Monthly Archives: August 2009

Review: Neuroprotection for Huntington’s Disease: Ready, Set, Slow

The paper reviewed here is ‘Neuroprotection For Huntington’s Disease: Ready, Set, Slow’ by Hersch and Rosas (2008) and freely available here. As the title suggests, this paper outlines neuroprotective strategies in Huntington’s Disease. In the introduction the authors define neuroprotection thus:

Neuroprotection can be defined quite literally as the preservation of neuronal structure, function and viability, or more generically as the slowing or prevention of neurodegeneration

The authors summarise some of the demographics and other information about Huntington’s Disease in the introduction placing the theme of neuroprotection in context. In the section ‘neurodegeneration’, the authors develop the theme that neurodegeneration occurs not only in the striatum but also in the cortex and that both are important contributors to the presentation in Huntington’s Disease. They also provide supporting evidence. In the section on neuroprotection in premanifest HD, the authors look at ‘phenoconversion’ (the conversion from prodromal Huntington’s Disease to manifest Huntington’s Disease), the PHAROS and PREDICT-HD studies and the difficulties of conducting clinical trials while avoiding genetic testing in prodromal Huntington’s Disease. In ‘Neuroprotection in Manifest HD’ the authors look at the many changes that occur in manifest Huntington’s Disease including a reduction in total functioning capacity (TFC). In ‘Measurement of Neuroprotection and Treatment Approval’, the difficulties in establishing useful outcome measures in trials of premanifest HD are discussed and they show that this is a particularly challenging area with a lack of useful biomarkers as well as a need to use primary outcome measures such as TFC which may not be particularly sensitive at this stage in the disease. They note the possible utility of a futility study which involves divergence on outcomes such as TFC from a predetermined threshold which is assumed to have clinical significance on the basis of statistically significant findings in prior studies. They also provide an indication of the sample sizes and follow-up periods that are required for the studies that are needed for FDA approval. The authors then look at the place of murine models although noting the significant limitations of such studies. In the next section, the authors consider the molecular target candidates (summarised in Table 1) before finishing with a section on candidate therapies although accepting that it is not exhaustive.

This was a useful review of neuroprotection in Huntington’s Disease. As with many reviews however there is no methodology section describing how the studies were selected although from my experience this approach has been frequently adopted in reviews. Perhaps this is because the issue of reproducibility isn’t as important with review papers because they represent in some part an interpretation of a field. The theme of neuroprotection I suspect will become increasingly important, not just in Huntington’s Disease but in other forms of dementia and will be interesting to see how this field develops.

STT 3 (My reasoning is as follows. Some of the treatments described here are currently in trials. If the trials are successful this may lead to approval which in turn depending on policy could then be used in treatment).

Steps To Treatment (STT)

STT = Steps To Treatment. An estimate of the number of steps between the results and translation into treatment. This is an opinion.

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Reflections on July 2009

July saw the 1st Anniversary of ‘The Amazing World of Psychiatry’ blog and the TAWOP Index links to previous articles (sometimes the links in the Index don’t work properly – technical issue). I will be putting some articles together (a little late) for the 1st Anniversary so watch this space! In the medical articles, two more papers from the ‘Puzzlingly High Correlations in fMRI Studies of Emotion, Personality and Social Cognition’ were reviewed, while in the psychology/psychotherapy articles a number of Winnicott’s papers were reviewed. For social psychiatry, there were a number of interesting issues examined in the papers reviewed including ‘What Should Psychiatrists Be Doing in the 1990’s’ and social networks in the prevention of dementia. Books reviewed included ‘Positive Psychology in a Nutshell’  and blogs reviewed included Brains on Purpose (which covers conflict resolution and other topics), Dr Jeff and Dr Tanya’s blog about psychiatry and the interesting ‘Small Gray Matters’. Various podcasts were reviewed. In the news, there was further support for computerised CBT, a large case-control study providing evidence that copy number variants contributed up to one-third of the risk for Schizophrenia, a relationship between centrally-acting ACE inhibitors and decreasing cognitive decline, a relationship between diet and cognitive decline and the efficacy of a web-based program in reducing alcohol consumption in college students, amongst other studies.

