PD : Braak H, Del Tredici K. 2017 locus coeruleus, periphery

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.

ncbi.nlm.nih.gov/pubmed/153...

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

ncbi.nlm.nih.gov/pubmed/126...

open access

jamanetwork.com/journals/ja...

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.

open access

ncbi.nlm.nih.gov/pubmed/282...

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 [20] crystalized

chiefly around the following points:...."

3 Replies

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  • hhhmmm WHAT? silvestrov translation please.

  • Heiko Braak has been researching PD since the late 1980s. Kelly Del

    Tredici has been a long-time colleague. Braak et al 2003 and 2004 set

    forth a model of PD wherein dopamine pathologies were portrayed as the

    fundamental focus for research and treatment in PD. However, by 2003 a

    number of studies had identified PD-related pathologies in brain nuclei

    other than the substantia nigra. One outstanding example was Zarow et al

    2003. Various researchers have explored cholinergic pathways and

    noradrenergic pathways, and treatments. Gradually, Dr. Braak's model

    became not so applicable to the newer findings. Non-motor symptoms and

    positive responses to non-dopaminergic pharmaceuticals continue to

    provide clues (eg, 4-5). The paper by Braak and Tredici 2017 is a

    wonderful essay by two sincere researchers who admit their focus has

    been too narrow. They took notice when peer reviewers began to respond

    less favorably.

    "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."

    (3)

    "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 [20] crystalized

    chiefly around the following points..." (3)

    Surely, dopaminergic therapies remain important. Nonetheless, further

    advances in treatment may derive from PD research exploring

    non-dopaminergic processes (eg, 6-7). Also, some researchers are

    exploring plant and supplement molecules that unfold misshapen alpha

    synuclein. See citations in my post on flavanoids. That Braak and Tredici are including a bigger domain for PD research will be helpful.

    4. Biomarker-driven phenotyping in Parkinson's disease: A translational missing link in disease-modifying clinical trials.

    Espay AJ, et al.

    Mov Disord. 2017 Mar;32(3):319-324.

    ncbi.nlm.nih.gov/pubmed/282...

    5. Norepinephrine deficiency in Parkinson's disease: the case for noradrenergic enhancement.

    Espay AJ, LeWitt PA, Kaufmann H.

    Mov Disord. 2014 Dec;29(14):1710-9.

    ncbi.nlm.nih.gov/pubmed/252...

    6. A Critical Role for Alpha-Synuclein in Development and Function of T Lymphocytes

    ncbi.nlm.nih.gov/pmc/articl...

    7. α-Synuclein inclusions in the skin of Parkinson's disease and parkinsonism

    ncbi.nlm.nih.gov/pmc/articl...

  • Thank you, I will take your word for it. (it is good right?)

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