Shruti Mishra

AV-1451 PET imaging of tau pathology in preclinical Alzheimer disease: Defining a summary measure

Abstract Utilizing [18F]‐AV‐1451 tau positron emission tomography (PET) as an Alzheimer disease (AD) biomarker will require identification of brain regions that are most important in detecting elevated tau pathology in preclinical AD. Here, we utilized an unsupervised learning, data‐driven approach to identify brain regions whose tau PET is most informative in discriminating low and high levels of [18F]‐AV‐1451 binding. 84 cognitively normal participants who had undergone AV‐1451 PET imaging were used in a sparse k‐means clustering with resampling analysis to identify the regions most informative in dividing a cognitively normal population into high tau and low tau groups. The highest‐weighted FreeSurfer regions of interest (ROIs) separating these groups were the entorhinal cortex, amygdala, lateral occipital cortex, and inferior temporal cortex, and an average SUVR in these four ROIs was used as a summary metric for AV‐1451 uptake. We propose an AV‐1451 SUVR cut‐off of 1.25 to define high tau as described by imaging. This spatial distribution of tau PET is a more widespread pattern than that predicted by pathological staging schemes. Our data‐derived metric was validated first in this cognitively normal cohort by correlating with early measures of cognitive dysfunction, and with disease progression as measured by &bgr;‐amyloid PET imaging. We additionally validated this summary metric in a cohort of 13 Alzheimer disease patients, and showed that this measure correlates with cognitive dysfunction and &bgr;‐amyloid PET imaging in a diseased population. HighlightsAV‐1451 binding in four key regions identifies tau‐positive individuals with preclinical AD.The SUVR cutoff for high and low tau PET is 1.25.Increased tau PET correlates with early cognitive impairment, and relates to &bgr;‐amyloid burden in preclinical AD individuals.The spatial pattern of AV‐1451 uptake in preclinical AD is more widespread than predicted by pathological staging.

Loss of white matter integrity reflects tau accumulation in Alzheimer disease defined regions

Objective White matter (WM) projections were assessed from Alzheimer disease (AD) gray matter regions associated with β-amyloid (Aβ), tau, or neurodegeneration to ascertain relationship between WM structural integrity with Aβ and/or tau deposition. Methods Participants underwent diffusion tensor imaging (DTI), PET Aβ ([18F]AV-45 [florbetapir]), and PET tau ([18F]AV-1451 [flortaucipir]) imaging. Probabilistic WM summary and individual tracts were created from either a composite or individual gray matter seed regions derived from Aβ, tau, and neurodegeneration. Linear regressions were performed for Aβ, age, tau and WM hyperintensities (WMH) to predict mean diffusivity (MD) or fractional anisotropy (FA) from the corresponding WM summaries or tracts. Results Our cohort was composed of 59 cognitively normal participants and 10 cognitively impaired individuals. Aβ was not associated with DTI metrics in WM summary or individual tracts. Age and WMH strongly predicted MD and FA in several WM regions, with tau a significant predictor of MD only in the anterior temporal WM. Conclusion Tau, not Aβ, was associated with changes in anterior temporal WM integrity. WMH, a proxy for vascular damage, was strongly associated with axonal damage, but tau independently contributed to the model, suggesting an additional degenerative mechanism within tracts projecting from regions vulnerable to AD pathology. WM decline was associated with early tau accumulation, and further decline may reflect tau propagation in more advanced stages of AD.

