This Is MS Multiple Sclerosis Knowledge & Support Community

In reference to previous discussion(s) in another thread regarding MS and cognition, I mentioned my own experience with cognitive decline (and the fact that it has now been totally reversed).

By happenstance, I ran across this abstract that mirrors my own experience and description of it! I found that rather serendipitous!

This may or may not be reassuring to you. Hopefully, it will be reassuring.

Any questions or comments, fire away, folks!!

Deb

J Clin Exp Neuropsychol. 2004 Jun;26(4):550-62. Related Articles, Links

Is speed of processing or working memory the primary information processing deficit in multiple sclerosis?

DeLuca J, Chelune GJ, Tulsky DS, Lengenfelder J, Chiaravalloti ND.

Kessler Medical Rehabilitation Research and Education Corporation, 1199 Pleasant Valley Way, West Orange, NJ 07052, USA. jdeluca@kmrrec.org

OBJECTIVE: To examine whether processing speed or working memory is the primary information processing deficit in persons with MS. DESIGN: Case-control study. SETTING: Hospital-based specialty clinic. PARTICIPANTS: 215 adults with clinically definite MS. MAIN OUTCOME MEASURE: Mean demographically corrected T-scores, prevalence rates of impairment and relative risk of impaired Processing Speed and Working Memory Index Scores from the WAIS-WMS III. RESULTS: Deficits in Processing Speed were much more common than Working Memory in all comparisons. This was observed for both relapsing remitting (RRMS) and secondary progressive MS (SPMS) subjects, but accentuated in the latter group. CONCLUSIONS: Results strongly suggest that the primary information processing deficit in persons with MS is in speed of processing.

PMID: 15512942 [PubMed - in process]

Actually it doesn't reassure me at all....

As I've said before cognitive decline scares me more than any other MS related symptom. 'Cogito ergo sum', I am the sum total of my memories and my ability to reason. Reduce these and I am reduced.

I realise that in reality there is no chance of me turning into the village idiot due to MS (No comments please Deb! ). I know people who have had MS for many years, who are much older than I, yet still function perfectly normally (intellectually that is). However I also feel that over the last few years my ability to perform complex mental tasks has been reduced. In addition I find it more difficult to concentrate on a task than I used to.

To be honest I feel that the whole cognitive issue receives much less acknowledgement within MS, and by medical care providers than it deserves. In many ways it gets the same response as clinical depression used to get, i.e. 'pull your socks up and just get on with it'.

It is interesting that the above study highlighted speed of processing as the primary deficit. Perhaps a neurotransmitter imbalance exists as part of the pathogenesis of MS.

I have a sneaking feeling that norepinephrine is going to come up in this discussion!

Robin

Good morning, Robin!

(No comments please Deb! )

Oh, you break my heart! You KNOW I had the perfect come-back line! Ok.........I'll be nice.

However I also feel that over the last few years my ability to perform complex mental tasks has been reduced. In addition I find it more difficult to concentrate on a task than I used to.

Actually, this is going to sound like a come-back line, but it truly isn't. I know what you mean. The problem with some of what you refer to can also just happen normally with the aging process. (Of course, I'm only still 29, right? And if you believe that...........hehehe........) Seriously, though, I do know how you feel. I found, though, that trying to force myself to remember something or concentrate better only made it worse.

To be honest I feel that the whole cognitive issue receives much less acknowledgement within MS, and by medical care providers than it deserves. In many ways it gets the same response as clinical depression used to get, i.e. 'pull your socks up and just get on with it'.

Oh.....man.....I totally agree with you there! I was FURIOUS over the attitude(s) I got from my medical "team". I got "Well, you sure seem smart enough to ME, even WITH any cognitive decline!" Oh, yea, buddie? I literally told my first neuro that I was sick and tired of him "poo-pooing" my cognitive problems. How would HE like it if suddenly he had to read an MRI slide and couldn't make head nor tails of it simply because it wouldn't "compute"? I make my LIVING with my mind! That got his attention. Although..........he still didn't believe there was much that could be done. Uh huh.........well, THAT was a challenge I couldn't refuse!

Perhaps a neurotransmitter imbalance exists as part of the pathogenesis of MS.

I believe that, also. But here's the rub, as they say. I didn't find where norephinephrine did a thing......maybe a little, but not really. Not for cognitive. BUT..........Robin..........go do some research on "racetam". I stumbled on that by total accident, too. And of course, the medical profession isn't listening to me about this............yet. And "racetam" itself got a "bad rap" a number of years ago because college students were taking it just before exams, etc. Anyway, I had never even heard of any racetam compounds before. (And I'm NOT pushing this drug on people at all........it's just another one of those doggone things I wish they'd RESEARCH here in the U.S.! Maybe we can get the Netherlands to look into it!)

