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Biomarkers and Clinical Outcome Measures

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Biomarkers and Clinical Outcome Measures

This topic page reorganises the 27 source notes filed under biomarkers-outcomes into reading-order axes. It does not replace the by-photo Markdown; every substantive claim links back to a source note or the canonical transcription. Where a source carries Uncertain Spans, that uncertainty is preserved here rather than smoothed out.

Overview

The corpus treats biomarkers and clinical outcome measures as nine overlapping problems. (1) A biomarker development / validation framework that walks from [BIOMARKER] taxonomy through analytical (technical) validation parameters, ELISA / MJFF assay-development phases, BMx Milestone Matrix, BAF / BAQ / BCS Biomarker Validation Milestones, and a Keytruda PD-L1 / MSI-H / dMMR worked example (20240722_184723, 20240722_184726, 20240722_184730, 20240722_184733, 20240722_184736, 20240722_184740). (2) Clinical motor / cognitive scales and the trial-design sample-size material that sits next to them — Original UPDRS (1987), MDS-UPDRS (2008), Holden 2018 PPMI longitudinal MDS-UPDRS, Simuni 2018 #198 Table 2, MoCA, and the MDS-UPDRS / DaTscan / [18F]AV-133 effect-size and sample-size estimates (20240722_184300, 20240722_184303, 20240722_184306). (3) NFL across PD / MSA cohorts, including the Nocker 2012 DAT sample-size table, Poewe 2015 / Wild 2009 atrophy framing, Chelban 2022 #310 cross-sectional + longitudinal MSA NFL, Mollenhauer 2020 DeNoPa, and an NfL is elevated with age framing (20240722_184213, 20240722_184250, 20240722_184253). (4) RBD as prodromal / stratification axis (GBA → RBD penetrance, RBD → PD / MSA / PDD-DLB conversion, GBA pathway in RBD, PSYCHIATRIC OUTCOMES IN PD table, Unmet Needs across PD Patient Populations slide), with the NCNP CSF / Kamiguchi RBD translational sample arrangements and a treatment-side LED reference page sharing the RBD / RBDQ nav clusters (20240722_183327, 20240722_184434, 20240722_184545). (5) Retinal imaging and Rob Rubens / Yan biomarker planning (Amydis AMDXP-2011P retinal tracer, Veys 2019 / Bodis-Wollner 2014 / Ortuño-Lizarán 2018 retina pathology, Sung 2019 / Elena 2019 OCT, Karayel 2021 2257w urine-CSF overlap, Higginbotham 2020 #1497 CSF proteomics module Figure S5, Yan grid GBA activator / GBA GT / Parkin GT / cGAS) (20240722_184440, 20240722_184600). (6) Synapse / synaptic change biomarker biology (Succinate / IL-1β / Warburg, Fleming 2012 #2652 surrogate-endpoint level taxonomy, Wilson 2020 #902 SV2A imaging, neuronal pentraxins, TDP43 / TMEM106B / TMEM175 endo-lysosomal current) (20240722_184513, 20240722_184519). (7) A Reference range / Ubiquitin-Proteasome System (UPS) detection block (UPS schematic, Parkin E3 Ligase TR-FRET kit, polyubiquitin TUBE / fluorescein-Ub assays) (20240722_184557). (8) Adjacent biomarker-planning pages whose first nav_path entry sits on a biomarker-related cluster but whose visible body covers SCOPA-AUT / Sigma-1R review / σ1R PET, the SharePoint URL reference table, the SILK DNA-QC / Mutations / SNP Database block, the biomarkers whole-page planning grid (Skin Biopsy, ESS, Prevalence, Species difference), and the HGVS variant nomenclature / FATHMM / Genotyping Methods / Genetic Testing strand filed under the Synaptic change in PD nav root (20240722_184503, 20240722_184506, 20240722_184613, 20240722_184626). (9) A GLP-1 agonist clinical-trial sample-size anchor (Exenatide-PD3 Vijiaratnam 2021 #2793 protocol, LIXIPARK Meissner 2024 #2771, Neuraly NLY01 NCT04154072) that sits in 기타 MOA들 but is filed in this section by the heuristic (20240722_184344), plus two off-axis admin / screening edges (20240722_184450, 20240722_184456).

The pilot synthesis page biomarkers covers a disjoint slice of the corpus — the GBA-PD pilot range (20240722_181748, _181752, _181756, _181800, _181805, _181809) filed under gba-pd-asyn where the GBA / GCase activity / GlcCer / GlcSph / α-syn matrix and the LEAP / MOVES-PD / ambroxol / PR001 biomarker lists live. It does not overlap with the 27 sources covered here; this page does not overwrite or merge that pilot. pS65-Ub / Parkin-linked biomarker material is on parkin, cytokine / pyroptosis / TSPO biomarker material is on inflammation, and the MC1 PET / 31P MRS / mtDNA-copy biomarker material is on mitochondria; this page links across rather than re-states.

