Abstract Body

Aims:

With over 15 years of PET amyloid Imaging, much has been accomplished using feasible tissue ratios, simplified dynamic imaging protocols, and F-18 labeled imaging agents for wide application. In recent years, the availability of selective F-18 labeled tau PET radioligands has expanded opportunity to improve our understanding of brain aging, of tau deposition in vivo, and of in vivo relationships between tau and amyloid accumulation in the development of cognitive decline and Alzheimer’s disease. The aim of this presentation is to review current PET methodology considerations for amyloid and tau PET imaging, particularly in the context of multisite studies and early disease detection.

Methods and Results:

The in vivo characteristics of the most widely used amyloid and tau PET imaging agents will be reviewed. Consideration will be given to persistent quantification issues, such as nonspecific and/or off-target signal and reference region delineation. This presentation will also review recent published studies involving data harmonization and targeting of very early neuropathological protein deposition.

Conclusions:

Methodology advances and validation efforts have helped to offset and further inform on potentially limiting factors that arise in amyloid and tau PET imaging. These efforts underscore the continued relevance of PET methodology considerations in our current amyloid and tau PET imaging applications.

Abstract Body

Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) is a U.S.-wide study evaluating the association between amyloid PET and health outcomes in patients with MCI and dementia. Participants were evaluated by dementia specialists. Amyloid scans were interpreted as “positive” or “negative.” Patient diagnosis and management plans were recorded prior to PET and again 90±30 days following PET. Medicare claims were followed for 12 months and compared to claims from a matched control group of Medicare beneficiaries with MCI/dementia who did not receive amyloid PET. 18,295 patients completed PET between February 2016 and January 2018 (median age 75, 51% female, 87% White, 60% MCI/40% dementia, 61% amyloid positive). A composite management endpoint (changes in AD drugs, other related drugs, counseling about safety and future planning) changed after PET in 60.2% of MCI and 63.5% of dementia patients, exceeding the pre-specified goal of ≥30% (p<0.001). Clinical diagnosis changed from AD to a non-AD condition (or vice versa) in 35.6%. 12 months hospitalization rates were 23.98% in IDEAS compared to 25.12% in controls (relative difference -4.52% [-8.55% - -0.30%]), short of the goal of ≥10% relative reduction. Amyloid-positive patients had a lower risk of 12-months hospitalizations than amyloid-negative patients (Odds Ratio 0.78 [0.71 – 0.87]). In summary, amyloid PET was associated with frequent changes in patient management and a modest reduction in 12-months hospitalizations. Launched in December 2020, New IDEAS will build on these findings in a more diverse cohort of Medicare beneficiaries, with a focus on African-Americans and Latinos and establishment of a biorepository.

Abstract Body

Aims

To use multimodal imaging to map important pathophysiological processes and delineate the outmost driving forces for the clinical phenotypes in Alzheimer´s disease (AD) and non-AD dementia.

Methods

We use a translational approach from multimodal tracer in vivo PET imaging to in vitro PET tracer binding in post-mortem brain tissue measuring amyloid, tau, astrogliosis and synapse loss.

Results

We observe a negative correlation between MAO-B inhibitor ¹¹C-deprenyl (astrogliosis) and ¹¹C-PIB (amyloid ) levels but a positive correlation between 11C-deprenyl and ¹⁸F-FDG (cerebral glucose metabolism) PET at early stages of preclinical /prodromal AD. This early sign of high astrogliosis may reflect an increase in neuroprotective astrocytic forms (A2) .In post-mortem AD brain an increased ³H-deprenyl binding positively correlates with amyloid load and probably represent the toxic astrocytic form (A1) although the astrocyte tracers deprenyl and BU99008 both show multiple binding sites in AD brain tissue. Deprenyl PET studies are for comparison ongoing in frontotemporal lobe dementia. Tau PET binding increases with progression of AD and show less correlation with PIB PET but negative correlation with FDG PET and cognition (episodic memory). Tau PET seems to better predict future cognitive decline than amyloid or FDG PET in AD. Characterization of the binding properties of the synapse protein tracer ³H-UCBJ is ongoing in post-mortem brain tissue to be continued by PET studies in early AD and non-AD dementia.

