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Is Narcolepsy Neurodegenerative?


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#1 Bafflegab

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Posted 01 September 2009 - 03:05 PM

In the August 18, issue of the journal, Neurology (2009;73:511-517), a team of researchers from the Sleep Disorder Research Project, in Tokyo, Japan, report their most recent study suggests that narcolepsy with cataplexy is not degenerative.

I'm going to try to make this quick and easy, so please no nit-picking.

The researchers examined (post-mortem) the brains of four narcoleptics with cataplexy for the presence of collections of intracellular protein (ubiquitinated inclusions), which is the hallmark of most neurodegenerative diseases. What the researchers found was that while PWN-C had a marked decrease in the amount of hypocretin cells, they did not find any other ubiquitinated inclusions. Not even in the PWN-C who also had dementia.

So, while the answer to the question, "Is my (or my child's) narcolepsy with cataplexy going to get worse over time?" may not be a definitive, "No." This is good news.

#2 sleepless sleeper

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Posted 01 September 2009 - 03:49 PM

I have attached a PDF document, which goes to prove that no one in the medical field seems to agree on much of anything narcolepsy related. It is the presentation of research on success rates when transplanting hypocretin cells.

In the Introduction, it states: "Narcolepsy is now identified to be a neurodegenerative disease because there is a massive loss of specific neurons in the brain."

Degeneration is the loss or destruction of cells, which is why they categorized N to be degenerative if there has been any amount of loss of hypocretin. The research that Bafflegab presents states that this is for people with N and C. What is mentioned is "The researchers examined (post-mortem) the brains of four narcolepticswith cataplexy for the presence of collections of intracellular protein(ubiquitinated inclusions), which is the hallmark of mostneurodegenerative diseases." Does this mean that other neurodeg. diseases use other hallmarks, or that no other measures can be used to determine neurodegeneration?

I apologize because you said no nitpicking, but I am fed up with the medical researchers contradicting each other. I want to know what is/has happened to me. None of us are ever going to be appropriately diagnosed and treated as long as the researchers/scientists keep doing this crap.

Thanks for the info, B. We def need as much info as we can get.

[attachment=211:transplant hypocretin.pdf]

#3 Saraiah

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Posted 01 September 2009 - 08:47 PM

Hi Bafflegab and Sleepless,

So, for the deeply confused among us (including me) :huh: , what exactly does "neurodegenerative" mean?

Thanks,

Saraiah

#4 Stacy D

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Posted 01 September 2009 - 10:22 PM

I wish they'd get their crap straight and agree on something, but I am going to say that my experience has definitely been progressive, I don't know about neuro-degenerative but I was doing some reading on Alzheimer's and Dementia and if you take the clear REM sleep problem away, I could easily be diagnosed with dementia. This is also happening pretty fast for me. A few months ago I could read except on really bad near-crash days. Now I can't read and comprehend much more than a headline on almost any day, with or without adderall. I get so confused, or "confuddled" as the dementia website said. My son came home with a newsletter from school today and I have no idea what it said. I tried to skim for dates and put them on my calendar but that was all I could do. I'm also having a hard time understanding people when they talk. They may as well be speaking gibberish; I know they have a point but I don't know what it is. I need things to be explained thoroughly and concisely.

Why is an MRI never done for N? It's a useful tool for so many other neurologic disorders, wouldn't it show something characteristic of narcolepsy? Also, why isn't the hypothalmus being studied more? It could explain why PWN have multiple auto-immune disorders. Or has this already been done and found inconclusive? I don't think the hypocretin thing should be all-or-nothing. It isn't that way or other hormones, there are acceptable ranges. They aren't going to tell me I don't have a Thyroid disorder just because I have a detectable level of TSH, right?

PS It took me about 30 minutes to write this post. I hope it's not too ramble-y. I tried to proofread and edit.

#5 Stacy D

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Posted 01 September 2009 - 10:25 PM

Hi Bafflegab and Sleepless,

So, for the deeply confused among us (including me) :huh: , what exactly does "neurodegenerative" mean?

Thanks,

Saraiah


From Wikipedia:


Neurodegenerative disease (Greek νέυρο-, néuro-, "nerval" and Latin dēgenerāre,"to decline" or "to worsen") is a condition in which cells of the brainand spinal cord are lost. The brain and spinal cord are composed ofneurons that perform different functions such as controlling movements,processing sensory information, and making decisions. Cells of thebrain and spinal cord do not readily regenerate en masse, so excessive damage can be devastating. Neurodegenerative diseases result from deterioration of neurons or their myelin sheaths, which may eventually lead to CNS-related dysfunction.[1]

A prime example would be Multiple Sclerosis.


#6 Nyx

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Posted 02 September 2009 - 02:33 AM

I believe they're basically saying that they set out to see if hypocretin-producing brain cells in the brains of people with narcolepsy and cataplexy showed the same signs as the brains of people with neurodegenerative diseases like Parkinson and Huntington. In those diseases they found protein accumulations (such as tau, synuclein, amyloid, etc.) in the hypocretin cells, so they figured they might find the same physical protein accumulations in the damaged hypocretin cells of a narcoleptic/cataplectic. Specifically, they were looking for ubiquitin, which is a marker that cells tag onto a protein to mark it for destruction. Ubiquitin tagged proteins are found in the brain cells of people with neurodegenerative disease, but they also believe that it can be just a result of aging. Of slightly less importance to our discussion here, they mention that there is some uncertainty within the medical community as to whether protein accumulation kills cells, or whether it's just a sign that the cells were accumulating proteins to protect themselves from the degeneration that was happening through some other means. They also explained that previous studies have found protein accumulations in the hypothalamus of patients with Niemann-Pick disease type C,12, which can cause narcolepsy as well. Anyway, the bottom line is that they didn't find any physical evidence of protein accumulations in the hypocretin cells of narcoleptics/cataplectics.