Source Coverage

27 source notes are assigned to the biomarkers-outcomes section. They sit across 22 first-level nav_path clusters (including the single Unclassified page whose first nav root is null because the front matter records nav_path only as a Word-pane note); the topic axes below collapse those clusters as follows:

nav root (first nav_path entry)sourcescovered axis
[BIOMARKER]3Biomarker development framework / analytical validation / Keytruda example
BIOMARKER1Biomarker development framework / Validity / BMx Milestone Matrix
Validation1Biomarker development framework / Validation milestones (BAF/BAQ/BCS)
Unclassified1Biomarker development framework / Sin 2015 pipeline / Fluid Biomarker Working Group
Outcome measures3Clinical scales (Original UPDRS / MDS-UPDRS / Schizophrenia edge)
MoCA (Montreal Cognitive Assessment)1Clinical scales (MoCA / Holden 2018 / sample-size)
MoCA (Montreal Cognitive...1Adjacent admin edge (relocation / SEPT14 / [Share]Folder)
NFL2NFL across PD / MSA cohorts / DTI-DWI-MRS-VMRI imaging biomarkers
MOA of NPC1NFL evidence table (NPC arimoclomol panel + Mollenhauer DeNoPa NfL trajectory)
RBD1RBD as prodromal / stratification axis
Transfer1RBD+PD translational questions / NCNP CSF sample / Kamiguchi
RBDQ-HO (REM sleep...1Adjacent established / experimental PD therapy + LED reference
Retina1Retinal imaging / OCT / Amydis tracer / Rob Rubens
Rob Rubens1Mizushima 2020 urine-CSF overlap / Yan biomarker grid / Figure S5 modules
SCOPA-AUT1Sigma-1R / σ1R PET / SILK adjacent strand / SharePoint reference table
SILK1DNA QC / Mutations / SNP Database (filed under SILK heading)
biomarkers1biomarkers whole-page planning grid (Skin Biopsy / ESS / Prevalence / Species)
Succinate1Succinate / Surrogate endpoint / Symptom / Synapse
Synapse1Synapse / Neuronal pentraxins / SV2A imaging / TMEM175
Synaptic change in PD1HGVS variant nomenclature / FATHMM / Genotyping / Genetic Testing
Reference range (normal range)1UPS schematic / Parkin TR-FRET kit / Ubiquitin detection methods
GT1GLP-1 agonist clinical-trial sample-size (Exenatide / Lixisenatide / Semaglutide / NLY01)

For exact nav_path strings and headings see biomarkers-outcomes and the matching by-nav indexes listed in related_topics_by_nav. The BIOMARKER (no brackets) nav root is the one that does not have a generated by-nav index, so the only entry point for that page is the section index and this topic page.

Across the 27 sources, the source-note frontmatter records 111 uncertain_span_count entries and 0 body-embedded figure assets. The zero-figure-embed count reflects the 2026-04-29 body-purity decision (docs/decisions/2026-04-29-body-purity-and-figure-only-embeds.md): the biomarker / outcome pages embed Keytruda ROC plots, MSI/MMR eligibility flow diagrams, the Sigma-1R Cell Mol Neurobiol 2020 schematic, Liu 2020 Warburg / Succinate / HIF-1α / NLRP3 cartoon, the Wilson 2020 SV2A bar graph, the TMEM175 endosome/lysosome current schematic, the UPS proteasome / TR-FRET schematic, the Veys 2019 / Bodis-Wollner 2014 retinal panels, the Higginbotham 2020 Figure S5 module composite, the GBA pathway in RBD bar panels, the PSYCHIATRIC OUTCOMES IN PD screenshot, and the Unmet Needs / Holden 2018 / Simuni Table 2 / Sin 2015 pipeline / Fluid Biomarker Working Group cells inside crops that also carry transcribable text, so they are kept as evidence rather than embedded. The 111 uncertain spans are retained as review targets and not resolved here.

Biomarker Development Framework, Taxonomy, and Validation Milestones

20240722_184723 is the BIOMARKER > Validity > Milestones > Milestone: MBM Only page. It opens the [BIOMARKER] block with Validity, Types of biomarkers, Type of BM, Milestones, Proposed flow in MBMIG, and BMx Milestone Matrix headings, then carries the Milestone: MBM Only table at the page bottom. 4 Uncertain Spans (clipped milestone-row labels at the top edge, header-row alignment in the BMx Milestone Matrix). The page is the entry point for the milestone framework that 184726 then expands.

20240722_184726 is the Validation > Biomarker milestones > BMx Assay Qualification > Biomarker type-specific definition of milestones page. It carries the Biomarker Validation Milestones arc with to BAF, to BAQ, to BCS, to BCS (IVC) rows, the Biomarker type-specific definition of milestones table, the Sato Sho / 20191004 DMPK activities for Acetylated Tubulin analysis Purpose / Progress block. 5 Uncertain Spans.

20240722_184730 is the single nav_path: [] (Unclassified) page; the front matter notes the Word navigation pane shows polygenic risk score > Steps of PRS STUDY while the body is the Biomarker Development, Validation, and Proteomics Approach chapter. It carries Top Notes (alpha tubulin / beta tubulin marker selection; LC/MS or ELISA Simoa modality selection), Stages of Biomarker Development (BM discovery → replication → assay/technical validation → qualification/correlation → utilization), Figure 17.1 Biomarker Development Pipeline. Source: Adapted from Sin et al. 2015 [7]. (Content development → Validation and qualification → Launch; Biomarker discovery → Biomarker replication → Analytical validation → Clinical validation → Clinical utility → Clinical use), the Fluid Biomarker Working Group 20190211v7.pptx BMx PJ Start / FA / TA / Execution / BMxS workflow, the BM Discovery → Validation (verification) Proteomics Approach table (CSF / Tissue (Brain) / Culture medium / BLOOD / Urine), and the Elements of Validation of a Biomarker block. The page status is codex_verified_draft rather than the standard codex_full_transcription_draft because the body was rebuilt from an OCR packet plus body-full image visual check after the original photo was clipped; 6 Uncertain Spans reflect that medium-confidence state and intentionally cover the dense Stages-of-development / Fluid-Biomarker-WG / Proteomics rows.

