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A Publication of the

Alzheimer's Disease Neuroimaging Initiative

defining alzheimer's disease


December 2005


Welcome to the third ADNI newsletter for research sites. This issue highlights the role and accomplishments of the Biomarker Core. I would like to encourage all Site P.I.s and Study Coordinators to visit our new home page at, beautifully created by Sarah Walter at the ADCS Coordinating Center. For scientific information go to the Scientist page. I wanted to provide all of you with a brief summary of the status of ADNI. As of 12/7/05 we have 23 out of 58 sites fully qualified. Of these, 15 sites have screened at least one subject. A total of 95 subjects have been screened and 35 subjects are actually enrolled in ADNI. The major hold-up continues to be MRI qualification and this is because of problems getting the letter agreements signed by each site, and the phantom scans. If you have any questions regarding MRI qualification, please email [email protected] Happy Holidays! Mike Weiner, M.D.



By Les Shaw, Ph.D., and John Q. Trojanowski, M.D., Ph.D. University of Pennsylvania School of Medicine ADNI Biomarker Core Co-Directors

The clinical diagnosis of Alzheimer's disease (AD) is imprecise but therapy is likely to be most effective when patients are treated early in the course of the disease. Hence, there is a compelling rationale for establishing an accurate diagnosis of AD at the earliest stage of this disorder so treatment can be initiated well before brain degeneration caused by AD becomes severe and widespread. Accordingly, there is an urgent need for informative biomarkers that can be used to develop more sensitive and specific diagnostic tests for AD. To address these compelling needs, the Alzheimer's Disease Neuroimaging Initiative (ADNI) was launched on October 13th, 2004 and charged with the mission to develop and validate improved methods for the diagnosis of AD and for monitoring AD progression. In addition, ADNI is tasked with developing improved methods in detecting the transition from mild cognitive impairment (MCI) to AD which will greatly reduce the time and cost of clinical trials of therapeutic compounds. The successful recruitment of several pharmaceutical companies as ADNI sponsors is significant. This alliance of public and private

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Updates FAQs Recruitment Enrollment

2 3 4 8

Penn Biomarker Core team members from left to right are: Virginia M.-Y. Lee, Margaret Knapik-Czajka, Magdalena Korecka, Magdalena Brylska, John Q. Trojanowski, Vivianna Van Deerlin and Les Shaw



A few research sites have had difficulty retrieving the forms they've uploaded as part of their screening and baseline visits. The below tips should help with scanning and uploading worksheets and MRI reports. Ü Scan in Black and White (NOT greyscale!) and low resolution Ü Save as a PDF file Ü The file you upload will replace the file previously saved! Ü Do not scan as a 'rich text' file. Ü Remember to black out any participant identifiers on MRI reports or on the worksheets you scan. Don't forget, requests for inclusion or exclusion exceptions should be made online by completing the exception request form, or by emailing Dr. Petersen at [email protected]


ADNI Help Desk -

Question A: Why does the database tell me I have a missing form when I filled out all the data from the screening visit? Answer to A: The participant menu and the quality assurance tools list errors for all forms, but some of those should not be handled by the site personnel since they are PET, MRI, or Biomarker results forms. If the forms says 'FOR INTERNAL USE ONLY' it should not be completed by research site personnel. Question B: Why is a fasting sample important for biomarkers? Answer to B: CSF analytes can fluctuate as a function of dietary intake. The best way to eliminate this confound is to require an overnight fast prior to collection of blood, urine and LP in the morning. Question C: Why can my site PI see the exception request when he/she is looking at the signature log, but cannot sign off on it? Answer to C: Site Principal Investigators have the ability to see pending signatures for exceptions, but cannot sign off on these because only Dr. Petersen has this level of privileges. Question D: Quality Assurance is reporting signatures missing from Eligibility Confirmation, Neurological and Physical Examination. Since these don't have a Pending status, I¹m not sure if this means the signatures are still missing or not. Answer to D: The status of "Pending" is only assigned to errors with pending 'human' generated queries associated with them. System generated errors will appear with no status if no query has been written up for it. For ADNI, sites should review all errors and resolve those that they can, regardless of whether there is a "P" or not. Please note that this is somewhat different than for the other ADCS trials, where we recommend that sites only focus on errors with Pending status. To check whether the signatures are still pending, you could check the signature log. If the signatures have been captured, the errors will no longer appear in Quality Assurance either when you click "Final Submit" to re-run the visit level checks for that participant or that evening when all of the checks get re-run. Question E: Can the baseline PET scan, 3T MRI or lumbar puncture be scheduled prior to the Baseline clinic visit? Answer to E: It is very important NOT to conduct the Baseline visit until you've received the scan assignment and final approval. The Baseline scans (3T or PET) should be done within 14 days of the visit, either before or after. See page 28 of the ADNI Procedures manual for more information.

