From above Nocker 2012.
Table 1: Calculated sample sizes for the number of patients needed in each group for a therapeutic trial to detect the effect of a putative disease-modifying drug therapy resulting in a reduction in relative DAT decline (power 80%)
| Effect size (%) | Striatum | Putamen | Caudate |
|---|---|---|---|
| 20 | 211 | 414 | 219 |
| 33 | 75 | 151 | 79 |
| 50 | 34 | 67 | 35 |
(Jeong, 2017 #1392)
(Lee, 2021 #1445) 원문 sci-hub에서 안 되네!, 김한준 Variability of FP-CIT PET Patterns Associated With Clinical Features of Multiple System Atrophy (Lee, 2021 #1445)
DTI
Slide ‘20220112 TAK-341 POM and Ph2 planning discussion- 011222’ (original data: (Poewe, 2015 #2134))
Potential MRI endpoints to assess drug effects
| Region | Estimate | LB | UB | Prob | N 5 year | Drug effect (slowing) | Es | Es over 1 year | Cohen's d | Powera |
|---|---|---|---|---|---|---|---|---|---|---|
| MD-Lentiform Putamen | 33.41 | 17.01 | 49.81 | 0.001 | 20.00 | 20% | 0.95 | 104 | 0.285 | 0.608 |
| MD-Putamen | 23.05 | 10.70 | 35.42 | 26.41 | 0.87 | 30% | 0.28 | 0.380 | 0.786 | |
| Putaminal Signal Hypointensity | 0.24 | 0.04 | 0.43 | 0.019 | 0.42 | 40% | 0.38 | 0.58 | 0.475 | 0.905 |
| MD-Middle Cerebellar Peduncle | 28.69 | 5.01 | 52.38 | 0.021 | 50.61 | 50% | 0.47 | 0.62 0.57 | 0.570 | 0.966 |
| FA-Middle Cerebellar Peduncle | -0.02 | -0.05 | 0.00 | 0.025 | 004 | 0.53 | α=0.1, one-sided test, n=60 completers/group, average putamen MD as endpoint. | |||
| FA-Head of the Caudate | 0.02 | 0.037 | 0.50 | 0.54 | ||||||
| MD-Right Putamen | 15.75 | -0.37 | 31.86 | 0.055 | 34.43 | 0.46 | ||||
| MD-Head of the Caudate Nucleus | 23.30 | -1.73 | 48.32 | 0.065 | 53.46 | 0.47 0.44 | ||||
| FA-Left Putamen | 0.01 | 0.03 | 0.075 | 60% | ||||||
| FA-Globus Pallidus | 0.091 | 0.40 | ||||||||
| sum Score of Putamen Abn on MRI | 0.34 | -0.15 | 0.82 | 0.163 | 20.00 | 1.04 0.32 0.35 | ||||
| Atrophy of the Cerebellum Score | 0.11 | -0.03 | 0.30 | 0.248 | 0.27 | 0.29 | ||||
| FA-Putamen | -0.01 | 0.291 | 0.26 | |||||||
| Putaminal Hyperintense Rim | -0.10 | 0.279 | 0.45 | 0.25 | ||||||
| Atrophy of the MCP Score | 0.09 | -0.09 | 0.299 | 0.39 | ||||||
| Pontine Atrophy Score | 0.07 | -0.08 | 0.21 | 0.364 | 0.31 | 0.23 | ||||
| Hot Cross Bun Sign of the Pons Score | 0.06 | 0.469 | 0.17 | 0.18 | ||||||
| Putaminal Atrophy | 0.08 | 0.491 | 0.16 | |||||||
| Hyperintensity in MCP | -0.16 | 0.10 | 0.624 | 0.12 | ||||||
| FA-Right Putamen | 0.911 | |||||||||
| MD-Globus Pallidus | -0.95 | -23.45 | 21.55 | 0.930 | 48.08 | |||||
Values are derived from placebo data from Poewe et al. 2015
SD calculated as [(UB-LB)/2]·sqrt(N)/qt(0.975, df=N-1) ~ [(UB-LB)/2]·2.13668R
Estimate is the adjusted mean estimate, LB is the lower bound of the 95% confidence interval, UB is the upper bound of the confidence Interval, P is the P value for H0: Change from baseline = 0 for 48 weeks
Es is the Cohen’s D effect size over 48 weeks, and Es over 1 year is the Cohen’s D effect size over 1 year estimated as (52.1429/48) · Es for 48 weeks
DWI
- {Seppi, 2006 #1432} A DWI study on 10 patients with MSA-P reported increasing putaminal diffusivity at follow-up and its correlation with UPDRS motor scores,
- {Pellecchia, 2011 #1431} DWI study found no correlation with the UPDRS activities of daily living and motor subscales despite the progression in diffusivity in the putamen, pons, and cerebellum.
