Autism and Cholesterol: A possible link?

Low levels of cholesterol associated with autism-like symptoms in Smith-Lemli-Opitz Syndrome.

A review of: Aneja, A., Tierney, E. (2008). Autism: The role of cholesterol in treatment. International Review of Psychiatry, 20(2), 165-170. DOI: 10.1080/09540260801889062

The Smith-Lemli-Opitz Syndrome (SLOS) is a genetic disorder characterized by alterations in the processing of cholesterol. Specifically, people with this disorder do not produce enough cholesterol resulting in a variety of morphological, physiological, and behavioral symptoms. Of interest to autism researchers is that people with SLOS have many of the same symptoms that characterize autism spectrum disorders, including language impairments and stereotyped behaviors. How is cholesterol related to ASDs within and outside the SLOS syndrome? In this article, Aneka and Tierney (2008) present a succinct summary and conceptualization of the possible role of cholesterol in the phenomenology of Autism. The authors reviewed the physiological mechanisms by which low levels of cholesterol may play a role in the behavioral phenotype found in kids with SLOS. The following mechanisms were discussed:
1. Cholesterol is necessary for normal embryonic and fetal development.
2. Cholesterol is a precursor of neuroactive steroids (possibly affecting anxiety)
3. Cholesterol is required for the growth of myelin membranes (affecting brain maturation).
4. Cholesterol can be a modulator in oxytocin receptor functioning (Oxytocin plays an important role in social behaviors).
5.Cholesterol is a modulator of the ligand binding activity and G-protein coupling of the serotonin1A (5-HT1A) receptor (affecting serotonin neuron development).

An examination of these factors is beyond the scope of this review, but they represent a sensible theory regarding the possible mechanisms by which low levels of cholesterol may lead to many of the behavioral symptoms present in autism. The authors then discussed the implication of these findings for assessment and possible treatment interventions. First, most comprehensive evaluations of autism may include genetic and laboratory testing, including testing for fragile X, heavy metals, etc. The authors stated that biochemical testing can be utilized to assess for low level of cholesterol (actually low levels relative to another compound - 7DHC). In my experience, requesting this test within a neuropsychological evaluation is not common. Actually I don’t remember ever conducting an evaluation of someone who had been recommended this test by anyone (neurologist, pediatricians, psychologist, etc). Finally, the authors reviewed previous studies that have examined the effectiveness of cholesterol supplementation in children with SLOS. Previous studies have found that children with SLOS that receive cholesterol supplementation show a reduction of autistic behaviors, irritability, attention problems, and improved affect.

Should cholesterol testing become a part of the standard assessment procedures of children with Autism?

Autism and family psychopathology: A Neuroprotective Effect?

An autism endophenotype may be identified on the basis of family psychopathology, but not in the direction you may think.

A review of: Lajiness-O’Neill, R., Menard, P. (2007). Brief Report: An Autistic Spectrum Subtype Revealed Through Familial Psychopathology Coupled with Cognition in ASD. Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-007-0464-3

A genotype refers to a specific genetic profile. A phenotype refers to the presentation (behaviors, physical features, etc) of a genotype. An endophenotype refers to specific characteristics (biological, social, cultural, etc, etc) that may influence the expression of a disorder-related genotype. In this very interesting study the researchers examined parental psychiatric history and the neurocognitive functioning of 24 kids with Autism Spectrum Disorders (5 Autism, 7 Asperger’s, 12 PDD NOS; average age 9.16) and 49 children with learning disability but not autism. Autism diagnosis was based on DSM-IV criteria via CARS and ADI-R. The researchers found a significant higher rate of mood disorders and anxiety on the maternal side of children with ASD as compared to children with LD. There was a significant higher rate of learning disabilities and ADHD in the paternal side of children with ASD as compared to children with LD. A surprising finding was noted: Children with ASD who had a history of mood disorders in the maternal side (n=9), demonstrated significantly higher visuospatial functioning when compared to children with ASD who did not have a maternal history of mood disorders (n=14). The authors reported that this is consistent with a different study that found maternal mood disorders to be associated with elevated cognitive and adaptive functioning in children with ASD (Cohen and Tsiouris, 2006). Thus, although maternal mood disorders were more common in children with ASDs than in children with LDs, high rates of of these mood disorders seem to serve a neuroprotective function.

High functioning autism vs. Asperger’s: the VIQ PIQ myth?

