The [18F]-JNJ-64326067-AAA ([18F]-JNJ-067) tau tracer was evaluated in healthy older controls (HCs), mild cognitive impairment (MCI), Alzheimer’s disease (AD), and progressive supranuclear palsy (PSP) participants. Seventeen subjects (4 HCs, 5 MCIs, 5 ADs, and 3 PSPs) received a [11C]-PIB amyloid PET scan, and a tau [18F]-JNJ-067 PET scan 0-90 minutes post-injection. Only MCIs and ADs were amyloid positive. The simplified reference tissue model, Logan graphical analysis distribution volume ratio, and SUVR were evaluated for quantification. The [18F]-JNJ-067 tau signal relative to the reference region continued to increase to 90 min, indicating the tracer had not reached steady state. There was no significant difference in any bilateral ROIs for MCIs or PSPs relative to HCs; AD participants showed elevated tracer relative to controls in most cortical ROIs (P < 0.05). Only AD participants showed elevated retention in the entorhinal cortex. There was off-target signal in the putamen, pallidum, thalamus, midbrain, superior cerebellar gray, and white matter. [18F]-JNJ-067 significantly correlated (p < 0.05) with Mini-Mental State Exam in entorhinal cortex and temporal meta regions. There is clear binding of [18F]-JNJ-067 in AD participants. Lack of binding in HCs, MCIs and PSPs suggests [18F]-JNJ-067 may not bind to low levels of AD-related tau or 4 R tau.
Aging is associated with declines in multiple components of the dopamine system including loss of dopamine-producing neurons, atrophy of the dopamine system’s cortical targets, and reductions in the density of dopamine receptors. Countering these patterns, dopamine synthesis appears to be stable or elevated in older age. We tested the hypothesis that elevation in dopamine synthesis in aging reflects a compensatory response to neuronal loss rather than a nonspecific monotonic shift in older age. We measured individual differences in striatal dopamine synthesis capacity in cognitively normal older adults using [18F]Fluoro-l-m-tyrosine positron emission tomography cross-sectionally and tested relationships with longitudinal reductions in cortical thickness and working memory decline beginning up to 13 years earlier. Consistent with a compensation account, older adults with the highest dopamine synthesis capacity were those with greatest atrophy in posterior parietal cortex. Elevated dopamine synthesis capacity was not associated with successful maintenance of working memory performance overall, but had a moderating effect such that higher levels of dopamine synthesis capacity reduced the impact of atrophy on cognitive decline. Together, these findings support a model by which upregulation of dopamine synthesis represents a mechanism of cognitive resilience in aging.
Background Recent research has suggested that the use of white matter (WM) reference regions for longitudinal tau PET imaging might result in more stable estimates of tau accumulation. However, tau tracers display affinity for the β‐sheet structure formed by proteins such as the myelin basic protein, a major component of axons, and thus WM lesions might influence tau tracer retention in the WM. Here, we explored whether [18F]flortaucipir shows reduced retention in WM lesions, assessed as WM hyperintensities (WMH), and further studied how [18F]flortaucipir retention in WM changes over time. Method We included data from 678 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who had undergone a baseline [18F]flortaucipir‐PET as well as T1 and FLAIR MRI scanning. WMH were automatically delineated in the FLAIR images using the Lesion Segmentation Toolbox in SPM12. To avoid partial volume effects, we eroded the WM and WMH masks so that all voxels within a distance of 3 mm from any non‐WM voxel were removed. The inferior portion of the cerebellar gray matter was used as the reference region to derive Standardized Uptake Value Ratios (SUVR). SUVR in WMH and normal‐appearing WM (NAWM) were compared using paired t‐tests. Among participants with at least one‐follow up [18F]flortaucipir scan (N=217, mean follow‐up time 1.5 years), longitudinal SUVR changes in the WM were estimated using Linear Mixed Models. Result Older age was associated with lower SUVR in both NAWM (r=‐0.10, p=0.007) and WMH (r=‐0.21, p<0.001) but not with [18F]flortaucipir retention in the medial temporal cortex after adjusting for amyloid‐β (Aβ) status and diagnosis (r=‐0.04, p=0.36, Meltzer‐corrected for partial volume effects). Compared to NAWM, WMH areas displayed significantly reduced SUVR independently of cognitive impairment and Aβ status (p<0.001, Figure 1). Longitudinal analyses revealed that SUVR in the WM decreased over time (‐0.009 SUVR/year, p=0.003), while medial temporal SUVR increased (0.009 SUVR/year, p=0.03). Conclusion Low [18F]flortaucipir retention in the WM is associated with advancing age and presence of WM lesions, supporting the hypothesis that [18F]flortaucipir retention in the WM might reflect its myelin content. These findings do not support the use of WM reference regions for [18F]flortaucipir PET imaging.
Background Current tau PET tracers have obvious shortcomings. 18F‐JNJ‐64326067 (18F‐JNJ‐067) is a new tau tracer that binds to aggregated tau in Alzheimer’s Disease (AD) brain tissue with Ki=2.4nM. Our objective was to evaluate 18F‐JNJ‐067 in individuals with AD (N=3), Mild Cognitive Impairment (MCI, N=3), Progressive Supranuclear Palsy (PSP, N=2) and healthy controls (HC, N=4). Method Following a 50‐70min 11C‐PIB PET scan (Siemens Biograph PET/CT), 12 subjects underwent 90 min dynamic PET scan after 18F‐JNJ‐067 injection. MPRAGEs were acquired on a Siemens 3T and segmented using FreeSurfer. Time activity and SUVR curves were viewed for commentary on steady state. Logan DVR quantification was calculated from 35‐90min (k2ref=0.025 min‐1 derived from SRTM2 analysis) using inferior cerebellar gray as a reference region. Data quantification was done in native space; images were warped to template space for visualization. Result Subject information is shown in figure 1; all AD and MCI subjects were PIB positive with MMSE scores from 18‐30, all PSP and HCs were PIB negative. Steady state was not reached in ROIs with high levels of tracer retention within 90 minutes (SUVR curves shown in figure 2). Figure 1 shows native space DVR quantification for ROIs. ADs had 18F‐JNJ‐067 binding in typical AD regions, one MCI had elevated binding, the others showed low binding (DVR images in figure 3). HCs showed no binding in entorhinal cortex, and had elevated signal in basal ganglia, midbrain, superior cerebellar gray, and white matter but no binding in the choroid plexus or meninges (figure 4). MMSE was correlated with Braak I/II (r2=0.80), Braak III/IV (r2=0.73) and Braak V/VI (r2=0.50) ROIs. Conclusion 18F‐JNJ‐067 shows relatively slow pharmacokinetics in brain regions with high target density, has low levels of probable off‐target binding in the basal ganglia and white matter but not elsewhere, and low entorhinal signal in HCs and MCIs. Binding in AD patients reflects a typical pattern of tau distribution seen with other tracers, and MCI patients are intermediate. Braak ROIs are significantly correlated to MMSE. These data suggest that 18F‐JNJ‐067 is suitable for investigation of the AD continuum.
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