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The truth behind *that* blood test for Alzheimer’s
Nothing could be better than you going to your GP and ordering a simple blood test for dementia?
Or could it?
There’s been an increasing awareness that the imparting of the initial diagnosis of a potential diagnosis is often botched up.
It’s often said it’s done in a hurry. There’s no form of pre-counselling or post-counselling support.
The scope for hyperbole of reporting of this paper was of course massive.
Ken Howard, who is living with a dementia himself, and who campaigns especially in this specialised area, put it succinctly in a tweet of his.
@KateSwaffer @WhoseShoes @legalaware Thanks .I really believe that the 15 mins following diagnosis can be used to change the rest of lives
— Ken Howard (@kenhowarduk) March 5, 2014
The Guardian boasted:
This is based on a concise report in Nature Medicine.
The full reference is: Mark Mapstone, Amrita K Cheema, Massimo S Fiandaca, Xiaogang Zhong, Timothy R Mhyre, Linda H MacArthur, William J Hall, Susan G Fisher, Derick R Peterson, James M Haley, Michael D Nazar, Steven A Rich, Dan J Berlau, Carrie B Peltz, Ming T Tan, Claudia H Kawas, Howard J Federoff. Plasma phospholipids identify antecedent memory impairment in older adults. Nature Medicine, 2014; DOI: 10.1038/nm.3466
By far the best report was by Laura Donnelly (@lauradonnlee) in the Telegraph:
That particular report was extremely good.
Take for example Donnelly’s care over this sentence:
“Existing drugs for Alzheimer’s disease work best if given early, and can lessen the symptoms, but do not slow overall progression of disease.”
This is absolutely spot on.
The BBC24 news on the other hand at 11 am said, with a headline read out by newsreader Joanna Gosling, “Scientists in the USA have developed a blood test which could accurately predict the onset of Alzheimer’s.”
In this study, researchers from Georgetown University Medical Centre in the US examined 525 healthy participants aged 70 and over and monitored them for five years. During the research 28 participants went on to develop the conditions, according to their reported criteria, and 46 were diagnosed at the start of the study.
Their composite neuropsychological score is a composite score across a number of domains – this is fair, but of course entirely arbitrary. One could argue (or not) it should have been more duly weighted to episodic memory which comprises the more typical early presentations of Alzheimer’s disease.
One of the first issues, as for many papers of this nature, is how reliable these diagnoses are. According to Professor Seth Love from Bristol, in most published series, the accuracy of clinical diagnosis of the different diseases that cause dementia is of the order of 70–80%. This means 20-30% have possibly the wrong diagnosis.
Therefore Love argues that establishing a precise diagnosis by post-mortem neuropathological examination will not, of course, benefit the individual patient but matters nonetheless, for several reasons.
It’s interesting also noting his response, as scientific adviser to Alzheimer’s BRACE (@AlzheimersBRACE) here, too.
Back to the study reported in Nature Medicine, midway through the research, the authors analysed 53 patients who already had one of the conditions and 53 “cognitively normal” people.
They discovered ten molecules that appeared to”reveal the breakdown of neural cell membranes in participants who develop symptoms of cognitive impairment or Alzheimer’s. They then tested other participants’ blood to see whether these “biomarkers” could predict whether or not they would go on to develop the conditions.
These are specialist assays. They are not ‘routine blood tests’ like a full blood count, liver function tests, or urea or electrolytes. Therefore they, if they were ever to be rolled out, would have considerable cost implications.
And there is an important biological issue why a build-up of toxic substances, if in the brain become manifest as a decline in thinking sufficiently bad to warrant a diagnosis of dementia, should effect cells in the rest of the body.
The separation of the brain and body through the blood-brain barrier is totemic.
The explanation of this by the authors is indeed long.
“The defined ten-metabolite profile features PCs and ACs, phospholipids that have essential structural and functional roles in the integrity and functionality of cell membranes. Deficits of the plasmalemma in AD have been described previously. Studies have shown decreased plasma PC levels and lysoPC/PC ratiosand increased cerebrospinal fluid (CSF) PC metabolites in patients with AD15, as well as decreased phosphatidylinositol in the hippocampus16 and other heteromodal cortical regions. Furthermore, amyloid-? may directly disrupt bilayer integrity by interacting with phospholipids. ACs are known to have a major role in central carbon and lipid metabolism occurring within the mitochondria. They have also been associated with regulation, production and maintenance of neurons through enhancement of nerve growth factor production, which is a known potent survival and trophic factor for brain cholinergic neurons, particularly those consistently affected by AD within the basal forebrain.”
