Monthly Archives: February 2011

The Amyloid Cascade Hypothesis

The paper reviewed here is ‘The Pathogenesis of Alzheimer’s Disease:A Reevaluation of the ‘Amyloid Cascade Hypothesis’ by R A Armstrong of Aston University, Birmingham. The article has a Creative Commons Attribution License and is freely available here. This is a relatively brief review article which asks the following questions

Is there a relationship between the plaques and tangles associated with Alzheimer’s Disease?
What is the relationship of these structures to pathogenesis?

In the introduction, Armstrong draws the reader’s attention to paradoxes in the Amyloid Cascade Hypothesis noting for instance that the plaques and tangles are spatially and temporally distinct in Alzheimer’s Disease pathogenesis. Armstrong then goes on to describe the Amyloid Cascade Hypothesis outlining the critical evidence supporting the relationship of Beta Amyloid to plaque formation while also identifying the more tenuous links that have joined the plaque formation with that of the neurofibrillary tangles.

Beta-Amyloid deposition in temporal gyrus (see Acknowledgements)

In the next section Armstrong then discusses criticisms of the Amyloid Cascade Hypothesis firstly considering evidence which characterises plaque formation as a physiological response (although this doesn’t necessarily preclude involvement in a subsequent pathological process) and reiterating the distinctions between plaques and tangles. On the basis of this discussion and further consideration of the evidence Armstrong proposes a revision of the Amyloid Cascade Hypothesis which is illustrated in the diagram below.

As I understand it, Armstrong is proposing that there are two stages of degeneration. In the first stage there are a number of types of brain injury that occur. These then trigger reactions (reactive processes) in the Beta Amyloid and tau which lead to secondary degeneration. Thus the plaques and tangles are not the primary drivers of degeneration and this explains a number of the apparent paradoxes in the original hypothesis. This is an elegant hypothesis further clarified by Armstrong’s subsequent remarks

‘The modified ACH suggests that it is ageing and the diseases associated with ageing that provide the “trigger” initiating the “cascade” of events leading to AD rather than the initial deposition of Aβ‘

and

‘First, the hypothesis predicts that significant signs of neuronal degeneration in AD should precede those of Aβ deposition and the effect of Aβ is secondary rather than primary in causing neurodegeneration. Second, it predicts that the pathogeneses of SPs and NFTs are not directly linked and the two lesions essentially arise independently’

Armstrong’s revised hypothesis is an important and elegant modification of the original hypothesis and if it holds true then it has significant implications for disease prevention and treatment. Given the large number of causes of primary degeneration it would mean that Alzheimer’s Disease diagnosis and treatment would become more complex and multifaceted. The hypothesis can be tested both through novel research and a systematic analysis of the research literature.

Acknowledgements

The diagram is from the above article and can be found here.

Index: An index of the site can be found here. The page contains links to all of the articles in the blog in chronological order. Twitter: You can follow ‘The Amazing World of Psychiatry’ Twitter by clicking on this link. Podcast: You can listen to this post on Odiogo by clicking on this link (there may be a small delay between publishing of the blog article and the availability of the podcast). It is available for a limited period. TAWOP Channel: You can follow the TAWOP Channel on YouTube by clicking on this link. Responses: If you have any comments, you can leave them below or alternatively e-mail justinmarley17@yahoo.co.uk. Disclaimer: The comments made here represent the opinions of the author and do not represent the profession or any body/organisation. The comments made here are not meant as a source of medical advice and those seeking medical advice are advised to consult with their own doctor. The author is not responsible for the contents of any external sites that are linked to in this blog.

News Round-Up: February 2011 1st Edition

1 Reply

Over at the Alzheimer’s Research Forum there is a look at new research which may shed light on early-onset Alzheimer’s Disease. Two studies are covered which look at in vitro research in murine fibroblasts comparing wild-type cells with presenilin gene knockout cells. The evidence from these studies suggests that these genes may play an important role in autophagy the process whereby a cell degrades its components.

