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INTRODUCTION: Evidence suggests microglial activation precedes regional tau and neurodegeneration in Alzheimer's disease (AD). We characterized microglia with translocator protein (TSPO) positron emission tomography (PET) within an AD progression model where global amyloid beta (Aβ) precedes local tau and neurodegeneration, resulting in cognitive impairment. METHODS: Florbetaben, PBR28, and MK‐6240 PET, T1 magnetic resonance imaging, and cognitive measures were performed in 19 cognitively unimpaired older adults and 22 patients with mild cognitive impairment or mild AD to examine associations among microglia activation, Aβ, tau, and cognition, adjusting for neurodegeneration. Mediation analyses evaluated the possible role of microglial activation along the AD progression model. RESULTS: Higher PBR28 uptake was associated with higher Aβ, higher tau, and lower MMSE score, independent of neurodegeneration. PBR28 mediated associations between tau in early and middle Braak stages, between tau and neurodegeneration, and between neurodegeneration and cognition. DISCUSSION: Microglia are associated with AD pathology and cognition and may mediate relationships between subsequent steps in AD progression. [ABSTRACT FROM AUTHOR]

Background: Psychosis is a debilitating cluster of symptoms occurring in some Alzheimer's Disease (AD) patients, and is defined by the presence of delusions and/or hallucinations. Previous studies suggest that psychosis in AD patients is associated with increased tau burden and accelerated cognitive decline. We sought to assess differences in tau burden between cognitively impaired patients with psychosis(+P) and those without psychosis(‐P). Method: Twenty‐six ADNI participants with psychosis (+P; 11.5% CDR0, 42.3% CDR0.5, 30.7% CDR1, 11.5% CDR2, 4% CDR3, 77±7yr old, 50% women, 16±3yr education, 92% White) and 26 without psychosis were matched by CDR, age, sex, education, and race (‐P; 11.5% CDR0, 42.3% CDR0.5, 30.7% CDR1, 11.5% CDR2, 4% CDR3, 77±6yr old, 54% women, 15±3yr education, 92% White). The +P group was defined based on any endorsement of hallucinations or delusions on Neuropsychiatric Inventory. Flortaucipir PET data were processed according to ADNI methods. Difference in tau burden was assessed using a paired t‐test on the ROI and voxel‐level between +P and ‐P groups in Braak regions as well as the amygdala, hippocampus, and frontal, temporal, and parietal lobes A follow‐up voxelwise t‐test was performed within the +P group between those with and without concurrent symptoms at the time of their scan. Analyses were corrected for amyloid‐level and voxel‐wise analyses were evaluated at p<0.001 without multiple comparisons correction. Result: Descriptively, participant‐level scans demonstrated a variety of tau patterns, often with right laterality. Tau was elevated for +P participants compared to ‐P in the amygdala (0.6 [0.25, 0.96]; p = 0.003) and the hippocampus (0.3 [0.04, 0.55]; p = 0.03), while marginally elevated in the frontal cortex (0.09 [‐0.002, 0.189]; p = 0.06) [Figure1]. Voxel‐wise, elevated tau was localized to the amygdala, hippocampus, thalamus, and right frontal lobe [Figure2]. Additionally, with concurrent delusion symptomatology, elevated tau was localized to Braak III/IV regions [Figure3]. Conclusion: Tau burden in the amygdala may be a potential biomarker of psychosis across the AD continuum. Right‐sided laterality is consistent with psychosis‐related structural changes and psychosis‐related tau binding needs to be assessed further. Given that early psychosis in AD is associated with faster cognitive decline, these results could inform the development of prognostic biomarkers. [ABSTRACT FROM AUTHOR]