This is a convoluted explanation which does not make clear whether the investigators had any particular hypothesis as to which molecules would be affected BEFORE the study.
The lack of the clear hypotheses BEFORE the study makes one immediately suspicious about whether the authors have corrected adequately for running lots of statistical comparisons after the study.
But I think this might be OK – as they have applied a statistical Bonferroni correction for multiple comparisons.
But it MIGHT NOT be OK.
This study is reported to be the first research that has been able to show differences in biomarkers in the blood between people with Alzheimer’s before the symptoms occur and people who will not go on to develop the condition. It’s worth noting that there are hundreds of ‘varieties’ of dementia, so this research whilst interesting will not be directly relevant to those dementias.
The finding has potential for developing treatment strategies for Alzheimer’s at an earlier stage – when therapy would be more effective at slowing or preventing onset of symptoms, according to the authors. But there has never been a consistent body of research demonstrating beneficial effects in the majority of patients slowing the rate of progression. Some might say that we should spending much effort into making sure that people are able to live well with dementia.
Prof Federoff, a professor of neurology at Georgetown University, said: “The lipid panel was able to distinguish with 90 per cent accuracy these two distinct groups: cognitively normal participants who would progress to mild cognitive impairment or Alzheimer’s disease within two to three years, and those who would remain normal in the near future.” (as reported in the Telegraph)
“Our novel blood test offers the potential to identify people at risk for progressive cognitive decline and can change how patients, their families and treating physicians plan for and manage the disorder.”
Note this conversion is to mild cognitive impairment (“MCI”) or Alzheimer’s Disease, however, and the two entities are very distinct. It is far from clear, in the experience of a reasonable body of academics, whether you can safely say MCI is a ‘predementia’ stage of dementia.
They are two completely different entities, a point completely glossed over by people with no medical training.
A “mild cognitive impairment” is a clinical diagnosis in which deficits in cognitive function are evident but not of sufficient severity to warrant a diagnosis of dementia (Nelson and O’Connor, 2008).
However, the evidence of progression of MCI (mild cognitive impairment) to DAT is currently weak. It might be attractive to think that MCI is a preclinical form of dementia of Alzheimer Type, but unfortunately the evidence is not there to back this claim up at present: only approximately 5-10% and most people with MCI will not progress to dementia even after ten years of follow-up (Mitchell and Shiri-Feshki, 2009).
This unnecessary conflation of MCI and dementia of Alzheimer’s type (dementia), widespread in many media reports, is extremely unhelpful therefore.
And above all, this will have to be replicated with a different group of patients, different clinicians making their probable diagnoses, and a different way of measuring the composite score (or implementing an altogether different neurocognitive assessment, if necessary.)
Dr Doug Brown, director of research and development at the Alzheimer’s Society, and who does not have a medical degree but did a PhD in Molecular Biology at Cambridge after doing his undergraduate degree in Biochemistry and Genetics in Sheffield, added:
“Having such a test would be an interesting development, but it also throws up ethical considerations.”
“If this does develop in the future people must be given a choice about whether they would want to know, and fully understand the implications.”
This is completely correct.
But the paper does not have an ethical discussion at all by the authors – chacun à son goût.
One of the good consequences of the #G8dementia is that there overall has been better awareness of the dementias. This can only be a good thing.
As there is better awareness, the need for accurate reporting is imperative. Massive congratulations therefore to Laura Donnelly who gave an extremely balanced and measured report of this article.
I have been most worried about the question ‘what happens next?’ once you make the diagnosis here of Alzheimer’s disease before the onset of symptoms.
I have always been concerned that the outcome from the medical model, diagnosis and investigations, has to be a medical treatment; in other words you always hear ‘we can intervene quicker with treatments’, with scant regard for living well strategies.
This is why it is so helpful to have Prof Martin Rossor (@martinrossor) at Qeuen Square, recently put in post as NIHR National Director for Dementia Research.
I think many academics would have allowed publication of these data, but probably wished for a more critical interpretation of the results. But Nature Medicine papers are notoriously short, and in the public interest, on the balance of probabilities, it was ‘better out than in’.
And news just in.
