Dementia risk in adult ADHD

"Adults with ADHD [attention-deficit hyperactivity disorder] have a 3.4-fold risk of developing dementia."

That was the conclusion reached by Nian-Sheng Tzeng and colleagues [1] who applied the 'big data' power of the Taiwanese National Health Insurance Research Database (NHIRD) to the question of whether yet more enhanced risk of adversity might be associated with a diagnosis of ADHD. Dementia by the way, reflects various symptoms/conditions pertinent to the decline of cognitive and other abilities.

Drawing on participant numbers in the hundreds, researchers determined that the risk of receipt of a dementia diagnosis in cases of adult ADHD was marginally higher compared with an asymptomatic (asymptomatic for ADHD) control group (5.4% vs. 4%). An association between ADHD diagnosis and risk of subsequent dementia remained after various, potentially interfering variables, were also taken into consideration ("age, gender, comorbidities, geographical area of residence, urbanization level of residence, and monthly income").

This is not the first time that enhanced risk of dementia in ADHD has been discussed in the peer-reviewed domain [2]. As per that previous report from Golimstok and colleagues - "there is no clear explanation for the association found" - science still does not have many clues as to why ADHD might preferentially predispose to certain types of dementia. I say this on the basis that we don't really know that much about the biology of either condition/diagnosis. That's not however to say that science is not getting closer to some important clues, as the report from Zhang and colleagues [3] talking about an animal model of Alzheimer's disease that also had "a high frequency of antecedent ADHD symptoms" is detailed. More studies are indicated.

To close, a link to an article marking the recent passing of the father of the ADHD diagnosis: Keith Conners together with a warning...

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[1] Tzeng NS. et al. Risk of Dementia in Adults With ADHD: A Nationwide, Population-Based Cohort Study in Taiwan. J Atten Disord. 2017 Jun 1:1087054717714057.

[2] Golimstok A. et al. Previous adult attention-deficit and hyperactivity disorder symptoms and risk of dementia with Lewy bodies: a case-control study. Eur J Neurol. 2011 Jan;18(1):78-84.

[3] Zhang Q. et al. Alzheimer's Model Develops Early ADHD Syndrome. J Neurol Neurophysiol. 2015;6(6):1-6.

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Vitamin D deficiency and dementia risk: a micropost

I'm a little late in getting to the paper by Thomas Littlejohns and colleagues [1] (open-access) reporting that: "vitamin D deficiency is associated with a substantially increased risk of all-cause dementia and Alzheimer disease". The media have been all over this study as per the BBC commentary (see here) and some rather more critical discussion by the NHS Choices website (see here).

I don't need to add anything further to discussions aside from saying that correlation might not necessarily be the same as causation and any mechanism linking vitamin D status and cognitive abilities is still something to be determined. But that's not to say that there aren't interesting things afoot for vitamin D outside of it's more traditional skeletal effects...

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[1] Littlejohns TJ. et al. Vitamin D and the risk of dementia and Alzheimer disease. Neurology. 2014. August 6.

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Stop that phenylalanine now!

I'm going slightly off-piste with this post not strictly related to autism; however remaining true to my interest in all things amino acids, and in particular one of those most interesting aromatic amino acids, phenylalanine.

Phenylalanine @ Wikipedia

A few months back Chemistry World carried a very interesting article by Jon Evans* on how the amino acid phenylalanine might very well have the capacity to form amyloid-like fibrils classically related to conditions like Alzheimers disease. The article was based on this study by Adler-Abramovich and colleagues** which reported on a few pretty important observations.

I've done amyloid or rather amyloid precursor protein (in relation to autism) on this blog before (see here). Fibrils as their name suggests, are fibre-like structures. Without trying to plagiarise the article or study, a few points are worth noting:

• The starting point was the metabolic condition phenylketonuria (PKU), probably the most famous of the inborn errors of metabolism.
• PKU... the problems with metabolising phenylalanine as a result of issues with phenylalanine hydroxylase leads to a build up of the amino acid which has some particularly nasty effects on the developing body and brain. Said phenylalanine levels normally controlled by lifetime dietary restriction of phenylalanine but also potentially another intervention (BH4).
• Adler-Abramovich et al observed that phenylalanine in solution tended to 'clump' together forming something that looked like amyloid-like fibrils. Further when such phenylalanine fibrils were added to cell lines, the fibrils showed some degree of toxicity. Even further, rabbits injected with said fibrils started to generate antibodies against them. Finally, after imaging the phenylalanine fibrils, there was a match between what they saw in the laboratory and what they saw in an engineered mouse model of PKU and indeed in real people diagnosed with PKU.
• Ipso facto: phenylalanine can form amyloid-like fibrils and such fibrils might account for the tissue damage observed in PKU.