Again at the Alzheimer’s Research Forum there is coverage of an initiative to standardise the collection of metabolic data – the Metabolomics Standards Initiative. Laboratories use mass spectromoter data to describe the metabolic contents of cells but currently laboratories use widely varying methods. A standardisation of methods should facilitate a comprehensive description of metabolites in cells. In turn this information can be used with genomic and other data to better characterise disease process and investigate therepeutics.

A small cross-sectional structural 3T MRI study showed a significant volume reduction in the Amygdala in peeople with Alzheimer’s Disease compared to a control group of healthy older adult participants.

A small (n=68) longitudinal study ~~found that~~ examining vascular risk factors ~~were a~~ provided evidence of a significant association between the presence of vascular risk factors and the rate of cognitive and functional decline in people with Alzheimer’s Disease and it would be interesting to see a large replication study with detailed psychometry. The researchers also found an association between the vascular risk factors and regional cerebral blood flow ~~differences~~ which differed between the groups when using SPECT.

A Cochrane Database Systematic Review on antidepressants for agitation and psychosis in dementia was published in February 2011. The authors concluded that there were few relevant studies although in some (but not all) of those identified the SSRI’s were associated with fewer side-effects when compared to antipsychotics as well as showing similar results on reduction in behavioural scores compared to comparator antipsychotics. However the performance of the antidepressant in comparison with placebo differed according to the behavioural scales used. The authors call for further studies in this area.

There is a case report on ‘cough syrup psychosis’ resulting from excessive use of cough syrup. The authors attributed the psychosis to the ingredient dextromethorphan.

One group of researchers examined the question of whether weight gain is a correlate of improvement with antipsychotic treatment in people with schizophrenia. They concluded that an increase in BMI accounted for only 3% of the change in PANNS scores and therefore weight gain was not an important correlate. They go on to discuss the therepeutic implications.

In a small 8-week study people with schizophrenia either played computer games or engaged in high intensity training (HIT) aerobic exercise. The researchers found a significant improvement in physical outcome measures including maximal oxygen uptake but not in PANNS scores. They recommended HIT in rehabilitation programs.

In Neuroscience Letters one group reports an association between a common FOXP2 gene variant rs2396753 and grey matter volume in people with Schizophrenia compared to a control group. The FOXP2 gene is thought to play an important role in language.

There are a number of proposed changes to the National Institute for Clinical Excellence proposed in the Health and Social Care Bill which is currently passing through parliament where evidence is being given to the Public Bill Committee. Included in these changes is a broadening of the body’s role to encompass a number of social care policies which has previously come under the jurisdiction of ~~remit of~~ the ~~now defunct~~ policy development function of the Social Care Institute for Excellence (SCIE).

Monkey Vocalisations, Predators and Thoughts on the Origins of Language

3 Replies

While observing a group of Bonnet Macaques in Tamil Nadu I was fortunate enough to have captured the above clip. The Macaques initially appeared preoccupied with the passing traffic but occasional glances can be observed amongst members of the group. While a young macaque plays on the ground a sudden vocalisation can be heard amongst some of the other macaques which quickly spreads throughout the group. They are then observed to look in the same direction and exhibit a synchronous vocalisation. Although the reader on watching the video might seem it was rather obvious that something was afoot its interesting to take a step back and examine what was going on. I was rather a little surprised by the sounds that were coming from the group and looked around to see what they were looking at. That’s when I caught sight of the bird. Due to my lack of knowledge in this area I’m a little embarassed to say that I wasn’t quite sure what the bird was even after reviewing the footage. Unfortunately with regards to the footage of the bird it is of a very poor quality. The reader will be able to make out that the wings are of a grey colour, there is an orange colouring in the head area and a white colouring of the underbelly. The bird is seen soaring before disappearing firsly obscured by the nearby bushes and then finally over the hill. A local person suggested that it was an eagle (A list of birds in Tamil Nadu is given here and there are a few possible matches including one type of falcon and several types of eagle).