The lead author, Mapstone, said nothing about the efficacy of current treatments in his BBC interview this afternoon. When asked by presenter Carole Walker about this major drawback in the rationale in the screening process, Mapstone argued the need to validate the results first in a larger and diverse population.
And of course Mapstone stated one of his intentions.
“It’s a very good point… it’s good at screening individuals… we hope it will be commercialised” (Mapstone)
— shibley (@legalaware) March 10, 2014
Nonetheless, this all has a feeling of ‘the shock doctrine‘ about it – where we’re supposed to be shocked so much, we’re meant to dig deep into our pockets to support Pharma. A bit of money for social care wouldn’t go amiss.
The English dementia policy: some personal thoughts
The last few years have seen a much welcome progression, for the better, for dementia policy in England. This has been the result of the previous Government, under which “Living well with dementia: the National Dementia Strategy” was published in 2009, and the current Government, in which the Prime Minister’s Dementia Challenge in 2012 was introduced.
Dementia is a condition which lends itself to the ‘whole person’, ‘integrated’ approach. It is not an unusual for an individual with dementia to be involved with people from the medical profession, including GPs, neurologists, geriatricians; allied health professionals, including nurses, health care assistants, physiotherapists, speech and language specialists, nutritionists or dieticians, and occupational therapists; and people in other professionals, such as ‘dementia advocates’ and lawyers. I think a lot can be done to help individuals with dementia ‘to live well'; in fact I have just finished a big book on it and you can read drafts of the introduction and conclusion here.
It is obviously critical that clinicians, especially the people likeliest to make the initial provisional diagnosis, should be in the ‘driving seat’, but it is also very important that patients, carers, family members, or other advocates are in that driving seat too. I feel this especially now, given that there is so much information available from people directly involved in with patients (such as @bethyb1886 or @whoseshoes or @dragonmisery) This patient journey is inevitably long, and to call it a ‘rollercoaster ride‘ would be a true understatement. That is why language is remarkably important, and that people with some knowledge of medicine get involved in articulating this debate. Not everyone with power and influence in dementia has a detailed knowledge of it, sadly.
I am very honoured to have my paper on the behavioural variant of frontotemporal dementia to be included as one of a handful of references in the current Oxford Textbook of Medicine. You can view this chapter, provided you do not use it for commercial gain (!), here.
I should like to direct you to the current draft of a video by Prof Alistair Burns, Chair of Psychiatry at the University of Manchester, who is the current National Clinical Lead for Dementia. You can contact him over any aspects of dementia policy on his Twitter, @ABurns1907. I strongly support Prof Burns, and here is his kind Tweet to me about my work. I agree with Prof Burns that once individuals can be given face-to-face a correct diagnosis of dementia this allows them to plan for the future, and to access appropriate services. The problem obviously comes from how clinicians arrive at that diagnosis.
I am not a clinician, although I studied medicine at Cambridge and did my PhD on dementia there too, but having written a number of reviews, book chapters, original papers, and now a book on dementia, I am deeply involved with the dementia world. I am still invited to international conferences, and I personally do not have any financial vested interests (e.g. funding, I do not work for a charity, hospital, or university, etc.) That is why I hope I can be frank about this. Clinicians will be mindful of the tragedy of telling somebody he or she has dementia or when he or she hasn’t, but needs help for severe anxiety, depression, underactive thyroid, or whatever. But likewise, we are faced with reports of a substantial underdiagnosis of dementia, for which a number of reasons could be postulated. Asking questions such as “How good is your memory?” may be a good basic initial question, but clinicians will be mindful that this test will suffer from poor specificity – there could be a lot of false positives due to other conditions.
At the end of the day, a mechanism such as ‘payment-by-results’ can only work if used responsibly, and does not create an environment for ‘perverse incentives’ where Trusts will be more inclined to claim for people with a ‘label’ of dementia when they actually do not have the condition at all. A double tragedy would be if these individuals had poor access to care which Prof Burns admits is “patchy”. In my own paper, with over 300 citations, on frontal dementia, seven out of eight patients had very good memory, and yet had a reliable diagnosis of early frontal dementia. Prof Burns rightly argues the term ‘timely’ should be used in preference to ‘early’ dementia, but still some influential stakeholders are using the term ‘early’ annoyingly. On the other hand, I wholeheartedly agree that the term ‘timely’ is much more fitting with the “person-centred care” approach, made popular in a widespread way by Tom Kitwood.
