Michael Navitsky

Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages

SEE THAL AND VANDENBERGHE DOI101093/BRAIN/AWW057 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Post-mortem Braak staging of neurofibrillary tau tangle topographical distribution is one of the core neuropathological criteria for the diagnosis of Alzheimers disease. The recent development of positron emission tomography tracers targeting neurofibrillary tangles has enabled the distribution of tau pathology to be imaged in living subjects. Methods for extraction of classic Braak staging from in vivo imaging of neurofibrillary tau tangles have not yet been explored. Standardized uptake value ratio images were calculated from 80-100 minute (18)F-AV-1451 (also known as T807) positron emission tomography scans obtained from n = 14 young reference subjects (age 21-39 years, Mini-Mental State Examination 29-30) and n = 173 older test subjects (age 50-95 years) comprising amyloid negative cognitively normal (n = 42), clinically-diagnosed mild cognitive impairment (amyloid positive, n = 47, and amyloid negative, n = 40) and Alzheimers disease (amyloid positive, n = 28, and amyloid negative, n = 16). We defined seven regions of interest in anterior temporal lobe and occipital lobe sections corresponding closely to those used as decision points in Braak staging. An algorithm based on the Braak histological staging procedure was applied to estimate Braak stages directly from the region of interest profiles in each subject. Quantitative region-based analysis of (18)F-AV-1451 images yielded region of interest and voxel level profiles that mirrored key features of neuropathological tau progression including profiles consistent with Braak stages 0 through VI. A simple set of decision rules enabled plausible Braak stages corresponding to stereotypical progression patterns to be objectively estimated in 149 (86%) of test subjects. An additional 12 (7%) subjects presented with predefined variant profiles (relative sparing of the hippocampus and/or occipital lobe). The estimated Braak stage was significantly associated with amyloid status, diagnostic category and measures of global cognition. In vivo (18)F-AV-1451 positron emission tomography images across the Alzheimers disease spectrum could be classified into patterns similar to those prescribed by Braak neuropathological staging of tau pathology.

Relationships between flortaucipir PET tau binding and amyloid burden, clinical diagnosis, age and cognition

The relation between tau, amyloid and cognition has yet to be fully defined. Using flortaucipir (18F-AV-1451) PET tau imaging in patients with varying amyloid and cognitive status, Pontecorvo et al. suggest that development of tau beyond the mesial temporal lobe is associated with, and may be dependent on, amyloid accumulation.

Kinetics of the Tau PET Tracer 18F-AV-1451 (T807) in Subjects with Normal Cognitive Function, Mild Cognitive Impairment, and Alzheimer Disease.

We report kinetic modeling results of dynamic acquisition data from 0 to 100 min after injection with the tau PET tracer 18F-AV-1451 in 19 subjects. Methods: Subjects were clinically diagnosed as 4 young cognitively normal, 5 old cognitively normal, 5 mild cognitive impairment, and 5 Alzheimer disease (AD). Kinetic modeling was performed using Logan graphical analysis with the cerebellum crus as a reference region. Voxelwise binding potential (BP) and SUV ratio (SUVR80−100) images were compared. Results: In AD subjects, slower and spatially nonuniform clearance from cortical regions was observed as compared with the controls, which led to focal uptake and elevated retention in the imaging data from 80 to 100 min after injection. BP from the dynamic data from 0 to 100 min correlated strongly (R2 > 0.86) with corresponding regional SUVR80−100−1 values. In the putamen, the observed kinetics (positive SUVR1−5−1 at the tracer delivery stage and plateauing time–SUVR curves for all diagnostic categories) may suggest either additional off-target binding or a second binding site with different kinetics. Conclusion: The kinetics of the 18F-AV-1451 tracer in cortical areas, as examined in this small group of subjects, differed by diagnostic stage. A delayed 80- to 100-min scan provided a reasonable substitute for a dynamic 0- to 100-min acquisition for cortical regions although other windows (e.g., 75–105 min) may be useful to evaluate.

