Monthly Archives: June 2010

Review: Exercise and the Brain: Something to Chew On

Exercise

The article reviewed here is ‘Exercise and the Brain: Something to Chew On’ by Henriette van Praag and freely available here.

The issue of exercise and the brain has been covered in some detail in the very interesting book Spark which was reviewed in an earlier post (see here). Given the mention of the role of exercise in the NIH  consensus statement on prevention of dementia and cognitive decline (see here) as well as the evidence supporting the Seattle exercise protocols the role of exercise in promoting healthy cognitive aging is becoming more apparent. Perhaps the story will be a little more complex than is suggested at the current time but it is an exciting area of research given the accessibility of exercise and the potential benefits. Finally this paper was published in the journal ‘Trends in Neurosciences’ which publishes concise reviews allowing the reader to gain a rapid and contemporary overview of a subject area.

Moving onto the contents, this is a brief article which focuses on the synergistic benefits of exercise and diet on cognition. The article gets off to a flying start with a lot of really useful pieces of information. Quoting from the introduction

There is also increasing evidence that dietary supplements enhance learning and memory. Of interest are the omega fatty acids, certain spices, teas and fruits

The author further points out that there is an interplay between the benefits of diet and exercise. The remainder of the article is divided up into the effects of exercise on cognition in humans and rodents, the effects of diet on cognition and the mechanisms of action for these effects. This latter point of exactly how exercise and diet contribute to cognition os obviously the key to developing therapeutic interventions. I thought the discussion around these mechanisms was extremely interesting and it was quite remarkable to hear of the evidence for so many different effects of diet and exercise on the biology of the brain, ranging from neurotransmitter levels, to the mechanism of Long Term Potentiation, dendritic spine density and neurogenesis.

There were a few of particular interest. A central theme which ran through the article was that of the benefits of flavonols. On the basis of this article these compounds are certainly worth a closer look in terms of cognitive health benefits.

Another thought I had while reading the article was that there is some scope for selection of articles which support a main argument, at least in this style of article. Perhaps these reviews can be used in conjunction with meta-analyses or even by articles where the author holds a diametrically opposed view. In any case, I think having a central argument is very useful in being able to manage the vast amount of research material out there.  In comparison with the NIH article referred to above, I find this article slightly easier to get to grips with. As well as citing the evidence, the author proposes a very concrete theoretical model for how these effects might be mediated. By providing these molecular and cellular mechanisms, van Praag is able to take a vast array of evidence and begin to piece it together. Without consideration of neurogenesis, neuronal structural changes and the posited intracellular pathways, how is it otherwise possible to integrate the effects of exercise and diet in a meaningful way?

The only difficulty is that the model is so finely detailed that at this level there are a large number of other factors which will influence the causal chain. These factors range from circadian rhythms all the way through to hormonal changes and genetics. Perhaps the model features very strong relationships which are maintained despite the background fluctuations (noise) in these other factors. At least it is a starting point and the interested reader could return to this article to test this model with other evidence and refine it as appropriate. For example, the relationship between BDNF, exercise and neurogenesis is certainly gaining traction and is just one part of the model described here. I would be interested to return to a similar model in say five years time and I suspect that it would be rather complicated. If that is the case, then it may even impact on the type of advice given to those wanting to use exercise and diet to prevent decline in cognition but we will have to wait and see.

Acknowledgements

Diagram of the flavonol: Author: Yikrazuul. Permission. This has been released into the public domain. http://en.wikipedia.org/wiki/File:Flavonol_num.svg

Call for Authors: If you are interested in writing an article or series of articles for this blog please write to the e-mail address below. Copyright can be retained. 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.

Review: National Institute of Health State-of-the-Science Conference Statement: Preventing Alzheimer Disease and Cognitive Decline

This is a review of a consensus statement on prevention of Alzheimer’s Disease which is freely available here and in a slightly more detailed form here.

