Does neuroinflammation fan the flame in neurodegenerative diseases?

I personaly think that this pertains to the origins of RSD/CRPS and the spread of this condition as well.

http://www.molecularneurodegeneratio...-1326-4-47.pdf

be well,
Sandra

Ok I was pretty tired when I posted this last night, there is a whole lot more to it than that, I think that neuroinflammation plays an important part in the beginnings of CRPS and the spread of it.. there are more studys that when put together make up the big picture.

Sandel, thank you for all your hard work, you make such an effort to keep all of us up to date with all of the latest research and articles. I really appreciate it Im sure some others do as well.
Many of the links you have posted have been a great help to me others have provided a great education. I really appreicate it. thanks cz

Hi Sandel, Thank you for the article- I agree with you. 15 years ago I had two tumors removed from breast and underarm lymph area. Right after the surgery, my arm swelled up. and the surgeons partner withdrew lots of fluid with a syringe. It was lime green. He did this at least 3 times. So one said the green color represents inflammation or infection. I've read on here that others had lime green color of fluid build up that needed to be withdrawn with syringe. That was the beginning of my RSD. It then turned into frozen shoulder (really RSD) Thank you so much for your research. I have been researching anti-oxidants, superfoods, etc. In fact our last RSD meeting here in Phoenix, we had a nutrionist that spoke about anti-oxidants superfoods. It was really good. Thanks again, and take care, loretta

Hi Sandel,


For further consideration here is a link I thought you would find interesting.

The association between ACE inhibitors and the complex regional pain syndrome: Suggestions for a neuro-inflammatory pathogenesis of CRPS

M. de Mosa, F.J.P.M. Huygenb, B.H.Ch. Strickera, J.P. Dielemana, M.C.J.M. Sturkenbooma

Received 15 August 2008; received in revised form 2 December 2008; accepted 23 December 2008. published online 05 February

Abstract
Antihypertensive drugs interact with mediators that are also involved in complex regional pain syndrome (CRPS), such a neuropeptides, adrenergic receptors, and vascular tone modulators. Therefore, we aimed to study the association between the use of antihypertensive drugs and CRPS onset. We conducted a population-based case-control study in the Integrated Primary Care Information (IPCI) database in the Netherlands. Cases were identified from electronic records (1996–2005) and included if they were confirmed during an expert visit (using IASP criteria), or if they had been diagnosed by a medical specialist. Up to four controls per cases were selected, matched on gender, age, calendar time, and injury. Exposure to angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, β-blockers, calcium channel blockers, and diuretics was assessed from the automated prescription records. Data were analyzed using multivariate conditional logistic regression. A total of 186 cases were matched to 697 controls (102 confirmed during an expert visit plus 84 with a specialist diagnosis). Current use of ACE inhibitors was associated with an increased risk of CRPS (ORadjusted: 2.7, 95% CI: 1.1–6.8). The association was stronger if ACE inhibitors were used for a longer time period (ORadjusted: 3.0, 95% CI: 1.1–8.1) and in higher dosages (ORadjusted: 4.3, 95% CI: 1.4–13.7). None of the other antihypertensive drug classes was significantly associated with CRPS. We conclude that ACE inhibitor use is associated with CRPS onset and hypothesize that ACE inhibitors influence the neuro-inflammatory mechanisms that underlie CRPS by their interaction with the catabolism of substance P and bradykinin.

http://www.painjournalonline.com/art...768-9/abstract


MsL

Sounds good in theory and maybe it is so. The only problem I have is this:

CRPS/RSD affects something like 9:1 women to men or so, right? Hypertension, the main indication for ACE inhibitors, runs in a ratio of close to 2:1 men to women. So therefore, most of the people that acquire CRPS/RSD are women, for which few (compared to men) are taking ACE inhibitors by virtue of men suffering from HTN at a significantly increased incidence.

So....since more men have HTN and are likely taking ACE inhibitors than women, why do women have RSD/CRPS at a 9:1 ratio compared to men???

Must be a confounding variable thing...

First off, to answer to the point raised by Dubious, the ratio of women to men being diagnosed with CRPS in any given year is actually closer to 3.4:1 pursuant to what appears to be regarded as the most definitive demographic study to date. de Mos M, de Bruijn AG, Huygen FJ, et al. The incidence of complex regional pain syndrome: a population-based study. Pain 2007;129:12–20, free full text at http://www.rsds.org/2/library/articl..._pain_2006.pdf

But the crucial point lies with the observation that "Hypertension, the main indication for ACE inhibitors, runs in a ratio of close to 2:1 men to women." I don't believe this is the case. Looking at the Godfather of all longitudinal studies, the Framingham (Mass.) Heart Study, we find that:

Incidence [of new cases of hypertension] increased with age in men from 3.3 per cent at ages 30-39 to 6.2 per cent at ages 70-79, and in women from 1.5 per cent at ages 30-39 to 8.6 per cent at ages 70-79. The rate of increase with age was greater in women than men such that under age 50 men had a higher incidence of definite hypertension than women, while the opposite was observed among
subjects older than age 50.

Changes in hypertension incidence over time were examined by comparing incidence rates for the 1950s, 1960s, and 1970s by sex and age . . . . No clear trend in incidence rates is evident in any age group for either sex.

