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Comment on: Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder

14 Feb

In 2008 a paper opened up a new area of research in autism risk factors: Autism: maternally derived antibodies specific for fetal brain proteins. The researchers at the U.C. Davis MIND Institute found that for a subset of autistic kids, they could find antibodies in the mothers’ sera that reacted to human fetal brain tissue. Other teams have found similar results, and the MIND researchers have continued to explore this topic.

In the present study, the researchers studied 131 ASD kids and 50 non-ASD controls. 10 of the ASD kids were born to mothers with the brain specific autoantibodies detected in their serum. Autism severity, by their measure, was the same for the two ASD groups. The rate of develpmental regression is the same for the two groups, but strikes me as rather high at 40-50% . Previous studies by this team and others indicated a higher rate of regression in the ASD kids in the maternal-autoantibody group.

Brain volumes were measured via MRI. Most children were tested during sleep. 10 children (all ASD) were tested under anesthesia. Scans were corrected for instrument distortions before volumes were measured. Brain volumes were higher for the ASD kids than the typical kids, consistent with previous results. However, the kids in the maternal autoantibody group had brain volumes even higher than the rest of the ASD kids. The kids in the maternal autoantibody group had brains 12% larger on average than the non ASD kids, while the rest of the ASD group had about 4.4% larger volumes.

The volume differences were not the same over the entire brain:

Furthermore, the frontal lobe was selectively enlarged in the ASD-IgG children relative to other ASD children, and both gray and white matter were similarly affected.

Previous work by the authors indicate the possibility that the autoantibodies themselves might cause brain differences resulting in autism. Their animal model was rhesus monkeys, whose mothers were injected with the autoantibodies.

The authors note there are a number of open questions:

Obviously, several questions remain: What are the brain antigens recognized by the 37/73 kDa maternal IgG autoantibodies, and what is their role normal neurodevelopment? What induces the production of these antibodies in some women but not in others? What is the mechanism by which these maternal autoantibodies alter brain development? Are there processes that could be implemented to block the deleterious effects of the antibodies? Studies are currently underway to address each of these issues and they will undoubtedly shed more light on the role that maternal
autoantibodies may play in ASD and abnormal brain enlargement in ASD.

Another open question they raise has to do with siblings of the autoantibody ASD kids. In specific, since these autoantibodies can persist in the mother’s serum for many years, it is likely that younger siblings are exposed to them as well. If these children do not develop ASD, what is the reason?

The brain volume differences are shown in summarized in this figure:

Antibodies figure

There is a large spread for the brain volumes for the non-autoantibody ASD kids. While on average they are larger, a number are comparable to the average for non-ASD kids. Also, there is a large overlap between the ASD groups from parents positive for the autoantibodies and without the autoantibodies. The kids in the autoantibody group are almost all at the high end of the distribution for the non-ASD kids.

The main thing this paper adds to the autoantibody story is evidence that this may represent a separate group within the ASD population. The work is being performed on members of the Autism Phenome Project. If this is a separate group, so far the evidence is only in brain volume. The authors note: “There were no differences in age, height, autism severity, or DQ between the two ASD groups. Furthermore, the two groups did not differ in the rate of parent reported history of regression.” So on other physical measures, and on autism-based measures, there are no differences. Obviously it would be valuable to see diffrences in autism-specific measures so we could back track how those measures are related to etiology and brain structure. But it is also interesting that this group does not have differences as it could indicate multiple pathways are not always distinct in the end result in autism development.

Nordahl, C., Braunschweig, D., Iosif, A., Lee, A., Rogers, S., Ashwood, P., Amaral, D., & Van de Water, J. (2013). Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder Brain, Behavior, and Immunity DOI: 10.1016/j.bbi.2013.01.084

ResearchBlogging.org


By Matt Carey

Scientist Patricia Rodier, Trailblazer in Early Origins of Autism, Dies

19 Jul

Autism researcher Patricia Rodier, Professor at the University of Rochester, has died. U. Rocherster discusses this on their website as Scientist Patricia Rodier, Trailblazer in Early Origins of Autism, Dies.

