Neil Buckholtz, Ph.D.

National Institute on Aging/NIH

70 yo

Normal

72 yo MCI

74 yo AD

CMRgI Abnormalities in Probable Alzheimer’s Dementia

From Reiman et al, New Engl J Med 1996

Importance of Brain Imaging/Fluid Biomarkers in Alzheimer’s Disease

1) Tools for research

2) Identifying markers for detection of early brain changes in pathogenesis of AD 3) Assessing brain markers of disease progression 4) Potential surrogate markers for assessment of interventions

Cognitive Continuum

Mild Cognitive

Impairment

Normal

Alzheimer's Disease

CP926864- 35

MILD COGNITIVE IMPAIRMENT

ORIGINAL CRITERIA

• MEMORY COMPLAINT

• MEMORY IMPAIRED FOR AGE

• NORMAL GENERAL COGNITIVE

FUNCTION

• NORMAL ACTIVITIES OF DAILY

LIVING

• NOT DEMENTED

Mild Cognitive Impairment

MCI AD 12%/yr Control AD 1-2%/yr

Petersen RC et al: Arch Neurol 56:303-308, 1999

50

60

70

80

90

100

50

60

70

80

90

100

Initial 12 24 36

48 exam

CP926864- 12

Months

Initial 12 24 36 48 exam Months

New Diagnostic Criteria

The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on workgroups on diagnostic guidelines for Alzheimer's disease. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH. Alzheimers Dement. 2011 May;7(3):263-9. The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Albert MS, Dekosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH. Alzheimers Dement. 2011 May;7(3):270-9. Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carril lo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH. Alzheimers Dement. 2011 May;7(3):280-92.

GOALS OF THE ADNI:

LONGITUDINAL MULTI-SITE OBSERVATIONAL

STUDY

• Major goal is collection of data and samples to establish a brain imaging, biomarker, and clinical database in order to identify the best markers for following disease progression and monitoring treatment response

• Determine the optimum methods for acquiring, processing, and distributing images and biomarkers in conjunction with clinical and neuropsychological data in a multi-site context

• “Validate” imaging and biomarker data by correlating with neuropsychological and clinical data.

• Rapid public access of all data and access to samples

STUDY DESIGN-ADNI1

• MCI (n= 400): 0, 6, 12, 18, 24, 36 months

• AD (n= 200): 0, 6, 12, 24 months

• Controls (n= 200): 0, 6, 12, 24, 36 months

• Clinical/neuropsychological evaluations, MRI (1.5 T) at all time points

• FDG PET at all time points in 50%

• 3 T MRI at all time points in 25%

• PIB sub-study on 120 subjects

• Blood and urine at all time points from all subjects; CSF from 50% of subjects 0, 1 yr, 2 yr (subset); DNA and immortalized cell lines from all subjects

• GWAS study

ADNI Public-Private Partnership Structure

NIBIB and other ICs

PI: Mike Weiner Administrative Core: UCSF

FDA

Biostatistics Core:

UCD: Beckett

Biomarkers Core:

UPenn: Trojanowski/ Shaw

Genetics Core: Indiana,Saykin

MRI Core:

Mayo: Jack

Clinical Core:

UCSD: Aisen

Mayo: Petersen

PET Core:

Berkeley:

Jagust

Informatics Core:

UCLA: Toga

Publications Core:

Harvard: Green

Pathology Core:

WashU: Morris

57 Clinical Sites: ADNI PIs and Cores

ADNI Executive Steering Committee

Private/Philanthropic +

Public

ADNI 2 Private Partner Scientific Board

23 companies, 1 government entity and

2 non-profit organizations

ADNI MRI

Standardization Methods

Steps taken before Subject

Enrollment Began

Our goal: Standardization of image qualities (CNR, spatial resolution, resistance to artifact, reliability) across sites/platforms, and consistency across time in the face of ongoing upgrades

Site equipment survey – determine technical specifications for each potential scanner in the study, select optimum scanner at each site

