"a single intravenous infusion of autologous umbilical cord blood" and autism

'Could stem cells offer hope for autism?' went one media headline referencing the very preliminary "phase I, open-label trial" published by Geraldine Dawson and colleagues [1] (open-access) detailing the experiences of a single intravenous infusion of autologous umbilical cord blood in 25 children with "a confirmed diagnosis of ASD [autism spectrum disorder]."

Well, the results were promising in respect of important issues such as safety in light of the tenet 'first do no harm': "Assessment of adverse events across the 12-month period indicated that the treatment was safe and well tolerated" and some potentially interesting effects were noted when it came to behaviour "across a wide range of outcome measures in this study." But much like another quite innovative study with a similar research design published quite recently (see here) one needs to be a little cautious about the limitations of this current study. Not least that: "As an uncontrolled open-label study, it is not possible to determine whether the observed behavioral changes were due to the treatment or reflect the natural course of development during the preschool period." I might add that any study mentioning the words 'stem cells and autism' in the same sentence is going to be subject to significant scrutiny (see here for example).

Although the Dawson paper is open-access, here are a few choice details:

• "All participants had to have an available autologous umbilical cord blood unit banked at a family or public cord blood bank."  This was a study using the participants own stored cord blood - blood 'left over' from the umbilical cord and/or placenta at birth - which was initially screened to make sure it was both viable and safe: "negative maternal infectious disease markers tested on the maternal donor or cord blood product (minimally including hepatitis B, hepatitis C, human immunodeficiency virus [HIV], human T-lymphotrophic virus [HTLV], and syphilis)." Cord blood contains stem cells; cells that have significant [mighty] morphing capabilities in terms of turning into different cell types. In amongst the various peer-reviewed research (and research hype) surrounding stem cells, their use with autism in mind has been slowly creeping into the public consciousness (see here for example) with appropriate caveats.
• Participants were given one infusion of their cord blood samples. They were fairly closely monitored over the study duration to ensure that any adverse effects (AEs) were catalogued. Researchers reported: "A total of 92 AEs were reported in 23 participants... with a median of three events per participant. All events were graded as Mild (71 events) or Moderate (21 events)." Further: "Twelve events (13%) were considered related to the infusion, with the most common being allergic reaction, manifested by urticartia and or/cough occurring on the day of infusion (5 events in 4 participants; all Mild; 2 requiring an additional dose of IV Benadryl). The most common unrelated AEs were agitation, skin changes, and typical childhood infections, reported between 2 days and 1 year post-infusion."
• Alongside looking for AEs, authors also reported some changes to the various behavioural schedules included for study. Looking at scores at baseline (pre-infusion) and then at 6 and 12 months, a pattern started to emerge based on group results. So: "Most of the observed behavioral changes occurred during the first 6 months and were sustained between 6 and 12 months post-infusion." The direction of the behavioural change were all positive (i.e. behavioural measures indicated improvement) and were spread out across both parent-reported and clinician-reported schedules. Interestingly too, eye gaze measurements for some 21 participants who were scanned also showed changes: "a 20% increase in odds of gazing at the actress’ eyes over time." Researchers also noted that: "children's nonverbal IQ was correlated with change for the majority of outcomes measures, with higher nonverbal IQ being associated with greater improvements in behavior." Such a finding might also tie into some other research looking at a group termed 'optimal outcome' (see here).

There is a scheme of research required to follow this preliminary study, of that there is no doubt. We don't for example, know exactly how any behavioural changes were tied into the infusion (or not) because among other things, no other physiological measurements were made over the course of the Dawson study pointing to possible mechanisms. This is not entirely unexpected given the preliminary nature of the study. I will also stress again that these results were based on participants' own stored cord blood samples not other donor samples just in case any incorrect generalisation of results is made. As an aside, I was quite interested to see the use of IV (intravenous) Benadryl in relation to some of those AEs. Benadryl is an antihistamine used to manage allergy symptoms. I've talked before on this blog about how treating allergy issues in relation to some individual cases of autism might have some interesting effects on the presentation of autistic symptoms too (see here). I wonder...

