Alzforum - Print Discussion

George Perry and Mark A. Smith led this live discussion on 14 August 2001. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Use of standard language is essential to convey ideas with the least encumbrance of misunderstanding. To this end, the amyloid field has the Amyloid Nomenclature Committee whose recommendations have been approved by the World Health Organization (1). Unfortunately, their recommendations (2), namely amyloid-β (Aβ) and Aβ protein precursor (AβPP), have not been broadly adopted by those who study Alzheimer disease. Variations in the nomenclature used to describe amyloid-β and its precursor include A4, βA, AP, APP, βPP, βAPP, AβPP and others. It would assist readers, and certainly editors of journals, if the field could adopt an accepted nomenclature for Aβ/AβPP and other phenomena relevant to Alzheimer disease. To this end, we propose that there be a discussion following a poll to hopefully establish a nomenclature that is accepted by the AD field.

(1993) Nomenclature of amyloid and amyloidosis. WHO-IUIS nomenclature sub-committee. Bull WHO Health Organization 71, 105-108. Abstract.

(1999) Westermark P, Araki S, Benson MD, Cohen AS, Frangione B, Masters CL, Saraiva MJ, Sipe JD, Husby G, Kyle RA, Selkoe D. Nomenclature of amyloid fibril proteins: Report from the meeting of the International Nomenclature Committee on Amyloidosis, August 8-9, 1998. Amyloid: Int J Exp Clin Invest 6, 63-66. View PubMed record..

Q. Is the failure by the field to adopt standard nomenclature the result of philosophical differences, or just ignorance or sloppiness (to which I plead guilty)? If the former, then it could be productive to have a discussion of the rationales for preferring one terminology over another, and to conduct a poll. If the latter, the solution would be to educate researchers in correct usage. We could issue a style sheet to journal editors, which would be given to authors. I'll begin right here on the ARF by adopting the WHO-approved nomenclature and carrying out a search and replace mission on all outlawed forms. (But someone will have to show me how to type Greek letters!)—June Kinoshita.

A. My opinion is that the failure to adopt a standard nomenclature is the result of an indifference to the need for uniformity of terms. Your approach to have a discussion and a poll may finally lead to a nomenclature that all can adopt.

Comment by Robert Kisilevsky—Posted 9 January 2001
The use of APP (amyloid precursor protein) by the "Alzheimer" research community is most unfortunate as there are about 25 different amyloid precursor proteins (APPs) at least half of which were discovered before the Alzheimer's form. To claim this general name for the Alzheimer's form is at best inappropriate and confusing. My preference (beta-protein) is the term coined by George Glenner who was the first to identify this protein. Thus the precursor becomes the beta-precursor protein or betaPP. Abeta is also acceptable (but is a compromise) in which case the precursor is designated AbetaPP.

Comment by Merrill Benson—Posted 15 January 2001
The recommendation by the Amyloidosis Nomenclature Committee to use Abeta for the fibril protein and AbetaPP for the precursor was a compromise that seemed good at the time. It still seems a good idea. The suggestion to strongly recommend that journals use this designation may help resolve the issue.

Comment by Juan F. Gomez-M—Posted 16 March 2001
Theoretical work about nomenclature is essential in any mature (?) discipline. But to develop an "axiomatic discourse" (hopefully, something with some superficial similarity to the Euclides'work on geometry!) we have to define the "primitives." It seems, however, that there are still problems in the basic definitions. Dr. Ming Chen propose fundamental differences between AD and senile dementia. Is this a condition or a disease? If we still do not agree about it, how we can agree about the name of a molecule (Presenilin, gamma-secretase) or its precursors (APP, betaPP or AbetaPP)?

To make the things more confusing, these proteins are also involved in normal function and neurogenesis. The problem can produce in the long-term skepticism and a crisis in AD research: a collection of opinions instead of well-defined facts. Clear building-block concepts is fundamental to construct databases with the fundamental facts, and it is important that the researchers answer those questions "before the literature base becomes much larger" (Dr. Norris). Moreover, thousands of dollars in experiments can have a better use if we know more precisely about what is exactly what we are researching. This discussion deserves more attention.