So firstly this is a National Institute of Health ‘State of the Science’ Conference statement – ‘Preventing Alzheimer Disease and Cognitive Decline’. There are 15 listed authors and the process by which the statement is arrived at is complex. Briefly stated and referring to the document this comprises

1. A systematic review of the literature

2. Presentations ‘during a 2-day public session’

3. ‘Questions and statements from conference attendees during open discussion periods that are part of the public session’

4. ‘Closed deliberations by the panel’

The consensus statement does not represent the NIH or government and is

an independent report of the panel

Before discussing the contents of the paper any further, its worth just pausing at this point and reflecting on the above. The question is a very significant one. An epidemic of dementia is predicted by the middle of the century and will occur in the context of aging demographics globally. So the issue of preventing dementia and cognitive decline is clearly very important and it’s good to see a very  creative approach to this problem. There is a difficulty with this approach however and that is the paper trail. From points 1-4 above you can see that much of the process by which the conclusions are arrived at are happening in the milieu of the conference and to some extent we are left with the end product of this process. However it is the process itself which would be very useful to look at.  If we consider the NICE guidelines, the lengthier documents contain details of the studies that have been examined. This makes it easier for the reader to cross-check with studies they think might have been useful to include. Here though it’s difficult to engage in the same type of analysis. We’re not presented with information on the presentations or the public sessions. This is a great opportunity for generating video footage and uploading to YouTube so that others can get a feel for the kind of discussions that were taking place and contextualising the end results. In terms of a paper trail, the systematic review could be published in the format of an article for closer inspection and systematic reviews themselves vary in quality.

Moving onto the contents – the summary paper divides up the discussion according to 6 questions.

Question 1 – ‘What factors are associated with the reduction of risk of Alzheimer’s Disease?

The consensus statement response here is non-specific. I would have preferred to have seen a point-by-point summary for the myriad risk factors that have been identified. The authors discuss the need for prospective studies (albeit much later in the article) but without further details it is difficult to know which of the many prospective studies have been discounted. Here for instance is a prospective longitudinal study showing a reduced prevalence of dementia associated with Mediterranean diet (it could be argued that they were interested more specifically in Alzheimer’s Disease however). In the News Round-Up from the end of last year, I included a number of references  for studies on dementia, more specifically Alzheimer’s Disease and cognitive decline and have included some of the relevant excerpts in the appendix below which can give the reader a flavour of the kind of interesting themes that might have been explored in such discussions. The authors point out that it is difficult to discriminate between cases with and without vascular involvement because of the complex interplay between vascular and Alzheimer’s Disease pathology but this is more a question of selection of studies with the relevant inclusion criteria (which would include for instance MRI exclusion of subjects with evidence of vascular pathology e.g. graded white matter hyperintensities).

Question 2 – ‘What factors are associated with the reduction of risk of cognitive decline in older adults?’

Although they identify hypertension as a strong risk factor for cognitive decline in older adults, I don’t think this is a particularly good question. It would make more sense to ask specific questions such as factors reducing the rate of decline in Mild Cognitive Impairment, healthy controls and the subtypes of dementia.

Question 3 – ‘What are the therapeutic and adverse effects of interventions to delay the onset of Alzheimer disease? Are there differences in outcomes among identifiable subgroups?

Again I think the first part o this question is just too broad although the second part is more sensible. The important point is about what the baseline characteristics of the sample population are. These would be expected to influence the likely benefits of interventions including antihypertensive medication, anticholinesterase inhibitors, exercise and so on. Unless the study is well powered, the heterogeneity of any baseline population implied by the question will likely dilute the valid effects.