I am assuming that there will be more to talk about in this area of autism research as a consequence of a concluding sentence made by the authors: "we have also included the clinician-rated CGI and additional measures as secondary endpoints in our next study, a phase II, double-blind randomized clinical trial designed to formally evaluate the efficacy of umbilical cord blood infusion in improving core symptoms of ASD." Accepting that there is still some PR to be done with regards to the issue of cord blood and stem cell use in relation to autism [2] (that also includes work related to modelling conditions like autism too [3]), I'll be interested to see whether the current Dawson results survive more rigorous scientific study...

To close, skin problems in Hollywood villains. No really, someone has actually studied this... 

----------

[1] Dawson G. et al. Autologous Cord Blood Infusions Are Safe and Feasible in Young Children with Autism Spectrum Disorder: Results of a Single-Center Phase I Open-Label Trial. Stem Cells Translational Medicine. 2017. April 5.

[2] Sharpe K. et al. In the Know and in the News: How Science and the Media Communicate About Stem Cells, Autism and Cerebral Palsy. Stem Cell Rev. 2016 Feb;12(1):1-7.

[3] Wen Z. Modeling neurodevelopmental and psychiatric diseases with human iPSCs. J Neurosci Res. 2017 May;95(5):1097-1109.

----------

Geraldine Dawson, Jessica M. Sun, Katherine S. Davlantis, Michael Murias,, Lauren Franz, Jesse Troy, Ryan Simmons, Maura Sabatos-DeVito, Rebecca Durham, & Joanne Kurtzberg (2017). Autologous Cord Blood Infusions Are Safe and Feasible in Young Children with Autism Spectrum Disorder: Results of a Single-Center Phase I Open-Label Trial. Stem Cells Translational Medicine : 10.1002/sctm.16-0474

Paediatric congenital heart disease and autism risk (again)

"Risk of autism spectrum disorder screening status in children with congenital heart defects was higher than expected from population rates."

So said the findings reported by Jessica Bean Jaworski and colleagues [1] who set about "to assess the rates of autism spectrum disorders in a large sample of children with a history of congenital heart defects and to assess medical, behavioral, and individual factors that may be associated with the risk of autism spectrum disorders." Covering a topic that has graced this blog before (see here) the results reiterate that there may be many roads to, and correlates associated with, a diagnosis of autism spectrum disorder (ASD). Congenital heart defects by the way, is a blanket term covering various issues related to the structure and function of the heart that are present at birth.

Based on the examination of nearly 200 children "with a history of congenital heart defects" the data produced invites quite a bit more investigation on (i) the prevalence of autism/ASD in cases of congenital heart defects and (ii) the mechanism of how said heart issues might *link* to the presentation of autism. On that last point, my previous post on this topic (see here) provided a few research ideas. Given also that congenital heart defects do require care across the lifespan, I assume that such care will also be similarly afforded to those diagnosed with a congenital heart defect and autism, save any further health inequalities appearing.

----------

[1] Bean Jaworski JL. et al. Rates of autism and potential risk factors in children with congenital heart defects. Congenit Heart Dis. 2017 Mar 16.

----------

Bean Jaworski JL, Flynn T, Burnham N, Chittams JL, Sammarco T, Gerdes M, Bernbaum JC, Clancy RR, Solot CB, Zackai EH, McDonald-McGinn DM, & Gaynor JW (2017). Rates of autism and potential risk factors in children with congenital heart defects. Congenital heart disease PMID: 28299880

Autism, ageing and comorbidity

I'm not spending too much time today on the findings published by Elizabeth Wise and colleagues [1] but did want to bring them to your attention. Looking at the presentation of "comorbidities and behavioral and neuropsychiatric symptoms" in relation to autism in the context of ageing, some important details were noted. Not least that "GI [gastrointestinal] disorders (68.9%) and seizure disorders (23%) were common, and 25.7% of the sample had a BMI [body mass index] >30" when looking at their 74 strong cohort of adults diagnosed with autism (DSM-5 autism by all accounts).

It's not new news that the label of autism rarely exists in some sort of diagnostic vacuum (see here and see here for other examples). The fact that GI disorders (whether functional or more pathological), epilepsy and/or seizure disorder and excess BMI have been picked out by Wise et al ties into an extensive peer-reviewed research body highlighting such issues. What is still missing from quite a lot of that literature is the hows-and-whys of such over-represented comorbidity and importantly, what can be done to manage/ameliorate them (see here for example) given that sometimes they can be just as 'disabling' as a diagnosis of autism itself.

