"and some will be largely free from symptoms of the disorder by adulthood"

The quote heading this post - "and some will be largely free from symptoms of the disorder by adulthood"- comes from a seminar article published in The Lancet by Catherine Lord and colleagues [1] on the topic of autism spectrum disorder (ASD). It follows a series of review and seminar articles published in this journal down the years on the topic of autism; covering various different angles, viewpoints and opinions.

I decided to work this quote up into a short blog entry because there are a couple of important implications stemming from such sentiments that coincide with other independent research findings. Not least are the ideas that: (a) for some, autism is not a life-long condition/state/diagnosis/disorder (see here) and (b) far from being static, the presentation of autism can and does change for whatever reason(s) (see here).

There are some caveats to those 'ideas' I've just described. Not least is the 'sweeping generalisation' caution that is required when it comes to autism, and it's very, very heterogeneous nature. Autism for most/many people is a life-long condition. For many people, particularly those who are profoundly autistic, symptoms/traits/characteristics are always going to be present to a significant degree and affect their (and others) lives every single day. This is a statement of fact.

But the sentiments expressed by Lord et al recognise that even where childhood autistic symptom presentation were often severe and 'disabling', that does not mean that this will always be so for some people as they age and mature. It draws attention to the idea that whether through the process of maturation, results of intervention or other increasingly used terms like 'masking', the presentation of autistic signs and symptoms can and do change both in frequency and intensity. This idea of 'fluidity' in the presentation of autism is something that is beginning to percolate through the peer-reviewed domain. Whilst there is probably going to be a sizable contribution from issues like masking autistic signs and symptoms, there is also a realisation that people change and adapt whether in behaviour or cognitive style depending on issues such as their environment.

This line of thinking has implications. It has implications for the use of the term 'autistic identity' where people see the label/diagnosis as an essential part of who they are; much in the same way that discussions about autism and sexuality seem to be converging in a similar manner. It has implications for the provision of services, particularly those 'bean counter' discussions about autism costs over a lifetime (see here) and eligibility criteria for an increasingly finite pot of money and resources. It also has implications for the idea that autism rarely exists in some sort of diagnostic vacuum (see here), and an intriguing question about whether, as overtly presented autism signs and symptoms wane for some, other important symptoms/conditions instead become more prominent. Y'know, like anxiety (see here) and/or depression (see here) or others (see here and see here)? And I'll again throw in some research on how 'being largely free from symptoms' might also impact on other important issues related to autism (see here) mentioned in a post not-so-long-ago on the topic of depression and autism (see here).

Oh, and there's more longitudinal investigation from this research group [2] too, including the quote: "Findings suggest that some older adolescents and adults with ASD may not exhibit the same difficulties observed in young children with ASD". Discuss.

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[1] Lord C. et al. Autism spectrum disorder. Lancet. 2018 Aug 2. pii: S0140-6736(18)31129-2.

[2] Bal VH. et al. Autism spectrum disorder symptoms from ages 2 to 19 years: Implications for diagnosing adolescents and young adult. Autism Res. 2018. Aug 12.

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"psychiatric diagnoses, psychiatric care and psychotropic medication" in older age adults with autism

Is 55 years old still considered older age?

Well, according to the findings reported by Lena Nylander and colleagues [1] it represents the lower end cut-off point for their study looking at "the pattern of coexistent psychiatric diagnoses and the utilisation of psychiatric care and psychotropic medication among any individuals found to have ASD [autism spectrum disorder] diagnoses." Said individuals were aged between 55 and 96 in 2012 and "had a registered diagnosis of any ASD—defined as an ICD-10 code."

Those individuals 'found to have ASD' were located via some of those very useful Scandinavian population registries, this time based in Sweden. As a function of their registration for 'municipal services' researchers were also able to access other collected records and subsequently mined data on "gender, other psychiatric diagnoses, psychiatric care utilisation and psychotropic medication [use]" for a group of increasing research and clinical importance in the context of autism (see here).

The results proved interesting. Of the 600 people included for study, most had received a diagnosis of childhood autism (~40%), most had not received a concomitant intellectual disability (ID) diagnosis (~60%) and quite a few had received more than one 'type' of autism diagnosis (~15%).

When it came to the receipt of other psychiatric diagnoses such as affective disorder, personality disorder, anxiety or psychotic disorder, several notable observations were made. As a function of the total group, including everyone whether diagnosed with an ID or not, around 50% of participants had received at least one psychiatric diagnosis. A nebulous category defined as "other psychiatric diagnosis" was most frequently mentioned, but when it came to a named class of condition(s), affective disorders led the way in terms of frequency irrespective of the presence of ID or not. Affective disorders covers quite a bit of diagnostic ground but typically includes labels/conditions such as depression and/or bipolar disorder; conditions that are no stranger to autism (see here and see here respectively). Anxiety and psychotic disorders were also mentioned as being present among this cohort too; again not for the first time (see here and see here).

