Welcome to the AD/PD™ 2021 Interactive Program
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- Live Session | 
- On Demand Session | 
- On Demand with Live Q&A
The viewing of sessions, cannot be accessed from this conference calendar. All sessions are accessible via the Main Lobby.
FOLLOWING THE LIVE DISCUSSION, THE RECORDING WILL BE AVAILABLE IN THE ON-DEMAND SECTION OF THE AUDITORIUM.
CLINICAL ADDED VALUE OF 18F-RO948 (TAU) PET
Abstract
Aims
To study the added value of 18F-RO948-PET for clinical diagnosis of patients with memory concerns in a Memory Clinic setting.
Methods
652 patients referred to the Memory Clinic, Skåne University Hospital were assessed according to standard clinical protocol with brain imaging, cognitive testing, blood tests and lumbar puncture (including Ab42, Ab42/Ab40-ratio, total-Tau, pTau181). Based on this investigation clinicians were asked to state a diagnosis and how certain they were on the etiology (scale 0-10). Participants then underwent 18F-RO948 PET. PET images were assessed visually and categorized into: A - normal, B - mild temporal Alzheimer’s Disease (AD)-type pathology, C – widespread AD-type pattern, D – inconclusive scan. With the information from the visual read the clinicians were again asked to state diagnosis and certainty.
Results
Patients got a pre-scan diagnosis (301 AD; 80 Vascular dementia; 38 FTD; 36 DLB; 94 non-progressive causes of cognitive impairment; 77 other causes (PD, PSP etc) and 26 not specified). Overall, in AD the certainty of etiology increased from 7.69 to 8.13 (Figure 1; p<0.0001) post-scan. The increase in etiological certainty was as expected larger when the visual read was positive (n=236, 7.98 vs 8.86; p<0.0001) and decreased with a negative or inconclusive read (6.47 vs 5.32; p = 0.02). In the non-AD group, the diagnostic certainty was lower, but increased with the additional data (6.40 vs 6.78; p=0.004).
Conclusions
Our results indicate a clear added value of tau PET even on top of an extensive etiological work-up in a specialized Memory Clinic setting.
ON THE IDENTIFICATION OF TAU-POSITIVE BRAIN REGIONS ACROSS AD-PATIENTS, IDENTIFIED BY NON-PARAMETRIC ANALYSIS OF 18F-PI-2620 PET IMAGING DATA.
Abstract
Aims
In vivo imaging of tau pathology in Alzheimer’s disease (AD) has advanced our understanding on the regional pattern of tau deposition. Importantly, heterogeneity among the individual patterns of tau accumulation has been reported obscuring the identification of common regions that display a positive signal in AD. Arriving at a common definition of positivity is of great clinical value for standardized diagnostic assessment. Here, we examined data from amyloid-positive AD patients and amyloid-negative healthy controls who underwent tau PET imaging with 18F-PI-2620.
Methods
We created standardized update value ratio (SUVr) images normalized to the pons. We adopted a non-parametric statistical approach that underlies a permutation algorithm (i.e., 5.000-10.000 repetition) to estimate the most robust clusters/voxels of positivity between AD patients and healthy controls with a significance threshold of FWE <.05.
Results
Differences emerged in regions including parahippocampal gyrus, temporal and occipital pole, cingulate gyrus, precuneus and pars opercularis. We further observed that tau pathology in the resulting mask was independently associated with clinical severity (i.e., ADAS-COG score) and patients with more amyloid pathology displayed more tau pathology in the identified regions.
Conclusions
In summary, we were able to identify a spatial pattern most reliably tau-positive in the cohort of AD patients. This pattern may reflect brain regions affected by AD-specific (as opposed to age-related) tau pathology. Furthermore, such a set of universally tau-positive regions may serve as a region of interest for highly standardized analysis of tau-PET data with potential for early detection, prognosis, staging and therapy monitoring.