But while it's good news that their study didn't confirm the theory of N/C as a neurodegenerative disease, they didn't really answer the question conclusively. The pointed out that the few hypocretin cells they found to study in the brains of the N/C patients could simply not show the protein accumulations because they were the few cells that survived and weren't damaged. Or they suggested that if protein accumulation is in fact a sign of the cell effectively protecting itself during a neurodegenerative process, that perhaps the lack of those proteins in the hypocretin cells instead shows that the hypocretin cells of N/C patients failed to try to protect themselves. They also pointed out that in the brains of the N/C patients that also suffered from dementia, that degenerative process caused protein accumulations in other parts of the brain, but were clearly absent in the hypocretin cells.

Also, of note, studies have found that while abnormally low levels of hypocretin are found in the cerebrospinal fluid of patients with both narcolepsy and cataplexy, as well as in some neurodegenertaive disorders that don't involve sleep disorders, the hypocretin levels are usually normal (or not as low) in people with narcolepsy alone.

Ok, onto a more general issue a few of you raised. I completely understand your frustration with conflicting opinions about the causes and manifestations of narcolepsy. Unfortuantely though, that's the way research works. One researcher will set out to prove that X causes narcolepsy, which prompts another researcher to disagree and set out to prove that X has nothing to do with narcolepsy, and that Y causes it instead. While the researchers duke it out (and other researchers attempt to reproduce their findings if they seem to have come up with a feasible answer), there will be conflicting information circulating, and a lot of uncertainty among scientists, doctors and patients. But I think it's just part of the process of trying to do good research to nail down an answer. The real problem seems to be that sleep medicine is lagging behind many other areas of medicine when it comes to research and understanding of the disease. Or how about the fact that they treat narcolepsy with provigil despite not having a clue as to how the drug even works or affects the brain? Pretty unbelievable. When I was following some fellows through a tour of our hospital's sleep center, they pointedly said that if anyone wants to do research in a field that will really have impact and offer lots of room for new discoveries, sleep medicine is wide open and in great need. It's scary how right they are.

Stacy D: I was just posting today in another forum about some interesting links on the very issue you raise about narcolepsy, treatments and memory loss. Basically, I said that I had previously thought that the memoryproblems narcoleptics suffer from were simply a function of being so tired (i.e., brain fog),and that memory and performance tests showed similar decreases in sleep deprived people without narcolepsy. And I'd read that researchstudies had determined that it's the specialized cells in thehypothalamus that produce the neurotransmitter hypocretin (regulates sleep, appetite, energy metabolism, etc.) have been damaged in narcoleptics, but I didn't remember reading about any other types of brain cells damaged (i.e. in areasthat facilitate memory). So I started poking around last night todouble check. At the very least, I wanted to see whether anyone elseshares my suspicion that drugs like provigil or ritalin could also be causing memory problems on top of the narcoleptic brain fog.

While I was searching online to see whether the only known cause ofnarcoleptic memory problems is fatigue, I came across a few interestinghypotheses. Happily I haven't found anything so far that supports thedamage of cells in other parts of the brain due to narcolepsy (unless of course the causeof the narcolepsy is related to trauma, coma, etc.). But check outposts 11-17 here for some really interesting discussions:

http://www.dailystre...b-memory/page-2

And then this is the article that they reference (that I actually stumbled across first):

http://feedback2wk.t...ASOPRESSIN.html

And then after reading your question about the use of MRIs, I found a recent article that looked at a variety of brain imaging results with respect to narcolepsy. Here is their summary:

Over the past decade, brain imaging studies have provided major insights into the functional neuroanatomy of normal human waking state, REM sleep or SWS. Yet, only a few studies looked at how brain activity might be altered in narcoleptic patients. Moreover, the neural correlates of other characteristic symptoms in narcoleptic patients such as cataplexy, hypnopompic/hypnagogic hallucinations or sleep paralysis remain largely unknown.

...........

Although human narcolepsy is associated with hypothalamic hypocretin/orexin dysfunction, no clear evidence for hypothalamic or pontine tegmentum abnormalities emerges from the structural imaging studies reviewed here, including MRI and spectroscopy data. By contrast, the few available functional imaging studies have consistently found hypoactivity in the hypothalamus. These findings suggest that narcolepsy is associated with abnormal hypothalamic function in the absence of consistent structural alterations detectable by current imaging methods. Higher-field MRI scanners with improved signal and spatial resolution might provide a more refined picture of the structural changes in narcolepsy. Neuroimaging data of narcolepsy during active tasks testing specific brain circuits,50 as well as during different sleep states are very promising.
One of the cardinal symptoms of narcolepsy, i.e., cataplexy, has been found to be associated with increased activity in areas involved in emotion and reward processing. These data collected on a total of 3 patients still need confirmation.

In addition to a hypocretin/orexin dysfunction, it has been suggested that the dopamine system might also be involved in pathophysiology of narcolepsy, based on postmortem studies showing an increase in striatal dopamine binding. However, the available neuroimaging results on living patients indicate that increases in dopamine activity might be due to long-term effects of prior treatment rather than intrinsic modifications due to the pathophysiology of narcolepsy.


I'm not sure if the link to the article will work, but here it is: http://www.pubmedcen...bmedid=18548822 . It's a 2008 study: Neuroimaging Insights into the Pathophysiology of Sleep Disorders, by Martin Desseilles, MD,Thanh Dang-Vu, MD, Manuel Schabus, PhD, Virginie Sterpenich, Pierre Maquet, MD, PhD, and Sophie Schwartz, PhD. But the bottom line is that they're not really sure of the usefulness of MRI imagine of narcoleptic brains yet. I would guess there are probably current studies checking that out right now, but until it's established, they're not going to be sending people for MRIs simply based on a diagnosis of narcolepsy alone. For one thing, an MRI costs thousands of dollars, and with the current healthcare crisis, they're not going to be eager to make widespread use of such an expensive test when the usefulness of the results is a big question mark. Then again, if your doctor feels your level of memory loss and confusion warrants an MRI to rule out contributory disorders, why not get some piece of mind?