Comment by Colin L Masters and Konrad Beyreuther—Posted 13 August 2001
While the International Committee on Amyloidosis has grappled with the complexities of unifying a disparate field, its conclusions relating to the proteins which accumulate in the two most important diseases [Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD)] are at variance with current usage.

In AD, APP is widely recognised as the precursor of Ab amyloid. This nomenclature allows for the designation of the a- and b-secretase products (APPa, APPb) whereas the proposed AbPP makes these extremely confusing. The alternate splice products (L-APP, APP-KPI, etc) are manageable, and the related family members (APLP 1, 2; APPL, etc) are easily accommodated. We suggest the APP be taken to mean "Alzheimer Precursor Protein", and thereby avoid the difficulties perceived in the Committee's deliberations.

In CJD, the PrP protein nomenclature is established, with a superscript to denote the various subtypes (Sc, CJD, GSS, FFI, etc). At which stage the normal cell product (PrPc) converts into the protease-resistant/b-sheet-enriched conformer, and then progresses eventually into a polymerised PrP amyloid fibril, is not fully understood. To indicate that APrPSc should be used for all categories of PrP other than PrPc is clearly problematic.

Finally, the Committee's decision to exclude all intracellular aggregates with the histochemical and other properties of amyloid is not helpful. These intracellular aggregates (and their precursors) may yet prove far more relevant in disease causation than extracellular accumulations. Amyloidologists are not doing themselves a favor by relegating them to the "too hard basket."

Participants: Colin Masters, Nico Stanculescu (host), Richard Bowen, Glenda Bishop, "J.P. Morgan", Mark Smith, George Perry, David Teplow, S.H. Kim, Steve DeKosky, Ming Chen, Craig Atwood, June Kinoshita

Colin Masters: I'm now on line. Clear skies in Melbourne...no foggy issues surrounding amyloid nomenclature. Anyone there?

Nico: Hello! I just spoke to the Case group (Smith and Perry) - they're on their "way" in...

Nico: Oh, yes, I think it was... the different "flavor" that was good.... the interaction with the audience, the two sides (and more!) to a hypothesis, etc...

Glenda Bishop: I was disappointed not to go. Too expensive for me here in Australia

Nico: So sorry about that, Glenda.... Initially, we also wanted to do a webcast of it but it was too expensive and we didn't have too many register for that....But perhaps next time we can have some scholarships for cases like yours.

Glenda Bishop: Hopefully next time won't be an issue. I should be working in America then

Gperry: We should present our opening positions as Colin and Konrad have already done?

Gperry: As I see it the major issue is one of standardization for indexing, editing and better conveyance of meaning. I agree the Amyloid nomenclature committee did not consult with the AD community , but the AD community did not fill the niche. Colin Masters: My position is that a utilitarian approach will always win over the impractical.

Gperry: The Amyloid nomenclature was endorsed by the WHO and several journals. If a new nomenclature is adopted, it must be utilitarian, practical, and represent a consensus. That is the point of this session.

Msmith: And that really is the point. We do not need new...just standard to which everyone adheres (even though it may not be their pet name!).

Teplow: I did not serve on the committee, but I feel that they did a good job and that the consistency they bring to the field is worth implementing.

Gperry: The WHO nomenclature is used in less than half the manuscripts I review.

Teplow: If we, as editors and reviewers, work towards the goal of implementing this standard, we should be successful, eventually.

Msmith: David, well said. The goal, I guess, is that once a standard nomenclature is agreed upon, it must become standard. At present this is clearly not the case...I blame the journals. Editors must be told that this is the standard… or not!

Teplow: I agree. The problem is to eliminate the egocentric behavior of coining your own terms in favor of a consistent and logical lexicon.

Gperry: Yes, but it is a major effort for me to standardize words in JAD now and for the previous 7 years at AJP.