A review of: Spek, A.A., Scholte, E.M., Berckelaer-Onnes, I.A. (2008). Brief Report: The Use of WAIS-III in Adults with HFA and Asperger Syndrome. Journal of Autism and Developmental Disorders, 38(4), 782-787. DOI: 10.1007/s10803-007-0446-5

I have documented in previous posts that clinicians and researchers have often proposed that high functioning autism and Asperger’s present a significantly different neurocognitive profile (see here and here). The belief is that children with AS tend to have a significant discrepancy between verbal and non-verbal abilities, with relatively higher verbal functioning as compared to non-verbal skills. On the other hand, children with high functioning autism tend to have relatively equal verbal and non-verbal skills. However, recently I’ve been encountering several studies that suggest that this may not be the case. As reported in this brief yet very elegant study from the Leiden University in the Netherlands, the researchers conducted a cognitive assessment of 16 adults with high functioning autism and 27 adults with Asperger’s syndrome using the WAIS-III (the most common adult IQ assessment instrument). Diagnoses were confirmed via ADI using DSM-IV criteria to differentiate HFA vs. AS. There were no differences between the groups in verbal vs. non-verbal performance (VIQ vs. PIQ). There was no pattern of high-verbal low-non-verbal scores in the Asperger’s group, with both groups scoring in the High Average range for both verbal and non-verbal composite scales. However, one global factor scale difference was observed. Adults with high functioning autism showed a significantly lower Processing Speed as compared to other factor skills such as Verbal Comprehension, Perceptual Organization, and Freedom from Distractibility. This finding was not observed in the Asperger’s group. Despite this difference (and some additional task-specific differences I didn’t mention in this review), the general findings of this study fail to support the idea that people with high functioning autism and Asperger’s can be differentiated on the basis of relative strength and weaknesses in their verbal vs. non-verbal performance as measured by standard intellectual assessment batteries.

How young is too young to diagnose autism?

A review of: Kleinman, J.M., Ventola, P.E., Pandey, J., Verbalis, A.D., Barton, M., Hodgson, S., Green, J., Dumont-Mathieu, T., Robins, D.L., Fein, D. (2008). Diagnostic Stability in Very Young Children with Autism Spectrum Disorders. Journal of Autism and Developmental Disorders, 38(4), 606-615. DOI: 10.1007/s10803-007-0427-8

In all clinical settings I have worked, there is usually a hesitation to provide a diagnosis of autism to children under 2 years of age, mostly because of the relatively limited amount of research showing stability of such early diagnoses. Instead, we were more likely to provide a PDD-NOS diagnosis (except in the most prototypical cases) and would change the diagnosis to autism within 24 months if the presentation of the disorder remained stable and diagnostic criteria were met. In this study the researchers examined the stability of diagnoses made during late infancy and early childhood. The study included 77 children (66 males) participating in a large multi-site study of early screening of autism. The children were assessed two times. At time 1, the kids were between 16-months and 35-month old (mean 27-months). At the second evaluation, the children were between 3 years-5 months and 6 years-10 months old (mean 4 years-5 months). Diagnoses were provided on the basis of 1) clinical judgment based on DSM-IV criteria, 2) Autism Diagnostic Interview (ADI-R) 3) the Autism Diagnostic Observation Schedule (ADOS) and 4) the Childhood Autism Rating Scale (CARS). At the first evaluation 46 kids were diagnosed with autism, 15 with PDD-NOS, and 16 as non-autistic. Based on clinical judgment diagnoses, 80% of the children with an autism or PDD-NOS diagnosis at time 1 remained in the same diagnostic category at time 2. Based on ADI-R, the stability was 67%. The ADOS stability was more similar to the clinical judgment at 83%. Finally, the CARS the stability dropped to 76%. Three findings are worth noting. First, regardless of diagnostic tool used, diagnoses obtained in early childhood and late infancy appear to be relatively stable with between 70 to 80% of children with a diagnosis of ASDs continuing to have the diagnosis 2 years later. Second, the low stability of the ADI-R in this young population was very surprising given the relatively high popularity of the ADI-R as a diagnostic tool. But more surprising is the equal stability of the ADOS compared to clinical judgment. Why is this surprising? Mostly because of the dramatic difference in cost between a clinical consultation and a full ADOS evaluation. Can the ADOS cost be justified if it is as reliable as a traditional clinical evaluation? It may be, because this data only addresses the issue of stability (reliability), not the validity of the diagnosis, which is highly dependent upon the training of the clinician. Thus, it is possible that the clinical judgment was stable (reached the same diagnosis at both times), but it is possible that while stable, the clinical judgment was invalid (it was wrong at both times). Although this is highly unlikely in this case (but likely in the real world where clinical diagnoses are provided by people with insufficient related training - such as most pediatricians and family physicians), this data only allow us to reach conclusions about the stability of these different diagnostic tools.