(I think a lot of people who visit this board knows what I'm going to say.) Anyway, I was having a rough time with spasticity and pain. The first TWO drugs that I was given by my doc made me sick, and didn't do a thing. I ran across Keppra in the news. And because Keppra was so safe as a chemical compound, it appeared, I asked to try it to relieve the pain and spasticity. So....ok, he thought the same. No problem. After about 30-45 days of being on it, I suddenly realized that I was thinking clearly again! And remember, I had been experiencing cognitive decline (which might be clinically considered "mild", but was extremely life-altering for me), for a little over, actually, THREE years! (For a while there I couldn't multi-task at all hardly, and I've always been famous for my multi-tasking abilities. I'm telling ya, if I wasn't depressed before, I was about to become so simply over the decline of my processing speed! Geez!) So..........the only thing medicine-wise that I was taking at that time was Keppra. (I had not started on any other drugs yet.) So, I thought.........wait a minute! The only thing that changed in my regimen over the prior three years was taking Keppra. So.....back to research I went to try to figure out how in the heck Keppra could have made a difference.

Robin.............racetam. My literal thoughts then to myself were: "You've GOT to be kidding me!" I bet it wouldn't work for Alzheimers (I won't go into all the details on that), BUT since I believe MS cognitive issues are from a different problem, and due to what little is known about levetiracetam's mechanisms of actions (and racetam's) my "guess" is that this "might" prove helpful in at least some folks with cognitive decline.

Again, it was serendipity. And the funny thing is, since "racetam" cannot be legally sold here in the U.S., it was really odd how it got through. It's not racetam alone, but it's a derivative. And it's an AED. The singular action of Keppra that is unlike ANY other AED on the market, that I have studied, is that it works SOLELY within the CNS. And it also inhibits Ca2 and assists with GABA. Moreso, even, than a norepinephrine reuptake inhibitor.

Interesting, huh?

Deb

EDIT: Oh, yea.....and MY belief as to what may be happening with MS and cognitive problems actually goes back to the axons this time, not necessarily completely with the synapses themselves. And I don't believe that it is "norepinephrine" itself that affects what I'm about to say, but I think it's the "drug" Norpramin that proves synergistic (I believe the same drug is called Pertofran in the U.K.? From Aventis, anyway. And I won't take the generic compounds. When I researched them, they didn't quite come up to par of the original drug, I hate to say. Good enough to get FDA approval - finally - but still not quite the exact duplicate.)

Anyway, Norpramin has been shown to enhance GAP43 expression. GAP43 promotes axonal and neuronal regrowth. Big time. (So does oleic acid, but I'm sure not as much as the medicinal compound, but I'm sure it wouldn't hurt to take oleic acid, also? I think that is contained in some fish oil compounds. I take that, too, now.) Anyway............GAP43 is a growth protein. My belief from my research is that enhancing GAP43 helps to repair and/or at least protect axons. There is a time window to help regenerate axonal damage, beyond which it becomes much more difficult to do, but it's there.

So....bottom line? Enhance GAP43 (along with some other tweaks here and there) and you've got something!

http://rgd.mcw.edu/tools/genes/genes_view.cgi?id=62071

Gene Report: Gap43

--------------------------------------------------------------------------------

Symbol: Gap43
Full Name: growth associated protein 43
Gene Description: may play a role in neurite outgrowth and nerve regeneration
Previous symbol: Basp2;
Previous name: brain abundant, membrane attached signal protein 2; growth accentuating protein 43; brain abundant membrane attached signal protein 2;

View Homologs: 2 found
mRNA: M16736
mRNA: M16228
mRNA: X06338
mRNA RefSeq: NM_017195
RGD Genome Annotation:
--------------------------------------------------------------------------------
Annotations:
Note Reference

Biological Process: mediates axon growth and synaptic plasticity 625586

Regulation: mRNA increased by nerve growth factor (NGF) due to the ARPP-19 dependent increase of mRNA half-life 625586

Ontology (?)
Term Evidence Reference

Molecular Function calmodulin binding IEA 737860

Biological Process neurogenesis IEP 728446
regulation of cell growth IEA 737860
tissue regeneration IEP 728776

Cellular Component axon IEA 737860
growth cone TAS 728446
membrane IEA 737860
--------------------------------------------------------------------------------
Mapping Data:
Map Locations for Gap43:
Marker Symbol Map Name Chr. Position
Gene Gap43 Cytogenetic 11 q11
genome assembly 11

External Database Links
GenBank Nucleotide
L21192 (L21192)
M88356 (M88356)
M16228 (M16228)
M16736 (M16736)
X06338 (X06338)
NM_017195 (NM_017195)

Swiss-Prot
P07936 (P07936)