20240722_184733 and 20240722_184736 are the two-page [BIOMARKER] > Validation > Analytical (=Technical) validation block. 184733 is the parameter-by-parameter table (Sensitivity, Specificity / Selectivity / Accuracy, Spike & recovery, Dilution linearity, Parallelism, Precision / Repeatability) anchored on the Biomarker development process overview and the upper-row table-structure cells; 5 Uncertain Spans. 184736 is the continuation that carries ELISA Validation, MJFF Phases of Assay Development, and Examples of Biomarker; 6 Uncertain Spans. The two pages should be read as a single multi-page validation matrix; specific tolerances and parameter ranges are table-primary on those pages and not re-quoted here.

20240722_184740 is the [BIOMARKER] > Examples of biomarker > Keytruda with MSI-H or dMMR worked-example page. It pairs (a) the Non-Small-Cell Lung Cancer (NCT01295827) — PD-L1 BM Define / Validation analysis (training group n=182 prototype assay; 2014 Gandhi 50% potential cut-point ORR / RR breakdown; PD-L1 Tumor Expression × ORR by irRC / RECIST / PFS / OS table) with (b) the Keytruda with MSI-H or dMMR clinical-validation block (Indication, MSI / MMR Eligibility Diagram, Definitions, Mechanism). 4 Uncertain Spans (Initial Correlation ROC plot legend PS / P2S / P3S / HS, the protocol amendment block, the 2014 Gandhi label cell, and the surrounding Korean inline notes inside the PD-L1 / BM cut-point cells). The crop containing the ROC plot also contains the surrounding explanation, so it is preserved as evidence rather than embedded.

Clinical Scales, Cohorts, Sample Size

20240722_184300 is the Outcome measures > Original UPDRS (1987) page that introduces both UPDRS (1987) and MDS-UPDRS' = Modified UPDRS (2008) headings plus an Organoids headline at the top. 5 Uncertain Spans (Organoids leftover row label, Original UPDRS sub-item alignment, clipped subscale labels at the bottom edge).

20240722_184303 is the mid-document UPDRS / MDS-UPDRS detail page. The visible body carries (a) the MDS-UPDRS Part III item list rows 3.7–3.18 with green / yellow highlight bands (3.7 Toe tapping, 3.8 Leg agility, 3.10 Gait, 3.11 Freezing of gait, 3.12 Postural stability, 3.13 Posture, 3.18 Constancy of rest tremor), (b) the inline MDS-UPDRS III = (UPDRS III × 1.2) + 2.3 conversion attributed to (Hughes 1992 #1756) with the source’s own Korean caveat 이건 h&y I or II 용이라는 듯, but I can't find it in the paper preserved verbatim, plus UPDRS III + 7 = MDS-UPDRS III (Hentz 2015 #568), (c) the MDS-UPDRS subscale taxonomy (tremor / PIGD / rigidity / axial / Non-motor with UPSIT, ESS, EDS, GDS, RBDSQ, SCOPA, STAI, MoCA), (d) the right-most Correlate with DATscan? (cross-sectional) (Yang 2023 #2458) PPMI yes/no column, (e) the IV complications of therapy row mapping items 32-34 (dyskinesia) / 35-39 (OFF) and the V H&Y staging row, and (f) the bottom TABLE 2. MDS-UPDRS total scores over time in treated and untreated PD patients (Simuni 2018 #198) with Baseline / Month 6 / 12 / 24 / 36 / 48 / 60 columns and yellow-highlighted Total / Part II Mean (SD) anchors at Baseline and Month 36. The Treated DA OFF Total / Part II / Part III row group continues onto 20240722_184317. 4 Uncertain Spans.

20240722_184306 is the MoCA (Montreal Cognitive Assessment) page. The upper block reproduces the Holden 2018 #1123 PPMI MDS-UPDRS summary table (Baseline / Month 12 / 24 / 36 / 48 / 60 with Total, Part I, Part II, Part III, Part IV rows; treatment-with-dopaminergic-medications row 0% / 57.9% / 83.3% / 90.9% / 95.4% / 90.7%) and the corresponding TABLE 1 Demographic and Clinical Characteristics block; the right-side Effect Size chart contrasts DaTscan ≈0.74 vs [18F]AV-133 ≈0.97 Cohen’s d, and the embedded TABLE 2 Sample Size Estimations for the Detection of Disease Modification in a Hypothetical 1-Year Placebo-controlled Clinical Trial records Slowing (+4 / +2: 480 / 142 total), Halting (0: 68), Reversal (-2 / -4: 40 / 28). The Milestone-based approach, Takeda UPDRS analysis, and the MoCA-to-MMSE conversion (van Steenoven 2014 vs Internal) table at the bottom continue onto 20240722_184320. 3 Uncertain Spans.

