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 personal medicine 
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Joined: Mon Sep 30, 2013 11:16 pm
Posts: 24
Post personal medicine
At the moment research seems to be focussed on finding over-arching cures/treatments and tests for this disease and other neuro-psychiatric and neuro-degenerative conditions.

However, I think it is fairly well established that there are probably a multitude of metabolic disorders that can cause Dementia with Lewy Bodies. Each individual with this disease may have one of many metabolic defects causing the disease and their metabolic defect may also find multiple expressions in different disease states. Yet I am confident that the vast majority, if not all, of the readers of this post have not had any significant effort made to identify their individual disorder that is causing the disease, so that their underlying disorder can be treated.

This must be a wrong approach to trying to beat Dementia with Lewy Bodies and other neuro-degnerative and neuro-psychiatric conditions.

Performing a range of metabolic tests and trying to identify the individual's disorder's signature abnormalities must be the way to go for many people. If recurring patterns of abnormalities are identified in individuals they should be investigated by professionals to try to establish the cause. Yet in my experience this does not happen. As far as I can see, there has not even been general research on whether amino acid abnormalities are present in Dementia with Lewy Bodies.

What is causing the failure to provide tailored medical intervention to individuals? Is there anything we can do about it?

I am talking about an institutionalised/systematic problem in the delineation of research and treatment roles. Meanwhile, your doctor is trying to do the best they can for you and give you the best care currently available.

In my case, I probably understand at least part of the mechanism of my disorder and I am investigating a possible cause. Once I know what is wrong with me, I can hopefully target treatment at my disorder. Meanwhile, I can trial treatments based on the what I do know about the mechanism of my disorder. But I only do this under the supervision of my doctor.


Mon Dec 09, 2013 4:31 am
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Joined: Thu Apr 21, 2011 9:07 pm
Posts: 245
Post Re: personal medicine
You are right that personalized medicine - better and more specific diagnosis, and more targeted treatment - will eventually be the answer. Or so we hope!

The biggest challenge right now is getting a suite of biomarkers that can be reliably measured during life and correlate with the definitive post-mortem findings. To do this, we need lots of biomarker data - neuroimaging of various sorts (PET, MRI), spinal fluid samples, blood samples, possibly other fluids - plus detailed clinical and neuropsychological data while folks are alive, and then post mortem on as many as possible. The number of things to measure and sift through as possible biomarkers is enormous. But this is the top priority at NIH for dementia, including work both at National Institute on Aging and at NINDS. NIH, helped by donations through the Foundation for NIH from Alzheimer's Association and a number of pharmaceuticals, has sponsored the Alzheimer's Disease Neuroimaging Initiative projects (ADNI) since 2004. (I'm actually head of one of the core research units for ADNI, nationally.) There are world-wide partnerships with similar studies - Australia, Japan, Europe, China, Brazil, Korea, India. We get postmortems on as many participants as possible, and of course find a number with LBD. So we are trying hard, but it's enormously complicated. And NIH funding is under siege right now from a pack of loons trying to out-crazy each other.

Anyway, please know that this is a major effort, engaging lots of us - not to mention many volunteers who patiently sit through all this testing! We are already planning for ADNI-3 and one of the topics under discussion is tau and synuclein imaging, and trying to get at the underlying diversity. Lots of really really brilliant people, absolutely dedicated to solving this, no matter how tough.

Laurel

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Laurel - mother (97) diagnosed April, 2011, with LBD; died May, 2014.


Fri Dec 13, 2013 2:09 am
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Joined: Mon Sep 30, 2013 11:16 pm
Posts: 24
Post Re: personal medicine
I know there is a lot of work going on and I am grateful to everyone involved.

But I still think the focus is too much on over-arching diagnostic test and finding a one-size fits all 'cure'. I think far more focus should be on researching each individuals abnormal test results and finding better treatments for them based on that research and clinical judgement. I also think that treating specialists should be trained to do this. That would manifoldly increase the amount of people working on resolving these diseases. It is wrong that Doctors should treat on the basis of clinical presentation alone and not on the basis of also trying to understand the patient's actual disorder.

