Monthly Archives: March 2011

Are the properties of the Neural Substrate for Attention Highly Heritable?

There’s an open-access paper by Fan and colleagues titled ‘Assessing the heritability of attentional networks’ which is available here. The researchers provide a background to the research in attention networks. For the purposes of this study the researchers are interested in three specific attentional networks

1. The orienting network which involves orientation towards a stimulus of interest. They detail some of the suspected neural correlates and associate this with the cholinergic system.

2. The executive network which is ‘resolving conflict between stimuli and responses’. The researchers identify some of the likely neural correlates and associate this network with dopamine.

3. The alerting network which ‘maintains the alert state’. Again the researchers identify the likely neural correlates and associate this network with noradrenaline.

They then provide a lot of good evidence to suggest that these networks can be associated with different mental illnesses and that there are good arguments for supposing that the properties of these networks should be highly heritable.

In their study design, the researchers have recruited monozygotic and dizygotic twins. In brief, the participants undertake neuropsychological tests which assess attentional responses. These are described in more detail in the materials and methods section. Dizygotic twin performances are then compared with those of monozygotic twins in order to better understand the genetic load of these networks.

One of the thoughts I had about this was the difficulty there is in reducing complex mental phenomena to simple models. This applies not just here but to many areas in the clinical neurosciences. Implicit in the models described above is that orienting responses are restricted in some way to a few regions in the brain and that there is a straightforward relationship with acetylcholine. Nevertheless a cursory examination of these assumptions reveals that these regions are interconnected with yet more regions. If you have a massively interconnected structure where is the justification for demarcating regions of function? Such justifications suggest a dichotomous function/non-function scenario whereas the truth might lie along the lines of a continuum with additional regions being recruited as necessary.

However such objections don’t offer a solution in place of the current approach. Indeed with this approach it is possible at least to get things wrong and it is through this act of getting things wrong that a better approximation to nature can be reached (although this might be another tenuous assumption). Nevertheless even if the entire model is invalid, the psychological phenomenon still remain valid but in the process a language has been developed. It is this language which is the important byproduct of the process because it enables the research community to formulate new more meaningful models and this specialised language would fit into what Kuhn describes as part of ‘normal science‘.

After the interesting build up in the paper, in their analysis the researchers suggest the study is underpowered and based on their calculations identify a suitable size for a replication study.

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.

Acetylcholinergic Deficit in Alzheimer’s Disease and Treatment

There is an open-access (creative commons attribution License 2.0) article by Cummings and Sabbagh titled ‘Progressive Cholinergic Decline in Alzheimer’s Disease: Consideration for Treatment with Donepezil 23 mg in patients with moderate to severe symptomatology’ available here. In the article, the authors look at some of the evidence suggesting an acetylcholinergic deficit in Alzheimer’s Disease and examine the dose effect of the acetylcholinesterase inhibitor Donepezil. There is a nice quote about the pragmatics of focusing on acetylcholine rather than Amyloid:-

The cholinergic abnormalities seen in AD are not viewed as the cause of the disorder, but cholinergic involvement is significant because it is universal, correlates with cognitive defects, and is one of the few pathophysiologic phenomena that can be addressed with currently approved treatment options

The authors go on to summarise some of the data on Donepezil at the two main doses including one study supporting a dose effect in advanced dementia without evidence of a statistically significant difference in adverse events between doses. The authors also discuss the FDA approval of a higher dose of Donepezil as per the title although this will be significant for the USA. They discuss the evidence supporting a theoretical justification of a higher dose and specifically focus on the reduction in Acetylcholinesterase inhibition. The main part of the article focuses on a discussion of a 24-week randomised double-blind trial of Donepezil at 23 mg in people with advanced dementia. This study was part of the data set that the FDA reviewed in their assessment and in which it was thus contextualised. The analysis is brief and it would be interesting to know which outcomes were selected in the trial design and what the results were for all of these outcomes. Another interesting point is about the difference in discontinuation rates. In addition is a more detailed exploration of the physiological function of the acetylcholinesterase inhibitors in the CNS. It will be interesting to follow further research in this area.

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: March 2011 3rd Edition

Dementia

There is a write-up of the 2011 International Conference on Alzheimer’s and Parkinson’s Disease in Barcelona at the Alzheimer’s Research Forum. Feedback from the conference includes a more critical discussion of the Amyloid hypothesis as well as a consideration of multimodal therapeutic approaches. There was a post-mortem study comparing brains of 4 people with Down Syndrome (average age 66) with 6 controls (average age 70). As Down Syndrome is associated with age related degenerative changes, this study was able to provide useful information in describing age related changes more accurately. The researchers were interested in the number of glial and neuronal cells in the neocortex in both groups using stereological analysis which means estimating 3-dimensional information about the brain from 2-dimensional microscopic slices. Based on their analysis the researchers estimated that in the brains of the sample group with Down Syndrome there were 30% less glial cells and 40% less neuronal cells than in the control group. Interestingly there were similar numbers of cells in the Basal Ganglia in both groups. This may represent a combination of neurodevelopmental and neurodegenerative processes and it will be interesting to how these results might be influenced by therapeutic interventions in future studies. The researchers in a recent case-control study in Spain (n=690) concluded from their analysis that variations in the Amyloid Precursor Protein gene did not contribute to risk of Late Onset Alzheimer’s Disease (LOAD) in their sample group although effect sizes can be small. A Spanish group write about their experience of a 3-year longitudinal study of Mild Cognitive Impairment. Although there is a body of evidence relating amnestic MCI with conversion to Alzheimer’s Disease in their study, the researchers found this was more likely to be associated with multi-domain MCI. An American group have published research in which they identify a syndrome which precedes MCI and which they refer to as Pre-MCI. For those with Pre-MCI 28% converted to MCI or dementia at 3-year follow-up whereas only 5% converted in the Non-Cognitive Impaired group. The researchers identified Pre-MCI as

At baseline, Pre-MCI subjects showed impairment on tests of executive function and language, higher apathy scores, and lower left hippocampal volumes (HPCV) in comparison to NCI subjects

The researchers in a small German neuroimaging study (n=31) provided evidence of a relationship between connectivity in frontal-parietal networks and attention (assessed using the Attentional Network Task)  in people with early Alzheimer’s Disease. A moderately sized study (n=239) in a sample of people over the age of 85 showed a significant inverse correlation between intracranial volume, which the researchers used as a proxy marker of premorbid brain volume and risk of Dementia and more specifically Alzheimer’s Disease and Vascular Dementia. Interestingly in the group with the largest intracranial volume, dementia risk was not associated with white matter lesions. There is a write-up of the 2010 Leon Thal Symposium which covered amongst other subjects the establishment of a registry as well as approaches to data gathering. An American group have estimated the incidence of dementia and cognitive impairment not-dementia in the USA and over a 6 year period they estimate that there are 1.4 times as many incident cases of dementia cognitive impairment not-dementia as cases of dementia cognitive impairment not-dementia. NICE have just published their revised Technology Appraisal for drugs for Alzheimer’s Disease here.

Miscellaneous

There is a write-up of one study which provides preliminary evidence of a benefit from Transcranial Magnetic Stimulation in post-stroke dysphagia. This was a small trial and it will be interesting to see the results of further studies in this area. One cross-sectional study provided evidence of a positive correlation between hippocampal volume and recovery from PTSD in war veterans although replication of these findings with a longitudinal design is needed.

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.