TEST-RETEST DATA FOR THE TAU PET IMAGING AGENT 18F-AV-1451 (PREVIOUSLY, 18F-T807)

cingulum, cingulum-hippocampal and superior longitudinal fasciculus (plus temporal branch). To identify areas of significant FC within the DMN, independent component analysis (ICA) was applied to the resting state fMRI scans. FC ROI was defined as the overlap between the grey matter area surrounding the specific DMN fiber tract terminal and the ICA-DMNmap. In a linear regression analysis, tract specificWMH ratio was tested as a predictor of the tract’s FC ROI value, controlled for age, global AV45-PET, diagnosis and education in the pooled group.Results:Higher WMH ratio in the IFOF was associated with decreased FC in the medial prefrontal cortex and the angular gyrus ROIs (t(73) 1⁄4 -2.295, p 1⁄4 .02) across all subjects. The WMH ratios in other tracts of the DMN were not associated with FC. Conclusions: The results suggest that WMH disrupt functional connectivity in a fiber-tract specific way, independent from beta-amyloid. Future research needs to address whether WMH in particular neural networks are associated with specific cognitive deficits.

MEASURING CHANGE IN BETA-AMYLOID BURDEN OVER TIME USING FLORBETAPIR-PET AND A SUBCORTICAL WHITE MATTER REFERENCE REGION

Background: Estimation of longitudinal change in beta amyloid (Ab) burden may be important to assess disease progression or response to therapy. Using ADNI florbetapir data we evaluated whether measurement of longitudinal amyloid accumulation in Ab positive subjects can be improved with an alternative reference region. Methods: 187 subjects (61 CN, 83 early MCI, 42 late MCI and 1 AD) from ADNI who underwent an initial florbetapir imaging session followed by a second scan at approximately 2 years were analyzed. PET images were spatially normalized to MNI space using a florbetapir PET template. Mean cortical SUVR (mcSUVr) values were calculated as the ratio of the average of 6 cortical regions (medial orbital frontal, parietal, temporal, anterior cingulate, posterior cingulate and precuneus) with respect to whole cerebellum. A pre-specified threshold of mcSUVr>1.10 was used to identify Ab+ subjects. An alternative cortical SUVR was determined using an atlas-based sub-cortical white matter area (centrum semiovale) as a reference region (mcSUVr wm). Change as well as correlation in SUVr (from baseline to 2 years) was examined in Ab+ cases for both mcSUVr and mcSUVr wm. Results: Relative to mcSUVr, the mean increase from baseline SUVr in all Ab+ cases(N1⁄4 84) was slightly reduced with the white matter reference region, and the variability (as measured by the standard deviation, or SD, of the change) was markedly reduced by comparison to the cerebellum reference region (DmcSUVr 1⁄4 2.7 6 7.4%, D mcSUVr wm 2.3 6 4.2%,). As a result, the signal to noise ratio (Dmean/SD) for detecting an increase in SUVr increased from 0.34 to 0.53. The correlation between baseline and endpoint SUVr also increased with the use of a white matter reference region (r 21⁄4 0.73 for mcSUVr; r 21⁄4 0.90 for mcSUVr wm). Conclusions:While limited by a lack of truth standard, the analyses show the white matter reference region was associated with less unexplained variance (27% for mcSUVr ; 10% for mcSUVr wm) and increased signal-to-noise ratio (0.34 vs 0.53), potentially providing increased power to detect slowing of amyloid accumulation in therapeutic trials.

Hippocampal sparing and limbic predominant tau subtypes of Alzheimer’s disease determined in vivo using [18F]-AV-1451 PET imaging

