20240722_184206

North American MSA Study Group (=NAMSA-SG) 12 US medical	{Gilman, 2005 #2189} University of California San Diego (Administrative and Data Cores, Project 3, Enrolling site) – Parkinson Institute (Project 1, Enrolling site) – University of Pennsylvania (Neuropathology Core, Project 2, Enrolling site) – Mayo Clinic (Project 4, Enrolling site) – Albert Einstein College of Medicine (Genetics Core) – University of Maryland (Enrolling site) – University of Rochester (Enrolling site) – Boston University (Enrolling site) – University Hospitals of Cleveland (Enrolling site) – Baylor College of Medicine (Enrolling site) – University of Michigan (Enrolling site) – University of Virginia (Enrolling site Subjects 175 subjects with probable MSA, both MSA-P and MSA-C Design Evaluations every 6 months for 5 years Location 12 neurology centers across the United States Assessments MMSE, EMSA-SG minimal data set, UMSARS, Composite Autonomic Symptoms Scale (COMPASS) and select change, SF-36 Health Survey, and Consensus Criteria assessment; yearly onsite follow-up exam and monthly survey data at 6, 18, 30, 42, and 54 months Median duration of illness from symptom onset to death: 9.8 years (95% CI, 8.8-10.7) Median time to death of 1.8 years from baseline visit No differences in median survival between MSA-P and MSA-C Severe autonomic failure at diagnosis (i.e., symptomatic orthostatic hypotension, neurogenic bladder, and fecal incontinence) was associated with 2.3 year shorter survival time Autonomic symptoms present in 80% of subjects at baseline. Scale Mean percent change at 12 months UMSARS I 21% UMSARS II 24% Total UMSARS 19%	Clinical Endpoints • Clinical: Motor exam, UMSARS (function/ADL inventory), global assessments of severity and change (clinician, patient) • Functional: Timed Up and Go Main clinical features Frequency Autonomic Failure (OH or urinary incontinence) 95% Orthostatic hypotension 78% Urinary incontinence 87% Incomplete bladder emptying 83% Constipation 87% Fecal incontinence 29% Erectile dysfunction 94% Parkinsonism 91% Bradykinesia 91% Rigidity 81% Postural instability 91% Resting tremor 34% Postural tremor 56%
European Multiple System Atrophy Study Group (EMSA-SG)	{Geser, 2005 #2069} {Wenning, 2013 #1077} Olivier Rascol, Wassilios G Meissner, Subjects 412 patients in registry; At least 141 subjects followed longitudinally; ~20% possible MSA, 77% probable MSA 63% as MSA-P, 34% as MSA-C 이중 part 가 Toulouse University Hospital, France (Sample of 147 patients) 일것. Design Evaluations every 6 months for two years Location 20 research groups in 11 countries Assessments UMSARS, UPDRS, MMSE, QoL measures, SF-36, BDI, global disability measures, COMPASS, Queen Square Cardiovascular Autonomic Function Test Battery; • MRI and DWI Mean age of symptom onset was 56 years Median survival was 9.8 years from time of symptom onset MSA-P and incomplete bladder emptying predicted shorter survival 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power. 65% received L-DOPA, of whom 31% experienced clinical benefit UMSARS Part 1 progressed 6.5 points in year 1 and 2.9 points in year 2 (total = 48 points) UMSARS Part 2 progressed 8.2 points in year 1 and 5.0 points in year 2 (total = 56 points) Progression is faster in early MSA 20220611 Jaya: – Do you have any need or desire for summary statistics for key MSA-relevant regions (e.g., putamen, MCP, pons) from external natural history studies or clinical trials? We are in the process of putting together scopes of work for data analysis requests from MSA KOLs. I was not sure if we needed such data or whether the data in the literature was sufficient We will be discussing a proposal to work with Dr. Wassilios Meissner at Monday's 341 CST which would allow us access to the French MSA Registry data. I wanted to share this with you because we may gain access to imaging and potentially fluid biomarker data via this collaboration (not raw data but summary data), so we may be needing your input soon on what we would want to request . Here is the link to the proposal we shared with Dr. Meissner, and you can see his comments on MRI and fluid biomarker data availability in the email below. 🗎 Draft scope of work for Dr. Meissner.docx Depending on approval from the CST, we will invite you to the follow-up conversation that we will be having with Dr. Meissner and Dr. Rascol to discuss in more detail what data we'd have access to.	Main clinical features Frequency Erectile failure 90% of men Bradykinesia 91% Rigidity 83% Postural instability 82% Incontinence 73% orthostatic hypotension 57% Gait freezing 40% parkinsonism 91% Incomplete bladder emptying 51% Rest tremor 36%
TALISMAN natural history study	Lundbeck to support Lu AF82422, (Anti-α-syn mAb, P2) in the EU and China; Separate protocols for the EU & China, as few objectives are region-specific. ☐ In addition to MSA disease progression assessment, the EU part will focus on biomarkers and China part on validation of Chinese version of UMSARS ☐ As per Lundbeck, combined analysis of data from the natural history study and results from the Ph2 AMULET study will be utilized for the Ph3 go/no-go decision for Lu AF82422 (link); Lu AF82422 is currently the only anti-α-syn mAb under clinical development for MSA. TALISMAN (global clinical study 20058N) is an observational, prospective, multicenter cohort study in 140 early-stage MSA patients across the EU and China Recruitment initiated in China on June 25 and recruitment in the EU is expected to start in September 2022 Expected primary completion date: May 5, 2024 (recruitment is expected to continue for 9 mths + 12 mths for primary endpoints evaluation) Primary endpoints: To describe early MSA disease progression changes in 6-mth intervals over 12-mths using UMSARS Part I and II (vs. baseline) Changes in biomarkers (plasma NfL & imaging outcomes; baseline vs. 6-mths vs. 12-mths); Biomarkers evaluation will be done for EU cohort only The Ph2 AMULET study for Lu AF82422 in MSA patients (US and Japan) is in early stages; Lundbeck commented that the current recruitment pace is slow in the US (link) Early NfL biomarker data from the Ph2 to serve as check-point for future development of Lu AF82422 Several non-industry sponsored MSA natural history studies are on-going in the US (link), EU (link), and China (link)
P + A + MS Clinical cohort	{Ndayisaba, 2022 #2190} The multidisciplinary P + A + MS clinic for patients with parkinsonism plus, ataxia, and MSA was established at Brigham and Women's Hospital, a principal teaching affiliate of Harvard Medical School, in 2016. a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal "n-of-few" clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including vMRI, FDG-PET, MIBG scan, PSG, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham Stem Cells Initiative (stem cells in neurodegeneration), we generate iPSC models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including a-syn triplication cases), 22 matched to whole-genome sequenced postmortem brain.