My research of my abnormal results tells me that I very probably have over-activation of a cortisol up-regulated pathway from proline to polyamines and that my urea cycle is therefore probably partially defective. Also, that it is possible that I have excessive nitric oxide (NO) causing over-activation of cGMP and under- activation of a pathway from NO to nitrosyl haemoglobin. And that a possible defect that could cause all of my results would be in soluble guanalyl cyclase which plays a role in the cGMP pathway and the nitrosyl haemoglobin pathway. Also, that defects in soluble guanalyl cyclase could be responsible for other cases of dementia. But whilst there is research on excessive nitric oxide causing dementia, there is as far as I can see no one actively working on this area.

I got given anti-psychotics that did me more harm than good and I was given them based on clinical judgement and clinical presentation. But treating myself, under the supervision of a doctor, based on knowing what is probably/possibly going wrong in my metabolism is producing significant positive results. Obviously finding the actual defect causing my abnormal results would potentially be curative for me, but in the meantime if I cut amines and nitrates/nitrites and substances that activate nitric oxide (sulphites) out of my diet I respond very well. I also respond well to treatments aimed at inhibiting polyamines and scavenging nitric oxide.

That effective treatments were never given to my grandmother, father, aunt and myself, who I think all have/had my disorder, and that I have had to do this myself, tells me the system is failing. As does my detailed review of research papers which tells me that research has historically taken a very much scatter-gun approach very much dependent on the interests of individual researchers.

What seems to me to be going wrong is that research into this should follow the following form:

1. Find abnormal biomarkers in individuals;
2. Seek to understand what the abnormal results mean to that individual;
3. Apply the knowledge thus gained to applying treatment.

But because research has been for over-arching biomarkers for diseases that probably have multiple causes the process has not reached step 1.

Also, even if a 'cure' for dementia is achieved, each individual's metabolic disorder probably has multiple disease expressions. In me, my disorder leaves me vulnerable to all diseases and disorders associated with high polyamines and high nitric oxide. Merely curing my dementia will probably not prevent many of these other disease outcomes. But finding a treating my metabolic defect might do that.


Fri Dec 13, 2013 10:40 pm
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Joined: Thu Apr 21, 2011 9:07 pm
Posts: 245
Post Re: personal medicine
Actually the real focus these days IS on "personalized medicine" - finding biomarkers that correlate with the diversity of outcomes across different individuals and can guide targeted treatment. The problem is that there are literally millions of potential biomarkers, so you can't just say, O, these 3 are different, because any one person will have hundreds or thousands that are different. You have to understand what is a meaningful difference, that correlates with the specific clinical problems. And then you have to know how to target the problem.

It's just a really, really complicated problem. What you suggest is very much what we are trying to do, but it's not at all simple even to figure out what are the right things to look at (out of millions of possibilities), let alone to demonstrate the clinical efficacy of treating a specific combination of biomarkers with a specific set of meds. So the first part is pulling the signal out of the noise (your specific disease-related biomarker, compared to all the other unrelated heterogeneity you carry). The second part is, given that we know the signal - say 2 mutations and an epigenetic gene suppression - you'd still have to figure out the right drug combination and demonstrate that it works not just in test tubes or mice, but in people like you.

If you try to rush this, without careful research, you wind up with the Duke mess (c.f. 60 Minutes, Potti, cancer biomarkers.)

So I agree totally with your vision of how it should work, but it is VERY hard to get there!!! (believe me, we are trying hard…)
Laurel

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Laurel - mother (97) diagnosed April, 2011, with LBD; died May, 2014.