Create a generic, non-platform specific MRI protocol

Organize vendor support

With vendor support, create a platform specific protocol for each scanner – 91 scanners, 48 distinct compiled versions of the ADNI protocol

Deliver protocol to each scanner electronically, not manual creation

Create an ADNI MRI procedures manual and deliver to sites

Phone/email training of MRI site personnel by ADNI MR tech

Site certification – phantom and human volunteer scans

Ongoing Standardization

Methods During Study Recertification of scanners after upgrades (79 scanners re- certified to

date, some numerous times)

Hands-on trouble shooting by ADNI technical personal (ie MR physicist,

MR tech, radiologist)

QA of images: visual + electronic inspection in 3 areas

protocol compliance – electronically check every relevant MRI

parameter against the master protocol for that system for each image

acquired in the study, also identify scanner upgrades that were not

reported by sites

Visual inspection and rating of image quality – request patient re scan

if necessary

Identify medical abnormalities – for inclusion/exclusion as well as

medical care purposes

MRI PHANTOM

Data and Sample Sharing

• Goal is rapid public access of all raw and processed data

• Central repository for all QA’d MRI and PET [Laboratory of Neuroimaging, UCLA (LONI)]

• Clinical data base at UCSD is linked to LONI

• Databases- in the public domain, available to all qualified investigators

• Sample sharing-Resource Allocation Review Committee

• No special access

• Data Sharing & Publication Committee (DPC)

-ADNI Data Use Agreement

ADNI1 Demographics

CP1307278-1

Normal controls MCI AD (n=229) (n=398) (n=192) P

Age, mean (SD) 76.4 (5.0) 75.3 (7.5) 75.8 (7.4) 0.15

Female (%) 48.0 35.4 47.4 0.002

Years of education, 15.6 (3.1) 16.0 (2.9) 14.7 (3.1) <0.001 mean (SD)

Apolipoprotein E e4: 26.6 53.5 65.6 <0.001 Positive (%)

Subject Evaluation

• Baseline/screening eval and q 6 mo. – Labs, Apo E

– Hamilton(S)

– Beck

– MMSE

– ANART

– ADAS-cog

– NPI

– CDR

– ADL

• Neuropsyc(B and q 6 mo) – Logical Memory(S)

– AVLT

– BNT

– Trails A &B

– Symbol digit

– Clock drawing

– Category fluency

3003731-7

ADAS Cog 11

3003731-9

MMSE

ADNI Progression Rates

Year Normal MCI MCI AD

0-1 1.4% (0.0-3.2) 16.0% (11.3-20.4)

1-2 2.4% (0.0-4.7) 23.9% (19.0-29.5)

Mean Cortical Thickness Change over 12 Months

Holland et al.

Dia

gn

os

ed

as

NC

D

iag

no

se

d a

s A

D

+2%

-2%

Lateral View Medial View

12 month CMRgl Decline in AD

P<0.001

P<0.001

12 month CMRgl Decline in MCI

P<0.001

Kewei Chen, Ph.D., Eric M. Reiman, M.D.

Banner Alzheimer's Institute

Translational Genomics Research Institute

University of Arizona

Arizona Alzheimer’s Consortium

Phoenix, Arizona, USA

Statistical ROI’s of 12-Month CMRglDecline AD

MCI

Human Amyloid Imaging in AD

Using Pittsburgh Compound-B

Very little

retention

Absence of

retention in

gray matter

Appearance in

expected gray

matter areas

Absence in

areas where

there is

no amyloid

Klunk et al., Annals of Neurology 2004

PIB Imaging: Chet Mathis

FDG

PIB

1

1.5

2

2.5

3

Me

an

Co

rtic

al

SU

VR

Cutoff > 1.46

PIB+

(Berkeley Data)

Normals

9/19 (47%)

PIB+

MCI

47/63 (68%)

PIB+

AD

17/19 (89%)