And while I don't really want to bring you down too, I was dismayed to find that there actually are some studies that have found damage in other parts of the brains of narcoleptics, so perhaps there is something more to our memory loss issues than just the effect of fatigue on the brain. I'll have to read up on those later. Here's the discussion from that same article:

Differences in brain morphology that are not identifiable by routine inspection of individual structural MRI can be investigated using voxel-based morphometry (VBM). VBM allows between-group, statistical comparisons of tissue composition (gray and white matter) across all brain regions, based on high-resolution scans. To date, VBM studies reported equivocal results in narcoleptic patients. An early study found no structural change in brains of patients with hypocretin-deficient narcolepsy,36 suggesting that functional abnormalities of hypocretin neurons could either be associated with microscopic alterations undetectable by VBM or not be associated with any structural changes whatsoever. Two subsequent studies did find cortical gray matter reduction in patients with narcolepsy, predominantly in frontal brain regions37 as well as in inferior temporal regions38 (Figure 3). Relative global gray matter loss was independent of disease duration or medication history and there were no significant subcortical gray matter alterations.38 Significant gray matter concentration decreases were found in the hypothalamus, cerebellum (vermis), superior temporal gyrus and right nucleus accumbens in 29 narcoleptic patients relative to unaffected healthy controls.39 Given the major projection sites of hypocretin-1 (the hypothalamus among others) and hypocretin-2 (the nucleus accumbens among others), the decreases in gray matter could reflect secondary neuronal losses due to the destruction of specific hypocretin projections. A recent VBM study corroborated significant reduction in hypothalamic gray matter volume in 19 patients compared with 16 controls.


Anyway, I don't mean to divert the thread, but I can't tell from the Narcolepsy Network's upcoming October meeting web site what topics the experts will be lecturing on, but I'd love to know. I get the feeling from the brochure that the meeting is more about support than the science and current research regarding narcolepsy and treatments, but who knows?

#7 Stacy D

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Posted 02 September 2009 - 04:31 AM

WOW! It's 5am and I'm almost at the end of my shift at work but I made special effort to read all of your post, I just may not have a complete or coherent reply, but here goes:

1. I am new to N but am overwhelmed (in a good way) and amazed at how supportive perfect strangers can be. It is so encouraging to see people on here helping others and putting as much effort as they can into researching what it wrong with us. I don't think I would be able to hold onto hope if it wasn't for NN, so thank you for all the effort you put into answering my questions.

2. I will have to come back to this post later to check out all of your links when I can concentrate a little better, but I am also happy to not see ideas discredited as often happens in groups. I am certainly no medical professional (as my supervisor reminded me yesterday when I tried telling him I most likely had N but it will be 3 more weeks before I see the doc to go over the test results), but I certainly know how I feel and it's great to have people listen and understand.

3. While the memory and comprehension problems I've been having are very similar to what anyone who is exhausted would have, it seems to be getting worse and the Adderall isn't helping much any more. It did at first. I am very curious if there is something else going on and maybe I can get lucky enough for the Army to do some brain scanning before they kick me out. I feel like there are too many connections to auto-immune and neuro-degenerative disorders to discredit them as being at least comorbid if not cause-and-effect and I hope research continues.

4. I wish they would start putting more effort into developing better drugs based on the data they do have. Research into causes and such needs to continue, but at the same time we need more effective treatment.

That's all I got for now. Thank you again.

#8 Saraiah

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Posted 02 September 2009 - 08:27 AM

Nyx, I second Stacy's opinion: Thank you for your detailed, technical post!! Even though I can't yet understand it all, I am super committed to learning about the causes of narcolepsy. Without your and Bafflegab's and others' careful research and explanations, it would be much harder to learn and understand this stuff. So, please keep it up! And thanks very much!

Man, I looked at the medical narcolepsy conference agenda and just drooled, thinking maybe I could pay to go or sneak in under the radar... Then I saw it was in Switzerland. Ah, well.

So, I'm really glad that you all have brought up this neurodegenerative business, because right after I was diagnosed with N in early July, I went straight to the local university library and started reading medical journal articles about narcolepsy. Here are my notes based upon the abstract of an article by:

S.J.Kim et al. (2009) Gray matter deficits in young adults with narcolepsy, Acta Neurologica Scandinavica, 119:1, 61-67.

"The study compared 17 young adult narcoleptics with cataplexy and 17 comparison subjects. Narcoleptic patients had gray matter volume decreases in the right hypothalamus and other regions, including the subcortical, prefrontal, limbic, and occipital areas. Narcoleptics also had lower gray matter at the bilateral hypothalamus, which correlated with the 'Ullanlinna Narcolepsy Scale Score."

I haven't had the chance to read the full article yet, since I missed it the first time that the university's Interlibrary Loan department sent notification that they'd received it to my email - a bit of a narcolepsy blip there in my awareness and organization. So, I've requested the article again. But while I'm waiting for it.... Does this scare anyone else besides me? I was really surprised when I read the abstract, because I thought that narcolepsy only involved neuronal death in the hypothalamus. But from these results, it appears that even young people with narcolepsy suffer the significant death of large numbers of neurons (brain cells) all over the brain.

Nyx, are you able to access the full article? Do you (and other narcolepsy geeks and scientists out there) think that the study was well-designed and that the results are trustworthy and deserving of attempts at replication (other scientists doing the same experiment to see if they find the same kind of results)?