With regards to 'psychiatric care utilisation', it was more typical to see psychiatric care used than not used as nearly two-thirds of the cohort had used some kind of psychiatric care over the period included for study examination. Most were categorised as "general adult psychiatric care" and: "The group with Asperger’s syndrome had the highest number of people who had spent time as psychiatric inpatients" reflected in the odds ratio (OR) generated from the study for this group (OR: 6.87, 95% CI 3.80–12.43).

Finally, on the topic of psychotropic medication use, researchers observed that "63% of patients without registered ID diagnosis and as many as 84% of those with ID in combination with ASD had been prescribed antipsychotic medication." Antipsychotics were the most frequent medication mentioned in records, closely followed by anxiolytics (to manage anxiety) and antidepressants. Around 1 in 5 participants received more than one type of medication (irrespective of the presence of ID or not).

An important picture emerges from the Nylander findings. A picture suggesting that psychiatric diagnoses feature fairly prominently in the clinical profile of many older age adults with autism, and their identification and intervention need to be more clearly recognised. Nylander also pointed out that certain sub-groups within the autism spectrum should perhaps be more closely followed in relation to their achieving and maintaining good mental health. So, without trying to focus too much attention on one label: "It seems that the group with Asperger’s syndrome, or ASD without ID, is especially vulnerable to psychiatric disorders" on the basis that: "Only 15 individuals, or 11%, of the group with Asperger’s syndrome had not been in contact with psychiatric care, and 43% had been psychiatric in-patients, which may be interpreted as a sign of vulnerability in these individuals." That word again  - vulnerability - arises in the context of autism (see here and see here for other examples). And here is yet another example (see here) illustrating that phrases like 'high-functioning' in the context of the autism spectrum, really don't do justice to the lived experience of autism and the effects of it's important add-ons.

And on the topic of ageing and autism, and specifically ageing well, there are the findings reported by Ye In Hwang and colleagues [2] to consider, and specifically: "A very small proportion (3.3%) of autistic adults were found to be aging well."

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[1] Nylander L. et al. Older Adults with Autism Spectrum Disorders in Sweden: A Register Study of Diagnoses, Psychiatric Care Utilization and Psychotropic Medication of 601 Individuals. J Autism Dev Disord. 2018. April 16.

[2] Hwang YI. et al. Aging Well on the Autism Spectrum: An Examination of the Dominant Model of Successful Aging. J Autism Dev Disord. 2018. May 2.

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"ASD characteristics in adulthood are differently perceived across age, sex, and informants"

The research tag-team that is Anne Lever and Hilde Geurts have provided peer-reviewed fodder for this blog before (see here and see here). Without wishing to cajole their research interests into a specific box, quite a bit of their time seems to be taken up by looking at autism in the context of ageing, alongside how the label of autism does not seem to have a monopoly on the presentation of certain autistic traits.

A recent paper published by this team [1] provides yet more blogging material, specifically focused on testing "the association between age and ASD [autism spectrum disorder] characteristics, including empathy and sensory sensitivity, in adults aged 19–79 years." A scientific hat-tip is offered to other research in this area [2] that previously observed that: "older age was associated with higher ratings of ASD traits and better cognitive performance."

Drawing on data derived from a participant group numbering above 400 (N=237 with autism and N=198 without autism) spanning the age ranges, a variety of self-report and informant-report (family members, friends, other significant others) were utilised. I should point out that the autism participant group seemed to be represented by the 'more able' part of the autism spectrum (I don't use the term 'functioning') insofar as most either being diagnosed with Asperger syndrome or PDD-NOS (pervasive developmental disorder - not otherwise specified), being predominantly independent or living with a partner or housemate in residential status terms and also with that reliance on self-report used throughout the study kept in mind. This is worth knowing given other discussions on under-represented groups when it comes to scientific study (see here) and how representative autism research may or may not be to the entire spectrum.

Among the measures included for analysis we have an old favourite - the Autism-Spectrum Quotient (AQ) - as well as the Interpersonal Reactivity Index (IRI) (measuring various aspects of empathy) and the Sensory Sensitivity Questionnaire (SSQ) (examining sensory hyper- or hyposensitivity). Obtained results were collated and subjected to quite a few statistical analyses.

