| SNCA HDO | LG | Systemic injection (easy to ad.) | ||
| SNCA degrader | Target entry | Systemic injection (easy to ad.) | ||
| GBA act | LG | GD/GBA-PD | LTI | |
| GBA GT | LG | GBA-PD | Preveil | |
| Parkin GT | pre-LG | Park2 PD | ||
| NLRP3 | pre-LG | PD | ||
| ACi | pre-LG | PD | ||
| mLRRK2 | Hit finding | Park8-PD (G2019S) | Denali |
Clinical subteam
| NDU Clinical subteam - proposed areas of focus | NSTM | |
|---|---|---|
| DaTscan sample size and interpretation of relation to clinical endpoints | ||
| UPDRS III sample size | ||
| Digital motor strategy and sample size requirements | ||
| Other biomarkers that may support decision making | ||
| ePOC decision making framework | ||
| Deliverables: SNCA ASO (~PROTAC/AUTAC) trial protype |
Quarterly Feedback
| NDU quarterly report -- 07-22-2022 -- Final.pptx |
Neurodegeneration
| Correlation with | |||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DA (CN nucleus) | DA (putamen) | HVA (CN) | HVA (putamen) | HVA (GP) | DAT | UPDRS III neuronal c (not just DA, any neurons) | |||||||||||||||||||||||||||||||||||||
| SNc neuronal loss | (Greffard, 2006 #1531) human | r=-0.671 | r=-0.865 | r=-0.79 | r=-0.787 | r=-0.762 |
Highly correlated, r=-0.83 or - The density of neuronal p... was correlated with r=...subscore of UPDRS item 22 (r=-0...001) bradykinesia subscore of UPDRS item 31 (r=-0...001). It correlated tremor subscore (item 20) | ||||||||||||||||||||||||||||||||||||
| (Bernheimer, 1973 #1749) Postmortem, 39 PD cases, no normal control, Disease duration 9.3 SD 0.9 js: cell loss was only graded (~5), so %cell loss doesn't exist. | |||||||||||||||||||||||||||||||||||||||||||
| SNc neuronal loss | (Clarke, 2001 #2018) — two-panel cell-loss kinetics graphs (% initial cell number vs Time (years post onset); ρ(τ) vs τ (years)) | ||||||||||||||||||||||||||||||||||||||||||
| SNc neuronal loss | (FEARNLEY, 1991 #2021) Human (used in Chaejin kim's slide) — Parkinson's disease (constant risk) model, % of normal cell number vs Duration of symptoms (years), 10 / 20 / 30 / 40 / 50 | ||||||||||||||||||||||||||||||||||||||||||
| SNc neuronal loss |
Table 1. Thresholds for symptom appearance at 13.2 d and level of degeneration in fully Parkinsonian animals at D25 (% of D0 values ± SD)
| r=0.875 {Bezard, 2001 #1748} MPTP monkey | {Bezard, 2001 #1748} MPTP monkey r=0.931 | {Bezard, 2001 #1748} correlation DAT (ARG) vs TH+ neuronal count is r=0.918 cf) correlation between DA (striatal) and DAT binding (striatum) is r=0.944 | |||||||||||||||||||||||||||||||||||||||
|
(A) TH immunohistochemistry — Number per section 0-1200 across D0, D6, D12, D15, D25 with star and plus markers; (B) y-axis 1200- partially clipped. 13.2일에 phenoconversion, 이때 SN TH neuronal loss is 43.2% | |||||||||||||||||||||||||||||||||||||||||||
| SNc neuronal loss | (Clarke, 2005 #2019) rat — Chemically-induced parkinsonism (rat), % initial cell number vs Time (weeks) | ||||||||||||||||||||||||||||||||||||||||||
| SNc neuronal loss | (Clarke, 2000 #2020) 6-OHDA rat — Chemically-induced rat model of Parkinson's disease (exponentially decreasing risk), % of neurons present in unlesioned striatum vs Time after chemical injection (weeks) | ||||||||||||||||||||||||||||||||||||||||||
| {Wakabayashi, 2006, postmortem} | In normal, pigmentation 정도 | In PD, Neuronal loss 정도 | LB occurrence 순서 (progression of LB is parallel to that of neuronal loss.) |
|---|---|---|---|
| paranigral nucleus (PN), | 중간정도 pigmented | Intermediate degree | 2 |