The idea that my brain is suffering an overall decrease in gray matter really hits me where I live. I'm not vain about my overweight body, or proud of my career, or worried about being "successful" in the way that U.S. culture values.... But I am very invested in my ability to think, to reason things out, to be creative and strategic, to be clever in solving problems, to write and express myself well. I never imagined that I would be diagnosed with a disease that would steal away some of my ability to use my mind; I've always imagined that if I were ever to become physically "disabled" (which is a word I have recently come to hate), I would eventually manage to remain happy, armed with a bright and expressive mind and a computer, ala Stephen Hawking. NOT that I imagine myself to be 1/100th as brilliant as he is, but just with him as a role model for what a person can do even when her mind is the only thing that still works.

When I went a couple of weeks ago to see my sleep specialist, I asked him about the results of the Kim et. al study, and whether the decrease in brain matter might be due to the effects of 1-2 decades of severe sleep deprivation (i.e. the narcoleptic brain not getting restorative sleep). He had NO idea what I was talking about - was completely unaware of the finding. I also asked him that since now we know that narcolepsy is most likely an autoimmune disorder, and because I have 2 other autoimmune disorders, whether there was anything I could do to calm my immune system down so that I wouldn't get any more autoimmune disorders. He looked at me as if I was nuts again, and told me that there was no evidence of narcolepsy being an autoimmune disorder. I told him about the May 2009 finding published by Stanford, and he told me that there was no such finding. So I just dropped the issue, seeing that he'd be no help in this department....

I've been reticient to bring the question up on Narcolepsy Network because I was afraid that other PWN would find the results as discouraging and worrisome as I do. But since we're talking about it anyway... I can't tell you what a relief it is to "say" this out loud, and to have other people thinking it over besides just me.

#9 Nyx

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Posted 02 September 2009 - 10:53 AM

Stacy & Saraiah: Thanks! I was worried I went a little overboard or posted a little too much detail/science here. Stacy - I too would like them to have better treatments, but unfortunately the best step is to nail down the cause of a disease in order to know how to best treat it. Sometimes they stumble onto a drug that works although they don't know why (i.e., provigil/nuvigil), but for the most part it's best when they understand the how and why. Otherwise you wonder if it's really a beneficial treatment, or if there could be problems down the line. For instance, if they don't know what's causing the problems, a treatment may end up being helpful in the short term, but actually lead to worse long term effects. That was my concern after reading some of the vasopressin/ritalin theories.

Saraiah: Yes, I do have access to the article, and I just took a really quick glance at it. I wouldn't get too depressed yet. It mentions that previous studies have been with relatively small sample sizes, had not accounted for many variables, and had very conflicting results. And the results this study set forth are based as well on a very small sample group (17 patients with N/C and 17 controls who don't have N/C), but they did try to control more variables, including only young narcoleptics with cataplexy and no other illnesses or issues. So just based on that, I'd even question whethere these findings (if they stand up to subsequent studies) would apply to narcoleptics without cataplexy. Basically, they were saying since the current theory is that N/C have hypocretin deficiencies, that there has been damage to the cells that produce hypocretin, which is located in the hypothalamus. So, they tried to use imaging studies to identify structural evidence of that damage. Looks like they used something called voxel-based morphometry (VBM), which I know nothing about yet. They say it's good for detecting subtle changes in small structures such as the hypothalamus, and has been used in other brain disorders. They again point out that the previous VBM studies on narcolepsy are all over the place, with some finding a decrease in gray matter in the hypothalamus, while others did not. They threw out some theories to explan the discrepancies, like age, the HLA typing (auto-immune markers), and the presence of other illnesses that could have skewed results (like psychiatric illnesses in N/C patients). So, they tried to eliminate as many variables as possible, and wanted to see if they could find a correlation between evidence of hypothalamic structural changes and the severity of a N/C's symptoms.

One difference they noted that was included in their patients that particularly sparked my interest was that they did include both patients who had never received drugs to treat their narcolepsy/cataplexy, as well as those that did. My developing hypothesis is that perhaps treating us with stimulants is making things better in the short term (I'm awake!) but perhaps having some long term side effects (i.e., increased memory deficits and/or much more sleepy without the drugs than patients were before (i.e., the "crashes" when the drugs wear off)). They noted that they did find one specific difference between these two types of patients, with those that had been treated with drugs having a lower gray matter volume in the right middle occipital cortex. But they did find that there were no overal differences in gray matter volume on a larger scale.

As for the main body of their results, they found there was a decrease in gray matter volumes in the bilateral hypothalamus of the N/C patients they compared to those without N/C, and they found that the degree of the volume change correlated with the severity of their symptoms. They hypothesized that:

Hypothalamic gray matter volume decrease may
be in line with the functional deficits of hypothalamus
in narcoleptic patients including decreased
glucose metabolism (10) and decreased cerebral
blood flow (11). Our findings support the notion
that structural abnormality, as well as functional
one, is present in the hypothalamus of narcoleptic
patients. Structural abnormality observed in the
narcoleptic hypothalamus may be related to the
hypocretin neuronal loss reported in previous postmortem
studies (8, 9).


However, they did note that they didn't in fact check for hypocretin deficiencies in the CSF of their subjects. That would have been pretty helpful. Check this discussion out where they quanitfy the change in severity and the hypocretin CSF N/C vs. N alone issue:

Hypothalamic gray matter volume decrease
correlated only with Ullanlinna Narcolepsy Scale
score (especially the cataplexy-related score), but
not with Epworth Sleepiness Scale score. Hypocretin
deficiency has been reported to be more
common in narcolepsy with cataplexy rather than
narcolepsy without cataplexy (27). Therefore,
structural changes in the hypothalamus of narcoleptic
patients, which may be associated with
hypocretin deficiency, might be more important
for the manifestation of cataplexy than that of
daytime sleepiness.


