Purpose In vivo measurement of the spatial distribution of neurofibrillary tangle pathology is critical for early diagnosis and disease monitoring of Alzheimer's disease (AD). Methods Forty-nine participants were scanned with 18 F-PI-2620 PET to examine the distribution of this novel PET ligand throughout the course of AD: 36 older healthy controls (HC) (age range 61 to 86), 11 beta-amyloid+ (Aβ+) participants with cognitive impairment (CI; clinical diagnosis of either mild cognitive impairment or AD dementia, age range 57 to 86), and 2 participants with semantic variant primary progressive aphasia (svPPA, age 66 and 78). Group differences in brain regions relevant in AD (medial temporal lobe, posterior cingulate cortex, and lateral parietal cortex) were examined using standardized uptake value ratios (SUVRs) normalized to the inferior gray matter of the cerebellum. Results SUVRs in target regions were relatively stable 60 to 90 min post-injection, with the exception of very high binders who continued to show increases over time. Robust elevations in 18 F-PI-2620 were observed between HC and Aβ+ CI across all AD regions. Within the HC group, older age was associated with subtle elevations in target regions. Mildly elevated focal uptake was observed in the anterior temporal pole in one svPPA patient. Conclusion Preliminary results suggest strong differences in the medial temporal lobe and cortical regions known to be impacted in AD using 18 F-PI-2620 in patients along the AD trajectory. This work confirms that 18 F-PI-2620 holds promise as a tool to visualize tau aggregations in AD.

Objective:To determine if memory tasks with demonstrated sensitivity to hippocampal function can detect variance related to preclinical Alzheimer’s disease (AD) biomarkers, we examined associations between performance in three memory tasks and CSF Aβ42/Aβ40 and p-tau181 in cognitively unimpaired older adults (CU).Methods:CU enrolled in the Stanford Aging and Memory Study (N=153; age 68.78 ± 5.81 yrs; 94 female) completed a lumbar puncture and memory assessments. CSF Aβ42, Aβ40, and phosopho-tau181 (p-tau181) were measured with the automated Lumipulse G system in a single-batch analysis. Episodic memory was assayed using a standardized delayed recall composite, paired associate (word-picture) cued recall, and a mnemonic discrimination task that involves discrimination between studied ‘target’ objects, novel ‘foil’ objects, and perceptually similar ‘lure’ objects. Analyses examined cross-sectional relationships between memory performance, age, and CSF measures, controlling for sex and education.Results:Age and lower Aβ42/Aβ40 were independently associated with elevated p-tau181. Age, Aβ42/Aβ40, and p-tau181 were each associated with a) poorer associative memory and b) diminished improvement in mnemonic discrimination performance across levels of decreased task difficulty (i.e., target-lure similarity). P-tau mediated the effect of Aβ42/Aβ40 on memory. Relationships between CSF proteins and delayed recall were similar but non-significant. CSF Aβ42 was not significantly associated with p-tau181 or memory.Conclusions:Tests designed to tax hippocampal function are sensitive to subtle individual differences in memory among CU, and correlate with early AD-associated biomarker changes in CSF. These tests may offer utility for identifying cognitively unimpaired older adults with preclinical AD pathology.

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Introduction: Alzheimer's disease (AD) is the most common form of dementia, characterized primarily by abnormal aggregation of two proteins, tau and amyloid beta. We assessed tau pathology and white matter connectivity changes in subfields of the hippocampus simultaneously in vivo in AD.Methods: Twenty-four subjects were scanned using simultaneous time-of-flight 18 F-PI-2620 tau positron emission tomography/3-Tesla magnetic resonance imaging and automated segmentation. Results:We observed extensive tau elevation in the entorhinal/perirhinal regions, intermediate tau elevation in cornu ammonis 1/subiculum, and an absence of tau elevation in the dentate gyrus, relative to controls. Diffusion tensor imaging showed parahippocampal gyral fractional anisotropy was lower in AD and mild cognitive impairment compared to controls and strongly correlated with early tau accumulation in the entorhinal and perirhinal cortices.Discussion: This study demonstrates the potential for quantifiable patterns of 18 F-PI2620 binding in hippocampus subfields, accompanied by diffusion and volume metrics, to be valuable markers of AD.

