Introduction

Our thanks to Practical Neurology for granting permission to reprint the full text of a recent article (.pdf) by John Trojanowski.

John Trojanowski, Les Shaw, and Anne Fagan led this live discussion on 1 June 2005. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript:

Live Discussion led by John Trojanowski, Les Shaw, and Ann Fagan on 8 July 2005.

Participants: John Ciallella (Cephalon), John Cirrito (Washington University), Clary B. Clish (Gene Logic, Inc.), Keith Crutcher (University of Cincinnati), Chiara Cupidi (University of Palermo, Italy), Mony de Leon (New York University), Anne Fagan (Washington University), Tom Fagan (Alzheimer Research Forum), John D. Fryer (Baylor College of Medicine), Marni Harris-White (GRECC-UCLA), David B. Hawver, pharmacologist (Neurology Drug Products Division, FDA), Rachel Locke (University of Pennsylvania), Patrick Lynn (Satoris, Inc.), Douglas Scharre (Ohio State University), Les Shaw (University of Pennsylvania), Hasan Siddiqi (University of Rhode Island), John Trojanowski (University of Pennsylvania), Diana J. Vincent (Medical University of South Carolina), Nancy E. Lombardo (Boston University).

Tom Fagan
Hi, Les!

Les Shaw
Hi, Tom.

Tom Fagan
We have a few others in the "foyer" about to join us.

Les Shaw
Hi, Anne.

Anne Fagan
Hi, Les. Nice to "meet" you.

Les Shaw
I look forward to the discussion.

Anne Fagan
Me, too. So many issues, so few answers at present!

Tom Fagan
Anne, what's your major focus these days?

Anne Fagan
Lots of exciting things, actually. Antecedent biomarkers are on the top of my list. I'm spearheading a project involving multiple investigators and multiple possible biomarker modalities in middle-aged folks and then following them over time. I'm working with Dr. Cynthia Csernansky, also, in creating a couple of related databases.

Les Shaw
Anne, what fluids and what markers?

Anne Fagan
I'm the principal investigator (PI) for the cerebrospinal fluid (CSF)/plasma portion, and there is an amyloid imaging section, structural magnetic resonance imaging (MRI) portion, and various clinical and psychological measures, including attentional measures. The great thing is that every subject in our study gets tested for everything. CSF markers include the usual suspects—Aβ(s), tau, phospho-tau, sulfatide, homocysteine, ApoE, cholesterol, some lipoprotein-related measures.

Les Shaw
Anne, are the patients cognitively normal and you follow them over time?

Anne Fagan
Yes, they are all at clinical dementia rating (CDR) 0 at entry.

Les Shaw
Very interesting.

Anne Fagan
Since we have a large age range, 45-74, we expect the older CDR 0s to "convert," as it were, quicker. We're recruiting based on positive versus negative family history of AD and can stratify by ApoE genotype also to lump into high/low risk groups to see if anything pops out initially.

Les Shaw
Anne, what is the power of ApoE for stratification?

Anne Fagan
Les, do you mean literal statistical power? Can't say offhand, but we know that more ApoE4-positive folks will likely go on to develop AD than ApoE4-negative folks, so we hope to enrich for preclinical AD that way.

Tom Fagan Okay, John Trojanowski is here now so we can get started in earnest. John, would you like to start the ball rolling?

John Trojanowski
Okay, Tom. Briefly, we will focus here on chemical analyte biomarkers in various bodily fluids such as CSF, urine, blood, etc., and while genetics may come up, too, we will save imaging biomarkers for another time. Back to the question Les raised on ApoE: It does seem to be critical to consider this for cohort assignment as demonstrated in the recent NEJM paper from R. Peterson on mild cognitive impairment (MCI), and we will do this as well in the Alzheimer Disease Neuroimaging Initiative (ADNI) study.

Anne Fagan
John, what's your gut feeling about the potential utility of urine showing decent biomarkers?

John Trojanowski
So far, urine has seemed fruitful for studies of isoprostanes, although it depends on which one is measured and the method, but I am not certain if other analytes in urine are informative (see related ARF milestone paper by Pratico et al., 2001 on isoprostanes in AD and also papers by Montine et al., 2005 and Bohnstedt et al., 2003 on detection.

