[Conductor71]

Hi,

This topic was broached under the Stalevo thread, but I think there has been sufficient interest to merit its own headline.

We discussed that Jankovic et al. at Baylor U had noted the clinical observation of two distinct subtypes of PD: Tremor-Dominant and Postural-Instability-Gait-Dominant.

Debi Brooks added that MJFF had funded research on subtypes and the potential impact they might have on clinical trials and treatments.

Based on additional questions and comments by Girija and Rick, I began to wonder whether there were any proof beyond clinical and PWP observation to the existence of PD subtypes, and I stumbled upon this research gem originally posted by Ann in Lyon:


At last, other works have largely confirm Braak's staging of LB-pathology in PD and added other considerations to the initial pattern with different morphological lesion patterns for the clinical subtypes of PD (Jellinger K.A).

a) The akinetic-rigid type shows more severe cell loss in the ventrolateral part of substantia nigra zona compacta (SNZC) that projects to the dorsal putamen than the medial part projecting to caudate nucleus and anterior putamen, with negative correlation between SNZC cell counts, severity of akinesia-rigidity, and dopamine loss in the posterior putamen. Reduced dopaminergic input causes overactivity of the GABA ergic inhibitory striatal neurons projecting via the "indirect loop" to SN zona reticulata (SNZR) and medial pallidum (GPI) leading to inhibition of the glutamatergic thalamo-cortical motor loop and reduced cortical activation.

b) The tremor-dominant type shows more severe neuron loss in medial than in lateral SNZC and damage to the retrorubral field A8 containing only few tyrosine hydroxylase and dopamine transporter immunoreactive (IR) neurons but mainly calretinin-IR cells. A8 that is rather preserved in rigid-akinetic PD (protective role of calcium-binding protein?) projects to the matrix of dorsolateral striatum and ventromedial thalamus. Together with area A10 it influences the strial efflux via SNZR to thalamus and from there to prefrontal cortex ".

This difference is noted in post-mortem analysis. Fascinating too is the research conducted by Mito, Yoshida, et al. (2005) Journal of the Neurological Sciences. Researchers scanned both PWP subtypes by SPECT and found that the PIGD dominant participants registered reduced blood flow in the anterior cortex, with no significant blood flow reduction in those who were Tremor dominant compared to the norm group. This, in turn, indicates there are different pathologies and neurochemical processes at work in each type.

This in part may explain why and how we experience PD so differently and hopefully leads to progress for much more effective treatments than what we now have. Girija had asked if these subtypes are now a first order of classification? I don't know if neurologists routinely classify newly diagnosed patients; I received a verbal reassurance from my MDS that because I presented with a tremor and that remained my main symptom that I had a "milder" form of PD. lol. as if this somehow lessens the blow. I do think that this research has exciting implications for refining diagnoses and helping us better understand what we're experiencing and to better chart a course of long term treatment. My neuros have done neither but here's' hoping that things will change; I'm left wondering where does the neurologist fit into all of this? Do any of them advocate on the need for change? PAN pressures lawmakers, we press for change with pharma and the research community, but who challenges the neurologist? I think I now need to respectfully start asking my doctors some of these questions.

Laura

[paula_w]

Because i have been catching up there this morning Laura, and you may have seen this too, but MJFF is waiting and ready and putting out an all call about PD subtype research.

http://www.pdonlineresearch.org/news...-subtypes-look

paula

[reverett123]

<<Rick,

I'm a bit mixed up. Where do the tremor-dominant and Postural-gait-dominant subtypes fit in here? Do you think that age and pathogenesis correlate with a certain subtype? I don't disagree just in need of a little clarification. I started a new thread on this with some further research findings that go beyond clinical observation. I'd love to see how your theory complements these findings.

Laur«>

I don't see a direct connection to the subtypes noted thus far although there may be. What I am saying is that the St. Jude's research confirms the work of others and that, taken together, they show that, in some cases but not all, an aggressive virus does indeed lead to an immune response involving the microglia and leading to PD That is probably what appened in 1918.

The above can occur at any age and time to symptoms would vary with the individual but the effects of aging would probably be a factor. Thus a variety of presentations.

However, Carvey et al have demonstrated an identical immune response involving the same microglia but originating in the womb from exposure to the bacterial endotoxin LPS. Like the viral insult, the bacterial one activates the same immune response although it seems not to manifest until puberty.

This versionis much more complex due to the recurring interaction with LPS over the years, the wide variance in sensitivities to LPS, the synergies between LPS and environmental factors such as pesticides, stress sensitivity, in short all the usual suspects. Since this one begins at puberty it would result in the complexities of young onset.

Finally, a third form exists with a similar cascade resulting from exposure to LPS without prenatal priming. This is what happened to Ilse Niehaus (google that), a young lab tech exposed by a wound to LPS from a salmonella lab culture. This presumably would account for origins in nocardia exposure as well.

Logically, those three subgroups should exist from what we know. There may be another teir of subtypes a an overlay on these. Heck if I know.