And then regarding our concern that there may be more widespread impact on the brain than solely the hypothalamus:

In the present study, gray matter volume
decreases in narcolepsy were also found in various
brain areas other than the hypothalamus. Structural
changes in many of these areas were related to
the clinical characteristics of narcoleptic patients.
There were correlations between nocturnal sleep
efficiency and gray matter volume in subcortical,
limbic and prefrontal areas. Frontal gray matter
changes in narcolepsy also correlated with the
symptom duration.


And then with regard to the brains of narcoleptic/cataplectics treated with drugs vs. not:

In addition, occipital gray
matter volume decrease was found only in drugexposed
narcoleptic patients. These findings suggest
that structural changes of various brain areas
in narcolepsy may be related to diverse clinical
characteristics in narcolepsy, such as nocturnal
sleep disturbance, symptom duration or medication.
However, the findings should be interpreted
with caution, as an uncorrected P-value of 0.001
may not be parsimonious enough, considering the
lack of a priori hypotheses for these regions.


I'd like to highlight that this study did question the import and reliability of their own data given the small sample size, other variables, and contradictory previous results. Personally, I'm still considering everything up in the air until there has been more replication and consensus of these findings. But thanks so much for sharing this article! I'll try to follow up on this later when I have time.

#10 sleepless sleeper

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Posted 02 September 2009 - 03:34 PM

OMG Sensory OVERLOAD

I cannot read all of the posts. It was difficult to get past the first post of Nyx, so I will have to come back later for the rest.

If degeneration is the deterioration of cells, then would the findings from the pdf that I posted be sufficient to say that n is deg?

What Nyx states is that n w/ c patients had less or no hypocretin (or did I misread, very real possibility), which only furthers the pdf's statement that n is neurodegenerative considering the loss of hypocretin. BG, however, states that it was pwn w/ c brains which the other scientists used for the research, which states no degeneration because lack of certain protein.

Considering that I have lost hypocretin, my lost neurons are not replicating, never will replicate, and further considering that I am not a lab rat and therefore will not receive a transplant of hypocretin (5% success rate anyway- if i remember correctly), would I not have/am suffered(ing) from neurodegeneration? Maybe it's my layman's stupidity. If that's the case, then I believe that some of the researchers suffer from the same thing. That or the term needs to be redefined: "Neurodegenerative diseases result from deterioration of neurons...". What is hypocretin/orexin? Neurons. Just because a specific protein is not found in the cells means nothing to me. There are no cells to contain this protein. Why is this protein not in the definition of degeneration? Nyx and BG, please HELP! You understand this stuff much better than I do.

There are too many of us that have experienced progression. Fortunately, there are also some of us that do not.

I've had narcolepsy for the majority of my life. It has progressed. According to several doctors, everything that I suffer from is my narcolepsy. I know that I had it in elementary school. It was much the same until teenage years. Before I finished college, my symptoms were worse, but still life was livable. I had no idea that I had narcolepsy, and I've always been a healthy person otherwise. N did not become awful for me until my first pregnancy, but life was still somewhat manageable as long as I did not drive anywhere. It was seven years ago last week that I found out I had narcolepsy. Four years ago I became pregnant with our second child, and my narcolepsy began providing extremely serious consequences to the point that everyday life became unlivable without help. Two years ago, my mother became ill and died, and from that I experienced some extremely stressful situations that made my n worse. Some of that seems to be improving somewhat, though, so maybe those consequences are mostly just caused by stress. I hope so. I do not want to have a neurodegenerative disease.

Having narcolepsy is bad enough, but to hear the term "degeneration" is scary to me. I'm not trying to argue this so that I can label myself as such, but I have a hard time understanding why in the world some researchers say that the loss of brain tissue is not good enough to use the label "degeneration". As pwn's, we are constantly being told things that seem contradictory. Some of us on here are told that we can't have n b/c we don't have c. Some are told that they aren't pwn because they dont have the right kind of c. Some are just told that they have sleep apnea (sarcasm, but true for a few).

Now we are told that although there is a loss of certain brain cells, which usually would suffice for the definition of degeneration, we do not qualify for the term degeneration because there is a lack of a specific protein in said brain cells.

Thanks everyone for input on this. It is helping. Slowly, but it is helping!

Thanks Nyx, for going into this field and for the extra time that you put into studying it.

#11 Saraiah

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Posted 02 September 2009 - 05:20 PM

We need to throw some money into a kitty and get you over there, so you can blog it for us.

I'll chip in the first hundred. A couple of dollars from everyone would go a long way toward filling my cup of curiosity. What about the NN scholarship fund for travel to the conference? A round-trip ticket out of JFK will run anywhere from $300 to $600, a room and board will roughly run another $300 (all USD), and registration fee of $711: you'd need at least $1,500 US dollars to make the trip. It would have to be a shoestring budget, unless there is an anonymous sugar-daddy (or momma) who could chip in, but that symposium is the single best place for information on the state of research into narcolepsy.

Interested?


(Nyx - no reading this until after your cardio exam!)

NYX!!! You are my hero/heroine!!! LET'S GET YOU TO THAT CONFERENCE. I'm in for $100 too, and more if I can figure out how to get it. (Hmm. Maybe it's time for a narcolepsy bake sale.) And if we can come up with enough money to send you to Switzerland to the narcolepsy conference, we need to send you with a SmartPen (mine if we can't get you one of your own) so that you can get a digital recording of the lectures which is tied to the notes that you write. Then, you could upload the notes on the Livescribe website, and all of us would be able to listen to the lectures that you heard, and be helped by the notes that you took. You wouldn't end up needing to blog quite so much that way - which is a good thing, because you have enough to do with med school already.