PIB+

Follow-Up of PIB-Positive ADNI MCI’s

PiB(+) 47

Converters to AD 21

PiB(-) 18

Converters to AD 3

ADNI PiB MCI’s

N = 65, 12 mo. follow-up

HC

(n=106)

MCI

(n=65)

PiB-ve Subjects: 74

Converters to naMCI 2 (3%)

PiB+ve Subjects: 32

Converters to MCI/AD 8 (25%)

PiB+ve Subjects: 45

Converters to AD 32 (71%)

PiB-ve Subjects: 20

Converters to AD: 1 (5%)

Converters to DLB: 2 (10%)

Converters to FTD: 1 (5%)

Converters to VaD: 1 (5%)

Prediction of Conversion (3 yrs):AIBL Study

Rowe et al

Follow-Up of ADNI PiB Controls

ADNI PiB Ctrl’s

N = 19, 24 mo. follow-up

PiB(+) 9

Converters to MCI 2

PiB(-) 10

Converters to MCI 0

Total Tau, p-Tau181p and Ab1-42 in

CSF of ADNI subjects at Baseline

using a bioanalytically validated

xMAP Luminex immunoassay

system and Innogenetics

immunoassay reagents

Clinical Core

Leslie M Shaw, John Trojanowski

University of Pennsylvania Medical Center

AD (n=102) Tau Ab1-42 P-Tau181P Tau/Ab1-42 P-Tau181P/Ab1-42

Mean±SD 122±58 143±41 42±20 0.9±0.5 0.3±0.2

MCI (n=200)

Mean±SD 103±61 164±55 35±18 0.8±0.6 0.3±0.2

NC (n=114)

Mean±SD 70±30 206±55 25±15 0.4±0.3 0.1±0.1

ADNI BASELINE CSF biomarker concentrations show the

expected average differences between AD and MCI and NC

p<0.0001, for each of the 5 biomarker tests for AD vs NC and for MCI vs NC.

For AD vs MCI:p<0.005, Tau; p<0.01, Ab1-42; p<0.01, P-Tau 181P; p<0.0005, Tau/Ab1-42; p<0.005, P-

Tau 181P/Ab1-42.

Mann-Whitney test for statistical differences used for these non-normally distributed data sets.

ADNI baseline visit CSF biomarkers-general statistics,

separated by APO E4+/-

concentration (pg/mL)

group ( apo E genotype) Tau Ab1-42 P-Tau 181P Tau/Ab1-42 P-Tau181P/Ab1-42

AD4+ (n=70) 121.41±53.07 131.61±27.42 42.24±19.32 0.97±0.48 0.34±0.19

AD4-(n=30) 122.07±67.92 171.27±53.07 40.43±21.72 0.8±0.49 0.27±0.17

Normal distribution (4+, 4-) no, yes yes,yes no, yes no, yes no, yes

p value 0.77 p<0.0001* 0.47 0.12 0.10

* parametric test

Control4+(n=27) 80.48±40.23 156.85±48.50 32.3±20.93 0.57±0.37 0.24±0.19

Control4-(n=87) 66.32±25.97 220.71±47.95 22.55±11.14 0.33±0.19 0.11±0.09

Normal distribution (4+, 4-) no, no yes, no no, no no, no no, no

p value 0.11 p<0.0001 0.03 p<0.0001 p<0.0001

MCI4+(n=105) 118.42±67.32 143.08±41.12 40.58±18.20 0.93±0.71 0.32±0.19

MCI4-(n=91) 86.31±46.93 186.33±59.48 30.33±16.71 0.55±0.40 0.20±0.15

Normal distribution (4+, 4-) no, no no, no no, no no, no no, no

p value p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001

ratio

**p value calculated using Mann-Whitney test for each biomarker

in each study group, segregated by APO E4, except for the one

instance for which both 4+ & 4- subgroups were both normally

distributed.

Each value in the table is the mean + SD for the respective

biomarker concentration in CSF.