Scanning Tips

Frequently Asked Questions

Incl/Excl Exceptions Requests Saturday Shipments Document Repository PET Manual Update

Saturday Shipments to NCRAD: (yellow top tubes at baseline) NCRAD does NOT receive samples on Saturdays. Hold samples at room temperature. Saturday Shipments to U Penn: Please be sure to check 'Saturday Shipment' and use the special Orange Label. If you check 'priority' these will only be delivered Monday-Friday! Please check out the document repository if you are new to the study or missed our recent Memos, Newsletters, or Procedure Manual Changes at Cognitive Testing Worksheets for all visits are now posted! Look under 'Stimuli and Worksheets'. The PET manual has recently been updated. Version 9 is posted on the document repository and on the ADNI public website (

Participants will only be randomized and receive a scan assignment once all systems errors are resolved. Follow these important steps to discover what is holding up your participant's randomization:

Errors Holding Up Randomization

1. 2. 3. 4.

Go to 'Quality Assurance' under 'Forms'. Select the ADNI project and then select the participant number under 'Participants'. Click 'generate new list'. All errors will be listed. Manually generated queries are from your clinical monitor and need to be closed by her/him. If you are missing APOE results and it has been 7 days from the visit, email [email protected] If you are missing MRI subject inclusion and it has been 5 days from the scan date, email [email protected]

Screen Fails

If you have a screen fail, please remember to: 1. Go to 'Participant Enrollment' and click 'fail' for that subject. 2. Enter the reason for the fail on the 'eligibility confirmation' form. 3. Complete the Inclusion Criteria and Exclusion Criteria forms to your best ability. Also complete the 'eligibility confirmation' form. For all screen fails, please enter as much data as you can on the subject. Keep in mind that the database logic is relaxed for screen fails, so it will not catch errors in the forms. Be very careful when entering this data! Diuretic medications should be stable 4 weeks prior to the screening visit. Any Change in diuretic medications should be reported on the concurrent medications log. Common Diuretics include: HCTZ, Thiazide, and Furosemide

Diuretic Medications

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Laboratory Supplies

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REMEMBER TO ORDER MORE APOE AND BIOMARKER KITS FROM COVANCE - unlike your screening kits, these are not on auto-resupply! You can order more by phoning Covance at: (800) 327-7270. If you need another tube for your Covance samples at screening, use a tube from a RETEST kit. Never use tubes from separate screening kits! Each of these tubes is pre-labeled with a different accession number, and if tubes from separate screening kits are used, your samples could be lost.


[email protected]

Slowly but surely ...