20240722_184344 sits under GT > Cell therapy > Inflammation > 기타 MOA들 and is filed in this section by the heuristic; the body covers the GLP-1 / NLR analogue pipeline (Liraglutide / Lixisenatide / Semaglutide / Exenatide / Peptron PT320 / Neuraly NLY01) with the Vijiaratnam 2021 #2793 Exenatide-PD3 sample-size box (MDS-UPDRS Part 3 OFF endpoint, SD=13.5 baseline-follow-up correlation 0.70, n=160 evaluable to detect 5.0 points at 90% power and α=0.05, 200 recruited assuming 20% attrition), the LIXIPARK Meissner 2024 #2771 P2 placebo / Lixi / placebo-corrected nested table, and the four-trial duration spread (semaglutide 4y, liraglutide 13.5m, lixisenatide 12m + 2m washout, NLY01 9m). 4 Uncertain Spans. The page is included here for its sample-size and outcome-design content; the GLP-1 mechanism and clinical-pipeline material itself sits in 기타 MOA들, not in this topic.

The two off-axis pages on this axis are 20240722_184450 and 20240722_184456. 184450 sits under Outcome measures > Sandy > Screenig > Scientst.com > Schizophrenia; the visible body carries an HLI 20210806 block, a Sandy / Screenig / Scientst.com / Schizoprenia strand (with the misspellings Screenig and Schizoprenia preserved verbatim from the source), and the body extends into postmortem / PET paragraphs that continue onto 20240722_184453. 4 Uncertain Spans. 184456 sits under MoCA (Montreal Cognitive... but the visible body carries Travel & Expense / Concur / okta / IT / Mobile relocation administrative tables and a SEPT14 block with a clipped [Share]Folder heading at the bottom. 4 Uncertain Spans. Both pages are filed in this section because the heuristic uses the first nav_path entry; readers interested in MoCA-cohort or schizophrenia-postmortem material should open the canonical pages directly rather than treat this topic page as a synthesis of those themes.

NFL Across PD / MSA Cohorts

20240722_184213 is the NFL nav-root page that opens with the trailing rows of the Nocker 2012 sample-size table (Effect size 20% / 33% / 50% × Striatum / Putamen / Caudate, n=211 / 414 / 219 → 75 / 151 / 79 → 34 / 67 / 35 to detect a power-80% reduction in DAT decline), then walks through DTI (Slide 20220112 TAK-341 POM and Ph2 planning discussion- 011222; wide Potential MRI endpoints to assess drug effects table with Region × Estimate / LB / UB / Probability / N 5 year / Drug effect / Cohen’s d / Power columns, footnote α=0.1, one-sided test, n=60 completers/group, average putamen MD as endpoint, anchored on Poewe 2015 #2134 placebo data with the SD = [(UB-LB)/2]·sqrt(N)/ qt(0.975, df=N-1) ~ [(UB-LB)/2]·2.13668 formula), DWI (Seppi 2006 #1432 / Pellecchia 2011 #1431 / Reginold 2014), MRS (2023 MDS abstract: water-scaled myoinositol mI/water positively correlates with UMSARS / NNIPPS while NAA/water correlates negatively), VMRI (Wild 2009 #1076 atrophy table; AD 2.0-3.0%/y; PD 0.3-0.8%; PDD 1.1%; MSA 1.0-2.5%; PSP 1.2-1.3%), the Imaging biomarkers Pons / Cerebellum / Putamen atrophy comparison (Seppi 2006 / Paviour 2006 #1430 ↔ #1438 reference-id wobble preserved verbatim, with d=1.77 and d=1.4 N-per-arm sample-size sub-tables for 0.2 / 0.3 / 0.4 / 0.5 slowing), and the NFL sub-block proper (Chelban 2022 #310: plasma NfL 39.9 pg/ml baseline → ~43 pg/ml peak, deceleration from y7; CSF 4329 IQR 2571-5862 vs HC 560 IQR 420-855; plasma-CSF correlation emerging from y3 onward; trial size 28 participants 14 per group for 30% reduction at 80% power; (Hofmann lab) interventional sirolimus/rapamycin SIMOA 1-year study). 6 Uncertain Spans.

20240722_184250 sits under MOA of NPC > NFL > Age > PD. Its upper section carries an arimoclomol NCT02612129 biomarker-analysis panel (24S-HC stability caveats from Tyrolt et al. 2014) and a neurophysiology row noting that NPC neurophysiological tests are not specific for NPC. The mid-page MOA of NPC table walks across cholesterol / lysosomal-acid lipase / sphingomyelin / cholesterol-and-lipid accumulation / NFT-in-subcortical-structures columns. The bottom NfL evidence table records MDS 2020 Brit Mollenhauer rows, Lin 2019 #1237 blood, Tremblay 2021 #2057 CSF PPMI, Liu 2022 #2316 PPMI Serum 555 / CSF 291, and Mollenhauer 2020 #1254 CSF DeNoPa with the multi-panel log2 NfL-vs-age trajectory that continues onto 20240722_184306. 2 Uncertain Spans. The Neta annotation NfL is elevated with age (with Make sure to see NFL section in MSA!) is preserved on the source page rather than re-stated as definitive prose here.

20240722_184253 is the NFL > PD page that anchors a [20230404 JS Datscan and CSF NFL effect size] block at the top and a Turnover sub-section below. It has 4 Uncertain Spans and connects back to 20240722_184240 (neurodegeneration section) and forward to 20240722_184310 (where the NfL turnover material continues). The cross-page logical sequence DATscan / NFL effect-size → turnover → into Pathogenicity of variant scales should be followed via related_photos, not reconstructed here.