In vivo [18F]-AV-1451 tau-PET imaging in sporadic Creutzfeldt-Jakob disease

Objective To determine whether specific patterns of [18F]-AV-1451 tau-PET retention are observed in patients with autopsy-proven sporadic Creutzfeldt-Jakob disease (CJD). Methods In vivo [18F]-AV-1451 PET neuroimaging was performed in 5 patients with sporadic CJD (median age, 66 years [63–74]), and results were compared to cognitively normal (CN) persons (n = 44; median age, 68 years [63–74]) and to participants with very mild Alzheimer disease (AD) dementia (n = 8; median age, 77 years [63–90]). Autopsy was completed in all patients with CJD, confirming the clinical diagnosis and permitting characterization of AD neuropathologic change (ADNC). Results All patients with CJD presented with rapidly progressive dementia, typical magnetic resonance brain imaging changes, and elevated CSF total tau (median = 6,519; range = 1,528–13,240 pg/mL). Death occurred within 9 months of symptom onset, with a median 1 month (0.2–3.3) interval from [18F]-AV-1451 PET to autopsy. No unique pattern of [18F]-AV-1451 retention was observed on visual inspection. Summary standardized uptake value ratios in patients with CJD (1.17, 1.08–1.36) were indistinguishable from CN persons (1.14, 0.84–1.54; p = 0.6), and well below those of participants with AD (2.23, 1.60–3.04; p ≤ 0.01). [18F]-AV-1451 retention in patients with CJD and CN persons was similar in brain areas frequently affected in AD and CJD. Neuropathologic analysis confirmed the clinical diagnosis in all patients with CJD. Four patients with CJD also had low-level ADNC (A1B1C0); one patient had intermediate-level ADNC (A2B2C1/2). Conclusion Increased [18F]-AV-1451 retention was not observed in patients with rapidly progressive dementia due to sporadic CJD. The [18F]-AV-1451 PET tracer maintains good specificity for paired helical tau filaments associated with AD dementia.

Longitudinal brain imaging in preclinical Alzheimer disease: impact of APOE ε4 genotype

While prior work reliably demonstrates that the APOE ɛ4 allele has deleterious group level effects on Alzheimer disease pathology, the homogeneity of its influence across the lifespan and spatially in the brain remains unknown. Further it is unclear what combinations of factors at an individual level lead to observed group level effects of APOE genotype. To evaluate the impact of the APOE genotype on disease trajectories, we examined longitudinal MRI and PET imaging in a cohort of 497 cognitively normal middle and older aged participants. A whole-brain regional approach was used to evaluate the spatial effects of genotype on longitudinal change of amyloid-β pathology and cortical atrophy. Carriers of the ɛ4 allele had increased longitudinal accumulation of amyloid-β pathology diffusely through the cortex, but the emergence of this effect across the lifespan differed greatly by region (e.g. age 49 in precuneus, but 65 in the visual cortex) with the detrimental influence already being evident in some regions in middle age. This increased group level effect on accumulation was due to a greater proportion of ɛ4 carriers developing amyloid-β pathology, on average doing so at an earlier age, and having faster amyloid-β accumulation even after accounting for baseline amyloid-β levels. APOE ɛ4 carriers displayed faster rates of structural loss in primarily constrained to the medial temporal lobe structures at around 50 years, although this increase was modest and proportional to the elevated disease severity in APOE ɛ4 carriers. This work indicates that influence of the APOE gene on pathology can be detected starting in middle age.

Tau and Amyloid Positron Emission Tomography Imaging Predict Driving Performance Among Older Adults with and without Preclinical Alzheimer’s Disease

Abnormal levels of Alzheimers disease (AD) biomarkers, measured by positron emission tomography imaging using amyloid-based radiotracers and cerebrospinal fluid, are associated with impaired driving performance in older adults. We examined whether preclinical AD staging, defined using amyloid imaging and tau imaging using the radiotracer T807 (AKA flortaucipir or AV-1451), was associated with receiving a marginal/fail rating on a standardized road test (n = 42). Participants at Stage 2 (positive amyloid and tau scans) of preclinical AD were more likely to receive a marginal/fail rating compared to participants at Stage 0 or 1. Stage 2 preclinical AD may manifest in worse driving performance.