1st Year Anniversary of TAWOP Blog

TAWOP Index

Medical Articles

Understanding the Mind by Measuring the Brain

Reply to Comments on ‘Puzzlingly High Correlations in fMRI Studies of Emotion, Personality and Social Cognition’

The Ubiquitin-Proteasome Pathway in Huntington’s Disease

Results of Phase III of the CATIE Schizophrenia Trial

Psychology/Psychotherapy Articles

Winnicott on the Antisocial Tendency

Winnicott on Paediatrics and Childhood Neurosis

Winnicott on Metapsychological and Clinical Aspects of Regression

A Meta-Analysis of Self-Help Therapy for Insomnia

Social/Epidemiological Articles

Modernising Mental Health Services for People Who are Deaf

Huntington Disease in County Donegal

What Should Psychiatrists Be Doing in the 1990’s?

Social Networks and Their Role in Preventing Dementia

Estimating Future Numbers of Adults with Profound Multiple Learning Disabilities in England

Book Reviews

An Introduction to Neuropathology

Huntington’s Disease. Second Edition

Positive Psychology in a Nutshell

What is This Thing Called Science

The Woman Who Couldn’t Forget

Blog Reviews

Dr Jeff and Dr Tanya’s Blog

The American Journal of Neuroradiology Blog

Origins – A History of Beginnings

Blog Review: Brains on Purpose

Small Gray Matters

Podcast Review

July 2009 – 1st Edition

Science Podcasts

July 2009 – 3rd Edition

Betts on Jungian Analytic Psychology #18

News Round-Up For July 2009

Research in Dementia

In a study of relevance to old age liaison services, the authors of a longitudinal study looking at older adults admitted as emergencies to hospital characterised the prevalence of dementia according to age stratifications. The authors found an as expected increase in prevalence with age rising to 75% over the age of 90 in women and 48.8% in men over the age of 90. 41.3% of admissions resulted from urinary tract infections or pneumonia(Sampson et al, 2009). In a case-control study of people with Late-Onset Alzheimer’s Disease (AD) (217 people with AD and 76 controls) there was found to be a significantly increased proportion of people with type A personality types compared to controls (Nicholas et al, 2009). In a small study comparing 13 people with frontotemporal dementia with 12 people with Alzheimer’s Disease and 20 people with Semantic Dementia using structural MRI longitudinally (1 year)  – there was found to be a significantly greater rate of atrophy in the frontal lobes in FTD than the other two groups and a similar rate of atrophy in the temporal lobe in semantic dementia and AD (Krueger et al, 2009).

Research in Mood Disorders

A randomised control trial looked at computerised CBT (cCBT) delivery in a primary healthcare setting. The 303 participants with depression were allocated to treatment as usual, cCBT (using the Colour Your Life program and without support) or cCBT plus treatment as usual. In the first two groups there was a relatively poor adherence to treatment but in the analysis there was found to be no significant difference between the groups on the primary outcome measure – BDI-II scores. The authors conclude that supported cCBT might fare better. It would be interesting to see if the program could be modified to increase adherence rates (de Graaf et al, 2009). In a study of 1147 parents (>60 years old) whose children migrated out of the district of the parent there was found to be a decreased prevalence of depression in the parents (article freely available here)(Abas et al, 2009). In an open-label flexible-dosing trial of Ziprasidone for acute bipolar mania (n=65), 98% of the adverse events were classed as mild to moderate in severity. Improvement in Mania Rating Scale scores was comparable across the examined subpopulations – those with mania alone, mixed episode and also with or without psychosis (Keck et al, 2009).

