Tau distribution in preclinical Alzheimer’s disease: Findings from the Knight Alzheimer’s Disease Research Center Stephanie A. Schultz, BS,1,2,3 Brian A. Gordon, PhD,2,3 Shruti Mishra, MD,2 Yi Su, PhD,2 John C. Morris, MD,1,3 Beau Ances, MD,PhD,1,3 Tammie L.S. Benzinger, MD,PhD,2,3 Departments of 1Neurology and 2Radiology; 3Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO
RESULTS
Ø The hallmark features of Alzheimer disease (AD) are β-amyloid plaques and neurofibrillary tangles (NFT)
Table 1. Participant characteristics
Ø PET imaging of β-amyloid has allowed for in vivo examination of regional plaque burden within preclinical stages of AD (pAD)
Characteristic Age, Years Female, % APOE4 positive, % Education, Years Mini Mental State Exam§
Ø During these pAD stages significant accumulation of β-amyloid and tau can occur decades before clinical symptoms manifest Ø The recent development of PET tau allows for examination of NFT accumulation in pAD individuals
OBJECTIVE METHODS Participants: Ø 110 volunteers (age range: 46-91 years) at the Knight Alzheimer’s Disease Research Center were included in this study ² Selected on the basis of having completed magnetic resonance imaging, tau PET, and β-amyloid PET imaging
Figure 3. Tau distribution in preclinical AD cohort compared to controls
Control (n=87)
Preclinical AD (n=23)
p-value
67 (8.5) 48.3 23.5 16.1 (2.2)
72.3 (7.7) 47.8 56.5 16.3 (1.8)
.008 .969 .002 .736
29.3 (1.1)
29.6 (0.8)
.182
Values are mean (SD) unless otherwise indicated. § Scored on scale of 0-30. 30 is the highest achievable score
Examine the distribution tau pathology in cognitively normal (CN) adults with preclinical AD
RESULTS
Figure 1. β-amyloid PET composite measure ROI Precuneus
Superior Frontal Rostral Middle Frontal Superior Temporal
Cognitive Status: Ø Individuals were classified as CN based on Clinical Dementia Rating=0 MRI Protocol: Ø T1 structural scans acquired on either a Biograph mMR or Trio 3T scanner Ø Images underwent volumetric segmentation using FreeSurfer to identify regions of interest (ROI) used in the PET analyses β-amyloid PET imaging: Ø Participants underwent a scan with florbetapir ([18F]AV-45) Ø Processed using a ROI approach using FreeSurfer Ø ROI values were corrected for partial volume effects Ø Amyloid deposition was summarized using the average across seven bilateral regions know to be associated with AD (Figure 1) Preclinical AD classification Ø Using a SUVR cutoff 1.219, individuals were classified as β-amyloid + or Ø β-amyloid+ individuals were classified as pAD (n=23) Tau PET imaging Ø Tau PET imaging was performed using [18F]AV-1451(T807, flortaucipr) Ø ROI values were corrected for partial volume effects Ø Data was extracted for each ROI defined using Freesurfer Ø Left and right hemisphere data was averaged together Statistical Analyses: Ø T-test and chi-square tests were used to test for group differences on demographics Ø Linear regressions were run to compare regional tau PET SUVR in pAD vs. control groups ² Adjusted for age and sex
Medial Orbitofrontal
Lateral Orbitofrontal
Middle Temporal
Figure 2. Mean tau PET deposition
Control
0.30
Beta Weight
BACKGROUND
0.00 Corresponding beta weights for regions where tau significantly differs in pAD and control cohorts
Table 2. Tau distribution in pAD cohort compared to controls Region
Controls mean SUVR (SD)
pAD mean SUVR (SD)
B (SE)
p-value
Amygdala
1.08 (.17)
1.24 (.28)
0.133 (.05)
.004
Banks of superior temporal sulcus
1.23 (.13)
1.36 (.19)
0.107 (.03)
.002
Entorhinal
1.03 (.22)
1.21 (.31)
0.173 (.06)
.003
Fusiform
1.22 (.12)
1.33 (.12)
0.096 (.03)
.001
Inferior parietal
1.23 (.15)
1.35 (.20)
0.114 (.04)
.002
Inferior temporal
1.26 (.15)
1.39 (.18)
0.111 (.04)
.002
Isthmus cingulate
1.20 (.16)
1.32 (.23)
0.103 (.04)
.013
Middle temporal
1.21 (.14)
1.31 (.14)
0.108 (.03)
.001
Parahippocampal
1.01 (.15)
1.09 (.17)
0.080 (.04)
.029
Posterior cingulate
1.23 (.14)
1.31 (.19)
0.081 (.04)
.025
Precuneus
1.20 (.15)
1.32 (.21)
0.115 (.04)
.003
Suprmarginal
1.16 (.13)
1.22 (.15)
0.061 (.03)
.043
Temporal pole
1.00 (.17)
1.06 (.22)
0.082 (.04)
.041
Beta weights and p-values for regions where tau significantly differs in pAD and control cohorts.
CONCLUSIONS Ø Our study reports patterns of NFTs in pAD in not only medial temporal lobe regions, as suggested by Braak and Braak staging, but more broadly throughout the cortex.
pAD
Ø The regions identified with high tau accumulation are comparable with recent studies examining tau PET in individuals with AD dementia. Ø Suggestive of widespread tau accumulation early in the disease process that intensifies with clinical onset. Ø These results suggest that tau mediated therapies should be considered earlier in the disease course in order to prevent cognitive decline.
ACKNOWLEDGMENTS
Mean tau deposition represented as SUVRs for control and preclinical AD participants
Support: P01 AG003991 (JM); P01 AG026276 (JM); P50 AG005681 (JM), and Avid Radiopharmaceuticals. We would also like to thank the Knight ADRC Study participants and their families.
Contact information: Email:
[email protected]