- (Reginold W. Parkinsonism Relat Disord 2014; 20:222-225) An association of the change in MCP diffusivity with UPDRS motor scores was demonstrated
MRS
2023 MDS abstract Alterity quantifies metabolic indicators of gliosis (myoinositol) and neuronal integrity (NAA) in MSA patients
#181: using MRS:
- Water-scaled myoinositol (mI/water) correlates positively with UMSARS and NNIPPS, while NAA/water correlates negatively
VMRI
{Wild, 2009 #1076} 2nd
TABLE 2. Rates of whole brain atrophy in Alzheimer’s disease, normal ageing and Parkinsonian disorders
| Disorder | Whole brain atrophy rate (%/yr) | References |
|---|---|---|
| AD | 2.0-3.0 | 25 |
| Normal ageing | 0.0-0.5 | |
| PD | 0.3-0.8 | 26, 29 |
| PDD | 1.1 | 27 |
| MSA | 1.0-2.5 | 18, 19, 29 |
| PSP | 1.2-1.3 | 28, 29 |
| HD |
cf) age-related atrophy typically occurs at less than 0.5% per year
- 18: (Horimoto, 2000 #1426): conventional MRI, the cerebral atrophy rate per year was 3.0% in patients with MSA-P and 1.9% in those with MSA-C.
- 19: (Konagaya, 2002 #1428)
- 20: (Freeborough, 1997 #1429)
- 여기 없는것: (Brenneis, 2007 #1427) {Paviour, 2006 #1438}, using semiautomated segmentation by BSI reported annual atrophy rates of 1.0%, 4.5%, and 3.2% in the whole brain, pons, and cerebellum, respectively, in patients with MSA-P, and the atrophy rates of the cerebellum and pons were correlated with (UPDRS) motor scores.
- {Pellecchia, 2011 #1431} {Seppi, 2006 #1432: diffusion MRI}
- Hauser TK, Luft A, Skalej M, et al. In MSA-C, an increased atrophy rate in the putamen and cerebellum compared with healthy controls has been reported.
- Minnerop M, Luders E, Specht K, et al. Mov Disord 2010; 25:2613-2620. Another study using VBM showed the progression of atrophy in the corpus callosum and the MCP in patients with MSA
Imaging biomarkers
| (Seppi et al., 2006, PMID: 16443375) 원문 X Seppi (2006) | {Paviour, 2006 #1430, (Pellecchia et al., 2011, PMID: 21466929)} 원문 X Paviour (2006) | |
|---|---|---|
| Atrophy(Tash) % change annualized % change Delta Trace(D) Pons / Cerebellum / Putamen (×10⁻³) | Atrophy(b5T) % change annualized 1.41 / 1.68 / 1.77 / 1.16 Putamen (×10⁻³) | |
| Mean | 4.5 / 3.2 | |
| SD | 1.9 / 0.05 / 0.089 |
N per arm for 80% power, alpha=0.05:
Assuming annualized change:
| d=1.77 slowing | 0.2 | 0.3 | 0.4 | 0.5 |
|---|---|---|---|---|
| d | 0.354 | 0.531 | 0.708 | 0.885 |
| n.2sided | 126.23268 | 56.64993 | 32.30531 | 21.04736 |
| n.1sided | 99.35483 | 44.54611 | 25.37231 | 16.50783 |
| d=1.4 slowing | 0.2 | 0.3 | 0.4 | 0.5 |
|---|---|---|---|---|
| d | 0.28 | 0.42 | 0.56 | 0.70 |
| n.2sided | 201.19092 | 89.95986 | 51.03487 | 33.02457 |
| n.1sided | 158.39905 | 70.78323 | 40.12347 | 25.93870 |
* Additional longitudinal data would be useful to confirm these assumptions. Discussion with groups working in this space such as the Innsbruck group could address this issue.
