| Parameter | Level | Healthy Control (HC) | Parkinson's Disease (PD) | Other Neurodegenerative Diseases (OND) | FDR adjusted P values (across groups) | |
|---|---|---|---|---|---|---|
| Serum, PPMI cohort, (should be early PD) cohort, HC 187명, PD 397명, mds updrs III : 1.2 VS 21, mds-updrs total score: 4.6 vs 32 | Baseline N | 61 | 98 | 17 | ||
| CSF NfL [pg/ml] | mean±SD | 543 ± 250 | 675 ± 384 | 1063 ± 670 | <0.01 | |
| median (min, max) | 494 (249, 1626) | 562 (170, 2477) | 830 (416, 2876) | |||
| 24 months Follow-up N | 60 | 88 | 18 | |||
| CSF NfL [pg/ml] | mean±SD | 566 ± 261 | 1170 ± 2486 | 1240 ± 987 | <0.01 | |
| median (min, max) | 515 (259, 1618) | 669 (169, 16449) | 887 (519, 3878) | |||
| 48 months N | 56 | 85 | 17 | |||
| CSF NfL [pg/ml] | mean±SD | 611 ± 290 | 751 ± 363 | 1025 ± 476 | 0.02 | |
| median (min, max) | 531 (271, 1630) | 688 (201, 1869) | 984 (426, 1677) | |||
| 72 Months N | 53 | 76 | 17 | |||
| CSF NfL [pg/ml] | mean±SD | 643 ± 228 | 977 ± 903 | 1016 ± 532 | 0.03 | |
| median (min, max) | 605 (395, 1384) | 762 (295, 5298) | 888 (582, 1938) | |||
1
- xliii) mean baseline serum NFL was higher in Parkinson’s disease patients (13 ± 7.2pg/mL) than in controls (1…?), P = 0.0336. → effect size d 계산해보니 0.14 (너무 작네!)
- xliv) NFL increased longitudinally in Parkinson’s disease patients versus controls (P < 0.01).
(Table 2), median serum NfL increased by 3.35% (PD국한 이니라 다 같은데?) per year of age (P < 0.0001), 표2보면, PD에서 더 오르지 않은데, 의미?) - xlv) ,
- xlvi) whereas some cognitive scoresshowed a negative association
- xlvii) We observed a slight increase in serum NfL over 72 m follow-up (이건 다른 cohort지칭하는 듯?)
TABLE 3. Associations between clinical measurements and age-, sex-, and levodopa-equivalent dosages adjusted log2NfL among patients with Parkinson’s disease in the PPMI cohort
| Variable | Estimate | Standard error | Lower bound | Upper bound | P | FDR-adjusted P |
|---|---|---|---|---|---|---|
| MDS-UPDRS part III | 1.3850 | 0.6214 | 0.1360 | 2.6340 | 0.0305 | 0.0731 |
| MDS-UPDRS total score | 3.4450 | 0.9802 | 1.4760 | 5.4150 | 0.0010 | 0.0115 |
| MoCA | -0.4153 | 0.2412 | -0.9001 | 0.0695 | 0.0915 | 0.1568 |
| HVLT-IR | -0.6134 | 0.3790 | -1.3750 | 0.1482 | 0.1120 | 0.1680 |
| HVLT-DG | -0.3019 | 0.1100 | -0.5230 | -0.0807 | 0.0085 | 0.0339 |
| HVLT-RT | -0.0286 | 0.0112 | -0.0512 | -0.0061 | 0.0138 | 0.0415 |
| SDMT | -1.3930 | 0.4657 | -2.3280 | -0.4567 | 0.0044 | 0.0261 |
| LNS | -0.0683 | 0.1339 | -0.3373 | 0.2007 | 0.6123 | 0.6679 |
| BJLO | -0.2431 | 0.1404 | -0.5253 | 0.0390 | 0.0896 | 0.1568 |
| DaT scan putamen (SBR) | -0.0244 | 0.0253 | -0.0752 | 0.0265 | 0.3398 | 0.4531 |
| DaT scan caudate (SBR) | -0.0225 | 0.0420 | -0.1069 | 0.0618 | 0.5937 | 0.6679 |
| DaT scan striatum (SBR) | 0.0038 | 0.0400 | -0.0766 | 0.0841 | 0.9254 | 0.9254 |
MoCA, education-adjusted Montreal Cognitive Assessment; SDMT, Symbol Digit Modality Test; LNS, Letter-Number Sequencing Test; BJLO, Benton Judgment of Line Orientation test; MDS-UPDRS, Movement Disorder Society Unified Parkinson’s Disease Rating Scale; DaT scan, dopamine transporter imaging; SBR, striatal binding ratio; HVLT-IR, Hopkins Verbal Learning Tests with immediate/total recall; HVLT-DG, Hopkins Verbal Learning Tests with discrimination recognition; HVLT-RT, Hopkins Verbal Learning Tests with retention (HVLT-RT).
