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

  • 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).

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.

Monkey Vocalisations, Predators and Thoughts on the Origins of Language

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.

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.