Conclusions

Multimodal PET tracer imaging will increase the precision of early diagnosis, clinical prognosis and development and assessment of outcome of new drug treatment strategies.

Aims

A next generation of tau PET tracers for imaging of Alzheimer’s disease and other dementias has recently been developed. Whilst the new compounds have now entered clinical studies, there is limited information available to assess their suitability for clinical applications. Head-to-head comparisons are urgently needed to understand differences in the radiotracer binding profiles.

Methods

We characterised the binding of the tau tracers PI2620, RO948, MK6240 and JNJ067 in human post-mortem brain tissue from a cohort of 25 dementia cases and age-matched controls, using quantitative phosphorimaging with tritium labelled radiotracers in conjunction with phospho-tau specific immunohistochemistry.

Results

The four tau radiotracers depicted tau inclusions composed of paired helical filaments with high specificity, both in cases with Alzheimer’s disease and in primary tauopathy cases with concomitant Alzheimer’s disease pathology. In contrast, cortical binding to primary tauopathy cases without paired helical filament tau was found to be within the range of age-matched controls. In basal ganglia tissue, tracer binding was not reduced by heterologous blocking with the selective monoamine oxidase B inhibitor L-deprenyl.

Conclusions

The head-to-head comaprison of next-generation tau PET tracers demonstrates that all four radiotracers bind with high specificity to cortical PHF-tau, whereas tracer binding to cortical inclusions characteristic of primary tauopathies is low. Several limitations of the first generation of tau tracers, largely associated with MAO-B off-target binding, appear to have been overcome. Our results suggest that the new tau PET tracers are suitable tools for distinguishing Alzheimer’s disease from controls as well as other dementias with high robustness.

Aims

Previous research has consistently found widespread tau aggregation in the presence of global amyloid-β (Aβ) pathology, but it remains unclear at what level of Aβ burden tau pathology accelerates. Here, we studied cross-sectional and longitudinal tau aggregation in relation to progressive stages of regional Aβ deposition as determined by a recently established PET-based staging approach.

Methods

We examined 424 subjects from the Alzheimer’s Disease Neuroimaging Initiative with concurrent T1 MRI, 18F-Florbetapir-PET (FBP), and 18F-Flortaucipir-PET (FTP) scans. 151 participants underwent at least one longitudinal FTP scan over a mean follow-up time of 1.6 years. A previously developed PET staging method for FBP was used to stratify participants into 4 progressive stages of regional Aβ deposition. Cross-sectional and longitudinal patterns of regional tau aggregation across Aβ stages were examined using multiple linear regression and mixed models, respectively, adjusted for age, sex, and clinical diagnosis.

Results

In accordance with previous findings, individual Aβ deposition patterns followed a highly consistent regional hierarchy that allowed staging >99% of individuals into one of four progressive Aβ stages. In cross-sectional analyses, only Aβ stages III and IV revealed elevated tau deposition in temporal, parietal, and frontal cortices compared to stage 0 (FDR<0.05). Confirming these cross-sectional findings, only stages III and IV showed faster longitudinal tau accumulation rates in the aforementioned areas (Fig. 1-3).

Conclusions

The induction of more severe and widespread tau pathology seems to occur at advanced stages of Aβ deposition, which only covers a subpopulation of Aβ-positive individuals as conventionally defined.

Aims

With the advent of disease-modifying therapeutic trials in early stages of Alzheimer’s disease (AD), disentangling normal age-related biomarker changes from AD-related pathological changes will be crucial to unravel therapy effectiveness in trial populations. Here, we aim to investigate the effects of age, the greatest risk factor of AD, on markers of amyloid-β (Aβ), tau, and neuroinflammation PET in late-onset AD.

