I have been perusing Braak et al 2004 and Zarow et al 2003 (1,2) and
focusing on a seeming contradiction regarding the locus coeruleus
(noradrenergic) . The seemingly contrary findings have been clarified in
a recently published essay by Braak and Tredici (3). Research by Braak,
Tredici, and colleagues has been influential. Their willingness to
incorporate recent findings not consistent with their [now antiquated]
6-stage model of PD is appreciated.
1. Stages in the development of Parkinson's disease-related pathology.
Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K.
Cell Tissue Res. 2004 Oct;318(1):121-34.
2. Neuronal loss is greater in the locus coeruleus than nucleus basalis
and substantia nigra in Alzheimer and Parkinson diseases.
Zarow C, Lyness SA, Mortimer JA, Chui HC.
Arch Neurol. 2003 Mar;60(3):337-41
3. Neuropathological Staging of Brain Pathology in Sporadic Parkinson's disease: Separating the Wheat from the Chaff.
Braak H, Del Tredici K.
J Parkinsons Dis. 2017;7(s1):S73-S87.
A relatively small number of especially susceptible nerve cell types
within multiple neurotransmitter systems of the human central,
peripheral, and enteric nervous systems (CNS, PNS, ENS) become involved
in the degenerative process underlying sporadic Parkinson's disease
(sPD). The six-stage model we proposed for brain pathology related to
sPD (Neurobiol Aging 2003) was a retrospective study of incidental and
clinically diagnosed cases performed on unconventionally thick tissue
sections (100 μm) from a large number of brain regions.The staging model
emphasized what we perceived to be a sequential development of
increasing degrees of Lewy pathology in anatomically interconnected
regions together with the loss of aminergic projection neurons in, but
not limited to, the locus coeruleus and substantia nigra. The same
weight was assigned to axonal and somatodendritic Lewy pathology, and
the olfactory bulb was included for the first time in a sPD staging
system. After years of research, it now appears that the earliest
lesions could develop at nonnigral (dopamine agonist nonresponsive)
sites, where the surrounding environment is potentially hostile: the
olfactory bulb and, possibly, the ENS. The current lack of knowledge
regarding the development of Lewy pathology within the peripheral
autonomic nervous system, however, means that alternative extra-CNS
sites of origin cannot be disregarded as possible candidates. The PD
staging system not only caused controversy but contributed a framework
for (1) assessing pathology in the spinal cord, ENS, and PNS in
relationship to that evolving in the brain, (2) defining prodromal
disease and cohorts of at-risk individuals, (3) developing potential
prognostic biomarkers for very early disease, (4) testing novel
hypotheses and experimental models of α-synuclein propagation and
disease progression, and (5) finding causally-oriented therapies that
intervene before the substantia nigra becomes involved. The
identification of new disease mechanisms at the molecular and cellular
levels indicates that physical contacts (transsynaptic) and
transneuronal transmission between vulnerable nerve cells are somehow
crucial to the pathogenesis of sPD.
[important correction by Braak and Tredici]
"....Reactions to the six-stage grading model have been essentially
encouraging [36–40], although the following anecdote is illustrative of
the climate in which some of the earlier differences of opinion took
place. In August 2009, we received an email from an American colleague
of a newly published experimental study: “In the discussions with the
authors and editors, it was suggested to take out the references to your
work so that our paper could be published .... I am not sure why your
findings are so controversial and bring up such strong emotions.”
Controversies surrounding the staging publication  crystalized
chiefly around the following points:...."