Striatal terminals are lost first

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

Jeffrey Kordower, C. Warren Olanow, Hemraj Dodiya, Yaping Chu, Thomas Beach, Charles Adler, Glenda Halliday and Raymond Bartus (listed at Ceregene Inc.). The brains came from the Sun Health Research Institute (Arizona) and Sydney brain banks; funding included a Parkinson's Disease Foundation centre grant to Rush, the brain banks' own funders (NIH, the Michael J. Fox Foundation, Australian NHMRC) and an NHMRC fellowship for Halliday. The paper carries no conflict-of-interest statement. The axon-first argument was laid out earlier by Robert Burke and colleagues.

What happened

The team examined brains from 28 people with Parkinson's who had lived 1 to 27 years after diagnosis, plus 9 controls, comparing the putamen and the substantia nigra. Group sizes were small: 1 case at 1 year, 4 at 3 years, 4 at 4 years, 3 at 5 years, and 2 at 22 years or more. Nigral cell counts were done in only 17 of the 28. Dopamine markers in the dorsal putamen fell to near zero from about 4 years after diagnosis. In the nigra, neurons positive for tyrosine hydroxylase (the dopamine-making enzyme) were already down 50–90% at the earliest time points. Neurons visible by their dark pigment (neuromelanin) declined more slowly: about 30–60% lost in the first several years and then gradual loss, always outnumbering the enzyme-positive cells. The authors concluded that loss of dopamine markers in the putamen outpaces loss of melanised nigral neurons. Brain 136(8):2419–2431, August 2013. Burke and O'Malley's Experimental Neurology review (published online 2012, print 246:72–83 in 2013; DOI 10.1016/j.expneurol.2012.01.011) argued that axon degeneration may be the earliest feature and uses distinct molecular mechanisms from cell-body death. It built on Cheng, Ulane and Burke (Ann Neurol 2010;67:715–725), which made a similar case.

Why it moved us toward a cure

It reframes the target. If cell bodies and their pigment persist longer than their markers and terminals, there may be a window in which surviving cells could be protected or coaxed to regrow, which bears on approaches like GDNF delivery (landmark 39). It is also consistent with scans of striatal dopamine terminals (landmark 79) showing marked loss, and links to the large-arbor energy idea in landmark 93.

Outcome

Open. Autopsy studies see one moment per person, mix different people, and tyrosine hydroxylase can be switched off in living cells, so "marker lost" is not "neuron dead". Early cases are few (the 1-year point is a single case). Whether protecting axons slows human disease has not been shown.

Sources

• Kordower et al., Brain 2013;136:2419–2431, DOI 10.1093/brain/awt192 · PubMed record
• Burke & O'Malley, "Axon degeneration in Parkinson's disease," Exp Neurol 2013;246:72–83
• Kordower et al. full text with funding and case table (PMC3722357)
• Cheng, Ulane, Burke, Ann Neurol 2010;67:715–725, DOI 10.1002/ana.21995
• Not yet verified: cause of death and medication of the donors (not given in the paper); any large imaging study reproducing the time course. No correction or retraction was found in Crossref or Europe PMC; PubPeer could not be reached.