Tau Ab1-42 p-

Tau181p

Tau/Ab1-

42

p-

tau181p/Ab1-42

LR TAA

ROC AUC 0.831 0.913 0.753 0.917 0.856 0.938

Threshold

values

93

ng/mL

192

ng/mL

23

ng/mL

0.39 0.10 0.22

Sensitivity (%) 69.6 6.4 67.9 85.7 91.1 100

Specificity (%) 92.3 76.9 73.1 84.6 71.2 76.9

Test accuracy

(%)

80.6 87.0 73.1 85.2 81.5 88.9

Positive

predictive value

(%)

90.7 81.8 67.9 85.7 77.3 82.4

Negative

predictive value

(%)

73.8 95.2 70.4 84.6 88.1 100

CSF biomarker cutpoints established using CSFs collected from

ADNI-independent autopsy-based AD and age-matched cognitively normal

subjects

Ab1-42 concentrations in CSF, collected at the baseline visit, of 37 ADNI MCI subjects who at their one year visit converted to a diagnosis of probable AD. The

data points for the MCI→AD converters are presented as a horizontal dot plot with the x axis scale identical to that of the Ab1-42 frequency plot for the entire

ADNI MCI group. The vertical line indicates the Ab1-42 cutoff concentration obtained from ROC analysis of an ADNI-independent cohort of autopsy-based AD

subjects’ CSF.

MCI converters to AD at YEAR

1(n=37)

MCI converters to normal

PIB vs CSF Biomarkers: Ab

Penn Autopsy

Sample (56 AD, 52

Cog normal)

192 pg/ml

50.0

100

150

200

250

300

1 1.2 1.4 1.6 1.8 2 2.2 2.4

MCI

AD

Control

CS

F Ab 1

-42

Mean Cortical SUVR

Total N = 55 (11 Control, 34 MCI, 10 AD)

GOAL: Leverage ADNI Plasma and CSF samples to assess the utility of

existing AD biomarker panels studies.

PLASMA STUDY:

• Baseline and 1 year ADNI plasma samples analyzed using RBM190 analyte

multiplex immunoassay platform (Luminex xMAP) containing proteins

previously reported in the literature to be altered as a result of cancer,

cardiovascular disease, metabolic disorders, inflammation, Alzheimer’s

disease

• All data posted to ADNI website and available as of Nov, 2010

• Project Team - completed statistical analyses; finalizing manuscript

CSF STUDY:

• ADNI CSF samples to be sent to RBM for analysis (July, 2011)

• Additional studies planned to qualify a Multiple Reaction Monitoring (MRM)

Mass Spectrometry panel and to examine Beta-Site APP Cleaving Enzyme

(BACE-1) levels and enzymatic activity in CSF.

ADNI Plasma

and CSF Proteomics Studies

• Using data from two independent cohorts (Penn & WU) we identified 16 analytes that were associated with MCI and AD and 5 of them were validated in a third independent cohort (ADNI).

• In addition two of the five analytes that were validated in the final step correlated with the CSF Aβ 1-42 and tau.

• Validation of new potential biomarkers using independent cohorts is a powerful and essential screening and validation tool.

• More work needed on analytes that were replicated in 2 cohorts (Penn&WU, WU&ADNI, Penn&ADNI)

Plasma RBM studies

Hippocampal atrophy rates (L+R) – free surfer data – in ADNI

subjects with CSF Ab1-42 >192 pg/mL or <192 pg/mL

Ab1-42

<192pg/mL

Ab1-42

>192pg/mL

ALL -5.6±4.7 -2.6±4.1

AD -8.0±5.9 -4.2±3.5

MCI -4.8±3.6 -2.9±3.7

NC -3.6±3.2 -2.2±4.3

Hippocampal % atrophy rates

(BL→12 mos), for ADNI subjects

with Ab1-42< 192 or >192 pg/mL

These data show that in ADNI AD, MCI and NC

subjects the rate of hippocampal atrophy

increases at a significantly higher rate in

subjects with Ab1-42 <192 pg/mL cutoff

concentration compared to those >192 pg/mL

Feb-09; N. Schuff

Test Sample Size

MMSE 803

RAVLT 607

ADAS 592

CDR SOB 449

POWER OF CLINICAL/COGNITIVE TESTS

25% CHANGE 1YR STUDY (2 ARM) :