It's a bit of a slow road toward start-up approval for some of you but we appreciate your patience and diligence! On the other hand - more than one third of participating sites are ready to enroll participants - with many following close behind. Congratulations!! Did you receive The ADNI ALERT, a periodic update of national and local outreach activities to help bolster recruitment? If you didn't get it or would like a copy of it, please send an e-mail to [email protected] In that newsletter, we described various recruitment activities as well as our national campaign - two segments of which were successfully launched: the Spanish Language Radio Media Tour with Dr. Ramon DiazArrastia, PI at the UT Southwestern and more recently - Maya Angelou's Public Service Announcements. (Print PSAs with Maya Angelou's image will also be available in the near future). Two other important parts of our national campaign have been postponed until after the holidays - in early January. The first one is NIA's national press release targeting national consumer and medical trade press and the second one consisting of a package of video footage featuring an inspirational personal story and interviews of ADNI study leaders. This video package will be distributed to local TV stations near study sites, along with information on how the stations can contact local site PI's for interviews. All national campaigns reference ADEAR's 800 number and/or web site: where callers can find out your site's name and contact information. What about Spanish Language recruitment materials? Besides the pamphlet, flyer, bookmark, LP information sheet, the PET scan and MRI brochures in Spanish, we now have the generic Lumbar Puncture demonstration DVD available with Spanish subtitles. Remember - all printable English and Spanish recruitment materials are downloadable from


Recruitment Connection


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organizations works synergistically within ADNI to accomplish five major objectives: 1) Develop standard AD neuroimaging methods for clinical trials 2) Improve methods for neuroimaging 3) Determine optimum methods for acquiring and processing brain images 4) Validate AD neuroimaging and biomarker findings from the ADNI 5) Provide a database for all ADNI findings that is accessible to investigators for further analysis (for more details, see Samples of blood and urine will be collected from all subjects, while cerebrospinal fluid (CSF) will be obtained from up to 50% of participants at baseline and one year later. Additional details on the structure, function and mission of the ADNI are available elsewhere (ref. 1 or The ADNI Biomarker Core was established by Co-Directors Les Shaw and John Trojanowski at the University of Pennsylvania School of Medicine 1 year ago, and in the past 12 months key Biomarker Core objectives, including the recruitment of talented Penn investigators to join the Biomarker Core team, have been accomplished. Other members of the Biomarker team are: Dr. Magdalena Korecka, Dr. Margaret Knapik-Czajka and Ms. Magdalena Brylska. Drs. Virginia M.-Y. Lee and Vivianna Van Deerlin are consultants to the Biomarker Core and APOE genotyping is performed by the Molecular Pathology Core Lab which is directed by Dr. Don Baldwin. (Cont'd on Page 6)

Did you receive The ADNI ALERT?


Ü Evaluated and purchased sample tracking and bar code labeling software. These systems are effective and already in use with biological samples from ADNI subjects beginning August, 2005. Ü Prepared detailed standard operating procedures (SOPs) for the collection, processing and shipping of ADNI biofluids. Provided training on biomarker SOPs for staff from 50 Clinical Sites. Collaborated with the ADNI Clinical Core to adapt the biomarker SOPs for the ADNI Procedure Manual that has been distributed to all ADNI Clinical Sites. Ü Obtained new space for the ADNI Biofluid Repository and established this repository to bank >250,000 aliquots of CSF, plasma, serum, urine and blood cells from ADNI subjects over the next 4 years. Purchased and installed freezers and other equipment, supplies, computers, database software for the ADNI Biofluid Repository. Ü Evaluated multiple kits/protocols/methods for studies the Biomarker Core will conduct to assess the diagnostic utility of assays that measure CSF levels of diverse species of Aß peptides, multiple different P-tau epitopes and proteolytic fragments thereof, members of the large family of isoprostanes and homocysteine. Ü Equipped and established the ADNI Analytical Laboratory. This includes a new mass spectrometer and a Luminex instrument for multiplex analysis of up to 100 different analytes using sample volumes far smaller than those needed for ELISA. Biomarker Core staff are now conducting multiplex analyses of CSF tau and Aß using the Luminex system with Innogenetics kits designed for Luminex multiplex assays. Ü Began bioanalytical validation of all assays/procedures in biological fluids. For example, the Biomarker Core has organized a collaborative study with a small number of ADNI pharmaceutical sponsors and investigators from academic institutions to begin to standardize and validate Luminex multiplex analyses of CSF tau and Aß with Innogenetics kits. Follow up studies involving additional collaborators are planned so that SOPs can be generated for Luminex multiplex assays of CSF tau and Aß. Ü Trained Biomarker Core staff on all aspects of sample receipt, log-in, aliquoting, storage, tracking, report generation, database usage, data transfer to repository include many functions that are web-based. Ü Developed SOPs, QC/QA protocols and incorporated them into manuals for use by all Biomarker Core activities.