Results: noted as a 'group difference' findings were reported observing that: "Adults with ASD reported higher scores on the SSQ and on all subscales of the AQ than adults without ASD." This is pretty much what would be expected, despite any qualms I might have about what the AQ actually measures (see here for more of them). Sensory issues being reported as being greater in those with a diagnosis of autism also ties in well with their inclusion in the DSM-5 schedule for diagnosing autism or ASD (see here).

Then: "Within the ASD group, age-related differences were observed in self-reported ASD traits and sensory sensitivity, with a peak among middle-aged adults." Alongside that previously 'hat-tipped' study, the authors conclude that "ASD characteristics are more heavily experienced in middle adulthood than in younger or older adults." This is interesting from quite a few perspectives; bearing in mind that such findings say nothing about the expression of autism in childhood and early adulthood. Appreciating that the self-report of autism or sensory traits may not be the same as everyday autism expression, such findings *might* have some relevance to various issues such as the rise and rise of adult autism diagnoses being given and indeed, how a diagnosis of autism for some (a few?) might not be a 'lifelong' issue (see here). I know that last point raises blood pressure in some quarters as words like 'masking' are banded around (with the need for far greater study), but there is good reason to think that like many other conditions/labels, autistic behaviours and/or traits ebb and flow according to environment and perhaps other factors, such as the presentation of comorbidity for example (as per the author's other work [3] already mentioned). In short, the presentation of autism is probably dynamic and fluidic, rather than just a static thing.

Onward: "we replicated earlier findings that females with ASD had more sensory issues and reported more ASD characteristics than males... whereas females without ASD manifested fewer ASD traits than non-ASD males.". Females with ASD (74 females vs. 163 males) 'reported more ASD characteristics than males'? Intriguing - "ASD females reported higher scores than ASD males on the AQ total score" - to say the least in light of other [childhood] findings [4] but not without cautions. I go back once again the question of what the AQ is actually measuring and whether for example, the typically higher rate of mood disorders generally noted in females could be a potential confounder when it comes to AQ scores in the context of that previous reference [3] from the authors. This area requires further investigation.

Finally: "Overall, the current results show poor to fair agreement between self- and other-reports of well-known proxies, even though the agreement of the overall group was similar to those previously reported for social responsiveness." Again, some potentially important lessons to be learned here insofar as the 'meaning of autism' to a person and those around them. Indeed I note the authors' offer one explanation: "the self may be more accurate about traits that describe unobservable thoughts and feelings due to privileged access (e.g. feelings of empathy and sensory sensitivity), whereas an informant would be more accurate about observable behavior (e.g., ASD traits)." Again, jumping back into 'hot potato' territory, such a finding may have implications for the whole 'self-diagnosed vs. formal diagnosis' debate that still continues at a pace (see here).

There is quite a bit more to take in from this latest paper from Lever & Geurts and definitely some food for thought. I'll leave you however with one final quote from the authors that is perhaps one of the more important take-away points from their study: "it is important to repeatedly assess self-reported ASD characteristics during adulthood." Who would argue with that in terms of getting wants, wishes, needs and requirements accurate and up-to-date?

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[1] Lever AG. & Geurts HM. Is Older Age Associated with Higher Self- and Other-Rated ASD Characteristics? Journal of Autism & Developmental Disorders. 2018. Jan 18.

[2] Happé FG. et al. Demographic and Cognitive Profile of Individuals Seeking a Diagnosis of Autism Spectrum Disorder in Adulthood. J Autism Dev Disord. 2016 Nov;46(11):3469-3480.

[3] Geurts HM. et al. Autism Characteristics in Older Adults with Depressive Disorders. The American Journal of Geriatric Psychiatry. 2016; 24: 164-169.

[4] Øien RA. et al. Sex-Differences in Children Referred for Assessment: An Exploratory Analysis of the Autism Mental Status Exam (AMSE). J Autism Dev Disord. 2018. Feb 8.

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"a leaky gut may play a critical role in the development of age-related inflammation and frailty"

The quote heading this post is taken from the findings reported by Yanfei Qi and colleagues [1] who set out to investigate whether "an aging-associated leaky gut is linked to the age-related inflammation and frailty."

'Leaky gut' is still something of a contentious claim in medical and scientific circles despite some increasing evidence to say that it is a real phenomenon and potentially relevant to several conditions (see here) including some parts of the autism spectrum (see here). Although leaky gut is perhaps a slight misnomer - we all have leaky guts to some degree - the more accurate term 'intestinal hyperpermeability' suggests that for several different reasons, parts of the gastrointestinal (GI) tract may, at times or more chronically, be slightly more permeable that they typically should be. This in turn means that the contents of the GI tract - food derivatives, gut bacteria, etc - might be more readily exposed to parts of the body that they really shouldn't be and onward, potentially pathogenic.

