLB), and stage them based on underlying biology and increasing degree of functional impairment. The objectives of this paper were to 1) develop both biologic and clinical data-informed definitions for the NSD-ISS; 2) apply these definitions across the disease continuum; and 3) evaluate time to onset of key clinical outcomes based on baseline NSD stage.Methods We utilized data from the PPMI, an observational study and PASADENA and SPARK, two independent interventional studies. Individuals currently defined by clinical features as PD, Prodromal, or Healthy Controls were classified based on biological, clinical, and functional anchors and assigned to one of seven NSD-ISS stages at baseline. Biomarker anchors included synuclein (S) assessed by cerebrospinal fluid (CSF) alpha-synuclein seed amplification assay (n-asyn SAA), dopamine (D) assessed by dopamine transporter imaging (DaTscan), and genetic status (G). Clinical and functional anchors were derived from MDS-UPDRS Parts I-III and the Montreal Cognitive Assessment. The onset of key clinical outcomes for each stage was assessed over 12 years of follow-up.Results Across the three studies 1,741 participants had SAA data and of these 1,030 (59%) were S+ consistent with NSD. Among sporadic PD, 683/736 (93%) were NSD and the distribution for Stages 2B, 3, and 4 was 25%, 63%, and 9%, respectively. Among these individuals, median (95% CI) time to developing a clinical outcome was 8.3 (6.2, 10.1), 5.9 (4.1, 6.0), and 2.4 (1.0, 4.0) years for those staged at baseline as 2B, 3, and 4, respectively.Conclusion We propose data driven biologic and clinical anchors for NSD-ISS. Our data highlight baseline heterogeneity of the individuals currently defined as early PD that impacts progression to clinically meaningful milestones. Validation of the anchors in longitudinal cohorts is necessary. | ||
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