I am still really enthused about the substantial progress which has been made in English dementia policy. I enclose Prof Burns’ latest update (draft), and the video I recorded yesterday at my law school, for completion.
Prof Alistair Burns, National Clinical Lead for Dementia
Me (nobody) in reply
Avoiding the rollercoaster: a policy for dementia must be responsible
The last few years have seen a much welcome progression, for the better, for dementia policy in England. This has been the result of the previous Government, under which “Living well with dementia: the National Dementia Strategy” was published in 2009, and the current Government, in which the Prime Minister’s Dementia Challenge in 2012 was introduced.
Dementia is a condition which lends itself to the ‘whole person’, ‘integrated’ approach. It is not an unusual for an individual with dementia to be involved with people from the medical profession, including GPs, neurologists, geriatricians; allied health professionals, including nurses, health care assistants, physiotherapists, speech and language specialists, nutritionists or dieticians, and occupational therapists; and people in other professionals, such as ‘dementia advocates’ and lawyers. I think a lot can be done to help individuals with dementia ‘to live well'; in fact I have just finished a big book on it and you can read drafts of the introduction and conclusion here.
It is critical obviously that clinicians, especially the people likeliest to make the initial provisional diagnosis, should be in the ‘driving seat’, but it is also very important that patients, carers, family members, or other advocates are in that driving seat too. I feel this especially now, given that there is so much information available from people directly involved in with patients (such as @bethyb1886 or @whoseshoes or @dragonmisery) This patient journey is inevitably long, and to call it a ‘rollercoaster ride‘ would be a true understatement. That is why language is remarkably important, and that people with some knowledge of medicine get involved in articulating this debate. Not everyone with power and influence in dementia has a detailed knowledge of it, sadly.
I am very honoured to have my paper on the behavioural variant of frontotemporal dementia to be included as one of a handful of references in the current Oxford Textbook of Medicine. You can view this chapter, provided you do not use it for commercial gain (!), here.
I should like to direct you to the current draft of a video by Prof Alistair Burns, Chair of Psychiatry at the University of Manchester, who is the current National Clinical Lead for Dementia. You can contact him over any aspects of dementia policy on his Twitter, @ABurns1907. I strongly support Prof Burns, and here is his kind Tweet to me about my work. I agree with Prof Burns that once individuals can be given face-to-face a correct diagnosis of dementia this allows them to plan for the future, and to access appropriate services. The problem obviously comes from how clinicians arrive at that diagnosis.
I am not a clinician, although I studied medicine at Cambridge and did my PhD on dementia there too, but having written a number of reviews, book chapters, original papers, and now a book on dementia, I am deeply involved with the dementia world. I am still invited to international conferences, and I personally do not have any financial vested interests (e.g. funding, I do not work for a charity, hospital, or university, etc.) That is why I hope I can be frank about this. Clinicians will be mindful of the tragedy of telling somebody he or she has dementia or when he or she hasn’t, but needs help for severe anxiety, depression, underactive thyroid, or whatever. But likewise, we are faced with reports of a substantial underdiagnosis of dementia, for which a number of reasons could be postulated. Asking questions such as “How good is your memory?” may be a good basic initial question, but clinicians will be mindful that this test will suffer from poor specificity – there could be a lot of false positives due to other conditions.
At the end of the day, a mechanism such as ‘payment-by-results’ can only work if used responsibly, and does not create an environment for ‘perverse incentives’ where Trusts will be more inclined to claim for people with a ‘label’ of dementia when they actually do not have the condition at all. A double tragedy would be if these individuals had poor access to care which Prof Burns admits is “patchy”. In my own paper, with over 300 citations, on frontal dementia, seven out of eight patients had very good memory, and yet had a reliable diagnosis of early frontal dementia. Prof Burns rightly argues the term ‘timely’ should be used in preference to ‘early’ dementia, but still some influential stakeholders are using the term ‘early’ annoyingly. On the other hand, I wholeheartedly agree that the term ‘timely’ is much more fitting with the “person-centred care” approach, made popular in a widespread way by Tom Kitwood.
I am still really enthused about the substantial progress which has been made in English dementia policy. I enclose Prof Burns’ latest update (draft), and the video I recorded yesterday at my law school, for completion.