Number (%) 70 (19.4) 66 (183) 165 (45.7) 60 (16.6) Age (years) 67.2 (6.6) 70.9 (8.0) 73.8(6.5) 73.3(7.7) Sex (% men) 47.1 57.6 57.6 51.7 APOE-74 (%) 23.2 59.1 67.9 16.7 AD after 24 months (%) 1.8 4.3 42.4 2.3 CSF Abeta pg/mL 233 (26) 146 (25) 137 (26) 232 (28) Florbetapir (SUVR) 1.02 (0.07) 1.29 (0.21) 1.34 (0.20) 1.00 (0.06) CSF tau pg/mL 54 (26) 93 (48) 112 (58) 60 (28) CSF p-tau pg/mL 28 (14) 48 (29) 51(24) 28 (15) WMH (z-score) 0.07 (0.93) -0.31(1.25) -0.71 (1.06) -0.46 (1.12) MMSE 28.9 (1.1) 28.6 (16) 27.5 (1-8) 28.1 (18) Immediate memory (z-score) -0.17 (0.75) -0.57 (0.67) -0.88 (0.61) -0.67 (0.65) Delayed memory (z-score) -0.24 (0.97) a,b,c -0.71 (0.82) -1.53 (0.85) -0.96 (0.90) Recognition memory (z-score) -0.22 (0.81) a,b,c -0.58(1.06) -1.21 (0.93) -0.78 (101) Verbal fluency (z-score) -0.26 (0.91) a,b,c -0.56 (1.42) -0.93 (0.90) -0.75 (0.87) Trail A (z-score) -0.17 (1.18) -0.58 (1.00) -130 (2.02) -0.72 (139) Trail B (z-score) -0.17 (0.85) -0.54 (1.18) -129 (1.73) -0.70 (123)

Relationships between cognitive assessments and spatial distribution of neuropathological tau as assessed by 18F AV-1451 PET scanning

Figure 1. Voxel-wise correlation between FAV-1451 SUVr and cognition. Laura Wisse, Ana M. Daugherty, Renaud La Joie, Ricardo Insausti, Michael A. Yassa, Valerie A. Carr, Arne D. Ekstrom, Geoffrey A. Kerchner, Susanne G. Mueller, Craig E. Stark, Lei Wang, Paul A. Yushkevich, Hippocampal Subfields Group, University of Pennsylvania, Philadelphia, PA, USA; Wayne State University, Detroit, MI, USA; Universit e de Caen Basse-Normandie, Caen, France; University of Castilla-La Mancha, Albacete, Spain; University of California Irvine, Irvine, CA, USA; Stanford University, Stanford, CA, USA; University of California Davis, Davis, CA, USA; Genentech, Inc., South San Francisco, CA, USA; Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA; Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Contact e-mail: lemwisse@gmail.com

Region-dependent kinetics of the Tau PET tracer [18 F]-AV-1451 (T807)

-0.021mm/yr, p1⁄40.02) and the PPC (-0.033mm/yr vs. -0.016mm/yr, p1⁄40.007). When controlling for baseline Ab burden as a continuous variable, the differences between Ab+ BDNF and Ab+ BDNF remained strong but did not reach significance (p<0.06). Significantly faster atrophy was also found in Ab+ compared to Abin all regions examined.Conclusions:BDNF was associated with faster cortical loss in the Ab+ group, suggesting an early and interactive effect of Ab and BDNF on neurodegeneration.

Standardization of amyloid quantitation with florbetapir standardized uptake value ratios to the Centiloid scale

Klunk et al. recently proposed a means of standardizing quantitation of amyloid burden from positron emission tomography scans to a common Centiloid scale, and we have applied that method to florbetapir.

COMPARISON OF REGIONAL FLORTAUCIPIR PET TO QUANTITATIVE TAU AND AMYLOID IMMUNOASSAY IN PATIENTS WITH ALZHEIMER’S DISEASE PATHOLOGY: A PILOT CLINICO-PATHOLOGICAL STUDY

P2-383 COMPARISON OF REGIONAL FLORTAUCIPIR PET TO QUANTITATIVE TAU AND AMYLOID IMMUNOASSAY IN PATIENTS WITH ALZHEIMER’S DISEASE PATHOLOGY: A PILOT CLINICOPATHOLOGICAL STUDY Andrew D. Siderowf, C. Dirk Keene, Thomas G. Beach, Thomas J. Montine, Anupa Arora, Michael D. Devous, Sr., Michael Navitsky, Ian Kennedy, Abhinay D. Joshi, Michael J. Pontecorvo, Ming Lu, Geidy E. Serrano, Shannon Rose, Angela Wilson, Leanne Hellstern, Natalie Coleman, Mark A. Mintun, Avid Radiopharmaceuticals, Philadelphia, PA, USA; University of Washington Pathology, Seattle, WA, USA; Banner Sun Health Research Institute, Sun City, AZ, USA; University of Washington School of Medicine, Seattle, WA, USA. Contact e-mail: siderowf@avidrp.com