PubMed
Gap43 (11839359)
Gap43 (11813888)
Gap43 (11703425)
Gap43 (3581170)
Gap43 (3428269)
Gap43 (2437653)
Gap43 (1532026)
Gap43 (12034726)
Gap43 (69641)
Gap43 (12701761)
Gap43 (12631465)
Gap43 (12597125)
Gap43 (12562512)
Gap43 (12485886)
Gap43 (12480131)
Gap43 (12210137)
Gap43 (12201630)
Gap43 (12105219)
Gap43 (12814368)
Gap43 (14637107)
Gap43 (14598294)
Gap43 (14519521)

Entrez Gene
Gap43 (29423)

UniGene
Rn.10928 (10928)

OMIM
162060 (162060)

GenBank Protein
NP_058891 (NP_058891)
AAA41189 (AAA41189)
AAA41191 (AAA41191)
AAA41190 (AAA41190)
AAA41192 (AAA41192)
CAA29644 (CAA29644)

Search Genbank for sequences associated with Gap43
--------------------------------------------------------------------------------
Curated References
1: Nedivi E, etal., J Neurosci 1992 Mar;12(3):691-704.
2: Irwin N, etal., Proc Natl Acad Sci U S A 2002 Sep 17;99(19):12427-31.
3: Tsuzuki K, etal., Acta Otolaryngol 2002 Mar;122(2):161-7.
4: NCBI rat LocusLink and RefSeq merged data July 26, 2002
5: Bartolome MV, etal., Histol Histopathol 2002 Jan;17(1):83-95.
6: Verze L, etal., Ann Anat 2003 Jan;185(1):35-44.
7: Uittenbogaard M, etal., J Neurochem 2003 Feb;84(4):678-88.
8: Kesterson KL, etal., Brain Res Dev Brain Res 2002 Dec 15;139(2):167-74.
9: Young E, etal., Hippocampus 2002;12(4):457-64.
10: Karns LR, etal., Science 1987 May 1;236(4801):597-600.

Search Pubmed for articles about Rat Gap43
--------------------------------------------------------------------------------
Nomenclature
Date Current Symbol Current Name Previous Symbol Previous name Status Description Reference

09-APR-03: Gap43 growth associated protein 43 APPROVED Symbol and Name updated 629477

14-MAR-03: Gap43 growth associated protein 43 Basp2 brain abundant, membrane attached signal protein 2 PROVISIONAL Data Merged 628472

07-AUG-02: Basp2 brain abundant, membrane attached signal protein 2 PROVISIONAL Symbol and Name status set to provisional 70820

10-JUN-02: Gap43 growth associated protein 43 APPROVED Name updated 70584
--------------------------------------------------------------------------------
RGD ID: 62071
Created: 11-APR-01
Last Modified: 26-FEB-04
Object Status: ACTIVE

And to the medical community that still insists on ignoring me? Try this one:

Biol Psychiatry. 2003 Mar 15;53(6):530-7. Related Articles, Links


Regulation of GAP-43 expression by chronic desipramine treatment in rat cultured hippocampal cells.

Chen B, Wang JF, Sun X, Young LT.

Department of Psychiatry, McMaster University, Hamilton, Canada.

BACKGROUND: The importance of molecular and cellular changes in hippocampus in major depression and in the mechanism of action of antidepressants has become increasingly clear. Identification of novel targets for antidepressants in hippocampus is important to understanding their therapeutic effects. METHODS: We used cDNA microarray to measure the expression patterns of multiple genes in primary cultured rat hippocampal cells. In situ hybridization and Northern and immunoblotting analysis were used to determine brain regional distribution and mRNA and protein levels of target genes. RESULTS: After comparing hybridized signals between control and desipramine treated groups, we found that chronic treatment with desipramine increased the expression of six genes and decreased the expression of two genes. One of the upregulated genes is growth associated protein GAP-43. In situ hybridization revealed that desipramine increased GAP-43 gene expression in dentate gyrus but not other brain regions. Northern and immunoblotting analysis revealed that desipramine increased GAP-43 mRNA and protein levels. GAP-43 expression is also increased by another antidepressant, tranylcypromine, but not by lithium or haloperidol. CONCLUSIONS: Because GAP-43 regulates growth of axons and modulates the formation of new connections, our findings suggest that desipramine may have an effect on neuronal plasticity in the central nervous system.
PMID: 12644358 [PubMed - indexed for MEDLINE]

Hmmmmmm,

This is a whole area that I have not considered. I take Gabapentin (another AED) for neuropathic pain and spasticity, but have not noticed cognitive effects one way or the other. To be honest though I've only been taking it for 3 weeks so it may be early days.

I think that I'm going to have to do a fair bit of research on this....

Oh well, at least it's exercise for those little grey cells!

