| {Wan, 2023 #2457} Good review | /6/Postmortem/ | all 4 measures (total and oligomeric forms of a-syn, and phosphorylated and phosphorylated oligomeric forms of a-syn) of a-syn were higher in patients with MSA compared to all other diagnostic groups, these were only significantly raised (p<0.001) in MSA compared to all other diagnostic groups, for phosphorylated and phosphorylated oligomeric forms of a-syn. | |
| Total aSyn: ↑/↑↑ in MSA vs HC | PS129-a-syn: ↑↑/↑↑ MSA vs HC patients with PD, DLB, PSP or MSA, and in 20 HC | ||
Oligomeric aSyn in MSA
| 20210714 Ootake | Oligomeric aSyn in MSA is heterogenous whereas it is not in PD. So progress is challenged. |
RT-QuIC in MSA
| 20210120 Juntendo univ collaboration protocol |
Acquisition of a Monoclonal Antibody That Recognizes a Specific a-Syn Aggregation Structure and Technology Transfer of the Immunoassay Construction Method. It has been suggested that the aggregated structure of alpha-syn is different in patients with PD and MSA. PD was outsourced using the RT-QuIC product of these patient's serum immunoprecipitation samples as the immunogen and MSA specific alpha-syn aggregates. If the antibody is successfully obtained, an ultrasensitive immunoassay, represented by Quanterix Single Molecular Array (Simoa), will be constructed by Takeda. Assay qualification will be performed using the aggregates (PFF) used for each immunogen as reference and samples from PD and MSA patients (Cerebrospinal fluid, plasma, and/or serum) will be evaluated. The serum RT-QuIC method under construction in Juntendo and the serum RT-QuIC method improved in this joint research will be transferred from Juntendo to Takeda. In addition, the results of RT-QuIC using CSF and serum samples from the same patient will be compared to confirm the correlation | ||
| (Rossi, 2020 #1620) | RT-QuIC, | RBD, MSA, DLB, PD, PAF | csf |
|
Method: Samples were run in quadruplicates and deemed positive when at least two out of four replicates reached the threshold, calculated as the average normalized fluorescence value of the first 10 h of the run of the 101 neuropathological control samples, plus 30 standard deviations. Results: 31명 msa 환자 중 오직 2명만 positive on RT-Quic! | |||
| (van Rumund, 2019 #1621) | the a-Syn RT-QuIC sensitivity for MSA was also quite low (35.2%, 6/17 positive cases), | ||
| 설명: Significant structural differences in a-Syn aggregates between MSA and PD are, indeed, increasingly recognized [59, 61, 68]. | |||
| {Shahnawaz, 2020 #313} | PMCA, PD와 다른 성격의 CSF aSyn in aggregation characteristics (kinetics)?, proteinase resistance, structure | ||
RBC aSyn in MSA
| (Li, 2020 #1622) | RBC | p<0.0001 [violin / scatter plot: y-axis "p-α-syn (pg/mg)" 0-30; two columns Control (n=220) ~10 vs MSA (n=107) ~20; significance bracket p<0.0001] | Since 99% of the a-syn in whole blood is present in red blood cells (RBCs) |
Skin aSyn in MSA
| Reference | Method | Result | |
|---|---|---|---|
| positive | (Donadio, 2020 #1672) |
Punch biopsies of 3 mm were taken from proximal and distal hairy skin sites. The proximal site was the cervical C7 paravertebral area, and distal hairy sites were located in the thigh (15 cm above the patella) and distal leg (10 cm above the lateral malleolus). A second skin biopsy was taken 3 to 4 cm from the first sample to assess for the distribution of abnormal phosphorylated a-syn at serine 129 (p-syn).13,21 Rabbit monoclonal p-syn (1:500; Abcam, 50 patients with parkinsonism and chronic orthostatic hypotension: 25 patients with MSA-P and 25 patients for PD+OH |
Intraneural p-syn positivity was found in 72% of patients with MSA-P, mainly in distal skin sites. More important, p-syn deposits in MSA-P differed from PD+OH because they were mainly found in somatic fibers of subepidermal plexi, whereas scant autonomic fiber involvement was found in only 3 patients. All patients with PD+OH displayed widely distributed p-syn deposits in the autonomic skin fibers of proximal and distal skin sites, whereas somatic fibers were affected only slightly in 4 patients with PD+OH. Js: from the paper, I can't find out how they discriminated somatic vs autonomic fibers |
| Donadio V, Incensi A, El-Agnaf O, et al. Skin a-syn deposits differ in clinical variants of synopathy: an in vivo study. Sci Rep 2018;8(1):14246 | Donadio 2020 의 보다 정확 한 paper, p-aSyn positivity rate 라고 함. | ||
| (Miglis, 2020 #1674) | This is just recap of Donadio 2020, pointing out limitation. | ||
| Positive | (Doppler, 2015 #1676) PMID: 26175301 | No full text, MSA (n = 12), idiopathic PD (n = 30), tauopathies (n = 15), and normal controls (n = 39) were analyzed. P-α-Syn within dermal nerves was detected by immunofluorescence staining. | p-a-Syn was found in 67% of patients with MSA and PD, but not in patients with tauopathy or controls when analyzing 15 consecutive sections. Sensitivity could be increased to 75% and 73%, respectively, by analyzing serial sections. In contrast to PD, where p-a-Syn clustered in autonomic fibers, deposits were mainly found in unmyelinated somatosensory fibers in MSA. |