Background: 18F‐Florbetaben (FBB) is a PET radioligand approved for determining binary amyloid status. According to the product label, FBB images may be acquired anytime 45‐130 minutes post injection. Protocols vary in the acquisition of FBB with respect to use of Early (50‐70 minutes‐post‐injection) or Late (90‐110 minutes‐post‐injection) frames. Identifying differences between Early and Late acquisitions of FBB data could aid in image interpretation and inform efforts towards harmonization across cohorts. We evaluated inter‐rater agreement of visual reads (VR) and differences in SUVR thresholds to characterize Early vs. Late frames. Method: Fifty‐three subjects were studied including 23 patients meeting clinical criteria for amnestic mild cognitive impairment or mild Alzheimer's disease and 30 cognitively normal controls. FBB images were acquired 50‐110 min post‐injection in 5‐min frames. Images were corrected for subject motion and separated into 50‐70 and 90‐110 min time windows. Three certified readers blind to cognitive status and time window provided a binary VR for each of the 106 data sets. Global standardized uptake value ratios (SUVRs) were calculated using a cerebellar gray matter reference. An ROC‐derived SUVR cut‐off value was determined for each window using a preliminary cohort (n=23) and evaluated in a larger cohort (n = 53). Result: Inter‐reader agreement was similar in 50‐70 min and 90‐110 min scans, (Fleiss Kappa= 0.597 and 0.598). SUVRs from 50‐70 min and 90‐110 min scans were highly correlated (r = 0.99, p<0.0001). SUVRs were greater in visually positive than in visually negative scans for both time windows (Fig. 1; p<0.0001). SUVRs were still increasing at 50‐70 min but became but plateaued at 90 min. ROC‐derived SUVR cut‐off values (Fig. 1; SUVR50‐70=1.342, SUVR90‐110=1.524) largely agreed with the majority consensus VR (49/53; 92.5%) across both time frames. Conclusion: Early and Late frame data were highly correlated, and both provided robust quantitative differences between visually positive and negative Ab groups. However, imaging at 90‐110 min provides more stable SUVRs and therefore is preferred for measuring longitudinal change in amyloid burden. [ABSTRACT FROM AUTHOR]

Introduction: Evidence suggests microglial activation precedes regional tau and neurodegeneration in Alzheimer's disease (AD). We characterized microglia with translocator protein (TSPO) positron emission tomography (PET) within an AD progression model where global amyloid beta (Aβ) precedes local tau and neurodegeneration, resulting in cognitive impairment., Methods: Florbetaben, PBR28, and MK-6240 PET, T1 magnetic resonance imaging, and cognitive measures were performed in 19 cognitively unimpaired older adults and 22 patients with mild cognitive impairment or mild AD to examine associations among microglia activation, Aβ, tau, and cognition, adjusting for neurodegeneration. Mediation analyses evaluated the possible role of microglial activation along the AD progression model., Results: Higher PBR28 uptake was associated with higher Aβ, higher tau, and lower MMSE score, independent of neurodegeneration. PBR28 mediated associations between tau in early and middle Braak stages, between tau and neurodegeneration, and between neurodegeneration and cognition., Discussion: Microglia are associated with AD pathology and cognition and may mediate relationships between subsequent steps in AD progression., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Psychosis in Alzheimer's disease (AD) is associated with worse outcomes, yet no established biomarkers exist for early diagnosis and intervention. We compared tau PET burden across older individuals with and without psychotic symptoms., Methods: [ 18 F]AV1451 tau PET binding was compared between 26 Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects with psychotic symptoms (delusions and/or hallucinations) and 26 ADNI subjects without psychotic symptoms, matched for age, sex, race/ethnicity, and clinical severity. Tau was assessed on a region-of-interest and voxel level, corrected for amyloid PET burden., Results: Tau was greater in individuals with psychotic symptoms in the amygdala in region-of-interest analyses, and in amygdala, thalamus, putamen, right hippocampus, right entorhinal cortex, and right frontal cortex in voxel-based analyses. When considering different onset and type of psychotic symptoms, tau binding was greatest in those with concurrent delusions., Conclusion: Elevated tau in limbic regions may be relevant for psychotic symptoms in aging and AD.