What was interesting was that on hearing the macaques my first thought was ‘what’s going on here?’. In other words it was enough to attract my attention. I imagined that the collective vocalisation of the group might be more intimidating to a bird of prey than that of a single individual within the group. The Old World Monkey ancestors diverged from our ancestors some 25 million years ago. Perhaps at that time our ancestors had already established that by collectively vocalising they would be more effective in warding off predators and thereby increasing their collective chances of survival. Thus there is a behaviour that is contingent on that of others in the group that potentially improves fitness. As an interesting aside the old world monkeys are arboreal and perhaps our own ancestors faced conflict with birds of prey during our evolution. In contrast the large greater apes wouldn’t have made easy targets.

So a second thought I had about the vocalisations was my own response. Could it be possible that there was some vestigial response that I had to these macaques – a useful remnant from millions of years of evolution – a conserved function if you will – that I would immediately recognise the warning signs that danger was approaching? A closer examination of the vocalisations (and readers can correct me) included a low-pitched ‘barking’ and a high pitched brief vocalisation. I wondered if the latter was the equivalent of a scream in a less powerful member of the group, while the more powerful members exhibited the barking sound – which I interpreted as an aggressive sound. In any case the bird quickly disappears.

The question this clip made me ask was ‘how did the macaques know how to synchronously produce these sounds?’. Furthermore do these activities in any way relate to the origins of language? During my observations of lemurs I have observed similar barking sounds and their ancestors have diverged from ours some considerable time earlier at approximately 63 million years ago.

The significance of the barking sound as well as the characteristic snout of the lemur are somewhat reminiscent of the dog and interestingly the dog’s ancestor diverged from our ancestor some 85 million years ago. However the lemurs on Madagascar have very few natural predators and so the purpose of their vocalisations is more likely to relate to territorial displays or conflict between males.

In summary the clips above show evidence of vocalisations within groups being used for purposes that would be consistent with the two main types of selective pressure and it is not unreasonable to suppose that these powerful drivers may well have contributed to the origins of language. In these cases vocalisations produce very clear signals, signals which over time could become more refined through competition.

Addendum

One of the readers has suggested that the bird in the above footage is a Great Hornbill. While this is not a ‘bird of prey’ or raptor, it is noted that the Great Hornbill preys on small mammals. I have amended the title of the article accordingly, replacing ‘birds of prey’ with ‘predators’ although the central argument in the article remains unchanged. I have included some footage of the Great Hornbill taken in Kerala to provide a comparison with the bird seen in the above footage for the interested reader.

Why Don’t We See in Slow Motion?

5 Replies

I was playing about with my camcorder and it got me thinking about how we see moving images. This is something we often take for granted because its such an integral part of what we do every day. Computer scientists working on visual processing know this intuitively easy skill is far from simple. Anyhow I got asking the question – if you can play a film at half-speed – why doesn’t the same thing happen ot visual processing? My first thought and i’m sure the reader’s will be that this isn’t too clever in the real world. If you see an animal or person moving toward you at half-speed, then you won’t have timte to respond quickly enough so it’s not veyry practical and indeed farirly dangerous depending on circumstances. Still, mutations in genes are necessarily clever and in some sensees are accidental so that it doesn’t matter whether we think they ought to occur. So there is still some use in returning to the subject of why we don’t tend to see in slow motion.

While it might not be immediately obvious, there are at least three ways of seeing in slow motion. In the first, the moving images are seen at say half speed. Using this approach you will get further and further behind present circumstances. In order to do this you would ahave to develop another skill in terms of holiding items in memory over ever increasing periods which would cause new problems. With the need for this latter skill, there is some similarity to the problems faced by the famous mnemonist Sheresheveskii who reported that he was unable to forget the events of the day. This in turn negates the ability to sift through the information and retain only what is thought to be important. However its likely that as time proceeds the visual images would degrade fairly quickly so that the utility of visual processing would be degraded beyond the simple point of impracticality.

The second possibility is that there is a ‘place’ or region in the brain where the ‘motion’ is detected. Indeed there is a region in the occipital cortex which may be involved in the processing of motion – the V3 region. So if someone was to see in slow motion it might be that this part of the brain fired half as often as normal and the ‘perceiving’ part of the brain received a signal half as often as a result. Then the person would see at ‘half speed’ if this model of perception and motion detection is viable.