Cross-sectional and longitudinal atrophy is preferentially associated with tau rather than amyloid β positron emission tomography pathology

Structural magnetic resonance imaging is a marker of gray matter health and decline that is sensitive to impaired cognition and Alzheimers disease pathology. Prior work has shown that both amyloid β (Aβ) and tau biomarkers are related to cortical thinning, but it is unclear what unique influences they have on the brain.

APOE4 EFFECT ON LONGITUDINAL VOLUMETRICS AND PIB ACCUMULATION IN PRECLINICAL ALZHEIMER DISEASE

performed a pattern separation paradigm using repeated, similar lures and novel foil items while being scanned in a 7T Siemens MRI scanner. We manipulated 4 levels of difficulty for similar lures (lures 1-4). For each subject, t-statistics were extracted in the hippocampal subfields using SPM12. We tested for group differences (APOE-e4 carriers vs. non-carriers) in novelty and pattern separation effects. Using representational similarity analysis (RSA), we investigated the correlation between first and second presentation of trials in each condition. We hypothesized that lower correlations reflect more distinct items representations, i.e. pattern separation. Results: Behaviourally, we found that APOE-e4 carriers as compared to non-carriers were less accurate in pattern separation of the most difficult lure1 items and were more likely to incorrectly label those lures as repeated items (Fig. 1A). In the fMRI data, we found a stronger novelty effect (first > repeat) in right DG of the APOE-e4 carriers as compared to non-carriers (Fig. 1Bi). We did not find any group differences for brain activity related to pattern separation (lure1 > repeat) (Fig. 1Bii). No significant differences in RSA patterns were found, due to the small sample size (Fig. 1C). Conclusions:Our analyses with a small group of participants reveal possible differences between APOE-e4 carriers and non-carriers in pattern separation in the DG and in other hippocampal subfields. References: 1. Yassa, M.A., et al., Neuroimage, 2010. 51(3): p. 1242-52. 2. Baker, S., et al., Curr Biol, 2016. 26(19): p. 26292634. 3.Berron, D., et al., J Neurosci, 2016. 36(29): p. 7569-79.

RELATIONSHIP BETWEEN TAU POSITRON EMISSION TOMOGRAPHY WITH [18F]-AV-1451 AND LONGITUDINAL CORTICAL ATROPHY IN ALZHEIMER DISEASE

injection of 18F-PI-2620. Venous blood is obtained to characterize the kinetics of parent compound andmetabolites. Results:Initial imaging data shows robust brain uptake and fast wash-out in nontarget regions with peak SUV 1⁄4 4-4.5. There was no increased uptake seen in choroid plexus, striatum, amygdala, or other regions noted in first generation tau agents. In AD, focal asymmetric uptake was evident in temporal and parietal lobes, precuneus, and cingulate. SUVr time curves demonstrate a plateau at 90-100 min post injection with resultant SUVrs of 2.5-2.8.in abnormal regions, whilst HV demonstrated shorter time to secular equilibrium (6070 min) and lower SUVrs (1.0-1.2) in comparable brain regions. Finally, PSP subjects demonstrated focal and symmetric increased uptake in the globus (SUVr1⁄41.99-2.11) and midbrain (SUVr1⁄42.41-2.58). Blood data confirmed fast kinetics with 20% of parent compound present at 60 min and the presence of polar metabolites. Conclusions: Initial PI-2620 PET first-in-human studies demonstrate excellent brain penetrance, favorable kinetics, and high target specificity with low nonspecific binding and high signal in regions of expected tau pathology.