One thought that I have - your med school gives scholarships for travel that serves underserved populations. I would make an extremely strong argument that people with narcolepsy are a deeply underserved population. Most of us get diagnosed 1-2 decades after we develop the illness, and some of us wait much longer than that. There is only one book on narcolepsy for the lay person; there are no publications that present research on narcolepsy in a way that lay people can understand it. By going to the Switzerland conference, you would be getting, recording, and disseminating the latest research to the information-starved community of people with narcolepsy; in addition, you could choose to make the information available to "sleep specialist" physicians, many of whom (I am learning) are woefully under- and mis-educated on the causes and treatment of narcolepsy. If you need a letter attesting to all of this to present to your med school, you let me know! I'll write it, and I bet there are 50 other people on Narcolepsy Network who would be willing to do the same.

And good luck on your exam!

#12 Stacy D

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Posted 02 September 2009 - 07:49 PM

I'm with Saraiah, we are underserved. I can probably also make a donation to the cause to get Nyx to the conference, as long as I get a souvenir :)

Sleepless, Nyx may have to correct me on this, but orexin/hypocretin are hormones so a reduction in them does not mean that neuro-degeneration exists. A comparison would be that a thyroid hormone deficiency does not necessarily indicate degeneration of the thyroid itself. This is just my understanding of how it all works, so I could be way off. It sounds so much less bad to describe N as a "hormone imbalance", though. :P



#13 Nyx

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Posted 02 September 2009 - 10:36 PM

Sleepless - I'm sorry I don't have more time right now to review a bunch of studies and give you a better answer to your questions (which I'd love to do tonight if I had the time!), but I'm dead tired and still have to study. But I'll give it an off the cuff attempt to the extent it also converges with Stacy's question. As far as I recall, hypocretin is a neurotransmitter, not a hormone or a neuron. But basically you could think of it as a "brain hormone." Now, I know I've seen a few statements thrown around about how there's a definite loss of hypocretin in the CSF (liquid surrounding your brain and spinal cord) for narcoleptics with cataplexy, and to a lesser extent in N without C, but I would like to read up a little more to be sure that that really is an absolute certainty. For example, if they've found that there are people who have symptoms of N and who have been diagnosed with N, but who have normal levels of hypocretin, then that suggests that perhaps there's a non-degenerative process involved. For example, perhaps in that person it's not that the brain cells that produce hypocretin have been destroyed, but instead that the receptors for the hypocretin have been destroyed or are dysfunctional for some other reason (damage, genetics, etc.).

Now, let's assume for the sake of argument that they have proved that people with both N and N/C have less or no hypocretin in their CSF. That still doesn't automatically mean that it's a neurodegenerative disease. For example, perhaps the reason there is no hypocretin isn't that the cells that produce it were destroyed, but that some intermediary product or step is flawed so that their cells simply can't produce the hypocretin correctly. Or perhaps their own antibodies are attacking the hypocretin itself. But I have a feeling the research is going to support the view that it's the cells that produce the hypocretin that are damaged or dysfunctional (at least that's my gut impression right now). Which brings us to the other popular theory that could also account for a loss or damage of hypocretin producing cells - that N is an auto-immune disorder. That perhaps our own cells are attacking the brain cells that produce hypocretin, and that we should be taking something to stop flare ups (like people with lupus take steroids).

While I haven't really researched this yet, my initial impression is that there are two primary camps right now: those that think they've found support for narcolepsy being a neurodegenerative disorder, and those that think they've found proof it's an auto-immune disorder. Personally, for now I've been thinking of narcolepsy as an idiopathic disease. They use the word idiopathic in medicine when they don't know why something is happening, but they can see the physical symptoms. Perhaps there's actually no one right answer for narcolepsy. Maybe there are people that were born with deficient levels of hypocretin (the imaging study above about loss of gray matter mentioned that some previous studies have found decreased hypocretin levels in narcoleptics as young as 6 years old (granted, I haven't confirmed that research yet)). I'd then call that congenital narcolepsy, or just call it a genetic disorder. Then there may be people who were in a car accident, or a had a stroke, or suffered some other trauma that actually damaged the part of the brain that either produces or receives the hypocretin. That could be traumatic narcolepsy. Then there could be people who have an auto-immune disfunction where their own body is in fact targeting the hypocretin, the hypocretin receptors or the hypocretin producing cells. Auto-immune narcolepsy. And then perhaps we have people who have a metabolic build-up or other process that damages the hypocretin producing or receiving cells, and thus they could have degenerative narcolepsy.

Again, this is just my throwing around ideas without real back up, but my point is that they don't yet KNOW the answer or answers yet. Thus at that symposium of narcolepsy experts, they have an expert that says N is neurodegenerative, who will sit right next to an expert that will argue it is not. Ditto with N as an auto-immune disorder. Off the cuff I'd say I favor the auto-immune theory over the neurodegenerative, but I will certainly be doing some research soon to see which position is actually better supported by the research. And even if it does turn out to be auto-immune, people with narcolepsy could experience progressively worsening symptoms over time (which is generally a hall mark of a degenerative disorder), but it would simply be because of uncontrolled periods where their body is continually attacking those cells. And that eventually, they could end up with no hypocretin at all. To compare it to something that perhaps you're familiar with, consider celiac disease. It's an auto-immune disorder where the body attacks the nutrient-absorptive cells in the GI tract. They've found that the trigger is gluten. So, when someone eats something with gluten in it, and their cells take it in, they get targeted for destruction and destroyed. As a result, whenever they eat bread, their body attacks the lining of their intestines, and they have terrible GI symptoms, and until the lining grows back, they are fatigued, lose weight, etc., because they can't absorb nutrients like they normally do. Over time these episodes can lead to tons of seemingly unrelated symptoms - which is a contributing reason why it also used to take people with celiac disease 10+ years to get diagnosed (they've had some good PR recently, and I think it's getting better). As it is, my father's mother died of that years ago. They called it "the wasting disease" and had her on a diet of bread and bananas. Brilliant. Anyway, sorry for digressing. But with celiac disease, it tends to suddenly manifest later in life, even though it appears it's a genetic disease, and that those genese have been sitting there all along. So, what makes someone suddenly start showing symptoms of celiac disease? What makes someone suddenly have their first bout of lupus? I'm sure there are many theories out there about triggering events like certain illnesses or stress, etc. Perhaps the same is true of narcolepsy - that the immune system went into overdrive, and in the process a cell that is meant to identify and attack invaders, but instead targets the hypocretin-producing cells, got through instead of being destroyed like it should have been. Perhaps in each person's DNA there are genes that code for an antibody that recognizes those hypocretin-producing cells, but that normally the safety net catches them - until the immune system is in overdrive and the safety net can't keep up.