Patricia Rodier, Ph.D., the first scientist to formulate and study the idea that autism can originate long before a child is born, died May 3 at Strong Memorial Hospital. She was 68.

An embryologist specializing in the nervous system, Dr. Rodier completely changed the way we think about the development of autism. While many believed that the disorder arose very late in pregnancy or in the early part of an infant’s life, Dr. Rodier’s research turned that widely held, but unproven, belief upside down. Her work established that genetic and environmental factors can also spur the development of the disorder as early as three weeks into a pregnancy, when the first cells of the nervous system start to develop.

Prof. Rodier became interested in autism relatively late in her career, but early in the modern era of autism research: 1994. She heard about a study showing a high prevalence of autism in adults who had been exposed to thalidomide prenatally. She gathered a team to investigate how autism develops early during gestation.

She wrote an article in 2000 for Scientific American, The Early Origins of Autism (also available online in full here). A lot has happened in autism research since then, but much of what she did and had to say is very relevant today. For example, she performed research using post-mortem brain tissue. She notes that the twin studies, even those available at the time, showed that more than simple inheritance was at play. She notes multiple prenatal environmental exposures which increased autism risk (thalidomide, maternal rubella infection and valproic acid). She notes how the data, even then, pointed to multiple genes being involved.

In short, many ideas which are considered “new” (e.g. multiple genes as a risk factor) or that “mainstream medicine refuses to consider” (e.g. environmental risk factors) are discussed in that 12 year old article.

Another part of Prof. Rodier’s research which became extremely relevant in the discussion of autism causation was her work on mercury exposures. From the U. Rochester webpage:

A professor in the Department of Obstetrics and Gynecology at the University of Rochester Medical Center, Dr. Rodier was also a world expert on mercury toxicity, studying how single exposures to the chemical during pregnancy influence a baby’s brain development. To this day, much of the research being done on mercury exposure and birth defects is based on Dr. Rodier’s early findings.

She was likely the one person in the world who had strong expertise in both autism development and mercury. She was called upon as a witness for the Omnibus Autism Proceeding (discussed here and here). Her expert report for the OAP is an excellent resource for people trying to make sense of the autism/mercury notion.

I exchanged emails with Prof. Rodier a few times to discuss her work. While I never actually spoke with her, the “voice” of her emails was always very kind. I found out about her passing when I was considering contacting her again recently. I wish her family well.

–by Matt Carey

Microglial Activation and Increased Microglial Density Observed in the Dorsolateral Prefrontal Cortex in Autism.

4 Aug

Here is a study that will likely be discussed for a long time to come. There has been a lot of interest in the study by John’s Hopkins researchers (Pardo, et al.) on microglial activity in the brains of autopsied autistics. A paper just released by Prof. Pardo together with Prof. Courchesne at UCSD shows markedly increased microglial cell activiation in 5 of 13 autistics, including children under 6.

The exact implications of this are not yet determined. The authors conclude the abstract with

“Given its early presence, microglial activation may play a central role in the pathogenesis of autism in a substantial proportion of patients. Alternatively, activation may represent a response of the innate neuroimmune system to synaptic, neuronal, or neuronal network disturbances, or reflect genetic and/or environmental abnormalities impacting multiple cellular populations.”

Here is the full abstract:

Biol Psychiatry. 2010 Aug 15;68(4):368-376.
Microglial Activation and Increased Microglial Density Observed in the Dorsolateral Prefrontal Cortex in Autism.

Morgan JT, Chana G, Pardo CA, Achim C, Semendeferi K, Buckwalter J, Courchesne E, Everall IP.