| medial group (MG | Heavily pigmented | Intermediate degree | 3 |
| dorsal group (DG | Heavily pigmented | Less neuronal loss | 4 |
| ventrolateral part (VL) | Less pigmented | Severe neuronal loss | 1 |
| {Tremblay, 2021 #2057} PPMI, early Longitudinal, 4-120, 157HC |
[Deformation-based morphometry, voxel-wise atrophy] 결론: Atrophy spread pattern 은 transneuronal (=transsynaptic) connectivity 와 regional factor (eg oligodendrocyte/endothelial cell들이 적은쪽으로 진행한다! (cf: Other routes of spreading include exosomes and tunneling nanotubes. Because these routes of transmission are membrane-bound, the aSYN in these structures is not accessible to antibodies) - No significant clusters presented significantly greater atrophy after 1 year - atrophy significantly progressed over 2 and 4 years in the caudate, nucleus accumbens, hippocampus and posterior cortical regions (atrophy 방향이 옆등 아니라 post-cortical 이다). The progression of atrophy was more pronounced in regions with a higher expression of genes related to synapses, Progression of atrophy in Parkinson's disease is in line with the prion-like propagation hypothesis of alpha-syn, synapses may be especially vulnerable to synopathy (Neibhboring region에서 more atrophy 였다는 관찰 했다는 ㄴ듯) - When investigating the association between the mean atrophy progression of the seven resting-state networks after 2 and 4 years and the change in clinical measures over the same time period, no significant correlations were found after correcting for multiple comparisons. - cortical regions containing relatively more oligodendrocytes and endothelial cells had reduced vulnerability to atrophy - SN may not show atrophy progression due to a floor effect (cell loss being already severe at presentation), - while the brainstem is difficult to assess with DBM. Cortical atrophy patterns may be expected to relate to cognitive impairment; however, no cognitive decline was observed in this patient group, possibly due to a form of attrition bias affecting the PPMI cohort, whereby more severely affected individuals tended not to undergo ... |
| {Pieperhoff, 2022 #2051} early PD 37명, HC 27명, longitudinal MRI |
js: 이대 정답이가 UPDRS = dynamic change + MRI volume change [baseline에서] - Group difference: SN에서(마저) 거우 2.98 or 3.32% 차이, 이외 sensory, motor and orbitofrontal cortices, areas in the frontal operculum, inferior frontal sulcus, hippocampus and entorhinal cortex, 에서 차이나나나 FDR에서 다 not signifincnat - UPDRS-III at baseline had negative associations mainly with regions in the left inferior parietal, occipital and inferior frontal cortex, and it ... |
Uncertain Spans
- The Greffard / Bernheimer correlation row’s red text in the right-most cell is laid out as broken phrases with ellipsis-like glyphs (
r=-0...001); the digit groups have been reproduced as visually read but the embedded periods are typographic artifacts of the source layout, not decimals. - “FDR에서 다 not signifincnat” —
signifincnatis a typo in the source (should besignificant); preserved verbatim. - “Neibhboring region에서 more atrophy 였다는 관찰 했다는 ㄴ듯” — the closing Korean filler
ㄴ듯reads ambiguously and may be a partial token. - “(B) y-axis 1200-” — the second panel of the TH immunohistochemistry figure starts at y-axis label
1200and is clipped at the row boundary; the bottom of the panel is not visible in the body crops. - “atrophy 방향이 옆등 아니라 post-cortical 이다” — the Korean phrase
옆등 아니라reads as옆도 아니라or similar; the visible glyph is옆등and is preserved verbatim.