Synuclein T cells highest near diagnosis

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

Cecilia Lindestam Arlehamn (first author), Alessandro Sette (senior author, La Jolla Institute for Immunology), David Sulzer (Columbia) and colleagues at several US movement-disorder centres (Nature Communications 11:1875, 20 April 2020). Funding: NIH (NINDS R01NS095435 and P50NS108675, and an Alzheimer's centre grant), the Parkinson's Foundation, the Michael J. Fox Foundation, and the JPB and William F. Richter Foundations.

What happened

Landmark 38 showed T cells (immune cells that recognise protein fragments) from patients reacting to alpha-synuclein. This study asked about timing.

• Case study. One individual diagnosed with motor Parkinson's in 2009 had stored blood cells from 1998 onwards. T cells reacting to a synuclein fragment (residues 61–75) were found in samples from 2005, 2006 and 2015. Overall responses between 1998 and 2006 were strong, which the authors describe as "more than a decade before the onset of motor PD symptoms and clinical diagnosis", and stronger than after diagnosis. The cells were mainly CD4 helper T cells. No samples were analysed between motor-symptom onset and diagnosis, and one stretch of data (2006–08) coincided with shingles.
• Cohorts. 77 patients and 69 controls: more patients responded above a set threshold (250 spot-forming cells per million, P=0.02). In 38 Alzheimer's patients and 41 controls there was no difference.
• Time since diagnosis. In 96 patients (two independent cohorts of 76 and 20), 39.7% (29 of 73) diagnosed less than 10 years earlier responded, against 8.6% (3 of 23) at 10 years or more (P=0.022).

Why it moved us toward a cure

If immune reactivity precedes symptoms, a blood test could mark a window for immune-modulating treatment. The first immune-targeted prevention trial, adalimumab in people with REM sleep behaviour disorder (landmark 225), is aimed at this early window, but it blocks the general inflammatory signal TNF and does not target these T cells.

Outcome

Open. The "before diagnosis" claim rests on one patient, and the cohort data show peak responses shortly after diagnosis, not before. A Movement Disorders commentary appeared (2020;35:1137); no correction or retraction is recorded. Patients and controls differed in sex, and the Alzheimer's comparison does not exclude a response to neuron loss in general. It is unproven whether the T cells cause damage.

Sources

• Lindestam Arlehamn et al., Nat Commun 2020;11:1875, DOI 10.1038/s41467-020-15626-w (PMC7171193; PMID 32313102)
• Not yet verified: whether PRISMS (landmark 225) was designed with this T-cell work in mind; independent replication; follow-up cohort data after 2020.