Anne Fagan
We're already seeing some differences in levels of Aβ42 in ApoE4-positive versus ApoE4-negative folks in our antecedent study, but not other CSF markers, although the data are very preliminary. It suggests that perhaps Aβ42 is the first thing to change. We must verify with follow-up, of course.

Tom Fagan
Anne, do you have indications that urine analysis might prove useful?

Anne Fagan
Tom, we aren't collecting urine. It may be too far down the line (i.e., processed) to be meaningful, but the idea is very clinically appealing.

John Trojanowski
Les, do you have information on other urine analytes?

Les Shaw
John, for AD, no.

John Trojanowski
Anne, what do the receiver operating curves (ROCs) look like in the studies you mention, and perhaps the group would benefit from a definition of antecedent, as this is not on everyone's radar screen. [ROCs can provide useful information on the sensitivity and specificity of clinical measurements.]

Anne Fagan
True, John. We haven't done formal ROC analysis yet. I use antecedent to mean biomarkers that indicate presence of neuropathologic AD (i.e., brain changes) but prior to clinical symptoms. Morris and Price and others at our Alzheimer Disease Research Center (ADRC) have published findings showing that a good percentage of clinically normal elderly folks who die from other causes actually have AD pathology but no clinical symptoms (see, for example, Galvin et al., 2005 and Price and Morris, 1999). Our goal is to be able to identify these folks since clinical variables, by definition, cannot define the presence of preclinical disease. The percentage of "preclinical" subjects is about 30.

John Trojanowski
Anne, so antecedent is restricted to prodromal AD as in MCI, or might it be earlier in populations such as those with familial AD (FAD) or Down syndrome?

Anne Fagan
Good question, John. I guess Down syndrome would also be considered preclinical, as would FAD cases prior to impairment. They'd be a good population to study. For what it's worth, I consider prodromal to mean prior to any cognitive symptoms, including prior to cognitive symptoms characteristic of MCI.

John Trojanowski
I agree with Anne that these analytes are the rising stars for early AD diagnosis with a promise to be useful for sorting out MCI, too, but more work is needed on this, and we need to add a new possibility—lipoxygenase metabolites as per work from Domenico Pratico at the University of Pennsylvania who just had a paper on this (see Yao et al., 2005).

Les Shaw
Anne, what will it take to convert to a true diagnostic biomarker in terms of studies and data needed?

John Fryer
John, what is the patient population you are collecting from and is it longitudinal?

John Trojanowski
The ADNI population is well described in the ADNI website where the redacted grant is publicly available, but briefly, the study is a 3-year longitudinal of 400 MCI, 200 AD, and 200 normal controls balanced for ApoE status. I can add that the Penn Biomarker Core led by Les Shaw and me will perform CSF tau, Aβ, isoprostane, and homocysteine measures, as well as plasma homocysteine and isoprostanes and urine isoprostanes, and we will cover as many species of Aβ, tau, and isoprostanes as we are capable of measuring. Since the data will be made public rapidly, all the ~50 sites participating in this will have access to these data.

Mony de Leon
What is the most specific diagnostic CSF marker in AD?

Anne Fagan
Mony, currently only autopsy findings are definitive. A number of CSF analytes (Aβ42, tau, perhaps isoprostanes or sulfatide) are promising but so far haven't fulfilled criteria for a true diagnostic biomarker.

John Fryer
Has anyone proposed to use an additional patient population, such as Parkinson disease (PD), to determine which changes are specific to Alzheimer's versus neurodegeneration?

Anne Fagan
John F., just did some analyses on PD CSF (with and without cognitive impairment). So far, no difference between the groups on our standard CSF analytes (Aβs, tau, etc).

June Kinoshita
Anne, to clarify, are you finding no difference between PD with and without dementia, or between AD and PD?

Anne Fagan
June, between PD with and without dementia…hot off the press as of yesterday afternoon—not published—not even put into my database yet! And still preliminary, of course. There are differences between AD and PD as perhaps one would expect.