Autism, IQ, and the Stanford–Binet

Title: Brief Report: Data on the Stanford–Binet Intelligence Scales (5th ed.) in Children with Autism Spectrum Disorder
Source: Coolican, J., Bryson, S.E., Zwaigenbaum, L. (2008). Brief Report: Data on the Stanford–Binet Intelligence Scales (5th ed.) in Children with Autism Spectrum Disorder. Journal of Autism and Developmental Disorders , 38(1), 190-197.

In 2003 the Stanford-Binet-Intelligence Scales published a new edition (The SB-5). The SB is one of the most commonly used IQ scales for the assessment of children with special needs because it is believed to provide a more valid estimate of the child’s cognitive capacities. Although such assertion is still debated, in my experience working at several outpatient and hospital settings, the SB was always the tool of choice when conducting assessment with children with autism. Now, the problem that clinicians and researchers encounter is that when a new version of the test is launched, there is little information, apart for what is provided by the publisher, about how children with specific neurodevelopmental disorders are expected to perform. Thus, a team a Dalhousie University in Canada provided this brief report on the performance on the SB-5 by children with ASDs. The study included 63 children (12 girls and 51 boy) who have received a diagnosis of Autism, Asperger’s, or PDD-NOS via ADI or ADOS evaluation. The final count included 32 children with autism, 20 children with Asperger’s, and 11 children with PDD-NOS. Here are the most relevant results: Age was not significantly associated with performance as expected. This means that when compared to very large population sample of peers of the same age, younger children and older children perform at the same level in relation to their peers. Thus, differences between these children and the population sample do not change with age. The average full scale IQ scores using the entire SB-5 for the groups were 67.75 for Autism, 105.60 for Asperger’s, and 82.18 for PDD-NOS. When using an abbreviated version of the SB-5, the results were slightly higher but this varied significantly by individual. When comparing the Verbal vs. Non-Verbal subscales, it was surprising that in all three groups the scores in these scales were very similar, without any major discrepancy between verbal and non-verbal performance. This is surprising because traditionally children with Asperger’s show a pattern of performance consistent with a Non-verbal learning disability. That is, you would expect a significant discrepancy with much higher verbal scores as compared to non-verbal scores.

Commentary: The issue of IQ and intellectual assessment in children with Austim is highly controversial. However, the controversy is largely political and outside the research and clinical world. I want to address two issues that seem to be commonly debated in the autism community. First I want to briefly explain when, why and how an intellectual assessment test is used. An intellectual assessment is never, or should never, be provided in isolation. That is, an IQ test for the sake of knowing an IQ score provides no clinical utility. IQ scores, outside the larger scope of a full neurocognitive or educational evaluation conducted to answer specific clinical questions, are simply meaningless. Instead, an intellectual assessment is provided as part of a larger evaluation to understand the specific patterns of relative neurocognitive strengths and weaknesses with the ultimate goal of providing recommendations for services, treatment, accommodations, etc , which will maximize the functional capacities of the child and will facilitate growth and improvement. Second, there is usually a debated as to whether these intellectual assessment tools truly reflect the capacities of the child. This is a very, very, very important question. For example, performance in these types of tests is highly influenced by social desirability (wanting to please). A typically developing child may be attentive to instructions in order to please the clinician. But what if the child simply has other priorities at that particular moment than to listen to the clinicians explain how to do this clearly boring task? Does poor performance on this task reflect limited capacity in the area of functioning assessed? That is, did the child performed poorly because he/she couldn’t do it, or simply because he/she didn’t want to do it? So to the extent that IQ tests measure TRUE capacity, or are reflective of the child’s TRUE abilities, we simply have to say we don’t know. We hope that our assessment tools tap and real capacities as much as possible, but it is nearly impossible to ascertain why someone did not perform well in a particular task. HOWEVER, what the test does, at least more accurately, is to assess for FUNCTIONAL capacity. From a purely theoretical perspective, we can say that it does not matter why the child performed poorly if such performance generalizes into other contexts and affect the functional capacity of the child (not being able to do school work, difficulty keeping a job, etc). Thus, to the extend that neurocognitive assessment tools reflect functional capacities and help us provide recommendations that result in REAL benefits for the child, then I see these tests as important tools if used correctly for the right reasons and in the right context.

Update - Clarification: I was asked to clarify the statement “the controversy is largely political and outside the research and clinical world”. I apologize and agree that I should have been more precise about what I meant with that statement. I did not mean to imply that there is no controversy regarding the relative utility or appropriates of particular instruments (SB vs. WISC vs. TONY vs. other non-verbal assessment tool, etc). I was making a commentary about the commonly accepted position that in the right context, intellectual assessment as part of a comprehensive evaluation provides useful clinical information that could benefit the child or adult with autism. In my experience, the utility of using intellectual assessment tools has not been an issue of major controversy in any of the clinical settings I have worked in, including large university-based hospitals and autism clinics. In addition, I just conducted another superficial review of the two top journals in autism during the last 24 months and I was unable to find articles that provide appropriate empirical support for the idea that intellectual assessments should not be conducted in children with autism, although there are compelling articles discussing the appropriateness of specific tests. However, I accept that it is possible that the controversy in the research and clinical arena about this issue could more pronounced than how I characterized it, and if that is the case I stand corrected.