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Background:The structure and computations associated with specific hippocampal subfields decline in aging and are also initial sites of Alzheimer's disease pathology.The degree to which age-associated changes in hippocampal-dependent memory are driven by early AD pathology among older normal adults remains unclear. Method:We enrolled one hundred ninety-nine clinically unimpaired (CU) older individuals into the Stanford Aging and Memory Study (SAMS, 117 Female, mean age= 68.9±6.2). Participants completed a lumbar puncture to collect cerebrospinal fluid (CSF), high-resolution fMRI (at 3T) during a visual associative memory paradigm, and ultra high-resolution structural MRI (at 7T) to assess MTL subregion integrity, as well as extensive cognitive assessment. Data collection is complete, and analysis of fMRI and 7T structural data of the 199 participants is currently underway. To examine neuronal computations underlying hippocampal dependent memory, we focused on fMRI metrics in a subset of 78 participants that quantify cortical reinstatement (the degree to which voxelwise patterns of activation during retrieval match activation patterns during encoding) in two a priori regions known to be important for visual associative memory (ventral temporal cortex, VTC; and angular gyrus, ANG). Additionally, we extracted univariate fMRI signal from the hippocampus during successful retrieval. Finally, hippocampal thickness from CA1 in a subset of 77 participants was manually delineated on 7T scans, and CSF was processed with Lumipulse to measure Ab 42 :Ab 40 ratio and p-tau 181. Result: Elevated p-tau 181 was associated with worse performance on the fMRIscanned visual associative memory task (Figure A), reduced cortical reinstatement strength in both VTC (r = -0.25, p = .027, Figure B) and ANG (r = -0.22, p = .048), as well as reduced CA1-SRLM thickness (r = -0.32, p = .004, Figure C). Although Ab 42 :Ab 40 ratios were related to p-tau 181, they were not independently associated with neuronal indices of hippocampal-dependent memory. Conclusion:CU with evidence of early tau abnormalities show worse hippocampaldependent memory and differences in fMRI and structural measurements in regions critical for successful associative memory. Initial consequences of AD pathology target specific hippocampal-cortical circuits, and this is measurable using advanced MRI techniques.

BackgroundPathological tau burden has been linked to neurodegeneration in AD patients. Although previous studies have linked brain atrophy in people at the preclinical stage of AD to early tau deposition, most evidence is based on cross‐sectional findings or retrospective changes before the tau measurement. This study examines longitudinal atrophy and cognitive decline following the assessment of tau, and specifically the relationship between whole brain tau measures and prospective changes in brain structure and memory.Methods124 cognitively normal older adults (> 65 yrs old) underwent FTP PET to measure voxel‐wise tau pathology and PiB PET to measure amyloid positivity at baseline. Rates of change in hippocampal volume (N=74) and memory (N=108) following the PET scan were correlated with whole brain (voxel‐wise) FTP‐PET data.ResultsProspective memory decline was related to tau deposition in the left temporal, parietal, and posterior regions, and the right parahippocampal gyrus (Figure 1), driven by Aß+ individuals (Figure 2). Prospective hippocampal atrophy was related to tau in the parahippocampal and entorhinal cortices (Figure 3), regardless of Aß status. The overlapping cluster in the right parahippocampal/entorhinal region suggested tau burden in this area was predictive of both hippocampal atrophy and memory decline (Figure 4). Finally, we explored how tau and hippocampal atrophy contributed to memory decline together. We found that memory decline in Aß‐ people was mediated by hippocampal atrophy (31.9%) and that there was very little direct effect of tau on memory decline. However, no mediation of hippocampal atrophy was found in Aß+ people, suggesting a strong effect of tau on memory decline in Aß+ people above and beyond hippocampal atrophy (Figure 5).ConclusionsOur findings suggest that tau effects on cognitive decline and neurodegeneration are already present in cognitively normal people, and that memory decline may be driven by different factors in normal aging and preclinical AD. Entorhinal tau in Aß‐ adults may be linked to age‐related hippocampal atrophy, which was related to memory decline, whereas degeneration in other regions, or other brain changes (e.g., network integrity, functional activity, etc.), may explain the detrimental effect of tau on memory in Aß+ people.

BACKGROUND AND PURPOSE: Diagnostic-quality amyloid PET images can be created with deep learning using actual ultra-lowdose PET images and simultaneous structural MR imaging. Here, we investigated whether simultaneity is required; if not, MR imaging-assisted ultra-low-dose PET imaging could be performed with separate PET/CT and MR imaging acquisitions. MATERIALS AND METHODS:We recruited 48 participants: Thirty-two (20 women; mean, 67.7 [SD, 7.9] years) were used for pretraining; 328 (SD, 32) MBq of [ 18 F] florbetaben was injected. Sixteen participants (6 women; mean, 71.4 [SD. 8.7] years of age) were scanned in 2 sessions, with 6.5 (SD, 3.8) and 300 (SD, 14) MBq of [ 18 F] florbetaben injected, respectively. Structural MR imaging was acquired simultaneously with PET (90-110 minutes postinjection) on integrated PET/MR imaging in 2 sessions. Multiple U-Net-based deep networks were trained to create diagnostic PET images. For each method, training was done with the ultra-low-dose PET as input combined with MR imaging from either the ultra-low-dose session (simultaneous) or from the standard-dose PET session (nonsimultaneous). Image quality of the enhanced and ultra-low-dose PET images was evaluated using quantitative signal-processing methods, standardized uptake value ratio correlation, and clinical reads. RESULTS:Qualitatively, the enhanced images resembled the standard-dose image for both simultaneous and nonsimultaneous conditions. Three quantitative metrics showed significant improvement for all networks and no differences due to simultaneity. Standardized uptake value ratio correlation was high across different image types and network training methods, and 31/32 enhanced image pairs were read similarly.CONCLUSIONS: This work suggests that accurate amyloid PET images can be generated using enhanced ultra-low-dose PET and either nonsimultaneous or simultaneous MR imaging, broadening the utility of ultra-low-dose amyloid PET imaging.