CSF total synuclein

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Brit Mollenhauer, Joseph Locascio, Walter Schulz-Schaeffer, Friederike Sixel-Döring, Claudia Trenkwalder and Michael Schlossmacher (Lancet Neurol, 2011; funders included the American Parkinson Disease Association, the Michael J. Fox Foundation and the US NIH). Ju Hee Kang, David Irwin, Alice Chen-Plotkin, Andrew Siderowf and the PPMI investigators (JAMA Neurol, 2013).

What happened

Because Lewy bodies are made of alpha-synuclein (landmark 5), researchers expected spinal-fluid (CSF) levels to change.

• Mollenhauer 2011: in training, autopsy and validation cohorts, people with Parkinson's, multiple system atrophy and dementia with Lewy bodies had lower CSF synuclein than people with Alzheimer's or other neurological disorders. In the validation cohort (inpatients referred with parkinsonism, 2003–06), a CSF cutoff of 1.6 pg/µL or lower gave 70.7% sensitivity and 52.8% specificity for Parkinson's. Area under the curve was 0.71, where 0.5 is chance and 1.0 is perfect. The authors noted low specificity but a high positive predictive value (90.7%) for any synucleinopathy, and suggested it for stratifying trial participants.
• Kang 2013: in the first 102 volunteers of PPMI (landmark 24; 63 drug-naive patients, 39 controls), CSF synuclein and tau were slightly but significantly lower in Parkinson's, with a marked overlap between groups. Lower synuclein tracked worse motor scores.

Why it moved us toward a cure

These papers set an early fluid benchmark, and Kang 2013 was the first CSF report from PPMI. Their weakness showed what a trial needed: a test that detects the misfolded form, not the total amount. That arrived with the seed amplification assay (landmark 9), which supersedes this approach for selecting participants.

Outcome

Superseded. Total CSF synuclein is not used to diagnose or enrol patients. It is also a weak tracker: in 173 PPMI patients and 112 controls, CSF synuclein stayed relatively stable over 12 months and did not follow motor scores (Mollenhauer 2017).

Sources

• Mollenhauer et al., Lancet Neurol 2011;10:230–240, DOI 10.1016/S1474-4422(11)70014-X
• Kang et al., JAMA Neurol 2013;70:1277–1287, DOI 10.1001/jamaneurol.2013.3861
• Mollenhauer et al., Neurology 2017;89:1959–1969, DOI 10.1212/WNL.0000000000004609
• Corrections: Europe PMC records an erratum for Mollenhauer 2011 (Lancet Neurol 2011;10(4):297; Crossref does not index it; content not read). No retraction was found for either paper.
• Not yet verified: the training-cohort group sizes in Mollenhauer 2011; what its erratum corrects; the full author list of Kang 2013.