RBD Prodromal / Stratification Axis

20240722_184434 is the RBD nav-root page. It records GBA → RBD penetrance (Gan-Or 2015 PMID 26401515: idiopathic RBD n=265 vs in-house controls n=189 OR=2.63 95% CI 1.30-5.29 P=0.0052 all variants, OR=3.46 1.40-8.56 P=0.0045 pathogenic; pooled European-controls OR=6.24 95% CI 3.76-10.35 P<0.0001; 10.2% European RBD with pathogenic GBA mutation, 14% if PD-risk variants p.E326K and T369M included), the Schenck 2013 PMID 23347909 RBD → PD conversion (≤81% phenoconvert), RBD → Dementia / MSA / PDD-DLB rows, the embedded PSYCHIATRIC OUTCOMES IN PD table (Baseline / Year 1-5 with GDS-15, STAI State, MDS-UPDRS Part I subscores, ESS, RBDSQ, QUIP), the Unmet Needs across Parkinson's Patient Populations Takeda corporate slide 22 (At Risk → Prodromal → Early/Mild → Intermediate/Moderate → Advanced/Severe; Disease Modification / Treatment of Non-Motor Symptoms / Treatment of Motor Response Complications), and the GBA pathway in RBD multi-panel Huebecker 2019 PMID 30703585 figure (GlcCer / LacCer / Gb3 / Gb4 / GM3 / GM2 / GM1a / GD1a CSF panels, Control / PD / RBD groups). 4 Uncertain Spans. Specific Huebecker panel asterisk-significance (*, **, ***, ****) marks stay on the source.

20240722_183327 is the Transfer > Team > Translational questions > RBD+PD page. It records the NCNP CSF sample arrangement and the Email: RE: RBDの研究・期間延長させていただけますでしょうか_263-5 — Kamiguchi, Hidenori translational logistics block (Japan-side RBD study period-extension thread). 4 Uncertain Spans. The page is operationally adjacent to the RBD axis rather than mechanism, but its Translational questions section names RBD+PD as one of the hand-off topics, so it sits here.

20240722_184545 sits under RBDQ-HO (REM sleep... but the visible body is the established / experimental PD therapy block and the LED reference table — Levodopa Wearing-off / Long-term complications (50% of patients in 5 years; Wearing-off, early morning / nocturnal akinesia, Delayed on, On-off rapid fluctuation, Drug-resistant off periods, Dyskinesia), the Tomlinson 2010 PMID 21069833 Levodopa Equivalent Dose definition, the wide TABLE 1. LEDs for antiparkinsonian drugs matrix (L-Dopa / COMT inhibitors / Nonergot DA agonists / etc. with Total LED rows like LD × 0.33 / LD × 0.5 / 1 mg salt / 100), the Established PD Therapy / Experimental PD Therapy schematic, and the Striatum / Substantia nigra / Corticostriatal Glutamatergic Afferent illustrations. 3 Uncertain Spans. The page is included in this section because its first nav_path entry is RBDQ-HO (REM sleep...; the LED material itself is a clinical-pharmacology reference rather than an outcome measure, but the LED table is consumed by trials that use MDS-UPDRS endpoints, and the Established / Experimental PD Therapy column banner functions as the dose-class anchor for those trials.

Retinal Imaging and Rob Rubens / Yan Biomarker Planning

20240722_184440 sits under Retina > Issues Retina > Rob Rubens and walks through the Amydis Inc. AMDXP-2011P retinal-tracer phase 1/2a PROBE trial (αSyn / TDP-43 detection, single IV bolus, Figure 1), the Sung 2019 #232 inner retinal thinning, the Veys 2019 #1093 review row, the multi-row Elena 2019 #1094 OCT-in-PD evidence (retinal nerve fibre layer thinning citations [12, 24, 70, 75, 84]), the Retina: a window of brain panel (iris photograph; α-synuclein (+) ganglion cell morphology in PD retina = degenerating neuron in the brain; aSYN / Control retinal-section IHC strip with NFL / GCL / IPL / INL / OPL / ONL layer labels, Veys 2019; Bodis-Wollner 2014 retinal section; Ortuño-Lizarán 2018 IHC and Brain-vs-Retina synucleinopathy scatter plot p<0.05 / p=0.6661 / p=0.7861), the OS Mechanism / ROS chemistry row (O2 → O2*-, OH*, ONOO-, H2O2), and the clipped Measurement of OS / Evidence in PD (mainly 2019 Raza) sub-tables. 4 Uncertain Spans. The retinal-window panel is mixed text+figure and is kept as evidence rather than embedded.

20240722_184600 is the Rob Rubens continuation. It opens with the Resource: Mizushima 2020 Karayel 2021 2257w urine vs CSF protein-overlap row (HBS and LCC cohorts; 63% of CSF-abundant proteins overlap urine-abundant, 46% reverse, 36% / 1080 of all identified proteins in both biofluids; Pearson r=0.49; ALB / PTGDS / ORM1 / SERPINA1 / B2M shared abundance), continues into the Yan biomarker-planning grid (GBA activator / GBA GT / Parkin GT / cGAS columns × month-stamped rows 20201110 / 20210422 / 20210520 / 20210527 / 20210610 / 20210713 / 20210720 with PE / Retinal / histology / PLR budget bullets; Tsujihata-san fibroblast availability for MC1; cGAMP prototype established), and then the Higginbotham 2020 #1497 CSF proteomics summary plus the Figure S5 5-panel module composite (A Synaptic / B Vascular / C Myelination / D Glial Immunity / E Metabolic) with M-numbers M12 / M1 / M16 / M6 / M2 / M4 / M18 / M5 / M3 / M33 / M38 and CSF -Log10 p-value vs Log2 AD-vs-CT volcano plots; PARK7 is yellow-highlighted in the Glial Immunity panel. 4 Uncertain Spans. The Korean inline commentary 결국은 you have to see fig S5 is preserved on the source page rather than reconciled here.

