Mapping the correlations between CSF Abeta and tau and hippocampal atrophy in 282 ADNI subjects

Liana G. Apostolova, Amity E. Green, Kristy S. Hwang,

Jonathan H. Morra, Jeffrey L. Cummings, Arthur W. Toga,

Clifford R. Jack Jr., John Q. Trojanowski, Leslie M. Shaw,

Michael W. Weiner, Paul Thompson

Disclosures

• This work was generously supported by – NIA K23 AG026803 (jointly sponsored by NIA, AFAR,

The John A. Hartford Foundation, The Atlantic Philanthropies, The Starr Foundation and an anonymous donor)

– UCLA ADRC NIA AG16570– The Kassel Parkinson’s Disease and the Turken

Foundations – The Easton Consortium

Background

• Cerebrospinal fluid (CSF) Abeta and tau are the most established and most promising fluid biomarkers in AD.

• Low Abeta and increased tau levels have consistently been reported in the CSF of AD subjects as well as those MCI subjects who progress to AD.

Frank RA et al., Neurobiol Aging 1998

Thal LJ et al, Alzheimer Dis Assoc Disord, 2006

Background cont.

• AD results in progressive hippocampal volume loss.

• Hippocampal atrophy is the most established imaging biomarker in AD.

• Advanced hippocampal atrophy in MCI is suggestive of underlying AD (OR for conversion to AD = 1.75)

Jack, 1999 and 2004

Objective:

• To investigate the associations between CSF Abeta and tau levels and hippocampal atrophy in the ADNI cohort at baseline

Subjects: Demographic Data

NCN=83

MCIN=140

ADN=59

p-value,ANOVA or Chi-Square

Age, yr 75.6 (5.3) 74.0 (7.3) 75.7 (7.9) 0.16

Gender, M:F 41:42 91:49 34:25 0.07

Education, yr 15.6 (2.9) 16.0 (3.0) 15.3 (3.2) 0.34

MMSE 29.1 (1.0) 26.9 (1.8) 23.4 (1.8) < 0.0001

Comparable to Shaw LM et al, Ann Neurol online pub

CSF Biomarker Analysis

• Multiplex xMAP Luminex platform

• Innogenetics immunoassay kit-based reagent with the following monoclonal antibodies (Ab)– 4D7A3 Ab for Abeta– AT120 Ab for total tau– AT270 Ab for pTau181p

• Day-to-day reproducibility showed less then 10% variation Shaw LM et al, Ann Neurol online pub

Mean CSF Biomarker Concentrations

Comparable to Shaw LM et al, Ann Neurol online pub

Automated Hippocampal Segmentation AdaBoost

Radial Distance Mapping

Mean Hippocampal Volumes

3D Abeta1-42 correlation maps

3D Tau correlation maps

3D pTau181p correlation maps

Volumetric vs. 3D radial distance associations with CSF biomarkers

Left Hippocampus,p-values

Right Hippocampus,p-values

Abeta1-42, pg/ml 0.023 0.003 0.008 0.0003

Tau, pg/ml 0.001 0.002 0.004 0.003

pTau181p, pg/ml 0.019 0.01 0.002 0.0008

Tau/Abeta1-42 <0.0001 0.0006 0.002 0.002

pTau181p/Abeta1-4 0.005 0.002 0.001 0.0007

Hippocampal volume

Hippocampal radial distance

Cumulative Distribution Function CSF biomarker association with 3D radial distance

DiscussionDiagnostic accuracy of premortem CSF biomarkers

BiomarkerThreshold value

ROC Sensitivity Specificity Diagnostic Accuracy

Abeta1-42

192 pg/ml0.91 96.4 76.9 87%

Tau 93 pg/ml

0.83 69.6 92.3 81%

pTau181p 23 pg/ml

0.75 67.9 73.1 70%

Tau/Abeta1-42

0.390.92 85.7 84.6 85%

pTau181p/Abeta1-42

0.10.86 91.1 71.2 82%

Shaw LM et al, Ann Neurol online pub

Summary• Hippocampal atrophy shows significant

correlations with CSF biomarkers in a study sample consisting of NC, MCI and AD

• 3D hippocampal surface maps show more significant associations with CSF biomarkers relative to hippocampal volumes

• Abeta, Tau/Abeta1-42 and pTau181p/Abeta1-4 show the strongest correlations with 3D maps of hippocampal atrophy

Future Directions

• Does progressive hippocampal atrophy associate with CSF biomarker changes?

• Would CSF biomarkers and hippocampal atrophy have an additive value for diagnosing early and presymptomatic AD?

• Can they be combined to sensitively track disease progression and therapeutic effects?