WHITE MATTER INTEGRITY REFLECTS TAU ACCUMULATION IN AD-DEFINED REGIONS

AD(EOAD) presents the unique opportunity to isolate effects ofAD pathology in NPS onset, independent from cerebrovascular disease and other age-associated co-morbidities.Methods:We administered the Geriatric Anxiety Inventory to twenty-one cognitively normal subjects (28-42 years old) from the Colombian kindred: ten mutation carriers and eleven age-matched non-carriers. All subjects had one parent with the PSEN-1 mutation, and thus bore a 50% risk of carrying it themselves; all were blind to their genetic status. All subjects underwent amyloid (Pittsburgh Compound B) and tau (Flortaucipir a.k.a AV-1451) PET imaging. SCD was measured using theMemory Complaint Scale-Spanish version. Pearson correlations were used to compare anxiety, SCD, cortical amyloid, and regional tau levels in inferior temporal lobe (IT) and entorhinal cortex (EC).Results:InPSEN-1 carriers, greater anxiety was associated with greater cortical amyloid (r1⁄40.817, p1⁄40.004), but not with tau (IT: r1⁄4-0.007, p1⁄40.985; EC: r1⁄40.036, p1⁄40.921). Greater SCD (self and informant) was also associated with greater cortical amyloid (self: r1⁄40.902, p1⁄40.001), but not tau (IT: r1⁄40.076, p1⁄40.846; EC: r1⁄40.018, p1⁄40.963). There were no differences between mutation carriers and non-carriers in anxiety (p1⁄40.911) or SCD (self: p1⁄40.848; informant: p1⁄40.614). Among mutation carriers, greater anxiety was associated with greater SCD (self: r1⁄40.957; p<0.001; informant: r1⁄40.932; p1⁄4<0.001). Conclusions:Preliminary findings support a relationship between anxiety, SCD, and amyloid (but not tau), among mutation carriers from the Colombian kindred of EOAD. Results suggest that anxiety in this cohort is redundant with SCD, and related to early changes in AD biomarkers, years before the estimated onset of mild cognitive impairment. Future longitudinal studies with larger samples and in relation to objective cognitive measures are needed to better understand anxiety and SCD in preclinical AD. B-amyloid Regions Diffusivity Diffusivity Diffusivity Anisotropy

SIMILARITIES AND DIFFERENCES IN PATTERNS OF [F18]-AV-1451 AND [F18]-FDG IN FRONTOTEMPORAL DEMENTIA

cohort.Methods:18 participants were included. 80-100minute [F] AV-1451 images were normalized to SUVR units by cerebellar grey matter. Measures from antecedent cross-sectional [F]FDG-PET, baseline [F]Florbetapir PET and MRI that were approximately 3yrs before the [F]AV-1451 scan (mean 1⁄4 3.2yrs; range 1⁄4 2.05.1yrs), and two-year change in florbetapir and MRI measures were explored as independent predictors of [F]AV-1451 SUVR values extracted from the whole cortex and the medial temporal lobe (MTL). [F]Florbetapir and []FDG scans were pre-processed as described [1]. [F]Florbetapir scans were intensity normalized by the whole cerebellum (baseline) and a composite of the cerebral white matter, brainstem, and whole cerebellum (longitudinal). [F]FDG intensity was normalized to the pons. Baseline global cortical [F]Florbetapir and mean parietal [F]FDG SUVR, as well as 2yr annualized percent change (APC) in global [F]Florbetapir were extracted. Baseline and 2-year hippocampal volumes (HV) were estimated using Freesurfer v5.1. Step-wise linear models predicting cortical or MTL [F]AV-1451 SUVR with the following predictors were assessed: cortical [F]Florbetapir SUVR, annual percent change (APC) in cortical [F]Florbetapir SUVR, mean parietal [F]FDG SUVR, HV, APC in HV, diagnosis (control or MCI/AD), age, gender, and time between scans. Results:Mean cortical [F]AV-1451 uptake was predicted only by diagnosis and cross-sectional mean cortical [F]Florbetapir SUVR. However, MTL [F]AV-1451 uptake was predicted by both mean cross-sectional cortical [F]Florbetapir uptake and cross-sectional HV. Conclusions: Overall, [F]AV-1451 uptake (representative of tau deposition) was predicted by the extent of cortical amyloid deposition ([F]Florbetapir uptake) approximately three years prior. Hippocampal atrophy may interact with this process. [1] Risacher et al. (2015) Alzheimer’s & Dementia, (11): 1417.