Question 4 – ‘What are the therapeutic and adverse effects of interventions to improve or maintain cognitive ability or functions? Are there different outcomes in identifiable subgroups

There is an interesting story here which is around the ACE inhibitors and there are a number of studies coming up with interesting results with ongoing debate although some of the evidence presented has related to morbidity in Alzheimer’s Disease rather than cognitive decline per se. The authors consider the antihypertensives generically. I wasn’t entirely clear on what the authors meant when they referred to the anticholinesterase inhibitors as influencing the rate of cognitive decline is their  indication. The authors do refer to specific subgroups in places but again I think the entire question should be considered in terms of specific subgroups.

Question 5 – ‘What are the relationships between the factors that affect Alzheimer disease and the factors that affect cognitive decline?’

I thought this was a more useful question to ask in the context of the statement and which can be described in terms of qualitative relationships. Diet, exercise, APOE4 status and depression were among the risk factors that were important for both cognitive decline and Alzheimer’s Disease. It’s important to note here though that the question revolves around shared risk factors.

Question 6 – This question focuses on what  research needs to be done.

The authors talk about a need for large studies and tighter criteria for mild cognitive impairment etc. This kind of question has been tackled by other groups. I think it is more useful to produce very focused study designs for this type of question as it is perhaps readily apparent that studies with large numbers and epidemiological studies would be good to design. However they are very costly and labour intensive and there should ideally be a very concrete pathway from the consensus statement to the actuation of these study designs.

My Conclusions

I think that it is a great idea to get lots of people in the field involved in discussing how to prevent cognitive decline and Alzheimer’s Disease. However, I have a number of thoughts on this.

1. There should be some documentation of the ‘behind-the-scenes processes’ including the public debates. I refer to ‘behind the scenes’ as all of the action that we the readers are not privy too i.e. the events of the conference.

2. For similar reasons, I would argue that video footage at key points in the discussion would be very useful uploaded to a free hosting service such as YouTube for dissemination of conclusions and the process leading to those conclusions. I’m sure someone could bring their digital camcorder along!

3. A social media format for engagement of the public and global scientists would be useful

4. The statement would probably benefit from considering very restricted clinical questions where there is more likelihood of arriving at useful responses in this setting.

5. Some of the time in the process arriving at the statement should be spent on the actual process itself. For instance if this process is repeated in a year’s time why should the answer be any better? Indeed would the same panel come up with a worse answer? It’s difficult to know.

6. There should be commentary on the concrete consequences of this meeting. Were grants issued for studies on the recommendations in this statement? Were stakeholders from grant-issuing bodies present at the conference?

Appendix – Excerpts from News Round-Up 2009 of relevance

‘A prospective study looking at people with Alzheimer’s Disease found a significant association between the use of antihypertensive medications and a lower rate of cognitive decline and higher MMSE scores at baseline even after controlling for blood pressure’

‘A 32-year prospective study – the Prospective Population Study of Women in Gothenburg found an association between central adiposity in middle age and prevalence of subsequent dementia. They did not find the same relationship between BMI and subsequent dementia but the central adiposity was associated with an approximate doubling of the prevalence of subsequent dementia’

‘A prospective California study with 9000 subjects provided evidence of an association between higher levels of cholesterols in people aged in their 40’s and the subsequent prevalence of Alzheimer’s Disease in their 60’s to 80’s. The article is freely available here’.

Call for Authors: If you are interested in writing an article or series of articles for this blog please write to the e-mail address below. Copyright can be retained. 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.

Review: The Medial Temporal Lobe and Recognition Memory

The paper reviewed here is ‘The Medial Temporal Lobe and Recognition Memory’ by Eichenbaum and Ranganath and freely available here.

Firstly the paper has been published in the ‘Annual Review of Neuroscience’. This is a journal with quite a high impact factor – for instance we can see here that the impact factor in 2003 was 30.17.  Of course, a journal can’t be judged by the impact factor alone which is influenced by a great many factors. For instance journals featuring a high number of review articles are said to have higher impact factors because review articles are more likely to be cited than original research articles. Additionally there should be some fluctuation in the quality of articles within a journal. Nevertheless it can be a useful marker for the popularity of the journal.

