Landmark 342 · Discovery
Locus coeruleus loss alongside the nigra
In short
The locus coeruleus, a small brainstem nucleus that makes noradrenaline, loses roughly 60% of its cells in Parkinson's, as severe as the nigra, and Braak's ascending staging has Lewy pathology in the lower brainstem before the nigra, so dopamine loss may not be where the disease starts.
- What it is
- Discovery
- Outcome
- Still being studied
- When
- 1992–2007
- Approach
- Keep vulnerable cells alive
- Research lane
- Selective vulnerability
- Last checked
- 19 Oct 2026
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
Dwight German and colleagues (UT Southwestern, Dallas, 1992); Chris Zarow, Helena Chui and colleagues (2003); Heiko Braak's group (staging); Karen Rommelfanger, Gary Miller, David Weinshenker and colleagues (2007). Funders are not stated in the abstracts.
What happened
- 1992: German's team reconstructed the whole locus coeruleus in post-mortem brains. Parkinson's, Alzheimer's and Down syndrome each showed about 60% cell loss. In Parkinson's the loss was even along the nucleus, and the neighbouring subcoeruleus lost 63%.
- 2003: Zarow counted neurons in 19 Parkinson's, 86 Alzheimer's and 13 control brains. In Parkinson's the locus coeruleus had the largest loss (effect size 6.47), above the substantia nigra (2.58) and nucleus basalis (0.85).
- Order of events: the staging scheme of landmark 6 has Lewy pathology start in the lower brainstem and ascend. That is the sequence of protein deposits, not a count of cells lost. Which stage the locus coeruleus falls in was not checked here.
- 2007: mice lacking noradrenaline (Dbh knockouts) were impaired on most motor tests, while MPTP-treated mice with 80% loss of striatal dopamine terminals showed no motor abnormalities. Some deficits were reversed by restoring noradrenaline or giving a dopamine agonist.
Why it moved us toward a cure
It widened the target. A treatment that protects or replaces only dopamine cells (landmark 267 describes where they die) would leave a second early casualty, and noradrenaline loss may account for non-motor symptoms.
Outcome
Open. Timing of cell loss in life is unproven: counts come from autopsy at one late time point, and Zarow's sample was 19 Parkinson's cases. No trial has yet aimed at the locus coeruleus.
Sources
- German et al., Ann Neurol 1992;32:667–676, DOI 10.1002/ana.410320510
- Zarow et al., Arch Neurol 2003;60:337–341, DOI 10.1001/archneur.60.3.337
- Rommelfanger et al., PNAS 2007;104:13804–13809, DOI 10.1073/pnas.0702753104
- Braak et al., Neurobiol Aging 2003;24:197–211, PMID 12498954 (abstract: initial lesions in the dorsal motor nucleus of the vagus and olfactory nucleus, ascending course)
- Not yet verified: Braak's stage numbers for the locus coeruleus and nigra (not in the abstract); the claim that some studies find greater nigral than coeruleus loss was dropped as unsourced.
How it connects
Built on
- builds on Braak staging: the disease spreads in order · 2003
Led to
None recorded.