AD

45

1.5T MRI Comparisons - AD (n=69)

Lab Variable SS/arm

Alexander L. Hippo. Formation 334

Dale Whole Brain 207

Schuff - FS Hippocampus 201

Dale Ventricles 132

Dale Hippocampus 126

Studholme Temporal lobe % change 123

Schuff - FS Ventricles 119

Studhome CV - % change 106

Fox VBSI % change 105

Fox BSI % change 71

Thompson CV - % change 54

ADNI Genotyping • Initial goal: high density genome wide scan

– Identified major microarray platforms for GWAS

• Compared marker selection strategies, HapMap coverage of genome, performance & reliability, as well as cost/sample

– Illumina platform was selected by consensus of the Genetics Committee & ISAB for this project

– TGen (Phoenix, AZ) was selected to perform the assays

– Illumina Human 610-Quad

Shen et al 2010: Overview B

ase

line

MR

I Sca

ns

FreeSurfer: 56 volume or cortical thickness measures

VBM: 86 GM density measures

QC’ed genotyping data

GWAS of Imaging Phenotypes

Strong associations represented by heat maps

R L L R

R L R

GWAS of candidate QT VBM of candidate SNP Refined modeling of candidate association

530,992 SNPs

142 QTs

Gene Identification with Imaging “Deep Phenotypes”: GWAS

Conclusion: Imaging Gene Discovery

Structural MRI + 600k SNPs =

GRIN2b as Novel Risk Factor for MTL deficits in Alzheimers

Stein et al 2010; ADNI

Amyloid Gene Pathway PET Study: [11C]PiB

Swaminathan et al,

Brain Imaging &

Behavior (2012)

DOI 10.1007/s11682-011-9136-1

DHCR24

(seladin - selective AD

indicator –

cholesterol

synthesis

pathway)

Continue to follow all EMCI, LMCI and NC from ADNI 1 and ADNI GO for 5 more years

Enroll:

100 additional EMCI (supplements 200 from GO)

150 new controls, LMCI, and AD

3T MRI at 3, 6, months and annually

F18 amyloid (AV-45)/FDG every other year

LP on 100% of subjects at enrollment

Genetics

Normal MCI AD

0 0.5 1

CDR 3004153-1

ADNI 1 (LMCI)

ADNI 2 (EMCI)

Inclusion Criteria for ADNI GO & 2*

CN EMCI LMCI AD

CDR 0 0.5 0.5 0.5-1

MMSE 24-30 24-30 24-30 20-26

LM-DR (cut-off scores)

Educ

0-7 3 3-6 2 2

8-15 5 5-9 4 4

16 9 9-11 8 8

Dementia No No No Yes

* Ron Petersen

EMCI have milder memory dysfunction than LMCI— approximately 0.5-1.5 SD below the mean for CN. They are CDR 0.5 as are LMCI. LMCI were ≥ 1.5 SD below the mean for memory function.

CSF Aβ42

Amyloid imaging

FDG-PET

MRI hipp

CSF tau

Cog

Fxn

The eMCI group: selected to be intermediate between NC and later MCI, at baseline.

Baseline eMCI – yellow – is intermediate in ADAS-Cog between NC (green) and MCI (blue).

Also intermediate in complete cortical florbetapir index; considerable heterogeneity in all groups except perhaps AD (red).

Volumetric summaries and FDG-PET measures show eMCI more like NC at baseline.

©2012 MFMER | 3188678-56

ECog Memory

0

1

2

3

4

CN EMCI LMCI AD

Self

Partner

New functional measure: everyday cognitive function (ECog). Can be self-reported or informant-reported (better!)