The authors here succeed in collecting together a vast amount of evidence from multiple areas – fMRI, neuropsychology, neuroanatomical and event-related potential studies to name just a few. Without going into too much detail, when I read the paper, coming away I found the central hypothesis about two streams of processing quite convincing. In essence what the authors argue is that there is a ‘what’ and a ‘where’ stream of processing in the Medial Temporal Lobe they integrate with the two distinct psychological phenomenon of recognition/familiarity and recollection. The ‘what’ stream relates to objects in the world and the ‘where’ contextualises these objects. The authors go on to argue that the parahippocampal gyrus is responsible for recognition and the hippocampus for recollection – by associating the ‘what’ information with information from cues. The model is a little bit more sophisticated than this however and the parahippocampal gyrus gets divided into anterior and posterior portions for the more subtle aspects of the model they present which also include the frontal and parietal cortices.

There is a lot of material here for reflection on and the MTL is an incredibly important structure for Alzheimer’s Disease (AD). There is a great deal of research that shows that the MTL volume is a predictor of cognitive decline and useful for instance in discriminating between people with Mild Cognitive Impairment who might go on to develop Alzheimer’s Disease and those who do not. There are still great difficulties in making these kind of predictions but a number of studies repeatedly show that more specifically the volume of the hippocampus is a very powerful predictor of cognitive performance and conversion to AD.

So the next question is whether or not routine neuropsychological tests could be used to work out the ratio of parahippocampal/hippocampal involvement in pathology such as AD. Having such a ratio if possible might be useful in distinguishing between different forms of dementia – for instance Frontotemporal Dementia versus Frontal Variant AD although at this stage this is very speculative. What’s great about papers like this though is that they can provide a starting point for working out potentially useful clinical applications of contemporary theoretical understanding.

Another nice feature of this paper is the discussion of recognition and recollection. I hadn’t really thought about this too much until reading the paper. The authors have provided convincing evidence not just for a distinction between the two but also for the further division of these constructs into further categories. So the way I interpreted it was as follows. If I see a bus stop as i’m walking down the street, I will almost immediately recognise it. It will be familiar to me. However it should take me a little more time to associate it with waiting for a bus. It’s hard for me to imagine that the latter would not be instantaneous but the authors have convinced me that it would be. Further, the feeling of familiarity would result from activity within the parahippocampal gyrus.

This also raises another interesting question – where am I experiencing the ‘familiarity’? Do I really feel familiarity because of the parahippocampal gyrus activity?  Now this is a fairly interesting question because of another phenomenon which will surely be familiar to the reader (no pun intended) – ‘deja vu’ – the feeling of having had an experience before. Classically associated with temporal lobe epilepsy, can we extrapolate and suggest that this would be the experience of parahippocampal activity? In other words, what does it feel like when we have activity in the parahippocampal gyrus – it feels like deja vu? I’m afraid I don’t have the answer to this – it remains as speculation but another example of the kind of interesting clinical ramifications that arise out of a discussion of the MTL.

The latter point about the parahippocampal gyrus activity experience is related to a more subtle point. If the hippocampus stores memories, when we experience those memories are we experiencing them in the hippocampus or is it activating the memories in interconnected areas e.g. the visual association cortex. This is quite an old question but a very good one nonetheless and the upshot of this is to ask whether or not it is ever sensible to inquire about the experience of activity in one area without mention of the other areas involved in a well recognised brain circuit. This in turn leads back to the question of whether we can talk about ‘what’ and ‘where’ streams in the hippocampus and parahippocampal gyrus without also including the other connected brain regions which might also be doing some of the processing.

This is a nice paper, very well explained and guiding the reader through all of the material needed to understand the authors’ conclusions. The material covered in the paper is also useful for informing clinical research questions.

Call for Authors: If you are interested in writing an article or series of articles for this blog please write to the e-mail address below. Copyright can be retained. 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.