[girija]

Laura,
THANK YOU SO MUCH. This information you posted in here seems to be extremely important to the classification of PD subtypes. I still have to sit with a "map of the brain" to understand these differences, If I manage to a get a picto version of the information you sent (thats one way these circuits stay in MY BRAIN and help me understand PD!!!) , I will certainly post it here
MJFF is asking for input on PD subtypes (Deb mentioned it in the other thread), can you please post your information on PDresearchonline? I think there is way non-members can do this. If you have difficulty, please let me know, I will post it on your behalf.
Once again, thanks a lot!

Girija

Originally Posted by Conductor71

Hi,

This topic was broached under the Stalevo thread, but I think there has been sufficient interest to merit its own headline.

We discussed that Jankovic et al. at Baylor U had noted the clinical observation of two distinct subtypes of PD: Tremor-Dominant and Postural-Instability-Gait-Dominant.

Debi Brooks added that MJFF had funded research on subtypes and the potential impact they might have on clinical trials and treatments.

Based on additional questions and comments by Girija and Rick, I began to wonder whether there were any proof beyond clinical and PWP observation to the existence of PD subtypes, and I stumbled upon this research gem originally posted by Ann in Lyon:


At last, other works have largely confirm Braak's staging of LB-pathology in PD and added other considerations to the initial pattern with different morphological lesion patterns for the clinical subtypes of PD (Jellinger K.A).

a) The akinetic-rigid type shows more severe cell loss in the ventrolateral part of substantia nigra zona compacta (SNZC) that projects to the dorsal putamen than the medial part projecting to caudate nucleus and anterior putamen, with negative correlation between SNZC cell counts, severity of akinesia-rigidity, and dopamine loss in the posterior putamen. Reduced dopaminergic input causes overactivity of the GABA ergic inhibitory striatal neurons projecting via the "indirect loop" to SN zona reticulata (SNZR) and medial pallidum (GPI) leading to inhibition of the glutamatergic thalamo-cortical motor loop and reduced cortical activation.

b) The tremor-dominant type shows more severe neuron loss in medial than in lateral SNZC and damage to the retrorubral field A8 containing only few tyrosine hydroxylase and dopamine transporter immunoreactive (IR) neurons but mainly calretinin-IR cells. A8 that is rather preserved in rigid-akinetic PD (protective role of calcium-binding protein?) projects to the matrix of dorsolateral striatum and ventromedial thalamus. Together with area A10 it influences the strial efflux via SNZR to thalamus and from there to prefrontal cortex ".

This difference is noted in post-mortem analysis. Fascinating too is the research conducted by Mito, Yoshida, et al. (2005) Journal of the Neurological Sciences. Researchers scanned both PWP subtypes by SPECT and found that the PIGD dominant participants registered reduced blood flow in the anterior cortex, with no significant blood flow reduction in those who were Tremor dominant compared to the norm group. This, in turn, indicates there are different pathologies and neurochemical processes at work in each type.

This in part may explain why and how we experience PD so differently and hopefully leads to progress for much more effective treatments than what we now have. Girija had asked if these subtypes are now a first order of classification? I don't know if neurologists routinely classify newly diagnosed patients; I received a verbal reassurance from my MDS that because I presented with a tremor and that remained my main symptom that I had a "milder" form of PD. lol. as if this somehow lessens the blow. I do think that this research has exciting implications for refining diagnoses and helping us better understand what we're experiencing and to better chart a course of long term treatment. My neuros have done neither but here's' hoping that things will change; I'm left wondering where does the neurologist fit into all of this? Do any of them advocate on the need for change? PAN pressures lawmakers, we press for change with pharma and the research community, but who challenges the neurologist? I think I now need to respectfully start asking my doctors some of these questions.

Laura

[ZucchiniFlower]

There is also Mixed Type! Plus, I think we may need to establish genomic types. The following study tests people with idiopathic PD with SPECT scans. Would those with known mutations like LRRK2 respond differently??

Striatal FP-CIT uptake differs in the subtypes of early Parkinson’s disease

In idiopathic Parkinson’s disease (PD), a tremor-dominant type (TDT), an akinetic-rigid type (ART), and a mixed type (MT) are distinguished.

http://www.springerlink.com/content/p401815x11517j79/

[paula_w]

pdonline research shows research thus far reported by mjff's todd sharer as showing 3 subtypes altho more research needed. as we thought, and this isn't that new, i heard about the two subtypes years ago and that rigidity/bradykinesia is worse on cognition and dementia. and the third type listed by sharer is a "worse prognosis". i saw somewhere in this thread that there is a mixed type. i personally could name people of each subtype after ten years in the community. For example, stitcher doesn't look like she has progressed since i met her. now that she has ceregene, hopefully she will remain stable. but all of my rigid friends are looking bad now [the ones my age who have had it awhile] they are falling with postural and gait involvment, which DBS doesn't help yet altho they are working on one for these symptoms.