NFL
| Study | Description and N of samples | Timepoints | Assay | Plasma / CSF results | Correlation |
|---|---|---|---|---|---|
| {Chelban, 2022 #310} |
Cross-sectional and longitudinal study: Follow up for a mean period of 2 years in N=44 MSA patients. N=212 MSA patients for cross-sectional analyses, MSA-P (n=106) and MSA-C (n=106), disease duration about 5-6y, Longitudinal CSF NFL data 는 없는듯. | Baseline with annual follow for a mean period of 2 years | Plasma + CSF, Simoa kit |
(fig3) Plasma NfL: 39.9 pg/ml at baseline → increased initially (up to ~43 pg/ml), (accelerated with the progression of motor impairment) → (from y7) followed by a deceleration (fig3a) The median concentration of NfL was significantly higher in MSA patients compared to HC for both the CSF (4329 pg/ml, IQR 2571-5862 versus 560 pg/ml, IQR 420-855, P<0.001) and for plasma (39.9 pg/ml, IQR 27-48 versus 9.1 pg/ml, IQR 8.7-9.8, P<0.001). NfL levels in plasma and CSF were moderately correlated in the MSA cohort (rho=0.40, p<0.001) and (B) highly correlated in the healthy control group (rho=0.7, p<0.001), ; There was no plasma-CSF correlation in the early stages (<3y from onset) (rho=0.03, P=0.8, n=40). A correlation emerged as symptoms became more established (3-7y) (rho= - 0.44, P<0.001, n=45) and strengthened as the disease progressed (>7y), with a very strong correlation, similar to HC, towards the late stages of MSA (rho=0.68, P<0.001, n=20) (Supplementary Fig. 2C). A trial with 28 participants (14 per group) would be able to detect a 30% reduction in annual (12m) NfL level at 80% power (Fig. 3B), js: but we need a slowing-based estimation? |
Baseline NfL vs UMSARS cross-sectional (N=212, rho=0.24, p<0.001) NfL vs UMSARS rate of change (N=44, rho=0.26, P=0.06) |
| (Hofmann lab) | Interventional (sirolimus/rapamycin), 1-year long study | Baseline and 12 months | SIMOA | email communication: N=12 19.9(15.3) annualized change (mean (SD)) | Annual change in UMSARS vs change in NfL (N=12): UMSARS (continues on next photo) |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Nocker 2012 sample size table effect-size column “20 / 33 / 50” header | exact effect-size values | Header row at the very top is partially clipped; values inferred from row labels. |
| Potential MRI endpoints table cells (FA-Middle Cerebellar Peduncle “004”) | “0.04” vs “004” | OCR shows “004” without decimal in one cell; image likely “0.04”; transcribed as visible. |
| MD-Putamen N 5 year cell “26.41” | placement | Several intermediate columns are sparsely filled; column placement of “26.41” inferred from row alignment. |
| Wild 2009 atrophy table HD row | empty | The Huntington disease row has no annual atrophy rate or reference; left blank as in source. |
| {Paviour, 2006 #1430} reference id | ”#1430” / “#1438” | Reference id appears as “#1430” earlier and “#1438” later in the same paragraph; transcribed as visible. |
| Imaging biomarkers atrophy values “1.41 / 1.68 / 1.77 / 1.16” | column / row alignment | The four annualized atrophy values are listed without explicit column labels; column placement inferred from the Pons / Cerebellum / Putamen header above. |