ADNI GO/2 Florbetapir (N=602)

1.11 threshold

ADNI Data

processed with

freesurfer &

whole

cerebellum

reference

Fre

qu

ency

56/194

29% positive

89/212

42% positive

83/132

63% positive

51/64

80% positive

Florbetapir cortical mean

fibrillar Aβ deposition in ADNI subject groups in comparison with 78 cognitively normal APOE e4 non-carriers

AD (n=53)

MCI (n=78)

eMCI (n=150)

0.05 e-14 P-value

Banner Alzheimer’s Institute

0.05 e-16 p-value

AD (n=53)

MCI (n=78)

eMCI (n=150)

cerebral glucose hypometabolism in ADNI patients in comparison with 78 cognitively normal APOE e4 non-carriers

Banner Alzheimer’s Institute

0.05 e-4 P-value

Banner Alzheimer’s Institute

cerebral glucose hypometabolism in 51 Aβ-positive eMCI patients in comparison with 99 Aβ-negative eMCI patients

ADNI GO & ADNI 2 CSF biomarkers Ab1-42 (pg/mL)

t-tau (pg/mL)

p-tau181 (pg/mL)

t-tau/Ab1-42 p-tau/Ab1-42

Normal (107)

233±71 73±34 41.3±20 0.37±0.27 0.21±0.15

EMCI (192)

231±72* 81±53** 44.4±28**

* 0.45±0.49*

*** 0.24±0.22****

*

LMCI (66)

181±68 103±55 63.8±40 0.68±0.45 0.42±0.31

AD (25)

151±52 134±59 70.1±33 0.97±0.49 0.54±0.33

* Ab1-42: p<0.000001 vs AD; p<0.00001 vs LMCI, p=0.83 vs NL. ** t-tau: p<0.000005 vs AD, p<0.005 vs LMCI,

p=0.86 vs NL. ***p-tau181:p<0.0005 vs AD, p<0.00005 vs LMCI; p=0.91 vs NL. ****

t-tau/ Ab1-42: p<0.0000001 vs AD, p<0.00005 vs LMCI, p=0.99 vs NL

*****p-tau181/ Ab1-42: p< 0.00005 vs AD, p<0.000001 vs LMCI; p=0.96 vs NL.

Baseline ADAScog results in ADNI subjects with CSF

Ab1-42 >192 pg/mL or <192 pg/mL

Baseline ADAScog results for ADNI subjects (mean±SD)