SYNAPTIC DENSITY IS ASSOCIATED WITH COGNITIVE PERFORMANCE IN EARLY ALZHEIMER’S DISEASE: A PET IMAGING STUDY WITH [11C]UCB-J
Abstract
Aims
Synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer’s disease (AD); however, this statement is based on limited neuropathological study. In this study we examined the relationship between synaptic density and cognitive performance in early AD using [11C]UCB-J PET and an extensive neuropsychological battery.
Methods
[11C]UCB-J binding was measured in 45 amyloid+ participants with AD (17 amnestic MCI and 28 mild dementia) and 20 amyloid– cognitively normal participants aged 50-85. Synaptic density was calculated as the distribution volume ratio (DVR) in a composite of AD-affected regions, using cerebellum as reference region. A neuropsychological battery assessed performance in five cognitive domains. Domain scores were generated for each AD participant by averaging z-scores within the domain, and global cognitive scores averaged the domain scores.
Results
In a multiple linear regression model controlling for age, sex, and education, synaptic density ([11C]UCB-J DVR) was a significant predictor of global cognitive performance in participants with AD (β=3.21, η2=0.29, P=0.0001; Figure 1A), as well as Verbal Memory (P=0.022; Figure 1B), Language (P=0.001; Figure 1C), Executive Function (P=0.001; Figure 1D), Processing Speed (P=0.001; Figure 1E), and Visuospatial Ability (P=0.001; Figure 1F). The association between synaptic density and global cognition survived partial volume correction (β=2.16, η2=0.23, P=0.001), and synaptic density was a stronger predictor of cognitive performance than gray matter volume.
Conclusions
These results confirm neuropathologic studies, demonstrating a significant association between synaptic density and cognitive performance, and suggest that this correlation extends to the early stages of AD.
VISUAL ASSESSMENT OF [18F]FLUTEMETAMOL PET IMAGES CAN DETECT EARLY AMYLOID PATHOLOGY AND GRADE ITS EXTENT
Abstract
Aims
Visual read (VR) guidelines of amyloid-β PET were developed to capture established pathology in clinical populations, whereas quantification is often used to detect early pathology in research settings. This study investigated the sensitivity of VR to detect early amyloid-β pathology as determined quantitatively, and studied the utility of regional uptake patterns to track progression.
Methods
[18F]flutemetamol PET images of 497 subjects (ALFA+ N=352;ADC N=145) were included, covering both subthreshold and established amyloid pathology. Scans were visually assessed according to product guidelines, recording the number of positive regions (0-5) and a final negative/positive classification. All scans were quantified using the standard Centiloid (CL) method. The agreement between VR-based classification and previously published CL-based cut-offs for early (CL=12) and established (CL=30) pathology was determined. An optimal CL cut-off maximizing sensitivity and specificity (Youden’s index) against VR was derived. The quantitative burden of observed regional patterns was determined and operationalized into 3 stages of VR positivity.
Results
VR showed excellent agreement against CL=12 (κ=.88, 95.0% [472/497]) and CL=30 (κ=.87, 94.8% [471/497]) cut-offs, with 86.5%/99.1% and 100%/93.1% sensitivity/specificity, respectively(Fig.1). ROC analysis resulted in an optimal CL=17 cut-off against VR (sensitivity=93.9%, specificity=98.2%). The posterior cingulate/precuneus and (medial orbito) frontal cortex were reported most frequently positive, either isolated (Stage 1: CL=22.1±6.3), co-occurring (Stage 2: CL=36.3±18.0) or in combination with other regions (Stage 3: CL=83.7±30.5,Fig2).
Conclusions
Our results show that VR is an appropriate method for assessing early amyloid pathology and grading the extent of visual amyloid positivity, which could be valuable to stratify patients.