Robin

Sorry......one more link:

http://www.uic.edu/classes/phar/phar402 ... ptors8.htm

Check out the paragraph that talks about nootropics (there's our racetam), the hyppocampus (there's our GAP43 activity from desipramine), etc. etc.

BUT..........I still can't get anyone, anywhere, to test these things for target or selective use in MS.

Deb

Hi, Robin!

I think you'll find that JUST an AED alone doesn't do as much as the combo AED and racetam. But I know you (dare I say that?) You'll find what I did.

Oh....and once you do some comparisons between levetiracetam with the other AEDs, you'll find the difference and uniqueness of its "selectivity" as opposed to the others.

Veeeeeeeerrrrrrry interesting!

Deb

P.S. Oh, yea........and I'm someone who likes to take as few pills as possible that will produce the broadest spectrum of action(s). But, who doesn't, I'd say?

But I know you (dare I say that?)

I think you probably do!

Whilst the term nootropic is new to me I have of course heard of 'smart drugs'. To be honest, being a born skeptic I had dismissed them as a fad. Having now done a little reading I'm not so sure, particularly regarding piracetam.

Also GAP-43 is of particular interest.

Don't you just love PubMed!

I am pathologically averse to 'self medication'. Monkeying with things that I don't fully understand is a recipe for disaster. However I am sufficiently intrigued to do a whole lot more reading.

Robin

Robin,

I was skeptical, also! Hence, why I said "You've GOT to be kidding" (to myself, that is.) Had I read or known anything beforehand? Well...........skeptic is my middle name. You know how I dissect things into minute pieces. Yep, until I looked up racetam (and its history, etc.), I had never heard of "nootropic", either.

Don't you just love PubMed!

Oh....no kidding!!! And what in the world did we ever do without the internet? I don't know about you, but I spent a lot of time in the library (I truly did). But to have THIS much access to information? Oh....man......I'm in heaven! (Well, almost.......... )

I hate taking medications, also. Absolutely HATE it! You should have seen the hard time I gave (well, ok....still "give") any (well, ok......."all") of my doctors.

Deb

EDIT: Oh, yea.........I figured you'd be intrigued. hehehe........

No way am I going to wade in this one too deep, but I do have a thought or two on this. You were talking about cognitive in regards to MS and age. As most of you know, my son is 16 and was diagnosed with MS 3 years ago. We watched his cognitive skills decline steadily. He went from a straight A honor roll student to barely passing. His only medications were Avonex and then Rebif. This was so frustrating to him, after being in all of the gifted and talented programs in the school system, as well as serving as captain of the debate team at his school. Not only did he have to give up every sport he loved because of this disease, but he also had to give up those activities as well, since he just didn't have what it took to stay in these programs. Last school year, we reached the point where we were happy with C's and D's on his report card, and were seriously contemplating switching him to special needs classes. He could not concentrate or remember anything. It was nothing for us to have to repeat something to him 3 or 4 times.

In June of this year during summer break from school, he stopped the interferons and started LDN. We could tell an immediate difference in his attention span at home, but the real test was when he started back to school. He is back on the honor roll with chemistry and Algebra II starting out his daily schedule, taking honors classes, and it is a breeze for him once again. Alot of other things in his life have returned to normal, too, but since we are discussing cognitive issues here, I will stick to that.

I realize that not everyone who experiences cognitive issues and has MS is on an interferon, and that is not what I am saying. I do know for a fact that the interferons caused severe depression with my son as they do for many people, and cognitive problems can go hand in hand with depression. I just find it interesting that he experienced the same problems at age 16 that many "old timers" with MS experience, but at a much worse degree.

I do not believe the LDN resolved his cognitive issues, so please don't get me wrong. But I do believe that stopping the interferons contributed to it immensely. I just wonder how many people are suffering from severe cognitive problems that have worsened with the interferons.

By the way, keep up the good work. I might not post that much, but I learn something everytime I read your postings! Hope you're having a wonderful Thanksgiving, Deb!

Kim

Hi Kim
It's very good news that your son has pulled out of his depression / cognitive problems. One of the great mysteries with MS is why certain treatments appear to help some and hinder others.

Deb, having researched the wotsits out of levetiracetam I've decided to ask my GP if he will switch my prescription from Gabapentin to Keppra. Thanks for your input.

Robin

Hi, Kim! I'm glad to hear your son is doing still doing well!! (And thank you!)

Hi,Robin! Really? Let me know how that goes (of course).

And yes, I have a houseful of guests as we speak! (Still sleeping, though). Uh......did I say something earlier about leading a boring life? HAH! Not THIS weekend!

Deb

Sorry to revive a post from 2004, but I have an interest in piracetam which was mentioned by Raven in this thread. Has anyone tried piracetam for MS related cognitive problems?

Does anyone have any stories to tell?

As an addendum, does anyone have experience with nootropics, be they natural or pharmaceuticals?