Andrew L. Dannenberg, Robert J. Garrison AND William B. Kannnel, Incidence of Hypertension in the Framingham Study, Am J Public Health 1988 Jun;78(6):676-9, 676-7, free full text at http://ajph.aphapublications.org/cgi...t/78/6/676.pdf

And if you check out Figure 1 at page 677 for "Two Year Incidence Per 100" (new cases noted over two year intervals) as a function of age, you'll see that the two lines intersect at age 50 and, if anything, the total area under the line for women is greater than it is for men. And in fact, according to a recent NIH study, while diuretics were the most likely drug treatment for both sexes, women were more likely to use ACE inhibitor then men: 11.3% vs. 8.7%. Gu Q, Burt VL, Paulose-Ram R, Dillon CF, Gender differences in hypertension treatment, drug utilization patterns, and blood pressure control among US adults with hypertension: data from the National Health and Nutrition Examination Survey 1999-2004, Am J Hypertens. 2008 Jul;21(7):789-98, abstract at http://www.ncbi.nlm.nih.gov/pubmed/1...m&ordinalpos=8 With any luck, that should resolve the apparent paradox.

But what I've been intending to bring up is this really amazing (if small) new study: Bernateck M, Karst M, Gratz KF, et al, The First Scintigraphic Detection of Tumor Necrosis Factor-Alpha in Patients with Complex Regional Pain Syndrome Type 1, Anesth Analg. 2009 Nov 12 [Epub ahead of print]:

Abstract
Tumor necrosis factor (TNF)-alpha has been identified as a pathogenic factor in many immunologically based diseases and complex regional pain syndrome (CRPS). In this case series, we used radiolabeled technetium anti-TNF-alpha antibody to scintigraphically [i.e., via nuclear medicine] image TNF-alpha in 3 patients with type 1 CRPS. The results show that TNF-alpha was localized only in affected hands of patients with early-stage CRPS. No uptake was seen in clinically unaffected hands and late-stage CRPS. Our findings support the growing evidence for neuroimmune disturbance in patients with CRPS and may have important further implications for specific anticytokine treatment in patients with CRPS.

PMID: 19910617 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/sites/entrez

I have a copy of the full text, but it's too large to post here. Hopefully, the RSDSA will put it up fairly quickly. In the meantime, I will be happy to share it with anyone who drops me a PM with their email address. But to put it in context, let me just share the following from the "Discussion" portion of the article:

This is the first report to scintigraphically detect TNF-[alpha] in situ [in the normal location, in place] in patients with CRPS, showing specific tracer accumulation in early-stage CRPS type 1 but not in the late stage and in osteoarthritis affected joints. The data add to the growing evidence of a neuroimmune disturbance in CRPS type 1. 8 –11

* * *

In conclusion, the 99mTc-labeled anti-TNF-[alpha] antibody infliximab produced positive scintigraphic foci [point at which rays converge or from which they diverge or appear to diverge] in early-stage type 1 CRPS but not in the late-stage patient and in osteoarthritis-affected joints. Our findings complement the recently published data of a neuroimmune disturbance and a local cytokine induced inflammation in early-stage CRPS type 1. 8–11 The use of labeled antibodies may offer the potential to stratify patients for targeted treatment options. Further methodical and controlled studies are needed.

Footnotes
8. Huygen F, De Bruijn A, De Bruin M, Groeneweg J, Klein J, Zijlstra FJ. Evidence for local inflammation in complex regional pain syndrome type 1. Mediators Inflamm 2002;11:47–51
9. Maihofner C, Handwerker H, Neundo¨ rfer B, Birklein F. Mechanical hyyperalgesia in complex regional pain syndrome: a role for TNF-alpha? Neurology 2005;65:311–3
10. Uceyler N, Eberle T, Rolke R, Birklein F, Sommer C. Differential expression patterns of cytokines in complex regional pain syndrome. Pain 2007;132:195–205
11. Schinkel C, Scherens A, Koller M, Roellecke G, Muhr G, Maier C. Systemic inflammatory mediators in post-traumatic complex regional pain syndrome (CRPS I)—longitudinal investigations and differences to control groups. Eur J Med Res 2009;14:130–5

So, bottom line, using TNF-[alpha] as a presumed marker for inflammatory cytokines in general, it appears to be (typically) found just in the early stage of the disease, as has been thought for some time, and then - most interestingly - only in the CRPS affected hands, and not disseminated throughout the body, or the rest of the limb, for that matter.

Which may also explain why Schinkel et al (f.n. 11, above) found significant concentrations in the blood serum of acute CRPS patients, not of TNF-[alpha] itself, but rather its "soluble Receptors I/II" (p = 0.01). http://www.ncbi.nlm.nih.gov/pubmed/1...m&ordinalpos=1 (Nice to see that study getting some notice.) And in this regard, see the discussion under "Cell Signalling," in the Wikipedia article "Tumor necrosis factor-alpha," and in particular the following, along with a nice diagram as to how the pieces fit together:

TNF-R1 is expressed in most tissues, and can be fully activated by both the membrane-bound and soluble trimeric forms of TNF, whereas TNF-R2 is found only in cells of the immune system . . . .

http://en.wikipedia.org/wiki/Tumor_n...s_factor-alpha But this is where the continental shelf drops off very steeply and to say I'm guessing on this last supposition would be to put it charitably. (Is there a molecular biologist in the house?)

Mike

For what its worth, I ran the abstract by a PhD epidemiologist friend who teaches epidemiology at a medical school. Based on the abstract, he said simply that it would appear that ACE inhibitors could be a risk factor, but not a trigger for CRPS.

I would still be curious to know what percentage of RSD/CRPS sufferers are on ACE inhibitors. I'll bet it's very low based on the heavy weighting of women to men and relatively young population, not likely to be prescribed them! And many others with hypertension are taking something other than ACE inhibitors, i.e. b-blockers, calcium channel blockers, etc.