Qi et al carried out some important analysis on two cohorts of differing ages (18-30 years old vs. 70 years and over) with regards to serum samples provided by participants. Markers of immune function, specifically inflammatory related compounds (e.g. tumour necrosis factor (TNF)-α and interleukin (IL)-6)) were assayed for, alongside levels of zonulin "a marker for leaky gut". Zonulin is something that I've covered quite recently on this blog in relation to autism research (see here). This biological data gathered by Qi and colleagues was also complemented by physiological measures such as "strength of plantar flexor muscles and number of steps taken per day."

Results: serum concentrations of zonulin were quite a bit - 22% - higher in the older participants compared to younger ones. Researchers also reported that levels of "high-mobility group box protein (HMGB1, a nuclear protein triggering inflammation)" were elevated in the older participants group too. They observed that zonulin levels also seemed to tie into concentrations of TNF-α and IL-6 (albeit not necessarily impressively). Zonulin levels also showed a potentially important *relationship* with "habitual physical activity" (those 'steps per day' data that was collected). The conclusion: "Serum zonulin was associated with both systemic inflammation and 2 key indices of physical frailty. These data suggest that a leaky gut may play a critical role in the development of age-related inflammation and frailty."

This is interesting stuff. It kinda accords with other independent data suggesting that generally speaking, gut barrier function does not necessarily have to deteriorate with age, but under certain circumstances such as age + inflammation, there might be effects to had [2]. Certain classes of medication might also show some involvement in this process too [3]. Although by no means a universal connection, I was interested in these results in the context of autism. Specifically how those Esnafoglu et al findings [4] reporting on 'significantly higher' serum zonulin levels in their cohort with autism, might also tie into reports of inflammatory markers being elevated in at least a subgroup of those on the autism spectrum (see here for example). I'd like to see the Qi study replicated with quite a few different labels and subgroups within labels...

In relation to the suggestion that serum zonulin levels negatively correlated with habitual physical activity (steps per day), again, there is a whole other research agenda to be [cautiously] followed. It's already known that certain patterns of exercise can affect (increase) intestinal permeability [5] although the specifics still require quite a bit more investigation (hint: exercising for 2 hours plus at a time is probably not great for gut function). As with everything in life, there is a balance to be struck between too little and too much of a good thing...

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[1] Qi Y. et al. Intestinal Permeability Biomarker Zonulin is Elevated in Healthy Aging. J Am Med Dir Assoc. 2017 Jul 1. pii: S1525-8610(17)30297-9.

[2] Valentini L. et al. Small intestinal permeability in older adults. Physiol Rep. 2014 Apr 22;2(4):e00281.

[3] Meier J. & Sturm A. The intestinal epithelial barrier: does it become impaired with age? Dig Dis. 2009;27(3):240-5.

[4] Esnafoglu E. et al. Increased Serum Zonulin Levels as an Intestinal Permeability Marker in Autistic Subjects. J Pediatr. 2017 May 11. pii: S0022-3476(17)30487-0.

[5] Costa RJS. et al. Systematic review: exercise-induced gastrointestinal syndrome-implications for health and intestinal disease. Aliment Pharmacol Ther. 2017 Aug;46(3):246-265.

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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).

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[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.

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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 brain levels of vitamin B12 in autism

I have to thank Dr Malav Trivedi for bringing my attention to some recent findings reported by Yiting Zhang and colleagues (including Malav) [1] (open-access) suggesting that: "levels of vitamin B12, especially its MeCbl [methylcobalamin] form, decrease with age in frontal cortex of control human subjects."

Further, researchers reported: "abnormally lower total Cbl [cobalamin] and MeCbl levels in subjects with autism and schizophrenia, as compared to age-matched controls." Some media on the findings can also be read here.

Working from the lab of Dr Richard Deth (quite a familiar name to this blog), researchers initially analysed a most precious sample medium (postmortem brain samples) obtained from various biobanks and including various patient groups. So alongside samples from 12 children with autism were samples from 9 people diagnosed with schizophrenia and some 43 'controls' with ages ranging between 19 weeks old and 80 years old. "Changes in Cbl species were compared with the status of methylation and antioxidant pathway metabolites" accompanied by data derived from a knock-out mouse model: "the influence of decreased GSH [glutathione] production on brain Cbl levels was evaluated in glutamate-cysteine ligase modulatory subunit knockout (GCLM-KO) mice in which GSH synthesis was impaired, leading to a brain GSH level decrease of 60–70%."