Department of Neuroscience, School of Medicine, University of California, San Diego, La Jolla, California.
Abstract

BACKGROUND: In the neurodevelopmental disorder autism, several neuroimmune abnormalities have been reported. However, it is unknown whether microglial somal volume or density are altered in the cortex and whether any alteration is associated with age or other potential covariates. METHODS: Microglia in sections from the dorsolateral prefrontal cortex of nonmacrencephalic male cases with autism (n = 13) and control cases (n = 9) were visualized via ionized calcium binding adapter molecule 1 immunohistochemistry. In addition to a neuropathological assessment, microglial cell density was stereologically estimated via optical fractionator and average somal volume was quantified via isotropic nucleator. RESULTS: Microglia appeared markedly activated in 5 of 13 cases with autism, including 2 of 3 under age 6, and marginally activated in an additional 4 of 13 cases. Morphological alterations included somal enlargement, process retraction and thickening, and extension of filopodia from processes. Average microglial somal volume was significantly increased in white matter (p = .013), with a trend in gray matter (p = .098). Microglial cell density was increased in gray matter (p = .002). Seizure history did not influence any activation measure. CONCLUSIONS: The activation profile described represents a neuropathological alteration in a sizeable fraction of cases with autism. Given its early presence, microglial activation may play a central role in the pathogenesis of autism in a substantial proportion of patients. Alternatively, activation may represent a response of the innate neuroimmune system to synaptic, neuronal, or neuronal network disturbances, or reflect genetic and/or environmental abnormalities impacting multiple cellular populations. Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

PMID: 20674603 [PubMed – as supplied by publisher]

John’s Hopkins FAQs: The meaning of neuroinflammatory findings in autism

30 Nov

In their recent series on autism the Chicago Tribune exposed how a Johns Hopkins team’s findings of neuroinflammation have been misused to justify unproven autism treatments.

The Tribune included very short piece, Researchers warn against misusing report. The piece includes a link with some very valuable information, but it is unfortunately somewhat obscure. The web address they list (chicagotribune.com/autismstudy) is unlinked, and actually links through to the Hopkins team’s FAQ.

That FAQ is definitely worth reading and referring to when you read or hear “neuroinflammation”.

The FAQ is rather thorough, and I am in danger of just copying the entire thing here. Since I haven’t asked for permission, I’ll quote a small fraction of the FAQ. Yes, I am aware of the irony there–cherry picking information from this team is exactly what has led to the problems the Tribune reported upon. So I’ll say it again: go and read the FAQ for yourself.

Here is part of question 2:

Is neuroinflammation always present in the brain of autistic patients?

NOT necessarily. Since autism is a disorder that is highly variable in the ways it presents, and may be associated with multiple causes, it is possible that our sample of cases does not represent the entire autistic spectrum.

Here’s part of question

Are microglial and astroglial reactions always bad for the brain?

NO. The microglia and astroglia in the CNS may have a two-sided role in the inflammatory responses of the brain: they can act both as direct effectors of injury and on the other hand as protectors of the brain.

I’ll include all of question 12:

If there is neuroinflammation in the brain of some autistic patients, is treatment with anti-inflammatory or immunomodulatory medications indicated?

At present, THERE IS NO indication for using anti-inflammatory medications in patients with autism. Immunomodulatory or anti-inflammatory medications such as steroids (e.g. prednisone or methylprednisolone), immunosupressants (e.g. Azathioprine, methotrexate, cyclophosphamide) or modulators of immune reactions (e.g. intravenous immunoglobulins, IVIG) WOULD NOT HAVE a significant effect on neuroglial activation because these drugs work mostly on adaptive immunity by reducing the production of immunoglobulins, decreasing the production of T cells and limiting the infiltration of inflammatory cells into areas of tissue injury. Our study demonstrated NO EVIDENCE at all for these types of immune reactions. There are ongoing experimental studies to examine the effect of drugs that limit the activation of microglia and astrocytes, but their use in humans must await further evidence of their efficacy and safety

Capitals are in the original.

The Hopkins team is the source when it comes to neuroinflammation in autism. If they chose to write this FAQ and emphasize some points in all capitals, it’s well worth taking them seriously.