Pardo letter on neuroinflamation

26 Mar

Neuroinflamation was a big subject in the Autism Omnibus. This was especially true in the “second theory of causation” hearings, which concentrated on thimerosal containing vaccines as a possible causative factor in autism.

Here’s a page from Dr. Aposhian’s presentation at the Omnibus (click to enlarge), which shows the basic logic flow.

aposhianslide76

Or, to put it simply–thimerosal gets changed to ethyl mercury which deposits mercury ions in the brain, causing neuroinflamation which causes autism.

Yes, there are a lot of of missing steps in order to prove this idea.   But, for now, let’s just think about neuroinflamation.  The term (neuroinflamation), as Dr. Aposhian makes clear in his report and slides, is somewhat new, having been coined in the 1990’s. Dr. Aposhian and others spent a lot of time discussing neuroinflamation, astrocytes and glial cells.

The research on neuroinflamation in regards to autism comes mainly from researchers at Johns Hopkins. In particular, Dr. Aposhian cites (on slide 79 of his presentation) the Vargas paper, pulling a quote:

Vargas et al., Neuroglialactivation and neuroinflammation in the brain of patients with autism. Ann Neurol57, 67-81, 2005,

“Our findings indicate that innate neuroimmunereactions play a pathogenic role in an undefined proportion of autistic patients…”

It is important to note that one of the authors on that paper was Dr. Andrew Zimmerman, whose expert report Kev recently blogged. That’s right, Dr. Zimmerman prepared an expert report for the government. The anchor author on the Vargas paper was Dr. Carlos Pardo.

It turns out that a letter from Dr. Pardo is included in the Omnibus docket as well. Here’s the introduction paragraph from Dr. Pardo’s letter:

As per our conversation last year, I would like to clarify some of the concepts regarding the role of neuroimmune response in the brain of patients with autism and the potential significance of such findings in the pathogenesis and pathobiology of the disorder.

Good–he’s trying to clarify some points of his paper. Just the sort of letter we want to read. It is rather thick on the science. Let me cherry pick one sentence, if I may:

These findings are inconsistent with the hypothesis of a potential toxic effect on astrocytes by neurotoxins or toxic material.

It strikes me that the families with claims in the vaccine court are in a really difficult position. Their lawyers and experts are arguing the thimerosal causation issue largely on the idea of neuroinflamation. The problem being that the key people in neuroinflamation and autism are experts for the other side.

The thimerosal cases depend on neuroinflamation. Does anyone else see this as a really tough battle to fight, given that the few world experts on the subject disagree with the contention that neuroinflamation in autistic brains is due to neurotoxins?

6 Responses to “Pardo letter on neuroinflamation”

  1. passionlessDrone March 26, 2009 at 18:28 #

    Hi Sullivan –

    Thanks for the link to the letter. Just goes to show how little we understand; the dual functions of these chemicals as immune modulators and neural functioning are proving to be very difficult to detangle.

    You might be interested in knowing that folks other than John’s Hopkins have reported similar findings in terms of immune activation in the CNS in autism.

    Chez reported large increases in tnf-alpha in the csf in children with autism.

    It turns out, tnf-alpha has recently been implicated in seizure generation in a variety of animal models; interesting considering the comorbidity of epilepsy in our cohort of interest. Also of potential interest are several papers recently that indicate that early life exposure to LPS can result in long term changes in levels of Tnf alpha and seizure succeptibility. These were animal models, so it is tough to navigate the prenatal to postnatal differences to humans.

    More recently, Li reported an active immune process in brains of children with autism, though in this case, they did report concurrent activation of the adaptive arm of the immune system. They had some similar findings from other groups, increased tnf-alpha, and MCP1 specifically.

    This paper post dates Pardo’s letter significantly. I’m not sure if what was found by Li is sufficient for us to reach different conclusions as to the possibility of immune activation being deleterious or not. But it is more pieces of the puzzle.

    – pD

  2. _Arthur March 26, 2009 at 20:40 #

    Dr. Kinsbourne presented expert reports and testified in both the MMR causation case, and the Thimerosal causation case.

    In Cedillo, he testified that he was very confident than the measles virus from the vaccine caused a neuroinflammation in the brain

    In King/Mead, he testified that he was very confident that thimerosal, once transmuted into methyl mercury, caused a neuroinflammation in the brain.

    At cross, it was pointed to him that his expert reports were identical, with the words “mercury” substituted in place of “measles virus”.

    Kinsbourne was particularly noncomittal about the dosage required to cause such alleged inflammation, not being a toxicologist.

    Day 3 of testimony, P. 911.

  3. Prometheus March 30, 2009 at 19:28 #

    As pD mentions, there have been some tantalizing bits of data suggesting the presence of neuroinflammation in the brains of autistic people. It is also worth mentioning that Dr. Pardo and Dr. Zimmerman were among the first to demonstrate this.

    However, it is a large jump from saying that autism is associated with neuroinflammation to stating that it is caused by neuroinflammation.