with

Ab1-42 <192 pg/mL or >192 pg/mL

Ab1-42

<192pg/m

L

Ab1-42

>192pg/mL

p

ALL n=385

18.2±8.4 12.0±6.4 <0.0001

NC n=106

11.3±4.9 9.4±4.2 0.078

EMCI n=190

15.2±5.7 11.8±5.4 <0.0005

LMCI n=65

21.5±6.1 15.8±7.4 <0.005

AD n=24

30.3±7.7 29.7±8.4 0.75

Baseline AV45 SUVR results in ADNI subjects with CSF

Ab1-42 >192 pg/mL or <192 pg/mL Baseline AV45 SUVR results for ADNI subjects

(mean±SD) with Ab1-42 <192 pg/mL or >192

pg/mL Ab1-42

<192pg/m

L

Ab1-42

>192pg/mL

p

ALL n=246

1.6±0.23 1.2±0.11 <0.0001

NC n=53

1.5±0.22 1.2±0.09 <0.0001

EMCI n=148

1.5±0.21 1.2±0.13 <0.0001

LMCI n=32

1.6±0.27 1.2±0.09 <0.0005

AD n=13

1.6±0.25 1.1±0.21 <0.05

AV45 SUVR vs CSF Ab1-42 in ADNI GO and ADNI 2 subjects

ALL

Ab1-42, pg/mL Ab1-42, pg/mL

AV

45

SU

VR

AV

45

SU

VR

NC

Spearman’s r=-0.73 Spearman’s r=-0.74

1.28 SUVR cutpoint as described by Landau and Jagust (ADNI web site)

0.0

0.2

0.4

0.6

0.8

1.0

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

EMCI to LMCI

Years

Pro

ba

bili

ty

strata

ApoE=e4+

ApoE=e4−

p = 0.001

ApoE=e4+

ApoE=e4−

82 79 57 29 21 17 12 6 4 0 0

142 139 91 59 53 39 36 27 18 6 2

Numbers at risk

Standardization: imaging, biomarkers

Neuroscience: relationships among biomarker trajectories elucidate neurobiology

Trials: new understanding of biomarkers has facilitated interventional studies in very early AD

Data sharing: ADNI has demonstrated the power of real-time public data sharing

Collaboration: academia, industry, non-profits, regulatory agencies world-wide

9/2009 N. Schuff

http://www.adni-info.org

http://www.loni.ucla.edu/ADNI

Parkinson’s disease

FTD

Autism

World-Wide Standardization

• Alzheimer’s Association efforts to

standardize CSF and hippocampal volume

measures

CAMD

• Utilization of ADNI data to develop

documents to qualify CSF and MRI

measures for regulatory purposes to FDA

and EMA for enrolling subjects at high risk

National Alzheimer’s Project Act (NAPA) Update

Draft framework for National Plan to Address Alzheimer’s proposed January 2012

National Plan released May 15

http://aspe.hhs.gov/daltcp/napa/

NAPA Goals

1. Prevent and effectively treat Alzheimer’s disease by 2025

2. Optimize care quality and efficiency

3. Expand patient and family support

4. Enhance public awareness and engagement

5. Track progress and drive improvement

Identify Research Strategies for Alzheimer’s Disease

NIH/NIA hosted AD Research Summit May 14-15,

2012

Research recommendations released May 18 • http://www.nia.nih.gov/newsroom/alzheimers-disease-research-summit-2012-recommendations

• Day One Webcast

• http://videocast.nih.gov/summary.asp?Live=11196

ADNI Data Investigators

Total Investigators 3135

Approved Investigators 2931

Disapproved Investigators 204

ADNI Data Applications

Disapproved Applications (204)

Asked to clarify

Nonsense users

176

28

OtherGovernment

Scanner MfgBiotech

PharmaceuticalUniversity/Research

0

200

400

600

800

1000

1200

1400

1600

1800

2007 2008 2009 2010 2011

Other

Government

Scanner Mfg

Biotech

Pharmaceutical

University/Research

ADNI Data Applications by Sector (cumulative)

ADNI Data Users

• B.A. – 92

• B.S. – 270

• M.A. – 70

• M.S. – 550

• M.D. – 644

• Ph.D. – 1509

Investigators (3135) by degree type:

Countries with ADNI Data Applicants

Countries with ADNI data applicants

Data Archived and Downloaded

• 140,000 images archived (raw and

processed)

• 1.2 million image downloads

• 90,000 downloads of non-image

data (clinical, genetic, proteomic,

summary) from 36 countries

ADNI Manuscripts

504 manuscripts utilized ADNI data

Published 274

Epub ahead of print 16

In Press 8

Under revision 2

In submission 191

Withdrawn 11

Under review by DPC 2

ADNI Manuscripts (reviewed)

Of the 504 manuscripts that utilized ADNI data, 469 were submitted

for ADNI DPC Review

Met initial criteria

Required onerevision

Withdrawn

220 238

11

ADNI Manuscripts (not reviewed)

35 manuscripts were not submitted to the ADNI DPC for review

Compliant with ADNI policies 6

Non-compliant with ADNI policies 29

Reasons authors cited for not submitting manuscripts for review:

• Didn’t submit this time, but will in the future (19)

• Forgot to submit, but have since (3)

• No response (8)

• Author reported paper to us after publication (5)