Research in Psychosis

The authors of a paper propose that Toxoplasma Gondii may produce psychosis in hosts as a mechanism to enhance fitness of the pathogen and advocate further research to test their hypothesis (da Silva and Langoni, 2009). The authors of a genome wide analysis (analysing the data from a previously published study) found significant evidence of an association between the research diagnostic criteria Schizoaffective Disorder Bipolar type and variations in the GABA receptor particularly GABRB1 which they argue is further evidence in support of the diagnosis of Schizoaffective Disorder and it will be interesting to see further studies examining this potential relationship more closely (article freely available here)(Hamshere et al, 2009).

News in Brief

A widely reported case-control study in Nature (also hereherehere and here although some of the reported sample sizes differ) looked at copy number variants in people with (n=3332) and without (n=3587) schizophrenia. The researchers found that there was a large number of variants that were associated with schizophrenia and were also found in people with bipolar disorder.  Furthermore these variants were estimated to contribute to a third of the risk for schizophrenia. Two further studies were conducted by different groups and the results from all three were pooled. Significant associations were found with the Major Histocompatability Complex on Chromosome 6 as well as the myosin gene.

There have been a lot of studies looking at the possible benefits of the ACE inhibitors in reducing the risk of dementia but a new study gives a twist to the story. This is a prospective study involving people without dementia at baseline and the researchers selected 1074 participants from the cohort. They found that taking a centrally-acting ACE-inhibitor was associated with a 65% decrease in cognitive decline (using a modified version of the Mini-Mental State Examination) and that taking a peripherally-acting ACE-inhibitor was associated with a 73% increased risk of dementia compared to those taking other antihypertensive medication. This study occurs in the context of other studies suggesting a benefit of the ACE-inhibitors in dementia on various outcome measures. However it is important to note that the participants in this study were being treated with antihypertensives and were thus a selective group. This may be an important finding and the investigation of the actions of the centrally-acting ACE-inhibitors may well give  some important insights into dementia. It will be very interesting to follow the necessary subsequent research in this area. The authors of a longitudinal Finnish study involving 2000 middle-aged subjects who were followed up over 20 years later provided further evidence that the APOE 4 variant was associated with a higher prevalence of Alzheimer’s Disease. A similar increase was also found in association with being separated from a partner before age fifty. A study has provided indirect evidence that Granulocyte Colony Stimulating Factor  (GCSF) might prevent the build up of Beta-Amyloid plaques in the brain which would be relevant in Alzheimer’s Disease. It will be interesting to follow further studies in this area.

Researchers at the University of California have identified an association between PTSD and increased risk of subsequent dementia using information from a database on 181,093 veterans over the age of 55-years although this association did not occur after controlling for depression, substance misuse and traumatic brain injury. An engineered protein that can be extracted from goat’s milk has and which interacts with the Beta-Amyloid protein has been suggested as a potential prophylactic agent for people who carry a variant of the Butylcholinesterase inhibitor gene.  Several studies were presented at the 2009 International Conference on Alzheimer’s Disease which this year was in Vienna. Thus evidence was presented that strictly adhering to a diet for hypertension – the Dietary Approaches to Stop Hypertension (DASH) Diet was associated with improved cognitive functioning compared to those who didn’t adhere as consistently. There were 3,831 participants over the age of 65 who were followed up over 11 years. Adherence to the diet was represented by an ‘adherence score’ and associations with cognition were also found for fruit and vegetables as well as low fat dairy products. In another of the studies, a prospective study of 3075 people aged 70-79 there was a significant association between sedentary lifestyle and lower cognitive scores (modified MMSE) as well as between declining scores and declining physical activity. Another of the studies, this time in post-menopausal women showed a benefit on cognition for moderate exercise but a detrimental effect for chronic strenuous exercise although the study included a small number of participants (90) and it would be interesting to see further replication studies.