Diagnosis of MSA – three levels

(Gilman et al., 2008, PMID: 18725592) Second consensus statement on the diagnosis of MSA

level	criteria	Additional features of possible MSA
Possible	Table 2 Criteria for possible MSA A sporadic, progressive, adult (>30 y)-onset disease characterized by Parkinsonism (bradykinesia with rigidity, tremor, or postural instability) or A cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction) and At least one feature suggesting autonomic dysfunction (otherwise unexplained urinary urgency, frequency or incomplete bladder emptying, erectile dysfunction in males, or significant orthostatic blood pressure decline that does not meet the level required in probable MSA) and At least one of the additional features shown in table 3	Table 3 Additional features of possible MSA Possible MSA-P or MSA-C Babinski sign with hyperreflexia Stridor Possible MSA-P Rapidly progressive parkinsonism Poor response to levodopa Postural instability within 3 y of motor onset Gait ataxia, cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction Dysphagia within 5 y of motor onset Atrophy on MRI of putamen, middle cerebellar peduncle, pons, or cerebellum Hypometabolism on FDG-PET in putamen, brainstem, or cerebellum Possible MSA-C

Uncertain Spans

location	transcription	uncertainty
TALISMAN bullet leading symbol	☐ placeholder glyph	The source uses an empty-square placeholder before each top-level bullet (likely a non-rendered symbol/icon); preserved as ☐.