Looking at postmortem frontal cortex brain samples, researchers reported that finding on levels of vitamin B12 - particularly the MeCbl vitamer -  decreasing with age. Bearing in mind the relatively small participant numbers included, the idea that lower brain tissue levels of total cobalamin and methylcobalamin were also present (almost unanimously) in the autism and schizophrenia groups could be important. I might at this point direct readers to previous discussions on vitamin B12 and autism on this blog (see here) including the research idea of supplementing (see here) with no medical advice given or intended.

There are a few other details worth pointing out from the Zhang findings. Analysis of thiols in brain samples across the autism vs control group revealed some potentially interesting data. So, methionine levels were quite a bit lower in the autism group [significantly lower] as were levels of "the methyl donor S-adenosylmethionine (SAM)." Both these compounds form an important part of the whole 'methylation of DNA' process (see here) among other things.

Glutathione, a compound that has seen its fair share of speculation with autism in mind (see here), was also on the research menu in the Zhang study. Interestingly and again bearing mind the small participant numbers, brain levels of this stuff were lower in the autism group as a whole but not significantly so when compared to controls. This finding might map on to other brain studies with autism in mind (see here). Likewise, cysteine (another potentially relevant compound to some autism) produced a similar finding.

I would encourage readers to take some time looking at the Zhang paper. In conjunction with other results reporting on some important elements to the emerging story (see here) I believe there are further studies to be done applicable to the notion that: "impaired methylation may be a critical pathological component" for at least some autism (see here). Indeed, other research papers have also discussed this issue [2]. The idea that studies about human ageing may likewise be informative to autism (and schizophrenia) research also carries quite a lot of traction too.

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[1] Zhang Y. et al. Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia. PLoS One. 2016 Jan 22;11(1):e0146797.

[2] Keil KP. & Lein PJ. DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? Environmental Epigenetics. 2016; 1-15.

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Zhang Y, Hodgson NW, Trivedi MS, Abdolmaleky HM, Fournier M, Cuenod M, Do KQ, & Deth RC (2016). Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia. PloS one, 11 (1) PMID: 26799654

Vitamin D and cognitive function (again)

Today I'd like to draw your attention to the paper by Natasja van Schoor and colleagues [1] and some further potential support for the idea that vitamin D levels might have some important connections to cognitive functioning.

I've tackled this subject before on this blog (see here) and specifically the idea that functional vitamin D levels below a certain point might 'correlate' with poorer cognitive functioning. This time around van Schoor et al report findings based on data collected from the "Longitudinal Aging Study Amsterdam (LASA)", an initiative that aimed to specifically look at 'the predictors and consequences of aging'.

Based on various measures of cognitive functioning and serum levels of 25-hydroxyvitamin D (25(OH)D) "determined using a competitive protein binding assay", researchers concluded that lower levels of vitamin D - "below 30 nmol/L" - seemed to be linked to poorer cognitive functioning and slower information processing speeds. Further, the authors suggest that serum levels of vitamin D in the range of "about 60 nmol/L" might be something to aim for when it comes to optimal functioning on tests of cognitive ability. I might add that these days we have much more accurate methods for assaying for vitamin D levels than were used in the van Schoor study.

I don't want this post to turn into some advert for vitamin D as being a nootropic of choice on the basis of these and other research results. Cognitive tests might be a good indicator for cognitive ability but that does not mean that everyone who is vitamin D insufficient or deficient is somehow less cognitively 'able' than those with higher levels. I doubt very much that nature designed things so simple.

That all being said, it is getting difficult to ignore the accumulating evidence suggesting that vitamin D levels may indeed confer something of an effect on cognitive ability even if with specific groups in mind (based on age for example). The idea of a 'connection' opens up some intriguing possibilities on how vitamin D may have quite a few more extra-skeletal effects than we've all perhaps appreciated. Indeed, perhaps the most intriguing prospect is that of another association - between vitamin D and frailty [2] - and how it might bridge the proposed association between frailty and cognitive impairment [3] for example.

As if to prove a point, yet more research has been published at the time of writing this post with vitamin D status and cognitive functions in mind [4] focussed on mild cognitive impairment and Alzheimer's disease. Add it to the list by all means; indeed without wishing to make connection where none may exist, I'd be minded to suggest that talk of microglia being linked to [some] cases of Alzheimer's disease (see here) may well benefit from future study of a possible vitamin D - microglia connection too [5].

Music: Shakira - Can't Remember to Forget You.

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[1] van Schoor NM. et al. Cross-sectional and longitudinal associations between serum 25-hydroxyvitamin D and cognitive functioning. Int Psychogeriatr. 2015 Dec 22:1-10.