The Retina and Rob Rubens strands in this section pair with the broader retinal / retina by-nav indexes and are adjacent to the PET-imaging section. The Rob Rubens page is also where the cross-program biomarker grid (GBA activator / GBA GT / Parkin GT / cGAS) appears as a single planning artifact spanning programs covered separately on parkin and the GBA-PD pilot.

Synaptic Biomarkers, SV2A, Surrogate Endpoint, UPS

20240722_184513 is the Succinate > Surrogate endpoint > Symptom > Synapse page. The Succinate block records LPS → Succinate → HIF-1α → IL-1β MOA, the Kumari 2020 #1870 PD vs HC effect size 0.5 (early PD vs HC 0.48), the UPDRS-motor / succinate r=0.24 p=0.03 correlation, and the Warburg-effect / PKM2 / glycolysis paragraph; the Liu 2020 #1875 hypoxia-NLRP3 cartoon is mixed text+figure and kept as evidence. The Surrogate endpoint block reproduces the Fleming 2012 #2652 Levels 1-4 Categorization of Outcome Measures (Level 1 true clinical efficacy: death, hospitalization composites, EDSS 7 progression in MS, etc.; Level 2 validated surrogate: HbA1c, BP, 6MWD ≥40m in PAH; Level 3 reasonably-likely-to-predict: viral load in HIV, durable CR in heme-onc, large PFS effects in solid tumors; Level 4 correlate of biological activity not at higher level). The `Synapse

anatomyblock carries the Pre (~1 μm) / Cleft (~20 nm) / Post (0.5-4 μm) schematic with Receptor / Scaffold / Ca²⁺ channel legend. 3Uncertain Spans`.

20240722_184519 is the Synapse > Neuronal pentraxins > Synaptic change in PD > Target Identification > TDP43 > TMEM106B > TMEM175 page. It carries the Functional synapse table (Pre-synapse / animal / human × Post- synapse / animal / human columns; Voltage or calcium fluctuations, Neurotransmitter release & vesicle recycling, Synchronous calcium activity rows mostly empty), the Functional vs Structural framing, the Neuronal pentraxins block (activity-dependent synaptic plasticity citations [1, 11, 32]), the Synaptic change in PD block with the embedded Wilson 2020 #902 SV2A imaging bar graph (Frontal Ctx, Parietal Ctx, Temporal Ctx, Occipital Ctx, Insula Ctx, Hippocampus, Caudate, Putamen, Thalamus, Brainstem, Median Raphe, Dorsal Raphe, Substantia Nigra, Locus Coeruleus), the Target Identification / Cerevance row partly obscured by red / orange / blue / black banner overlays, the TDP43 block, the TMEM106B block, and the TMEM175 (Transmembrane Protein 175) block with the mCherry-Rab5-Q79L fluorescence panel and the endosome / lysosome inward-current / pipette-solution / bath-solution / ΔΨ schematic. 5 Uncertain Spans. SV2A imaging here is a biomarker-side counterpart of the MC1 PET / 31P MRS / mtDNA material on mitochondria.

20240722_184557 is the Reference range (normal range) page that doubles as the UPS / ubiquitin biomarker reference. It opens with Figure 1-1 Schematic representation of the UPS (E1 → E2 → E3 / Substrate cycle; 19S cap + 20S core proteasome with α/β rings; β-ring chymotrypsin- / trypsin- / caspase-like sites with MG-132 inhibitor arrow; adapted from Tsai 2014 / McNaught 2006 / Goldberg 2012), records UPS impairment in PD substantia nigra (McNaught 2003 #1176 / 2001 #1177 chymotrypsin- 39% / trypsin- 42% / postacidic-like 33% reduced hydrolysing activities; PA700 reduced in SNc, increased in frontal cortex / striatum; PA28 nearly undetectable in SNc), enumerates the four ubiquitin genes (UBB, UBC, UBA52, RPS27A) and the 76-amino-acid 8.6 kDa ubiquitin protein, then walks through Detection methods (Parkin E3 Ligase TR-FRET kit; Antibody A / B / C; the TUBE fluorescein-Ub TR-FRET assay schematic and the DUB-blocked-substrate diagram), Ubiquitination sites defined on lysines (on the protein substrate겠지!), Assessment of UPS, and urine. 3 Uncertain Spans. The TR-FRET assay panel is the link between this page and the Parkin biomarker stack on parkin.

Biomarker-Adjacent Strands Filed Under Other Heads

20240722_184503 sits under SCOPA-AUT > Shipment > Sigma-1 Receptor (σ1R) > σ1R PET > SILK. The visible body opens with the wide internal-resource SharePoint URL reference table (ARNWG / team site of Neuroscience DDU / NSRB / sDIB / PRF (Pipeline Review Forum) / Consortia / Neuroscience cross-department workshop / Biomarker One-Pager (NSTM) / Biomarker Tracker (NSTM) / Kamiguchi-san’s group / NLRP3i / Bio- Orchestra / NSTA / RSLT 202004 / CNS / 원천징수영수증 / GPT playbook URLs), the Shipment Narita / Nanka Express / Yamato onu / BW3F-20 / Matsui Hideki / Where? workflow row, the Sigma-1 Receptor Fundamental Functions of Sig-1R (SIGMAR1) on ER Stress Regulation in Neurodegenerative Disorders Cell Mol Neurobiol 2020 review schematic (Mitochondria / ER / Cytoplasm cartoon with MtCu / VDAC / IP3R / Sig-1R / TCA / ATP / Ca²⁺ / BiP / IRE1 / xbp1 / 5b labels and the abbreviations glossary band), an anavex corporate logo, and the Early / Advanced sub-table whose Advanced column rows continue onto 20240722_184506. 5 Uncertain Spans. SCOPA-AUT itself is a clinical-scale heading but the scale’s own definition and scoring are not on this page.