The third possibility is that the perceiving part of the brain operates half as often as usual and so even with the motion detection going on correctly, the experiencing happens half as often. An obvious difficulty with this model is that motion processing and perception might be closely related rather than segregated. It doesn’t really matter though because the interesting thing is that people don’t seem to complain of seeing at half-speed or at least i’m not aware of them if they do.

This is the curious thing though. Why do we so effortlessly see at the ‘right’ speed? The more I think about this, the stranger it seems and it leads to an endless series of other interesting question. Do we all see at the same speed? Are the motions we are detecting continuous or discrete? (Most likely discrete and limited by the firing rates of the rods and cones in the retina) Does our perceptual apparatus fill in the gaps as it does with static images exemplified by certain optical illusions? Do other species see at different rates? Take a fly for instance. If you move your hand towards the fly, it will ahve moved by the time your hand had arrived. They can move very quickly. So quickly in fact that it almost gives the illusion that they are seeing and moving twice as quickly as we are. This might be possible if the firing rate of their rods and cones were twice as fast as ours. However a more straightforward explanation is that the journey from the fly retina to the brain and then back to movement is likely to be much shorter than ours given our size difference. This would mean that a fly could respond more quickly to visual information than we might be able to.

In all likelihood the absence of frequent complaints of slowing of vision probably means that vision works in a completely different way to that of filming devices. It is more likely to be a combination of multiple modular approaches to visual problem solving which have clear objectives and which combine to produce the visual stream of consciousness. Indeed there are various studies such as this and this which hint at more subtle mechanisms for motion processing which occur in widespread brain circuits that may include the cerebellum.

In the process of examining this issue, i’ve taken slowed down footage and compiled several videos. So what does life look like in slow motion? It has lots of birds! Actually birds are really great to see in slow motion. Without slowing them down it is very difficult to get an understanding of the elegance of their movements. However by watching the footage in slow motion it becomes apparently just how remarkable these creatures are in keeping themselves high in the air with a simple combination of muscles and feathers. Slow motion filming is a strange netherworld – not quite a portrait nor is it a real-time representation of the world. To make it interesting there has to be a little bit of movement at least. If you take the opportunity to look around you as you read this you might be surprised at just how still the world is. The multitude of inanimate objects by their very definition are still and given motion through our actions. The main players in the world of motion (well macro-motion that is) are us, animals and machines that have been set in motion by us with the obvious exceptions (wind-associated movements, sea, rain, sun, moon etc).

Perhaps the most interesting finding I had from this footage was that I developed a sense of motion sickness when looking at a boat moving slowly in the sea. Whereas I don’t normally get motion sickness and it couldn’t properly be called such since there was no corresponding motion for a mismatch to occur it did suggest to me that an artefact in visual motion processing might be an interesting lead to pursue in understanding this phenomenon. Maybe this approach might lead to other findings.

TAWOP: Evolutionary Psychiatry Resources (Last Updated 7.4.12)

6 Replies

Evolutionary psychiatry is the application of evolutionary theory to the study of mental illnesses. Evolutionary theory encompasses evolutionary biology, psychology and related disciplines. The principles of natural selection, sexual selection and group selection are used within these branches to explain how certain characteristics have developed in populations over time. Furthermore the unit of evolution is the gene which through mutation in successive generations codes for gene products with altered function. Typically it will be argued that when Gene X mutated, it conferred a certain advantage or fitness for the individual while at the same time resulting in an illness. Such is the advantage of the gene that it remains from one generation to the next despite the association with illness. Thus the explanations are of the form – this illness exists because of this mutation in Gene X which also results in Characteristic Y which is advantageous.

Where it starts to get even more interesting is in attempting to demarcate illness from health. One of the big questions that concerns psychiatrists drafting diagnostic manuals is where health ends and illness begins. Indeed there is also wider debate in society about this question which even emerges in health movements. One central arguments used against mental illness labels has focused on what is termed social constructivism in diagnostic formulation. In other words, some people critical of psychiatric diagnoses will argue that we choose diagnoses according to social convention. They will say that what we refer to in some cases is not an actual (biological) illness but rather it is a social construct – an agreement within society that certain behaviours or experiences are sufficiently different from those of the general population that with the use of an arbitrary threshold we can assign an illness label or else we can simply sanction certain behaviours altogether as illness behaviours.