Wise and colleagues also noted that: "the point prevalence of behavioral and neuropsychiatric symptoms (BNPS) declined significantly for 12 of 13 BNPS over a mean of 25 years while many other features of ASD remained stable." Accepting the relatively small cohort studied, this is an interesting finding and ties into other research looking at what happens to something like psychiatric comorbidity in the context of ageing and autism (see here). There is a caution attached to the idea that behavioural and psychiatric comorbidity might be quite fluid across the lifespan in relation to autism insofar as sex/gender potentially being an important variable (see here).

----------

[1] Wise EA. et al. Aging and Autism Spectrum Disorder: A Naturalistic, Longitudinal Study of the Comorbidities and Behavioral and Neuropsychiatric Symptoms in Adults with ASD. J Autism Dev Disord. 2017. Mar 16.

----------

Wise EA, Smith MD, & Rabins PV (2017). Aging and Autism Spectrum Disorder: A Naturalistic, Longitudinal Study of the Comorbidities and Behavioral and Neuropsychiatric Symptoms in Adults with ASD. Journal of autism and developmental disorders PMID: 28303420

Decreased urinary creatinine levels associated with autism (again)

One finding in particular stood out from those reported by Lussu and colleagues [1] following some nifty metabolomic investigations: decreased levels of urinary creatinine in their cohort of participants diagnosed as on the autism spectrum (n=21) compared with "controls (n = 21), these being siblings of autistic patients."

Based on the "use of 1 H-NMR metabolomics to analyze the global biochemical signature of ASD [autism spectrum disorder] patients" researchers turned again to a favourite topic of this blog - metabolomics -  and how the detection and identification of small molecules in various biofluids (urine, blood, saliva, etc) might be particularly informative. Metabolomics is, in essence, all about two things: (i) the analytical technology used to analyse a sample and (ii) the statistical technology used to make sense of the chemical analysis. If one assumes that a biofluid like urine literally contains thousands of compounds and small molecules, you get a flavour for the task facing researchers in this area.

I've talked metabolomics a few times on this blog with autism in mind (see here and see here for examples) but have chosen to zoom in on the Lussu findings in relation to an interesting compound called creatinine. Creatinine is a break-down product of creatine phosphate typically found in muscle. It's generally used as a rough-and-ready guide to the dilution of a urine sample given that it is produced at quite constant rate (see here).

In my day job, I continue to have some interest when it comes to creatinine (urinary) in the context of autism as per some research published a decade or so back [2]. My colleagues and I reported: "Controlling for sample pH and body mass index [BMI], a significant decrease in urinary creatinine concentration was found in the PDD [pervasive developmental disorder] group compared to controls." Other [independent] researchers have also reported similar things [3] when it comes to blood levels of creatinine in the context of autism.

Unfortunately I don't yet have a good explanation as to why creatinine seems to be on the low side when it comes to at least some autism bearing in mind issues such as BMI can seemingly affect values. I do find in interesting that muscle mass may have a bearing on urinary creatinine excretion and could perhaps stretch an association with [some] autism on the basis of more generalised issues with muscle function or tone (see here). That low urinary creatinine *may* also point to issues with kidney function is also interesting and invites quite a bit more study on this organ in relation to autism...

Music: Acceptable in the 80's.

----------

[1] Lussu M. et al. The urinary 1 H-NMR metabolomics profile of an italian autistic children population and their unaffected siblings. Autism Res. 2017 Mar 11.

[2] Whiteley P. et al. Spot urinary creatinine excretion in pervasive developmental disorders. Pediatr Int. 2006 Jun;48(3):292-7.

[3] West PR. et al. Metabolomics as a tool for discovery of biomarkers of autism spectrum disorder in the blood plasma of children. PLoS One. 2014 Nov 7;9(11):e112445.