November 2005 · Issue 1 The ADNI A lert is a periodic update of national and local outreach activities to help bolster recruitment. The Imagine logo, pictured above, is the umbrella theme of the study, and will be used on outreach material. Many of the materials use the toll-free number (800-438-4380) and Web site ( of the Alzheimer's Disease Education and Referral Center (ADEAR) of the National Institute on Aging. ADEAR will refer callers to sites in their local area. Stay tuned for more materials and updates to assist in study recruitment efforts.

Materials You Can Use Ready Now

We have a number of recruitment materials already circulating at the sites. These can be localized with your center's information and distributed at doctors' offices, senior centers, libraries and other channels that reach our target audiences. Materials include a brochure, flyer, poster, bookmark and health professional laminated cards. Brochures and DVDs about the lumbar puncture, and brochures about the MRI and PET scan procedures, are available upon request. If you desire any of the above items, please contact Ann Wehling at [email protected] or visit the ADCS Web site at fault.asp

NIA Press Release

November 2005

The National Institute on Aging (NIA) will send out a national press release on study recruitment. It will reinforce the importance of the trial and list all the local sites. The release will target national consumer and medical trade press. Study coordinators will receive a copy of the press release simultaneous to its release, and are encouraged to alert their institutions' press office and make sure a PI is available for media interviews if requested.

Putting a Face on the Issue: Ann Hedreen November 2005

Ann Hedreen created a compelling, Emmynominated documentary about her mother's struggle with Alzheimer's and her family's participation in a research study. To encourage TV coverage of ADNI recruitment, we are developing a package of video footage of her story, along with footage of ADNI principal investigators. This will be distributed to local TV station news markets with study sites, along with information on how the stations can contact local site PIs for interviews.

Reaching Diverse Audiences: Spanish Language Radio Media Tour

November 2005

Dr. Raymond Diaz-Arrastia, PI at the University of Texas, Southwestern, will be the Hispanic spokesperson for a national radio media tour. During live and taped interviews, Dr. Diaz-Arrastia will reference 1-800-4384380 and the Web site to help direct listeners to participating sites. We will target radio stations in markets with sites that have confirmed Spanish language capabilities.

Maya Angelou Radio and Print Public Service Announcements (PSAs) November 2005

Alzheimer's disease is an issue close to Maya Angelou's heart. The noted poet and author has recorded radio PSAs for ADNI's use, which will be sent to public service directors at select stations in markets with ADNI sites. The Coordinating Center at UCSD will send more information soon, including a list of the stations that will receive the PSA in your area. Study coordinators may contact the stations in their area to encourage PSA play. The ads reference 1-800-438-4380 and the Web site: Print PSAs with Maya Angelou's image will also be available in the near future.

Partnerships: Advocacy Groups and Medical Societies

December 2005

ADNI will develop partnerships with various groups to extend the reach of our recruitment message. National groups whose members or mission dovetail with our recruitment strategy, such as seniors, caregiving or Alzheimer's disease organizations, are encouraged to run our drop-in materials, place information in their newsletters, post information on the Web and more. We will inform you of our successes with national groups so you can reach out to their local chapters, should you wish.

About the Imagine logo (pictured above): It is important that this logo be a consistent part of any recruitment materials the public sees. Please use it freely on all ADNI materials you create. For assistance with any recruitment & retention related issues, please e-mail me at [email protected] Best wishes, Ann Wehling, Recruitment Coordinator

Community Outreach: Speaker's Kit

November 2005

One of the most successful ways to recruit study participants is for a physician to conduct a community program on Alzheimer's disease and the ADNI study. To help with this, a speaker's kit for PIs and study coordinators is in the works. This kit will include 15-and 30minute PowerPoint presentations and speaker's notes for use at community talks. The kit will also include flyers, brochures, posters, a community distribution plan and evaluation forms.