In one study, antibodies against ABeta peptide were found to decrease with advancing age and in people with Alzheimer’s Disease. Interestingly health control subjects were found to have antibodies against a number of antigens from plaques found in rare forms of dementia although the significance of this is far from clear. In another study, severe Chronic Obstructive Airways Disease was associated with significantly decreased performance on a validated 35-point cognitive scale compared to performance in a control group without COPD after controlling for possible confounders. The authors of a meta-analysis looking at 118 neuropsychological tests in the discrimination of Vascular Dementia and Alzeheimer’s Disease concluded that only 2 tests were effective in discrimination – the emotional recognition and delay recall tasks – but concluded that multiple sources of information were needed for the purposes of discrimination. In a similar vein, a team at the Mayo Clinic have been developing an MRI protocol for discriminating Alzheimer’s Disease, Frontotemporal Lobar Degeneration and Lewy Body Dementia. The protocol is referred to as the STAND-Map protocol (Structural Abnormality Index). The protocol is apparently effective at discriminating ‘75-80%’  of cases although the results are due to be presented at a conference and it will be interesting to have a closer look at the breakdown of figures. Mutations in the protein LRKK2 are associated with Parkinson’s Disease and the authors a new study found that another protein referred to as CHIP binds to LRKK2 and modifies the levels of LRKK2 and it will be interesting to see the results of further studies in this area. A widely reported study showed an improvement in aged mice’s memory and attention when given large amounts of caffeine and an associated reduction in levels of Beta-Amyloid. Asystematic review of first and second generation antipsychotics found no evidence of efficacy in prevention of delirium in hospitalised patients and equivalent efficacy in treatment of delirium. In an interesting prospective study in older adults (n=49), MRI white matter hyperintensities were associated with a significant risk of developing dementia and the researchers correlated the volume of these lesions with the risk of developing dementia. A number of findings in Alzheimer’s Disease Research were reported at the British Pharmacological Society’s Summer Meeting in Edinburgh including evidence of a protective effect of flavinoids against the neurotoxic effects of Beta-Amyloid plaques. The REVEAL study provides evidence that disclosing information about APOE4 carrier-status to children of parents with Alzheimer’s Disease does not result in significant short-term psychological distress. A receptor has been found in the basal forebrain which responds to ABeta Protein in Amyloid plaques and may be related to the effects of plaques on acetylcholine levels.

An intriguing study with many ramifications involved looking at the effects of anger on measures of carotid artery flow in 3  groups of subjects of increasing age. The researchers found that anger was associated with vasodilation of the carotid arteries and that this effect did not occur in those with hypertension suggesting a possible mechanism for stress associated myocardial infarct. The authors of a recent survey of people who remained at home in New Orleans during Hurricane Katrina suggest on the basis of the results their decisions may be related to valuing a sense of community and that they did not view themselves as ‘powerless’. Repeating positive self-statements was associated with a decrease in self-esteem in those with already low self-esteem compared to those with high self-esteem in one study. The authors of a genetic study conducted in samples from a number of different ethnic groups have reported an association between perfect pitch and chromosome 8. A small fMRI study provided evidence of increased activity in the inferior frontal sulcus during language tasks involving identification of different pronunciations. The authors suggest that this region is involved in categorisation for both language and non-language activities.

A randomised placebo-controlled trial (using placebo patches) of nicotine patches involving 400 smokers compared those taking nicotine patches before stopping smoking versus taking placebo. Both groups then used the nicotine patches for 10 weeks. At 10 weeks 22% of the first group had abstained from smoking compared to 11%  of those taking the placebo before stopping smoking. Adults grow new neurons in the brain – referred to as neurogenesis. The authors of a recently published study found an association between neurogenesis in mice and an improved ability to form more finely detailed spatial maps of the environment suggesting that these new cells are functional which in turn implies that they are integrating with other neurons that form memory.  Data from the Dunedin study in New Zealand provided evidence that certain aspects of the family history was useful in stratifying risk of recurrence of specific mental illnesses. The authors of a Cochrane review concluded that preventive psychological intervention (CBT and counselling) after trauma may not prevent onset of PTSD symptoms. This study was looking at prevention rather than treatment of PTSD. However in treatment of PTSD there is a good evidence base for psychological treatments. Researchers are beginning a study into the use of echolocation in blind people to help them navigate around the environment – this involves producing a clicking sound with the use of the tongue on the palate. The echoes from the clicks should allow determination of objects in the environment and this has already been used.