June Kinoshita
Anne, at the pathology level, do PD patients with dementia have AD pathology while PD without dementia have no AD pathology? I imagine it is not quite so clear-cut, but it's interesting that you don't see differences at the biomarker level.

Anne Fagan
June, these samples are from a big bank in Rochester. I don't think any autopsy information is available. I'll have to check on that.

John Trojanowski
John T agrees with Anne and adds that Lewy body variant of AD (LBVAD) may be possible to distinguish from PD or PD with dementia (PDD) by the AD biomarker profile of CSF tau, Aβ, and isoprostanes, but I do not know about sulfatides, which I neglected to mention also is on the roster of analytes the ADNI Biomarker Core will examine in CSF.

Anne Fagan
John T, we're still working out some methodological bugs with sulfatide, but our published data were very promising and warrant exploration. Glad to hear you're doing that.

John Trojanowski
Okay, Anne, and we had input from folks at Washington University on how to do the sulfatide assays, and these data also will be made public on the ADNI website within a few months of study completion.

Anne Fagan
Another issue is ultimate ease of measurement. It seems like some of the metabolites and various other things are measured by labor-intensive methods such as high-performance liquid chromatography (HPLC). I guess we need to find the marker first and then hone down the measurement issues.

John Trojanowski
While some of these tests are labor-intensive, Les does mass spectrometry measurements on many analytes other than for AD, so perhaps he can give a sense of labor, costs, and turnaround for this type of measurement as they are routine in some pathology and laboratory medicine diagnostic units.

Tom Fagan
All, given the potential labor required, is cost a major impediment to validating biomarkers?

Anne Fagan
Tom, I don't think cost should be an issue yet, but it will be ultimately as things are taken to the clinic.

John Trojanowski
I do not think this is a problem, Tom, but if we have not lost Les, he can weigh in here as this is an area he has expertise with in lab diagnostics.

Les Shaw
Most major medical centers and clinical labs have mass spectrometry equipment and expertise for certain types of tests—toxicology, drug monitoring metabolic diseases. Once the equipment and the expertise to run these is in place, the costs are very competitive compared with costs for immunoassays, for example, and that type of cost is reasonable. I foresee more mass spectrometry applications, for example, the low molecular weight biomarkers once clinically validated coming into routine practice in the future.

Tom Fagan
Anne, what about enrollment numbers? Is ADNI or your study sufficiently powerful enough statistically, or will a broader net need to be cast, eventually?

Anne Fagan
Tom, the answer for our study is likely no. A wider net would be good. Even though we defined our enrollment numbers according to proper power calculations, I predict greater numbers will eventually be needed, especially if the effect is relatively small, as one would perhaps predict in a preclinical disease state—nature of the beast, and all.

Patrick Lynn
Has anyone seen robust biomarkers for AD in serum or plasma? This is an area of our research.

Anne Fagan
Patrick, we haven't looked carefully at plasma yet, although we collect it (fasted) so we can go back at any time as interesting possibilities emerge. Tough to work with, given all the proteases, etc.

Hasan Siddiqi
How about using SELDI-TOF (surface-enhanced laser desorption and ionization-time of flight) mass spectroscopy to look for novel biomarkers in plasma?

Anne Fagan
SELDI-TOF is certainly a possibility. I predict biomarkers that mark brain processes will be in low abundance, especially in plasma/serum. Tough to do, though.

Les Shaw
Mass spectroscopy methods for certain drugs and toxins, for example, and metabolic diseases are now fairly standard for routine or semi-routine testing. Most drug study method validations using mass spectroscopy and using it for the clinical trials is now what is typical, and I foresee this more and more for many of the biomarkers we are interested in for AD. What is needed more than anything, for the methodology part, is lab-to-lab comparisons and standardization.

June Kinoshita
Hear, hear!

Tom Fagan
Les, what is being done to standardize among different labs? I would imagine this must be one of the major aims of the ADNI, right?

Anne Fagan
Standardization will be a major issue, dare I say, problem?, and one that must be attacked head-on at the inception of studies, if possible.