#14 sleepless sleeper

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Posted 03 September 2009 - 10:22 AM

I greatly appreciate the attempts, but herein lies our confusion, I think:

Hypocretin/Orexin (in the brain, as opposed to hypocretin produced in renal system) is a neuropeptide. Somehow it came up in the discussion that I had with my sleep doctor when I saw him. He states that it is a neuron. There are several medical publications regarding this. The opening sentence of the Study Objects in the pdf provided is this:

"The sleep disorder narcolepsy is now considered a neurodegenerative disease because there is a massive loss of neurons containing the neuropeptide, hypocretin, ..."

I have links to many pubs on this, and I've never seen hypocretin in the brain called a hormone. Are hormones proteins? I don't know! argh! This is confusing.

Nyx, I'll pitch in a hundred bucks for the cause. We want you there!

Excellent suggestion, BG.

#15 Nyx

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Posted 03 September 2009 - 10:50 AM

I greatly appreciate the attempts, but herein lies our confusion, I think:

Hypocretin/Orexin (in the brain, as opposed to hypocretin produced in renal system) is a neuropeptide. Somehow it came up in the discussion that I had with my sleep doctor when I saw him. He states that it is a neuron. There are several medical publications regarding this. The opening sentence of the Study Objects in the pdf provided is this:

"The sleep disorder narcolepsy is now considered a neurodegenerative disease because there is a massive loss of neurons containing the neuropeptide, hypocretin, ..."

I have links to many pubs on this, and I've never seen hypocretin in the brain called a hormone. Are hormones proteins? I don't know! argh! This is confusing.

Nyx, I'll pitch in a hundred bucks for the cause. We want you there!

Excellent suggestion, BG.


Sleepless: Running late again, but here's some clarification. I think you're just getting stuck in semantics. Don't worry so much about what it's called. Basically, when they say "hypocretin neurons," they don't mean that hypocretin is a neuron, simply that they've found that there are a small discrete number of cells in the brain in a very specific place that have hypocretin in them, so they call them hypocretin neurons.

Sorry to do this so quick and cheap, but here are a few helpful quotes I'm going to paste from wikipedia:

http://en.wikipedia.org/wiki/Orexin

Orexins, also called hypocretins, are the common names given to a pair of excitatory neuropeptide hormones that were simultaneously discovered by two groups of researchers in rat brains.


Although these peptides are produced by a very small population of cells in the lateral and posterior hypothalamus, they send projections throughout the brain.


Orexin seems to promote wakefulness. Recent studies indicate that amajor role of the orexin/hypocretin system is to integrate metabolic,circadian and sleep debtinfluences to determine whether an animal should be asleep or awake andactive. Orexin/hypocretin neurons strongly excite various brain nucleiwith important roles in wakefulness including the dopamine, norepinephrine, histamine and acetylcholine systems and appear to play an important role in stabilizing wakefulness and sleep.

The discovery that orexin/hypocretin dysregulation causes the sleep disorder narcolepsy[4] in mice subsequently indicated a major role for this system in sleepregulation. Recently, transgenic mice have been engineered to lack thegene for orexin. Transitioning frequently and rapidly between sleep andwakefulness, these mice display many of the symptoms of narcolepsy.Researchers are using this animal model of narcolepsy to study thedisease.[5] Narcolepsy results in excessive daytime sleepiness, inability to consolidate wakefulness in the day (and sleep at night), and cataplexy,which is the loss of muscle tone in response to strong, usuallypositive, emotions. Dogs that lack a functional receptor fororexin/hypocretin have narcolepsy, while animals and people lacking theorexin/hypocretin neuropeptide itself also have narcolepsy.


In humans, narcolepsy is associated with a specific variant of the human leukocyte antigen (HLA) complex.[8]Furthermore, genome-wide analysis shows that, in addition to the HLAvariant, narcoleptic humans also exhibit a specific genetic mutation in the T-cell receptor alpha locus.[9]In conjunction, these genetic anomalies cause the autoimmune system toattack and kill the critical hypocretin neurons. Hence the absence ofhypocretin-producing neurons in narcoleptic humans may be the result of an autoimmune disorder.[10]


Some ongoing research involving hypocretin/orexin:

Several drugs acting on the orexin system are under development, either orexin agonists for the treatment of conditions such as narcolepsy, or orexin antagonists for insomnia.No non-peptide agonists are yet available, although synthetic Orexin-Apolypeptide has been made available as a nasal spray. Severalnon-peptide antagonists are in development however; SB-649,868 is under development by GlaxoSmithKline for sleep disorders and is a non-selective orexin receptor antagonist. Another OX1 and OX2 receptor antagonist (ACT-078573, almorexant) is a similar compound under development for primary insomnia by Actelion.