위표보면 datscan correlation,
| {Bridel, 2019 #1407} | CSF | Metaanalysis | Fold change (95% CI) compared to HC: 1.08 (0.87-1.33) yearly increase in CSF NfL in % (95%CI), p-value: 3.50 (2.76-4.24), **** |
| {Bäckström, 2015 #2315} | CSF, 99 PD, 30 Hc | longi | At baseline NFL, median (IQR), ng/L: HC 878 (667-1120) vs PD: 1143 (706-1864), vs MSA 1215 (881-2052) In PD, high NFL, low Aß1-42, and high heart fatty acid–binding protein at baseline were related to future PDD. CSF NfL levels were relatively stable despite disease progression in PD over 12 months, 9 we |
[20230404 JS Datscan and CSF NFL effect size]
| HC | PD | DaTscan HC Mean striatum | PD | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CSF NFL | mean / SD | mean | SD | group dif d | long change d | ||||||||
| mean | SD | mean | SD | group dif d | long change d | ||||||||
| baseline | DeNoPa | 543 | 250 | 675 | 384 | 0.41 | |||||||
| baseline | PPMI (Liu 2022) | 98.7 | 99.9 | ||||||||||
| baseline | PPMI (Tremblay 2021) | 없네 | 없네 | 11.3 | 6.3 | 0.19 | 2.56 | 0.57 | 1.41 | 0.4 | 2.34 | 0.45 | |
| Y1 | PPMI | 12.6 | 7.3 | 1.24 | 0.4 | ||||||||
| Y2 | PPMI | 13.6 | 7.5 | 1.16 | 0.4 | ||||||||
| Y3 | PPMI | 0.33 | |||||||||||
| Y4 | PPMI | 1.01 | 0.4 | ||||||||||
| Y5 | PPMI | 0.81 | 0.1 | ||||||||||
| csf longi change | PPMI | {Tremblay, 2021 #2057} | |||
| csf longi change | DeNoPa | {Mollenhauer, 2020 #1254} | not shown in the above table | ||
| csf crosssectional | DeNoPa | {Mollenhauer, 2020 #1254} | |||
| Datscan crosssectional | PPMI | {Simuni, 2020 #2273} | |||
| Datscan longi change | PPMI | {Simuni, 2018 #2272} |
| ↑ vs HC (Baseline) | Longi change | Correlation with UPDRS | ||
|---|---|---|---|---|
| p-aSyn | CSF | 1.2X | NA | NA |
| Blood | 16X (No overlap) | NA | Weak correlation (r=0.27) | |
| NFL | CSF | 1.25x | stable | |
| Blood | 1.4x, 1.6x, 1.1x | Slight increase | modest correlation (r=0.42) |
Turnover
- Neurofilaments are the major cytoskeletal proteins of neurons in both the CNS and peripheral nervous system.
- blood NfL is not specific for one disease and its levels can also be influenced by physiological processes including body - mass - index, diabetes, and hypertension.
- The kinetics of NfL was explored in diseases with a known timepoint for the neuronal damage, whereas in chronic diseases such as (ADand other) it is difficult to investigate acute changes over time. Therefore, it may be difficult to determine with a single measurement when the peak of NfL is reached and when the levels are normalized. Because blood NfL levels are measured as a concentration, a change in the blood volume can affect NfL levels.
- the confounding effect of comorbidities was controlled for using longitudinal measurements. Blood NfL is a nonspecific measure of neurodegeneration without the diagnostic power of the AD core CSF biomarkers. 86 However, the simplicity of a blood NfL measurement enables the monitoring of neurodegeneration over time and provides a tool for detecting the effect of prospective treatments. 97
| synthesis | Release into ECF/CSF/Blood | Degradation in blood | ||
|---|---|---|---|---|
| Biofluid 입장에선 이것도 input (ie production) | Half-life (=The half-life of a protein is defined as the time it takes for the concentration of the radiolabeled target protein to be reduced by 50% relative to the level at the beginning of the chase., =the time it takes for half of the protein to be broken down or eliminated from the body) | |||
| Human | (Barro, 2020 #2702) NFL is released into the cerebrospinal fluid (CSF) and blood following damage to both central 1 and peripheral neurons. 2, 3, 4 | -neta: 35days (from the d review but they are quoting this from (Bergman, 2016 #2418)) | (Bergman, 2016 #2418) This is in MS patients! 대략 2m 인구로 보이나, interval이 sparse에서 정확히 알기 어려움. | |
| mouse | (Nixon, 1986 #2416) the degradation of radiolabeled NF proteins in two exponential rates. There was a rapid loss (10% per week) of radiolabeled NF proteins during 6 weeks (t1/2 20 d) followed by a slower loss (1.5% per week) during 4 months (t1/2 5...) | A | ||
| mouse | (Yuan, 2021 #2441) Intracellular NfPs have long half-lives ranging from 55 days in axons ((Nixon, 1986 #2416); Yuan et al., 2015a) to 64-72 days at synapses (Heo et al., 2018), |
(Yuan, 2021 #2441) serum or plasma NfL levels in healthy individuals are about 2.5% of the levels in CSF and correlate highly with the 40-fold higher NfL concentrations [in] CSF with typical R values ranging from 0.6 to 0.7
| Synthesis → | Release into ECF/CSF/Blood → | In fluid (degradation in blood), half-life calculator: https://www.calculator.net/half-life-calculator.html?type=1&nt=&n0=100&t=80&t12=40&x=58&y=4 | Degradation in blood ... | ||
|---|---|---|---|---|---|
| (Row body cut at page boundary; continues onto 20240722_184310.) | |||||
Uncertain Spans
- “mean baseline serum NFL was higher in Parkinson’s disease patients (13 ± 7.2pg/mL) than in controls (1…?)” — the closing control-arm value is partially clipped by the body crop edge; only the leading digit
1is unambiguously visible. - “(t1/2 5…)” — the closing slow-loss half-life value reads as
5followed by clipped digits at the row boundary; the full Nixon 1986 half-life value continues onto the next page. - “(ADand other)” — the source typesets
ADand otherwithout a space; preserved verbatim. - “scoresshowed” / “ehesion-bound” / “signifincnat”-type compound typos — preserved verbatim where they appear;
scoresshowedappears in the xlvi) bullet.