In attempting to address these difficulties without being caught in the cycle of arguments about social conventions there is an interesting approach to investigating whether illness labels have a biological connection. This moves away from the approach discussed in the first paragraph and focuses instead on the languages of anthropology and primatology. I argue that these languages are better suited to answering these questions than the more constrained language used to describe the functions of genes at the molecular level whilst also holding validity. The areas of anthropology and primatology of relevance can be seen as extensions of evolutionary theory. In other words if we trace our ancestors back far enough we start to have common ancestors with living creatures. Our nearest living relative is the Chimpanzee although their ancestors diverged from ours some 8 million years ago (although the best estimates vary from time to time). However we need to accept the principles of selection in order to validate this understanding as well as to try to understand why we are now so different.

Having this tool allows us to look at our nearest relatives the Great Apes as well as the New and Old World Monkeys and ask what do we have in common? and what separates us? When we look at the question of what we have in common it enables a deeper understanding which can be absolutely relevant to the question of demarcating health and illness. If a critic questions an illness label, then they can use arguments along the lines of – the illness does not really exist and even though people manifest these behaviours then if we simply changed the description of the illness these people would no longer be ill. Statistical thresholds for experience or behaviour prevalence while helpful in forming an argument aren’t entirely convincing by themselves. Similarly the use of pharmacological explanations can be helpful but there might still be difficulties in linking neurotransmitter findings from research studies with phenomenology given the relative incompatibility of the descriptive languages.

However we may turn to our primate relatives and ask if certain behaviour are evident. Of course we do not readily have access to phenomenology but we do have the next reasonable alternative – observation of behaviours. If behaviours are frequently observed then they begin to take on a predictive quality and a language is developed as well as an implied understanding based on that language. We can then say do Chimpanzees have a well developed language or do they have a culture. Once we can begin to answer these questions with even a reasonable degree of success this inexorably leads to the next question of what happens when these functions are absent? It may be for instance that most of the Chimpanzees in a group engage in sharing of food in exchange for grooming for instance. Once such behaviours have been observed, research communities not have a language for describing altruism in these communities based on long term observations. Finally we can now see that if there are individuals that deviate from the general rules found within the community and where there are associated functional impairments do we have a basis for describing a mental illness? If such descriptions are on a firm foundation then we can then link this in with the bigger picture of how our primate relative relates to us in the evolutionary tree. We can start to meaningfully talk about evolutionary psychology – certain psychological functions which have been conserved over millions of years. We can then identify loss of these functions in individual humans and chimpanzees and argue more convincingly that we are looking not at a social construct but rather difficulties with a function which has been conserved over several million years.

There will no doubt be other benefits from the application of evolutionary psychiatry. What is evident is that the student of this approach can begin with an application to a specific question (has depression developed only in the Great Apes? and have the features of depression been observed in all of the Great Apes?) and utilise specific principles (e.g the principle of natural selection) in conjunction with empirical data (observations in the field) in attempting to answer that question. Many genomes have now been sequenced and they offer us the possibility of comparing small changes between genomes of humans and other living primates but also quite remarkably between modern humans and archaic humans. I have assembled here a number of resources on this blog related to the field of evolutionary psychiatry and will continue to add them as they become available.

Articles

A Celebration of 150 Years of Darwin’s Publication of ‘On the Origin of Species’

Lemurs: Can Field Work Be Useful for Evolutionary Psychiatry?

Neanderthal Articles

Monkey Vocalisations and Thoughts on the Origins of Language

Do Only Humans Smile

The Origins of a Kiss

Chimpanzees Kissing

Videos

A Short Video on Human Evolution

Dunbar’s Theory on Grooming, Language, Laughter and Music in Human Evolution

The Good Enough Squirrel Monkey