Multiple System Atrophy (MSA)

Improving Diagnostic Confidence for Complex Clinical Presentations

Multiple system atrophy (MSA) is a rare, rapidly progressive neurodegenerative disorder characterized by a combination of autonomic dysfunction, parkinsonism, cerebellar ataxia, and pyramidal signs. Clinically, differentiating MSA from Parkinson’s disease (PD), progressive supranuclear palsy (PSP), and other atypical parkinsonian syndromes is challenging. This is especially true in early stages, due to overlapping features and limited response to levodopa.

The SAAmplify-ɑSYN seed amplification assay (SAA) provides in vivo detection of misfolded ɑ-synuclein aggregates in cerebrospinal fluid (CSF). While both multiple system atrophy and PD exhibit ɑ-synuclein pathology, their distinct fibril formation (in oligodendrocytes and neurons, respectively) and seeding kinetics can aid in differential diagnoses. Clinically, SAAmplify-ɑSYN can help:

• Provide evidence of synucleinopathy in patients with atypical parkinsonism or mixed presentations
• Improve diagnostic accuracy and clarification in cases with overlapping motor, autonomic, and cerebellar features
• Support early biological diagnosis in prodromal cases
• Guide clinical trial enrollment and prognostication

Multiple System Atrophy Stages and Clinical Characteristics

MSA typically presents in individuals between the ages of 50 and 60 and progresses rapidly. The clinical course is often categorized into:

1. Prodromal Stage: Subtle isolated autonomic symptoms such as neurogenic orthostatic hypotension (nOH), urinary incontinence or retention, erectile dysfunction, and idiopathic REM sleep behavior disorder (iRBD), without meeting criteria for parkinsonism or cerebellar syndrome.
2. Clinically Manifested Stage: Emergence of motor symptoms like rigidity, bradykinesia, and/or cerebellar signs (ataxia, dysarthria, gait instability) along with worsening autonomic dysfunction. These can be further classified into:‍
   
   • MSA-P (parkinsonian type): Dominated by parkinsonian features and resembles Parkinson’s disease (PD).‍
   • MSA-C (cerebellar type): Presents primarily with cerebellar ataxia and is more common in East Asian populations.
3. Advanced Stage: Severe autonomic and motor impairment, dysphagia, respiratory complications, and loss of ambulation.

Unlike PD patients, MSA patients show poor or no response to levodopa and they tend to develop postural instability and falls earlier in the disease course.

MSA Diagnostic Criteria and Tools

According to the 2022 Movement Disorder Society (MDS) criteria¹, MSA diagnosis is stratified into three clinical categories:

1. Neuropathologically Established MSA: Postmortem confirmation of widespread glial cytoplasmic inclusions containing ɑ-synuclein in striatonigral or olivopontocerebellar structures
2. Clinically Established MSA:
   1. Essential: Adult-onset (>30 years), progressive disease, negative family history
   2. Core: One autonomic feature (e.g., nOH within 3 minutes, urinary retention/PVR > 100mL) and either poorly levodopa-responsive parkinsonism or cerebellar syndrome (e.g., gait/limb ataxia, dysarthria)
   3. Plus: ≥2 supportive features (e.g., stridor, early falls, Babinski sign) and ≥1 MRI marker (e.g., putaminal atrophy, hot cross bun sign)
3. Clinically Probable MSA:
   1. ≥2 core features (autonomic, parkinsonian, or cerebellar) in any combination
   2. Plus: ≥1 supportive feature (e.g., early dysphagia, jerky tremor); MRI markers not required

Exclusion criteria include:

• Sustained levodopa response
• Unexplained anosmia
• Early hallucinations or dementia
• MRI evidence of alternative diagnosis

Clinical Use Cases

• Atypical Parkinsonism and Autonomic Dysfunction
  • SAAmplify-ɑSYN “Detected” result in patients with early nOH and poor levodopa response supports MSA diagnosis over PD or PSP
• Cerebellar Syndromes with Autonomic Features
  • In patients with gait ataxia and urinary dysfunction, SAAmplify-ɑSYN helps differentiate MSA from tauopathies or other ataxias
• Prodromal Syndromes
  • SAAmplify-ɑSYN can support diagnosis in patients with isolated autonomic failure or iRBD prior to overt motor involvement
• Rapidly Progressive Parkinsonism
  • Early ɑ-synuclein testing with SAAmplify-ɑSYN aids diagnosis when imaging or clinical features remain ambiguous, expediting appropriate care planning and trial referral.
• Clinical Trial Stratification
  • Identifying patients’ ɑ-synuclein status aids in recruitment for disease-modifying trials.

ɑ-Synuclein Pathology and Its Role in Multiple System Atrophy

MSA is defined by oligodendroglial accumulation of misfolded ɑ-synuclein in the form of glial cytoplasmic inclusions (GCIs). This pathology leads to widespread neuronal degeneration, particularly affecting the basal ganglia, cerebellum, and autonomic centers. The distinct conformational strains of ɑ-synuclein in MSA differ from those in PD and DLB, likely contributing to its aggressive course and unique biomarker profile².

Diagnostic Innovation

SAAmplify-ɑSYN is a highly sensitive, autopsy-validated assay for detecting misfolded ɑ-synuclein in CSF. SAAmplify-ɑSYN is a qualitative test that detects the presence of misfolded ɑ-synuclein seeds in CSF. The principle of the assay is similar to prion amplification technologies: if misfolded ɑ-synuclein “seeds” are present in the patient’s CSF, they induce aggregation of the recombinant protein in vitro. These aggregates incorporate a fluorescent dye and emit a signal that can be read over time. The readout is binary (“Detected” or “Not Detected”). Samples are run in triplicate with stringent controls. In research studies³, the assay has shown the ability to differentiate PD/DLB from multiple system atrophy synucleinopathies, and clinical validations are underway to better understand sensitivity and specificity.

In Practice: Incorporating Alpha-Synuclein as a Biomarker for Multiple System Atrophy

MSA is a rapidly progressive and clinically heterogeneous synucleinopathy with poor levodopa response, early autonomic failure, and limited treatment options. Accurate diagnosis is essential but is often delayed or never corrected due to overlap with other neurodegenerative disorders. The integration of the alpha-synuclein test SAAmplify-ɑSYN into clinical workflows provides a biologically grounded tool that enhances confidence, enables earlier identification, and supports enrollment in disease-modifying trials. As precision diagnostics evolve, SAAmplify-ɑSYN offers clinicians a powerful means to guide timely and informed care decisions in MSA.

References:

¹Wenning GK, et al. The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy. Movement Disorders vol. 37, 6 (2022):1131-1148. doi:10.1002/mds.29005

²Yang, Y et al. Structures of α-synuclein filaments from human brains with Lewy pathology. Nature vol. 610,7933 (2022): 791-795. doi:10.1038/s41586-022-05319-3

³Ma, Y et al. Sensitivity and specificity of a seed amplification assay for diagnosis of multiple system atrophy: a multicentre cohort study. The Lancet. Neurology vol. 23,12 (2024): 1225-1237. doi:10.1016/S1474-4422(24)00395-8

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