----------

Lussu M, Noto A, Masili A, Rinaldi AC, Dessì A, De Angelis M, De Giacomo A, Fanos V, Atzori L, & Francavilla R (2017). The urinary 1 H-NMR metabolomics profile of an italian autistic children population and their unaffected siblings. Autism research : official journal of the International Society for Autism Research PMID: 28296209

On the under-studied populations within the autism spectrum

I don't typically post on a Sunday, but given that today - 2nd April - is World Autism Awareness Day I've decided to make an exception. The theme of today's post is based around the notion that the autism spectrum is truly wide and heterogeneous, and although this is fairly universally acknowledged, the current peer-reviewed research literature on autism is perhaps not yet so accepting. So...

Consistent with the idea that scientific research seems to go through cycles of themes/interests, the commentary paper by Bhismadev Chakrabarti [1] (open-access) continues an important theme talking about the representativeness of autism research (see here). Specifically how: "Research on the autistic phenotype has focused mostly on higher functioning individuals on the spectrum, neglecting those on the lower end."

OK, first things first. The idea of 'functioning' in relation to the autism spectrum is something that some people (including myself) find a little problematic. Yes, I know what it is trying to describe in terms of ability levels, adaptive skills and the level of support seemingly required as examples. But like many things when it comes to the autism spectrum, the [sweeping] generalisation that high-functioning autism automatically means 'can function' autism and low-functioning autism conversely means 'can't' doesn't really do justice to the complexity underneath such categorisations. I say all that acknowledging that no simple, viable alternative currently exists to replace 'functioning' at the present time.

Chakrabarti takes the reader through the issues of research representativeness based on the findings reported by Jack & Pelphrey [2] and their research review of neuroimaging studies in relation to autism. They concluded that: "There is a paucity of neuroimaging research on ASD [autism spectrum disorder] + ID [intellectual disability], ASD + MV [minimally verbal], and ASD + R [developmental regression], and what findings do exist are often contradictory, or so sparse as to be ungeneralizable."

I'm gonna pull out a couple of key points raised by Chakrabarti that are worthy of lots more research and clinical inspection.

First: "Should we be thinking of these different populations (MV, R and ID) as distinct subgroups within ASD?" Set within the context of 'the plural autisms' (see here) and how autism as a singular label seems to have very little usefulness as a research starting point (see here), it strikes me that Chakrabarti's suggestion of 'phenotypic dimensions' is quite a good one. The fact that developmental regression gets a look-in is also quite important (see here and see here) (no, not every single case of autism was present before or at birth/early infancy).

Second, on the question of 'neuroimaging phenotypes' akin to some of the parameters set out in the RDoC alternative to DSM (see here) I think we have to wait and see. From what we already know about neuroimaging results when it comes to the autism spectrum as a whole, there is no one 'brain area' seemingly linked to all diagnoses of autism (see here) as things currently stand, bearing in mind the limitations of the technology currently used. I don't doubt however that specific groups of people on the autism spectrum might be more likely to show definite collective brain pathology (see here) particularly where certain over-represented comorbidity might complete the clinical picture. The current state of findings in this area also has implications for the use of problematic terms such as 'neurotypical' to denote not-autism (I personally have no idea what neurotypical looks like on a brain scan nor in terms of development, behaviour, maturation or comorbidity).

I'm hoping that papers/commentaries such as the one from Chakrabarti are a call to action when it comes to making autism research 'work' for everyone on the autism spectrum. That and acknowledging that the existing - skewed - research base might be missing some important details when it comes to the very wide and very heterogeneous autisms...

To close and without getting too political, I want to link to a piece that was published in the Huffington Post this week (see here) discussing the idea of 'celebrating' world autism awareness day. It's something that I've seen quite a lot of these past years. Reiterating that the autism spectrum is indeed wide and heterogeneous, I found the article to very moving particularly the writer's notion that: "What I will do is celebrate my son for who he is... But I won’t celebrate the struggles we call autism." Appreciating that autism as a label is 'identity' for some on the spectrum, such sentiments reaffirm the requirement to ensure that all voices on the autism spectrum are heard, and that 'celebration' is reserved for people and their achievements, not their labels...

----------

[1] Chakrabarti B. Commentary: Critical considerations for studying low-functioning autism. J Child Psychol Psychiatry. 2017 Apr;58(4):436-438.

[2] Jack A. & A Pelphrey K. Annual Research Review: Understudied populations within the autism spectrum - current trends and future directions in neuroimaging research. J Child Psychol Psychiatry. 2017 Apr;58(4):411-435.