Methods

238 participants (120 amyloid- and tau-negative [A-] and 118 amyloid-positive [A+]) from the TRIAD cohort underwent ¹⁸F-AZD4694 amyloid-PET and ¹⁸F-MK620 tau-PET. A subset also underwent ¹¹C-PBR28 neuroinflammation-PET, plasma Ptau181 and Aβ_1-42/Aβ_1-40 concentration measures, and 1-year follow-up tau-PET. We investigated the association between age and all PET modalities as well as between age and plasma concentrations using linear regression models, adjusting for sex, education, APOE-ε4, and the remaining PET or plasma variables. In addition, we investigated whether there is a significant difference in these associations between the A- and A+ groups (i.e., interaction-effect age*Aβ-status on PET/plasma biomarkers).

Results

Younger A+ subjects showed increased plasma Ptau181 and tau-PET in Braak3and4 predominant areas at baseline as well as increased tau-PET SUVR changes in Braak1and2 predominant areas after 1-year follow-up compared to older A+ individuals, while there was no age-effect on tau-PET in A-. Second, while we detected a significant main effect of age on neocortical Aβ and orbitofrontal neuroinflammation SUVR, the effect of age on both markers did not significantly differ between A+ and A-.

Conclusions

Future clinical trials should consider age as an important stratification factor particularly when targeting tau in late-onset AD.

Aims

To determine the relationship between neuropsychiatric symptoms and beta-amyloid deposition in cognitively unimpaired older adults and to assess mediating effects of either objective or self-perceived cognitive performance.

Methods

Screening data from 4492 cognitively unimpaired adults, age 65-85, enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study were used in this cross-sectional analysis: demographics, Geriatric Depression Scale (GDS), “state” items of the State Trait Anxiety Inventory (STAI), Preclinical Alzheimer’s Cognitive Composite (PACC), Cognitive Function Index (CFI), and beta-amyloid PET SUVR in an Alzheimer’s composite cortical region. We used linear regression to estimate the associations between SUVR and GDS and STAI scores while adjusting for potential confounders. To assess mediation we reran the models while additionally adjusting for CFI or PACC scores.

Results

4342 subjects were included (mean age: 71.3, 59% female), GDS ranged 0-13 (median: 1), and STAI ranged 6-24 (median: 10). Beta-amyloid SUVR was modestly associated with STAI; mean STAI score was estimated to be 0.29 points higher (95% CI: 0.046, 0.526; p-value = 0.019) for each 0.5 point increase in amyloid SUVR. Self-perceived cognitive decline (CFI) attenuated the relationship between STAI and SUVR, while objective cognitive function (PACC) did not. There was no significant relationship between GDS and SUVR (p-value = 0.35).

Conclusions

In cognitively unimpaired older adults with low levels of depression and anxiety, the relationship between beta-amyloid deposition and anxiety was significant, although small. CFI attenuation of this relationship suggests that anxiety may be partly due to perceived cognitive decline resulting from cortical beta-amyloid deposition.

Aims

To study the effect of reduced injected dose of the tau PET tracer [¹⁸F]RO948 on standardised uptake value ratios (SUVR) to determine a lowest injected dose that allows for accurate in vivo quantification of tau burden.

Methods

Participants were examined on a Siemens Biograph mCT flow scanner for a 20-minute list-mode acquisition, performed 70 minutes post-injection of 370 MBq [¹⁸F]RO948. Injected dose was manipulated from the list-mode data using 75%, 50%, 25% and 10% of the total injected dose. Reconstructions were performed with scatter, attenuation, random and dead-time corrections.

The inferior cerebellum grey-matter was used to calculate SUVR with each subject yielding SUVR for composite region-of-interests (ROIs) corresponding to Braak regions of tau pathology.

Results

(1) Relative change as function of injected dose

(2) Images at different radioactive dose

Dose-dependent changes were greatest in the Braak I/II ROI in which our participants showed highest tracer retention. Initial results show on average less than two percent change in SUVR when reducing dose from 100% to 50%. A more significant change was observed at 1mCi. The variance increased when lowering the dose. Images remained visually comparable at the 50% injected dose to 100% suggesting these images could still be visually assessed in a clinical setting.

Conclusions

Our findings suggest that a 50% lower injected tracer-dose yields robust tracer retention signal. To further validate these results, we will replicate our analyses in data from Alzheimer’s disease patients from the Swedish BioFinder study in order to compare the diagnostic value of reduced-dose and full-dose [18F]RO948 PET scans.