20240722_184506 is the biomarkers whole-page planning grid (column heads What biomarkers may be most sensitive to disease progression?, What might be good biomarkers for mitochondrial function in PD?, Stratification by GBA activity, mutation, lysosomal pannel). The visible body cycles through Skin Biopsy (2 mm punch biopsy protocol references; Auburger 2012 / Antony 2020 / Au-Burbulla and Au-Krüger JoVE 2012; NINDS ICF S4 protocol); Sleep / Outcome measures (Epworth Sleepiness Scale, 8 questions, 0-3 scale, 0-24 range, with 0-5 / 6-10 / 11-12 / 13-15 / 16-24 sleepiness bands and the 10점 초과자가 concern annotation); Prevalence (CUMULATIVE PREVALENCE OF COGNITIVE AND PSYCHIATRIC DISORDERS IN PD slide: 50-70% of PD patients screen positive or are treated for depression / anxiety / cognitive impairment / fatigue / insomnia / sleepiness / RBD in first 5 years; 25% for psychosis and apathy); Species difference (Kung 2005 Body weight 70 kg / 250 g / 25 g, Brain weight 1.5 kg / 1.5 g / 0.4 g, Striatum weight 40 g / 0.05 g / 0.03 g, D2/D3 receptor 13.6 / 19.8 / 20 nmol/kg in human / rats / mice); STMN2; Speech; Stratification. 2 Uncertain Spans (VarElect Lyso-sPD bottom row clipped). The page’s first nav_path entry is the lower-cased biomarkers, distinct from the [BIOMARKER] chapter that drives the validation framework axis above.

20240722_184613 sits under SILK but the visible body is a DNA-QC / Mutations / SNP Database planning block (Three major purpose of DNA QC: Nucleic Acid Quantification × Purity × Integrity; absorbance / fluorescence methods; NanoDrop / Qubit / Femto pulse / Agarose Gel / Capillary Electrophoresis; Mutations classification table with Germline / Somatic rowspan rollups; SNP Database catalogue with example variant rows). 4 Uncertain Spans. The mismatch between the page navigation pane (SILK; 20240722_184503 body expands SILK as Stable Isotope Labeling Kinetics per Sato 2018 Neuron / C2N Diagnostics) and the visible body (DNA QC / SNP) is real on the source and preserved here.

20240722_184626 sits under Synaptic change in PD but the visible body is the HGVS variant-nomenclature primer (extension variants like p.32/Argext?, multi-change descriptions [Ala25Thr; Gly28Val] in cis vs trans, NEW Mosaicism / and Chimerism // notation), the FATHMM-MKL prediction-score block (≤0.5 Neutral, ≥0.7 Pathogenic in COSMIC), the Genotyping Methods table, the Sequencing volume vs Number of Samples figure (Single site / Single gene / Multi gene >5 / >100 / Exome / Whole genome × NGS Amplicon / qPCR-Sanger / Sanger / NGS Enrichment / NGS Exome / NGS Whole-genome rows; axes Variant screening → Discovery), and the Genetic Testing Description / Pros / Cons table that continues onto the following page. 4 Uncertain Spans. The Synaptic change in PD title is the section’s own placeholder; the body content is genetic-testing methodology adjacent to the genetics-pathway section rather than a synapse-biomarker axis.

Source Table

All 27 sources, in capture-time order, with the per-page uncertain-span and embedded-image counts copied from front matter. nav path is the full nav_path recorded in the source note; the single entry shown as Unclassified corresponds to a page whose nav_path field is null in the source frontmatter.

stemnav path / headingsource notecanonicaluncertain spansembedded images
20240722_183327Transfer > Team > Translational questions > RBD+PDnotemd40
20240722_184213NFLnotemd60
20240722_184250MOA of NPC > NFL > Age > PDnotemd20
20240722_184253NFL > PDnotemd40
20240722_184300Outcome measures > Original UPDRS (1987)notemd50
20240722_184303Outcome measures > Original UPDRS (1987) > MDS-UPDRS’ = Modified… > (Simuni, 2018 #198)notemd40
20240722_184306MoCA (Montreal Cognitive Assessment)notemd30
20240722_184344GT > Cell therapy > Inflammation > 기타 MOA들notemd40
20240722_184434RBDnotemd40
20240722_184440Retina > Issues Retina > Rob Rubensnotemd40
20240722_184450Outcome measures > Sandy > Screenig > Scientst.com > Schizophrenianotemd40
20240722_184456MoCA (Montreal Cognitive…notemd40
20240722_184503SCOPA-AUT > Shipment > Sigma-1 Receptor (σ1R) > σ1R PET > SILKnotemd50
20240722_184506biomarkersnotemd20
20240722_184513Succinate > Surrogate endpoint > Symptom > Synapsenotemd30
20240722_184519Synapse > Neuronal pentraxins > Synaptic change in PD > Target Identification > TDP43 > TMEM106B > TMEM175notemd50
20240722_184545RBDQ-HO (REM sleep…notemd30
20240722_184557Reference range (normal range)notemd30
20240722_184600Rob Rubensnotemd40
20240722_184613SILKnotemd40
20240722_184626Synaptic change in PDnotemd40
20240722_184723BIOMARKER > Validity > Milestones > Milestone: MBM Onlynotemd40
20240722_184726Validation > Biomarker milestones > BMx Assay Qualification > Biomarker type-specific definition of milestonesnotemd50
20240722_184730Unclassifiednotemd60
20240722_184733[BIOMARKER] > Validation > Analytical (=Technical) validationnotemd50
20240722_184736[BIOMARKER] > Validation > Analytical (=Technical) validationnotemd60
20240722_184740[BIOMARKER] > Examples of biomarker > Keytruda with MSI-H or dMMRnotemd40