[2] Wong YY. et al. Low vitamin D status is an independent predictor of increased frailty and all-cause mortality in older men: the Health in Men Study. J Clin Endocrinol Metab. 2013 Sep;98(9):3821-8.

[3] Robertson DA. et al. Frailty and cognitive impairment--a review of the evidence and causal mechanisms. Ageing Res Rev. 2013 Sep;12(4):840-51.

[4] Yeşil Y. et al. Vitamin D status and its association with gradual decline in cognitive function. Turk J Med Sci. 2015;45(5):1051-7.

[5] Hur J. et al. Regulatory Effect of 25-hydroxyvitamin D3 on Nitric Oxide Production in Activated Microglia. Korean J Physiol Pharmacol. 2014 Oct;18(5):397-402.

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van Schoor NM, Comijs HC, Llewellyn DJ, & Lips P (2015). Cross-sectional and longitudinal associations between serum 25-hydroxyvitamin D and cognitive functioning. International psychogeriatrics / IPA, 1-10 PMID: 26691864

Significantly shorter leukocyte telomere length in childhood autism

"These results provided the first evidence that shorter leukocytes telomere length is significantly associated with childhood autism." So said the results reported by Zongchang Li and colleagues [1] (open-access) based on quite a well-powered study (for an initial research foray anyway) looking at "110 autism patients (male 98 and female 12) and 129 healthy controls (male 98 and female 31)".

On the behalf of scientists everywhere,
I am ashamed to count you amongst us.

Quite a good introduction to telomeres can be found here and how: "Telomeres have been compared with the plastic tips on shoelaces, because they keep chromosome ends from fraying and sticking to each other, which would destroy or scramble an organism's genetic information." Because I couldn't have said it better myself, I won't try, other than to direct you to some of the other collected research on telomere length being related to all-manner of things including ageing [2], schizophrenia [3] and possibly even social environment [4].

The Li paper is open-access but here are a few pointers:

• Based on the fact that: "increasing evidence has demonstrated that leukocytes telomere length is also associated with increased risk of some psychiatric diseases including schizophrenia, mood disorders and anxiety disorders" authors set about looking at leukocytes telomere length (LTL) in cases of paediatric autism compared with aged-matched asymptomatic controls. Clinical assessment of autism by the way, was based on DSM-IV criteria as well as assessment "using the childhood autism rating scale (CARS) and autism behavior checklist (ABC)."
• Real-time PCR was the analytical weapon of choice for looking at relative telomere length (RTL) - "a modified version of the quantitative real-time PCR method originally described by Cawthon" [5] apparently - though I hasten to add, that I'm no expert on the ins-and-outs of this technique.
• Results: "there was a significantly shorter leukocyte telomere length in patients with childhood autism" compared with controls. Taking it another way: "When participants were divided into long and short groups according to the median RTL value of healthy controls, we observed a significantly increased presence of autism for individuals with shorter RTL... compared with those with longer RTL." The age side of things also seemed to hold true for the Li results as per their results revealing: "a significant inverse correlation between RTL and age in controls". You will however note the 'in controls' part of that last sentence which did not hold [significantly] true for autism cases.
• Interestingly, authors also reported that: "among the subjects with childhood autism those who received family training interventions have significantly longer RTL than those without family training interventions." They did find that clinical symptoms were decreased in those taking part in such intervention but drew back from suggesting a link given that lower clinical symptoms scores were also noted in those with "medication exposure" without any corresponding effect on RTL.
• The conclusion: a bit of a first attempt looking at telomere length in relation to autism finding something potentially important but with the need for further, independent replication. Also, a little more investigation on the hows, whys and implications of such results are required.

The first thing that crossed my mind having read the Li paper was the the idea that shorter telomere length is related to DNA damage and "genomic instability" and how that might play out with regards to autism. Not so long ago on this blog, I discussed the recent paper by Penelope Main and colleagues [6] (see here) who, from a slightly different analytical perspective, concluded: "it appears unlikely that genomic instability is a feature of the aetiology of autism". Quite the contrast by all accounts.

That being said, Li et al do discuss the possibility that: "telomeric DNA was highly sensitive to be damaged by the oxidative stress" which does bring their results and other findings from Main and colleagues [7] potentially back into some sort of stellar alignment as linking back into quite a body of research talking about oxidative stress and autism in mind [8]. I say that acknowledging that there is much more research to do in this area but templates for such an association might already exist [9] in the peer-reviewed arena.