Share your good news with us. Email recruitment tips to Ann Wehling at [email protected]

In the Know: Newsletter

Spring 2006

A bi-annual newsletter for study participants will roll off the presses in 2006. It will reinforce the value of study participation and create a sense of community among participants, as well as update them on the study's progress. Ann Wehling will coordinate with sites about the desired number of copies needed for each location.

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In addition to its important function as the Biofluid Repository for all biological samples obtained from ADNI subjects, the Biomarker Core will investigate the diagnostic utility of several promising AD biomarkers. While these studies focus on a limited number of analytes, other investigators may request access to biological samples from ADNI subjects that are banked for this purpose. An independent body known as the Resource Allocation Review Committee (RARC), chaird by Dr. Tom Montine, has been established to review requests by scientists from industry or academia to obtain sets of banked ADNI biological fluid samples for biomarker studies. it will be possible to correlate the imaging and biomarker data with neuropsychological and behavioral data on ADNI participants. Ideal AD biomarkers should: 1) Detect a fundamental feature of AD neuropathology and brain degeneration 2) Be validated in autopsy confirmed cases of the disease 3) Have a diagnostic sensitivity >80% for detecting AD and a specificity of >80% for distinguishing AD from other dementias (ref 2, 3).


(Cont'd from Page 5)


(Cont'd from Page 6)

investigating the potential diagnostic utility of measuring a panel of diverse species of tau and Aß by multiplex analyses with the Luminex system. In summary, the ADNI Biomarker Core at Penn contributes to the ADNI mission by supporting efforts to develop more informative biomarker assays for the diagnosis of AD, especially in its early stages or even in its prodromal phase known as MCI, and to facilitate clinical trials of new therapeutic compounds for the treatment of AD.


We cannot emphasize enough how important it is to follow ADNI procedures for biomarker results! Procedures for the collection, documentation, processing and shipment of biofluids are described in the ADNI Procedures Manual. The Biomarker Core would like to remind all sites of several important points based on our experience to date:

Finding the "pregnancy test equivalent" for diagnosing AD at its earliest stages remains elusive

Moreover, AD biomarker assays that are reliable, reproducible, non-invasive, and inexpensive will have the broadest clinical utility, while clinical trials of new AD therapies will benefit significantly from AD biomarkers that reflect beneficial effects of disease modifying interventions. However, finding the "pregnancy test equivalent" for diagnosing AD at its earliest stages remains elusive. Recognition that mild cognitive impairment (MCI) is a prodromal phase of AD has intensified the search for analytes indicative of the transition from normal cognitive function to MCI as well as the progression from MCI to AD.


HOMOCYSTEINE: Homocysteine is a sulfur-containing amino acid derived from the metabolism of methionine. Several studies suggest an association between elevated levels of homocysteine in plasma and an increase in the relative risk of AD. Homocysteine levels in plasma samples will be determined by a well-validated enzyme immunoassay. The Biomarker Core will identify the most effective bioanalytical method to investigate the utility of measuring homocysteine levels in CSF to aid in the early diagnosis of AD. OXIDATIVE/NITROSATIVE DAMAGE: Oxidative/nitrosative damage is implicated in the pathogenesis of AD, and levels of 8,12-iso-iPF2 -VI isoprostanes are elevated in urine, blood and CSF of AD patients. Moreover, levels of this isoprostane correlate with memory impairments, CSF tau levels and the number of APOE4 alleles. Levels of 8,12-iso-iPF2 -VI and other members of the isoprostane family of lipid peroxidation products can be measured in CSF, blood, urine and brain using a newly developed HPLC/tandem mass spectrometry (MS) methodology with an optimized ionization technique. Studies conducted by the Biomarker Core will assess the utility of 8,12iso-iPF2 -VI as a diagnostic marker of AD and MCI as well as seek to identify other isoprostanes that might be potentially informative biomarkers of AD or MCI.. CSF SULFATIDES: Recent studies suggests that CSF sulfatides measured by HPLC/tandem mass spectrometry may be potential AD biomarkers. These preliminary findings will be evaluated further by the Biomarker Core. TAU AND Aß: Tau and Aß are components of the two neuropathological diagnostic hallmarks of AD (tangles and plaques respectively), and they are the most frequently studied candidates for diagnostic AD biomarkers. Both are best studied in CSF using extensively characterized ELISAs. The Biomarker Core will extend these findings by