Sat Dec 14, 2013 12:47 am
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Joined: Mon Sep 30, 2013 11:16 pm
Posts: 24
Post Re: personal medicine
I think we are at cross purposes. You appear to be talking about personalized medicine being based on finding biomarkers that correlate with a diversity of outcomes across different individuals. I am saying that research should not be so focussed on doing this, and that personalised medicine should be focussed on finding each individual's abnormal biomarkers and figuring out what they mean for that individual.

Also, the 'answer' will very likely not be complicated. The concept that these disorders are supremely complicated is an unhelpful attitude that permeates the medical world. When the cause of these disorders are understood, they will be something astonishingly simple, such as B3 deficiency being identified as the cause of pellagric dementia. The effects are complicated, but in most people I very much doubt the cause will be.

My abnormal test results and my understanding of what these mean in terms of the misfiring of metabolic pathways explain the disease history of my family in considerable and surprising detail. I do not flatter myself that I am unique. If I can get as far as I have for me without medical training, it can be done for others.


Sat Dec 14, 2013 2:12 am
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Joined: Thu Apr 21, 2011 9:07 pm
Posts: 245
Post Re: personal medicine
Agree that for the biomarkers we understand, we can do what you suggest and try to treat directly. Unfortunately, what we understand - evidence-based - is not nearly as much as one might wish. I'm glad that you are in the fortunate position that your own symptoms correlate so clearly to something we do understand and can treat directly. I wish that were true in more cases!

My mother, for example, is remarkably healthy if you look at standard lab tests (and I mean a WIDE variety, blood levels of pretty much anything one could name as a possible evidence-based thing to test, MRI, CT, and so on.) Everything is "normal" and has been for many years. Nonetheless, she has what we presume to be Lewy body dementia, with increasing physical weakness. The answer may not be complicated but it is not traceable to anything we currently know medically. Nothing metabolic, environmental, or known genetically accounts for her symptoms (we do have a clinical label for the syndrome, but that's not the same as a causal attribution.) Her doctors are very thoughtful, bright, experienced clinicians. I'm pretty good at this stuff myself, after 40 years in the medical field. Some of the best people in the country have reviewed all that we know, and we just don't have an answer.

So yes, we do need more research to figure out where to look when the answer is not contained in what we know already. We have to figure out where the clues to abnormality are, when they are not in what we already look at routinely. That's how we figure out how to "find each individual's abnormal biomarkers and… what they mean…" - we look at a lot of biomarkers, and a lot of people, and we try to extend our understanding of what constitutes abnormal and what its implications might be. I don't know how much time you spend reading the medical literature - I read (and write) it professionally - and I don't see a lot of people claiming things are "supremely complicated." More often, people are modest and guarded about what they do not understand, appropriately so. Sure, there is a tendency on the part of young clinicians to look for zebras, and case reports feature the odd cases rather than the standard ones, but in general, both in clinical practice and in research, we start by looking for simple explanations and then testing whether they withstand scrutiny.

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Laurel - mother (97) diagnosed April, 2011, with LBD; died May, 2014.


Mon Dec 16, 2013 3:07 am
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Joined: Mon Sep 30, 2013 11:16 pm
Posts: 24
Post Re: personal medicine
I know you have tried very hard already, perhaps because of your medical background.

If she has not had them done already, you might try (I note you said metabolic abnormalities have been ruled out so you may have had these tests done already):

serum amino acids;
urine amino acids;
urinary creatinine;
vitamins B2 (biotinidase), B3, B6 and B12; and
methemoglobin.

It is a long shot, and if they show abnormalities it would just be the start of a journey you may not reach the end of. I would think there is a good possibility that at least serum amino acid taurine may be low.

And if she has any reactions to food at all and is well enough, trial her (with the help of a dr and dietician) on the food elimination diet practiced by the Royal Prince Alfred Hospital Allergy clinic in Sydney. But cut out the celery, leak, chives and spring onion from the elimination diet as they contain or may contain nitrates, and only drink nitrate free water.