Diminished Cingulate Respose in Children with High Functioning Autism: A possible neural marker?

Title: Self Responses along Cingulate Cortex Reveal Quantitative Neural Phenotype for High-Functioning Autism
Authors: Pearl H. Chiu, M. Amin Kayali, Kenneth T. Kishida, Damon Tomlin, Laura G. Klinger, Mark R. Klinger and P. Read Montague
Source: Neuron 57, 463–473, February 7, 2008

I first heard about this article at the Autism Vox, which led to an interesting discussion on the difficulty in applying findings from basic science into the creation of diagnostic tools. This was a very interesting piece, but as I mentioned on the Autism Vox discussion, I think we are far from the creation of an FMRI test of autism (see the Autism Vox discussion). In summary, the researchers examined 16 adolescents with high functioning autism and 20 typically developing adolescents in their responses to a computer game called the Multi-round Trust Game. In this game the children received computer money (points) from another player in the form of an investment. During the transaction, the investment increased, so the receiving child obtained more than what the “investor” actually sent. Then the receiving child must decide how much of what he received should be returned to the investor. The key finding was that both groups of kids (Children with autism and typically developing) looked the same, in regards to their brain activation as seen on an fMRI, when the “Other” person was making a decision. The authors refer to this as the “Other Response”. However, when the children were making their own responses (called “Self Response”) the children with Autism lack a particular activation in the Cingulate Cortex (located deep in the center of the brain and usually activated during some social interactions including TofM tasks). This pattern of response was similar to the pattern presented by typically developing kids when playing against a computer instead of an actual person. The conclusion from the authors is that these children with autism may be “impaired in the capacity to represent the social intend of their OWN behavior” while understanding the actions of other (but not necessarily the intentions of others).

Commentary: Here is where the logic gets fussy. Since the two groups of children had a similar response patterns to the “Other” response, the authors argued that such “other” response must refer to a representation of the simple actions of others, but not the “intentions” of others. So the lack of cingulate cortex activation during “self” responses are interpreted as a diminished capacity to understand you own social “intentions” (or I interpret this that as “consequences”) and this is used to explain why children with autism have difficulty on theory of mind tasks. The authors argued that if you can’t represent your own social intentions, it will be difficult to represent the social intentions of others. Now, the problem is that in this game there was no difference between the two groups of kids when the “Other” was responding. Why? If children with autism have difficulty representing the social intentions of others, you would expected to see a difference between these two groups, unless you assume that 1) the typically developing kids also had problems representing the social intentions of others OR 2) during this game there was no need to represent the social intentions of others. In conclusion, what this study clearly shows is reduced Cingulate Cortex activation during “self” responses, suggesting that children with autism have a different brain activation pattern when performing actions that have social intentions, or consequences on someone else. Here is a review from MIT.

Teachers and Parents know!

Title: Rapid quantitative assessment of autistic social impairment by classroom teachers.
Study Authors: Constantino, John N; LaVesser, Patrica D; Zhang, Yi; Abbacchi, Anna M; Gray, Teddi; Todd, Richard D.
Source: Journal of the American Academy of Child & Adolescent Psychiatry. Vol 46(12) Dec 2007, 1668-1676.

A very interesting study about the ability of teachers and parents to correctly identify autism symptoms in children when using a specific guide. The researchers had teachers, parents, and expert clinicians assess a total of 577 children. Of these 406 had a diagnosis of PDD, Asperger's, or Autism. The parents and teachers used the Social Responsiveness Scale (SRS) to guide their own assessments. The clinicians used the ADI or the ADOS. The researchers (I should disclosed these researchers are the creators of the Social Responsiveness Scale) found that when the parents and teachers assessments using the SRS are combined, this combined assessment is very similar, in regards to its ability to identify symptoms, to the results from the formal clinician ADI or ADOS evaluation. In addition, teachers reports provided similar information as that provided by the ADOS. The implication is that under conditions where resources are limited, the SRS responses from teachers and parents can provide the child’s clinicians with very useful information, specially in the absence of a full ADOS assessment. The researchers correctly state that this does not mean that a full assessment is not necessary, but that the SRS provides an alternative for when an ADOS is not possible. Most parents know that it is sometimes difficult to find clinicians that are certified to use the ADOS, and sometimes these evaluations are prohibitively expensive when not covered by insurance.