KINETIC MODELING OF DYNAMIC PIB: A NEW BIDIRECTIONAL VESSEL TRACKING TOOL
Abstract
Aims
In Alzheimer’s disease, dynamic PET with 11C-labeled Pittsburgh compound B (PiB) can be used to evaluate both cerebral amyloid-beta deposits and perfusion. While PIB-derived perfusion provides valuable information, reliable determination of the arterial input function is challenging. We developed an automated image-derived input function (IDIF) algorithm and assessed its performance by (a) comparing AIF agreement between left and right carotid arteries; (b) assessing inver-observer reliability.
Methods
This retrospective study analyzed 11 dynamic PiB PET brain studies of elderly (66-87 years old) subjects (128x128x79, 2.0x2.0x2.6 mm3 voxels, 25 frames). Two observers independently tracked the left and right internal carotid arteries (ICA, left: LCA, right: RCA) using a novel bidirectional IDIF algorithm. The method involves initial user-supplied search region, followed by bi-directional vessel tracking. Processing parameters included: vessel diameter 4 mm, segmented vessel length <20 mm. Analysis included: 1) absolute frame-by-frame agreement in time-activity curves (TACs) between LCA and RCA, 2) time difference between peaks for LCA and RCA, and 3) interobserver agreement for all measurements.
Results
The frame-by-frame TAC agreement was 17.4%+/-3.7% (mean+/-stdev). The LCA-RCA peak time difference was 8.2+/-6.0 sec . For areas under LCA and RCA TACs, the intraclass correlation (absolute agreement) was 0.671. The interobserver agreement on TAC was 4.8%+/-4.2% and peak ICA time difference between observers was 2.0+/-4.1 sec.
Conclusions
The IDIF tool provides reliable arterial segmentation from dynamic PiB, with high inter-observer agreement, despite low SNR in dynamic PiB PET. The tool does not require coregistered structural MRI for vessel tracking.
A FULLY AUTOMATED PLASMA ABETA ASSAY INCORPORATING APOE4 STATUS PREDICTS AMYLOID POSITIVITY DETERMINED BY A CENTILOID THRESHOLD OF AMYLOID PET
Abstract
Aims
Amyloid pathology is a defining feature of Alzheimer’s disease (AD). Amyloid positron emission tomography (PET) is used to assess amyloid pathology, but its use may be limited by cost and accessibility. Recently, we developed plasma Aβ1-40 and Aβ1-42 immunoassays on our fully automated system (HISCLTM series). Here, we evaluated the performance of our plasma immunoassay to predict amyloid positivity defined by a centiloid threshold.
Methods
149 samples were assessed from the Eisai Elenbecestat Phase 3 program who underwent amyloid PET. The centiloid cut point of 32.20 was determined by predicting amyloid positivity defined by visual read and maximizing the Youden index. To assess the overall performance of plasma Aβ1-42/Aβ1-40 ratio, area under the curve (AUC) was obtained by performing receiver operating characteristic (ROC) analysis using logistic regression. The model incorporating APOE4 status was also evaluated. Furthermore, correlation between plasma Aβ1-42/Aβ1-40 ratio and centiloids was assessed.
Results
The plasma Aβ1-42/Aβ1-40 ratio predicted amyloid PET positivity with an AUC of 0.82 and a sensitivity and specificity equal to 78%. Including APOE4 status as a predictor increased the overall performance (AUC = 0.87), and the sensitivity and specificity were 94% and 71%, respectively. The plasma Aβ1-42/Aβ1-40 ratio was also found to correlate with centiloids values (Spearman rank correlation coefficient = -0.57).
Conclusions
We have observed plasma Aβ1-42/Aβ1-40 ratio can predict amyloid pathology. Incorporating APOE4 status in addition to plasma Aβ1-42/Aβ1-40 ratio achieved high predictive performance, with a high sensitivity. To further assess clinical utility of our assay system, additional sample sets will be evaluated.