Again, perhaps showing my lack of insight into this area, a quick read around this topic also pointed to another possible area of interest when it comes to telomeres and autism: telomerase. This enzyme which apparently might serve as a bit of a double-edged sword when it comes to reversing ageing (see here) but also being a key expression ingredient in tumor cells (see here), has something of an important effect on telomeres with regards to prevent shortening. As far as I can ascertain, the sum total of current research on telomerase and autism is zero aside from peripheral discussion of issues with genes such as PINX1 noted in some cases of autism and it's described inhibition of telomerase activity [10]. I'd be minded to suggest that looking at the activity of telomerase as well as telomere length might be an important part of any future scientific inquiry with autism in mind.

I might also suggest that further research inquiry be focused on the possible ways and means that telomere length might be affected by intervention as per the possible effects from family intervention detailed in the Li data. I'm not specifically talking about the psychological aspects, which I'll leave others to decide whether they're important or not, but rather other data on for example, how exercise might show a beneficial effect on telomere length [11] and whether this might be pertinent to at least some cases of autism (see here). Dare I also even mention the possible relation between vitamin D and telomeres [12] again in light of some recent findings with autism in mind, bearing in mind correlation is not the same as causation?

Finally: a paradox... The 'Leukocyte Telomere Length and the Father’s Age Enigma' [13]? Older fathers apparently pass on longer telomeres to their offspring, but older paternal age is also apparently a risk factor for autism. OK, the Li paper looked at telomere data in children with an average age of about 4 years so there may be some scope for factors to affect telomere length in the time from entry into the world. They also did report on father and mother age for autism participants (see here) but not for controls so unfortunately we can't say too much more on that topic. Again, perhaps something to be looked at in subsequent studies?

Music to close: Street Fighting Man by the Stones (with hat-tip to Fantastic Mr Fox).

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[1] Li Z. et al. Shorter telomere length in peripheral blood leukocytes is associated with childhood autism. Sci Rep. 2014 Nov 17;4:7073.

[2] Müezzinler A. et al. A systematic review of leukocyte telomere length and age in adults. Ageing Research Reviews. 2013; 12: 509–519.

[3] Kota LN. et al. Shortened telomere in unremitted schizophrenia. Psychiatry Clin Neurosci. 2014 Nov 27. doi: 10.1111/pcn.12260.

[4] Mitchell C. et al. Social disadvantage, genetic sensitivity, and children’s telomere length. PNAS. 2014; 111: 5944–5949.

[5] Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res. 2002 May 15;30(10):e47.

[6] Main PA. et al. Lack of Evidence for Genomic Instability in Autistic Children as Measured by the Cytokinesis-Block Micronucleus Cytome Assay. Autism Res. 2014 Nov 4. doi: 10.1002/aur.1428.

[7] Main PA. et al. Necrosis is increased in lymphoblastoid cell lines from children with autism compared with their non-autistic siblings under conditions of oxidative and nitrosative stress. Mutagenesis. 2013 Jul;28(4):475-84.

[8] Rossignol DA. & Frye RE. Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Front Physiol. 2014 Apr 22;5:150.

[9] Yu WY. et al. Short telomeres in patients with chronic schizophrenia who show a poor response to treatment. J Psychiatry Neurosci. 2008 May;33(3):244-7.

[10] Zhou XZ. et al. The telomerase inhibitor PinX1 is a major haploinsufficient tumor suppressor essential for chromosome stability in mice. J Clin Invest. 2011 Apr;121(4):1266-82.

[11] Ludlow AT. et al. Do telomeres adapt to physiological stress? Exploring the effect of exercise on telomere length and telomere-related proteins. Biomed Res Int. 2013;2013:601368.

[12] Richards JB. et al. Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women. Am J Clin Nutr. 2007 Nov;86(5):1420-5.

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Li Z, Tang J, Li H, Chen S, He Y, Liao Y, Wei Z, Wan G, Xiang X, Xia K, & Chen X (2014). Shorter telomere length in peripheral blood leukocytes is associated with childhood autism. Scientific reports, 4 PMID: 25399515

Diagnosing autism late: after psychosis

The case report from Marly Simoncini and colleagues [1] (open-access) is the topic of today's post. Describing the case of Mr. A, a young man who attempted suicide during a psychotic episode, the paper tracks the developmental history and diagnostic evaluation of this person culminating in a diagnosis of autism spectrum disorder (ASD) "that had been completely overlooked".

The best thing we can do is go on with our daily routine

The paper is open-access and I would encourage readers to take some time to look through the narrative. Not only are some of the more commonly cited features of autism in childhood described in the paper as per his toy preferences and his wish to "play alone for hours with a few toys" but also other potentially important points: "He continued with selecting his food (white and squared foods only) and drinking milk only from his infant feeding bottle, until he was an adolescent". The outcome of various psychometric assessments specific to autism are also discussed, including his scores on the ADOS and ADI (see here) eventually placing him on the autism spectrum.