A recent Cochrane review looked at interventions for reducing alcohol misuse in university students and the authors examined 22 controlled trials with a cumulative total of 7275 college students finding that web-based/computer feedback was associated with a significant reduction in a number of outcome measures including drinking frequency, quantity, binge drinking and peak blood alcohol content. Patterns of substance misuse are being studied in Oregon, USA by analysing waste water before it is treated.  A small fMRI study provided preliminary evidence that improvement in multitasking through training is associated with changes in activity in the posterior prefrontal cortex. A small study has provided initial evidence of a significant association between performance on a smell-test and response to Donepezil according to clinical impression in people with mild-to-moderate Alzheimer’s Disease. A study of young-onset dementia (n=235) found a high prevalence of psychiatric and behavioural disorders. 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.

The authors of another Cochrane review concluded that there was insufficient evidence at this point to recommend the combination of Clozapine with another antipsychotic for treatment-resistant schizophrenia. In another Cochrane review which included data from 11 randomised-controlled trials with a cumulative total of 2441 adults identified as heavy drinkers, the authors found benefits for brief interventions with a reduction in alcohol consumption at 1-year follow-up although there weren’t found to be benefits for self-reported alcohol consumption and number of binges. In another Cochrane review there was found to be a significant benefit for the use of TCA’s or SSRI’s in the treatment of depression in primary care in adults (under the age of 65) based on analysis of 14 studies comparing TCA’s or SSRI’s with placebo with a cumulative total of 2283 participants*. In a study looking at prevalence of dementia in later life in low and middle-income countries and involving data from 14, 960 participants there was found to be a significant and inverse relationship between fish consumption and prevalence of dementia in later life. Another study didn’t show a benefit of DHA in mild-to-moderate Alzheimer’s Disease  on the ADAS-Cog after 18 months of treatment although another study did show a benefit for older adults with mild memory impairment Evidence for a possible role of fibroblast growth factor (Ffg) in development of the frontal cortex through radial glial cells was provided in one study and there is the suggestion that alterations in the Ffg may have a significant influence on the size of the frontal cortex in humans. In a series of recent studies a large number of acetylation switches(3600) have been found in a similarly large number of proteins (1750) which may be of relevance to a number of diseases and it will be interesting to see the results of subsequent research based on these results. A new ultrasound tool which samples at 125 Hz is being used in attempt to better classify African click languages. New radiocarbon dating, dates human remains in Gough’s Cave, Somerset to 14,700 years ago while a female Gibbon has been observed to slam a metal door in way which accentuated her territorial song suggesting a distant beginning for the use of percussion.