We cannot emphasize enough how important it is to follow ADNI procedures for biomarker results!

1) The APO E Genotyping Draw Data Form should be completed online as soon as the sample is drawn! Once the form is completed online, a copy should be printed and included with the APO E whole blood sample. 2) Be sure to attach the shipping package label onto the shipping package for all biomarker fluids. The unique barcode "license plate" specific for one patient and one particular visit and set of biofluids is embedded in this label. The same license plate number will appear on biofluid labels for that patient and that specific visit. 3) For Saturday deliveries, please be sure to check 'Saturday Shipment' and use the special Orange Label. If you check 'priority' these will only be delivered Monday-Friday! ACKNOWLEDGEMENTS The authors acknowledge support for the research summarized here from the NIH (UO1 AG-024904, AG09215, AG10124, AG11542, AG14382, AG14449, AG17586, NS044233) and the Alzheimer's Association. They also thank the patients and their caregivers who have made this research possible. Due to space limitations in this brief essay, literature citations are restricted to reviews and consensus reports wherein references to the primary literature may be found. REFERENCES 1. Mueller, S.G., Weiner, M.W., Thal, L.J., Petersem, R.C., Jack, C.R., Jagust, W., Trojanowski, J.Q., Toga, A.W., Beckett, L. Ways toward an early diagnosis in Alzheimer's disease: The Alzheimer's Disease Neuroimaging Initiative (ADNI). Alzheimer's & Dementia: J. Alzheimer's Assoc., 1:55-66, 2005. 2. Frank RA, Galasko D, Hampel H, Hardy J, de Leon M, Mehta PD, Rogers J, Siemers E, Trojanowski JQ. Biological markers for therapeutic trials in Alzheimer's disease Proceedings of The Biological Measures Working Group: NIA Initiative on Neuroimaging in Alzheimer's Disease. Neurobiol. Aging, 24:521-536, 2003. 3. Reagan Institute of the Alzheimer's Association and NIA Working Group on Biological Markers of Alzheimer's Disease. Consensus report of the Working Group on Biological Markers of Alzheimer's Disease. Neurobiol Aging, 19:109-116, 1998.

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ENROLLMENT FIGURES AS OF 12/7/05 (sorted by randomizations)

Site Initials Site Number Screens Screen Fails Randomized* Baseline M6 M12 M18 M24 M36 Unsched. Early Disc.


11 22 23 100 99 67 35 7 18 123 27 73 32 136 10

14 12 15 9 8 12 3 3 6 6 2 2 1 1 1

4 7 5 4 2 3 1 0 1 1 1 0 0 0 0

10 5 4 4 3 3 2 2 1 1 0 0 0 0 0

10 5 3 3 0 2 0 1 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0














*Includes only participants who have completed screening process and been assigned to a scan category


Site Initials Site Number NL MCI AD Total


100 123 18 7 67 99 35 23 22 11

3 0 0 1 1 1 1 2 2 7

1 1 1 1 0 2 1 2 2 0

0 0 0 0 2 0 0 0 1 3

4 1 1 2 3 3 2 4 5 10








Washington University St. Louis has generously offered to share with other ADNI sites their telephone screening tool used for the Memory in Aging Project. The inquiry form is completed over the phone and is used to gauge the participant's interest and medical history. This call is then followed with a telephone CDR. The inquiry form is now available on the ADNI document repository ( under 'administrative'.


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