Teplow: George, I wonder if you could provide style sheets, which list nomenclature, much as JBC does. That is, to the authors.

Gperry: At JAD and AJP we adopted the WHO standard, and it appeared in the instructions. Even then half used divergent terms.

Colin Masters: I missed something, now back on line. Is there any agreement on the use of AbetaPP?

Msmith: With the advent of electronic manuscript submissions, I think is easier than you might think...also, if editors insist on this revision then it will get done...only a small hoop.

Teplow: Could we set up some sort of working group at Neuroscience this year to implement this strategy?

Msmith: But that's neither the WHO standard, nor everyone's standard ...and that's the problem.

Teplow: I think a major problem is the fact that only 12 of the converted are even discussing the issue here.

Dekosky: I agree with Colin that Abeta and APP are the terms most used, in my experience. George, if people are not using the 'standard' terms even in journals that require them, it is clear that there is not a standard USE, even though there may be a Standard (by WHO or WHOever).

Gperry: Yes, David the rest go on using what is convenient, not what links our work.

Richard Bowen: I think Colin has a good idea. Pick certain journals and for a specified time period see what is the most common usage in the submitted manuscripts.

Msmith: If I can throw a wrench in here...beta is impossible to e-mail or Medline search.

Gperry: Steven the point of this session is to lay the groundwork for a standard usage that all could accept. That should be done?

Colin Masters: Exactly why we tried to avoid it in the beginning, but were over-ruled.

Teplow: I think a survey is irrelevant. The point is that we need a standard and that the standard needs to be implemented. I advocate our discussing HOW to implement the standard.

Dekosky: Yes, I was going to comment that people use it even though it is difficult to use the Greek character and awkward to spell out.

Gperry: The problem with only addressing what works is that it does not integrate our AD work into the amyloidosis field as a whole. A term such as APP forsakes other amyloids as significant.

Richard Bowen: Have any other fields had the same problem recently and what have they done?

Teplow: Colin, I like APP, but I always use ABPP for the reasons I mentioned earlier.

June: AbetaPP certainly doesn't trip off the tongue. Is there an alternative besides APP?

Colin Masters: George, the original idea came as a memorial to the work of George Glenner.

Gperry: Yes Glenner is deserving of honor, but the group should suggest terms that are workable and speakable. Abeta is difficult in either regard.

Colin Masters: I don't think we can ever get away now from the Abeta usage June How about beta-APP and beta-amyloid?

Craig: I don't believe that we should be elitist and separate ourselves from other amyloids. Abeta is only one amyloid after all.

Teplow: No takers on my suggestion to move towards mechanisms of implementation?

Teplow: Well, I would volunteer to coordinate a meeting among us, or other interested parties.

Teplow: George, that's wonderful. Also, as a board member at Amyloid, maybe I could get Alan to also publish something.

Colin Masters: As a courtesy, you should probably invite someone from the amyloid club.

Gperry: June we invited several to this session. Only Colin was so kind as to appear.

Teplow: Maybe all of you that are interested in this working group could email me and then I could establish a list.

Gperry: Teplow's suggestion of a working group is a good one if augmented with an analysis of the frequency of use of various terms and most importantly involves the major opinion makers and Journals.

June: But if you are looking at frequency of use, this suggests you do want to reopen the question of choosing standard terminology.

Teplow: As I said, this is an important issue to me, and therefore I would be happy to coordinate the effort in collaboration with you guys.

Gperry: Beta-amyloid is now used much less than Abeta. Colin Masters: We also need to consider the use of alpha, beta gamma delta and epsilon for the secretase sites.

Teplow: The first question we need to answer is, "What are the important questions?'

June: How about: Can we agree on the WHO standards, or do they need to be changed?

Gperry: The major issue is reaching a consensus on standard terms that can be universally adopted.

Teplow: Prior to this meeting, it would help if a list of issues could be assembled for discussion. This should be done pre facto so people can come prepared.