John Trojanowski
To add to what Les mentions, this standardization is a major effort and focus of the Biomarker Core which will interact with pharmaceutical companies and diagnostic companies to make the best academic/industry standards for the analytes that we measure. So we are hopeful that CLIA-approved AD diagnostics will come out of this effort 3-5 years hence. (CLIA, or Clinical Laboratory Improvement Amendments, is a branch of Centers for Medicare and Medicaid Services that regulates all laboratory testing carried out on humans in the US.)

John Fryer
John T. and Anne, how often are your patients imaged and does the imaging include amyloid imaging agents?

John Trojanowski
John F., the imaging is magnetic resonance imaging (MRI) and positron emission tomography (PET) at different schedules for the different cohorts. No imaging ligands are part of this study.

Anne Fagan
John F, our studies include MRI as well as Pittsburgh compound B (PIB) PET (see ARF related news story). Imaging will be done over time but I can't recall offhand the intervals. I know CSF will be taken every 3 years. Perhaps it will be the same for imaging. I'll have to go back to the grant to be sure.

John Trojanowski
In ADNI, there is no PIB, and the CSF is to be from ~30%-50% or more of all subjects obtained at baseline and after 1 year. Other fluid draws are more frequent and over longer periods of the study, and this, too, is all available on the ADNI website by accessing the grants.

Hasan Siddiqi
Does anyone think the biggest issues with plasma biomarkers is specificity/sensitivity in relation to CSF biomarkers?

Anne Fagan
I don't have a feeling for that, Hasan.

Clary Clish
Hi, I am Clary Clish from Gene Logic, Inc. I am developing a liquid chromatography-mass spectrometry (LC-MS)-based biomarker analysis platform for a wide range of disease states including AD.

Tom Fagan
Clary, can you give us some idea of the scope of your project, how many patient samples, etc.?

Clary Clish
My efforts are focused on small, endogenous molecules and I am just getting started on AD. Method development is going to begin with CSF, plasma, and urine samples from preclinical subjects. We are going to target compounds that are in some way tied to the pathophysiology and potentially dysregulated.

Anne Fagan
For what it's worth, we've also begun a CSF proteomics project using two-dimensional difference gel electrophoresis (2D-DIGE)-based methods combined with LC-MS. A fishing expedition but one that we hope will pay off down the line.

June Kinoshita
I love fishing expeditions, Anne. Most, dare I say all?, of the biomarker candidates that are being looked at are based on studies in AD patients. How do we know that the same biomarkers will indicate the presence of preclinical stages? What do you all think about casting a wider net and carrying out some proteomic and genomic fishing expeditions? Good idea or waste of dollars?

Anne Fagan
June, our efforts on antecedent biomarkers dovetail nicely with our work on AD subjects. We also are collecting CSF/plasma from very mild and mild AD cases. Maybe I'm naïve, but I think that what one finds in clinical AD will probably be found earlier—just depends how far back we can detect the change. Does that make sense?

June Kinoshita
Yes, it does.

Anne Fagan
Also, June, proteomics projects are tough to get funded (I should know!) for just that reason—they are too "fishy," especially with the present NIH funding situation.

John Trojanowski
Further on ADNI, while the analytes we measured were chosen with their potential promise to be informative (based on published reports) and budget in mind, there are opportunities of add-on studies to the ADNI biomarker work, and folks interested in this should check the ADNI website or the public announcement (.pdf) that appeared on the NIA website last year. But realize that requests for add-on studies are vetted by a resource allocation review committee (RARC) of advisors to ADNI and it will not be possible to apply to duplicate studies of analytes already covered by the ADNI proposal.

Anne Fagan
John T, I'm sure you've thought about data management for the ADNI. Do you have someone that is spearheading this specific part? I, unfortunately, could not attend the bioinformatics meeting in Washington, DC, a few weeks ago.

John Trojanowski
Anne, the data collection is in the petabyte domain of intensity, and it is coordinated by the Clinical Core at UCSD under the direction of Leon Thal in collaboration with Art Toga at the laboratory for neuroimaging (LONI) at UCLA. This is all Web-based, and data mining will be possible by frequent postings of data on a public website at the ADNI website. And, June, focused fishing will be possible through add-on studies to ADNI as mentioned above, but funding for this will be through competitive grant applications, following approval by the RARC, to access banked ADNI biosamples.