Best wishes


Tue Dec 17, 2013 7:37 pm
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Joined: Thu Apr 21, 2011 9:07 pm
Posts: 245
Post Re: personal medicine
Thanks for interesting thoughts! She has actually had most of those tests at some point a couple of years ago, and she was normal right down the line. I had wondered about B12 in particular but nope, just fine.

At this point, since she is 97 1/2 and increasingly frail, we won't do any more testing; we only do what we need to keep her as comfortable as possible. We are fortunate that she knows all of us and remembers our daily visits and takes some comfort in that.

She's having increasing trouble with swallowing - it seems to be the executive function, just carrying out the action - so I pretty much feed her whatever appeals to her and goes down easily. As Charlie, her neurologist, put it last week, "If she wants to eat ice cream, that's fine; you can live a long time on ice cream!" My dad brings her grapes every day, and I feed her whatever seems appealing from the menu (tonight she ate some shrimp stir-fry soup, with rice and little bay shrimp, a few bites of stuffing, and of course ice cream, mint chocolate chip this time, a favorite.)

We're pretty philosophical about it. She and my dad both made it to 95 with essentially no health problems, so they must have been doing something right! Even with best possible care and favorable genetics, you can't live forever, and to have 95 healthy years and still share your lives with each other and your children and grandchildren is not to be discounted. (I'd probably take a more aggressive approach if she were even 10 years younger. As it is, I feel like we've done as much testing and treatment as warranted, and now it is time to provide compassionate supportive care.)

But thanks for patient thoughtful commentary - it may help someone else, or maybe the next family member to get into the 90's!
Laurel

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Laurel - mother (97) diagnosed April, 2011, with LBD; died May, 2014.


Wed Dec 18, 2013 1:56 am
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Joined: Mon Sep 30, 2013 11:16 pm
Posts: 24
Post Re: personal medicine
I agree with your approach. It is the best way for your mum.

A final thought: if you did not look at the test results yourself, get hold of copies and check them. I was told several times my results were normal by treating doctors when they were abnormal. I think this was because the abnormalities were not understood so, to the doctor, they did not mean anything.

Thank you for your insights.


Wed Dec 18, 2013 4:38 pm
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Joined: Thu Apr 21, 2011 9:07 pm
Posts: 245
Post Re: personal medicine
Hi again,
One of the nice things about having HIPAA clearance signed by both parents, and having electronic medical records, is that I'm actually authorized to see all the lab results as soon as the doctor has them (raw numbers, not just "normal" or "abnormal"). You're right - it really is important to keep track! Even borderline findings may be important if they are part of a pattern. For example, I can pull up her history and track changes over the last 8 years, since they moved to be closer to us and started getting their care in our medical center. A value that is on the low side but not abnormal would tell me something different if it were a big change from the last 5 years, than if she'd been that way all along. Her doctors are also really good and that is a great comfort. Her PCP actually makes "house calls" - he stops by the care unit after work to check up on her, every month or so, rather than have me bring her over to the office.

Since she has been in this little unit that houses 12-14 people, 11 months now, there have been, I think, 8 deaths, and one more is likely very soon. (Some people only move in at the very end, when it is clear they have very little time left.) Lewy body is so unpredictable, who knows what to expect. We are just trucking along, doing the best we can, and trying to honor her wishes - she was very clear before, and even now, she can tell us what she wants, for the most part.

It's not easy, though, is it? I'm grateful for the support and kindness of folks here!
Laurel

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Laurel - mother (97) diagnosed April, 2011, with LBD; died May, 2014.


Sun Dec 22, 2013 1:03 am
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Joined: Mon Sep 30, 2013 11:16 pm
Posts: 24
Post Re: personal medicine
No, it is not easy. It is a very hard disease.

But it was good to hear that there is going to be more focus at a political level on resolving dementia. I don't think it will be too long now to find a solution, but that is never going to be quick enough for those already suffering.

Best wishes,


Fri Dec 27, 2013 3:38 am
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