Msmith: Perhaps June could incorporate David's suggestion by way of a online questionnaire?

June: Sure, I can create an online questionnaire. This has to involve a representative cross section of the community.

Gperry: Prior to a meeting, a list of terms and alternatives might be assembled.

Teplow: I suggest Neuroscience, at least initially. Then, if necessary, our European colleagues who can't attend could be informed in Sweden next summer.

Gperry: Neuroscience should be the start, but Stockholm should iron out the final form.

Craig: Is the issue about what the AD community wants or what is a standard for amyloid diseases in general.

Teplow: That's why I'm suggesting some sort of email coordination of the effort.

Gperry: Question: Should we be concerned about the standardization with the amyloid community or adopt our own terms?

Gperry: I think Neuroscience only covers AD, prion and amyloids related to neuropathy, that is unless one also includes tau and synuclein.

June: Maybe we should invite someone from National Library of Medicine. One reason for standard nomenclature is you need a controlled vocabulary to search the literature.

June: Sometimes these things happen organically. But in the case of APP, problem is non-AD people use it to mean other things.

Gperry: The consensus is to have a meeting, face to face, at Neuroscience to see where we go from here. Prior to that meeting, facts and a draft document could be made. David, I would be happy to co-chair this with you.

June: I can post the draft documents on the www.alzforum.org site and invite comments from the community.

Craig: Sounds good, but will it be dominated by AD workers and not other workers on amyloid?

Gperry: As the hour comes to an end I am delighted we now have the framework to go ahead.

June: Unfortunately, not. But there must be some kind of scientific society for the study of amyloidoses.

Msmith: Okay, I for one would be happy to be part of the working group but must go soon to fix a leaking bathtub!

Gperry: Colin you may be correct in us dealing with our problem and then reaching out.

June: So, George, will you email all of those participating in today's chat, plus other "stakeholders," and get the ball rolling?

Colin Masters: Look forward to hearing from you. We must solve this one way or another.

June: I've got to go throw water on my daughters. Thanks to all for showing up!!

Teplow: It looks like things are winding down. Why don't you and I get the ball rolling George.

Gperry: I also need to leave. I will work with David to get facts to form the basis of a questionnaire and a draft.


	Comments on Live Discussion

	Comment by: David Teplow
	Submitted 17 November 2000 \| Permalink	Posted 17 November 2000
	There is nothing that upsets me faster than scientists using inappropriate and imprecise terminology and nomenclature. With respect to the Alzheimer's disease lexicon, the WHO and the International Nomenclature Committee on Amyloidosis have ALREADY dealt with this issue. I refer you to Bull. WHO 71:105-108 (1993) and Amyloid: Int. J. Exp. Clin. Invest. 6:63-66 (1999). You may also get a kick out a recent short commentary I wrote concerning the suggestion of altering the amyloid term itself (see Teplow Neurobiol. Aging 21:563-564 (2000)). The issues of BACE, gamma-secretase, etc., does need clarification. View all comments by David Teplow

	Comment by: David O. Norris
	Submitted 17 November 2000 \| Permalink	Posted 17 November 2000
	Yes, at least some consensus would be appreciated, especially for people new to this field. For example, at the recent Neuroscience meeting in New Orleans, people were hedging on the latter case (presenilin-1 or gamma- secretase?) even to the extent of questioning whether or not they are the same protein. And then what about beta-secretase? And there should be agreement on the abbreviations used as well. A position statement from somewhere on this terminology indeed would be welcome before the literature base becomes much larger. View all comments by David O. Norris

	Comment by: Bart De Strooper, ARF Advisor
	Submitted 29 January 2001 \| Permalink	Posted 29 January 2001
	I agree that it would be useful to accept a uniform nomenclature. For instance literature searches in Pub med would be more efficient. Sloppiness is probably the most important reason for the current situation and the forum is a good place to discuss the problem. The beta-symbol is a problem in electronic documents. A good starting point for the discussion would be a proposal not only for A-beta-PP, but also for the presenilins in different species, and the mutations. Also the different rules for protein or genes in different species (capitals or not, italics or not, etc.) is a problem. I am not very good in those things, but maybe you can ask somebody to make a proposal. Once there is some consensus I will certainly use the nomenclature in all next papers from my laboratory. View all comments by Bart De Strooper