Anne Fagan
John T, will people be able to download data and use them at their discretion or will there be some guidance/policing of who does what with what data?

John Trojanowski
Anne, yes, this will be possible with approvals, access codes, etc., and the data will be de-identified, but the idea is to encourage data mining and publication with consultation with an ADNI publication committee.

Anne Fagan
John T, a publication committee is a great idea.

John Trojanowski
Further on Anne's query about data management, an attractive aspect of the ADNI is the fact that all data, clinical, biomarker, imaging, etc., will be made public so bioinformatics and biostatics gurus can mine the data for developing better data analysis tools and new correlations, etc. My question to Anne is: Will the data collected in the study she mentions be made public and can investigators apply to add-on studies to examine aliquots of the biosamples collected for this new study?

Anne Fagan
Also, to answer your question, John T, we are in the process of developing a relational database for our antecedent study (termed ACS for Adult Child Study) for in-house analyses…tricky to even coordinate 4-6 investigators within the project, let alone between institutions. Hopefully this proof-of-principle database can then be adopted by other institutions for their own in-house analyses. Ultimately, we will make the data public but there are some important issues that need to be addressed first, such as what I just brought up: how to make sure that the data are "used" appropriately, for lack of a better word. And yes, our samples will certainly be available to other investigators through our usual (competitive) tissue request and review process. Information can be found on our ADRC website.

John Ciallella
Is anyone tracking blood glucose as a biomarker, given a possible link between diabetes and AD?

Anne Fagan
Great question, John C. We have not proposed to test blood glucose, but certainly could do so with appropriate collaborations. The AD/insulin/diabetes connection is very interesting to me, although I'm just learning about it. [See related ARF Live Discussions: Is Alzheimer's a Type 3 Diabetes? led by Suzanne de la Monte and Insulin Resistance: A Common Axis Linking Alzheimer's, Depression and Metabolism? led by Natalie Rasgon.]

Nancy E. Lombardo
Earlier this week during the AlzForum chat on insulin resistance, AD, and depression, Suzanne de la Monte, Natalie Rasgon, June, myself, and others were wondering whether the current leading studies of biomarkers for AD, including the National Institute on Aging (NIA) neuroimaging study, are including biomarkers for insulin resistance, especially in the brain.

John Trojanowski
Nancy, this is not covered in the ADNI Biomarker core list of analytes to be studied at the University of Pennsylvania, and we selected analytes, the ones mentioned above, with budget limitations in mind, but others can pursue studies of other analytes through the ADNI add-on study mechanisms, and funding for this must be obtained by the investigators wishing to study the other analytes, so there are mechanisms in place for hypothesis-driven as well as exploratory metabolomic, proteomic, and other "omic" approaches. Since the samples are precious and limited, the RARC will adjudicate who will gain access to samples. Also, a certain percentage of the aliquots will be held in reserve until the end of the ADNI grant to enable us to take advantage of new technologies that emerge in the next few years.

Tom Fagan
All, someone mentioned familial AD (FAD) earlier, but I think I missed the gist, so is anyone following FAD patients in preclinical stages?

Anne Fagan
Tom, we are not following FAD families. Alison Goate here at Washington University is doing some genetic studies with them. It would be great to get CSF/plasma but these families are all over the world. Again, it brings up the issue of variability in sample collection and analysis protocols between labs.

June Kinoshita
Tom regarding FAD subjects, there is one study that I know of with individuals who are positive for an FAD mutation and have not developed symptoms yet. I think there are more people out there who would volunteer if we could only find a way to connect with them. That's where the early-onset AD (EOAD) Web page idea comes in.

Tom Fagan
June, yes, that was one of the things on my mind! It also occurs to me that many FAD patients might be slightly scared to get involved, for fear of finding out the worst, but as treatments start to become available, they might be more inclined.

Anne Fagan
June, what's the EOAD Web page idea?