I admit to being really quite excited about this work. Modern science knows quite a bit about PKU following the very astute observations made by Dr. Asbjørn Følling. One area however that has always required a little more study was exactly how the build-up of phenylalanine caused the problems that it does; maybe part of that question has been answered with this work.

My mind also goes back to those other aromatic amino acids like tryptophan and tyrosine and whether similar fibrils could be formed from these compounds. The answer, according to the published scientific literature so far, is a very possible yes; as per studies like this one from Cecchini and colleagues*** although quite a lot of the investigations in this area goes well above my state of knowledge.

So, once again amino acids do their stuff. It makes you wonder whether Alzheimer's disease, at least some cases, might also reflect issues with phenylalanine. Logically also whether interventions like a low phenylalanine diet or even BH4 supplementation (see here) might reflect possible areas of intervention requiring much further study?

To finish, I'm sure many of you had the same 'could try harder' reports from school as I did when I was a kid. But to get something like this.... from your Dad?

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* Evans J. Anti-social amino acids gang up. Chemistry World. August 2012.

** Adler-Abramovich L. et al. Phenylalanine assembly into toxic fibrils suggests amyloid etiology in phenylketonuria. Nat Chem Biol. 8: 701-706.

*** Cecchini P. et al. The role of tryptophan in protein fibrillogenesis: relevance of Trp7 and Trp14 to the amyloidogenic properties of myoglobin. PEDS. 2012; 25: 199-203.

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Adler-Abramovich L, Vaks L, Carny O, Trudler D, Magno A, Caflisch A, Frenkel D, & Gazit E (2012). Phenylalanine assembly into toxic fibrils suggests amyloid etiology in phenylketonuria. Nature chemical biology PMID: 22706200

P-glycoprotein: lock on transporters

During a post a while back, I did promise that I would discuss an interesting compound called P-glycoprotein in relation to the blood-brain barrier and its helping, transporting hand. Well here is it is. A recent article titled "P-glycoprotein: Why this drug transporter may be clinically important" attracted my attention in timely fashion discussing drug interactions which, as coincidence would have it, is something that I have also been reading about recently.

This paper by van Assema and colleagues* cropped up on my Twitter radar recently. In it, the authors describe how problems with a pretty important transporter system, P-glycoprotein (otherwise known as ATP-binding cassette sub-family B member 1, ABCB1) might put some fundamental observations in Alzheimer's disease (AD) into perspective.

I don't want to rehash the whole AD story because it has been summarised in other posts. The watchwords are: beta-amyloid peptide fragment, reactivity, and plaques. Dr/Prof. van Assema and team carried out some investigations on P-glycoprotein function in a small number of patients with AD compared with controls. They reported lower P-glycoprotein functioning and concluding that the ability to transport things out of the brain through the blood-brain barrier might be problematic at least in some cases of AD. 

This is not the first time that P-glycoprotein has been implicated in AD. This paper and its accompanying commentary hinted at similar things in a mouse model looking at transporting those pesky beta-amyloid peptides away and reducing the accumulation. I note that there is some growing interest in this and related areas following the news that AD might have some interesting spreading capability. 

As per my previous post on amyloid precursor protein, AD is not autism. Indeed, the evidence seems quite the contrary when it comes to looking at both the precursor protein and plasma levels of the nasty peptide fragment/s in relation to autism.

Having said that P-glycoprotein has been looked at in cases of autism; specifically to account for the variable effectiveness of some medications given to manage peripheral issues such as hyperactivity. This paper by McCracken and colleagues** suggested that individual responses to the drug guanfacine might be influenced quite strongly by certain genetic differences in the p-glycoprotein gene. So the presence of a certain mutation (SNP) might account for lower levels of P-glycoprotein, which in turn means less 'hold my hand' transport of the drug across the blood-brain barrier to exert an effect. 

Acknowledging that the blood-brain barrier is a highly complex barrier and that we need to tread cautiously in terms of what we allow in and out across this barrier, there is a whole new world to be explored here perhaps rivaling that other barrier of great interest in relation to autism and a few other things. 

* van Assema et al. Blood–brain barrier P-glycoprotein function in Alzheimer's disease. Brain. November 2011.

** McCracken JT. et al. Possible influence of variant of the P-glycoprotein gene (MDR1/ABCB1) on clinical response to guanfacine in children with pervasive developmental disorders and hyperactivity. Journal of Child & Adolescent Psychopharmacology. February 2010.