Prof Alistair Burns, National Clinical Lead for Dementia
Me (nobody) in reply
A new way of diagnosing the earliest stages of Alzheimer's Disease?
Alzheimer’s disease is the most common form of dementia in the UK, characterized by profound memory problems in affected individuals. Currently there is no single test or cure for dementia, a condition that affects over 800,000 people in the UK. The prospect of disease modification has intensified the need to diagnose very early Alzheimer’s Disease with high accuracy. The ultimate goal is possibly to identify and treat asymptomatic individuals with early stages of Alzheimer’s Disease, or those at high risk of developing the disease. By definition, such individuals will be asymptomatic, and disease biomarkers or high-risk traits will be require identification. For pre-symptomatic treatment trials, demonstration of disease modification will ultimately require evidence of delay to symptom-onset or conversion to Alzheimer’s Disease.
In a paper reported recently, UK experts say they may have found a way to check for Alzheimer’s years before symptoms appear. A lumbar puncture test (a test to get spinal fluid from an individual via his back) combined with a brain scan can identify patients with early tell-tale signs of dementia, they believe. Ultimately, doctors could use this to select patients to try out drugs that may slow or halt the disease. Although there are many candidate drugs and vaccines in the pipeline, it is hard for doctors to test how well these work because dementia is usually diagnosed only once the disease is moreadvanced. Researchers at the Institute of Neurology, University College of London, working with the National Hospital for Neurosurgery and Neurosurgery, Queen Square, London, believe they can now detect the most common form of dementia – Alzheimer’s disease – at its earliest stage, many years before symptoms appear.
Their approach checks for two things – shrinkage of the brain and lower than normal levels of a protein, called amyloid, in the cerebrospinal fluid (CSF) that bathes the brain and spinal cord. Experts already know that in Alzheimer’s there is loss of brain volume and an unusual build up of amyloid in the brain, meaning on the whole less amyloid in the CSF. There is, however, rather conflicting evidence for a relationship between measures of amyloid burden and brain volume in healthy controls, The research team reasoned that looking for these changes might offer a way of detecting the condition long before than is currently possible. To confirm this, they recruited 105 healthy volunteers to underwent a series of checks. All subjects were drawn from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a multi-centre publicly/privately-funded longitudinal study investigating adult subjects with Alzheimer’s Disease, ‘mild cognitive impairment’ of the memory variety, and normal cognition. Participants undergo baseline and periodic clinical and neuropsychometric assessments and serial MRI.
The volunteers had lumbar puncture tests to check their spinal cerebrospinal fluid (CSF) for levels of amyloid and MRI brain scans to calculate brain shrinkage. The results, published in Annals of Neurology (reference provided below), revealed that the brains of those normal individuals with low CSF levels of amyloid (38% of the group), shrank twice as quickly as the other group. They were also five times more likely to possess the APOE4 cholesterol risk gene and had higher levels of another culprit Alzheimer’s protein, tau. Crucially, the results may allow doctors to pursue avenues to test which drugs might be beneficial in delaying or preventing dementia.
Potential limitations of the study include the relatively high percentage of amyloid-positive normal controls, which may or may not reflect the true population prevalence of individuals with significant amyloid pathology in this age range. There are also a number of issues relating to the reproducibility, reliability, and reporting of biomarker levels in spinal fluid, which need to be standardized to allow for cross-study comparisons.
Notwithstanding that, the scope for further research is enormous. Whether excess rates of brain atrophy in apparently cognitively normal aged patients with CSF profiles suggestive of AD inevitably lead to cognitive impairment, and if so over what time frame, needs to be established. If this proves to be the case, the results we present have significant implications for very early intervention, demonstrating that biomarkers may be used not only to identify Alzheimer’s Disease pathology in asymptomatic individuals, but also to demonstrate and quantify pr-esymptomatic clinical dementia. This suggests that disease-modifying trials in asymptomatic individuals with the aim of preventing progression to cognitive impairment and dementia may be feasible one day.
Reference:
Increased brain atrophy rates in cognitively normal older adults with low cerebrospinal fluid A?1-42. Jonathan M. Schott MD, Jonathan W. Bartlett PhD, Nick C. Fox MD, Josephine Barnes, for the Alzheimer’s Disease Neuroimaging Initiative Investigators Article first published online: 22 DEC 2010 DOI: 10.1002/ana.22315
You can view this paper here.
(c) Dr Shibley Rahman 2010