June
Anne, the idea of the EOAD Web page is to set up an informational page on the Alzforum directed to people with early-onset AD in their families and for researchers who are interested in working with them. They have some different medical needs and issues, for example, genetic counseling, family issues, etc., and might benefit from support and advice from other EOAD families. They also may have a very high level of motivation to participate in research because their children may have the mutations. So an EOAD online community would support patients and families and also nurture alliances between affected individuals and researchers.

Anne Fagan
June, great idea with the FAD families. I love AlzForum!

June
Thanks, Anne!

John Fryer
Anne, how long is this longitudinal study currently funded for?

Anne Fagan
John F, the study just got funded for 5 years—not enough time to do any validation, of course, but we hope it will continue for many years!!

Hasan Siddiqi
I heard that some group recently found another type of plaque associated with AD…not too sure on the specifics. Anyone have more information on this?

Anne Fagan
What do people think about the concept of incentives for researchers to adopt certain collection and analytical procedures in order to better compare data between labs? Too controlling? I think one of the big problems with biomarker, especially antecedent studies, is lack of enough statistical power. How can we as a scientific community pool our resources (samples, data, etc.) to move forward at a more rapid pace?

Les Shaw
Anne, that's a good way to bring up the importance of the collection and procedures standardization needs. I think building the spirit of collaboration and promoting this is key.

Anne Fagan
Les, I agree whole-heartedly.

Clary Clish
Anne, I think your idea about standardization, particularly for sample collection and storage, is a good one. The analytical protocols that follow afterward are more challenging as they may be hardware-dependent.

Anne Fagan
I absolutely agree with you, Clary. Even in my own project we use two different protocols to measure Aβ42. While the values are highly correlated, they are not the same, and that's using the same experimenter and the exact same samples!

Les Shaw
Further to collaboration, too, I believe we in academia benefit a lot from engaging with our pharma colleagues who bring certain strengths to the table like issues of standardization since they have FDA hoops to go through for drug studies.

John Fryer
John, how comprehensive is the neurological examination of your patients over time and will this be on the ADNI Web posting also, or will HIPAA regulations prevent that (see related Live Discussion on the impact of the Health Insurance Portability and Accountability Act (HIPAA) on research)?

John Trojanowski
John F, there is not enough room here to mention the inclusion/exclusion criteria to be used at the ~50 participating ADNI sites, but these are available for identifying normal, MCI, and AD patients in the ADNI grants that are available to the public at the ADNI website, and moreover, the SOPs for all of the studies to be done including biomarkers, which was an amazing accomplishment by Les Shaw, will go up on the ADNI website too, so we hope that others will take advantage of this public access to ADNI data and study design as we all go forward with biomarker studies for AD as well as related dementias such as frontotemporal dementias (FTDs), Parkinson disease with dementia (PDD), etc.

Hasan Siddiqi
Is tau a current neuroimaging target?

Tom Fagan
Hasan, I don't believe there are any ligands yet that are useful for tau imaging, but there was a paper recently on natural tau fluorescence, but no indication that this might be useful in vivo (see Bing et al., 2005).

June
Hasan, I believe Gary Small at UCLA has been working on tau imaging ligands.

Tom Fagan
Oops! Okay, June trumps me with Gary's studies.

June
Don't hold me to it, though!

Tom Fagan
Okay, folks, we are nearing the end of our scheduled hour, but please feel free to continue chatting as long as you wish. But before people start drifting off, I just wanted to thank John, Les, and Anne for agreeing to devote some of their valuable time to this chat.

John Fryer
I have a meeting, best of luck to you all.

John Trojanowski
Okay, and please all check the ADNI website periodically for new items on progress, data, and other options to make use of the incredible amount of data that will flow from ADNI and will benefit from analysis by many investigators including those beyond the ADNI investigators. With that, I say ciao to all until next time.

Anne Fagan
Thanks to everyone for an animated discussion! Hopefully this will be the first of many.

June
Ciao, John. Thanks, Anne and Les!

Les Shaw
Goodbye, all.

Anne Fagan
Thank you, June. Wish I could type better!