    It is even a larger leap to claim that vaccines or “toxins” caused the neuroinflammation seen in autism.

    If we stick to the data, all we can say is that autopsy specimens (limited numbers) and cytokine profiles suggest the presence of neuroinflammation in autism. This may be a generalized finding or limited to a smaller subset – we do not know at this time.

    Speculation about vaccines or “toxins” or “environmental factors” being the cause of this neuroinflammation are just that – speculation. Until the data are gathered to support those “hypotheses”, they are no more than idle guessing.

    Prometheus

  4. passionlessDrone March 30, 2009 at 21:08 #

    Hi Prometheus –

    What I’m struggling to see is a valid mechanism for teasing out the cause of immune activation in a condition with so many little things wrong.

    By way of example, early life exposure to LPS has been shown to cause similar profiles in animal models. Also, having a seizure early in life seems to be able to cause such differences into adulthood. Peripheral inflammation has been shown to create similar increases. Genetics is most likely there. So everytime I try to conceive a model of identifying the drivers of inflammation, my head hurts. From an animal perspective, it seems like we need a four or five tier knockout mouse just to get started.

    However, it is a large jump from saying that autism is associated with neuroinflammation to stating that it is caused by neuroinflammation.

    Anyways, as to if neuroinflammation is causing autism, (or some subsets of autistic behaviors), wouldn’t trials of anti inflammatory agents known to attenuate neuroinflammation give us some indication as to a causal relationship? I believe that minocycline is in clinical trials currently, with this being a proposed mechanism by which behaviors could be altered. There are some other agents (resolvins) I believe could be eventually be quite exciting in that area as well.

    What if instead of asking “does neuroinflammation cause autism?”, we ask, “can this situation be good for children?” though? I can’t see how to paint a scenario where increased tnf alpha and increased IL-6 (among others) are in any way good for a developing child. It seems pretty clear that tnf alpha plays a part in seizure generation, something we know this population has problems with. Similarly, IL-6 seems to be linked to seizures in some cases. We also seem to observe increased inflammatory markers in other neurological disorders.

    It is even a larger leap to claim that vaccines or “toxins” caused the neuroinflammation seen in autism.

    Toxins, yeah. I’m starting to think that early life challenges to the immune system could be a much bigger problem. Of course, this wouldn’t just be vaccines, and could likely include be pre natal, but again the complexities of modeling are difficult. There are some rodent studies that show increased propensity to seizures, colitis, and increased tnf alpha production after exposure to LPS, or indeed, just plain old tnf-alpha during very critical developmental timeframes.

    Anyways, OK!

    – pD

  5. Joseph March 30, 2009 at 22:06 #

    Anyways, as to if neuroinflammation is causing autism, (or some subsets of autistic behaviors), wouldn’t trials of anti inflammatory agents known to attenuate neuroinflammation give us some indication as to a causal relationship?

    Perhaps, but there are concerns that anti-inflammatory drugs have psychiatric side-effects.

    Conversely, anti-depressants seem to have anti-inflammatory effects.

    It doesn’t look like the mechanisms are well understood.

  6. Prometheus March 31, 2009 at 19:00 #

    pD comments:

    Anyways, as to if neuroinflammation is causing autism, (or some subsets of autistic behaviors), wouldn’t trials of anti inflammatory agents known to attenuate neuroinflammation give us some indication as to a causal relationship?

    There are – or will be – some trials underway for anti-inflammatory agents that can work in the CNS. So far, the clinical trials haven’t been very convincing.

    Of course, if neuroinflammation isn’t a common feature of autism (or is unrelated to autism), treating all autistic children with anti-inflammatory drugs will be largely ineffective. Some autistic children will appear to improve on the drugs, but a number will improve without any intevention, so careful controls are needed.

    What if instead of asking “does neuroinflammation cause autism?”, we ask, “can this situation be good for children?” though?

    Good of you to think of that question. However, I would phrase it as “Does this degree of neuroinflammation cause harm?”

    You see, we don’t have the answer to that question yet. While it may seem obvious that inflammation is “bad”, and should be stopped at any cost, it isn’t necessarily so. Sometimes inflammation is keeping something worse from happening.

    Once again, the “obvious” answer is not necessarily the correct one.

    Let’s just take this in stepwise fashion to see how the issue of neuroinflammation in autism should be addressed.

    [1] Are CSF cytokines a reliable indicator of neruoinflammation in autism?

    [2] Is neuroinflammation present in all children with autism or merely a subset?

    [3] Is neuroinflammation a cause of autism, does it prolong or exacerbate autism or is it simply a feature of autism?

    [4] Does reducing neuroinflammation improve the symptoms/signs of autism?

    [5] What is the cause (or causes) of neuroinflammation in autism and is it (are they) preventable/treatable?

    Once we have solid answers to these questions, we’ll know what neuroinflammation has to do with autism – not before.

    Idle speculation as to what “might” cause neuroinflammation in autism before it has been established as a regular feature of autism (let alone a cause or exacerbating factor) is less than pointless.

    Prometheus

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