| neurophysiology |
Biomarker analysis in clinical trial of arimoclomol (NCT02612129) J Inherit Metab Dis. 20... the CSF and plasma after the initial administered (Tyrolt et al., 2014). As a result of thermogluation after initial dosing in lab, [40]-HC may not be elevated in response to anysubsequent doses... not beeffective as a marker to monitor therapy long term. | |||||
| neurophysiology | neurophysiological tests still fall short in providing invaluable information for the diagnostic workup of NPC diagnosis because findings are not specific for NPC and may not be found in all cases of NPC. | |||||
MOA of NPC
| Within lysosome | |||||||
|---|---|---|---|---|---|---|---|
| Normal | Cholesterol in the lysosome is mostly derived from low density lipoprotein (LDL) via the process of endocytosis. | NPC2 binds cholesterol → conveys cholesterol to NPC1's NTD (N-terminal domain) → cholesterol is moved to NPC1's SSD (sterol sensing domain) → | (by some unknown mechanism) cholesterol exit lysosome i) to ER for esterification ii) golgi iii) plasma membrane | ||||
| cholesterol is diffused into lysosomal membrane and then exposed to face cytosol | |||||||
| NPC | unesterified cholesterol cannot exit lysosome NPC does not arise from defective substrate degradation but from transport defect! | ↑ (compensatory) cellular synthesis/update of cholesterol (by TFEB etc) | accumulation of cholesterol and other lipids in many types of cells, including lipid-laden macrophages (called foam cells) and neuronal and glial cells 101–103 | neuronal distension, axonal swelling, and the formation of axonal spheroids 112–115. | NFT in subcortical structures, including hippocampus, thalamus, and striatum in NPC 24, 118 (LBs are not characteristic) | ||
| Lysosomal cholesterol accumulation | ↑ lysosomal pH | ↓ lysosomal acid lipase activity | oxidized cholesterol derivatives (oxysterol) in the serum and CSF (이는 그 양이 적어 cholesterol-3β,5α6β-triol과 cholestane-3β,5α,6β-triol) | ||||
| Lysosomal accumulation of various lipids (ie not just cholesterol) | 이 lipids 중 sphigomyelin이 lysosome membrane에 구멍냄 | Lipids leak into cytosol | Mitochondrial damage | ||||
| Physico-chimical interactions between lipids |
NfL
Age
- Neta: – NfL is elevated with age https://www.nature.com/articles/s41467-020-14612-6
PD
Make sure to see NFL section in MSA!
| MDS 2020: Brit Mollenhauer | a. | Not as much as in other diseases eg AD, ALS because Nigrostriatal dopamine axons are unmyelinated, when NFL comes from myelinated axons, high expression of NfL in large-caliber myelin-ated axons (Zetterberg, 2016 #907) | |
| (Lin, 2019 #1237) | blood |
178 participants, including 116 with PD, 22 with (MSA), and 40 healthy controls. We measured plasma NfL levels with electrochemiluminescence immunoassay. a mean follow-up interval of 3 year → Plasma NfL levels were significantly higher in the MSA group than in the PD (1.6x내) and healthy groups (35.8 ± 6.2, 17.6 ± 2.8, and 10.6 ± 2.3 pg/mL, respectively, p < 0.001). In the PD group, NfL levels were significantly elevated in patients with advanced Hoehn-Yahr stage and patients with dementia (p < 0.001). NfL levels were modestly correlated with UPDRS part III scores (r = 0.42, 95% confidence interval 0.46–0.56, p < 0.001). After a mean follow-up of 3.4 ± 1.2 years, a Cox regression analysis adjusted for age, sex, disease duration, and baseline cognitive status showed that higher baseline NfL levels were associated with higher risks for motor or cognition progression (p = 0.029 and p = 0.015, respectively). | |
| (Tremblay, 2021 #2057), Longitudinal, | CSF: PPMI cohort, (n=74), no HC | Bl: 11.3 (6.3) → y1: 12.6 (7.3) (양 ↑ 11%) → y2: 13.6 (7.5) (양 ↑ 8%) | |
| (Liu, 2022 #2316) | PPMI CSF & blood:, longi | Serum: 555 CSF: 291 |
baseline CSF NfL levels were higher in PD (99.9 pg/ml) than controls (98.7 pg/ml) (1.01배비, P = 0.624). Baseline serum NfL levels were higher in PD groups (12.5 pg/ml) than controls (11.5 pg/ml) (1.09배비, P = 0.003) Baseline, both CSF and Serum NFL correlated with total and in updrs, datscan mean caudate/striatum (suppl table1) (correlation coefficient not shown) Longi CSF nfl change: no difference between PD and HC Longi Serum nfl change: faster in PD Longitudinally: i) CSF NFL changes ↑ (and mena caudate), ii) serum NfL change Baseline nfl: correlation between CSF and serum (p<0.001, but correlation coefficient not shown) Longi nfl change: correlation between CSF and serum (p=0.001, but correlation coefficient not shown) |
| (Mollenhauer, 2020 #1254) | CSF: DeNoPa (De Novo Parkinson's disease) Cohort, n: baseline 98, → 24m 88 → 48m 85 → 72m 76 | The strong correlation between CSF and serum NfL (by Spearman's rank ^P=0.723; P <10 × 10⁻⁶; |
Long change: now correlation but clearly differentiated p<0.05 ? In numerous previous CSF studies (conducted before ultrasensitive technologies were available), the meanNfL levels in DND (other cognate or neurodegenerative disorders) were markedly increased compared with MCs, such as in MS (4.5-fold increase), TBI (3-fold increase), PSP, corticobasal degeneration, MSA (3- to 4.25-fold increase) as well as in other, more slowly progressing neurodegenerative disorders such as ... |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Top neurophysiology row | result of thermogluation after initial dosing in lab, [40]-HC may not be elevated in response to anysubsequent doses | OCR returns thermogluation and anysubsequent doses as run-together strings; preserved verbatim. |
| MOA of NPC oxysterol cell | oxidized cholesterol derivatives (oxysterol) ... cholestane-3β,5α,6β-triol | The bracketed Korean clarification reads as written in the source; the chemical glyphs 3β,5α,6β are reconstructed from OCR + visual reading. |