Background

Review of concept

During the last 15 years or so, we have seen considerable advances in our understanding of the biology of Alzheimer disease (AD). Amyloid-β and phosphorylated tau, the major components of amyloid plaques and neurofibrillary tangles, respectively, have been identified, as have enzymes that are required in their production, such as the γ- and β-secretases and tau kinases like GSK3β. Potential risk factors, such as apolipoprotein E variants, IDE polymorphisms, and homocysteine have also been revealed, and great strides have been made in structural and functional brain imaging techniques. The stage is now set to translate these advances into tests that will aid in the diagnosis of AD.

But AD can begin long before there are any overt symptoms. What would really make an impact is the discovery of an antecedent chemical biomarker, one that would predict, with appreciable certainty, who will get AD, much like the different forms of cholesterol can predict who will get cardiovascular disease.

Currently, there are no biological fluid analytes that would seem to make good antecedent biomarkers. But with the Alzheimer Disease Neuroimaging Initiative (ADNI) (see ARF related news story), and numerous academic and private research labs around the globe hunting for AD biomarkers, that may soon change. However, there are still challenges. How should potential biomarkers be validated and what are the most promising candidates? How should data be collected, analyzed, standardized? What new technologies can accelerate the search?

Read John Trojanowski's recent review in Practical Neurology, then join us for our live forum. We anticipate a discussion that focuses mostly on the scope, goals, and logistics of the biomarker core of ADNI and other biomarker initiatives. Potential topics for discussion include:

• What is the impact of variability in clinical evaluation and diagnostic methods in our search for biomarkers?
• Must we adopt universal methodologies for measuring specific candidate markers (e.g., specific antibodies and ELISA protocols), or are there alternative strategies that will permit meaningful comparisons to be made among data obtained by different methods in different labs?
• Is the concept of a central repository (i.e., a "tissue bank") feasible or even useful?
• What way(s) would be best to manage and disseminate all the eventual biomarker data collected from around the country/world?
• Is there a place for defined incentives for researchers to adopt certain collection and analytical protocols (e.g., funding, data, or collaboration access)?

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References

News Citations

1. Sorrento: ADNI Imagines the Future of AD Imaging 24 Mar 2005
2. Philadelphia: All Eyes on PIB Imaging—Is It Coming Along? 27 Jul 2004

Webinar Citations

1. Making a BioMark on Alzheimer Disease 1 Jun 2005

Paper Citations

1. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ, Alzheimer's Disease Cooperative Study Group. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005 Jun 9;352(23):2379-88. Epub 2005 Apr 13 PubMed.
2. Praticò D, Uryu K, Leight S, Trojanoswki JQ, Lee VM. Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci. 2001 Jun 15;21(12):4183-7. PubMed.
3. Montine TJ, Montine KS, McMahan W, Markesbery WR, Quinn JF, Morrow JD. F2-isoprostanes in Alzheimer and other neurodegenerative diseases. Antioxid Redox Signal. 2005 Jan-Feb;7(1-2):269-75. PubMed.
4. Bohnstedt KC, Karlberg B, Wahlund LO, Jönhagen ME, Basun H, Schmidt S. Determination of isoprostanes in urine samples from Alzheimer patients using porous graphitic carbon liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2003 Oct 25;796(1):11-9. PubMed.
5. Galvin JE, Powlishta KK, Wilkins K, McKeel DW, Xiong C, Grant E, Storandt M, Morris JC. Predictors of preclinical Alzheimer disease and dementia: a clinicopathologic study. Arch Neurol. 2005 May;62(5):758-65. PubMed.
6. Price JL, Morris JC. Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease. Ann Neurol. 1999 Mar;45(3):358-68. PubMed.
7. Yao Y, Clark CM, Trojanowski JQ, Lee VM, Praticò D. Elevation of 12/15 lipoxygenase products in AD and mild cognitive impairment. Ann Neurol. 2005 Oct;58(4):623-6. PubMed.
8. Bing G, Nguyen XV, Liu M, Markesbery WR, Sun A. Biophysical and biochemical characterization of the intrinsic fluorescence from neurofibrillary tangles. Neurobiol Aging. 2006 Jun;27(6):823-30. PubMed.

Other Citations

1. full text of a recent article

External Citations

1. ADNI website
2. public announcement
3. ADRC website

Further Reading