| Positive | Gibbons poster | Twenty-nine individuals with MSA, 22 individuals with PD and 10 healthy control subjects | Patients with MSA had evidence of peripheral phosphorylated a-syn deposits in all subjects (P<0.001 vs controls, where no a-syn was detected) at proximal and distal biopsy sites. Significant differences in syn deposition between MSA subjects and PD subjects (P<0.01) was noted at all biopsy sites |
| Negative | Zange 2015 autonomic n 만 봄. | skin from the ventral forearm of 10 patients with multiple system atrophy and 10 with Parkinson's disease, together with six control subjects with essential tremor, were examined by immunohistochemistry. |
All patients with PD expressed phosphorylated SNCA in sympathetic skin nerve fibres, correlating with an age-independent denervation of autonomic skin elements. In contrast, no phosphorylated SNCA was found in autonomic skin nerve fibres of patients with MSA and essential tremor control subjects |
| Almost negative | (Haga, 2015 #1673), | 38 patients with idiopathic PD (26 treated with levodopa and 12 levodopa-naïve) and 13 age-matched patients with MSA, Skin biopsies from the lower leg and/or anterior chest wall |
Phosphorylated a-syn aggregates were identified on cutaneous nerves in two patients with PD (5.3%) but in none of the patients with MSA, and IENFD was significantly lower in patients with PD when compared to those with MSA. There was no difference in IENFD between levodopa-treated and levodopa-naïve patients with PD Js: it is not clear whether they looked at both somatic and autonomic |
Autonomic Failure
- Onset: 56.2 y (sd 8.4) {Wenning et al., 2013; PMID: 23391524}
- The median time from initial symptom to combined motor and autonomic dysfunction was 2 years (range 1-10) {Watanabe, 2002 #1418}
- Median intervals from onset to aid-requiring walking, confinement to a wheelchair, a bedridden state and death were 3, 5, 8 and 9 years, respectively. {Watanabe, 2002 #1418}
- Extending the duration of orthostatic blood pressure measurements from 3 to 10 minutes significantly increases sensitivity to capture delayed orthostatic hypotension and correctly diagnose a number of additional MSA patients.13,34,35
- An emphasis on the severity of adrenergic failure using robust indices such as blood pressure recovery time instead of a reliance on sensitivity in the detection of (mild) orthostatic hypotension improves the diagnosis of MSA.36,37
- Similarly, the distribution of anhidrosis on a thermoregulatory sweat test distinguishes MSA from PD with good sensitivity and specificity.36
- Open bladder neck during filling, detrusor-sphincter dyssynergia during voiding, and postvoid residual volume >100 mL are characteristic urodynamic/sonographic findings of MSA.38,39
Brain Bank
| Bank | Notes | Counts | |
|---|---|---|---|
| BBB | total 4235 samples from 56 donors | ||
| Imperial | MSA 있다 | ||
| Brigham and Women's Hospital | {Ndayisaba 2022} 13 MSA-p and 5 MSA-c (and 3 combined) i don't have info to request tissues from them and could only think about contacting the authors of the attached paper who established the tissue cohort. Roy Alcalay recommended. | ||
| NY Brain Bank at Columbia University | MSA 있다 | Columbia: 30 brains (half fixed, half frozen) {Lin, 2022 #2070} used this brain bank. | |
| {Ndayisaba 2022} 13 MSA-p and 5 ... | PDBP has MSA samples from Univ of Florida. | ||
| UC Brain bank | Queen Square Brain Bank for Neurological Disorders (QSBB) = UCL: NETA · 분명 MRC BB 의 일부인데 db 에는 X. | ||
| edinburgh | 3 | ||
| KCL | 14 | ||
| Newcastle | 4 | ||
| oxford | 15 | ||
| Manchester | 1 | ||
| Bristol | 2 | ||
| Sheffield | 1 | ||
| Cambridge | 3 | ||
| NCNP: | 논문엔 많았는데 (우즉) DB 엔 X. | ||
| Roy Alcalay's recommendation. UCL: A lot of, only ~three matched CSF & plasma, John Hardy and Chelban, Viorica <v.chelban@ucl.ac.uk> | |||
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Top continuation row “(Wan, 2023 #2457) Good review” | reference id #2457 | OCR shows “N2457” with “N” preceding the digits; transcribed as “#2457”. |
| Oligomeric aSyn in MSA author “Ootake" | "Ootake” | Author spelling may be “Ootaki” or “Ootake”; transcribed as seen. |
| RBC plot y-axis label “p-α-syn (pg/mg)“ | y-axis label | Label is small; transcribed as “p-α-syn (pg/mg)” from the most legible reading. |
| Brain Bank counts (3 / 14 / 4 / 15 / 1 / 2 / 1 / 3) | edinburgh-Cambridge per-bank counts | Counts per UK MRC BB sub-bank are tiny single digits next to bank names; transcribed from visible glyphs. |
| Donadio 2018 paper Sci Rep volume “8(1):14246” | volume / page | OCR shows “8(1):14246”; transcribed as visible. |
| Brain Bank “(Lin, 2022 #2070)” reference id | #2070 | Reference id 2070 is small; transcribed from visible glyphs. |