Amyloid precursor protein and autism

A cobbler should stick to his last. Meaning that people should generally stick to what they know and do best. I think most people would feel comfortable with this phrase. We would after all never (knowingly or willingly) go for surgery at a bakery or have our teeth fixed by a plumber. Likewise I probably wouldn't want my doctor to butcher my pork chops, even if she was handy with a scalpel.

I hope that I am not getting too out of my depth with this quite biochemistry-heavy post on some new findings on the amyloid precursor protein in relation to autism spectrum conditions. I have consulted with a few people who know a little more about this than I, just to check a few facts, but please do not assume I am an expert in this area. We will see if I do the science and research justice.

I start with some definition and description. Those with a medical or scientific background or possibly some family experience will probably already have heard of amyloid precursor protein (APP) in relation to Alzheimer's disease (AD). AD is the most common cause of dementia and the condition's profile is being elevated by people such as Sir Terry Pratchett (he of the Discworld novels). Without going too deeply into AD, the characteristic brain pathology of the condition is noted by the presence of neurofibrillary tangles and amyloid plaques. The plaques are made up of certain accumulated breakdown products of APP.

Nobody really knows how such pathology comes about in terms of genes and environment, but amongst the various investigations being undertaken into AD, one of the more widely suggested hypotheses involves APP and in particular, its peptide fragments, beta-amyloid, which are the main constituent of the plaques found in AD. Like any peptide, beta-amyloid is formed as a result of enzymatic processes involving a protease acting on APP, specifically the beta- and gamma-secretases. There are various other processes involved in this chain of events potentially related to AD but that's as far as I am going for now. I would perhaps also mention about the various pharmacotherapeutic measures currently available to tackle AD, based around two main classes of drug: the acetylcholinesterase inhibitors, which increase acetylcholine (often depleted in AD) and the glutamate-blocker, memantine.  I have talked about acetylcholinesterase inhibitors previously in relation to autism (here). I note that memantine has also been trialled in cases of autism with some indications of positive symptom response.

A recent paper by Ray and colleagues* (open access copy available here) looked at some of the products of amyloid precursor protein (APP) in plasma from people with autism. The paper is a quite complicated one and not the easiest piece to follow, hence my use of bullet-points to break the methods and selected findings down:

• A total of 39 participants were included for study: 15 diagnosed with severe autism (CARS score of 37+), 6 with mild-moderate autism (CARS: 30-36.5) and 18 asymptomatic controls. There was no significant difference across the mean ages of the groups.
• Various measures of the residues and peptides derived from APP in plasma were analysed alongside levels of brain-derived neurotrophic factor (BDNF). The main reason seems to be the study's focus on BDNF and specific APP breakdown products being neurotrophic (related to neuronal growth or survival) on the back of the data looking at head circumference in autism.
• There was no significant difference across the groups in terms of the mean total of total secreted amyloid precursor protein (sAPP) (that is the combined species based on the actions of the various forms of the secretase on APP).
• Levels of sAPP-alpha, the residue of the non-plaque associated form of APP, were elevated in the more severely affected autism group compared with controls.
• Levels of sAPP-beta, the residue associated with plaques from APP, were reduced in the more severely affected autism group compared with controls.
• Levels of the beta-amyloid peptides involved in plaque formation, including the most insoluble and toxic peptide, beta-amyloid-42, were also reduced in the more severely affected autism group compared with controls.

These are interesting findings. Plasma levels of beta-amyloid peptides (particularly 42) are associated with cognitive decline and onset of AD. I would however caution before making too many statements about the study results and risk of AD based on things like the small participant numbers included in the current study, and also their young age.

This is not the first time that this particular research group have published in this area. Indeed in a previous study based on even smaller participant numbers, they reported increased total sAPP in severe autism relative to other groups and controls; contrasting with no overall difference in the current study. Perhaps more interesting however was the confirmation from the recent study of higher levels of non-plaque related sAPP combined with lower levels of plaque-related beta-amyloid-40 peptide in severe autism. Likewise another group has confirmed some of theses findings.

I would like to believe that there may be some good sense in conducting further, large-scale study of levels of sAPP-alpha in autism which some have suggested might be a potential biomarker for autism. There are also a few other potential tie-ins to sAPP-alpha which might also necessitate some further investigation including a peripheral nicotinic effect, the use of statins, and the effect of selected neuropeptides.

As per my initial caveat, I would perhaps advise interested readers to do a little confirmatory reading before taking my observations as any kind of truth. If on the other hand you need someone to name your Star Wars villains, well I'm yer man..

* Ray B. et al. Increased secreted amyloid precursor protein-α (sAPPα) in severe autism: proposal of a specific, anabolic pathway and putative biomarker. PLoS ONE. 2011: 6:6