PREDICTION OF PLASMA PHOSPHORYLATED TAU 181 AND 217 FOR AMYLOID AND TAU PET IN THE POPULATION-BASED MAYO CLINIC STUDY OF AGING
Abstract
Aims
We assessed the utility of plasma phosphorylated tau (P-tau) 181 and 217 as biomarkers of AD pathophysiology in a population-based setting and examined interclass correlation coefficients (ICC) to determine intra-individual variability over serial samples.
Methods
We included 1,329 Mayo Clinic Study on Aging participants (1,161 cognitively unimpaired, 153 MCI, 15 dementia), median age of 69 (range 30-98); 1,066 had amyloid PET and 495 tau PET. P-tau 181 and 217 was measured on the MSD platform; previous cutpoints were used for analyses. Elevated amyloid (A+) was defined as SUVR≥1.48 using PiB PET; elevated tau (T+) as SUVR≥1.25 using F-18-AV-1451. Area under the Receiver Operating Curve (AUROC) and diagnostic statistics were used to assess the accuracy of plasma P-tau for amyloid and tau PET. ICCs of P-tau levels were calculated.
Results
Among all participants, plasma P-tau181 predicted A+ with an AUROC of 0.71, 51% sensitivity, 92% specificity, and 81% positive predictive value (PPV). For P-tau217 and A+, the AUROC was 0.74, 51% sensitivity, 96% specificity, 90% PPV. Plasma P-tau181 predicted T+ with an AUROC of 0.59, 22% sensitivity, 95% specificity, 54% PPV. For P-tau 217, the AUROC was 0.63, 34% sensitivity, 92% specificity, 53% PPV. Both P-tau181 and 217 levels increased with clinical severity (CU<MCI<dementia, p<0.001). The ICC (95% CI) for Ptau181 was 0.92 (0.92, 0.93) and for Ptau217 was 0.95 (0.95, 0.96).
Conclusions
In this population-based sample, both plasma P-tau181 and 217 had good discrimination for A+, but discrimination for T+ was lower. There was low intra-individual variability over serial samples.
BASELINE [18F]GTP1 TAU PET IS PROGNOSTIC OF COGNITIVE DECLINE IN THE TAURIEL STUDY
Abstract
Aims
[18F]GTP1 PET was used as an exploratory biomarker to assess tau pathology in the Tauriel Study (NCT03289143), a Phase 2 randomized, double-blind, placebo-controlled, parallel-group clinical trial that assessed the safety and efficacy of semorinemab in patients with prodromal-to-mild Alzheimer’s disease over 73 weeks.
Methods
Cognitive testing and [18F]GTP1 PET imaging were performed at baseline, Week 49 and Week 73. Pearson correlations of baseline [18F]GTP1 SUVR with longitudinal change in cognitive endpoints were calculated to assess [18F]GTP1’s prognostic relationship with subsequent disease progression. A multivariate linear regression “added variable” analysis was conducted to assess the added benefit of [18F]GTP1 beyond established baseline assessments (age, sex, BMI, ApoE4 genotype, AD diagnosis, and baseline MMSE, CDR-SB, ADAS-Cog13, and ADCS-ADL scores) for explaining additional variance in longitudinal changes in cognition and/or function.
Results
313 participants had baseline [18F]GTP1 SUVR and evaluable CDR-SB data at Week 73. Statistically significant correlations were seen between baseline [18F]GTP1 SUVR and change in CDR-SB (r = 0.35, p < 0.001) and ADAS-Cog13 (r = 0.35, p < 0.001) at Week 73, respectively (Figure 1). The variance explained by the base CDR-SB model (non-[18F]GTP1 baseline assessments only; R2 = 0.22), increased by 17% after including [18F]GTP1 (R2 = 0.26). The variance explained by the base ADAS-Cog13 model (R2 = 0.13) increased by 65% after including GTP1 (R2 = 0.21) (Figure 1).
Conclusions
These results illustrate the value of tau PET imaging for not only elucidating underlying tau pathology, but also as a prognostic tool for predicting future clinical progression.