----------

Chakrabarti B (2017). Commentary: Critical considerations for studying low-functioning autism. Journal of child psychology and psychiatry, and allied disciplines, 58 (4), 436-438 PMID: 28346760

Yet more bumetanide and autism findings

Bumetanide, a loop diuretic medicine typically used to treat heart failure, is probably not something that most people would associate with 'attenuating' some of the presented characteristics of autism. This Na-K-Cl cotransporter (NKCC) blocking drug (influencing chloride concentrations in neurons and impacting on the actions of gamma-Aminobutyric acid, GABA) has however made quite a few appearances in the peer-reviewed autism research literature (see here and see here) and beyond (see here). The results of a further "multicenter phase 2B study primarily to assess dose/response and safety effects of bumetanide" in relation to autism [1] (open-access) add to the research in this area.

The names on this recent paper are familiar ones to the bumetanide-autism story as 'dose' and 'adverse effects' were the primary factors in this most recent gold-standard "double-blind, randomized, placebo-controlled, multisite dose-ranging study." Looking at some 88 participants diagnosed with an autism spectrum disorder (ASD) and "spanning across the entire pediatric population (2–18 years old)" various doses of [liquid] bumetanide or a placebo were given over 3 months. Assessments were carried out using various schedules including the Childhood Autism Rating Scale (CARS). As per the 'phase 2B' status of this research, the name of the game was optimising effective dosage of bumetanide against safety (side-effects) including gathering data on pharmacokinetics.

Results: "our results showed that bumetanide is safe but is associated with adverse events related to diuresis and dehydration." It's perhaps not surprising that a medicine classed as a loop diuretic does what it says on the tin. Authors describe various adverse effects - treatment emergent adverse events (TEAEs) - associated with bumetanide use: "The most frequent adverse events were hypokalemia, increased urine elimination, loss of appetite, dehydration and asthenia." Several participants withdrew from the study as a result of them.

Further: "The results of this dose-ranging study demonstrated the highest efficacy of bumetanide 2 mg twice a day on both primary and secondary end points." Various improvements were noted in the CARS and other scores as a consequence of the use of bumetanide (at various dosages): "23 bumetanide-treated and only one placebo showed more than six-point reduction in CARS from screening to day 90."  Marrying the safety (TEAEs) and effectiveness data (CARS et al) together, the authors concluded that: "bumetanide improves the core symptoms of ASD and presents a favorable benefit/risk ratio particularly at 1.0 mg twice daily."

I know for some any adverse effects from a 'treatment' option with autism in mind is going to be too much. I respect this view particularly in light of the medical tenet: first do no harm. But I don't think these latest results from Lemonnier and colleagues can just be ignored in terms of the potential hows-and-whys of response to bumetanide in relation to the presentation of autistic behaviours. Many (all) medications 'indicated' for the management of core or peripheral features associated with a diagnosis of autism have a risk profile attached to them (see here for example) but are still often quite widely used. This is not an excuse, just a statement of fact until someone, somewhere develops side-effect free versions of medicines in use. There is also another angle to this 'risk' profile to consider: "There was no simple relation between TEAEs and efficacy." What this tells us is that those 'best' responders to bumetanide were not necessarily the same participants who experienced adverse effects from the [active] medication; for example: "none of the moderate hypokalemic patients (<3 mm l−1) were high responder patients with at least 6 points in CARS change from screening to day 90." Sweeping generalisations are not required.

Where next for bumetanide?  Well, I don't doubt we will be hearing more from this group as they report: "this trial must be viewed as a source of data on the safety and dose-ranging usage of bumetanide and it provides further support to justify a large multisite European Phase III trial." Large, multi-centre trials are both expensive and take a considerable amount of planning so I'm not expecting to see anything too soon. But I don't think we've heard the last of bumetanide and autism...

----------

[1] Lemonnier E. et al. Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders. Translational Psychiatry. 2017; 7: e1056.

----------

Lemonnier, E., Villeneuve, N., Sonie, S., Serret, S., Rosier, A., Roue, M., Brosset, P., Viellard, M., Bernoux, D., Rondeau, S., Thummler, S., Ravel, D., & Ben-Ari, Y. (2017). Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders Translational Psychiatry, 7 (3) DOI: 10.1038/tp.2017.10