	Comment by: Ming Chen
	Submitted 21 February 2001 \| Permalink	Posted 21 February 2001
	Question: Are Alzheimer's Disease and "Senile Dementia" the Same Disease? This perhaps is the most important "nomenclature" problem. AD used to refer to "pre-senile" dementia (PSD; middle age dementia). This name clearly distinguished it from senile dementia (SD; dementia after age 60). However, since 1970s, they are redefined as the same disease (AD), mainly because they have the same symptoms and same hallmarks (plaques and tangles). This definition is the basis for AD research today. However, it recently came to our attention that if PSD/AD and SD are the same disease, then it would be difficult to explain: 1. After intensive studies, it has been confirmed that AD does exist in two major forms: early-onset and late-onset, corresonding essentially to PSD and SD. 2. Most PSD has been successfully linked to gene mutations, head injury and other severe insults, but SD remains largely as a mystery. If they are the same disease, then they should have the same causes (like AIDS). 3. While PSD remains a rare disease in the middle age people today, SD rate has increased exponentially and surpassed 50% after age 90. This makes SD in sharp contrast to conventional diseases (no more than a few percent). If they are the same disease, then why does one increase so much, but the other not? So, while it is usually correct to define diseases by pathologies but not by patients'ages (like AIDS or influenza), is it also correct for AD? View all comments by Ming Chen

	Comment by: Ming Chen
	Submitted 15 August 2001 \| Permalink	Posted 15 August 2001
	Clarification of the confusing terms such as Aβ, βA, APP, βAPP or AβPP will help the field if they can be standardized. But here, I would like to reiterate the key importance of another "nomenclature" problem, i.e., "Alzheimer's disease" or "senile dementia"? The latter condition had been known since ancient time, but the former was defined by Dr. Alois Alzheimer in a 56-year-old patient. Dr. Alzheimer considered such rare cases as "pre-senile" or "midlife" dementia thus quite different from "senile dementia". So, the term "Alzheimer's disease" was defined mainly on the basis of its onset age difference from senile dementia. But since 1970s, the two conditions have been re-defined as the "same disease" on the rationale that they both exhibit the same symptoms and same hallmarks. According to this new definition, senile dementia should be caused by similar pathogens that are known today to underlie pre-senile dementia such as gene mutations, vascular diseases or other severe insults. But, is this definition correct? We know that vision, hearing, or heart failures can also strike juvenile or middle-aged persons in rare cases, and these are certainly caused by inherited or invading pathogenic factors. But if the "same" failures occur in VERY OLD people, are they also due to the same factors? Yet, juvenile-onset cataracts (lens protein deposition) can affect young people in rare cases which have exactly the same symptoms and hallmarks of SENILE cataracts. Do we, therefore, believe that they have the same underlying causes? Failure of a new or middle-aged car is apparently due to manufacture error or accident, but is the eventual failure of a VERY OLD car or its parts also due to the same reasons? If they are not but officially defined as such, then what will happen to our investigations which are desperately looking for the cause of mainly the LATE-ONSET sporadic dementia because only this type of dementia has a horribly high prevalence and thus threats society the most today? The AD research field may need to face these difficult questions. Very recently, we have discussed them in more details (Ref. 1). References: 1. Chen, M., Fernandez, H.L. Alzheimer movement re-examined 25 years later: is it a "disease" or a "senile condition" in medical nature? Front. Biosci. 2001; 6, e30-40 (free full text): http://www.bioscience.org/2001/v6/e/chen2/fulltext.htm View all comments by Ming Chen

Live Discussion: Nomenclature Discussion