A committee found evidence of an association between Agent Orange exposure in Vietnam war veterans and risk of developing Parkinson’s Disease based on an an analysis of  16 studies looking at the effects of the herbicides. The authors conclude however that other types of study are needed to examine this association in more detail. A new Xenon delivery system has been developed which may have benefits in protecting against hypoxia-induced brain injury in humans. A single-blinded study (n=78) looked at improving attention (4 types described) in people who had developed a stroke by using Attention Process Training. Although they did find an improvement in attention with this training, at 6-months. A research team at the University of Vermont have been analysing text strings in blogs to estimate how ‘happy’ people are by looking at sentences with the words ‘I feel..’ in them. They were able to use 10 million sentences (from this site) and amongst their many findings they noted that people increasingly used the word ‘proud’ at the time of President Obama’s election, that Michael Jackson’s death was associated with a big drop in the valence scores (valence scores were calculated by rating each type of emotional word to estimate) and that teenagers were more likely to use the word ’sad’ in the sentence. As the 2012 Olympics approaches a new report has been published which reviews evidence from over 500 papers as well as expert interviews on crowd behaviours – the Understanding Crowd Behaviours Report. A computer simulation of organisms which uses simple variations in behaviour showed that turn-taking developed when organisms with different behaviours ‘locked’ into each other’s behaviour. In essence this suggests that individuals pursuing their own interests can engage in turn-taking behaviour. However this does not negate the possibility that turn-taking can occur for altruistic reasons particularly as decision-making is influenced by many factors in more complex organisms.  The authors of a meta-analysis looking at data involving over 8000 subjects concluded that people are more likely to discount information that contradicts the beliefs they already hold and that this tendency is influenced by a number of factors including personality type as well as the context of these beliefs. The authors of a paper looking at studies reported as randomised controlled trials in China identified 2235 studies and contacted the authors/coauthors. They report that less than 7% of the studies referred to as randomised controlled trials involved true randomisation. However this will not be limited to China and is relevant to the wider issue of research methodology.

* The authors note that a number of the trials were funded by pharmaceutical companies.

References

Abas MA, Punpuing S, Jirapramukpitak T, Guest P, Tangchonlatip K, Leese M, Prince M.Br J Psychiatry. 2009 Jul;195(1):54-60. Rural-urban migration and depression in ageing family members left behind.

de Graaf LE, Gerhards SA, Arntz A, Riper H, Metsemakers JF, Evers SM, SeverensJL, Widdershoven G, Huibers MJ.Clinical effectiveness of online computerised cognitive-behavioural therapywithout support for depression in primary care: randomised trial. Br J Psychiatry. 2009 Jul;195(1):73-80.

da Silva RC, Langoni H. Toxoplasma gondii: host-parasite interaction and behavior manipulation. Parasitol Res. 2009 Jun 23. [Epub ahead of print].

Hamshere ML, Green EK, Jones IR, Jones L, Moskvina V, Kirov G, Grozeva D, Nikolov I, Vukcevic D, Caesar S, Gordon-Smith K, Fraser C, Russell E, Breen G, St Clair D, Collier DA, Young AH, Ferrier IN, Farmer A, McGuffin P; Wellcome Trust Case Control Consortium, Holmans PA, Owen MJ, O’Donovan MC, Craddock N. Br J Psychiatry. 2009 Jul;195(1):23-9. Genetic utility of broadly defined bipolar schizoaffective disorder as a diagnostic concept.

Keck P E, Versiani M, Warrington L, Loebel A D, Horne L. Long-Term Safety and Efficacy of Ziprasidone in Subpopulations of Patients with Bipolar Mania.  J Clin Psychiatry. 2009. 70(6). 844-851.

Krueger CE, Dean DL, Rosen HJ, Halabi C, Weiner M, Miller BL, Kramer JH. Alzheimer Dis Assoc Disord. 2009 Jun 30. [Epub ahead of print].Longitudinal Rates of Lobar Atrophy in Frontotemporal Dementia, Semantic Dementia, and Alzheimer’s Disease.

Nicholas H, Moran P, Foy C, Brown RG, Lovestone S, Bryant S, Boothby H. Int J Geriatr Psychiatry. 2009 Jul 6. [Epub ahead of print]. Are abnormal premorbid personality traits associated with Alzheimer’s disease? – A case-control study.

Sampson EL, Blanchard MR, Jones L, Tookman A, King M. Br J Psychiatry. 2009 Jul;195(1):61-6. Dementia in the acute hospital: prospective cohort study of prevalence and mortality.

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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

The Amazing World of Psychiatry: A Psychiatry Twitter

The Amazing World of Psychiatry is now up on Twitter where there will be news and other updates. There are already quite a few psychiatry related twitterers already. You can follow the Twitter here.

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).

Responses

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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