there is only one drug that several participants declared a cure, and it seems like the UK had more of them but maybe that's because they were on it for 3 years, - gdnf. they had a different pump catheter that was not approved in the US .so a medtronic was used. ok so maybe they are finding better neurotrophic factors than gdnf. but Amgen also didn't hold to their word on follow up. Shouldn't these people have been followed up for subtypes? Was anything handled correctly in that trial? Now some have died, but their medical records and physicians should be able to group them in those three rather broad areas to see if there is a pattern to the ones that claimed recovery. isn't this just logical? we tried as patients and succeeded in getting follow up conditions of several of the patients on Grassroots Connection. But we weren't familiar with subtypes at the time and didn't ask them that.

with gdnf being pump infused, it was a continuous monthly treatment, not gene therapy. they didn't give it enough time. what a screw up sorry but i still get upset over it..

it's not too late to try to establish whether the gdnf participants who did not have dislodged catheters and found it successful were of a particular subtype. what other treatment has done as well? why not do this before doing another trial? and perhaps they are. but i have yet to hear a cere 120 patient claim to be cured. if i am wrong i'd be happy to be corrected and it sounds like dosing is going to be varied; they were able thru autopsy to do discover delivery problems. i applaud them for sticking with it and seeing the 18 mos [?] improvement...follow up is imperative....Amgen just totally abandoned them.

now apparently no one wants to try the gdnf with the pump infusion because gene therapy is now all the rage. i don't know of anyone claiming anything spectacular with gene therapy trials so far but realize that the field is young. But the gdnf gene therapy trial is now the only human delivery gdnf trial i know of coming up in the US. By the NIH - and including people who have believed in it since before Amgen owned it. Delivery? not sure some new device and gene therapy. This means they don't know what dose, and they can't turn it off.

It just seems logical to study the people in the Amgen trials first. we found many of them all by ourselves.

The subtypes are not cut and dry. i remember the days when my neuro said mine was as slow progressing as he has ever seen. but he drew a horizontal line and then plunged it down a fast moving vertical slant. that drop does come. question is - how much is meds and how much the illness?

everyone is a word wizard.....when the online community is a goldmine.

and they wonder why we think they have no urgency, just a career. prove me wrong, please. i have to issue these challenges - we deserve thoroughness. if we are just going to be abandoned to die, then why should we go thru the torture of a clinical trial with sham surgery first?

we want to trust, why wouldn't we want to trust? but first we need to understand. i'm grateful for pdonline research. as you can see, we are paying attention. hopefully, these are understandable logical questions.

paula

correction: actually we did know about the subtypes mentioned in this thread then, but they were not the issue or receiving the attention that they are today.

launch in 20 min. jets guarding air space are circling and too loud to sleep anyway.

[paula_w]

http://www.eurekalert.org/pub_releas...-usc082809.php

it's a start. love this community.

paula

[aftermathman]

I argued some time ago in another thread that there is only one PD, that we all end up with the same prognosis, however with time I think I could have been wrong.

I agree that the Neuros need to be engaged in this process. My Neuro has seen enough PD to know that there are major differences between PWP, "everyone's Cancer is not the same" was a quote I remember from him.

He often talks to me of the differences in disease progression between different types of patients, however the main thrust of his sub types is age, young onset versus "older age" onset. I have never asked him if he agrees with different sub types of PD based on disease presentation.

I find this whole field fascinating, many thanks for the pdonlineresearch link, I was unaware of it.

Paula, I still believe Steven Gill at Frenchay in Bristol has developed a more effective GDNF delivery unit and got rights from Amgen, but I don't know the timescale of a trial.

Neil.

[Debi Brooks]

While many neurologists and patients have been able to plainly see that PD (symptom constellation and disease progression) vary within the patient population, we have yet to scientifically validate clear subtypes. And, that still remains the case. The "three groups" are loosely defined and there are experts in the field that still disagree with the observations and specific descriptions of such subtypes. That is why it is said that further work is needed. It’s not clear additional subtypes will be described and it’s not clear that these early classes will be completely validated. But, everyone agrees that if we can validate the subtypes it will be extremely useful.

Debi

[paula_w]

Neil,

I heard that too and we even wondered at first if it was going to be used in the NIH gene therapy trial, but we don't know the answer; don't know if it was ever FDA approved. I'm confused about devices getting approval as well as the treatment.

paula

Originally Posted by aftermathman

I argued some time ago in another thread that there is only one PD, that we all end up with the same prognosis, however with time I think I could have been wrong.

I agree that the Neuros need to be engaged in this process. My Neuro has seen enough PD to know that there are major differences between PWP, "everyone's Cancer is not the same" was a quote I remember from him.

He often talks to me of the differences in disease progression between different types of patients, however the main thrust of his sub types is age, young onset versus "older age" onset. I have never asked him if he agrees with different sub types of PD based on disease presentation.

I find this whole field fascinating, many thanks for the pdonlineresearch link, I was unaware of it.

Paula, I still believe Steven Gill at Frenchay in Bristol has developed a more effective GDNF delivery unit and got rights from Amgen, but I don't know the timescale of a trial.

Neil.