The important story of how this case report illustrates how much further we need to go in terms of awareness of autism across the lifespan is also complemented by the discussions on how the autism spectrum seems (in some cases) to merge with other spectrums. The authors note: "signs and symptoms of both a psychotic disorder and an ASD might run isolated or in clusters during the entire lifespan, often not reaching the threshold for a categorical diagnosis until adulthood". I might add that the 'autism overlooked' part of this study is probably not something common to modern-day autism (see here).

Treading quite carefully, I have, on a few occasions on this blog, talked about how there may overlapping presentation of autism and psychosis in some cases (see here and more recently here). Indeed not so long ago, I read a very personal account of a mother caring for a child on the autism spectrum and her experiences of a meltdown: "... apparently it used to be called ‘childhood schizophrenia’ and as I watched Ethan totally lost to me at that moment, in what looked like a possessed fit, I could see how it could have been labelled as schizophrenia". I should point out that schizophrenia is not the same as a 'possessed fit' (see here) but can, and does, present as a range of psychological symptoms as part of the psychosis spectrum (see here).

Of course, one should not forget that a diagnosis of autism is seemingly protective of nothing in terms of other somatic or psychiatric conditions to be present. It might also be nothing more than coincidence that autism and psychosis ran parallel in the case of Mr. A. That being said and on the back of other texts such as the go-to paper by Tom Berney [2], I do wonder if greater thought needs to be put into looking at autism across the lifespan. How, in amongst the sometimes fluidic changes in presentation according to factors such as maturation [3], further screening for issues such as psychosis should be more regularly implemented in order to mitigate any negative effects they may have both for the person concerned and their loved ones?

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[1] Simoncini M. et al. Lifetime Autism Spectrum Features in a Patient with a Psychotic Mixed Episode Who Attempted Suicide. Case Reports in Psychiatry. 2014: 459524.

[2] Berney TP. Asperger syndrome from childhood into adulthood. Adv Psychiatr Treat. 2004; 10: 341-351.

[3] Helles A. et al. Asperger syndrome in males over two decades: stability and predictors of diagnosis. Journal of Child Psychology and Psychiatry. 2014. 3 October.

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Simoncini, M., Miniati, M., Vanelli, F., Callari, A., Vannucchi, G., Mauri, M., & Dell’Osso, L. (2014). Lifetime Autism Spectrum Features in a Patient with a Psychotic Mixed Episode Who Attempted Suicide Case Reports in Psychiatry, 2014, 1-4 DOI: 10.1155/2014/459524

Aging in autism

Not so long ago I remember talking to a friend of mine about politics, the state of the country and a few other things as you do. Myself not being particularly political but nevertheless enjoying programmes like BBC Question Time, we happened to get on to the topic of Presidents and Prime Ministers and he came out with quite a memorable comment about wisdom and running countries. To quote: 'People who run countries should be at least 60 years old' he said. 'Only then does a person have both experience and wisdom'. Of course he is right. Indeed were his thoughts to be enshrined in various constitutional laws, I dare say we might all find ourselves in a slightly less chaotic world.

This point nicely brings me to a new paper recently published in the journal Gerontology by Francesca Happe (apologies for the lack of the acute accent on the final 'e') and Rebecca Charlton*. The paper is open-access and can be downloaded here and discusses the various research conducted on aging and autism.

I won't go into the paper point-by-point but there are some interesting findings and conclusions to be drawn from the collected works on aging in autism, some perhaps mirroring other conditions. What happens to symptoms (and comorbidities), how to ensure that services and support networks are properly positioned to meet the needs of older people with autism and probably most relevant to this blog, making sure that other conditions associated with aging are screened for and managed appropriately, to name but a few.

As the children of today move into adulthood, there is already growing interest in things like transition (school-college-big wide world), adult care and support for those who require it and the provision of suitable employment opportunities for people with autism. The Happe paper moves one step ahead of all that, to a time when people with autism are faced with the prospect that we all share, growing old, and the delights and challenges that brings.

I touched briefly on the issue of siblings and the role they will be asked to play for their brothers/sisters 'when mum and dad aren't around'. I know no-one likes to think about their own mortality; but nevertheless it is something everyone needs to plan for; parents, family, support organisations and State. Things like medicines management, mobility and access to services and quality of life are other themes that need to be considered.  With the quite astounding rise in the numbers of cases of autism witnessed worldwide over the past few years, we perhaps need to start investigating and planning now how to ensure our lifelong commitment to people with autism spectrum conditions fulfills its promises.

* Happe F. & Charlton RA. Aging in autism spectrum disorders: a mini-review. Gerontology. August 2011.