Info on the history of the names orexin and hypocretin:

Masashi Yanagisawa and colleagues at the University of Texas Southwestern Medical Center at Dallas, coined the term orexin to reflect the orexigenic (appetite-stimulating) activity of these hormones.[1]

Luis de Lecea, Thomas Kilduff, and colleagues also reported discovery of these same peptides, dubbing them hypocretins to indicate that they are synthesized in the hypothalamus and to reflect their structural similarity to the hormone secretin (i.e., hypothalamic secretin).[2]

The name of this family of peptides is currently in dispute. Thename "orexin" has been rejected by some due to evidence that theorexigenic effects of these peptides may be incidental or trivial(i.e., hypocretin induced subjects eat more because they are awakemore), while other groups maintain that the name "hypocretin" isawkward, pointing out that many neuropeptides have names that areunrelated to their most important functions, and that waking is one ofthe important factors that supports feeding behavior. Both "orexin" and"hypocretin" will likely continue to appear in published works until apreferred name has been accepted by the scientific community.



Does that help?

#16 psocoptera

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Posted 03 September 2009 - 12:04 PM

Nyx - PANDAS is, in some ways, similar to the theories of autoimmune causes for narcolepsy. It is a pediatric obsessive compulsive and tic disorder that appears to be the result of an autoimmune attack on the brain following ordinary strep throat.

#17 Stacy D

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Posted 03 September 2009 - 04:26 PM

Nyx - PANDAS is, in some ways, similar to the theories of autoimmune causes for narcolepsy. It is a pediatric obsessive compulsive and tic disorder that appears to be the result of an autoimmune attack on the brain following ordinary strep throat.


So, then, I guess it could be both auto-immune and neuro-degenerative? I am going to enroll in every N study I can at NIH so we can get some answers!


#18 sleepless sleeper

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Posted 03 September 2009 - 06:08 PM

Nyx, you are AMAZING and THANK YOU! I will most definitely contribute $ for you to go to the conference if you can take the time.

Also, when I got off here earlier, I remembered that my doctor said it was a neurotransmitter and not a neuron, BUT I like your suggestion to not worry over it... semantics...

Excellent suggestion, however, it still appears to me that info on N is at times contradictory. I suppose that means new research is replacing old and that there is more to be learned.

#19 Nyx

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Posted 03 September 2009 - 09:16 PM

If anyone does have access to pubmed or research articles, there's a great review from the narcolepsy experts at Stanford on the prevailing views and research on narcolepsy that I was skimming through during class today (anticoagulants just aren't as interesting): "Hypocretin/orexin and narcolepsy: new basic and clinical
insights," S. Nishino, M. Okuro, N. Kotorii, E. Anegawa,1 Y. Ishimaru, M. Matsumura and T. Kanbayashi, Acta Physiol (Oxf). 2009 Jun 25. Of course, the main author, Dr. Nishino, will be at the symposium in Switzerland speaking, as well as some of the top published proponents of autoimmune research (Dr. Mignot), and degenerative aspects (Dr. Peyron), etc.

Hope the link works for those of you who'd like to take a look at it:

http://www3.intersci...66961/HTMLSTART

And here's the abstract (i.e., their own summary of their article):

Narcolepsy is a chronic sleep disorder, characterized by excessive daytime
sleepiness (EDS), cataplexy, sleep paralysis and hypnagogic hallucinations.
Both sporadic (95%) and familial (5%) forms of narcolepsy exist in humans.
The major pathophysiology of human narcolepsy has been recently discov-
ered based on the discovery of narcolepsy genes in animals; the genes
involved in the pathology of the hypocretin/orexin ligand and its receptor.
Mutations in hypocretin-related genes are rare in humans, but hypocretin
ligand deficiency is found in a large majority of narcolepsy with cataplexy.
Hypocretin ligand deficiency in human narcolepsy is probably due to the
post-natal cell death of hypocretin neurones. Although a close association
between human leucocyte antigen (HLA) and human narcolepsy with cata-
plexy suggests an involvement of autoimmune mechanisms, this has not yet
been proved. Hypocretin deficiency is also found in symptomatic cases of
narcolepsy and EDS with various neurological conditions, including
immune-mediated neurological disorders, such as Guillain–Barre syndrome,
MA2-positive paraneoplastic syndrome and neuromyelitis optica (NMO)-
related disorder. The findings in symptomatic narcoleptic cases may have
significant clinical relevance to the understanding of the mechanisms of
hypocretin cell death and choice of treatment option. The discoveries in
human cases lead to the establishment of the new diagnostic test of narco-
lepsy (i.e. low cerebrospinal fluid hypocretin-1 levels for ‘narcolepsy with
cataplexy’ and ‘narcolepsy due to medical condition’). As a large majority of
human narcolepsy patients are ligand deficient, hypocretin replacement
therapy may be a promising new therapeutic option, and animal experiments
using gene therapy and cell transplantations are in progress.



Perhaps when I get some time I'll try to summarize the main points.

#20 sleepless sleeper

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Posted 04 September 2009 - 03:58 PM

Oh, man, I hate to do this, but this was published June 25 this year. It states, "Although a close association
between human leucocyte antigen (HLA) and human narcolepsy with cata-
plexy suggests an involvement of autoimmune mechanisms, this has not yet
been proved." Is this not what was proven in May?

Also it says, "The major pathophysiology of human narcolepsy has been recently discov-
ered based on the discovery of narcolepsy genes in animals... " What do they mean by "recently"? It's been a very long time.

See? To me these are contradictive to what has already been published. The first point may have just been timing (but a month in this field is a long time), but the second one is definitely old -very old- news.

"hypocretin replacement
therapy may be a promising new therapeutic option, and animal experiments
using gene therapy and cell transplantations are in progress." I asked my doctor about this a few years ago and he said that it would probably be a couple of decades for a new, true synthetic of orexin. I know that modafinil (sp?) is suppose to help with that, but it's not a true replacement. The cell transplantation experiments are sad to think of. This is what the pdf is that I attached in my original posting here. What's getting me is this: If there was no degeneration, then why are they trying to research transplants of cells that have died?

SORRY NYX! I couldn't help it.

Good luck with studies, and if there's anything that I can do to help you with phone calls, etc, let me know. I'm sure that you truly are strapped for time.