What is the sensitivity of skin biopsy for alpha synuclein in multi-system atrophy (MSA)?

Sensitivity of Skin Biopsy for Alpha-Synuclein in Multiple System Atrophy

The sensitivity of skin biopsy for detecting phosphorylated alpha-synuclein in multiple system atrophy (MSA) is approximately 63-80%, with higher specificity approaching 95-97%, making it a valuable diagnostic tool for differentiating MSA from other parkinsonian disorders. 1, 2

Diagnostic Value of Skin Biopsy in MSA

Sensitivity and Specificity

• Recent meta-analysis data shows that skin alpha-synuclein seeding amplification assays (SAAs) have:
  • Overall sensitivity of 88% for synucleinopathies 1
  • Specifically for MSA: sensitivity of 63% (range 24-90%) 1
  • High specificity of 97% for MSA 1

Comparison to Other Biospecimens

• Skin biopsies demonstrate higher sensitivity (92%) compared to:
  • Cerebrospinal fluid (90% sensitivity)
  • Olfactory mucosa (64% sensitivity) 1

Clinical Utility

• In a 2024 study of patients with suspected synucleinopathies, skin biopsy detection of phosphorylated alpha-synuclein led to:
  • Change in diagnosis in 66% of patients
  • Change in treatment in 55% of patients
  • Overall clinical care changes in 78% of patients 3

Differentiating MSA from Parkinson's Disease

Skin biopsy can effectively distinguish between MSA and Parkinson's disease (PD) based on:

1. Pattern of deposition:

   • MSA patients show greater phosphorylated α-synuclein deposition than PD patients 4
   • MSA demonstrates more widespread peripheral distribution of α-synuclein 4

2. Nerve fiber density:

   • PD patients typically have reduced nerve fiber densities compared to MSA patients across all fiber types 4

3. Combined assessment:

   • When α-synuclein deposition is combined with distribution pattern analysis, diagnostic accuracy exceeds 90% sensitivity and specificity in distinguishing MSA from PD 4

Technical Considerations

Biopsy Procedure

• Skin punch biopsies are minimally invasive and can be performed in outpatient settings
• Multiple biopsy sites increase diagnostic yield (typically posterior cervical and leg regions) 2
• Samples should be properly preserved for immunohistochemical analysis

Detection Methods

• Two primary techniques are used:
  • Real-time quaking-induced conversion (RT-QuIC): 95% sensitivity, 100% specificity 2
  • Protein misfolding cyclic amplification (PMCA): 80% sensitivity, 90% specificity 2

Clinical Applications

When to Consider Skin Biopsy

• Most beneficial in patients with:
  • Parkinsonism with prominent action tremor (93% diagnostic change rate)
  • Lower-extremity predominant parkinsonism (90% diagnostic change rate)
  • Parkinsonism with predominant cognitive dysfunction (76% diagnostic change rate) 3

Limitations

• Skin biopsy should be used as part of a comprehensive diagnostic approach
• MRI remains the optimal imaging modality for differentiating MSA from PD, with characteristic findings including putaminal atrophy, brainstem atrophy, and the "hot cross bun" sign in MSA-C 5, 6
• DAT scans can confirm parkinsonism but cannot reliably distinguish between different parkinsonian syndromes 6

Future Directions

The ongoing multi-center Synuclein-One study aims to further determine the sensitivity, specificity, accuracy, and precision of α-synuclein detection within punch skin biopsies in patients with clinically established synucleinopathies using standardized methods suitable for large-scale analysis 7.