Totals across the 27 sources: uncertain_span_count = 111, embedded_image_count = 0. These are review surface area; the zero-figure-embed count reflects the 2026-04-29 body-purity decision (docs/decisions/2026-04-29-body-purity-and-figure-only-embeds.md) under which mixed text-and-figure crops on these pages are kept as evidence rather than embedded.

Uncertainties Carried Forward

This page deliberately does not paraphrase the BMx Milestone Matrix cells, the Biomarker type-specific milestone matrix, the Sin 2015 biomarker development pipeline boxes, the Fluid Biomarker Working Group BMx PJ Start / FA / TA / Execution / BMxS deliverables, the analytical validation parameter table cells, the Keytruda PD-L1 ROC plot legend, the MSI / MMR eligibility-diagram outcomes, the Holden 2018 PPMI longitudinal table, the Simuni 2018 #198 Table 2 %-changes, the MoCA-MMSE conversion table values, the Nocker 2012 DAT sample-size table, the Poewe 2015 / Wild 2009 atrophy-rate ranges, the Chelban 2022 NfL absolute concentrations, the Mollenhauer DeNoPa NfL trajectory log2 values, the Huebecker GBA-pathway-in-RBD panel-significance asterisks, the Wilson 2020 SV2A regional bar graph, the Tomlinson 2010 LED conversion factors, the Karayel 2021 urine-CSF overlap percentages, the Higginbotham Figure S5 module mappings, the Fleming 2012 Levels-of-evidence enumeration, the McNaught 2003 / 2001 SNc proteasome-activity %-reductions, or the Vijiaratnam 2021 Exenatide-PD3 SD / correlation / power numbers. Specific uncertainty hot spots worth checking before any downstream extraction:

The Sandy / Screenig / Scientst.com / Schizoprenia misspellings on 20240722_184450 and the Ubiquitination sites defined on lysines (on the protein substrate겠지!) mixed-language heading on 20240722_184557 are preserved verbatim as the source’s own typography rather than reconciled.

  • biomarkers-outcomes — section index for all 27 sources
  • biomarkers — pilot synthesis covering the disjoint GBA-PD pilot range (20240722_181748 etc.) under sections/gba-pd-asyn; not overwritten by this topic
  • parkin — sibling topic; pS65-Ub, Parkin / PARKN-linked biomarker material, MJFF MC1 PET in Parkin-PD planning
  • inflammation — sibling topic; cytokine / pyroptosis / TSPO / Microglial Imaging biomarker work
  • mitochondria — sibling topic; MC1 PET / 31P MRS / mtDNA-copy / Padmanabhan biomarker pipeline
  • gba-pd / gba-therapeutics — sibling topics that the pilot biomarkers page anchors against
  • alpha-synuclein — alias entry point routing to corpus α-synuclein evidence (relevant for Amydis AMDXP-2011P, Veys 2019, Ortuño-Lizarán 2018)
  • biomarker — [BIOMARKER] first-nav_path index
  • biomarkers — lower-cased biomarkers first-nav_path index
  • validation — Validation first-nav_path index
  • outcome-measures — Outcome measures first-nav_path index
  • moca-montreal-cognitive-assessment / moca-montreal-cognitive — MoCA by-nav indexes
  • nfl — NFL by-nav index
  • moa-of-npc — MOA of NPC by-nav index (NPC arimoclomol panel)
  • rbd / rbdq-ho-rem-sleep — RBD / RBDQ by-nav indexes
  • transfer — Transfer by-nav index (RBD+PD translational thread)
  • retina / rob-rubens — Retina / Rob Rubens by-nav indexes
  • scopa-aut / silk — SCOPA-AUT / SILK by-nav indexes
  • succinate / synapse / synaptic-change-in-pd — Synapse / Synaptic-change by-nav indexes
  • reference-range-normal-range — Reference range by-nav index
  • gt — GT by-nav index (also referenced by the inflammation topic for the AAV / Capsid page)
  • unclassified — Unclassified by-nav index that holds the nav_path: [] page covering biomarker development pipeline / Sin 2015 / Fluid Biomarker Working Group
  • pet-imaging — sibling section for PET / DATscan / VMAT-2 / [18F]AV-133 detail not synthesised here
  • genetics-pathway — sibling section for the Genotyping Methods / FATHMM / HGVS variant material that 184626 anchors against
  • clinical-pd — sibling section for the LED / established / experimental PD therapy block that 184545 carries
  • msa — sibling section for the MSA NfL / UMSARS / NNIPPS material that 184213 references
  • source-catalog — all 447 sources in capture order
  • nav-path-index — 376 distinct nav_paths

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